Daniel Chang

All Publications

Predicting Pancreatic Cancer Resectability and Outcomes Based on an Objective Quantitative Scoring System. Pancreas Toesca, D. A., Jeffrey, R. B., von Eyben, R., Pollom, E. L., Poullos, P. D., Poultsides, G. A., Fisher, G. A., Visser, B. C., Koong, A. C., Chang, D. T. ; 48 (5): 622–28
Abstract

To quantitatively assess the probability of tumor resection based on measurements of tumor contact with the major peripancreatic vessels.This is a retrospective cohort study of pancreatic cancer patients treated between January 2001 and December 2015 in a single academic comprehensive cancer center. Radiographic measurements of the circumferential degree and length of solid tumor contact with major peripancreatic vessels were obtained from diagnostic pancreatic protocol computed tomography images and tested for correlation with tumor resection and margin status.Of 294 patients analyzed, 113 (38%) were resected, with 71 (63%) with negative margins. Based on the individual measurements of vascular involvement, a resectability scoring system (RSS) was created. The RSS correlated strongly with resection (P < 0.0001) and R0 resection (P < 0.0001) probabilities. Moreover, the RSS correlated with overall survival (P < 0.0001) and metastasis-free survival (P < 0.0001), being able to substratify resectable (P = 0.022) and unresectable patients (P = 0.014) into subgroups with different prognosis based on RSS scores.Based on a comprehensive and systematic quantitative approach, we developed a scoring system that demonstrated excellent accuracy to predict tumor resection, surgical margin status, and prognosis.

View details for PubMedID 31091207
Reirradiation with stereotactic body radiation therapy after prior conventional fractionation radiation for locally recurrent pancreatic adenocarcinoma. Advances in radiation oncology Koong, A. J., Toesca, D. A., von Eyben, R., Pollom, E. L., Chang, D. T. ; 2 (1): 27–36
Abstract

Locally recurrent pancreatic cancer after prior radiotherapy is a therapeutic challenge with limited treatment options. This study examines the safety and efficacy of stereotactic body radiation therapy (SBRT) for locally recurrent pancreatic adenocarcinoma after prior conventional fractionation radiotherapy (CRT).Outcomes from all patients treated with SBRT for locally recurrent pancreatic adenocarcinoma after prior CRT at our institution were reviewed. A total of 23 patients were identified. Prior CRT median dose was 50.4 Gy (range, 30-60 Gy). Twelve patients (52%) had previously undergone surgery and received CRT as neo- or adjuvant treatment. Nine patients (39.1%) were reirradiated with SBRT with a dose of 25 Gy in a single fraction, and 14 patients (60.8%) received a 5-fraction SBRT schedule with a median dose of 25 Gy (range, 20-33 Gy) in 5 fractions (1-5 fractions).Median follow-up time was 28 months (range, 9-77 months). The median planning target volume was 46 cm(3) (range, 14-89 cm(3)). Median overall survival from diagnosis and from reirradiation were 27.5 months (range, 10-77 months) and 8.5 months (range, 1 month to not reached) respectively. The cumulative incidence of local failures at the last follow-up was 19%. For the 4 patients who presented with local failure, one was treated with a single fraction of 25 Gy, and the other 3 were treated with 25 Gy in 5 fractions. Three patients presented regional failure, with a cumulative incidence of 14%, all with concurrent distant progression. The cumulative incidence of distant progression was 64% at last follow-up. After reirradiation, 6 patients (26.1%) developed a grade 2 or 3 gastrointestinal toxicity, 4 of them occurring among patients treated with a single-fraction SBRT regimen.Our report shows that SBRT for reirradiation of locally recurrent pancreas adenocarcinoma is a feasible option with good local control and acceptable toxicity rates, especially with a multifraction schedule.

View details for PubMedID 28740913
Deep Learning-Based Autosegmentation of Portal Vein for Prediction of Central Liver Toxicity After SBRT 59th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Ibragimov, B., Toesca, D. A., Chang, D. T., Koong, A. C., Xing, L. : E672
View details for DOI 10.1016/j.ijrobp.2017.06.2221
Can looking at density differences between liver parenchyma and oligometastatic lesions predict outcomes and toxicities in patients receiving stereotactic body radiation therapy for metastatectomy? 2018 Gastrointestinal Cancers Symposium (GI-ASCO) Jin, W., Toesca, D. A., Osmundson, E., Shaffer, J. L., Koong, A. C., Chang, D. T. : 479
View details for DOI 10.1200/JCO.2018.36.4_suppl.479
Prediction of pancreatic cancer surgical outcomes and prognosis based on an objective resectability scoring system 2018 Gastrointestinal Cancers Sysmposium (GI-ASCO) Toesca, D. A., Jeffrey, B., von Eyben, R., Poullos, P. D., Poultsides, G. A., Fisher, G. A., Visser, B. C., Koong, A. C., Chang, D. T. : 446
View details for DOI 10.1200/JCO.2018.36.4_suppl.446
The Impact of Chemotherapy Regimen and Radiation Dose of Stereotactic Body Radiation Therapy for Locally Advanced Pancreatic Adenocarcinoma 59th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Toesca, D. A., Pollom, E. L., von Eyben, R., Koong, A. C., Chang, D. T. : E193
View details for DOI 10.1016/j.ijrobp.2017.06.1063
SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Ma, C., Olevian, D., Miller, C., Herbst, C., Jayachandran, P., Kozak, M. M., Chang, D. T., Pai, R. K. 2019
Abstract

DNA mismatch repair protein deficient colon cancer frequently displays reduced CDX2 expression, and recent literature has suggested that negative CDX2 expression is a poor prognostic biomarker in colon cancer. We have recently demonstrated that SATB2 is an immunohistochemical marker that is complementary to CDX2. Using a tissue microarray approach, we evaluated SATB2 and CDX2 immunohistochemical expression in 514 patients with colonic adenocarcinoma including 146 with mismatch repair protein deficient tumors and correlated expression with histopathologic variables, molecular alterations, and survival. Overall, SATB2-negative and/or CDX2-negative expression was identified in 33% of mismatch repair protein deficient tumors compared with only 15% of mismatch repair protein proficient tumors (p<0.001) and in 36% of BRAF V600E mutated compared with only 13% of BRAF wild-type tumors (p<0.001). Both SATB2-negative and CDX2-negative colonic adenocarcinomas more often displayed lymphatic invasion, venous invasion, and perineural invasion (all with p<0.05). SATB2-negative expression was also more frequently identified in tumors with mucinous or signet ring cell differentiation (p<0.01 for both). In a multivariable analysis of survival in patients with mismatch repair protein deficient tumors (n=131), only tumor stage (p=0.01) and SATB2-negative and/or CDX2-negative expression (p=0.009) independently predicted disease-specific survival. Of the 99 patients with stage II or III mismatch repair protein deficient tumors, death from disease only occurred in patients with either SATB2-negative or CDX2-negative tumors, and no patients with SATB2-positive/CDX2-positive tumors developed recurrence or died of disease. SATB2 and CDX2 expression had no effect on patient survival in mismatch repair protein proficient, BRAF-mutated, or KRAS-mutated tumors. In summary, our results suggest that SATB2 and CDX2 are prognostic biomarkers in patients with mismatch repair protein deficient colon cancer and that inclusion of SATB2 and CDX2 immunohistochemistry may be helpful as part of a comprehensive pathologic risk assessment in mismatch repair protein deficient colon cancer.

View details for PubMedID 30962505
The Burden of Mental Health Disorders Among Elderly Patients with Gastrointestinal Malignancies Harris, J., Xiang, M., Chang, D., Pollom, E. ELSEVIER SCIENCE INC. 2019: E30–E31
View details for DOI 10.1016/S0360-3016(19)30470-5

View details for Web of Science ID 000463350600070
Hepatobiliary Cancers, Version 2.2019 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Benson, A. B., D'Angelica, M., Abbott, D. E., Abrams, T. A., Alberts, S. R., Anaya, D. A., Anders, R., Are, C., Brown, D., Chang, D. T., Cloyd, J., Covey, A. M., Hawkins, W., Iyer, R., Jacob, R., Karachristos, A., Kelley, R., Kim, R., Palta, M., Park, J. O., Sahai, V., Schefter, T., Sicklick, J. K., Singh, G., Sohal, D., Stein, S., Tian, G., Vauthey, J., Venook, A. P., Hammond, L. J., Darlow, S. D. 2019; 17 (4): 303–10
Abstract

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.

View details for PubMedID 30959462
Impact of Accuracy of Survival Predictions on Quality of End-of-Life Care Among Patients With Metastatic Cancer Who Receive Radiation Therapy. Journal of oncology practice Sborov, K., Giaretta, S., Koong, A., Aggarwal, S., Aslakson, R., Gensheimer, M. F., Chang, D. T., Pollom, E. L. 2019: JOP1800516
Abstract

PURPOSE:: For patients treated with palliative radiation, we examined the association between life expectancy predictions by radiation oncologists and aggressive end-of-life care.MATERIALS AND METHODS:: We included decedents from a study that assessed the ability of oncologists to predict survival of patients with metastatic cancer who received radiation. We identified patients who died within 12 months of study enrollment to assess accuracy of predictions. Aggressive end-of-life care was defined by the National Quality Forum, ASCO Quality Oncology Practice Initiative metrics, and advanced radiation modalities in the last month of life. Survival predictions were categorized as follows: correct (< 12 months), 12 to 18 months, 18 to 24 months, and more than 24 months. We assessed association between prediction and aggressive end-of-life care using a generalized estimation equation.RESULTS:: Of 489 decedents, we identified 467 encounters with survival estimates. Overall, 156 decedents (32%) met at least one metric of aggressive end-of-life care. Factors associated with aggressive end-of-life care included younger age, female sex, primary cancer diagnosis, no brain metastases, and private insurance. In each encounter when an oncologist predicted survival, 363 predictions (78%) were correct (< 12 months), 54 (11%) incorrectly predicted 12 to 18 months, 27 (6%) predicted 18 to 24 months, and 23 (5%) predicted more than 24 months. Compared with patients who had encounters that had correct survival predictions, patients predicted to live more than 24 months were more likely to meet at least one metric of aggressive end-of-life care (odds ratio, 2.55; 95% CI, 1.09 to 5.99; P = .03).CONCLUSION:: Inaccurate survival predictions by oncologists are associated with more aggressive end-of-life care for patients with advanced cancer.

View details for DOI 10.1200/JOP.18.00516

View details for PubMedID 30620629
Markerless pancreatic tumor target localization enabled by deep learning. International journal of radiation oncology, biology, physics Zhao, W., Shen, L., Han, B., Yang, Y., Cheng, K., Toesca, D. A., Koong, A. C., Chang, D. T., Xing, L. 2019
Abstract

To estimate the impact of radiotherapy (RT) on non-breast second malignant neoplasms (SMNs) in young women survivors of stage I-IIIA breast cancer.Women aged 20-44 years diagnosed with stage I-IIIA breast cancer (1988-2008) were identified in Surveillance, Epidemiology, and End Results (SEER) 9 registries. Bootstrapping approach and competing risk proportional hazards models were used to evaluate the effect of RT on non-breast SMN risk. The analysis was repeated in racial subgroups. Radio-tolerance score (RTS) analysis of normal airway epithelium was performed using Gene Expression Omnibus (GEO) datasets.Within records of 30,003 women with primary breast cancer, 20,516 eligible patients were identified (including 2,183 African Americans [AAs] and 16,009 Caucasians). The 25-year cumulative incidences of SMN were 5.2% and 3.6% (RT vs. no-RT) for AAs with 12.8-year and 17.4-year (RT vs. no-RT) median follow-up (HR=1.81, 95% bootstrapping confidence intervals [BCIs] [1.02, 2.50], P < 0.05); and 6.4% and 5.9% (RT vs. no-RT) for Caucasians with 14.3-year and 18.1-year (RT vs. no-RT) median follow-up (HR=1.10, 95% BCI [0.61, 1.40], P > 0.05). The largest portion of excess RT-related SMN risk was lung cancer (AA: HR=2.08, 95% BCI [1.02, 5.39], P < 0.05; Caucasian: HR=1.50, 95% BCI [0.84, 5.38], P > 0.05). STEPP analysis revealed higher post-RT non-breast SMN risk essentially throughout entire age range 20-44 years, with larger HR for RT in AAs. RTS of normal airway epithelium from young AA women was significantly lower than that from young Caucasian women (P = 0.038).With a projected 25-year follow-up, RT is associated with elevated risk of non-breast SMNs, particularly second lung cancer, in young women survivors of stage I-IIIA breast cancer, especially higher in AA women than Caucasian women.

View details for DOI 10.1016/j.ijrobp.2019.05.071

View details for PubMedID 31201892
Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer GENETICS IN MEDICINE Yurgelun, M. B., Chittenden, A. B., Morales-Oyarvide, V., Rubinson, D. A., Dunne, R. F., Kozak, M. M., Qian, Z., Welch, M. W., Brais, L. K., Da Silva, A., Bui, J. L., Yuan, C., Li, T., Li, W., Masuda, A., Gu, M., Bullock, A. J., Chang, D. T., Clancy, T. E., Linehan, D. C., Findeis-Hosey, J. J., Doyle, L. A., Thorner, A. R., Ducar, M. D., Wollison, B. M., Khalaf, N., Perez, K., Syngal, S., Aguirre, A. J., Hahn, W. C., Meyerson, M. L., Fuchs, C. S., Ogino, S., Hornick, J. L., Hezel, A. F., Koong, A. C., Nowak, J. A., Wolpin, B. M. 2019; 21 (1): 213–23
Abstract

Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses.Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression.We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05).Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

View details for PubMedID 29961768
Microsatellite Instability and Adjuvant Chemotherapy in Stage II Colon Cancer. American journal of clinical oncology Koenig, J. L., Toesca, D. A., Harris, J. P., Tsai, C. J., Haraldsdottir, S., Lin, A. Y., Pollom, E. L., Chang, D. T. 2019
Abstract

Randomized control trials and population-based studies do not demonstrate a definitive benefit for adjuvant chemotherapy (ACT) in stage II colon cancer (CC). Tumor sidedness and microsatellite instability (MSI) status may predict response to ACT, but previous studies have limited microsatellite data. We assessed the efficacy of ACT and possible interaction with MSI status and tumor sidedness in patients with resected stage II CC diagnosed between 2010 and 2013 using the National Cancer Database.Overall survival was evaluated with the Kaplan-Meier method and multivariate and propensity score matched Cox proportional hazards models. The interaction between receipt of ACT, MSI status, and tumor sidedness was evaluated. The efficacy of ACT was assessed in patient subgroups by MSI status and tumor sidedness.Among 6964 stage II CC patients with known MSI status, 1497 (21.5%) received ACT, 843 had MSI tumors, and 6121 had microsatellite stable (MSS) tumors. In multivariate and propensity score matched analyses, ACT was associated with improved survival after adjusting for factors including high-risk features, MSI status, and tumor sidedness (multivariate hazard ratio, 0.52; P<0.001). There was no interaction between receipt of ACT and MSI status (P=0.25). Patients with MSS tumors benefitted from ACT (multivariate hazard ratio, 0.47; P<0.001), even without other high-risk features. Patients with MSI tumors did not (P=0.671). ACT was associated with improved survival regardless of tumor sidedness.MSS alone may warrant ACT in stage II CC while patients with MSI tumors may not derive significant benefit from ACT.

View details for DOI 10.1097/COC.0000000000000554

View details for PubMedID 31166206
Worsening of Child-Pugh Score after Stereotactic Body Radiation Therapy Significantly Impacts Survival of Patients Treated for Hepatocellular Carcinoma Toesca, D. S., Wu, Y., Koong, A., Von Eyben, R., Osmundson, E. C., Shaffer, J., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2018: E64
View details for DOI 10.1016/j.ijrobp.2018.07.498

View details for Web of Science ID 000447811600149
Can Demographic Factors or Academic Metrics of Red Journal Reviewers Predict the Quality of their Reviews? Jamorabo, D., Deek, M. P., Rehman, H., Motwani, S. B., Yom, S. S., Zietman, A. L., Jabbour, S. K., Chang, D. T. ELSEVIER SCIENCE INC. 2018: E390
View details for DOI 10.1016/j.ijrobp.2018.07.1157

View details for Web of Science ID 000447811601181
Validation of a RPA prognostic model to predict overall survival in patients treated with bone metastases Giaretta, S., Von Eyben, R., Usoz, M., Aggarwal, S., Chang, D. T., Kidd, E. A. ELSEVIER SCIENCE INC. 2018: E440
View details for DOI 10.1016/j.ijrobp.2018.07.1277

View details for Web of Science ID 000447811601298
Quality of End of Life Care among Metastatic Cancer Patients Receiving Radiation Therapy Sborov, K., Giaretta, S., Koong, A., Aggarwal, S., Von Eyben, R., Chang, D. T., Gensheimer, M. F., Pollom, E. ELSEVIER SCIENCE INC. 2018: E423
View details for DOI 10.1016/j.ijrobp.2018.07.1235

View details for Web of Science ID 000447811601257
Association Between Accuracy of Survival Predictions and Quality of End of Life Care Among Metastatic Cancer Patients Receiving Radiation Therapy Sborov, K., Giaretta, S., Koong, A., Aggarwal, S., Von Eyben, R., Chang, D. T., Gensheimer, M. F., Pollom, E. ELSEVIER SCIENCE INC. 2018: S168
View details for DOI 10.1016/j.ijrobp.2018.07.031

View details for Web of Science ID 000447811602596
Tumor Expression of Insulin-like Growth Factor-1 Receptor is Associated With Disease Recurrence and Mortality in Resected Pancreatic Ductal Adenocarcinoma Morales-Oyarvide, V., Du, C., da Silva, A., Costa, A., Kozak, M. M., Dunne, R. F., Rubinson, D. A., Perez, K., Masugi, Y., Hamada, T., Welch, M. W., Brais, L. K., Zellers, C. L., Yuan, C., Babic, A., Ducar, M., Thorner, A. R., Meyerson, M., Aguirre, A., Kulke, M. H., Ng, K., Clancy, T. E., Findeis-Hosey, J. J., Chang, D. T., Hornick, J. L., Fuchs, C. S., Ogino, S., Koong, A. C., Heze, A. F., Nowak, J. A., Wolpin, B. M. LIPPINCOTT WILLIAMS & WILKINS. 2018: 1410–11
View details for Web of Science ID 000449304600188
Sarcopenia in Overweight or Obese Patient is an Adverse Prognostic Factor in Pancreatic Cancer Nwachukwu, C. R., Wu, Y., Toesca, D. S., Von Eyben, R., Pollom, E., Chang, D. T. ELSEVIER SCIENCE INC. 2018: E76
View details for DOI 10.1016/j.ijrobp.2018.07.425

View details for Web of Science ID 000447811600176
Predicting Survival after Liver SBRT by Deep Learning-Based Analysis of Treatment Dose Plans Ibragimov, B., Toesca, D., Chang, D. T., Koong, A. C., Xing, L. ELSEVIER SCIENCE INC. 2018: E56
View details for DOI 10.1016/j.ijrobp.2018.07.479

View details for Web of Science ID 000447811600130
Single Institution Experience with Stereotactic Body Radiation Therapy for Treatment of Adrenal Gland Metastases Koong, A., Toesca, D. S., Von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2018: E91–E92
View details for DOI 10.1016/j.ijrobp.2018.07.361

View details for Web of Science ID 000447811600212
Automated Survival Prediction in Metastatic Cancer Patients Using High-Dimensional Electronic Medical Record Data. Journal of the National Cancer Institute Gensheimer, M. F., Henry, A. S., Wood, D. J., Hastie, T. J., Aggarwal, S., Dudley, S. A., Pradhan, P., Banerjee, I., Cho, E., Ramchandran, K., Pollom, E., Koong, A. C., Rubin, D. L., Chang, D. T. 2018
Abstract

Background: Oncologists use patients' life expectancy to guide decisions and may benefit from a tool that accurately predicts prognosis. Existing prognostic models generally use only a few predictor variables. We used an electronic medical record dataset to train a prognostic model for patients with metastatic cancer.Methods: The model was trained and tested using 12588 patients treated for metastatic cancer in the Stanford Health Care system from 2008 to 2017. Data sources included provider note text, labs, vital signs, procedures, medication orders, and diagnosis codes. Patients were divided randomly into a training set used to fit the model coefficients and a test set used to evaluate model performance (80%/20% split). A regularized Cox model with 4126 predictor variables was used. A landmarking approach was used due to the multiple observations per patient, with t0 set to the time of metastatic cancer diagnosis. Performance was also evaluated using 399 palliative radiation courses in test set patients.Results: The C-index for overall survival was 0.786 in the test set (averaged across landmark times). For palliative radiation courses, the C-index was 0.745 (95% confidence interval [CI] = 0.715 to 0.775) compared with 0.635 (95% CI = 0.601 to 0.669) for a published model using performance status, primary tumor site, and treated site (two-sided P<.001). Our model's predictions were well-calibrated.Conclusions: The model showed high predictive performance, which will need to be validated using external data. Because it is fully automated, the model can be used to examine providers' practice patterns and could be deployed in a decision support tool to help improve quality of care.

View details for PubMedID 30346554
Development of deep neural network for individualized hepatobiliary toxicity prediction after liver SBRT MEDICAL PHYSICS Ibragimov, B., Toesca, D., Chang, D., Yuan, Y., Koong, A., Xing, L. 2018; 45 (10): 4763–74
View details for DOI 10.1002/mp.13122

View details for Web of Science ID 000446995000056
Automated survival prediction in metastatic cancer patients using high-dimensional electronic medical record data Gensheimer, M. F., Henry, A. S., Wood, D. J., Hastie, T. J., Aggarwal, S., Dudley, S., Pradhan, P., Banerjee, I., Cho, E., Ramchandran, K., Pollom, E., Koong, A., Rubin, D., Chang, D. T. OXFORD UNIV PRESS. 2018: 548
View details for Web of Science ID 000459277303282
Introduction. Seminars in radiation oncology Chang, D. T. 2018; 28 (4): 265–66
View details for DOI 10.1016/j.semradonc.2018.06.002

View details for PubMedID 30309636
Loss of SATB2 Expression in Colorectal Carcinoma Is Associated With DNA Mismatch Repair Protein Deficiency and BRAF Mutation AMERICAN JOURNAL OF SURGICAL PATHOLOGY Ma, C., Olevian, D. C., Lowenthal, B. M., Jayachandran, P., Kozak, M. M., Chang, D. T., Pai, R. K. 2018; 42 (10): 1409–17
Abstract

The special AT-rich sequence binding protein (SATB2) has been reported to be a specific immunohistochemical marker for colorectal carcinoma; however, correlation of SATB2 expression with molecular alterations commonly assessed in colorectal carcinoma has not been performed. We examined the immunohistochemical expression of SATB2 in 586 adenocarcinomas of the gastrointestinal (GI) tract and pancreas to assess its utility in diagnosis and analyze the clinicopathologic and molecular characteristics of colorectal carcinoma stratified by SATB2 expression. SATB2 and CDX2 expression were evaluated in 266 adenocarcinomas of lower GI tract origin (246 colorectal and 20 appendiceal mucinous), 208 adenocarcinomas of upper GI tract and small intestinal origin (74 esophagus/esophagogastric junction, 103 stomach, 20 duodenal, and 11 jejunoileal), and 112 pancreatic ductal adenocarcinomas. SATB2 expression was more frequently identified in adenocarcinomas of lower GI tract origin (222/266, 83%) compared with upper GI tract, small intestinal, or pancreatic origin (26/320, 8%) (P<0.001). Compared with CDX2 alone, dual positive expression for SATB2 and CDX2 (SATB2/CDX2) has a significantly higher specificity for adenocarcinoma of lower GI tract origin (94% vs. 57%, P<0.001). In colorectal carcinoma, loss of SATB2 expression was more frequently observed in DNA mismatch repair (MMR) protein deficient tumors (31%) compared with MMR protein proficient tumors (13%) (P<0.01). A BRAF V600E mutation was more frequently identified in colorectal carcinomas with loss of SATB2 expression compared with those with positive SATB2 expression (29% vs. 3%) (P<0.001). In summary, SATB2 expression is a relatively specific marker of lower GI tract origin; however, loss of SATB2 expression is more commonly seen in colorectal carcinoma with MMR protein deficiency and BRAF mutation.

View details for PubMedID 30001238
Stereotactic body radiation therapy for adrenal gland metastases: Outcomes and toxicity. Advances in radiation oncology Toesca, D. A., Koong, A. J., von Eyben, R., Koong, A. C., Chang, D. T. 2018; 3 (4): 621–29
Abstract

Purpose: This study aimed to report on our institutional experience in the use of stereotactic body radiation therapy (SBRT) for the treatment of adrenal gland metastases. Specifically, we examined the outcomes and toxicity from this treatment modality on adjacent organs at risk.Methods and Materials: Data were retrieved from patients with adrenal metastases who were treated with SBRT between 2008 and 2017. Patients with primary adrenal malignancies were excluded. Toxicities were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Time-to-event rates were calculated from the date of SBRT delivery.Results: In total, 35 patients with adrenal metastases were identified. Four patients were treated for bilateral disease. The median dose was 40Gy (range, 20-54Gy) in 5 fractions (range, 1-6 fractions). The median follow-up time was 37 months (range, 14-451 months) from disease diagnosis and 7 months (range, 1-54 months) from the SBRT start date. With death treated as a competing risk event, the cumulative incidence of local failure was 7.6% at 1 year after SBRT and 19.2% at 3 years. The median overall survival (OS) time was 19 months (95% confidence interval, 8-54 months) and tumor size correlated with survival (P=.0006). Patients with metastases <2.9cm had a median OS of 54 months compared with 11 months for those with adrenal metastases ≥2.9cm (P=.01). Incidence of grade 2 toxicity was 17% with no case of grade ≥3 toxicity. SBRT did not impact renal function with a mean estimated decline in glomerular filtration rate of only 2.6±8mL/min/1.73m2 compared with baseline. Combined kidneys V5 and combined renal cortex V17.5 did not correlate with a change in estimated glomerular filtration rate (P=.7 and P=.9, respectively).Conclusions: SBRT offers excellent local control for the treatment of adrenal gland metastases with very low toxicity rates and no significant short-term impact on renal function.

View details for PubMedID 30370363
Clinical Case Panel: Treatment Alternatives for Inoperable Hepatocellular Carcinoma. Seminars in radiation oncology Toesca, D. A., Barry, A., Sapisochin, G., Beecroft, R., Dawson, L., Owen, D., Mouli, S., Lewandowski, R., Salem, R., Chang, D. T. 2018; 28 (4): 295–308
Abstract

Surgical resection or liver transplantation offers the best chance of cure for patients with hepatocellular carcinoma (HCC). Unfortunately, most patients are not good candidates for liver resection due to locally advanced disease or compromised liver function. Moreover, liver transplantation waiting lists are long. For those cases not amenable for resection, a variety of local treatment modalities are available, such as image-guided ablative procedures, transarterial chemoembolization, and radioembolization, as well as external beam radiation. HCC presentation can vary considerably in size, number, and location of lesions. The management of inoperable HCC is, therefore, quite complex, and there is a lack of consensus on the best local treatment modality for each type tumor presentation. Here, we present 4 clinical case scenarios representative of commonly seen cases in the clinical setting, with different therapeutic perspectives from institutions with high expertise in the management of HCC.

View details for DOI 10.1016/j.semradonc.2018.08.001

View details for PubMedID 30309640
Development of deep neural network forindividualized hepatobiliary toxicity prediction after liver SBRT. Medical physics Ibragimov, B., Toesca, D., Chang, D., Yuan, Y., Koong, A., Xing, L. 2018
Abstract

BACKGROUND: Accurate prediction of radiation toxicity of healthy organs-at-risks (OARs) critically determines the radiation therapy (RT) success. The existing dose volume histogram-based metric may grossly under/over-estimate the therapeutic toxicity after 27% in liver RT and 50% in head-and-neck RT. We propose the novel paradigm for toxicity prediction by leveraging the enormous potential of deep learning and go beyond the existing dose/volume histograms.EXPERIMENTAL DESIGN: We employed a database of 125 liver stereotactic body RT (SBRT) cases with follow-up data to train deep learning-based toxicity predictor. Convolutional neural networks (CNNs) were applied to discover the consistent patterns in 3D dose plans associated with toxicities. To enhance the predicting power, we first pre-train the CNNs with transfer learning from 3D CT images of 2644 human organs. CNNs were then trained on liver SBRT cases. Furthermore, non-dosimetric pre-treatment features, such as patients' demographics, underlying liver diseases, liver-directed therapies, were inputted into the fully-connected neural network for more comprehensive prediction. The saliency maps of CNNs were used to estimate the toxicity risks associated with irradiation of anatomical regions of specific OARs. In addition, we applied machine learning solutions to map numerical pre-treatment features with hepatobiliary toxicity manifestation.RESULTS: Among 125 liver SBRT patients, 58 were treated for liver metastases, 36 for hepatocellular carcinoma, 27 for cholangiocarcinoma and 4 for other histologies. We observed that CNN we able to achieve accurate hepatobiliary toxicity prediction with the AUC of 0.79, whereas combining CNN for 3D dose plan analysis and fully-connected neural networks for numerical feature analysis resulted in AUC of 0.85. Deep learning produces almost 2 times fewer false positive toxicity predictions in comparison to DVH-based predictions, when the number of false negatives, i.e. missed toxicities, was minimized. The CNN saliency maps automatically estimated the toxicity risks for portal vein (PV) regions. We discovered that irradiation of the proximal portal vein is associated with two-times higher toxicity risks (risk score: 0.66) that irradiation of the left portal vein (risk score: 0.31).CONCLUSIONS: The framework offers clinically accurate tools for hepatobiliary toxicity prediction and automatic identification of anatomical regions that are critical to spare during SBRT. This article is protected by copyright. All rights reserved.

View details for PubMedID 30098025
Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) Utilizing Free-Text Clinical Narratives. Scientific reports Banerjee, I., Gensheimer, M. F., Wood, D. J., Henry, S., Aggarwal, S., Chang, D. T., Rubin, D. L. 2018; 8 (1): 10037
Abstract

We propose a deep learning model - Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) for estimating short-term life expectancy (>3 months) of the patients by analyzing free-text clinical notes in the electronic medical record, while maintaining the temporal visit sequence. In a single framework, we integrated semantic data mapping and neural embedding technique to produce a text processing method that extracts relevant information from heterogeneous types of clinical notes in an unsupervised manner, and we designed a recurrent neural network to model the temporal dependency of the patient visits. The model was trained on a large dataset (10,293 patients) and validated on a separated dataset (1818 patients). Our method achieved an area under the ROC curve (AUC) of 0.89. To provide explain-ability, we developed an interactive graphical tool that may improve physician understanding of the basis for the model's predictions. The high accuracy and explain-ability of the PPES-Met model may enable our model to be used as a decision support tool to personalize metastatic cancer treatment and provide valuable assistance to the physicians.

View details for PubMedID 29968730
Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) Utilizing Free-Text Clinical Narratives SCIENTIFIC REPORTS Banerjee, I., Gensheimer, M., Wood, D. J., Henry, S., Aggarwal, S., Chang, D. T., Rubin, D. L. 2018; 8
View details for DOI 10.1038/s41598-018-27946-5

View details for Web of Science ID 000437097800006
The role of bone marrow and spleen irradiation in the development of acute hematologic toxicity during chemoradiation for esophageal cancer. Advances in radiation oncology Chin, A. L., Aggarwal, S., Pradhan, P., Bush, K., von Eyben, R., Koong, A. C., Chang, D. T. 2018; 3 (3): 297–304
Abstract

Purpose: The purpose of this study was to determine the impact of splenic and thoracic bone marrow irradiation on hematologic toxicity in the setting of chemoradiation therapy for esophageal cancer.Methods and materials: We analyzed 60 patients with carcinoma of the distal esophagus or gastroesophageal junction who received concurrent chemoradiation in the preoperative or definitive setting. Dosimetric and volumetric parameters were calculated for the spleen, thoracic spine, and posterior ribs. The primary endpoint was grade ≥3 hematologic toxicity (HT3+). Associations were assessed using logistic and linear regression models.Results: Twenty-one patients (35%) experienced HT3+, including 18 patients with leukopenia and 5 with thrombocytopenia. Higher spleen V5-V20 was correlated with a lower risk of HT3+ on multivariable analysis (odds ratio: 0.83 per 10cm3 increase in V10; P=.013). A dose-dependent decrease in spleen volume was observed after radiation therapy, and a greater decrease was independently associated with a lower risk of HT3+ (odds ratio: 0.93 per 1% volume decrease; P=.014). Dosimetric parameters of the thoracic spine were not significantly associated with HT3+.Conclusions: A greater decrease in spleen size after radiation therapy and a higher spleen V5-V20 were independently associated with a lower risk of severe hematologic toxicity. Splenic irradiation may mitigate leukopenia associated with chemoradiation therapy.

View details for DOI 10.1016/j.adro.2018.02.005

View details for PubMedID 30202799
Comparing Modalities Using the National Cancer Database: Concerns With Rajyaguru et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Pollom, E. L., Feng, M., Chang, D. T. 2018: JCO2018780403
View details for DOI 10.1200/JCO.2018.78.0403

View details for PubMedID 29945518
Convolutional Neural Networks for Identifying Correlation Between Dose Patterns Associated with Poor Survival and Early Local Recurrence After Metastatic Liver SBRT Ibragimov, B., Yuan, Y., Toesca, D., Chang, D., Koong, A., Xing, L. WILEY. 2018: E415
View details for Web of Science ID 000434978003001
Loss of ARID1A Expression Predicts Worse Overall Survival in Patients with Resected Pancreatic Adenocarcinoma and Is Associated with Inactivating Mutations of the ARID1A Gene da Silva, A., Morales-Oyarvide, V., Rubinson, D. A., Kozak, M. M., Wang, W., Agostini-Vulaj, D., Huber, A., Chang, D. T., Clancy, T. E., Hezel, A. F., Ogino, S., Wolpin, B. M., Nowak, J. A. NATURE PUBLISHING GROUP. 2018: 675
View details for Web of Science ID 000429308604249
Loss of ARID1A Expression Predicts Worse Overall Survival in Patients with Resected Pancreatic Adenocarcinoma and Is Associated with Inactivating Mutations of the ARID1A Gene da Silva, A., Morales-Oyarvide, V., Rubinson, D. A., Kozak, M. M., Wang, W., Agostini-Vulaj, D., Huber, A., Chang, D. T., Clancy, T. E., Hezel, A. F., Ogino, S., Wolpin, B. M., Nowak, J. A. NATURE PUBLISHING GROUP. 2018: 675
View details for Web of Science ID 000459341003202
Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma JAMA ONCOLOGY Qian, Z., Rubinson, D. A., Nowak, J. A., Morales-Oyarvide, V., Dunne, R. F., Kozak, M. M., Welch, M. W., Brais, L. K., Da Silva, A., Li, T., Li, W., Masuda, A., Yang, J., Shi, Y., Gu, M., Masugi, Y., Bui, J., Zellers, C. L., Yuan, C., Babic, A., Khalaf, N., Aguirre, A., Ng, K., Miksad, R. A., Bullock, A. J., Chang, D. T., Tseng, J. F., Clancy, T. E., Linehan, D. C., Findeis-Hosey, J. J., Doyle, L. A., Thorner, A. R., Ducar, M., Wollison, B., Laing, A., Hahn, W. C., Meyerson, M., Fuchs, C. S., Ogino, S., Hornick, J. L., Hezel, A. F., Koong, A. C., Wolpin, B. M. 2018; 4 (3): e173420
Abstract

Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes.To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection.This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017.The DFS and OS among patients with resected pancreatic adenocarcinoma.Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations.Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.

View details for PubMedID 29098284
Microsatellite instability and adjuvant chemotherapy in stage II colon cancer. Koenig, J. L., Lin, A. Y., Pollom, E. L., Chang, D. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.4_suppl.767

View details for Web of Science ID 000436174100741
A 20-year comparison of definitive chemoradiation with 5-FU versus capecitabine in anal cancer patients treated at Stanford. Pumpalova, Y. S., Kozak, M. M., von Eyben, R., Fisher, G. A., Kunz, P. L., Chang, D., Haraldsdottir, S. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.4_suppl.710

View details for Web of Science ID 000436174100686
Management of Borderline Resectable Pancreatic Cancer. International journal of radiation oncology, biology, physics Toesca, D. A., Koong, A. J., Poultsides, G. A., Visser, B. C., Haraldsdottir, S., Koong, A. C., Chang, D. T. 2018; 100 (5): 1155–74
Abstract

With the rapid development of imaging modalities and surgical techniques, the clinical entity representing tumors that are intermediate between resectable and unresectable pancreatic adenocarcinoma has been identified has been termed "borderline resectable" (BR). These tumors are generally amenable for resection but portend an increased risk for positive margins after surgery and commonly necessitate vascular resection and reconstruction. Although there is a lack of consensus regarding the appropriate definition of what constitutes a BR pancreatic tumor, it has been demonstrated that this intermediate category carries a particular prognosis that is in between resectable and unresectable disease. In order to downstage the tumor and increase the probability of clear surgical margins, neoadjuvant therapy is being increasingly utilized and studied. There is a lack of high-level evidence to establish the optimal treatment regimen for BR tumors. When resection with negative margins is achieved after neoadjuvant therapy, the prognosis for BR tumors approaches and even exceeds that for resectable disease. This review presents the current definitions, different treatment approaches, and the clinical outcomes of BR pancreatic cancer.

View details for PubMedID 29722658
Strategies for prediction and mitigation of radiation-induced liver toxicity. Journal of radiation research Toesca, D. A., Ibragimov, B., Koong, A. J., Xing, L., Koong, A. C., Chang, D. T. 2018
Abstract

Although well described in the 1960s, liver toxicity secondary to radiation therapy, commonly known as radiation-induced liver disease (RILD), remains a major challenge. RILD encompasses two distinct clinical entities, a 'classic' form, composed of anicteric hepatomegaly, ascites and elevated alkaline phosphatase; and a 'non-classic' form, with liver transaminases elevated to more than five times the reference value, or worsening of liver metabolic function represented as an increase of 2 or more points in the Child-Pugh score classification. The risk of occurrence of RILD has historically limited the applicability of radiation for the treatment of liver malignancies. With the development of 3D conformal radiation therapy, which allowed for partial organ irradiation based on computed tomography treatment planning, there has been a resurgence of interest in the use of liver irradiation. Since then, a large body of evidence regarding the liver tolerance to conventionally fractionated radiation has been produced, but severe liver toxicities has continued to be reported. More recently, improvements in diagnostic imaging, radiation treatment planning technology and delivery systems have prompted the development of stereotactic body radiotherapy (SBRT), by which high doses of radiation can be delivered with high target accuracy and a steep dose gradient at the tumor - normal tissue interface, offering an opportunity of decreasing toxicity rates while improving tumor control. Here, we present an overview of the role SBRT has played in the management of liver tumors, addressing the challenges and opportunities to reduce the incidence of RILD, such as adaptive approaches and machine-learning-based predictive models.

View details for PubMedID 29432550
Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival BRITISH JOURNAL OF CANCER Morales-Oyarvide, V., Rubinson, D. A., Dunne, R. F., Kozak, M. M., Bui, J. L., Yuan, C., Qian, Z., Babic, A., Da Silva, A., Nowak, J. A., Khalaf, N., Brais, L. K., Welch, M. W., Zellers, C. L., Ng, K., Chang, D. T., Miksad, R. A., Bullock, A. J., Tseng, J. F., Swanson, R. S., Clancy, T. E., Linehan, D. C., Findeis-Hosey, J. J., Doyle, L. A., Hornick, J. L., Ogino, S., Fuchs, C. S., Hezel, A. F., Koong, A. C., Wolpin, B. M. 2017; 117 (12): 1874–82
Abstract

Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC).In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy.Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all Ptrend<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both Pinteraction<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence.American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.

View details for PubMedID 28982112
Carcinoid Syndrome Complicating a Pancreatic Neuroendocrine Tumor A Case Report PANCREAS Gerson, J. N., Witteles, R. M., Chang, D. T., Beygui, R. E., Iagaru, A. H., Kunz, P. L. 2017; 46 (10): 1381–85
Abstract

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms. These tumors can produce a wide variety of hormones that can lead to syndromes of hormone excess, such as carcinoid syndrome. We present the case of a 47-year-old man who presented with right upper quadrant abdominal pain and emesis. He was found to have metastatic pancreatic NET and was treated with systemic chemotherapy. He subsequently developed dyspnea on exertion and was found to have severe right-sided heart disease secondary to elevated levels of serum serotonin. He was successfully treated with surgical tricuspid and pulmonic valve replacement. True carcinoid syndrome with pancreatic NETs is rare, but, as a treatable complication of the disease, is an important entity for which oncologists should be familiar.

View details for PubMedID 29040196
Alterations in KRAS, CDKN2A, TP53, and SMAD4 Predict Disease-Free Survival in Resected Pancreatic Ductal Adenocarcinoma Morales-Oyarvide, V., Qian, Z., Rubinson, D. A., Nowak, J. A., Dunne, R. F., Kozak, M., Welch, M., Brais, L. K., Da Silva, A., Li, T., Li, W., Masuda, A., Yang, J., Shi, Y., Gu, M., Masugi, Y., Bui, J., Zellers, C., Yuan, C., Babic, A., Khalaf, N., Aguirre, A., Ng, K., Miksad, R., Bullock, A., Chang, D., Tseng, J., Clancy, T., Linehan, D., Findeis-Hosey, J., Doyle, L., Thorner, A., Ducar, M., Wollison, B., Laing, A., Hahn, W., Meyerson, M., Fuchs, C. S., Ogino, S., Hornick, J., Hezel, A., Koong, A., Wolpin, B. M. LIPPINCOTT WILLIAMS & WILKINS. 2017: 1420–21
View details for Web of Science ID 000414520800170
Improved Metastasis- and Disease-Free Survival With Preoperative Sequential Short-Course Radiation Therapy and FOLFOX Chemotherapy for Rectal Cancer Compared With Neoadjuvant Long-Course Chemoradiotherapy: Results of a Matched Pair Analysis INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Markovina, S., Youssef, F., Roy, A., Aggarwal, S., Khwaja, S., DeWees, T., Tan, B., Hunt, S., Myerson, R. J., Chang, D. T., Parikh, P. J., Olsen, J. R. 2017; 99 (2): 417–26
Abstract

To compare treatment and toxicity outcomes between a phase 2 institutional trial of near total neoadjuvant therapy (nTNT) for locally advanced rectal cancer and a similar historical control cohort treated at Washington University in St. Louis with the current US standard of care, defined as neoadjuvant chemoradiotherapy (NCRT), total mesorectal excision (TME), and adjuvant FOLFOX chemotherapy; to expand the comparison to an additional institution, patients treated with similar NCRT at Stanford University were included.Sixty-nine patients with cT3-4N0-2M0 rectal adenocarcinoma enrolled on the Washington University in St. Louis phase 2 study of nTNT were included for analysis. Patients treated at the same institution with conventional NCRT and adjuvant FOLFOX were matched for exact cTNM stage. Forty-one patients treated with NCRT at Stanford University were included in a second analysis. Kaplan-Meier analysis with log-rank test was used to compare local control, distant metastasis-free survival, disease-free survival, and overall survival.Median follow-up was 49 and 54 months for nTNT and NCRT, respectively. Pathologic complete response and T-downstaging rates were 28% versus 16% (P=.21) and 75% versus 41% (P<.001) in the nTNT and NCRT cohorts, respectively. Three-year disease-free survival (85% vs 68%, P=.032) was significantly better in the nTNT group. Actuarial 3-year local control (92% vs 96%, P=.36) and overall survival (96% vs 88%, P=.67) were similar. The Stanford cohort had significantly lower clinical stage. After controlling for clinical stage, age, tumor location, institution, and number of chemotherapy cycles, nTNT treatment remained significantly associated with lower risk of recurrence (P=.006).Patients treated with nTNT had higher T-downstaging and superior distant metastasis-free survival and disease-free survival compared with conventional NCRT when matched for tumor location and exact cTNM stage. Near total neoadjuvant therapy remained a significant multivariate predictor for improved outcome when including patients treated with NCRT at another institution.

View details for PubMedID 28871992
A Pilot Curriculum for Transitioning Radiation Oncology Residents Kumar, K. A., Prionas, N. D., Balazy, K. E., Kozak, M., Xiang, M., Moding, E. J., Chang, D. T. ELSEVIER SCIENCE INC. 2017: E125
View details for DOI 10.1016/j.ijrobp.2017.06.896

View details for Web of Science ID 000411559101059
Outcomes after Stereotactic Body Radiotherapy for Treatment of Hepatocellular Carcinoma Toesca, D. S., Osmundson, E., Shaffer, J., Von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2017: E192–E193
View details for Web of Science ID 000411559101221
Efficacy and Safety of Stereotactic Body Radiation Therapy for Treatment of Inoperable Intrahepatic and Perihilar Cholangiocarcinoma Toesca, D. S., Osmundson, E., Shaffer, J., Von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2017: E192
View details for Web of Science ID 000411559101220
Outcomes and Characteristics of Patients Treated with Emergent Radiotherapy Dudley, S. A., Aggarwal, S., Grade, M. M., Kumar, K. A., Turner, B. E., Liu, Y., Von Eyben, R., Chang, D. T., Knox, S. J. ELSEVIER SCIENCE INC. 2017: S221–S222
View details for DOI 10.1016/j.ijrobp.2017.06.545

View details for Web of Science ID 000411559108024
Impact of IMRT on Health Care Costs Among Elderly Patients with Anal Squamous Cell Carcinoma Chin, A. L., Pollom, E., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2017: S38
View details for DOI 10.1016/j.ijrobp.2017.06.101

View details for Web of Science ID 000411559106166
Stereotactic body radiation for pancreatic cancer: results of an international survey of practice patterns JOURNAL OF RADIATION ONCOLOGY Parekh, A., Rosati, L. M., Chang, D. T., Goodman, K. A., Pawlik, T. M., Koong, A. C., Herman, J. M. 2017; 6 (3): 273–78
View details for DOI 10.1007/s13566-016-0267-2

View details for Web of Science ID 000408448500005
The Prognostic Significance of Pretreatment Hematologic Parameters in Patients Undergoing Resection for Colorectal Cancer AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Kozak, M. M., von Eyben, R., Pai, J. S., Anderson, E. M., Welton, M. L., Shelton, A. A., Kin, C., Koong, A. C., Chang, D. T. 2017; 40 (4): 405–12
View details for DOI 10.1097/COC.0000000000000183

View details for Web of Science ID 000406228900014
Normal Tissue Constraints for Abdominal and Thoracic Stereotactic Body Radiotherapy. Seminars in radiation oncology Pollom, E. L., Chin, A. L., Diehn, M., Loo, B. W., Chang, D. T. 2017; 27 (3): 197-208
Abstract

Although stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy has become an established standard of care for the treatment of a variety of malignancies, our understanding of normal tissue dose tolerance with extreme hypofractionation remains immature. Since Timmerman initially proposed normal tissue dose constraints for SBRT in the 2008 issue of Seminars of Radiation Oncology, experience with SBRT has grown, and more long-term clinical outcome data have been reported. This article reviews the modern toxicity literature and provides updated clinically practical and useful recommendations of SBRT dose constraints for extracranial sites. We focus on the major organs of the thoracic and upper abdomen, specifically the liver and the lung.

View details for DOI 10.1016/j.semradonc.2017.02.001

View details for PubMedID 28577827
Radiation Therapy for Colorectal Liver Metastases CURRENT COLORECTAL CANCER REPORTS Qian, Y., Kumar, K. A., Dudley, S. A., Koong, A. C., Chang, D. T. 2017; 13 (3): 240–49
View details for DOI 10.1007/s11888-017-0368-3

View details for Web of Science ID 000404295300008
Comparison of Survival by Different Palliative Radiation Therapy Fractionation Schedules Dudley, S. A., Aggarwal, S., Qian, Y., Chaudhuri, A., Kumar, K., Chang, D. T. ELSEVIER SCIENCE INC. 2017: E39
View details for DOI 10.1016/j.ijrobp.2017.02.185

View details for Web of Science ID 000403079100127
Assessment of hepatic function decline after stereotactic body radiation therapy for primary liver cancer. Practical radiation oncology Toesca, D. A., Osmundson, E. C., von Eyben, R., Shaffer, J. L., Koong, A. C., Chang, D. T. 2017; 7 (3): 173-182
Abstract

This study aims to determine how the albumin-bilirubin (ALBI) score compares with the Child-Pugh (CP) score for assessing liver function following stereotactic body radiation therapy (SBRT).In total, 60 patients, 40 with hepatocellular carcinoma (HCC) and 20 with cholangiocarcinoma (CCA), were treated with SBRT. Liver function panels were obtained before and at 1, 3, 6, and 12 months after SBRT. Laboratory values were censored after locoregional recurrence, further liver-directed therapies, or liver transplant.A significant decline in hepatic function occurred after SBRT for HCC patients only (P = .001 by ALBI score; P < .0001 by CP score). By converting radiation doses to biologically equivalent doses by using a standard linear quadratic model using α/β of 10, the strongest dosimetric predictor of liver function decline for HCC was the volume of normal liver irradiated by a dose of 40 Gy when assessing liver function by the ALBI score (P = .07), and the volume of normal liver irradiated by a dose of 20 Gy by using the CP score (P= .0009). For CCA patients, the volume of normal liver irradiated by a dose of 40 Gy remained the strongest dosimetric predictor when using the ALBI score (P = .002), but no dosimetric predictor was significant using the CP score. Hepatic function decline correlated with worse overall survival for HCC (by ALBI, P = .0005; by CP, P < .0001) and for CCA (by ALBI, P = NS; by CP, P = .008).ALBI score was similarly able to predict hepatic function decline compared with CP score, and both systems correlated with survival.

View details for DOI 10.1016/j.prro.2016.10.003

View details for PubMedID 28343896
NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017. Journal of the National Comprehensive Cancer Network Benson, A. B., D'Angelica, M. I., Abbott, D. E., Abrams, T. A., Alberts, S. R., Saenz, D. A., Are, C., Brown, D. B., Chang, D. T., Covey, A. M., Hawkins, W., Iyer, R., Jacob, R., Karachristos, A., Kelley, R. K., Kim, R., Palta, M., Park, J. O., Sahai, V., Schefter, T., Schmidt, C., Sicklick, J. K., Singh, G., Sohal, D., Stein, S., Tian, G. G., Vauthey, J., Venook, A. P., Zhu, A. X., Hoffmann, K. G., Darlow, S. 2017; 15 (5): 563-573
Abstract

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding locoregional therapy for treatment of patients with hepatocellular carcinoma.

View details for PubMedID 28476736
Perfusion CT measurements predict tumor response in rectal carcinoma ABDOMINAL RADIOLOGY Kino, A., Shaffer, J., Maturen, K. E., Schmiedeskamp, H., Koong, A. C., Chang, D. T., Fleischmann, D., Kamaya, A. 2017; 42 (4): 1132-1140
View details for DOI 10.1007/s00261-016-0983-5

View details for Web of Science ID 000399166800010
Assessing local progression after stereotactic body radiation therapy for unresectable pancreatic adenocarcinoma: CT versus PET. Practical radiation oncology Toesca, D. A., Pollom, E. L., Poullos, P. D., Flynt, L., Cui, Y., Quon, A., von Eyben, R., Koong, A. C., Chang, D. T. 2017; 7 (2): 120-125
Abstract

Evaluation of local tumor progression (LP) has typically been defined by contrast-enhanced computed tomography (CT) imaging after stereotactic body radiation therapy (SBRT) for locally advanced pancreatic cancer (PDAC). The purpose of this study is to determine the benefit of adding 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging to CT for LP assessment of PDAC after SBRT.We retrospectively reviewed pretreatment, follow-up images, and outcomes of all patients treated with definitive SBRT for unresectable PDAC between December 2002 and December 2015 at our institution. For each patient, we independently analyzed LP both by CT and by FDG-PET criteria, using the Response Evaluation Criteria In Solid Tumors version 1.1 and the FDG-PET Response Evaluation Criteria In Solid Tumors version 1.0, respectively.Among 206 patients treated with definitive SBRT for unresectable PDAC, we identified 30 with LP on follow-up. Four did not undergo follow-up FDG-PET. Median time to LP after SBRT was 7.5 months (range, 2-25 months). Of the 26 patients with LP who had follow-up FDG-PET, 21 were diagnosed by FDG-PET (80.7%), 14 by CT (53.8%), and 9 by both FDG-PET and CT (34.6%). Use of CT alone revealed only 53.8% of cases of LP detected when FDG-PET and CT were combined. The cumulative incidence of LP, based on competing risk of death, at 1 and 2 years after SBRT was 9.6% and 16.7% by CT and 11% and 29.1% by FDG-PET, respectively.FDG-PET increases the chance of detecting LP of unresectable PDAC after SBRT and can have an important impact on reported outcomes. We recommend obtaining FDG-PET to assess treatment response when evaluating efficacy of SBRT and taking its use into account when comparing clinical data.

View details for DOI 10.1016/j.prro.2016.09.002

View details for PubMedID 28274396
Hematologic Nadirs During Chemoradiation for Anal Cancer: Temporal Characterization and Dosimetric Predictors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lee, A. Y., Golden, D. W., Bazan, J. G., Kopec, M., Pelizzari, C. A., Aggarwal, S., Chang, D. T., Liauw, S. L. 2017; 97 (2): 306-312
Abstract

Pelvic bone marrow (BM) constraints may offer a means to reduce the toxicity commonly associated with chemoradiation for anal cancer. We conducted a bi-institutional analysis of dose-volume metrics in a time-sensitive fashion to devise practical metrics to minimize hematologic toxicity.Fifty-six anal cancer patients from 2 institutions received definitive radiation therapy (median primary dose of 54 Gy) using intensity modulated radiation therapy (IMRT, n=49) or 3-dimensional (3D) conformal therapy (n=7) with concurrent 5-fluorouracil (5-FU) and mitomycin C. Weekly blood counts were retrospectively plotted to characterize the time course of cytopenias. Dose-volume parameters were correlated with blood counts at a standardized time point to identify predictors of initial blood count nadirs.Leukocytes, neutrophils, and platelets reached a nadir at week 3 of treatment. Smaller volumes of the pelvic BM correlated most strongly with lower week 3 blood counts, more so than age, sex, body mass index (BMI), or dose metrics. Patients who had ≥750 cc of pelvic BM spared from doses of ≥30 Gy had 0% grade 3+ leukopenia or neutropenia at week 3. Higher V40 Gy to the lower pelvic BM (LP V40) also correlated with cytopenia. Patients with an LP V40 >23% had higher rates of grade 3+ leukopenia (29% vs 4%, P=.02), grade 3+ neutropenia (33% vs 8%, P=.04), and grade 2+ thrombocytopenia (32% vs 7%, P=.04) at week 3. On multivariate analysis, pelvic BM volume and LP V40 remained associated with leukocyte count, and all marrow subsite volumes remained associated with neutrophil counts at week 3 (P<.1).Larger pelvic BM volumes correlate with less severe leukocyte and neutrophil nadirs, suggesting that larger total "marrow reserve" can mitigate cytopenias. Sparing a critical marrow reserve and limiting the V40 Gy to the lower pelvis may reduce the risk of hematologic toxicity.

View details for DOI 10.1016/j.ijrobp.2016.10.010

View details for PubMedID 28068238
The Impact of Intensity Modulated Radiation Therapy on Hospitalization Outcomes in the SEER-Medicare Population With Anal Squamous Cell Carcinoma. International journal of radiation oncology, biology, physics Pollom, E. L., Wang, G., Harris, J. P., Koong, A. C., Bendavid, E., Bhattacharya, J., Chang, D. T. 2017
Abstract

We examined the impact of intensity modulated radiation therapy (IMRT) on hospitalization rates in the Surveillance, Epidemiology, and End Results (SEER)-Medicare population with anal squamous cell carcinoma (SCC).We performed a retrospective cohort study using the SEER-Medicare database. We identified patients with nonmetastatic anal SCC diagnosed between 2001 and 2011 and treated with chemoradiation therapy. We assessed the relation between IMRT and first hospitalization by use of a multivariate competing-risk model, as well as instrumental variable analysis, using provider IMRT affinity as our instrument.Of the 1165 patients included in our study, 458 (39%) received IMRT. IMRT use increased over time and was associated more with regional and provider characteristics than with patient characteristics. The 3- and 6-month cumulative incidences of first hospitalization were 41.9% (95% confidence interval [CI], 37.3%-46.4%) and 47.6% (95% CI, 43.0%-52.2%), respectively, for the IMRT cohort and 46.7% (95% CI, 43.0%-50.4%) and 52.1% (95% CI, 48.4%-55.7%), respectively, for the non-IMRT cohort. IMRT was associated with a decreased hazard of first hospitalization compared with 3-dimensional radiation techniques (hazard ratio, 0.70; 95% CI, 0.58-0.84; P=.0002). Instrumental variable analysis suggested an even greater reduction in hospitalizations with IMRT after controlling for unmeasured confounders. There was a trend toward improved overall survival with IMRT, with an adjusted hazard ratio of 0.77 (95% CI, 0.59-1.00; P=.05).The use of IMRT is associated with reduced hospitalizations in elderly patients with anal SCC. Further work is warranted to understand the long-term health and cost impact of IMRT, particularly for patient subgroups most at risk of toxicity and hospitalization.

View details for DOI 10.1016/j.ijrobp.2017.01.006

View details for PubMedID 28258896
Cost-effectiveness of Stereotactic Body Radiation Therapy versus Radiofrequency Ablation for Hepatocellular Carcinoma: A Markov Modeling Study. Radiology Pollom, E. L., Lee, K., Durkee, B. Y., Grade, M., Mokhtari, D. A., Wahl, D. R., Feng, M., Kothary, N., Koong, A. C., Owens, D. K., Goldhaber-Fiebert, J., Chang, D. T. 2017: 161509-?
Abstract

Purpose To assess the cost-effectiveness of stereotactic body radiation therapy (SBRT) versus radiofrequency ablation (RFA) for patients with inoperable localized hepatocellular carcinoma (HCC) who are eligible for both SBRT and RFA. Materials and Methods A decision-analytic Markov model was developed for patients with inoperable, localized HCC who were eligible for both RFA and SBRT to evaluate the cost-effectiveness of the following treatment strategies: (a) SBRT as initial treatment followed by SBRT for local progression (SBRT-SBRT), (b) RFA followed by RFA for local progression (RFA-RFA), (c) SBRT followed by RFA for local progression (SBRT-RFA), and (d) RFA followed by SBRT for local progression (RFA-SBRT). Probabilities of disease progression, treatment characteristics, and mortality were derived from published studies. Outcomes included health benefits expressed as discounted quality-adjusted life years (QALYs), costs in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analysis was performed to assess the robustness of the findings. Results In the base case, SBRT-SBRT yielded the most QALYs (1.565) and cost $197 557. RFA-SBRT yielded 1.558 QALYs and cost $193 288. SBRT-SBRT was not cost-effective, at $558 679 per QALY gained relative to RFA-SBRT. RFA-SBRT was the preferred strategy, because RFA-RFA and SBRT-RFA were less effective and more costly. In all evaluated scenarios, SBRT was preferred as salvage therapy for local progression after RFA. Probabilistic sensitivity analysis showed that at a willingness-to-pay threshold of $100 000 per QALY gained, RFA-SBRT was preferred in 65.8% of simulations. Conclusion SBRT for initial treatment of localized, inoperable HCC is not cost-effective. However, SBRT is the preferred salvage therapy for local progression after RFA. (©) RSNA, 2017 Online supplemental material is available for this article.

View details for DOI 10.1148/radiol.2016161509

View details for PubMedID 28045603
Central liver toxicity after SBRT: An expanded analysis and predictive nomogram. Radiotherapy and oncology Toesca, D. A., Osmundson, E. C., Eyben, R. v., Shaffer, J. L., Lu, P., Koong, A. C., Chang, D. T. 2017; 122 (1): 130-136
Abstract

To further explore the correlation of central biliary tract (cHBT) radiation doses with hepatobiliary toxicity (HBT) after stereotactic body radiation therapy (SBRT) in a larger patient dataset.We reviewed the treatment and outcomes of all patients who received SBRT for primary liver cancer (PLC) and metastatic liver tumors between July 2004 and November 2015 at our institution. The cHBT was defined as isotropic expansions (5, 10, 15, 20 and 25mm) from the portal vein (PV). Doses were converted to biologically effective doses by using the standard linear quadratic model with α/β of 10 (BED10). HBT was graded according to the Common Terminology Criteria for Adverse Events v4.03.Median follow-up was 13months. Out of the 130 patients with complete follow-up records analyzed, 60 (46.1%) had liver metastases, 40 (30.8%) had hepatocellular carcinoma (HCC), 26 (20%) had cholangiocarcinoma (CCA) and 4 (3.1%) patients other PLC histologies. Thirty-three (25.4%) grade 2+ and 28 (21.5%) grade 3+ HBT were observed. Grade 3+ HBT was seen in 13 patients (50%) with CCA, 7 patients (17.5%) with HCC and 7 (11.7%) patients with liver metastases. SBRT doses to the cHBT were highly associated with HBT, but only for PLC patients when analyzed by histological subtype. The 15mm expansion from the PV (cHBT15) proved to be an appropriate surrogate for the cHBT. The strongest cHBT15 dose predictors for G3+ HBT for PLC were the VBED1040⩾37cc (p<0.0001) and the VBED1030⩾45cc (p<0.0001).SBRT doses to the cHBT are associated with occurrence of HBT only in PLC patients. Limiting the dose to the cHBT to VBED1040<37cc and VBED1030<45cc when treating PLC patients with SBRT may reduce the risk of HBT.

View details for DOI 10.1016/j.radonc.2016.10.024

View details for PubMedID 27865544
Impact of Intensity-Modulated Radiotherapy on Health Care Costs of Patients With Anal Squamous Cell Carcinoma. Journal of oncology practice Chin, A. L., Pollom, E. L., Qian, Y., Koong, A. C., Chang, D. T. 2017: JOP2017024810
Abstract

Drivers of variation in the cost of care after chemoradiotherapy for the management of anal squamous cell carcinoma (SCC) have not been fully elucidated. We sought to characterize the direct and indirect impact of radiotherapy modality on health care costs among patients with anal SCC.A retrospective cohort study was performed using the 2014 linkage of the SEER-Medicare database. We identified 1,025 patients with anal SCC diagnosed between 2001 and 2011 and treated with chemoradiotherapy. Propensity score matching was used to balance baseline differences between patients treated with intensity-modulated radiotherapy (IMRT) and those treated with three-dimensional conformal radiotherapy (3D-CRT). Differences in total, cancer-attributable, and procedure-specific costs between groups were measured.Radiation-related, patient out-of-pocket, and total costs in the 1-year period after radiotherapy start were all higher for the IMRT group than the 3D-CRT group (median total cost, $35,890 v $27,262, respectively; P < .001). Patients who received IMRT had lower cumulative costs associated with urgent hospitalizations and emergency department visits at both 9 months and 1 year after treatment start compared with a matched cohort of patients who received 3D-CRT (median, $711 v $4,957 at 1 year, respectively; P = .021).Although total costs of care were higher for IMRT compared with 3D-CRT, primarily as a result of higher radiotherapy-specific costs, IMRT was associated with decreased unplanned health care utilization costs starting at 9 months after treatment start. Radiotherapy-centered episodes of care may need to encompass a longer time horizon to capture the full cost savings associated with more advanced radiation modalities.

View details for DOI 10.1200/JOP.2017.024810

View details for PubMedID 29035618
Cost-Effectiveness of Radiation and Chemotherapy for High-Risk Low-Grade Glioma. Neuro-oncology Qian, Y., Maruyama, S., Kim, H., Pollom, E. L., Kumar, K. A., Chin, A. L., Harris, J. P., Chang, D. T., Pitt, A., Bendavid, E., Owens, D. K., Durkee, B. Y., Soltys, S. G. 2017
Abstract

The addition of PCV (procarbazine, lomustine, vincristine) chemotherapy to radiotherapy (RT) for patients with high-risk (≥ 40 years old or sub-totally resected) low-grade glioma (LGG) results in an absolute median survival benefit of over 5 years. We evaluated the cost-effectiveness of this treatment strategy.A decision tree with an integrated three-state Markov model was created to follow patients with high risk LGG after surgery treated with RT vs. RT+PCV. Patients existed in one of 3 health states: stable, progressive, and dead. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Analysis was conducted from the healthcare perspective. Deterministic and probabilistic sensitivity analysis explored uncertainty in model parameters.Modeled outcomes demonstrated agreement with clinical data in expected benefit of addition of PCV to RT. The addition of PCV to RT yielded an incremental benefit of 4.77 quality-adjusted life-years (QALYs) (9.94 for RT+PCV vs. 5.17 for RT alone) at an incremental cost of $48,635 ($188,234 for RT+PCV vs. $139,598 for RT alone), resulting in an incremental cost-effectiveness ratio of $10,186 per QALY gained. Probabilistic sensitivity analysis demonstrates that within modeled distributions of parameters, RT+PCV has 99.96% probability of being cost-effectiveness at a willingness-to-pay threshold of $100,000 per QALY.The addition of PCV to RT is a cost-effective treatment strategy for patients with high-risk LGG.

View details for PubMedID 28666368
Does radiotherapy still have a role in unresected biliary tract cancer? Cancer medicine Pollom, E. L., Alagappan, M., Park, L. S., Whittemore, A. S., Koong, A. C., Chang, D. T. 2017; 6 (1): 129-141
Abstract

The benefits of radiotherapy for inoperable biliary tract cancer remain unclear due to the lack of randomized data. We evaluated the impact of radiotherapy on survival in elderly patients using the SEER-Medicare database. Patients in the SEER-Medicare database with inoperable biliary tract tumors diagnosed between 1998 and 2011 were included. We used multivariate logistic regression to evaluate factors associated with treatment selection, and multivariate Cox regression and propensity score matching to evaluate treatment selection in relation to subsequent survival. Of the 2343 patients included, 451 (19%) received radiotherapy within 4 months of diagnosis. The use of radiotherapy declined over time, and was influenced by receipt of chemotherapy and patient age, race, marital status, poverty status, and tumor stage and type. Median survival was 9.3 (95% CI 8.7-9.7) months among patients who did not receive radiation and 10.0 (95% CI 9.1-11.3) months among those who received radiation, conditional on having survived 4 months. In patients who received chemotherapy (n = 1053), receipt of radiation was associated with improved survival, with an adjusted hazard ratio of 0.82 (95% 0.70-0.97, P = 0.02). In patients who did not receive chemotherapy (n = 1290), receipt of radiation was not associated with improved survival, with an adjusted hazard ratio of 1.09 (95% 0.91-1.30, P = 0.34). Propensity-scored matched analyses showed similar results. Despite the survival benefit associated with the addition of radiotherapy to chemotherapy, the use of radiation for unresectable biliary tract cancers has declined over time.

View details for DOI 10.1002/cam4.975

View details for PubMedID 27891822
Multiplex Proximity Ligation Assay to Identify Potential Prognostic Biomarkers for Improved Survival in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy. International journal of radiation oncology, biology, physics Rao, A. D., Liu, Y., von Eyben, R., Hsu, C. C., Hu, C., Rosati, L. M., Parekh, A., Ng, K., Hacker-Prietz, A., Zheng, L., Pawlik, T. M., Laheru, D. A., Jaffee, E. M., Weiss, M. J., Le, D. T., Hruban, R. H., De Jesus-Acosta, A., Wolfgang, C. L., Narang, A. K., Chang, D. T., Koong, A. C., Herman, J. M. 2017
Abstract

To explore seromarker levels for associations with outcomes in locally advanced pancreatic cancer (LAPC) patients who received chemotherapy and stereotactic body radiation therapy (SBRT).Serum from LAPC patients in 2 prospective trials of hypofractionated SBRT (5-6.6 Gy × 5) was collected before SBRT. Proximity ligation assay quantified the expression levels of 36 pancreatic cancer-specific candidate seromarkers: Axl, BMP2, CA 125, CA 19-9, CEA, CXCL-1/6/9/10, EGFR, Gas6, Her2, IGF-2, IGFBP-2/3/7, IL-6/6Ra/7/8/12, mesothelin, MMP-1/2/3/7, osteopontin, PDGFRa, PDK1, PF4, RegIV, SPARC, TGF-β, VEGF-A/D, and YKL40. Seromarker values were log transformed owing to log-normal distribution of the values, and Cox regression analysis was performed to assess for any association with overall survival. The Benjamini-Hochberg method was used to control for a false discovery rate (FDR) of only 10%.Sixty-four patients with LAPC were included. No clinical factors (including surgical resection, receipt of pre-SBRT chemotherapy, receipt of post-SBRT chemotherapy, performance status, and age) or potential biomarkers in the panel were associated with improved survival in this cohort after application of the FDR correction. Potential prognostic factors for improved survival for future investigation included surgical resection (P=.007, adjusted P=.153) and the serum expression of IL-8 (P=.006, adjusted P=.153), CA 19-9 (P=.031, adjusted P=.377), and MMP-1 (P=.036, adjusted P=.377).These data explore the expression of a panel of proteins in pre-SBRT serum of LAPC patients in the context of a conservative FDR correction. None of the clinical factors or expression levels of the serum proteins were found to be associated with survival; however, IL-8, CA 19-9, and MMP-1 were highlighted as possible candidates warranting inclusion in future seromarker studies in the ongoing efforts to identify tools for risk stratification and treatment allocation in LAPC.

View details for PubMedID 29157747
Nonoperative Management of Rectal Cancer: A Modern Perspective. Oncology (Williston Park, N.Y.) Qian, Y., Chin, A. L., Toesca, D. A., Koong, A. C., Chang, D. T. 2017; 31 (10): e13–e22
Abstract

Nonoperative management of rectal cancer is an emerging treatment approach that aims to enable carefully selected patients to avoid the morbidity of radical surgical resection, while benefiting from the same excellent rates of tumor control achieved with radical surgery-based combined-modality therapy. The success of nonoperative management in this setting is based on the accurate assessment of tumor eradication after chemoradiotherapy, without pathologic verification. Therefore, clinical evidence of complete response-based on physical examination, endoscopic procedures, and imaging-must be utilized as a marker to predict for pathologic complete response and thus help select the patients who are most appropriate for nonoperative management. Initial evidence from retrospective and prospective single-arm and cohort studies has demonstrated high rates of local control and disease-free survival with nonoperative management of rectal cancer, compared with historical results of combined-modality therapy. Several trials and registries are prospectively investigating nonoperative management vs standard treatment of rectal cancer. At this time, combined-modality therapy with total mesorectal excision remains the standard of care for patients with locally advanced rectal cancer; nonoperative management should not be routinely offered outside of clinical trials.

View details for PubMedID 29083469
Combining deep learning with anatomy analysis for segmentation of portal vein for liver SBRT planning. Physics in medicine and biology Ibragimov, B., Toesca, D., Chang, D., Koong, A., Xing, L. 2017
Abstract

Automated segmentation of portal vein (PV) for liver radiotherapy planning is a challenging task due to potentially low vasculature contrast, complex PV anatomy and image artifacts originated from fiducial markers and vasculature stents. In this paper, we propose a novel framework for automated PV segmentation from computed tomography (CT) images. We apply convolutional neural networks (CNN) to learn consistent appearance patterns of PV using a training set of CT images with reference annotations and then enhance PV in previously unseen CT images. Markov Random Fields (MRF) were further used to smooth the CNN enhancement results and remove isolated mis-segmented regions. Finally, CNN-MRF-based enhancement was augmented with PV centerline detection that was based on PV anatomical properties such as tubularity and branch composition. The framework was validated on a clinical database with 72 CT images of patients scheduled to liver stereotactic body radiation therapy. The obtained segmentation accuracy was DSC = 0.83 and η = 1.08 in terms of the median Dice coefficient and mean symmetric surface distance, respectively, when segmentation is encompassed into the PV region of interest. The obtained results indicate that CNN can be used for accurate segmentation of PV and potentially integrated into liver radiation therapy planning.

View details for PubMedID 28994665
Perfusion CT measurements predict tumor response in rectal carcinoma. Abdominal radiology Kino, A., Shaffer, J., Maturen, K. E., Schmiedeskamp, H., Koong, A. C., Chang, D. T., Fleischmann, D., Kamaya, A. 2016
Abstract

To evaluate the capacity of perfusion CT imaging to distinguish between complete and incomplete responders after neoadjuvant chemoradiation therapy for rectal carcinoma, with particular attention to segmentation technique.17 patients were evaluated in this prospective IRB-approved study. For each patient, a perfusion CT acquisition was obtained prior to the initiation of chemoradiation, at 1-2 weeks after the start of chemoradiation, and at 12 weeks after the start of chemoradiation therapy. From each dataset, three perfusion parameters were measured, each in two different ways: a region of interest incorporating only "hot spots" of greatest enhancement and whole-tumor measurements.In univariate analysis, blood volume and permeability differed significantly between responders and non-responders. In logistic regression analysis evaluating predictors of the "complete response" outcome, only two predictors were retained as statistically significant: peak hot spot blood volume 1-2 weeks into therapy (OR 10.25, p = 0.0026) and hot spot permeability decline at 12 weeks after the initiation of therapy (OR 5.62, p = 0.03). The overall likelihood ratio test for this model supported the conclusion that hot spot blood volume and hot spot permeability decline were significant predictors of the complete pathologic response outcome (p < 0.0001).In this pilot study, peak tumor blood volume and decline in tumor permeability, when measured in "hot spots" of greatest enhancement, were strong predictors of complete therapeutic response in rectal cancer after neoadjuvant therapy.

View details for DOI 10.1007/s00261-016-0983-5

View details for PubMedID 28008455
Robotic intrafractional US guidance for liver SABR: System design, beam avoidance, and clinical imaging. Medical physics Schlosser, J., Gong, R. H., Bruder, R., Schweikard, A., Jang, S., Henrie, J., Kamaya, A., Koong, A., Chang, D. T., Hristov, D. 2016; 43 (11): 5951-?
Abstract

To present a system for robotic 4D ultrasound (US) imaging concurrent with radiotherapy beam delivery and estimate the proportion of liver stereotactic ablative body radiotherapy (SABR) cases in which robotic US image guidance can be deployed without interfering with clinically used VMAT beam configurations.The image guidance hardware comprises a 4D US machine, an optical tracking system for measuring US probe pose, and a custom-designed robot for acquiring hands-free US volumes. In software, a simulation environment incorporating the LINAC, couch, planning CT, and robotic US guidance hardware was developed. Placement of the robotic US hardware was guided by a target visibility map rendered on the CT surface by using the planning CT to simulate US propagation. The visibility map was validated in a prostate phantom and evaluated in patients by capturing live US from imaging positions suggested by the visibility map. In 20 liver SABR patients treated with VMAT, the simulation environment was used to virtually place the robotic hardware and US probe. Imaging targets were either planning target volumes (PTVs, range 5.9-679.5 ml) or gross tumor volumes (GTVs, range 0.9-343.4 ml). Presence or absence of mechanical interference with LINAC, couch, and patient body as well as interferences with treated beams was recorded.For PTV targets, robotic US guidance without mechanical interference was possible in 80% of the cases and guidance without beam interference was possible in 60% of the cases. For the smaller GTV targets, these proportions were 95% and 85%, respectively. GTV size (1/20), elongated shape (1/20), and depth (1/20) were the main factors limiting the availability of noninterfering imaging positions. The robotic US imaging system was deployed in two liver SABR patients during CT simulation with successful acquisition of 4D US sequences in different imaging positions.This study indicates that for VMAT liver SABR, robotic US imaging of a relevant internal target may be possible in 85% of the cases while using treatment plans currently deployed in the clinic. With beam replanning to account for the presence of robotic US guidance, intrafractional US may be an option for 95% of the liver SABR cases.

View details for PubMedID 27806580
Patient-reported outcomes of a multicenter phase 2 study investigating gemcitabine and stereotactic body radiation therapy in locally advanced pancreatic cancer. Practical radiation oncology Rao, A. D., Sugar, E. A., Chang, D. T., Goodman, K. A., Hacker-Prietz, A., Rosati, L. M., Columbo, L., O'Reilly, E., Fisher, G. A., Zheng, L., Pai, J. S., Griffith, M. E., Laheru, D. A., Iacobuzio-Donahue, C. A., Wolfgang, C. L., Koong, A., Herman, J. M. 2016; 6 (6): 417-424
Abstract

We previously reported clinical outcomes and physician-reported toxicity of gemcitabine and hypofractionated stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC). Here we prospectively investigate the impact of gemcitabine and SBRT on patient-reported quality of life (QoL).Forty-nine LAPC patients received 33 Gy SBRT (6.6 Gy daily fractions) upfront or after ≤3 doses of gemcitabine (1000 mg/m(2)) followed by gemcitabine until progression. European Organization for Research and Treatment of Cancer QoL core cancer (QLQ-C30) and pancreatic cancer-specific (European Organization for Research and Treatment of Cancer QLQ-PAN26) questionnaires were administered to patients pre-SBRT and at 4 to 6 weeks (first follow-up [1FUP]) and 4 months (2FUP) post-SBRT. Changes in QoL scores were deemed clinically relevant if median changes were at least 5 points in magnitude.Forty-three (88%) patients completed pre-SBRT questionnaires. Of these, 88% and 51% completed questionnaires at 1FUP and 2FUP, respectively. There was no change in global QoL from pre-SBRT to 1FUP (P = .17) or 2FUP (P > .99). Statistical and clinical improvements in pancreatic pain (P = .001) and body image (P = .007) were observed from pre-SBRT to 1FUP. Patients with 1FUP and 2FUP questionnaires reported statistically and clinically improved body image (P = .016) by 4 months. Although pancreatic pain initially demonstrated statistical and clinical improvement (P = .020), scores returned to enrollment levels by 2FUP (P = .486). A statistical and clinical decline in role functioning (P = .002) was observed in patients at 2FUP.Global QoL scores are not reduced with gemcitabine and SBRT. In this exploratory analysis, patients experience clinically relevant short-term improvements in pancreatic cancer-specific symptoms. Previously demonstrated acceptable clinical outcomes combined with these favorable QoL data indicate that SBRT can be easily integrated with other systemic therapies and may be a potential standard of care option in patients with LAPC.

View details for DOI 10.1016/j.prro.2016.05.005

View details for PubMedID 27552809
Reirradiation With Stereotactic Body Radiation Therapy After Prior Conventional Fractionation Radiation for Locally Recurrent Pancreatic Adenocarcinoma 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Toesca, D. A., Pollom, E., Nwachukwu, C. R., von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2016: E205–E205
View details for Web of Science ID 000387655802501
Hematologic Toxicity During Anal Cancer Treatment: The Importance of Pelvic Bone Marrow Volume and Limiting Radiation Dose to a Critical Marrow Volume Lee, A. Y., Golden, D., Bazan, J. G., Pelizzari, C., Aggarwal, S., Chang, D. T., Liauw, S. ELSEVIER SCIENCE INC. 2016: E216
View details for DOI 10.1016/j.ijrobp.2016.06.1133

View details for Web of Science ID 000387655802527
Fractionation of Palliative Radiation Therapy in Metastatic Breast Cancer-Selection and Survival Qian, Y., Aggarwal, S., Dudley, S. A., Durkee, B. Y., Kumar, K. A., Chaudhuri, A. A., Pollom, E., von Eyben, R., Chang, D. T., Horst, K. C. ELSEVIER SCIENCE INC. 2016: E513
View details for DOI 10.1016/j.ijrobp.2016.06.1915

View details for Web of Science ID 000387655803571
Effectiveness of Radiation Therapy for Low- to Intermediate-Grade Neuroendocrine Tumors Carter, J. N., Aggarwal, S., Radish, K., Allen, J. R., Koong, A. C., Chang, D. T., Loo, B. W., Diehn, M., Kunz, P. L., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2016: E202–E203
View details for DOI 10.1016/j.ijrobp.2016.06.1100

View details for Web of Science ID 000387655802495
Physician Assessment Versus the Graded Prognostic Assessment (GPA) for Brain Metastases Aggarwal, S., Prionas, N. D., Carter, J. N., Pradhan, P., Bui, J. L., Fujimoto, D. K., von Eyben, R., Koong, A. C., Chang, D. T., Ho, C. K., Soltys, S. G. ELSEVIER SCIENCE INC. 2016: E126
View details for DOI 10.1016/j.ijrobp.2016.06.908

View details for Web of Science ID 000387655802307
Impact of Spleen and Thoracic Spine Irradiation on Acute Hematologic Toxicity During Chemoradiation for Esophageal Cancer Chin, A. L., Aggarwal, S., Bush, K., von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2016: E147
View details for DOI 10.1016/j.ijrobp.2016.06.961

View details for Web of Science ID 000387655802359
Can Gender Predict Differences in Behavior, Manuscript Ratings, and Quality of Reviews Among Red Journal Reviewers? Jamorabo, D., Chang, D. T., Bennett, K., Zietman, A. L., Jabbour, S. K. ELSEVIER SCIENCE INC. 2016: E419
View details for DOI 10.1016/j.ijrobp.2016.06.1684

View details for Web of Science ID 000387655803346
Multiplex Proximal Ligation Assay Identifies Potential Prognostic Biomarkers for Improved Survival in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy Rao, A. D., Liu, Y., Hsu, C. C., Parekh, A., Rosati, L. M., Ng, K., Hacker-Prietz, A., Zheng, L., Pawlik, T. M., Laheru, D. A., Jaffee, E. M., Weiss, M. J., Le, D. T., Hruban, R. H., De Jesus-Acosta, A., Wolfgang, C. L., Chang, D. T., Koong, A. C., Herman, J. M. ELSEVIER SCIENCE INC. 2016: E597–E598
View details for DOI 10.1016/j.ijrobp.2016.06.2126

View details for Web of Science ID 000387655804046
Multicohort Analysis of Effect of Ionizing Radiation on Transcription Identifies Conserved Gene Signature and Clinically Relevant Novel Radiosensitizers Turner, B. E., Jiang, D., Khatri, P., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2016: E590
View details for DOI 10.1016/j.ijrobp.2016.06.2106

View details for Web of Science ID 000387655804028
Serum Protein Expression and Associations With Conversion to Resectable Status Following Chemotherapy and Stereotactic Body Radiation Therapy in Locally Advanced Pancreatic Adenocarcinoma Rosati, L. M., Liu, Y., Rao, A. D., Hsu, C. C., Parekh, A., Ng, K., Hacker-Prietz, A., Zheng, L., Laheru, D. A., Jaffee, E. M., Le, D. T., De Jesus-Acosta, A., Hruban, R. H., Pawlik, T. M., Weiss, M. J., Wolfgang, C. L., Chang, D. T., Herman, J. M., Koong, A. C. ELSEVIER SCIENCE INC. 2016: S44
View details for DOI 10.1016/j.ijrobp.2016.06.117

View details for Web of Science ID 000387655804434
Comparison of Survival by Different Palliative Radiation Therapy Fractionation Schedules Dudley, S. A., Qian, Y., Aggarwal, S., Chaudhuri, A. A., Kumar, K. A., Chang, D. T. ELSEVIER SCIENCE INC. 2016: E515
View details for DOI 10.1016/j.ijrobp.2016.06.1919

View details for Web of Science ID 000387655803575
Radiation Therapy Fractionation Practice Patterns in End-of-Life Care Aggarwal, S., Prionas, N. D., Carter, J. N., Kumar, K. A., Pradhan, P., Bui, J. L., von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2016: E508–E509
View details for DOI 10.1016/j.ijrobp.2016.06.1903

View details for Web of Science ID 000387655803560
Accuracy of Predicting Survival Outcomes in Palliative Radiation Therapy Patients Aggarwal, S., Prionas, N. D., Carter, J. N., Pradhan, P., Bui, J. L., von Eyben, R., Ho, C. K., Hancock, S. L., Soltys, S. G., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2016: S148–S149
View details for DOI 10.1016/j.ijrobp.2016.06.360

View details for Web of Science ID 000387655804673
Cost-Effectiveness of Local Therapies for Inoperable, Localized Hepatocellular Carcinoma Pollom, E., Lee, K., Durkee, B. Y., Grade, M., Mokhtari, D., Weeks, B., Feng, M., Wahl, D. R., Kothary, N., Koong, A. C., Owens, D., Goldhaber-Fiebert, J., Chang, D. T. ELSEVIER SCIENCE INC. 2016: E138
View details for DOI 10.1016/j.ijrobp.2016.06.938

View details for Web of Science ID 000387655802337
Hepatobiliary Toxicity Association With Central Biliary Tract Dose After Stereotactic Body Radiation Therapy: An Expanded Analysis 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Toesca, D. A., Osmundson, E., Shaffer, J., von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2016: S141–S142
View details for Web of Science ID 000387655804657
Increased Visceral to Subcutaneous Fat Ratio Is Associated With Decreased Overall Survival in Pancreatic Cancer 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Nwachukwu, C. R., Toesca, D. A., Liu, Y., Koong, A., von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2016: E220–E220
View details for Web of Science ID 000387655802537
The Impact of FDG Positron Emission Tomography for Assessment of Local Progression of Unresectable Pancreatic Adenocarcinoma After Stereotactic Body Radiation Therapy 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Toesca, D. A., Pollom, E., Nwachukwu, C. R., von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2016: E205–E205
View details for Web of Science ID 000387655802500
Assessment of Hepatic Function Decline After Stereotactic Body Radiation Therapy for Primary Liver Tumors Using the Albumin-Bilirubin (ALBI) Score 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Toesca, D. A., Osmundson, E., Shaffer, J., von Eyben, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2016: E203–E204
View details for Web of Science ID 000387655802497
Stereotactic Body Radiation Therapy After Surgical Resection for Locally Recurrent Pancreatic Adenocarcinoma 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Nwachukwu, C. R., Toesca, D. A., Pollom, E., von Eyben, R., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2016: E158–E158
View details for Web of Science ID 000387655802386
Quantitative Analysis of (18)F-Fluorodeoxyglucose Positron Emission Tomography Identifies Novel Prognostic Imaging Biomarkers in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy. International journal of radiation oncology, biology, physics Cui, Y., Song, J., Pollom, E., Alagappan, M., Shirato, H., Chang, D. T., Koong, A. C., Li, R. 2016; 96 (1): 102-109
Abstract

To identify prognostic biomarkers in pancreatic cancer using high-throughput quantitative image analysis.In this institutional review board-approved study, we retrospectively analyzed images and outcomes for 139 locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy (SBRT). The overall population was split into a training cohort (n=90) and a validation cohort (n=49) according to the time of treatment. We extracted quantitative imaging characteristics from pre-SBRT (18)F-fluorodeoxyglucose positron emission tomography, including statistical, morphologic, and texture features. A Cox proportional hazard regression model was built to predict overall survival (OS) in the training cohort using 162 robust image features. To avoid over-fitting, we applied the elastic net to obtain a sparse set of image features, whose linear combination constitutes a prognostic imaging signature. Univariate and multivariate Cox regression analyses were used to evaluate the association with OS, and concordance index (CI) was used to evaluate the survival prediction accuracy.The prognostic imaging signature included 7 features characterizing different tumor phenotypes, including shape, intensity, and texture. On the validation cohort, univariate analysis showed that this prognostic signature was significantly associated with OS (P=.002, hazard ratio 2.74), which improved upon conventional imaging predictors including tumor volume, maximum standardized uptake value, and total legion glycolysis (P=.018-.028, hazard ratio 1.51-1.57). On multivariate analysis, the proposed signature was the only significant prognostic index (P=.037, hazard ratio 3.72) when adjusted for conventional imaging and clinical factors (P=.123-.870, hazard ratio 0.53-1.30). In terms of CI, the proposed signature scored 0.66 and was significantly better than competing prognostic indices (CI 0.48-0.64, Wilcoxon rank sum test P<1e-6).Quantitative analysis identified novel (18)F-fluorodeoxyglucose positron emission tomography image features that showed improved prognostic value over conventional imaging metrics. If validated in large, prospective cohorts, the new prognostic signature might be used to identify patients for individualized risk-adaptive therapy.

View details for DOI 10.1016/j.ijrobp.2016.04.034

View details for PubMedID 27511850
Dosimetric analysis of isocentrically shielded volumetric modulated arc therapy for locally recurrent nasopharyngeal cancer SCIENTIFIC REPORTS Lu, J., Huang, B., Xing, L., Chang, D. T., Peng, X., Xie, L., Lin, Z., Li, M. 2016; 6
Abstract

This study aimed to investigate the dosimetric characteristics of an isocentrically shielded RapidArc (IS-RA) technique for treatment of locally recurrent nasopharyngeal cancer (lrNPC). In IS-RA, the isocenter was placed at the center of the pre-irradiated brainstem (BS)/spinal cord (SC) and the jaws were set to shield the BS/SC while ensuring the target coverage during the whole gantry rotation. For fifteen patients, the IS-RA plans were compared with the conventional RapidArc (C-RA) regarding target coverage, organ-at-risk (OAR) sparing and monitor units (MUs). The relationship between the dose reduction of BS/SC and some geometric parameters including the angle extended by the target with respect to the axis of BS/SC (Ang_BSSC), the minimum distance between the target and BS/SC (Dist_Min) and the target volume were evaluated. The IS-RA reduced the BS/SC doses by approximately 1-4 Gy on average over the C-RA, with more MUs. The IS-RA demonstrated similar target coverage and sparing of other OARs except for slightly improved sparing of optic structures. More dose reduction in the isocentric region was observed in the cases with larger Ang_BSSC or smaller Dist_Min. Our results indicated that the IS-RA significantly improves the sparing of BS/SC without compromising dosimetric requirements of other involved structures for lrNPC.

View details for DOI 10.1038/srep25959

View details for PubMedID 27173670
Radiation dose escalation by simultaneous modulated accelerated radiotherapy combined with chemotherapy for esophageal cancer: a phase II study ONCOTARGET Chen, J., Guo, H., Zhai, T., Chang, D., Chen, Z., Huang, R., Zhang, W., Lin, K., Guo, L., Zhou, M., Li, D., Li, D., Chen, C. 2016; 7 (16): 22711-22719
Abstract

The outcomes for patients with esophageal cancer (EC) underwent standard-dose radical radiotherapy were still disappointing. This phase II study investigated the feasibility, safety and efficacy of radiation dose escalation using simultaneous modulated accelerated radiotherapy (SMART) combined with chemotherapy in 60 EC patients. Radiotherapy consisted of 66Gy at 2.2 Gy/fraction to the gross tumor and 54Gy at 1.8 Gy/fraction to subclinical diseases simultaneously. Chemotherapy including cisplatin and 5fluorouracil were administered to all patients during and after radiotherapy. The data showed that the majority of patients (98.3%) completed the whole course of radiotherapy and concurrent chemotherapy. The most common ≥ grade 3 acute toxicities were neutropenia (16.7%), followed by esophagitis (6.7%) and thrombopenia (5.0%). With a median follow-up of 24 months (5-38) for all patients and 30 months (18-38) for those still alive, 11 patients (18.3%) developed ≥ Grade 3 late toxicities and 2 (3.3%) of them died subsequently due to esophageal hemorrhage. The 1- and 2-year local-regional control, distant metastasis-free survival, disease-free survival and overall survival rates were 87.6% and 78.6%, 86.0% and 80.5%, 75.6% and 64.4%, 86.7% and 72.7%, respectively. SMART combined with concurrent chemotherapy is feasible in EC patients with tolerable acute toxicities. They showed a trend of significant improvements in local-regional control and overall survival. Further follow-up is needed to evaluate the late toxicities.

View details for DOI 10.18632/oncotarget.8050

View details for PubMedID 26992206
Cost-Effectiveness of Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. Journal of clinical oncology Durkee, B. Y., Qian, Y., Pollom, E. L., King, M. T., Dudley, S. A., Shaffer, J. L., Chang, D. T., Gibbs, I. C., Goldhaber-Fiebert, J. D., Horst, K. C. 2016; 34 (9): 902-909
Abstract

The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study showed a 15.7-month survival benefit with the addition of pertuzumab to docetaxel and trastuzumab (THP) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2) -overexpressing metastatic breast cancer. We performed a cost-effectiveness analysis to assess the value of adding pertuzumab.We developed a decision-analytic Markov model to evaluate the cost effectiveness of docetaxel plus trastuzumab (TH) with or without pertuzumab in US patients with metastatic breast cancer. The model followed patients weekly over their remaining lifetimes. Health states included stable disease, progressing disease, hospice, and death. Transition probabilities were based on the CLEOPATRA study. Costs reflected the 2014 Medicare rates. Health state utilities were the same as those used in other recent cost-effectiveness studies of trastuzumab and pertuzumab. Outcomes included health benefits expressed as discounted quality-adjusted life-years (QALYs), costs in US dollars, and cost effectiveness expressed as an incremental cost-effectiveness ratio. One- and multiway deterministic and probabilistic sensitivity analyses explored the effects of specific assumptions.Modeled median survival was 39.4 months for TH and 56.9 months for THP. The addition of pertuzumab resulted in an additional 1.82 life-years gained, or 0.64 QALYs, at a cost of $713,219 per QALY gained. Deterministic sensitivity analysis showed that THP is unlikely to be cost effective even under the most favorable assumptions, and probabilistic sensitivity analysis predicted 0% chance of cost effectiveness at a willingness to pay of $100,000 per QALY gained.THP in patients with metastatic HER2-positive breast cancer is unlikely to be cost effective in the United States.

View details for DOI 10.1200/JCO.2015.62.9105

View details for PubMedID 26351332
Cost-effectiveness of pertuzumab in HER2+metastatic breast cancer Qian, Y., Durkee, B. Y., Pollom, E. L., King, M., Dudley, S. A., Shaffer, J. B., Chang, D. T., Gibbs, I. C., Goldhaber-Fiebert, J. D., Horst, K. C. AMER ASSOC CANCER RESEARCH. 2016
View details for DOI 10.1158/1538-7445.SABCS15-P6-11-01

View details for Web of Science ID 000375622403068
A Novel Biomarker Panel Examining Response to Gemcitabine with or without Erlotinib for Pancreatic Cancer Therapy in NCIC Clinical Trials Group PA.3 PLOS ONE Shultz, D. B., Pai, J., Chiu, W., Ng, K., Hellendag, M. G., Heestand, G., Chang, D. T., Tu, D., Moore, M. J., Parulekar, W. R., Koong, A. C. 2016; 11 (1)
Abstract

NCIC Clinical Trials Group PA.3 was a randomized control trial that demonstrated improved overall survival (OS) in patients receiving erlotinib in addition to gemcitabine for locally advanced or metastatic pancreatic cancer. Prior to therapy, patients had plasma samples drawn for future study. We sought to identify biomarkers within these samples.Using the proximity ligation assay (PLA), a probe panel was built from commercially available antibodies for 35 key proteins selected from a global genetic analysis of pancreatic cancers, and used to quantify protein levels in 20 uL of patient plasma. To determine if any of these proteins levels independently associated with OS, univariate and mulitbaraible Cox models were used. In addition, we examined the associations between biomarker expression and disease stage at diagnosis using Fisher's exact test. The correlation between Erlotinib sensitivity and each biomarkers was assessed using a test of interaction between treatment and biomarker.Of the 569 eligible patients, 480 had samples available for study. Samples were randomly allocated into training (251) and validation sets (229). Among all patients, elevated levels of interleukin-8 (IL-8), carcinoembryonic antigen (CEA), hypoxia-inducible factor 1-alpha (HIF-1 alpha), and interleukin-6 were independently associated with lower OS, while IL-8, CEA, platelet-derived growth factor receptor alpha and mucin-1 were associated with metastatic disease. Patients with elevated levels of receptor tyrosine-protein kinase erbB-2 (HER2) expression had improved OS when treated with erlotinib compared to placebo. In conclusion, PLA is a powerful tool for identifying biomarkers from archived, small volume serum samples. These data may be useful to stratify patient outcomes regardless of therapeutic intervention.ClinicalTrials.gov NCT00040183.

View details for DOI 10.1371/journal.pone.0147995

View details for PubMedID 26808546
Albumin and Neutrophil-Lymphocyte Ratio (NLR) Predict Survival in Patients With Pancreatic Adenocarcinoma Treated With SBRT. American journal of clinical oncology Alagappan, M., Pollom, E. L., von Eyben, R., Kozak, M. M., Aggarwal, S., Poultsides, G. A., Koong, A. C., Chang, D. T. 2016: -?
Abstract

To determine if pretreatment nutritional status and inflammatory markers correlate with survival in patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiotherapy (SBRT).We retrospectively reviewed 208 patients with newly diagnosed, locally advanced pancreatic adenocarcinoma treated with SBRT at our institution from 2002 to 2014. Laboratory values were collected before SBRT, including hemoglobin, platelets, albumin, red blood cell, white blood cell, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, and tumor markers CA 19-9 and CEA. Patients were followed every 3 months with computed tomography (CT) and/or positron emission tomography-CT imaging to monitor for local recurrence and overall survival (OS).Median follow-up after SBRT was 7.5 months (interquartile range, 4.6 to 12.0 mo) for all patients. Median OS for patients with NLR>5 compared with NLR≤5 was 6.9 and 8.5 months, respectively (P=0.0057). On univariate analysis, receipt of chemotherapy (P=0.05, hazard ratio [HR]=0.69), increased albumin (P=0.002, HR=0.64), increased red blood cell (P=0.05, HR=0.75), increased lymphocyte count (P=0.002, HR=0.66), decreased CEA (P=0.01, HR=0.96), and NLR≤5 (P=0.01, HR=0.65) correlated with improved OS. On multivariate analysis, higher albumin (P=0.03, HR=0.70), receipt of chemotherapy (P=0.007, HR=0.56), and NLR≤5 (P=0.02, HR=0.66) correlated with better survival.Preradiotherapy low albumin levels and NLR>5 correlate with decreased survival in patients with locally advanced pancreatic adenocarcinoma treated with SBRT, indicating the prognostic value of systemic inflammatory markers (such as NLR) and a role of nutritional supplementation to improve outcomes in these patients. Further investigation is warranted.

View details for PubMedID 26757436
Statin and Metformin Use Prolongs Survival in Patients With Resectable Pancreatic Cancer. Pancreas Kozak, M. M., Anderson, E. M., von Eyben, R., Pai, J. S., Poultsides, G. A., Visser, B. C., Norton, J. A., Koong, A. C., Chang, D. T. 2016; 45 (1): 64-70
Abstract

The aim of this study was to investigate the impact of statin and metformin therapy on disease outcome for patients with pancreatic ductal adenocarcinoma (PDAC).This retrospective study included 171 PDAC patients who underwent surgical resection at the Stanford Cancer Institute between 1998 and 2013. No patients received neoadjuvant therapy. Statin and metformin use was defined as use during initial consult and continuing upon discharge from the hospital after surgery. Dose of each medication was recorded, as was the type of statin taken.The median follow-up for all patients was 11.23 months (range, 0.2-105.0 months). Among the 171 patients included in our analysis, 18 patients (10.5%) took metformin and 34 patients (19.9%) took statins. Statin use was associated with better overall survival (OS) in patients with PDAC (P = 0.011). Metformin use was also associated with better OS (P = 0.035). The use of statins remained significant on multivariate analysis for OS (P = 0.014; hazards ratio, 0.33; 95% confidence interval, 0.139-0.799), but metformin use did not (P = 0.33; hazards ratio 0.60, 95% confidence interval, 0.211-1.675).Statin and metformin use is associated with improved OS in patients with resectable PDAC. These medications should be further investigated for possible long-term use in the general population.

View details for DOI 10.1097/MPA.0000000000000470

View details for PubMedID 26474429
Serum Transforming Growth Factor-beta 1 Change After Neoadjuvant Chemoradiation Therapy Is Associated With Postoperative Pulmonary Complications in Esophageal Cancer Patients Undergoing Combined Modality Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lu, S., Hsu, F., Tsai, C., Wu, J., Lee, J., Huang, P., Hsu, C., Koong, A. C., Chang, D. T., Cheng, J. C. 2015; 93 (5): 1023-1031
Abstract

Our aim was to investigate the association of clinical factors, dosimetric parameters, and biomarkers with postoperative pulmonary complications (PPCs) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated by neoadjuvant concurrent chemoradiation therapy (CCRT) under strict pulmonary dose constraints and esophagectomy.We prospectively enrolled 112 patients undergoing trimodality treatment (including radiation therapy [40 Gy], concurrent taxane-/5-fluorouracil-based regimens, and radical esophagectomy) for ESCC. A PPC was defined as pneumonia or acute respiratory distress syndrome within 30 days after surgery. Serum samples were collected before and within 1 month after CCRT. The association of serum biomarkers with PPCs was detected by proximity ligation assay (PLA) and verified by enzyme-linked immunosorbent assay. Associations of clinical factors, lung dosimetric parameters, and biomarkers with PPC were tested statistically.Thirty-three patients (29.5%) had PPCs. None of the dosimetric parameters was associated with PPCs. Preoperative functional vital capacity (FVC) was significantly associated with PPCs (P=.004). Of the 15 PLA-screened biomarkers, posttreatment transforming growth factor-β1 (TGF-β1) was borderline significantly associated with PPCs (P=.087). Patients with PPCs had significantly larger pre-CCRT to post-CCRT decrease in serum TGF-β1 concentration (-11,310 vs -5332 pg/mL, P=.005) and higher pre-CCRT to post-CCRT percent decline in serum TGF-β1 concentration (-37.4% vs -25.0%, P=.009) than patients without PPCs. On multivariate analysis, preoperative FVC (P=.003) and decrease in TGF-β1 >7040 pg/mL (P=.014) were independent factors associated with PPCs.Preoperative FVC and decrease in serum TGF-β1 level after dose-limited CCRT to the lung are associated with the development of PPCs.

View details for DOI 10.1016/j.ijrobp.2015.08.035

View details for Web of Science ID 000366572800015
Low Toxicity in Inflammatory Bowel Disease Patients Treated With Abdominal and Pelvic Radiation Therapy AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS White, E. C., Murphy, J. D., Chang, D. T., Koong, A. C. 2015; 38 (6): 564-569
Abstract

To determine the short-term and long-term toxicity of abdominal and pelvic radiation therapy in a cohort of patients with inflammatory bowel disease (IBD). We hypothesize that with newer techniques, such as intensity-modulated radiation therapy (IMRT) and 3-dimensional conformal radiotherapy (3D-CRT), patients with IBD can safely undergo abdominal and pelvic radiation, with low risk for major acute or late toxicity.Nineteen consecutive patients with IBD (14 with ulcerative colitis, 5 with Crohn disease) who were treated with abdominal or pelvic external beam radiation therapy at Stanford University from 1997 to 2011 were identified. Fourteen patients were treated with IMRT and 5 were treated with 3D-CRT. Treated sites included prostate (n=8), gastric/esophageal (n=5), rectal/anal (n=3), and liver (n=3) tumors. Charts were reviewed and toxicity was graded according to the Common Terminology Criteria for Acute Events version 4.0. Median follow-up was 32.5 months. Fisher exact test was used to determine if any clinical and/or treatment factors were associated with toxicity outcomes.Acute grade ≥3 toxicity occurred in 2 patients (11%). Late grade ≥3 toxicity occurred in 1 patient (6%). Acute grade ≥2 toxicity occurred in 28% of patients treated with IMRT versus 100% of patients treated with 3D-CRT (P=0.01). Acute grade ≥2 gastrointestinal toxicity was lower in patients treated with IMRT versus 3D-CRT (14% vs. 100%, respectively, P=0.002). Late grade ≥2 toxicity occurred in 21% of patients. Higher total dose (Gy) and biologically effective dose (Gy) were associated with increased rates of late grade ≥2 toxicity (P=0.02 and 0.03, respectively).These data suggest that select patients with IBD can safely undergo abdominal and pelvic radiation therapy. The use of IMRT was associated with decreased acute toxicity. Acute and late severe toxicity rates were low in this patient population with the use of modern radiation techniques.

View details for DOI 10.1097/COC.0000000000000010

View details for PubMedID 24401668
Stress and Burnout Among Residency Program Directors in United States Radiation Oncology Programs INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Aggarwal, S., Kusano, A. S., Carter, J. N., Gable, L., Thomas, C. R., Chang, D. T. 2015; 93 (4): 746-753
Abstract

To evaluate stressors among radiation oncology residency program directors (PDs) and determine the prevalence and indicators of burnout.An anonymous, online, cross-sectional survey was offered to PDs of US radiation oncology programs in the fall of 2014. Survey content examined individual and program demographics, perceptions surrounding the role of PD, and commonly encountered stressors. Burnout was assessed using the validated Maslach Burnout Inventory-Human Services Survey.In total, 47 of 88 PDs (53%) responded to the survey. Although 78% of respondents reported feeling "satisfied" or "highly satisfied" with their current role, 85% planned to remain as PD for <5 years. The most commonly cited stressors were satisfying Accreditation Council for Graduate Medical Education/Residency Review Committee requirements (47%), administrative duties (30%) and resident morale (28%). Three-quarters of respondents were satisfied that they became PDs. Overall, 11% of respondents met criteria for low burnout, 83% for moderate burnout, and 6% for high burnout. Not having served as a PD at a prior institution correlated with high depersonalization (OR 6.75, P=.04) and overall burnout (odds ratio [OR], 15.6; P=.04). Having more years on faculty prior to becoming PD correlated with less emotional exhaustion (OR, 0.44, P=.05) and depersonalization (OR, 0.20, P=.04). Finally, having dedicated time for PD duties correlated with less emotional exhaustion (OR, 0.27, P=.04).Moderate levels of burnout are common in U.S. radiation oncology PDs with regulatory stressors being common. Despite this, many PDs are fulfilled with their role. Longitudinal studies assessing dynamic external factors and their influence on PD burnout would be beneficial.

View details for DOI 10.1016/j.ijrobp.2015.08.019

View details for PubMedID 26530741
Phase 2 Study of Simultaneous Modulated Accelerated Radiation Therapy Combined With Chemotherapy for Esophageal Squamous Cell Carcinoma: Early Outcomes Chen, J., Li, D., Zhai, T., Chang, D. T., Guo, H., Zhang, W., Guo, L., Zhou, M., Li, D., Chen, C. ELSEVIER SCIENCE INC. 2015: S13
View details for DOI 10.1016/j.ijrobp.2015.07.037

View details for Web of Science ID 000373215301699
Dosimetric Predictors of Surgical Complications From Esophagectomy After Neoadjuvant Chemoradiation for Esophageal Cancer Shah, J. L., Johannet, P., Shaffer, J., Holcombe, C., Koong, A. C., Berry, M., Chang, D. T. ELSEVIER SCIENCE INC. 2015: E131
View details for DOI 10.1016/j.ijrobp.2015.07.881

View details for Web of Science ID 000373215300332
Stereotactic Body Radiation for Pancreatic Cancer: Results of an International Survey of Practice Patterns Parekh, A., Rosati, L. M., Chang, D. T., Goodman, K. A., Koong, A. C., Herman, J. M. ELSEVIER SCIENCE INC. 2015: E132
View details for DOI 10.1016/j.ijrobp.2015.07.884

View details for Web of Science ID 000373215300335
CEA as a Predictor of Pathologic Tumor Response Following Long Course Neoadjuvant Chemoradiation Therapy for Rectal Cancer Shaffer, J., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2015: E167
View details for DOI 10.1016/j.ijrobp.2015.07.978

View details for Web of Science ID 000373215300427
How Common is Stress and Burnout Among Residency Program Directors in United States Radiation Oncology Programs? Aggarwal, S., Kusano, A. S., Carter, J. N., Thomas, C. R., Chang, D. T. ELSEVIER SCIENCE INC. 2015: E374
View details for DOI 10.1016/j.ijrobp.2015.07.1501

View details for Web of Science ID 000373215301001
Posttreatment PET-CT is Predictive of Local Control After Liver Stereotactic Body Radiation Therapy White, E. C., Shaffer, J., Kumar, K. A., Binkley, M. S., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2015: E181
View details for DOI 10.1016/j.ijrobp.2015.07.1012

View details for Web of Science ID 000373215300460
Radiomic Analysis of FDG-PET Identifies Novel Prognostic Imaging Biomarkers in Locally Advanced Pancreatic Cancer Patients Treated With SBRT Cui, Y., Song, J., Pollom, E., Shirato, H., Chang, D. T., Koong, A. C., Li, R. ELSEVIER SCIENCE INC. 2015: S4–S5
View details for DOI 10.1016/j.ijrobp.2015.07.017

View details for Web of Science ID 000373215301679
Fractionation of palliative radiotherapy in metastatic breast cancer: Selection and survival Qian, Y., Dudley, S., Durkee, B. Y., Kumar, K., Chaudhuri, A., Pollom, E. L., Aggarwal, S., Horst, K. C., Chang, D. AMER SOC CLINICAL ONCOLOGY. 2015
View details for DOI 10.1200/jco.2015.33.29_suppl.201

View details for Web of Science ID 000378107000196
Survival comparison of patients treated with one versus five fraction palliative radiotherapy Dudley, S., Qian, Y., Chaudhuri, A., Kumar, K., Aggarwal, S., Chang, D. AMER SOC CLINICAL ONCOLOGY. 2015
View details for DOI 10.1200/jco.2015.33.29_suppl.200

View details for Web of Science ID 000378107000195
Stereotactic body radiation therapy and central liver toxicity: A case report. Practical radiation oncology Shaffer, J. L., Osmundson, E. C., Visser, B. C., Longacre, T. A., Koong, A. C., Chang, D. T. 2015; 5 (5): 282-285
View details for DOI 10.1016/j.prro.2015.04.011

View details for PubMedID 26127008
Expert Consensus Contouring Guidelines for Intensity Modulated Radiation Therapy in Esophageal and Gastroesophageal Junction Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Wu, A. J., Bosch, W. R., Chang, D. T., Hong, T. S., Jabbour, S. K., Kleinberg, L. R., Mamon, H. J., Thomas, C. R., Goodman, K. A. 2015; 92 (4): 911-920
Abstract

Current guidelines for esophageal cancer contouring are derived from traditional 2-dimensional fields based on bony landmarks, and they do not provide sufficient anatomic detail to ensure consistent contouring for more conformal radiation therapy techniques such as intensity modulated radiation therapy (IMRT). Therefore, we convened an expert panel with the specific aim to derive contouring guidelines and generate an atlas for the clinical target volume (CTV) in esophageal or gastroesophageal junction (GEJ) cancer.Eight expert academically based gastrointestinal radiation oncologists participated. Three sample cases were chosen: a GEJ cancer, a distal esophageal cancer, and a mid-upper esophageal cancer. Uniform computed tomographic (CT) simulation datasets and accompanying diagnostic positron emission tomographic/CT images were distributed to each expert, and the expert was instructed to generate gross tumor volume (GTV) and CTV contours for each case. All contours were aggregated and subjected to quantitative analysis to assess the degree of concordance between experts and to generate draft consensus contours. The panel then refined these contours to generate the contouring atlas.The κ statistics indicated substantial agreement between panelists for each of the 3 test cases. A consensus CTV atlas was generated for the 3 test cases, each representing common anatomic presentations of esophageal cancer. The panel agreed on guidelines and principles to facilitate the generalizability of the atlas to individual cases.This expert panel successfully reached agreement on contouring guidelines for esophageal and GEJ IMRT and generated a reference CTV atlas. This atlas will serve as a reference for IMRT contours for clinical practice and prospective trial design. Subsequent patterns of failure analyses of clinical datasets using these guidelines may require modification in the future.

View details for DOI 10.1016/j.ijrobp.2015.03.030

View details for PubMedID 26104943
Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pollom, E. L., Deng, L., Pai, R. K., Brown, J. M., Giaccia, A., Loo, B. W., Shultz, D. B., Quynh Thu Le, Q. T., Koong, A. C., Chang, D. T. 2015; 92 (3): 568-576
Abstract

Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

View details for DOI 10.1016/j.ijrobp.2015.02.016

View details for Web of Science ID 000355636800018
Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy. International journal of radiation oncology, biology, physics Pollom, E. L., Deng, L., Pai, R. K., Brown, J. M., Giaccia, A., Loo, B. W., Shultz, D. B., Le, Q. T., Koong, A. C., Chang, D. T. 2015; 92 (3): 568-576
Abstract

Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

View details for DOI 10.1016/j.ijrobp.2015.02.016

View details for PubMedID 26068491
TU-CD-BRB-08: Radiomic Analysis of FDG-PET Identifies Novel Prognostic Imaging Biomarkers in Locally Advanced Pancreatic Cancer Patients Treated with SBRT. Medical physics Cui, Y., Song, J., Pollom, E., Shirato, H., Chang, D., Koong, A., Li, R. 2015; 42 (6): 3604-?
Abstract

This study aims to identify novel prognostic imaging biomarkers in locally advanced pancreatic cancer (LAPC) using quantitative, high-throughput image analysis.86 patients with LAPC receiving chemotherapy followed by SBRT were retrospectively studied. All patients had a baseline FDG-PET scan prior to SBRT. For each patient, we extracted 435 PET imaging features of five types: statistical, morphological, textural, histogram, and wavelet. These features went through redundancy checks, robustness analysis, as well as a prescreening process based on their concordance indices with respect to the relevant outcomes. We then performed principle component analysis on the remaining features (number ranged from 10 to 16), and fitted a Cox proportional hazard regression model using the first 3 principle components. Kaplan-Meier analysis was used to assess the ability to distinguish high versus low-risk patients separated by median predicted survival. To avoid overfitting, all evaluations were based on leave-one-out cross validation (LOOCV), in which each holdout patient was assigned to a risk group according to the model obtained from a separate training set.For predicting overall survival (OS), the most dominant imaging features were wavelet coefficients. There was a statistically significant difference in OS between patients with predicted high and low-risk based on LOOCV (hazard ratio: 2.26, p<0.001). Similar imaging features were also strongly associated with local progression-free survival (LPFS) (hazard ratio: 1.53, p=0.026) on LOOCV. In comparison, neither SUVmax nor TLG was associated with LPFS (p=0.103, p=0.433) (Table 1). Results for progression-free survival and distant progression-free survival showed similar trends.Radiomic analysis identified novel imaging features that showed improved prognostic value over conventional methods. These features characterize the degree of intra-tumor heterogeneity reflected on FDG-PET images, and their biological underpinnings warrant further investigation. If validated in large, prospective cohorts, this method could be used to stratify patients based on individualized risk.

View details for DOI 10.1118/1.4925593

View details for PubMedID 26128895
Smad4 inactivation predicts for worse prognosis and response to fluorouracil-based treatment in colorectal cancer. Journal of clinical pathology Kozak, M. M., von Eyben, R., Pai, J., Vossler, S. R., Limaye, M., Jayachandran, P., Anderson, E. M., Shaffer, J. L., Longacre, T., Pai, R. K., Koong, A. C., Chang, D. T. 2015; 68 (5): 341-345
Abstract

To determine whether expression of Smad4, a tumour suppressor found to be absent in 10% of colorectal cancer (CRC), is associated with outcomes in patients with CRC.Tumour samples from 241 consecutive patients with CRC who underwent upfront colon resection between 2005 and 2009 were obtained. Triplicate tissue cores from resected primary colon tumours and matched normal controls were used to construct the tissue microarrays (TMAs). We examined the expression of Smad4 using immunohistochemistry. Clinicopathological records were obtained for all patients. TMAs were reviewed by two pathologists and scored as either 'positive' or 'negative' for nuclear staining. In total, 21 of 241 tumours (8.6%) were Smad4 negative.Loss of Smad4 expression correlated with significantly worse overall survival (OS) (p=0.011) and disease-free survival (DFS) (p=0.024). Patients with loss of Smad4 expression had a median OS of 31 months compared with 89 months positive Smad4 expression. Loss of Smad4 remained significant on multivariate analysis for OS (p=0.0097). In patients with node-positive disease, loss of Smad4 predicts for worse DFS (p=0.012). In patients with metastatic and recurrent disease, Smad4 loss predicts for worse OS (p=0.012). Of the patients that received capecitabine over the course of their treatment, those with Smad4 loss (n=13) had significantly worse DFS (p=0.003) and OS (p=0.0007).Loss of Smad4 expression is associated with worse DFS and OS in multiple subsets of patients with CRC. Further studies are required to validate our findings and ascertain the role of Smad4 status in the management of this disease.

View details for DOI 10.1136/jclinpath-2014-202660

View details for PubMedID 25681512
Survival benefit for adjuvant radiation therapy in minor salivary gland cancers. Oral oncology Zeidan, Y. H., Pekelis, L., An, Y., Holsinger, F. C., Kong, C. S., Chang, D. T., Le, Q. 2015; 51 (5): 438-445
Abstract

The goal of the current study is to investigate the role of adjuvant radiation therapy (adjuvant RT) in minor salivary gland tumors (mSGT) using an established national database.The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients treated with or without adjuvant RT for mSGT from 1988 to 2008. Regression analyses were performed to identify factors associated with improved overall survival (OS).Most tumors were located within the oral cavity (75%) followed by nasal cavity/paranasal sinuses (15%). Multivariate Cox analysis showed that adjuvant RT was associated with better OS compared to surgery alone. Using logistic regression analysis, we provide a novel web based tool for predicting survival impact of adjuvant RT in patients with mSGT.Adjuvant RT is associated with improved survival in patients with mSGT and adverse clinicopathologic factors such as advanced T/N category, adenoid cystic histology, high grade, and nasopharynx location.

View details for DOI 10.1016/j.oraloncology.2015.02.096

View details for PubMedID 25771077
Predictors of Toxicity Associated With Stereotactic Body Radiation Therapy to the Central Hepatobiliary Tract INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Osmundson, E. C., Wu, Y., Luxton, G., Bazan, J. G., Koong, A. C., Chang, D. T. 2015; 91 (5): 986-994
Abstract

To identify dosimetric predictors of hepatobiliary (HB) toxicity associated with stereotactic body radiation therapy (SBRT) for liver tumors.We retrospectively reviewed 96 patients treated with SBRT for primary (53%) or metastatic (47%) liver tumors between March 2006 and November 2013. The central HB tract (cHBT) was defined by a 15-mm expansion of the portal vein from the splenic confluence to the first bifurcation of left and right portal veins. Patients were censored for toxicity upon local progression or additional liver-directed therapy. HB toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0. To compare different SBRT fractionations, doses were converted to biologically effective doses (BED) by using the standard linear quadratic model α/β = 10 (BED10).Median follow-up was 12.7 months after SBRT. Median BED10 was 85.5 Gy (range: 37.5-151.2). The median number of fractions was 5 (range: 1-5), with 51 patients (53.1%) receiving 5 fractions and 29 patients (30.2%) receiving 3 fractions. In total, there were 23 (24.0%) grade 2+ and 18 (18.8%) grade 3+ HB toxicities. Nondosimetric factors predictive of grade 3+ HB toxicity included cholangiocarcinoma (CCA) histology (P<.0001), primary liver tumor (P=.0087), and biliary stent (P<.0001). Dosimetric parameters most predictive of grade 3+ HB toxicity were volume receiving above BED10 of 72 Gy (VBED1072) ≥ 21 cm(3) (relative risk [RR]: 11.6, P<.0001), VBED1066 ≥ 24 cm(3) (RR: 10.5, P<.0001), and mean BED10 (DmeanBED10) cHBT ≥14 Gy (RR: 9.2, P<.0001), with VBED1072 and VBED1066 corresponding to V40 and V37.7 for 5 fractions and V33.8 and V32.0 for 3 fractions, respectively. VBED1072 ≥ 21 cm(3), VBED1066 ≥ 24 cm(3), and DmeanBED10 cHBT ≥14 Gy were consistently predictive of grade 3+ toxicity on multivariate analysis.VBED1072, VBED1066, and DmeanBED10 to cHBT are associated with HB toxicity. We suggest VBED1072 < 21 cm(3) (5-fraction: V40 < 21 cm(3); 3-fraction: V33.8 < 21 cm(3)), VBED1066 < 24 cm(3) (5-fraction: V37.7 < 24 cm(3); 3-fraction: V32 < 24 cm(3)) as potential dose constraints for the cHBT when clinically indicated.

View details for DOI 10.1016/j.ijrobp.2014.11.028

View details for PubMedID 25659885
Phase 2 Multi-institutional Trial Evaluating Gemcitabine and Stereotactic Body Radiotherapy for Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma CANCER Herman, J. M., Chang, D. T., Goodman, K. A., Dholakia, A. S., Raman, S. P., Hacker-Prietz, A., Iacobuzio-Donahue, C. A., Griffith, M. E., Pawlik, T. M., Pai, J. S., O'Reilly, E., Fisher, G. A., Wild, A. T., Rosati, L. M., Zheng, L., Wolfgang, C. L., Laheru, D. A., Columbo, L. A., Sugar, E. A., Koong, A. C. 2015; 121 (7): 1128-1137
Abstract

This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC).A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m(2) ) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT.The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections.Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy. Cancer 2015;121:1128-1137. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

View details for DOI 10.1002/cncr.29161

View details for Web of Science ID 000351615800022

View details for PubMedID 25538019

View details for PubMedCentralID PMC4368473
The Prognostic Significance of Pretreatment Hematologic Parameters in Patients Undergoing Resection for Colorectal Cancer. American journal of clinical oncology Kozak, M. M., von Eyben, R., Pai, J. S., Anderson, E. M., Welton, M. L., Shelton, A. A., Kin, C., Koong, A. C., Chang, D. T. 2015: -?
Abstract

The prognostic value of several hematologic parameters, including platelet, lymphocyte, and neutrophil counts, has been studied in a variety of solid tumors. In this study, we examined the significance of inflammatory markers and their prognostic implications in patients with colorectal cancer (CRC).Patients with stage I-III CRC who underwent surgical resection at the Stanford Cancer Institute between 2005 and 2009 were included. Patients were excluded if they did not have preoperative complete blood counts performed within 1 month of surgical resection, underwent preoperative chemotherapy or radiation, had metastatic disease at diagnosis, or had another previous malignancy. We included 129 eligible patients with available preoperative complete blood counts in the final analysis.A preoperative neutrophil-to-lymphocyte ratio of>3.3 was significantly associated with worse disease-free (DFS) and overall survival (OS) (P=0.009, 0.003), as was a preoperative lymphocyte-to-monocyte ratio of ≤2.6 (P=0.01, 0.002). Preoperative lymphopenia (P=0.002) was associated with worse OS but not DFS (P=0.09). In addition, preoperative thrombocytosis was associated with worse DFS (P=0.006) and OS (P=0.010). Preoperative leukocytosis was associated with worse OS (P=0.048) but not DFS (P=0.49). Preoperative hemoglobin was neither associated with OS (P=0.24) or DFS (P=0.15).Pretreatment lymphopenia, thrombocytosis, a decreased lymphocyte-to-monocyte ratio, and an elevated neutrophil-to-lymphocyte ratio independently predict for worse OS in patients with CRC.

View details for PubMedID 25756348
Pretreatment lab values to predict overall survival in patients with primary unresectable pancreatic adenocarcinoma treated with SBRT Alagappan, M., Pollom, E. L., von Eyben, R., Kunz, P. L., Fisher, G. A., Ford, J. M., Poultsides, G. A., Visser, B. C., Norton, J. A., Kamaya, A., Columbo, L., Koong, A., Chang, D. AMER SOC CLINICAL ONCOLOGY. 2015
View details for DOI 10.1200/jco.2015.33.3_suppl.433

View details for Web of Science ID 000356883800431
Serum Transforming Growth Factor-β1 Change After Neoadjuvant Chemoradiation Therapy Is Associated With Postoperative Pulmonary Complications in Esophageal Cancer Patients Undergoing Combined Modality Therapy. International journal of radiation oncology, biology, physics Lu, S. L., Hsu, F. M., Tsai, C. L., Wu, J. K., Lee, J. M., Huang, P. M., Hsu, C. H., Koong, A. C., Chang, D. T., Cheng, J. C. 2015; 93 (5): 1023–31
Abstract

Our aim was to investigate the association of clinical factors, dosimetric parameters, and biomarkers with postoperative pulmonary complications (PPCs) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated by neoadjuvant concurrent chemoradiation therapy (CCRT) under strict pulmonary dose constraints and esophagectomy.We prospectively enrolled 112 patients undergoing trimodality treatment (including radiation therapy [40 Gy], concurrent taxane-/5-fluorouracil-based regimens, and radical esophagectomy) for ESCC. A PPC was defined as pneumonia or acute respiratory distress syndrome within 30 days after surgery. Serum samples were collected before and within 1 month after CCRT. The association of serum biomarkers with PPCs was detected by proximity ligation assay (PLA) and verified by enzyme-linked immunosorbent assay. Associations of clinical factors, lung dosimetric parameters, and biomarkers with PPC were tested statistically.Thirty-three patients (29.5%) had PPCs. None of the dosimetric parameters was associated with PPCs. Preoperative functional vital capacity (FVC) was significantly associated with PPCs (P=.004). Of the 15 PLA-screened biomarkers, posttreatment transforming growth factor-β1 (TGF-β1) was borderline significantly associated with PPCs (P=.087). Patients with PPCs had significantly larger pre-CCRT to post-CCRT decrease in serum TGF-β1 concentration (-11,310 vs -5332 pg/mL, P=.005) and higher pre-CCRT to post-CCRT percent decline in serum TGF-β1 concentration (-37.4% vs -25.0%, P=.009) than patients without PPCs. On multivariate analysis, preoperative FVC (P=.003) and decrease in TGF-β1 >7040 pg/mL (P=.014) were independent factors associated with PPCs.Preoperative FVC and decrease in serum TGF-β1 level after dose-limited CCRT to the lung are associated with the development of PPCs.

View details for PubMedID 26475065
Stereotactic body radiation therapy in pancreatic cancer: the new frontier EXPERT REVIEW OF ANTICANCER THERAPY Moningi, S., Marciscano, A. E., Rosati, L. M., Ng, S. K., Forbang, R. T., Jackson, J., Chang, D. T., Koong, A. C., Herman, J. M. 2014; 14 (12): 1461-1475
Abstract

Pancreatic cancer (PCA) remains a disease with a poor prognosis. The majority of PCA patients are unable to undergo surgical resection, which is the only potentially curative option at this time. A combination of chemotherapy and chemoradiation (CRT) are standard options for patients with locally advanced, unresectable disease, however, local control and patient outcomes remains poor. Stereotactic body radiation therapy (SBRT) is an emerging treatment option for PCA. SBRT delivers potentially ablative doses to the pancreatic tumor plus a small margin over a short period of time. Early studies with single-fraction SBRT demonstrated excellent tumor control with high rates of toxicity. The implementation of SBRT (3-5 doses) has demonstrated promising outcomes with favorable tumor control and toxicity rates. Herein we discuss the evolving role of SBRT in PCA treatment.

View details for DOI 10.1586/14737140.2014.952286

View details for Web of Science ID 000346639100008

View details for PubMedID 25183386
Single-versus Multifraction Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma: Outcomes and Toxicity INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pollom, E. L., Alagappan, M., von Eyben, R., Kunz, P. L., Fisher, G. A., Ford, J. A., Poultsides, G. A., Visser, B. C., Norton, J. A., Kamaya, A., Cox, V. L., Columbo, L. A., Koong, A. C., Chang, D. T. 2014; 90 (4): 918-925
Abstract

We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma.We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy.Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival.Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control.

View details for DOI 10.1016/j.ijrobp.2014.06.066

View details for Web of Science ID 000344734300029
Single- versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: outcomes and toxicity. International journal of radiation oncology, biology, physics Pollom, E. L., Alagappan, M., von Eyben, R., Kunz, P. L., Fisher, G. A., Ford, J. A., Poultsides, G. A., Visser, B. C., Norton, J. A., Kamaya, A., Cox, V. L., Columbo, L. A., Koong, A. C., Chang, D. T. 2014; 90 (4): 918-925
Abstract

We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma.We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy.Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival.Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control.

View details for DOI 10.1016/j.ijrobp.2014.06.066

View details for PubMedID 25585785
LEF-1 is Frequently Expressed in Colorectal Carcinoma and Not in Other Gastrointestinal Tract Adenocarcinomas: An Immunohistochemical Survey of 602 Gastrointestinal Tract Neoplasms APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Kermanshahi, T. R., Jayachandran, P., Chang, D. T., Pai, R. 2014; 22 (10): 728-734
Abstract

LEF-1 is a DNA-binding protein that interacts with β-catenin and activates Wnt-responsive target genes. We analyzed the immunohistochemical expression of LEF-1 in 602 gastrointestinal and pancreatobiliary neoplasms in an attempt to (1) investigate the utility of LEF-1 immunohistochemistry as an ancillary marker in gastrointestinal/pancreatobiliary neoplasia, and (2) to perform a clinicopathologic and survival analysis of colorectal carcinoma stratified by LEF-1 expression. LEF-1 nuclear positivity was frequently identified in colorectal carcinoma (89/241, 37%) and only infrequently identified in other neoplasms: 11% esophagus/esophagogastric adenocarcinomas, 7% gastric adenocarcinomas, 1% pancreatic ductal adenocarcinomas, 4% pancreatic intraductal papillary mucinous neoplasms, and in no cases of appendiceal mucinous neoplasms or pancreatic mucinous cystic neoplasms. LEF-1 expression was identified in 35% of colorectal carcinomas that lacked CK20 and CDX2 expression. In colorectal carcinomas, LEF-1-positive tumors more frequently harbored KRAS mutations compared with LEF-1-negative tumors (39% vs. 16%, P=0.005). Patients with moderate/strong LEF-1-positive colorectal carcinoma had a trend of worse overall survival compared with patients with colorectal carcinomas with weak/negative LEF-1 expression (5 y overall survival, 31% vs. 47%, P=0.15). In conclusion, LEF-1 is most commonly expressed in colorectal carcinoma and infrequently observed in the upper gastrointestinal tract and pancreatic adenocarcinoma. LEF-1 Immunohistochemistry may be especially useful as an ancillary diagnostic marker in colorectal carcinomas, which lack the expression of both CK20 and CDX2. LEF-1 expression is associated with the presence of KRAS mutations and may have prognostic value as a trend of worse overall survival is seen in patients with LEF-1-positive colorectal carcinoma.

View details for DOI 10.1097/PAI.0000000000000109

View details for PubMedID 25394300
Dosimetric Modeling of Central Liver Toxicity After SBRT to the Liver 56th Annual Meeting of the American-Society-for-Radiation-Oncology Osmundson, E., Wu, Y., Bazan, J. G., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2014: S382–S382
View details for Web of Science ID 000342331401326
Pooled Analysis of Stereotactic Body Radiation Therapy for Liver Tumors: Results From 5 Institutions Shaffer, J., Feng, M. U., Pollom, E., Stenmark, M. H., Tang, M., Monroe, A. T., Merrell, K. W., Lee, P., Olivier, K. R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2014: S380–S381
View details for DOI 10.1016/j.ijrobp.2014.05.1223

View details for Web of Science ID 000342331401321
Serum Vascular Endothelial Growth Factor-A and Transforming Growth Factor-beta 1 Can Predict Pathological Response and Disease-Free Survival of Esophageal Cancer Patients Treated with Neoadjuvant Chemoradiation Therapy Followed by Esophagectomy Chiang, Y., Cheng, J., Graber, M., Hsu, F., Tsai, C., Lee, J., Chang, D., Koong, A. ELSEVIER SCIENCE INC. 2014: S9–S10
View details for DOI 10.1016/j.ijrobp.2014.05.087

View details for Web of Science ID 000342331400021
Lower Pelvis Bone Marrow Dose Constraints to Reduce Hematologic Toxicity in the Treatment of Anal Cancer Lee, A. Y., Bazan, J. G., Pelizzari, C. A., Chang, D. T., Liauw, S. L. ELSEVIER SCIENCE INC. 2014: S33
View details for DOI 10.1016/j.ijrobp.2014.05.142

View details for Web of Science ID 000342331400074
Pooled Analysis of Liver Stereotactic Body Radiation Therapy for Colorectal Metastases: Results From 5 Institutions Shaffer, J., Feng, M. U., Pollom, E., Stenmark, M. H., Tang, M., Monroe, A. T., Lee, P., Merrell, K. W., Olivier, K. R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2014: S376
View details for DOI 10.1016/j.ijrobp.2014.05.1210

View details for Web of Science ID 000342331401308
The Prognostic Significance of Pretreatment Hematologic Parameters in Patients Undergoing Resection for Colorectal Cancer Kozak, M., Pai, J., Von Eyben, R., Anderson, E., Koong, A., Chang, D. T. ELSEVIER SCIENCE INC. 2014: S397
View details for DOI 10.1016/j.ijrobp.2014.05.1268

View details for Web of Science ID 000342331401366
Statin Use as a Predictor of Outcome in Colorectal Cancer Anderson, E., Von Eyben, R., Kozak, M., Pai, J., Limaye, M., Jayachandran, P., Vossler, S., Schaffer, J., Pai, R., Koong, A., Chang, D. ELSEVIER SCIENCE INC. 2014: S395–S396
View details for DOI 10.1016/j.ijrobp.2014.05.1265

View details for Web of Science ID 000342331401363
Pooled Analysis of Liver Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Results From a Multi-institution Study Chang, D. T., Shaffer, J., Pollom, E., Stenmark, M. H., Tang, M., Merrell, K. W., Lee, P., Olivier, K. R., Koong, A. C., Feng, M. U. ELSEVIER SCIENCE INC. 2014: S376
View details for DOI 10.1016/j.ijrobp.2014.05.1211

View details for Web of Science ID 000342331401309
Surgical Outcomes Following Chemotherapy and Stereotactic Body Radiation Therapy in Patients With Borderline and Unresectable Pancreatic Cancer Moningi, S., Dholakia, A. S., Raman, S., Hacker-Prietz, A., Pawlik, T., Zheng, L., Pollom, E., Weiss, M., Laheru, D., Wolfgang, C., Chang, D. T., Koong, A. C., Herman, J. M. ELSEVIER SCIENCE INC. 2014: S366–S367
View details for DOI 10.1016/j.ijrobp.2014.05.1186

View details for Web of Science ID 000342331401284
Stereotactic Body Radiotherapy for Pancreatic Adenocarcinoma: Single versus Multi-Fraction Pollom, E., Alagappan, M., Cox, V., Kamaya, A., Kunz, P., Poultsides, G., Visser, B., Koong, A., Chang, D. ELSEVIER SCIENCE INC. 2014: S50
View details for DOI 10.1016/j.ijrobp.2014.05.184

View details for Web of Science ID 000342331400113
Hepatobiliary Cancers, Version 2.2014 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Benson, A. B., D'Angelica, M. I., Abrams, T. A., Are, C., Bloomston, P. M., Chang, D. T., Clary, B. M., Covey, A. M., Ensminger, W. D., Iyer, R., Kelley, R. K., Linehan, D., Malafa, M. P., Meranze, S. G., Park, J. O., Pawlik, T., Posey, J. A., Scaife, C., Schefter, T., Sigurdson, E. R., Tian, G. G., Vauthey, J., Venook, A. P., Yen, Y., Zhu, A. X., Hoffmann, K. G., McMillian, N. R., Sundar, H. 2014; 12 (8): 1152-1182
Abstract

Hepatobiliary cancers include a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma), gall bladder, and bile ducts (cholangiocarcinomas). Gallbladder cancer and cholangiocarcinomas are collectively known as biliary tract cancers. Gallbladder cancer is the most common and aggressive type of all the biliary tract cancers. Cholangiocarcinomas are diagnosed throughout the biliary tree and are typically classified as either intrahepatic or extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinomas are more common than intrahepatic cholangiocarcinomas. This manuscript focuses on the clinical management of patients with gallbladder cancer and cholangiocarcinomas (intrahepatic and extrahepatic).

View details for Web of Science ID 000340218200009

View details for PubMedID 25099447
Baseline Metabolic Tumor Volume and Total Lesion Glycolysis Are Associated With Survival Outcomes in Patients With Locally Advanced Pancreatic Cancer Receiving Stereotactic Body Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Dholakia, A. S., Chaudhry, M., Leal, J. P., Chang, D. T., Raman, S. P., Hacker-Prietz, A., Su, Z., Pai, J., Oteiza, K. E., Griffith, M. E., Wahl, R. L., Tryggestad, E., Pawlik, T., Laheru, D. A., Wolfgang, C. L., Koong, A. C., Herman, J. M. 2014; 89 (3): 539-546
Abstract

Although previous studies have demonstrated the prognostic value of positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer has yet to be well established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiation therapy (SBRT).Thirty-two patients with LAPC in a prospective clinical trial received up to 3 doses of gemcitabine, followed by 33 Gy in 5 fractions of 6.6 Gy, using SBRT. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUVmax and SUVpeak) on pre-SBRT PET scans were calculated using custom-designed software. Disease was measured at a threshold based on the liver SUV, using the equation Livermean + [2 × Liversd]. Median values of PET parameters were used as cutoffs when assessing their prognostic potential through Cox regression analyses.Of the 32 patients, the majority were male (n=19, 59%), 65 years or older (n=21, 66%), and had tumors located in the pancreatic head (n=27, 84%). Twenty-seven patients (84%) received induction gemcitabine prior to SBRT. Median overall survival for the entire cohort was 18.8 months (95% confidence interval [CI], 15.7-22.0). An MTV of 26.8 cm(3) or greater (hazard ratio [HR] 4.46, 95% CI 1.64-5.88, P<.003) and TLG of 70.9 or greater (HR 3.08, 95% CI 1.18-8.02, P<.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19-22.21, P=.029) and TLG (HR 3.34, 95% CI 1.07-10.48, P=.038) remained independently associated with overall survival in separate multivariate analyses.Pre-SBRT MTV and TLG are potential predictive factors for overall survival in patients with LAPC and may assist in tailoring therapy.

View details for DOI 10.1016/j.ijrobp.2014.02.031

View details for Web of Science ID 000337219400018
Postradiotherapy CA19-9 Kinetics Correlate With Outcomes in Patients With Pancreatic Adenocarcinoma PANCREAS Shultz, D. B., Chan, C., Shaffer, J. L., Kunz, P. L., Koong, A. C., Chang, D. T. 2014; 43 (5): 777-783
Abstract

We sought to determine if carbohydrate antigen 19-9 (CA19-9 ) nadir (nCA19-9), time to nadir (TTN), and doubling time (DT) after radiotherapy (RT) correlate with outcomes in pancreatic ductal adenocarcinoma.We examined the records of 102 patients treated with RT for primary, nonmetastatic pancreatic ductal adenocarcinoma between August 1998 and July 2011. Of these, 33 patients were treated with postoperative chemoradiotherapy (PORT) and 69 patients with definitive chemoradiotherapy (CRT).Among the patients treated with PORT, TTN and DT were associated with both overall survival (OS; P = <0.01 for both) and freedom from progression (FFP; P = <0.01 for both). In patients treated with CRT, nCA19-9 and TTN correlated with both OS (P = <0.01 and P = 0.02, respectively) and FFP (P = 0.01 and <0.01, respectively). On multivariable analysis, in patients treated with PORT, TTN remained independently correlated with OS and FFP (P = 0.01; hazard ratios [HR], 6.43 and P = 0.02; HR, 4.00, respectively), whereas DT remained independently correlated to FFP (P = 0.04; HR, 0.27). In patients treated with CRT, controlling for pretreatment CA19-9, nCA19-9 and TTN independently correlated with OS (P = <0.01; HR, 3.0 and P = 0.03; HR, 2.56, respectively) and FFP (P = 0.04; HR, 2.31 and P = <0.01; HR, 4.0, respectively).CA19-9 kinetics after RT correlate with disease progression and survival and could serve as a prognostic tool to guide treatment decisions.

View details for Web of Science ID 000338132700016
High Serum Levels of Vascular Endothelial Growth Factor-A and Transforming Growth Factor-ß1 Before Neoadjuvant Chemoradiotherapy Predict Poor Outcomes in Patients with Esophageal Squamous Cell Carcinoma Receiving Combined Modality Therapy. Annals of surgical oncology Cheng, J. C., Graber, M. S., Hsu, F., Tsai, C., Castaneda, L., Lee, J., Chang, D. T., Koong, A. C. 2014; 21 (7): 2361-2368
Abstract

This study was aimed at using proximity ligation assay (PLA) followed by enzyme-linked immunosorbent assay (ELISA) to identify serum biomarkers that predict treatment response and survival for patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant concurrent chemoradiotherapy (CCRT) followed by esophagectomy.Seventy-nine patients with ESCC receiving CCRT of taxane-based/5-fluorouracil-based chemotherapy and 40 Gy followed by surgery were enrolled. Serum samples were collected before and <1 month after CCRT. Fifteen biomarkers were analyzed using PLA. Biomarkers significantly correlating with pathological response/survival were verified by ELISA. Associations of the serum level of biomarkers and clinical factors with pathological response, disease-free survival (DFS), and overall survival (OS) were evaluated by analysis of variance and log-rank tests.Thirty patients had complete response (38 %), 37 had microscopic residual disease (47 %), and 12 had macroscopic residual disease (15 %). With a median follow-up of 52.8 months, the median DFS was 43 months. Among the 15 biomarkers screened by PLA, vascular endothelial growth factor (VEGF)-A and transforming growth factor (TGF)-β1 were significantly associated with pathological response and/or DFS. These biomarkers were further analyzed by ELISA to confirm initial biomarker findings by PLA. After ELISA of these two markers, only VEGF-A levels were significantly correlated with pathological response. On multivariate analysis, patients with combined high pre-CCRT VEGF-A and TGF-β1 levels (greater than or equal to the median), independent of pathological response, had significantly worse DFS (11 months vs. median not reached; p = 0.007) and OS (16 vs. 46 months; p = 0.07).Pre-CCRT serum VEGF-A and TGF-β1 levels may be used to predict pathological response and survivals for ESCC patients receiving combined-modality therapy.

View details for DOI 10.1245/s10434-014-3611-z

View details for PubMedID 24623035
Baseline metabolic tumor volume and total lesion glycolysis are associated with survival outcomes in patients with locally advanced pancreatic cancer receiving stereotactic body radiation therapy. International journal of radiation oncology, biology, physics Dholakia, A. S., Chaudhry, M., Leal, J. P., Chang, D. T., Raman, S. P., Hacker-Prietz, A., Su, Z., Pai, J., Oteiza, K. E., Griffith, M. E., Wahl, R. L., Tryggestad, E., Pawlik, T., Laheru, D. A., Wolfgang, C. L., Koong, A. C., Herman, J. M. 2014; 89 (3): 539-546
Abstract

Although previous studies have demonstrated the prognostic value of positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer has yet to be well established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiation therapy (SBRT).Thirty-two patients with LAPC in a prospective clinical trial received up to 3 doses of gemcitabine, followed by 33 Gy in 5 fractions of 6.6 Gy, using SBRT. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUVmax and SUVpeak) on pre-SBRT PET scans were calculated using custom-designed software. Disease was measured at a threshold based on the liver SUV, using the equation Livermean + [2 × Liversd]. Median values of PET parameters were used as cutoffs when assessing their prognostic potential through Cox regression analyses.Of the 32 patients, the majority were male (n=19, 59%), 65 years or older (n=21, 66%), and had tumors located in the pancreatic head (n=27, 84%). Twenty-seven patients (84%) received induction gemcitabine prior to SBRT. Median overall survival for the entire cohort was 18.8 months (95% confidence interval [CI], 15.7-22.0). An MTV of 26.8 cm(3) or greater (hazard ratio [HR] 4.46, 95% CI 1.64-5.88, P<.003) and TLG of 70.9 or greater (HR 3.08, 95% CI 1.18-8.02, P<.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19-22.21, P=.029) and TLG (HR 3.34, 95% CI 1.07-10.48, P=.038) remained independently associated with overall survival in separate multivariate analyses.Pre-SBRT MTV and TLG are potential predictive factors for overall survival in patients with LAPC and may assist in tailoring therapy.

View details for DOI 10.1016/j.ijrobp.2014.02.031

View details for PubMedID 24751410
A novel biomarker panel examining response to gemcitabine (G) with or without erlotinib (E) for pancreatic cancer (PA) therapy in NCIC clinical trials group PA.3. Shultz, D., Pal, J., Graber, M., Heestand, G. M., Chang, D., Parulekar, W. R., Tu, D., Moore, M. J., Koong, A. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.15_suppl.4133

View details for Web of Science ID 000358613203296
Lumbosacral spine and marrow cavity modeling of acute hematologic toxicity in patients treated with intensity modulated radiation therapy for squamous cell carcinoma of the anal canal. Practical radiation oncology Cheng, J. C., Bazan, J. G., Wu, J., Koong, A. C., Chang, D. T. 2014; 4 (3): 198-206
Abstract

To identify various dosimetric parameters of bone marrow cavity that correlate with acute hematologic toxicity (HT) in patients with anal squamous cell carcinoma treated with definitive chemoradiation therapy (CRT).We analyzed 32 patients receiving CRT. The whole pelvic bone marrow (PBM) and the lumbosacral spine (LSS) subregion were contoured for each patient. Marrow cavities were contoured using the Hounsfield units (HUs) of 100, 150, 200, and 250 as maximum density threshold levels. The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. The endpoint was grade ≥3 HT (HT3+). Normal-tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Maximal likelihood estimate was used to compare the parameter set. Logistic regression was used to test associations between HT and both dosimetric and clinical parameters.Ten patients (31%) experienced HT3+. While dose to both LSS and PBM significantly predicted for HT3+, LSS was superior to PBM by logistic regression and LKB modeling. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.21, n = 1, and TD50 = 32 Gy for LSS. The NTCP fits were better with the whole bone than with marrow cavity using any HU threshold. Mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3+, respectively. Mean dose and low-dose radiation parameters (V5, V10, V15, V20) of whole bone or bone cavities of LSS were correlated most significantly with HT3+.For predicting the risk of HT3+, whole-bone contours were superior to marrow cavity and LSS was superior to PBM by LKB modeling. The results confirm PBM and LSS as parallel organs when predicting hematologic toxicity. Recommended dose constraints to the LSS are V10 ≤80%. An LSS mean dose of 23.5 Gy is associated with a 10% risk of HT.

View details for DOI 10.1016/j.prro.2013.07.011

View details for PubMedID 24766688
Stereotactic Body Radiotherapy in the Treatment of Pancreatic Cancer SEMINARS IN RADIATION ONCOLOGY Trakul, N., Koong, A. C., Chang, D. T. 2014; 24 (2): 140-147
Abstract

Most patients diagnosed with pancreatic cancer are unable to have a curative surgical resection. Chemoradiation is a standard of care treatment for patients with locally advanced unresectable disease, but local failure rates are high with conventionally fractionated radiotherapy. However, stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy offers an alternative type of radiation therapy, which allows for the delivery of high-dose, conformal radiation. The high doses and shorter overall treatment time with SBRT may provide advantages in local control, disease outcomes, quality of life, and cost-effectiveness, and further investigation is currently underway. Here, we review the technology behind SBRT for pancreatic malignancy and its future direction in the overall management of pancreatic cancer.

View details for DOI 10.1016/j.semradonc.2013.11.008

View details for Web of Science ID 000333435300010
Stereotactic body radiotherapy in the treatment of pancreatic cancer. Seminars in radiation oncology Trakul, N., Koong, A. C., Chang, D. T. 2014; 24 (2): 140-147
Abstract

Most patients diagnosed with pancreatic cancer are unable to have a curative surgical resection. Chemoradiation is a standard of care treatment for patients with locally advanced unresectable disease, but local failure rates are high with conventionally fractionated radiotherapy. However, stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy offers an alternative type of radiation therapy, which allows for the delivery of high-dose, conformal radiation. The high doses and shorter overall treatment time with SBRT may provide advantages in local control, disease outcomes, quality of life, and cost-effectiveness, and further investigation is currently underway. Here, we review the technology behind SBRT for pancreatic malignancy and its future direction in the overall management of pancreatic cancer.

View details for DOI 10.1016/j.semradonc.2013.11.008

View details for PubMedID 24635871
Combined-modality Therapy for Rectal Cancer Analysis of Potential Differences in Disease Presentation, Treatment Adherence, and Treatment Outcome According to Race AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Tonlaar, N., Song, S., Hong, J. C., Minsky, B. D., Chang, D. T., Polite, B. N., Liauw, S. L. 2014; 37 (2): 122-125
Abstract

OBJECTIVES:: Population-based studies suggest African Americans (AAs) with rectal cancer have a worse overall outcome compared with non-AAs. This relationship was explored in a cohort of rectal cancer patients treated with preoperative chemoradiation therapy (CRT) and surgery at 2 academic cancer centers. METHODS:: A total of 146 patients (26 AA, 120 non-AA) underwent treatment with curative intent. The median age was 57 years. Median dose was 50.4 Gy, given with 5-fluorouracil-based concurrent chemotherapy. Differences in disease presentation, adherence to recommended therapy, and treatment outcome (freedom from failure) by race were analyzed. Median follow-up was 34 months from completion of CRT. RESULTS:: AAs had longer time from diagnosis to start of therapy (median, 45 vs. 35 d; P<0.01) and from CRT completion to surgery (median, 42 vs. 46 d; P=0.03). AA patients presented with more favorable disease (20% stage I, 33% stage III) compared with non-AA patients (0% stage I, 48% stage III, P<0.01). AA patients were less likely to receive adjuvant chemotherapy (58% vs. 89%, P=0.01). Log-rank analysis showed AAs were not more likely to recur after therapy (freedom from failure at 3 y, 100% for AA patients vs. 81% for non-AA patients, P=0.09). The difference in time from preoperative therapy to surgery and a lower rate of adjuvant therapy in AA patients did not seem to result in inferior disease outcome for this cohort. CONCLUSIONS:: Further study is necessary to explore the reasons underlying the delays in therapy and lower rates of adjuvant chemotherapy for AA patients.

View details for DOI 10.1097/COC.0b013e318271ae2c

View details for Web of Science ID 000333713100004
Radiotherapy for adenoid cystic carcinomas of the head and neck: clinical outcomes and patterns of failure JOURNAL OF RADIATION ONCOLOGY Shultz, D. B., Zeidan, Y. H., Murphy, J. D., Hara, W., Kaplan, M. J., Le, Q., Chang, D. T. 2014; 3 (1): 49–56
View details for DOI 10.1007/s13566-013-0098-3

View details for Web of Science ID 000218741800005
Outcomes and toxicity of SBRT for patients with unresectable pancreatic adenocarcinoma Pollom, E. L., Alagappan, M., Chan, C., Shultz, D., Kunz, P. L., Koong, A., Chang, D. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.3_suppl.317

View details for Web of Science ID 000333682100318
A novel biomarker panel examining response to adjuvant pancreatic cancer therapy in RTOG 9704 Heestand, G. M., Murphy, J., Moughan, J., Regine, W., Luo, J., Graber, M., Kunz, P. L., Fisher, G. A., Guha, C., Lin, B., Mowat, R. B., Gaur, R., Buyyounouski, M. K., Chen, Y., Chang, D., Koong, A. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.3_suppl.176

View details for Web of Science ID 000333682100180
Clinical deployment of automatic treatment planning for pancreas SBRT patients Moore, J. A., Yang, W., Evans, K., Dholakia, A., Koong, A., Chang, D., Goodman, K. A., Herman, J. M., McNutt, T. R. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.3_suppl.219

View details for Web of Science ID 000333682100222
Pre-SBRT metabolic tumor volume and total lesion glycolysis to predict survival in patients with locally advanced pancreatic cancer receiving stereotactic body radiation therapy Dholakia, A., Chaudhry, M., Leal, J. P., Chang, D., Raman, S. P., Su, Z., Hacker-Prietz, A., Pai, J., Griffith, M. E., Wahl, R. L., Tryggestad, E., Pawlik, T. M., Laheru, D. A., Wolfgang, C., Koong, A., Herman, J. M. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.3_suppl.189

View details for Web of Science ID 000333682100193
Effects of gemcitabine and stereotactic body radiotherapy on quality of life in locally advanced pancreatic cancer Dholakia, A., Chang, D., Goodman, K. A., Sugar, E., Hacker-Prietz, A., Columbo, L., Griffith, M. E., Wild, A., Moningi, S., Pawlik, T. M., Fisher, G. A., Ellsworth, S. G., Koong, A., Herman, J. M. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.3_suppl.278

View details for Web of Science ID 000333682100281
False positive 18F-fluorodeoxyglucose positron emission tomography/computed tomography liver lesion mimicking metastasis in 2 patients with gastroesophageal cancer. Practical radiation oncology Paudel, N., Kunz, P. L., Poultsides, G. A., Koong, A. C., Chang, D. T. 2014; 4 (6): 368-371
View details for DOI 10.1016/j.prro.2013.11.005

View details for PubMedID 25407856
Postradiotherapy CA19-9 Kinetics Correlate With Outcomes in Patients With Pancreatic Adenocarcinoma. Pancreas Shultz, D. B., Chan, C., Shaffer, J. L., Kunz, P. L., Koong, A. C., Chang, D. T. 2014; 43 (5): 777–83
Abstract

We sought to determine if carbohydrate antigen 19-9 (CA19-9 ) nadir (nCA19-9), time to nadir (TTN), and doubling time (DT) after radiotherapy (RT) correlate with outcomes in pancreatic ductal adenocarcinoma.We examined the records of 102 patients treated with RT for primary, nonmetastatic pancreatic ductal adenocarcinoma between August 1998 and July 2011. Of these, 33 patients were treated with postoperative chemoradiotherapy (PORT) and 69 patients with definitive chemoradiotherapy (CRT).Among the patients treated with PORT, TTN and DT were associated with both overall survival (OS; P = <0.01 for both) and freedom from progression (FFP; P = <0.01 for both). In patients treated with CRT, nCA19-9 and TTN correlated with both OS (P = <0.01 and P = 0.02, respectively) and FFP (P = 0.01 and <0.01, respectively). On multivariable analysis, in patients treated with PORT, TTN remained independently correlated with OS and FFP (P = 0.01; hazard ratios [HR], 6.43 and P = 0.02; HR, 4.00, respectively), whereas DT remained independently correlated to FFP (P = 0.04; HR, 0.27). In patients treated with CRT, controlling for pretreatment CA19-9, nCA19-9 and TTN independently correlated with OS (P = <0.01; HR, 3.0 and P = 0.03; HR, 2.56, respectively) and FFP (P = 0.04; HR, 2.31 and P = <0.01; HR, 4.0, respectively).CA19-9 kinetics after RT correlate with disease progression and survival and could serve as a prognostic tool to guide treatment decisions.

View details for PubMedID 24632549
In reply to Leung. International journal of radiation oncology, biology, physics Chang, D. T., Haffty, B. G., Wilson, L. D. 2014; 88 (1): 241-242
View details for DOI 10.1016/j.ijrobp.2013.10.018

View details for PubMedID 24331676
Impact of chemotherapy on normal tissue complication probability models of acute hematologic toxicity in patients receiving pelvic intensity modulated radiation therapy. International journal of radiation oncology, biology, physics Bazan, J. G., Luxton, G., Kozak, M. M., Anderson, E. M., Hancock, S. L., Kapp, D. S., Kidd, E. A., Koong, A. C., Chang, D. T. 2013; 87 (5): 983-991
Abstract

To determine how chemotherapy agents affect radiation dose parameters that correlate with acute hematologic toxicity (HT) in patients treated with pelvic intensity modulated radiation therapy (P-IMRT) and concurrent chemotherapy.We assessed HT in 141 patients who received P-IMRT for anal, gynecologic, rectal, or prostate cancers, 95 of whom received concurrent chemotherapy. Patients were separated into 4 groups: mitomycin (MMC) + 5-fluorouracil (5FU, 37 of 141), platinum ± 5FU (Cis, 32 of 141), 5FU (26 of 141), and P-IMRT alone (46 of 141). The pelvic bone was contoured as a surrogate for pelvic bone marrow (PBM) and divided into subsites: ilium, lower pelvis, and lumbosacral spine (LSS). The volumes of each region receiving 5-40 Gy were calculated. The endpoint for HT was grade ≥3 (HT3+) leukopenia, neutropenia or thrombocytopenia. Normal tissue complication probability was calculated using the Lyman-Kutcher-Burman model. Logistic regression was used to analyze association between HT3+ and dosimetric parameters.Twenty-six patients experienced HT3+: 10 of 37 (27%) MMC, 14 of 32 (44%) Cis, 2 of 26 (8%) 5FU, and 0 of 46 P-IMRT. PBM dosimetric parameters were correlated with HT3+ in the MMC group but not in the Cis group. LSS dosimetric parameters were well correlated with HT3+ in both the MMC and Cis groups. Constrained optimization (0
View details for DOI 10.1016/j.ijrobp.2013.09.017

View details for PubMedID 24161422
Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: experience from two institutions. Journal of gastrointestinal oncology Wild, A. T., Hiniker, S. M., Chang, D. T., Tran, P. T., Khashab, M. A., Limaye, M. R., Laheru, D. A., Le, D. T., Kumar, R., Pai, J. S., Hargens, B., Sharabi, A. B., Shin, E. J., Zheng, L., Pawlik, T. M., Wolfgang, C. L., Koong, A. C., Herman, J. M. 2013; 4 (4): 343-351
Abstract

Limited treatment options exist for isolated local recurrence of pancreatic ductal adenocarcinoma (PDA) following surgical resection accompanied by neoadjuvant or adjuvant chemoradiation therapy (CRT). While select patients are eligible for re-resection, recurrent lesions are often unresectable. Stereotactic body radiation therapy (SBRT) represents a possible minimally invasive treatment option for these patients, although published data in this setting are currently lacking. This study examines the safety, efficacy, and palliative capacity of re-irradiation with SBRT for isolated local PDA recurrence. All patients undergoing SBRT at two academic centers from 2008-2012 were retrospectively reviewed to identify those who received re-irradiation with SBRT for isolated local recurrence or progression of PDA after previous conventionally fractionated CRT. Information regarding demographics, clinicopathologic characteristics, therapies received, survival, symptom palliation, and toxicity was obtained from patient charts. Kaplan-Meier statistics were used to analyze survival and the log-rank test was used to compare survival among patient subgroups. Eighteen patients were identified. Fifteen had previously undergone resection with neoadjuvant or adjuvant CRT, while 3 received definitive CRT for locally advanced disease. Median CRT dose was 50.4 Gy [interquartile range (IQR), 45.0-50.4 Gy] in 28 fractions. All patients subsequently received gemcitabine-based maintenance chemotherapy, but developed isolated local disease recurrence or progression without evidence of distant metastasis. Locally recurrent or progressive disease was treated with SBRT to a median dose of 25.0 Gy (range, 20.0-27.0 Gy) in 5 fractions. Median survival from SBRT was 8.8 months (95% CI, 1.2-16.4 months). Despite having similar clinicopathologic disease characteristics, patients who experienced local progression greater than vs. less than 9 months after surgery/definitive CRT demonstrated superior median survival (11.3 vs. 3.4 months; P=0.019) and progression-free survival (10.6 vs. 3.2 months; P=0.030) after SBRT. Rates of freedom from local progression at 6 and 12 months after SBRT were 78% (14 of 18 patients) and 62% (5 of 8 patients), respectively. Effective symptom palliation was achieved in 4 of 7 patients (57%) who reported symptoms of abdominal or back pain prior to SBRT. Five patients (28%) experienced grade 2 acute toxicity; none experienced grade ≥3 acute toxicity. One patient (6%) experienced grade 3 late toxicity in the form of small bowel obstruction. In conclusion, re-irradiation with hypofractionated SBRT in this salvage scenario appears to be a safe and reasonable option for palliation of isolated local PDA recurrence or progression following previous conventional CRT. Patients with a progression-free interval of greater than 9 months prior to isolated local recurrence or progression may be most suitable for re-irradiation with SBRT, as they appear to have a better prognosis with survival that is long enough for local control to be of potential benefit.

View details for DOI 10.3978/j.issn.2078-6891.2013.044

View details for PubMedID 24294505

View details for PubMedCentralID PMC3819776
The role of adjuvant chemoradiation in the treatment of pancreatic cancer JOURNAL OF RADIATION ONCOLOGY Trakul, N., Koong, A. C., Chang, D. T. 2013; 2 (4): 391–400
View details for DOI 10.1007/s13566-013-0121-8

View details for Web of Science ID 000218739500006
Cone beam CT imaging with limited angle of projections and prior knowledge for volumetric verification of non-coplanar beam radiation therapy: a proof of concept study. Physics in medicine and biology Meng, B., Xing, L., Han, B., Koong, A., Chang, D., Cheng, J., Li, R. 2013; 58 (21): 7777-7789
Abstract

Non-coplanar beams are important for treatment of both cranial and noncranial tumors. Treatment verification of such beams with couch rotation/kicks, however, is challenging, particularly for the application of cone beam CT (CBCT). In this situation, only limited and unconventional imaging angles are feasible to avoid collision between the gantry, couch, patient, and on-board imaging system. The purpose of this work is to develop a CBCT verification strategy for patients undergoing non-coplanar radiation therapy. We propose an image reconstruction scheme that integrates a prior image constrained compressed sensing (PICCS) technique with image registration. Planning CT or CBCT acquired at the neutral position is rotated and translated according to the nominal couch rotation/translation to serve as the initial prior image. Here, the nominal couch movement is chosen to have a rotational error of 5° and translational error of 8 mm from the ground truth in one or more axes or directions. The proposed reconstruction scheme alternates between two major steps. First, an image is reconstructed using the PICCS technique implemented with total-variation minimization and simultaneous algebraic reconstruction. Second, the rotational/translational setup errors are corrected and the prior image is updated by applying rigid image registration between the reconstructed image and the previous prior image. The PICCS algorithm and rigid image registration are alternated iteratively until the registration results fall below a predetermined threshold. The proposed reconstruction algorithm is evaluated with an anthropomorphic digital phantom and physical head phantom. The proposed algorithm provides useful volumetric images for patient setup using projections with an angular range as small as 60°. It reduced the translational setup errors from 8 mm to generally <1 mm and the rotational setup errors from 5° to <1°. Compared with the PICCS algorithm alone, the integration of rigid registration significantly improved the reconstructed image quality, with a reduction of mostly 2-3 folds (up to 100) in root mean square image error. The proposed algorithm provides a remedy for solving the problem of non-coplanar CBCT reconstruction from limited angle of projections by combining the PICCS technique and rigid image registration in an iterative framework. In this proof of concept study, non-coplanar beams with couch rotations of 45° can be effectively verified with the CBCT technique.

View details for DOI 10.1088/0031-9155/58/21/7777

View details for PubMedID 24140954
Chemoradiotherapy Before and After Surgery for Locally Advanced Esophageal Cancer: A SEER-Medicare Analysis ANNALS OF SURGICAL ONCOLOGY Hong, J. C., Murphy, J. D., Wang, S. J., Koong, A. C., Chang, D. T. 2013; 20 (12): 3999-4007
Abstract

The optimal combination and timing of therapy for esophageal cancer remains controversial. The Surveillance, Epidemiology, and End Results (SEER)-Medicare registry was used to assess neoadjuvant and adjuvant therapy.Patients diagnosed with nonmetastatic T3+ or N1+ esophageal adenocarcinoma (ACA) or squamous cell carcinoma (SCC) from 1995 to 2002 who underwent surgical resection within 6 months of diagnosis were studied. Medicare data defined preoperative chemoradiotherapy (preCRT), preoperative radiotherapy (preRT), postoperative CRT (postCRT), chemotherapy and surgery (CT + S), and surgery alone.Of 419 eligible patients, 126 received preCRT, 55 preRT, 40 postCRT, 29 CT + S, and 169 surgery alone. PreCRT yielded median overall survival (OS) of 37 months, greater than surgery alone (17 months, p = 0.002) and postCRT (17 months, p = 0.06). PreRT (20 months, p = 0.20), postCRT (p = 0.88), and CT + S (20 months, p = 0.42) were not associated with OS benefit versus surgery alone. For SCC, preCRT improved survival versus surgery alone (p = 0.01), with a trend for ACA (p = 0.07). ACA (22 months) had greater OS than SCC (17 months) (p = 0.03). ACA, younger age, and married status were associated with increased OS. Adjusting for these, preCRT had longer OS versus surgery alone (p = 0.02) and postCRT (p = 0.03). Chemotherapy agents and surgical approach did not affect OS.In the SEER-Medicare cohort, preCRT significantly improved survival versus surgery alone and postCRT for locally advanced esophageal cancer, particularly for SCC. PreRT, postCRT, and CT + S were not associated with longer survival.

View details for DOI 10.1245/s10434-013-3072-9

View details for PubMedID 23800897
Factors that Determine Academic Versus Private Practice Career Interest in Radiation Oncology Residents in the United States: Results of a Nationwide Survey INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chang, D. T., Shaffer, J. L., Haffty, B. G., Wilson, L. D. 2013; 87 (3): 464-470
Abstract

To determine what factors US radiation oncology residents consider when choosing academic or nonacademic careers.A 20-question online survey was developed and sent to all US radiation oncology residents to assess factors that influence their career interest. Residents were asked to rate their interest in academics (A) versus private practice (PP) on a 0 (strong interest in A) to 100 (strong interest in PP) scale. Responses were classified as A (0-30), undecided (40-60), and PP (70-100). Residents were also asked to rank 10 factors that most strongly influenced their career interest.Three hundred thirty-one responses were collected, of which 264 were complete and form the basis for this analysis. Factors that correlated with interest in A included having a PhD (P=.018), postgraduate year level (P=.0006), research elective time (P=.0003), obtaining grant funding during residency (P=.012), and number of publications before residency (P=.0001), but not number of abstracts accepted in the past year (P=.65) or publications during residency (P=.67). The 3 most influential factors for residents interested in A were: (1) baseline interest before residency; (2) academic role models; and (3) research opportunities during residency. The 3 most influential factors for residents interested in PP were: (1) baseline interest before residency; (2) academic role models; and (3) academic pressure and obligations.Interest in A correlated with postgraduate year level, degree, and research time during residency. Publications before but not during residency correlated with academic interest, and baseline interest was the most influential factor. These data can be used by residency program directors to better understand what influences residents' career interest.

View details for DOI 10.1016/j.ijrobp.2013.07.002

View details for PubMedID 23972721
Long-Term Outcomes of Surgery Followed by Radiation Therapy for Minor Salivary Gland Carcinomas LARYNGOSCOPE Zeidan, Y. H., Shultz, D. B., Murphy, J. D., Chan, C., Kaplan, M. J., Colevas, A. D., Kong, C., Chang, D. T., Le, Q. 2013; 123 (11): 2675-2680
Abstract

Postoperative radiation therapy is often used in patients with high-risk salivary gland carcinomas. In this study we evaluated the outcomes and prognostic factors in patients with minor salivary gland cancers treated with adjuvant radiation therapy.Retrospective cohort study.We performed a retrospective analysis of 90 patients treated with curative intent. Median follow-up was 71 months. Fifty-eight patients (64%) had adenoid cystic carcinomas, 22 (24%) had adenocarcinomas, and 10 (11%) had mucoepidermoid cancers. Primary disease site included 39 (43%) sinonasal, 35 (39%) oral cavity, 10 (11%) oropharynx, and six (7%) others. Twenty-seven patients (30%) were treated with intensity-modulated radiation therapy.Eight local, four neck, and 24 distant relapses were detected. Local control rates at 5 and 10 years were 90% and 88%, respectively. Advanced T stage was associated with worse local control. Distant metastasis rates were 24% and 28% at 5 and 10 years, respectively. Tumor stage, histology, perineural invasion, and lymphovascular space invasion were significant predictors of distant metastasis on univariate analysis. However, on multivariate analysis only the American Joint Committee on Cancer stage was significant. Overall survival rates were 76% and 63% at 5 and 10 years, respectively. More advanced T stage and N stage correlated with worse overall survival.Tumor stage remains the best predictor for locoregional and distant disease control of minor salivary gland cancers. Postoperative radiation therapy for high-risk patients results in excellent long-term locoregional disease control. Further work is needed to improve systemic control.

View details for DOI 10.1002/lary.24081

View details for PubMedID 23553253
Clinicopathologic Features of Synchronous Colorectal Carcinoma A Distinct Subset Arising From Multiple Sessile Serrated Adenomas and Associated With High Levels of Microsatellite Instability and Favorable Prognosis AMERICAN JOURNAL OF SURGICAL PATHOLOGY Hu, H., Chang, D. T., Nikiforova, M. N., Kuan, S., Pai, R. K. 2013; 37 (11): 1660-1670
Abstract

Analysis of synchronous colorectal carcinomas can provide a unique model to examine the underlying molecular alterations in colorectal carcinoma, as synchronous tumors arise in a background of common genetic and environmental factors. We analyzed the clinicopathologic and molecular features of synchronous colorectal carcinomas compared with solitary carcinomas to correlate the histologic findings with molecular alterations and to identify the prognostic significance, if any, of synchronous colorectal carcinoma. Of the 4760 primary colorectal carcinomas resected for the years 2002 to 2012 at our institution, 58 patients (1.2%) harbored 2 invasive primary adenocarcinomas and comprise the synchronous colorectal carcinoma study group. A control group of consecutively resected solitary colorectal carcinomas from 109 patients was also analyzed. Compared with solitary colorectal carcinomas, synchronous colorectal carcinomas more frequently were identified in older patients (median age 70 vs. 60 y; P=0.001), involved the right colon (42/58, 72% vs. 47/109, 43%; P=0.0003), were more often microsatellite instability-high (MSI-H) (21/58, 36% vs. 13/109, 12%; P=0.0005), and were more frequently associated with precursor sessile serrated adenomas (SSAs) (13/58, 22% vs. 2/109, 2%; P=0.0001). A statistically significant difference in overall survival was identified between patients with synchronous and solitary colorectal carcinomas (5 y overall survival 92% vs. 56%, P=0.02). A unique subgroup of 13 synchronous colorectal carcinomas demonstrated tumors arising from SSAs (SSA-associated). All SSA-associated synchronous colorectal carcinomas were seen in patients above 65 years of age, and 12/13 (92%) occurred in women. Most patients (12/13, 92%) with SSA-associated synchronous colorectal carcinomas demonstrated involvement of the right colon, and tumors were frequently stage I or II (9/13, 69%) and low grade (11/13, 85%). In 12/13 (92%) SSA-associated synchronous colorectal carcinomas, both tumors exhibited loss of MLH1 and PMS2 immunohistochemical expression with concurrent BRAF V600E mutation. Nine of 13 (69%) patients with SSA-associated colorectal carcinoma harbored additional SSAs. Three of 13 (15%) patients with SSA-associated synchronous colorectal carcinoma met the World Health Organization criteria for serrated polyposis. Notably, no patient with SSA-associated synchronous colorectal carcinoma developed disease recurrence or died of disease at last follow-up. In conclusion, synchronous colorectal carcinomas are enriched with MSI-H tumors, particularly those arising from SSAs, which contributes to the overall improved survival for patients with synchronous tumors compared with patients with solitary tumors. We demonstrate that SSA-associated synchronous colorectal carcinomas have a striking predilection for elderly women, are associated with a favorable prognosis, and are MSI-H and BRAF V600E positive.

View details for PubMedID 23887157
Safety of (90)y radioembolization in patients who have undergone previous external beam radiation therapy. International journal of radiation oncology, biology, physics Lam, M. G., Abdelmaksoud, M. H., Chang, D. T., Eclov, N. C., Chung, M. P., Koong, A. C., Louie, J. D., Sze, D. Y. 2013; 87 (2): 323-329
Abstract

Previous external beam radiation therapy (EBRT) is theoretically contraindicated for yttrium-90 ((90)Y) radioembolization (RE) because the liver has a lifetime tolerance to radiation before becoming vulnerable to radiation-induced liver disease. We analyzed the safety of RE as salvage treatment in patients who had previously undergone EBRT.Between June 2004 and December 2010, a total of 31 patients who had previously undergone EBRT were treated with RE. Three-dimensional treatment planning with dose-volume histogram (DVH) analysis of the liver was used to calculate the EBRT liver dose. Liver-related toxicities including RE-induced liver disease (REILD) were reviewed and classified according to Common Terminology Criteria for Adverse Events version 4.02.The mean EBRT and RE liver doses were 4.40 Gy (range, 0-23.13 Gy) and 57.9 Gy (range, 27.0-125.9 Gy), respectively. Patients who experienced hepatotoxicity (≥grade2; n=12) had higher EBRT mean liver doses (7.96 ± 8.55 Gy vs 1.62 ± 3.39 Gy; P=.037), the only independent predictor in multivariate analysis. DVH analysis showed that the fraction of liver exposed to ≥30 Gy (V30) was the strongest predictor of hepatotoxicity (10.14% ± 12.75% vs 0.84% ± 3.24%; P=.006). All patients with V30 >13% experienced hepatotoxicity. Fatal REILD (n=2) occurred at the 2 highest EBRT mean liver doses (20.9 Gy and 23.1 Gy) but also at the highest cumulative liver doses (91.8 Gy and 149 Gy).Prior exposure of the liver to EBRT may lead to increased liver toxicity after RE treatment, depending on fractional liver exposure and dose level. The V30 was the strongest predictor of toxicity. RE appears to be safe for the treatment of hepatic malignancies only in patients who have had limited hepatic exposure to prior EBRT.

View details for DOI 10.1016/j.ijrobp.2013.05.041

View details for PubMedID 23849697
A Phase 2 Multicenter Study to Evaluate Gemcitabine and Fractionated Stereotactic Body Radiation Therapy for Locally Advanced Pancreatic Adenocarcinoma Dholakia, A. S., Chang, D. T., Goodman, K. A., Raman, S. P., Hacker-Prietz, A., Griffith, M. E., Colombo, L., Laheru, D. A., Koong, A. C., Herman, J. M. ELSEVIER SCIENCE INC. 2013: S28
View details for DOI 10.1016/j.ijrobp.2013.06.077

View details for Web of Science ID 000324503600067
Generation of Consensus Contour Atlas for Esophageal Cancer IMRT Wu, A. J., Goodman, K. A., Chang, D. T., Hong, T. S., Jabbour, S. K., Kleinberg, L. R., Mamon, H. J., Thomas, C. R., Bosch, W. R. ELSEVIER SCIENCE INC. 2013: S293
View details for DOI 10.1016/j.ijrobp.2013.06.767

View details for Web of Science ID 000324503601152
Brain Metastases and Resection Cavities From Colorectal Carcinoma Treated With Stereotactic Radiosurgery Have Poor Local Control Compared to Noncolorectal Histology Pai, J., Wang, Z., Shaffer, J. L., Gibbs, I. C., Chang, D. T., Koong, A. C., Chang, S. D., Harsh, G. R., Li, G., Soltys, S. G. ELSEVIER SCIENCE INC. 2013: S161
View details for DOI 10.1016/j.ijrobp.2013.06.415

View details for Web of Science ID 000324503600398
Clinical and Dosimetric Predictors of Perioperative Pulmonary Complications in Esophageal Cancer Patients Treated With Neoadjuvant Chemoradiation Shah, J. L., Shaffer, J. L., Bazan, J. G., Cheng, J. C., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2013: S300–S301
View details for DOI 10.1016/j.ijrobp.2013.06.789

View details for Web of Science ID 000324503601173
Anemia During Radiation Therapy Correlates With Outcomes in Pancreatic Cancer Chan, C., Shultz, D. B., Shaffer, J. L., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2013: S304–S305
View details for DOI 10.1016/j.ijrobp.2013.06.800

View details for Web of Science ID 000324503601184
Predicting Liver Volume Changes After Stereotactic Body Radiation Therapy for Liver Tumors Shaffer, J., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2013: S323
View details for DOI 10.1016/j.ijrobp.2013.06.850

View details for Web of Science ID 000324503601233
Risk of Hepatobiliary Toxicity After SBRT to the Liver for Central Liver Tumors Osmundson, E., Bazan, J. G., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2013: S328
View details for DOI 10.1016/j.ijrobp.2013.06.864

View details for Web of Science ID 000324503601246
(18)Flurodeoxyglucose-PET Baseline Avidity Predicts for Inferior Outcomes in Patients With Locally-Advanced Pancreatic Cancer Treated With Gemcitabine and Stereotactic Body Radiation Therapy Dholakia, A. S., Chang, D. T., Goodman, K. A., Raman, S. P., Leal, J. P., Laheru, D. A., Wolfgang, C. L., Chaudhry, M., Koong, A. C., Herman, J. ELSEVIER SCIENCE INC. 2013: S308–S309
View details for DOI 10.1016/j.ijrobp.2013.06.810

View details for Web of Science ID 000324503601194
Factors that Determine Academic Versus Private Practice Career Interest in Radiation Oncology Residents in the United States: Results of a Nationwide Survey Chang, D. T., Shaffer, J. L., Haffty, B. G., Wilson, L. D. ELSEVIER SCIENCE INC. 2013: S486
View details for DOI 10.1016/j.ijrobp.2013.06.1284

View details for Web of Science ID 000324503601654
SMAD4 Inactivation and Prognosis in Colorectal Cancer Pai, J., Kozak, M. M., Limaye, M. R., Jayachandran, P., Anderson, E. M., Shaffer, J. L., Longacre, T. A., Pai, R. K., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2013: S342
View details for DOI 10.1016/j.ijrobp.2013.06.900

View details for Web of Science ID 000324503601280
Plasma SPARC Following Stereotactic Body Radiation Therapy (SBRT) Predicts for Progression-Free Survival in Locally-Advanced Pancreatic Cancer Pai, J., Chiu, W., Shultz, D. B., Graber, M., Columbo, L., Wild, A., Kumar, R., Herman, J. M., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2013: S668
View details for DOI 10.1016/j.ijrobp.2013.06.1771

View details for Web of Science ID 000324503602416
Radiotherapy for nonadenoid cystic carcinomas of major salivary glands. American journal of otolaryngology Chung, M. P., Tang, C., Chan, C., Hara, W. Y., Loo, B. W., Kaplan, M. J., Fischbein, N., Le, Q., Chang, D. T. 2013; 34 (5): 425-430
Abstract

To report outcomes in patients treated with postoperative radiotherapy for nonadenoid cystic carcinomas of the major salivary glands.From 1998-2011, 37 patients with nonadenoid cystic carcinomas of the major salivary gland underwent postoperative radiotherapy. The median radiation dose was 60 Gy (range, 45-70 Gy). TNM distribution included T1-2 (n=16, 44%), T3-T4 (n=21, 56%), N0 (n=19, 51%), and N+ (n=18, 49%). Histologies included adenocarcinoma (n=13, 35%), squamous cell carcinoma (n=8, 22%), mucoepidermoid carcinoma (n=8, 22%), and other (n=8, 21%). Median follow-up was 4.7 years for all patients (range, 0.3-14.1 years) and 5.0 years for living patients (range, 1.2-12.2 years).Five-year local-regional control, overall survival (OS), and cancer-specific survival (CSS) were 97%, 76%, and 84%. On univariate analysis, OS was significantly worse for patients ≥65 years old (p=0.04). CSS was significantly worse for positive perineural invasion (p=0.02), extraparenchymal extension (p=0.04), and in patients who received no chemotherapy (p=0.02). Doses >60 Gy was significantly worse for OS (p=0.003) and CSS (p=0.003), although these patients had higher TNM (>T2, p=0.01) and trended towards a higher rate of extraparenchymal extension (p=0.08). Four patients (11%) developed ≥grade 2 toxicities; 3 patients developed early toxicities and one patient developed late toxicities.Radiotherapy for salivary gland tumors provides excellent local-regional control when combined with surgery. Distant metastasis is the predominant pattern of failure, although chemotherapy seemed to improve cancer-specific survival.

View details for DOI 10.1016/j.amjoto.2013.03.007

View details for PubMedID 23583094
Patterns of Care in Palliative Radiotherapy: A Population-Based Study JOURNAL OF ONCOLOGY PRACTICE Murphy, J. D., Murphy, J. D., Nelson, L. M., Chang, D. T., Mell, L. K., Le, Q. 2013; 9 (5): E220–E227
View details for DOI 10.1200/JOP.2012.000835

View details for Web of Science ID 000214657300006
Patterns of care in palliative radiotherapy: a population-based study. Journal of oncology practice / American Society of Clinical Oncology Murphy, J. D., Nelson, L. M., Chang, D. T., Mell, L. K., Le, Q. 2013; 9 (5): e220-7
Abstract

Approximately one half of the radiotherapy (RT) prescribed in the United States is delivered with palliative intent. The purpose of this study was to investigate the patterns of delivery of palliative RT across the United States.Using the Surveillance, Epidemiology, and End Results-Medicare linked database, 51,610 patients were identified with incident stage IV breast, prostate, lung, or colorectal cancer diagnosed between 2000 and 2007 and observed through 2009. Multivariate logistic regression determined predictors of palliative RT.Forty-one percent of the study population received palliative RT, including 53% of patients with lung cancer, followed by those with breast (42%), prostate (40%), and colorectal cancers (12%). Multivariate analysis revealed that older patients (P<.001) and those with higher Charlson comorbidity scores (P<.001) were less likely to receive palliative RT. Black patients with prostate cancer were 20% less likely (P<.001), and black patients with colorectal cancer were 28% less likely (P<.001), than white patients to receive palliative RT. Among those treated with RT, 23% of patients with lung cancer died within 2 weeks of completing treatment, followed by those with colorectal (12%), breast (11%), and prostate cancers (8%). In addition to tumor site, significant predictors (P<.05) of death within 2 weeks of receiving RT included increased age, increased comorbidity, and male sex.Inequality in the receipt of palliative RT exists among the elderly and patients with comorbid conditions and varies with race. In addition, a significant number of patients die shortly after receiving RT. Understanding these patterns of care, along with further research into the underlying causes, will improve access and quality of palliative RT.

View details for DOI 10.1200/JOP.2012.000835

View details for PubMedID 23943892
Signet Ring Cell Colorectal Carcinoma A Distinct Subset of Mucin-poor Microsatellite-stable Signet Ring Cell Carcinoma Associated With Dismal Prognosis AMERICAN JOURNAL OF SURGICAL PATHOLOGY Hartman, D. J., Nikiforova, M. N., Chang, D. T., Chu, E., Bahary, N., Brand, R. E., Zureikat, A. H., Zeh, H. J., Choudry, H., Pai, R. K. 2013; 37 (7): 969-977
Abstract

We evaluated a consecutive series of signet ring cell colorectal carcinomas in an attempt to correlate the histopathologic pattern of infiltration with molecular alterations and prognosis. Of the 4760 primary colorectal carcinomas surgically resected between the years 2002 and 2012, 53 (1%) were composed of >50% signet ring cells. Of the 53 signet ring cell carcinomas, 40 (75%) were composed of >50% extracellular mucin with signet ring cells floating within pools of mucin and were subclassified as mucin-rich signet ring cell carcinomas. Thirteen (25%) carcinomas were characterized by diffusely infiltrating carcinomas with minimal to no extracellular mucin and were subclassified as mucin-poor signet ring cell carcinomas. All 13 mucin-poor signet ring cell carcinomas were either stage III or IV, whereas many cases of mucin-rich signet ring cell carcinoma were stage I or II (17 cases) (P=0.005). Compared with mucin-rich tumors, mucin-poor signet ring cell carcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (13/13, 100% vs. 22/40, 55%; P=0.002), venous invasion (6/13, 46% vs. 3/40, 8%; P=0.004), and perineural invasion (11/13, 85% vs. 9/40, 23%; P=0.0001). Twenty-three of 53 (43%) signet ring cell carcinomas demonstrated high levels of microsatellite instability (MSI-H). Twenty-two of 23 (96%) MSI-H signet ring cell carcinomas were mucin rich; only 1 MSI-H signet ring carcinoma was mucin poor (P=0.0033). Mucin-poor signet ring cell carcinoma had significantly reduced overall and recurrence-free survival compared with mucin-rich signet ring cell carcinomas (P=0.0035 and 0.0001, respectively), even when adjusting for tumor stage. Mucin-poor signet ring cell carcinoma had a higher propensity for peritoneal dissemination (5/13, 38%) compared with mucin-rich signet ring cell carcinoma (5/40, 12.5%), although this was not statistically significant (P=0.052). Finally, MSI-H and microsatellite-stable signet ring cell carcinomas had similar overall and recurrence-free survival (P=0.2266 and 0.1055, respectively), even when adjusting for tumor stage. In conclusion, we identified a unique subset of signet ring cell colorectal carcinoma with diffuse infiltration and minimal to no extracellular mucin (mucin-poor signet ring cell carcinoma), which lacks MSI-H and has a dismal prognosis with an aggressive clinical course often with peritoneal dissemination. Further, our results confirm that MSI does not affect survival in colorectal signet ring cell carcinomas.

View details for Web of Science ID 000330377200004

View details for PubMedID 23681075
Seventh Edition (2010) of the AJCC/UICC Staging System for Gastric Adenocarcinoma: Is there Room for Improvement? ANNALS OF SURGICAL ONCOLOGY Patel, M. I., Rhoads, K. F., Ma, Y., Ford, J. M., Visser, B. C., Kunz, P. L., Fisher, G. A., Chang, D. T., Koong, A., Norton, J. A., Poultsides, G. A. 2013; 20 (5): 1631-1638
Abstract

The gastric cancer AJCC/UICC staging system recently underwent significant revisions, but studies on Asian patients have reported a lack of adequate discrimination between various consecutive stages. We sought to validate the new system on a U.S. population database.California Cancer Registry data linked to the Office of Statewide Health Planning and Development discharge abstracts were used to identify patients with gastric adenocarcinoma (esophagogastric junction and gastric cardia tumors excluded) who underwent curative-intent surgical resection in California from 2002 to 2006. AJCC/UICC stage was recalculated based on the latest seventh edition. Overall survival probabilities were calculated using the Kaplan-Meier method.Of 1905 patients analyzed, 54 % were males with a median age of 70 years. Median number of pathologically examined lymph nodes was 12 (range, 1-90); 40 % of patients received adjuvant chemotherapy, and 31 % received adjuvant radiotherapy. The seventh edition AJCC/UICC system did not distinguish outcome adequately between stages IB and IIA (P = 0.40), or IIB and IIIA (P = 0.34). By merging stage II into 1 category and moving T2N1 to stage IB and T2N2, T1N3 to stage IIIA, we propose a new grouping system with improved discriminatory abilityIn this first study validating the new seventh edition AJCC/UICC staging system for gastric cancer on a U.S. population with a relatively limited number of lymph nodes examined, we found stages IB and IIA, as well as IIB and IIIA to perform similarly. We propose a revised stage grouping for the AJCC/UICC staging system that better discriminates between outcomes.

View details for DOI 10.1245/s10434-012-2724-5

View details for PubMedID 23149854
A Phase 2 Multi-institutional Study to Evaluate Gemcitabine and Fractionated Stereotactic Radiotherapy for Unresectable, Locally Advanced Pancreatic Adenocarcinoma. Practical radiation oncology Wild, A. T., Chang, D. T., Goodman, K. A., Laheru, D. A., Zheng, L., Raman, S. P., Columbo, L. A., Wolfgang, C. L., Koong, A. C., Herman, J. M. 2013; 3 (2): S4-5
View details for DOI 10.1016/j.prro.2013.01.016

View details for PubMedID 24674559
Dosimetric analysis of organs at risk during expiratory gating in stereotactic body radiation therapy for pancreatic cancer. International journal of radiation oncology, biology, physics Taniguchi, C. M., Murphy, J. D., Eclov, N., Atwood, T. F., Kielar, K. N., Christman-Skieller, C., Mok, E., Xing, L., Koong, A. C., Chang, D. T. 2013; 85 (4): 1090-1095
Abstract

To determine how the respiratory phase impacts dose to normal organs during stereotactic body radiation therapy (SBRT) for pancreatic cancer.Eighteen consecutive patients with locally advanced, unresectable pancreatic adenocarcinoma treated with SBRT were included in this study. On the treatment planning 4-dimensional computed tomography (CT) scan, the planning target volume (PTV), defined as the gross tumor volume plus 3-mm margin, the duodenum, and the stomach were contoured on the end-expiration (CTexp) and end-inspiration (CTinsp) phases for each patient. A separate treatment plan was constructed for both phases with the dose prescription of 33 Gy in 5 fractions with 95% coverage of the PTV by the 100% isodose line. The dose-volume histogram (DVH) endpoints, volume of duodenum that received 20 Gy (V20), V25, and V30 and maximum dose to 5 cc of contoured organ (D5cc), D1cc, and D0.1cc, were evaluated.Dosimetric parameters for the duodenum, including V25, V30, D1cc, and D0.1cc improved by planning on the CTexp compared to those on the CTinsp. There was a statistically significant overlap of the PTV with the duodenum but not the stomach during the CTinsp compared to the CTexp (0.38 ± 0.17 cc vs 0.01 ± 0.01 cc, P=.048). A larger expansion of the PTV, in accordance with a Danish phase 2 trial, showed even more overlapping volume of duodenum on the CTinsp compared to that on the CTexp (5.5 ± 0.9 cc vs 3.0 ± 0.8 cc, P=.0003) but no statistical difference for any stomach dosimetric DVH parameter.Dose to the duodenum was higher when treating on the inspiratory than on the expiratory phase. These data suggest that expiratory gating may be preferable to inspiratory breath-hold and free breathing strategies for minimizing risk of toxicity.

View details for DOI 10.1016/j.ijrobp.2012.07.2366

View details for PubMedID 23273994
Dosimetric Analysis of Organs at Risk During Expiratory Gating in Stereotactic Body Radiation Therapy for Pancreatic Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Taniguchi, C. M., Murphy, J. D., Eclov, N., Atwood, T. F., Phd, K. N., Christman-Skieller, C., Mok, E., Xing, L., Koong, A. C., Chang, D. T. 2013; 85 (4): 1090-1095
Abstract

To determine how the respiratory phase impacts dose to normal organs during stereotactic body radiation therapy (SBRT) for pancreatic cancer.Eighteen consecutive patients with locally advanced, unresectable pancreatic adenocarcinoma treated with SBRT were included in this study. On the treatment planning 4-dimensional computed tomography (CT) scan, the planning target volume (PTV), defined as the gross tumor volume plus 3-mm margin, the duodenum, and the stomach were contoured on the end-expiration (CTexp) and end-inspiration (CTinsp) phases for each patient. A separate treatment plan was constructed for both phases with the dose prescription of 33 Gy in 5 fractions with 95% coverage of the PTV by the 100% isodose line. The dose-volume histogram (DVH) endpoints, volume of duodenum that received 20 Gy (V20), V25, and V30 and maximum dose to 5 cc of contoured organ (D5cc), D1cc, and D0.1cc, were evaluated.Dosimetric parameters for the duodenum, including V25, V30, D1cc, and D0.1cc improved by planning on the CTexp compared to those on the CTinsp. There was a statistically significant overlap of the PTV with the duodenum but not the stomach during the CTinsp compared to the CTexp (0.38 ± 0.17 cc vs 0.01 ± 0.01 cc, P=.048). A larger expansion of the PTV, in accordance with a Danish phase 2 trial, showed even more overlapping volume of duodenum on the CTinsp compared to that on the CTexp (5.5 ± 0.9 cc vs 3.0 ± 0.8 cc, P=.0003) but no statistical difference for any stomach dosimetric DVH parameter.Dose to the duodenum was higher when treating on the inspiratory than on the expiratory phase. These data suggest that expiratory gating may be preferable to inspiratory breath-hold and free breathing strategies for minimizing risk of toxicity.

View details for DOI 10.1016/j.ijrobp.2012.07.2366

View details for Web of Science ID 000315809300047
Clinicopathologic Features of Synchronous Colorectal Carcinoma: A Distinct Subset Arising from Multiple Sessile Serrated Adenomas and Associated with High-Levels of Microsatellite Instability and Favorable Prognosis Hu, H., Chang, D. T., Nikiforova, M. N., Kuan, S., Pai, R. K. NATURE PUBLISHING GROUP. 2013: 155A
View details for Web of Science ID 000314789300647
Clinicopathologic Features of Synchronous Colorectal Carcinoma: A Distinct Subset Arising from Multiple Sessile Serrated Adenomas and Associated with High-Levels of Microsatellite Instability and Favorable Prognosis Hu, H., Chang, D. T., Nikiforova, M. N., Kuan, S., Pai, R. K. NATURE PUBLISHING GROUP. 2013: 155A
View details for Web of Science ID 000314444401050
Future directions in combined modality therapy for rectal cancer: reevaluating the role of total mesorectal excision after chemoradiotherapy ONCOTARGETS AND THERAPY Solanki, A. A., Chang, D. T., Liauw, S. L. 2013; 6: 1097-1110
Abstract

Most patients who develop rectal cancer present with locoregionally advanced (T3 or node-positive) disease. The standard management of locoregionally advanced rectal cancer is neoadjuvant concurrent chemoradiotherapy (nCRT), followed by radical resection (low-anterior resection or abdominoperineal resection with total mesorectal excision). Approximately 15% of patients can have a pathologic complete response (pCR) at the time of surgery, indicating that some patients can have no detectable residual disease after nCRT. The actual benefit of surgery in this group of patients is unclear. It is possible that omission of surgery in these patients, termed selective nonoperative management, can limit the toxicities associated with standard, multimodal combined modality therapy without compromising disease control. In this review, we discuss the clinical experiences to date using selective nonoperative management and various attempts at escalation of nCRT to improve the number of patients who have a pCR. We also explore several clinical, laboratory, imaging, histopathologic, and genetic biomarkers that have been tested as tools to predict which patients are most likely to have a pCR after nCRT.

View details for DOI 10.2147/OTT.S34869

View details for Web of Science ID 000323029400001

View details for PubMedID 23983475

View details for PubMedCentralID PMC3747849
Metabolic Tumor Volume Predicts Disease Progression and Survival in Patients with Squamous Cell Carcinoma of the Anal Canal JOURNAL OF NUCLEAR MEDICINE Bazan, J. G., Koong, A. C., Kapp, D. S., Quon, A., Graves, E. E., Loo, B. W., Chang, D. T. 2013; 54 (1): 27-32
Abstract

PET imaging has become a useful diagnostic tool in patients with anal cancer. We evaluated the prognostic value of metabolic tumor volume (MTV) in patients with anal cancer treated with definitive chemoradiotherapy.Patients with anal cancer who underwent PET imaging for pretreatment staging or radiation therapy planning from 2003 to 2011 were included. PET parameters included MTV and maximum standardized uptake value (SUVmax). Total MTV (MTV-T) was defined as the sum of the volumes above a standardized uptake value 50% of the SUVmax within the primary tumor and involved nodes. Kaplan-Meier and Cox regression models were used to test for associations between metabolic or clinical endpoints and overall survival (OS), progression-free survival (PFS), and event-free survival (EFS). Results: Thirty-nine patients were included. Median follow-up for the cohort was 22 mo. Overall, 6 patients died and 9 patients had disease progression. The 2-y OS, PFS, and EFS for the entire cohort were 88%, 74%, and 69%, respectively. Higher MTV-T was associated with worse OS (P = 0.04), PFS (P = 0.004), and EFS (P = 0.002) on univariate analysis. Patients with an MTV greater than 26 cm(3) had worse PFS than did those with an MTV of 26 cm(3) or less (33% vs. 82%, P = 0.003). SUVmax was not prognostic for any outcome. Higher T classification (T3/T4 vs. T1/T2) was associated with worse PFS and EFS. When adjusting for T classification, MTV-T remained a significant predictor for PFS (P = 0.01) and EFS (P = 0.02).MTV-T yields prognostic information on PFS and EFS beyond that of established prognostic factors in patients with anal cancer.

View details for DOI 10.2967/jnumed.112.109470

View details for PubMedID 23236018
Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Patients Treated With Intensity-Modulated Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal 53rd Annual Meeting of the American-Society-of-Radiation-Oncology (ASTRO) Bazan, J. G., Luxton, G., Mok, E. C., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 700–706
Abstract

To identify dosimetric parameters that correlate with acute hematologic toxicity (HT) in patients with squamous cell carcinoma of the anal canal treated with definitive chemoradiotherapy (CRT).We analyzed 33 patients receiving CRT. Pelvic bone (PBM) was contoured for each patient and divided into subsites: ilium, lower pelvis (LP), and lumbosacral spine (LSS). The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. Endpoints included grade ≥3 HT (HT3+) and hematologic event (HE), defined as any grade ≥2 HT with a modification in chemotherapy dose. Normal tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT and dosimetric/clinical parameters.Nine patients experienced HT3+ and 15 patients experienced HE. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.175, n = 1, and TD(50) = 32 Gy. With this model, mean PBM doses of 25 Gy, 27.5 Gy, and 31 Gy result in a 10%, 20%, and 40% risk of HT3+, respectively. Compared with patients with mean PBM dose of <30 Gy, patients with mean PBM dose ≥30 Gy had a 14-fold increase in the odds of developing HT3+ (p = 0.005). Several low-dose radiation parameters (i.e., PBM-V10) were associated with the development of HT3+ and HE. No association was found with the ilium, LP, or clinical factors.LKB modeling confirms the expectation that PBM acts like a parallel organ, implying that the mean dose to the organ is a useful predictor for toxicity. Low-dose radiation to the PBM was also associated with clinically significant HT. Keeping the mean PBM dose <22.5 Gy and <25 Gy is associated with a 5% and 10% risk of HT, respectively.

View details for DOI 10.1016/j.ijrobp.2011.12.072

View details for PubMedID 22414279
Reduced Toxicity in Inflammatory Bowel Disease Patients Treated With Intensity Modulated Radiation Therapy (IMRT) White, E., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2012: S355
View details for DOI 10.1016/j.ijrobp.2012.07.937

View details for Web of Science ID 000310542901082
Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Patients Receiving Pelvic IMRT and Concurrent Chemotherapy 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Bazan, J. G., Luxton, G., Kozak, M. M., Anderson, E. M., Hancock, S. L., Kapp, D. S., Kidd, E. A., Hara, W. Y., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2012: S350–S350
View details for Web of Science ID 000310542901069
SBRT as a Novel Treatment Option for Locally Recurrent Pancreatic Cancer After Failure of Definitive Multimodality Therapy: A Multi-institutional Case Series 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Wild, A., Hiniker, S. M., LIMAYE, M. R., Chang, D. T., Laheru, D. A., Tran, P. T., Pawlik, T. M., Wolfgang, C. L., Koong, A. C., Herman, J. M. ELSEVIER SCIENCE INC. 2012: S323–S323
View details for Web of Science ID 000310542900821
Postchemoradiotherapy Positron Emission Tomography Predicts Pathologic Response and Survival in Patients With Esophageal Cancer 53rd Annual Meeting of the American-Society-of-Radiation-Oncology (ASTRO) Jayachandran, P., Pai, R. K., Quon, A., Graves, E., Krakow, T. E., La, T., Loo, B. W., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 471–77
Abstract

To correlate the prechemoradiotherapy (CRT) and post-CRT metabolic tumor volume (MTV) on positron emission tomography (PET) scanning with the pathologic response and survival in patients receiving preoperative CRT for esophageal cancer.The medical records of 37 patients with histologically confirmed Stage I-IVA esophageal cancer treated with CRT with or without surgical resection were reviewed. Of the 37 patients, 21 received preoperative CRT (57%) and 16 received definitive CRT (43%). All patients had a pre-CRT and 32 had a post-CRT PET scan. The MTV was measured on the pre-CRT PET and post-CRT PET scan, respectively, using a minimum standardized uptake value (SUV) threshold x, where x = 2, 2.5, 3, or the SUV maximum × 50%. The total glycolytic activity (TGA(x)) was defined as the mean SUV × MTV(x). The MTV ratio was defined as the pre-CRT PET MTV/post-CRT MTV. The SUV ratio was defined similarly. A single pathologist scored the pathologic response using a tumor regression grade (TRG) scale.The median follow-up was 1.5 years (range, 0.4-4.9). No significant correlation was found between any parameters on the pre-CRT PET scan and the TRG or overall survival (OS). Multiple post-CRT MTV values and post-TGA values correlated with the TRG and OS; however, the MTV(2.5(Post)) and TGA(2.5(Post)) had the greatest correlation. The MTV(2) ratio correlated with OS. The maximum SUV on either the pre-CRT and post-CRT PET scans or the maximum SUV ratio did not correlate with the TRG or OS. Patients treated preoperatively had survival similar compared with those treated definitively with a good PET response (p = 0.97) and significantly better than that of patients treated definitively with a poor PET response (p < 0.0001).The maximum SUV was not a predictive or prognostic parameter. The MTV(2.5) and TGA(2.5) were useful markers for predicting the response and survival on the post-CRT PET scan. The MTV(2) ratio also correlated with survival. Post-CRT PET can potentially guide therapy after CRT.

View details for DOI 10.1016/j.ijrobp.2011.12.029

View details for PubMedID 22381904
Esophageal tolerance to high-dose stereotactic ablative radiotherapy DISEASES OF THE ESOPHAGUS Abelson, J. A., Murphy, J. D., Loo, B. W., Chang, D. T., Daly, M. E., Wiegner, E. A., Hancock, S., Chang, S. D., Le, Q., Soltys, S. G., Gibbs, I. C. 2012; 25 (7): 623-629
Abstract

Dose-volume parameters are needed to guide the safe administration of stereotactic ablative radiotherapy (SABR). We report on esophageal tolerance to high-dose hypofractionated radiation in patients treated with SABR. Thirty-one patients with spine or lung tumors received single- or multiple-fraction SABR to targets less than 1 cm from the esophagus. End points evaluated include D(5cc) (minimum dose in Gy to 5 cm(3) of the esophagus receiving the highest dose), D(2cc) , D(1cc) , and D(max) (maximum dose to 0.01 cm(3) ). Multiple-fraction treatments were correlated using the linear quadratic and linear quadratic-linear/universal survival models. Three esophageal toxicity events occurred, including esophagitis (grade 2), tracheoesophageal fistula (grade 4-5), and esophageal perforation (grade 4-5). Chemotherapy was a cofactor in the high-grade events. The median time to development of esophageal toxicity was 4.1 months (range 0.6-6.1 months). Two of the three events occurred below a published D(5cc) threshold, all three were below a D(2cc) threshold, and one was below a D(max) threshold. We report a dosimetric analysis of incidental dose to the esophagus from SABR. High-dose hypofractionated radiotherapy led to a number of high-grade esophageal adverse events, suggesting that conservative parameters to protect the esophagus are necessary when SABR is used, especially in the setting of chemotherapy or prior radiotherapy.

View details for DOI 10.1111/j.1442-2050.2011.01295.x

View details for PubMedID 22168251
Positron Emission Tomography for Predicting Pathologic Response After Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer 50th Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Chennupati, S. K., Quon, A., Kamaya, A., Pai, R. K., La, T., Krakow, T. E., Graves, E., Koong, A. C., Chang, D. T. LIPPINCOTT WILLIAMS & WILKINS. 2012: 334–39
Abstract

To investigate whether before and after chemoradiotherapy (CRT) positron emission tomography (PET) predict for pathologic response after preoperative CRT in patients with locally advanced rectal adenocarcinoma.Thirty-five patients who underwent pre-CRT and post-CRT PET scans before surgery were included. All patients were staged with endoscopic ultrasound or high resolution CT. CRT was given with 50.4 Gy at 1.8 Gy per fraction and concurrent 5-fluorouracil-based chemotherapy. Surgery occurred at a median of 46 days (range, 27 to 112 d) after completing CRT. The maximum standardized uptake value (SUV(max)) and the metabolic tumor volume (MTV) using various minimum SUV thresholds (2, 2.5, 3) on the PET scans (MTV(2.0), MTV(2.5), MTV(3.0)) were determined. Post-CRT PET scans were done 3 to 5 weeks after completion of CRT. Pathologic response was assessed using the tumor regression grade (TRG) scale. Patients with complete or near-complete response (TRG=0 to 1) were considered pathologic responders. The pre-CRT and post-CRT PET scan SUV(max) and MTV values were correlated with TRG. The ΔSUV(max) and ΔMTV were correlated with TRG.No correlation was seen with SUV(max) (P=0.99), MTV(2.0) (P=0.73), MTV(2.5) (P=0.73), or MTV(3.0) (P=0.31) on the pre-CRT PET between pathologic responders versus nonresponders. No correlation was noted between SUV(max) (P=0.49), MTV(2.0) (P=0.73), MTV(2.5) (P=0.49), or MTV(3.0) (P=0.31) on the post-CRT PET scan and pathologic response. Finally, the ΔSUV(max) (P=0.32), ΔMTV(2.0) (P=0.99), ΔMTV(2.5) (P=0.31), ΔMTV(3.0) (P=0.31) did not correlate with pathologic response.Changes seen on PET have limited value in predicting for pathologic response of rectal cancer after preoperative neoadjuvant therapy.

View details for DOI 10.1097/COC.0b013e3182118d12

View details for PubMedID 21422989
Intrafraction Verification of Gated RapidArc by Using Beam-Level Kilovoltage X-Ray Images INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Li, R., Mok, E., Chang, D. T., Daly, M., Loo, B. W., Diehn, M., Quynh-Thu Le, Q. T., Koong, A., Xing, L. 2012; 83 (5): E709-E715
Abstract

To verify the geometric accuracy of gated RapidArc treatment using kV images acquired during dose delivery.Twenty patients were treated using the gated RapidArc technique with a Varian TrueBeam STx linear accelerator. One to 7 metallic fiducial markers were implanted inside or near the tumor target before treatment simulation. For patient setup and treatment verification purposes, the internal target volume (ITV) was created, corresponding to each implanted marker. The gating signal was generated from the Real-time Position Management (RPM) system. At the beginning of each fraction, individualized respiratory gating amplitude thresholds were set based on fluoroscopic image guidance. During the treatment, we acquired kV images immediately before MV beam-on at every breathing cycle, using the on-board imaging system. After the treatment, all implanted markers were detected, and their 3-dimensional (3D) positions in the patient were estimated using software developed in-house. The distance from the marker to the corresponding ITV was calculated for each patient by averaging over all markers and all fractions.The average 3D distance between the markers and their ITVs was 0.8 ± 0.5 mm (range, 0-1.7 mm) and was 2.1 ± 1.2 mm at the 95th percentile (range, 0-3.8 mm). On average, a left-right margin of 0.6 mm, an anterior-posterior margin of 0.8 mm, and a superior-inferior margin of 1.5 mm is required to account for 95% of the intrafraction uncertainty in RPM-based RapidArc gating.To our knowledge, this is the first clinical report of intrafraction verification of respiration-gated RapidArc treatment in stereotactic ablative radiation therapy. For some patients, the markers deviated significantly from the ITV by more than 2 mm at the beginning of the MV beam-on. This emphasizes the need for gating techniques with beam-on/-off controlled directly by the actual position of the tumor target instead of external surrogates such as RPM.

View details for DOI 10.1016/j.ijrobp.2012.03.006

View details for PubMedID 22554582
Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head-and-Neck Cancer Outcomes INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chu, K. P., Murphy, J. D., La, T. H., Krakow, T. E., Iagaru, A., Graves, E. E., Hsu, A., Maxim, P. G., Loo, B., Chang, D. T., Quynh-Thu Le, Q. T. 2012; 83 (5): 1521-1527
Abstract

We previously showed that metabolic tumor volume (MTV) on positron emission tomography-computed tomography (PET-CT) predicts for disease recurrence and death in head-and-neck cancer (HNC). We hypothesized that increases in MTV over time would correlate with tumor growth and biology, and would predict outcome. We sought to examine tumor growth over time in serial pretreatment PET-CT scans.From 2006 to 2009, 51 patients had two PET-CT scans before receiving HNC treatment. MTV was defined as the tumor volume ≥ 50% of maximum SUV (SUV(max)). MTV was calculated for the primary tumor, nodal disease, and composite (primary tumor + nodes). MTV and SUV velocity were defined as the change in MTV or SUV(max) over time, respectively. Cox regression analyses were used to examine correlations between SUV, MTV velocity, and outcome (disease progression and overall survival).The median follow-up time was 17.5 months. The median time between PET-CT scans was 3 weeks. Unexpectedly, 51% of cases demonstrated a decrease in SUV(max) (average, -0.1 cc/week) and MTV (average, -0.3 cc/week) over time. Despite the variability in MTV, primary tumor MTV velocity predicted disease progression (hazard ratio 2.94; p = 0.01) and overall survival (hazard ratio 1.85; p = 0.03).Primary tumor MTV velocity appears to be a better prognostic indicator of disease progression and survival in comparison to nodal MTV velocity. However, substantial variability was found in PET-CT biomarkers between serial scans. Caution should be used when PET-CT biomarkers are integrated into clinical protocols for HNC.

View details for DOI 10.1016/j.ijrobp.2011.10.022

View details for PubMedID 22270168
Combined Modality Therapy for Rectal Cancer: The Relative Value of Posttreatment Versus Pretreatment CEA as a Prognostic Marker for Disease Recurrence ANNALS OF SURGICAL ONCOLOGY Song, S., Hong, J. C., McDonnell, S. E., Koong, A. C., Minsky, B. D., Chang, D. T., Liauw, S. L. 2012; 19 (8): 2471-2476
Abstract

To evaluate the prognostic significance of the first postsurgery carcinoembryonic antigen (CEA) level in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation (nCRT) and total mesorectal excision.A total of 100 patients underwent nCRT and had baseline and posttreatment CEA levels recorded within 6 months of surgery. The median radiotherapy dose was 50.4 Gy. Eighty-six patients received adjuvant 5-fluorouracil-based chemotherapy. Prognostic factors were analyzed for possible associations with freedom from failure (FFF) by univariate and multivariate analyses. Median follow-up was 30 months.The median CEA (ng/ml) levels at baseline before nCRT, after nCRT, and after total mesorectal excision were 3.6, 1.7, and 1.3, respectively. Pathologic complete response was observed in 22%. FFF at 36 months was 78%. Local failure and distant failure occurred in 4 and 20% of the patients, respectively. On univariate analysis, pathologic complete response, margin status, and both pretreatment and postsurgery CEA levels were associated with recurrence (all P < 0.05). On multivariate analysis, pathologic complete response (P < 0.007), margin status (P < 0.001), and postsurgery CEA level (P = 0.003), but not baseline CEA level (P = 0.2), were found to be associated with recurrence.After nCRT for rectal cancer, postsurgery CEA level may have more prognostic value than pretreatment level. Patients with a postsurgery CEA level of >2.5 ng/ml have higher rates of recurrence and may warrant closer surveillance.

View details for DOI 10.1245/s10434-012-2266-x

View details for Web of Science ID 000306789000009

View details for PubMedID 22327251
Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features MODERN PATHOLOGY Chang, D. T., Pai, R. K., Rybicki, L. A., DiMaio, M. A., Limaye, M., Jayachandran, P., Koong, A. C., Kunz, P. A., Fisher, G. A., Ford, J. M., Welton, M., Shelton, A., Ma, L., Arber, D. A., Pai, R. K. 2012; 25 (8): 1128-1139
Abstract

Recent literature suggests an increasing incidence of colorectal carcinoma in young patients. We performed a histologic, molecular, and immunophenotypic analysis of patients with sporadic early-onset (≤40 years of age) colorectal carcinoma seen at our institution from the years 2000-2010 and compared these tumors to a cohort of consecutively resected colorectal carcinomas seen in patients >40 years of age. A total of 1160 primary colorectal adenocarcinomas were surgically resected for the years 2000 through 2010. Of these, 75 (6%) were diagnoses in patients ≤40 years of age of which 13 (17%) demonstrated abnormalities in DNA mismatch repair, 4 (5%) were in patients with known germline genetic disorders (two patients with familial adenomatous polyposis, one patient with juvenile polyposis, and one patient with Li-Fraumeni syndrome), and three patients (4%) had long-standing chronic inflammatory bowel disease. The sporadic early-onset colorectal carcinoma group comprised a total of 55 patients (55/1160, 5%) and were compared with a control group comprising 73 consecutively resected colorectal carcinomas with proficient DNA mismatch repair in patients >40 years of age. For the early-onset colorectal carcinoma group, most cases (33/55, 60%) were diagnosed between the age of 35 and 40 years of age. Compared with the control group, the early-onset colorectal carcinoma group was significantly different with respect to tumor location (P<0.007) with 80% (44/55 cases) identified in either the sigmoid colon (24/55, 44%) or rectum (20/55, 36%). Morphologically, early-onset colorectal carcinomas more frequently displayed adverse histologic features compared with the control colorectal carcinoma group such as signet ring cell differentiation (7/55, 13% vs 1/73, 1%, P=0.021), perineural invasion (16/55, 29% vs 8/73, 11%, P=0.009) and venous invasion (12/55, 22% vs 4/73, 6%, P=0.006). A precursor adenomatous lesion was less frequently identified in the early-onset colorectal carcinoma group compared with the control group (19/55, 35% vs 39/73, 53%, P=0.034). Of the early-onset colorectal carcinomas, only 2/45 cases (4%) demonstrated KRAS mutations compared with 11/73 (15%) of the control group colorectal adenocarcinomas harboring KRAS mutations, although this difference did not reach statistical significance (P=0.13). BRAF V600E mutations were not identified in the early-onset colorectal carcinoma group. No difference was identified between the two groups with regard to tumor stage, tumor size, number of lymph node metastases, lymphatic invasion, tumor budding, mucinous histology, or tumor-infiltrating lymphocytes. Both groups had similar recurrence-free (P=0.28) and overall survival (P=0.73). However, patients in the early-onset colorectal carcinoma group more frequently either presented with or developed metastatic disease during their disease course compared with the control colorectal carcinoma group (25/55, 45% vs 18/73, 25%, P=0.014). In addition, 8/55 patients (15%) in the early-onset colorectal carcinoma group developed local recurrence of their tumor while no patients in the control colorectal carcinoma group developed local recurrence (P<0.001), likely due to the increased incidence of rectal carcinoma in the patients with early-onset colorectal carcinoma. Our study demonstrates that colorectal carcinoma is not infrequently diagnosed in patients ≤40 years of age and is not frequently the result of underlying Lynch syndrome or associated with other cancer-predisposing genetic conditions or chronic inflammatory conditions. These tumors have a striking predilection for the distal colon, particularly the sigmoid colon and rectum and are much more likely to demonstrate adverse histologic factors, including signet ring cell differentiation, venous invasion, and perineural invasion.

View details for DOI 10.1038/modpathol.2012.61

View details for PubMedID 22481281
Orthovoltage Intraoperative Radiotherapy for Locally Advanced and Recurrent Colorectal Cancer DISEASES OF THE COLON & RECTUM Daly, M. E., Kapp, D. S., Maxim, P. G., Welton, M. L., Tran, P. T., Koong, A. C., Chang, D. T. 2012; 55 (6): 695-702
Abstract

Locally advanced and recurrent colorectal cancers pose a significant therapeutic challenge. Orthovoltage intraoperative radiotherapy provides one potential means of improving disease control at the time of surgery.This study sought to analyze outcomes and identify prognostic factors of patients treated with orthovoltage intraoperative radiotherapy for locally advanced or recurrent colorectal cancer.This study is a retrospective chart review conducted at a tertiary medical center.Between January 1990 and July 2009, 55 patients underwent intraoperative radiotherapy to a total of 61 sites for locally advanced (n = 14) or recurrent (n = 41) cancers of colon (n = 18) or rectum/rectosigmoid junction (n = 37).Median dose was 12 Gy (range, 7.5-20 Gy). Among locally advanced rectal/rectosigmoid cases, surgery included abdominoperineal resection (n = 3) or low anterior resection (n = 9). Seven treated sites had gross residual (R2) disease, 28 had pathologic or clinical microscopic residual disease (R1), and 15 were complete resections (R0). Treated sites included sacrum (n = 22), anterior pelvis/pelvic sidewall (19), sacrum and sidewall (n = 1), aortic bifurcation (n = 2), vaginal cuff (n = 2), psoas (n = 3), perivesicular region (n = 2), and other (n = 10).Outcomes measures included in-field local control, locoregional control, overall survival, and grade ≥3 toxicity.At a median follow-up of 27 months (range, 4-237) among living patients, 2-year Kaplan-Meier estimates of in-field local control, locoregional control, and overall survival were 69%, 51%, and 59%. Margin status predicted for improved locoregional control (p = 0.01) and overall survival (p = 0.01). Seventeen patients (31%) developed a grade 3 to 5 toxicity following surgery with intraoperative radiotherapy.This study was limited by its retrospective nature and relatively small sample size.Local control with intraoperative radiotherapy for locally advanced and recurrent colorectal cancers is good despite the high risk of residual disease. Among carefully selected patients, multimodality regimens including intraoperative radiotherapy may permit long-term survival.

View details for DOI 10.1097/DCR.0b013e31824d464c

View details for Web of Science ID 000304368500011

View details for PubMedID 22595850
Real-Time Telerobotic 3D Ultrasound for Soft-Tissue Guidance Concurrent with Beam Delivery Hristov, D., Schlosser, J., Kirmizibayrak, C., Shamdasani, V., Salisbury, K., Chang, D., Metz, S. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2012: 3934–35
View details for DOI 10.1118/1.4736056

View details for Web of Science ID 000308905805516
A phase II multi-institutional study to evaluate gemcitabine and fractionated stereotactic body radiotherapy for unresectable, locally advanced pancreatic adenocarcinoma 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Herman, J. M., Chang, D. T., Goodman, K. A., Wild, A. T., Laheru, D., Zheng, L., Diaz, L. A., Dung Thi Le, D. T., Raman, S. P., Leal, J. P., Chaudhry, M. A., Sugar, E., Columbo, L. A., Tom, A., Limaye, M. R., Edil, B. H., Oteiza, K., Hacker-Prietz, A., Wolfgang, C. L., Koong, A. AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000318009805038
Intensity-Modulated Radiotherapy for Tumors of the Nasal Cavity and Paranasal Sinuses: Clinical Outcomes and Patterns of Failure 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Wiegner, E. A., Daly, M. E., Murphy, J. D., Abelson, J., Chapman, C. H., Chung, M., Yu, Y., Colevas, A. D., Kaplan, M. J., Fischbein, N., Quynh-Thu Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 243–51
Abstract

To report outcomes in patients treated with intensity-modulated radiotherapy (IMRT) for tumors of the paranasal sinuses and nasal cavity (PNS/NC).Between June 2000 and December 2009, 52 patients with tumors of the PNS/NC underwent postoperative or definitive radiation with IMRT. Twenty-eight (54%) patients had squamous cell carcinoma (SCC). Twenty-nine patients (56%) received chemotherapy. The median follow-up was 26.6 months (range, 2.9-118.4) for all patients and 30.9 months for living patients.Eighteen patients (35%) developed local-regional failure (LRF) at median time of 7.2 months. Thirteen local failures (25%) were observed, 12 in-field and 1 marginal. Six regional failures were observed, two in-field and four out-of-field. No patients treated with elective nodal radiation had nodal regional failure. Two-year local-regional control (LRC), in-field LRC, freedom from distant metastasis (FFDM), and overall survival (OS) were 64%, 74%, 71%, and 66% among all patients, respectively, and 43%, 61%, 61%, and 53% among patients with SCC, respectively. On multivariate analysis, SCC and >1 subsite involved had worse LRC (p = 0.0004 and p = 0.046, respectively) and OS (p = 0.003 and p = 0.046, respectively). Cribriform plate invasion (p = 0.005) and residual disease (p = 0.047) also had worse LRC. Acute toxicities included Grade ≥3 mucositis in 19 patients (37%), and Grade 3 dermatitis in 8 patients (15%). Six patients had Grade ≥3 late toxicity including one optic toxicity.IMRT for patients with PNS/NC tumors has good outcomes compared with historical series and is well tolerated. Patients with SCC have worse LRC and OS. LRF is the predominant pattern of failure.

View details for DOI 10.1016/j.ijrobp.2011.05.044

View details for PubMedID 22019239
BRAF-mutated, Microsatellite-stable Adenocarcinoma of the Proximal Colon: An Aggressive Adenocarcinoma With Poor Survival, Mucinous Differentiation, and Adverse Morphologic Features AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Jayachandran, P., Koong, A. C., Chang, D. T., Kwok, S., Ma, L., Arber, D. A., Balise, R. R., Tubbs, R. R., Shadrach, B., Pai, R. K. 2012; 36 (5): 744-752
Abstract

The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic adenocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n=78), mismatch repair protein immunohistochemistry (n=91), or both MSI PCR and mismatch repair immunohistochemistry (n=12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80% vs. 75/161, 47%; P=0.008), mean number of lymph node metastases (4.5 vs. 2.2; P=0.01), perineural invasion (8/20, 40% vs. 13/161, 8%; P=0.0004), and high tumor budding (16/20, 80% vs. 83/161, 52%; P=0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P=0.0002) and signet ring histology (P=0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54% and a 1-year disease-free survival of 56%. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P=0.03 and unadjusted log-rank P=0.0002, respectively) and disease-free survival (unadjusted log-rank P=0.02 and unadjusted log-rank P=0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95% CI, 2.60-16.94; and 6.08, 95% CI, 2.11-17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.

View details for DOI 10.1097/PAS.0b013e31824430d7

View details for PubMedID 22314188
Intensity-Modulated Radiotherapy for Pancreatic Adenocarcinoma 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Abelson, J. A., Murphy, J. D., Minn, A. Y., Chung, M., Fisher, G. A., Ford, J. M., Kunz, P., Norton, J. A., Visser, B. C., Poultsides, G. A., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2012: E595–E601
Abstract

To report the outcomes and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for pancreatic adenocarcinoma.Forty-seven patients with pancreatic adenocarcinoma were treated with IMRT between 2003 and 2008. Of these 47 patients, 29 were treated adjuvantly and 18 definitively. All received concurrent 5-fluorouracil chemotherapy. The treatment plans were optimized such that 95% of the planning target volume received the prescription dose. The median delivered dose for the adjuvant and definitive patients was 50.4 and 54.0 Gy, respectively.The median age at diagnosis was 63.9 years. For adjuvant patients, the 1- and 2-year overall survival rate was 79% and 40%, respectively. The 1- and 2-year recurrence-free survival rate was 58% and 17%, respectively. The local-regional control rate at 1 and 2 years was 92% and 80%, respectively. For definitive patients, the 1-year overall survival, recurrence-free survival, and local-regional control rate was 24%, 16%, and 64%, respectively. Four patients developed Grade 3 or greater acute toxicity (9%) and four developed Grade 3 late toxicity (9%).Survival for patients with pancreatic cancer remains poor. A small percentage of adjuvant patients have durable disease control, and with improved therapies, this proportion will increase. Systemic therapy offers the greatest opportunity. The present results have demonstrated that IMRT is well tolerated. Compared with those who received three-dimensional conformal radiotherapy in previously reported prospective clinical trials, patients with pancreatic adenocarcinoma treated with IMRT in our series had improved acute toxicity.

View details for DOI 10.1016/j.ijrobp.2011.09.035

View details for PubMedID 22197234
Modern Radiation Therapy Techniques for Pancreatic Cancer GASTROENTEROLOGY CLINICS OF NORTH AMERICA Trakul, N., Koong, A. C., Maxim, P. G., Chang, D. T. 2012; 41 (1): 223-?
Abstract

Radiation therapy is a rapidly evolving field, and recent technical advances have spurred an increasing number of new treatments as well as marked improvements in previously existing treatments. Despite a growing body of published evidence demonstrating that radiotherapy for the treatment of pancreatic cancer is improving in efficacy and safety, the ultimate effect on patient outcomes remains to be seen. It is an unfortunate fact that the majority of pancreatic cancer patients will ultimately have metastases and succumb to distant disease. Thus, improvements in local tumor control engendered by these recent advances will have little impact on overall survival without the coincident development of better systemic treatment regimens.

View details for DOI 10.1016/j.gtc.2011.12.011

View details for PubMedID 22341260
Cost-effectiveness of modern radiotherapy techniques in locally advanced pancreatic cancer CANCER Murphy, J. D., Chang, D. T., Abelson, J., Daly, M. E., Yeung, H. N., Nelson, L. M., Koong, A. C. 2012; 118 (4): 1119-1129
Abstract

Radiotherapy may improve the outcome of patients with pancreatic cancer but at an increased cost. In this study, the authors evaluated the cost-effectiveness of modern radiotherapy techniques in the treatment of locally advanced pancreatic cancer.A Markov decision-analytic model was constructed to compare the cost-effectiveness of 4 treatment regimens: gemcitabine alone, gemcitabine plus conventional radiotherapy, gemcitabine plus intensity-modulated radiotherapy (IMRT); and gemcitabine with stereotactic body radiotherapy (SBRT). Patients transitioned between the following 5 health states: stable disease, local progression, distant failure, local and distant failure, and death. Health utility tolls were assessed for radiotherapy and chemotherapy treatments and for radiation toxicity.SBRT increased life expectancy by 0.20 quality-adjusted life years (QALY) at an increased cost of $13,700 compared with gemcitabine alone (incremental cost-effectiveness ratio [ICER] = $69,500 per QALY). SBRT was more effective and less costly than conventional radiotherapy and IMRT. An analysis that excluded SBRT demonstrated that conventional radiotherapy had an ICER of $126,800 per QALY compared with gemcitabine alone, and IMRT had an ICER of $1,584,100 per QALY compared with conventional radiotherapy. A probabilistic sensitivity analysis demonstrated that the probability of cost-effectiveness at a willingness to pay of $50,000 per QALY was 78% for gemcitabine alone, 21% for SBRT, 1.4% for conventional radiotherapy, and 0.01% for IMRT. At a willingness to pay of $200,000 per QALY, the probability of cost-effectiveness was 73% for SBRT, 20% for conventional radiotherapy, 7% for gemcitabine alone, and 0.7% for IMRT.The current results indicated that IMRT in locally advanced pancreatic cancer exceeds what society considers cost-effective. In contrast, combining gemcitabine with SBRT increased clinical effectiveness beyond that of gemcitabine alone at a cost potentially acceptable by today's standards.

View details for DOI 10.1002/cncr.26365

View details for PubMedID 21773972
HER2 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma in a US Population: Clinicopathologic Analysis With Proposed Approach to HER2 Assessment APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Kunz, P. L., Mojtahed, A., Fisher, G. A., Ford, J. M., Chang, D. T., Balise, R. R., Bangs, C. D., Cherry, A. M., Pai, R. K. 2012; 20 (1): 13-24
Abstract

Recent evidence suggests that trastuzumab, a monoclonal antibody which targets HER2, in combination with chemotherapy is a therapeutic option in patients with HER2-positive gastric or gastroesophageal junction cancer. Widely accepted guidelines for HER2 testing in gastric and gastroesophageal junction cancer have not been established. The purpose of this study was to analyze the incidence and patterns of HER2 expression in gastric and gastroesophageal junction cancer using a tissue microarray approach, which closely simulates small biopsies routinely tested for HER2. One hundred sixty-nine patients, including 99 primary gastric adenocarcinomas and 70 primary gastroesophageal junction carcinomas were analyzed for HER2 overexpression by immunohistochemistry and HER2 gene amplification by fluorescence in situ hybridization using scoring schemes proposed by both American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) and the results of the recently published Trastuzumab for Gastric Cancer (ToGA) trial. In our analysis, 19 adenocarcinomas were HER2 positive, defined as either a HER2/CEP17 ratio >2.2 and/or a 3+ HER2 immunohistochemistry score with either the ASCO/CAP or ToGA scoring schemes. Of the 19 HER2-positive adenocarcinomas, 8 (42%) exhibited a characteristic strongly intense basolateral membranous staining pattern which would be interpreted as negative (1+) using the accepted ASCO/CAP scoring scheme for HER2 assessment in breast carcinoma, but were correctly labeled as 3+ positive using the proposed ToGA scoring scheme. Of the 19 HER2-positive adenocarcinomas, 8 (42%) demonstrated heterogeneous HER2 protein expression by immunohistochemistry. Twelve of 99 (12%) gastric carcinomas were positive for HER2. Of these, HER2 was more often identified in intestinal-type adenocarcinomas (10 of 52, 19%) compared with diffuse (2 of 34, 6%) adenocarcinoma. Seven of 70 (10%) gastroesophageal junction carcinomas were positive for HER2 of which all were intestinal type (7 of 58, 12%). HER2 status or primary tumor site did not correlate with patient survival. Gastric and gastroesophageal junction adenocarcinomas typically display a characteristic basolateral membranous pattern of HER2 expression which is often heterogeneous rendering routine evaluation of HER2 status on small tissue samples challenging.

View details for DOI 10.1097/PAI.0b013e31821c821c

View details for PubMedID 21617522
Penile metastases originating from a pancreatic primary tumor: a case report J Radiat Oncol Tello, T. L., Zeidan, Y. H., Bush, K., Schwartz, E., Kunz, P., Chang, D. T. 2012; 2 (1): 107-112
Evaluation of a metal artifact reduction technique in tonsillar cancer delineation PRACTICAL RADIATION ONCOLOGY Abelson, J. A., Murphy, J. D., Wiegner, E. A., Abelson, D., Sandman, D. N., Boas, F., Hristov, D., Fleischmann, D., Daly, M. E., Chang, D. T., Loo, B. W., Hara, W., Le, Q. 2012; 2 (1): 27–34
View details for DOI 10.1016/j.prro.2011.06.004

View details for Web of Science ID 000422312600005
Evaluation of a metal artifact reduction technique in tonsillar cancer delineation. Practical radiation oncology Abelson, J. A., Murphy, J. D., Wiegner, E. A., Abelson, D., Sandman, D. N., Boas, F. E., Hristov, D., Fleischmann, D., Daly, M. E., Chang, D. T., Loo, B. W., Hara, W., Le, Q. 2012; 2 (1): 27-34
Abstract

Metal artifacts can degrade computed tomographic (CT) simulation imaging and impair accurate delineation of tumors for radiation treatment planning purposes. We investigated a Digital Imaging and Communications in Medicine-based metal artifact reduction technique in tonsillar cancer delineation.Eight patients with significant artifact and tonsil cancer were evaluated. Each patient had a positron emission tomography (PET)-CT and a contrast-enhanced CT obtained at the same setting during radiotherapy simulation. The CTs were corrected for artifact using the metal deletion technique (MDT). Two radiation oncologists independently delineated primary gross tumor volumes (GTVs) for each patient on native (CTnonMDT), metal corrected (CTMDT), and reference standard (CTPET/nonMDT) imaging, 1 week apart. Mixed effects models were used to determine if differences among GTVs were statistically significant. Two diagnostic radiologists and 2 radiation oncologists independently qualitatively evaluated CTs for each patient. Ratings were on an ordinal scale from -3 to +3, denoting that CTMDT was markedly, moderately, or slightly worse or better than CTnonMDT. Scores were compared with a Wilcoxon signed-rank test.The GTVPET/nonMDT were significantly smaller than GTVnonMDT (P = .004) and trended to be smaller than GTVMDT (P = .084). The GTVnonMDT and GTVMDT were not significantly different (P = .93). There was no significant difference in the extent to which GTVnonMDT or GTVMDT encompassed GTVPET/nonMDT (P = .33). In the subjective assessment of image quality, CTMDT did not significantly outperform CTnonMDT. In the majority of cases, the observer rated the CTMDT equivalent to (53%) or slightly superior (41%) to the corresponding CTnonMDT.The MTD modified images did not produce GTVMDT that more closely reproduced GTVPET/nonMDT than did GTVnonMDT. Moreover, the MTD modified images were not judged to be significantly superior when compared to the uncorrected images in terms of subjective ability to visualize the tonsilar tumors. This study failed to demonstrate value of the adjunctive use of a CT corrected for artifacts in the tumor delineation process. Artifacts do make tumor delineation challenging, and further investigation of other body sites is warranted.

View details for DOI 10.1016/j.prro.2011.06.004

View details for PubMedID 24674033
Combined-modality Therapy for Rectal Cancer: Analysis of Potential Differences in Disease Presentation, Treatment Adherence, and Treatment Outcome According to Race. American journal of clinical oncology Tonlaar, N., Song, S., Hong, J. C., Minsky, B. D., Chang, D. T., Polite, B. N., Liauw, S. L. 2012
Abstract

OBJECTIVES:: Population-based studies suggest African Americans (AAs) with rectal cancer have a worse overall outcome compared with non-AAs. This relationship was explored in a cohort of rectal cancer patients treated with preoperative chemoradiation therapy (CRT) and surgery at 2 academic cancer centers. METHODS:: A total of 146 patients (26 AA, 120 non-AA) underwent treatment with curative intent. The median age was 57 years. Median dose was 50.4 Gy, given with 5-fluorouracil-based concurrent chemotherapy. Differences in disease presentation, adherence to recommended therapy, and treatment outcome (freedom from failure) by race were analyzed. Median follow-up was 34 months from completion of CRT. RESULTS:: AAs had longer time from diagnosis to start of therapy (median, 45 vs. 35 d; P<0.01) and from CRT completion to surgery (median, 42 vs. 46 d; P=0.03). AA patients presented with more favorable disease (20% stage I, 33% stage III) compared with non-AA patients (0% stage I, 48% stage III, P<0.01). AA patients were less likely to receive adjuvant chemotherapy (58% vs. 89%, P=0.01). Log-rank analysis showed AAs were not more likely to recur after therapy (freedom from failure at 3 y, 100% for AA patients vs. 81% for non-AA patients, P=0.09). The difference in time from preoperative therapy to surgery and a lower rate of adjuvant therapy in AA patients did not seem to result in inferior disease outcome for this cohort. CONCLUSIONS:: Further study is necessary to explore the reasons underlying the delays in therapy and lower rates of adjuvant chemotherapy for AA patients.

View details for PubMedID 23211225
A rare case of an aldosterone secreting metastatic adrenocortical carcinoma and papillary thyroid carcinoma in a 31-year-old male. Rare tumors Wanta, S. M., Basina, M., Chang, S. D., Chang, D. T., Ford, J. M., Greco, R., Kingham, K., Merritt, R. E., Kunz, P. L. 2011; 3 (4)
Abstract

We report a rare synchronous presentation of adrenocortical carcinoma (ACC) and papillary thyroid carcinoma (PTC). A 31-year-old male first presented with a large left adrenal mass that was identified during the workup for refractory hypertension due to hyperaldosteronism. The mass was removed surgically with pathology showing ACC. The patient was then treated with adjuvant radiation therapy and mitotane chemotherapy. Four months post ACC resection, metastatic ACC to the right upper lung and PTC in the left lobe of the thyroid were found in surveillance imaging. He subsequently developed pulmonary, contralateral adrenal and brain metastases from his ACC. Li Fraumeni syndrome and Multiple Endocrine Neoplasia Type I (MEN I) were considered, but testing of both P53 and menin genes showed no mutation. We also performed a review of the literature and found three similar cases, however gene mutation analysis was not performed..

View details for DOI 10.4081/rt.2011.e45

View details for PubMedID 22355500

View details for PubMedCentralID PMC3282450
SINGLE-FRACTION STEREOTACTIC BODY RADIATION THERAPY AND SEQUENTIAL GEMCITABINE FOR THE TREATMENT OF LOCALLY ADVANCED PANCREATIC CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Schellenberg, D., Kim, J., Ciristman-Skieller, C., Chun, C. L., Columbo, L. A., Ford, J. M., Fisher, G. A., Kunz, P. L., Van Dam, J., Quon, A., Desser, T. S., Norton, J., Hsu, A., Maxim, P. G., Xing, L., Goodman, K. A., Chang, D. T., Koong, A. C. 2011; 81 (1): 181-188
Abstract

This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator-based single-fraction stereotactic body radiotherapy (SBRT).Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity-modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT.All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year.Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT.

View details for DOI 10.1016/j.ijrobp.2010.05.006

View details for Web of Science ID 000294093300025

View details for PubMedID 21549517
Stereotactic Body Radiotherapy for Colorectal Liver Metastases A Pooled Analysis CANCER Chang, D. T., Swaminath, A., Kozak, M., Weintraub, J., Koong, A. C., Kim, J., Dinniwell, R., Brierley, J., Kavanagh, B. D., Dawson, L. A., Schefter, T. E. 2011; 117 (17): 4060-4069
Abstract

This study was undertaken to determine outcomes of stereotactic body radiotherapy for colorectal liver metastases in a pooled patient cohort.Patients with colorectal liver metastases from 3 institutions were included if they had 1 to 4 lesions, received 1 to 6 fractions of stereotactic body radiotherapy, and had radiologic imaging ≥ 3 months post-treatment. Sixty-five patients with 102 lesions treated from August 2003 to May 2009 were retrospectively analyzed. A tumor control probability (TCP) model was used to estimate the 3-fraction dose required for > 90% local control after converting the schedule into biologically equivalent dose (BED), single-fraction equivalent dose, or linear quadratic model-based single-fraction dose.Forty-seven (72%) patients had ≥ 1 chemotherapy regimen before stereotactic body radiotherapy, and 27 (42%) patients had ≥ 2 regimens. The median follow-up was 1.2 years (range, 0.3-5.2 years). The median dose was 42 gray (Gy; range, 22-60 Gy). When evaluated separately by multivariate analysis, total dose (P = .0015), dose/fraction (P = .003), and BED (P = .004) all correlated with local control by lesion. On multivariate analysis, nonactive extrahepatic disease was associated with overall survival (OS; P = .046), and sustained local control was closely correlated (P = .06). By using single-fraction equivalent dose, BED, or linear quadratic model-based single-fraction dose in the TCP model, the estimated dose range needed for 1-year local control > 90% is 46 to 52 Gy in 3 fractions.Liver stereotactic body radiotherapy is well tolerated and effective for colorectal liver metastases. The strong correlation between local control and OS supports controlling hepatic disease even for heavily pretreated patients. For a 3-fraction regimen of stereotactic body radiotherapy, a prescription dose of ≥ 48 Gy should be considered, if normal tissue constraints allow.

View details for DOI 10.1002/cncr.25997

View details for PubMedID 21432842
Intensity-Modulated Radiation Therapy Versus Conventional Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal CANCER Bazan, J. G., Hara, W., Hsu, A., Kunz, P. A., Ford, J., Fisher, G. A., Welton, M. L., Shelton, A., Kapp, D. S., Koong, A. C., Goodman, K. A., Chang, D. T. 2011; 117 (15): 3342-3351
Abstract

The purpose of this study was to compare outcomes in patients with anal canal squamous cell carcinoma (SCCA) who were treated with definitive chemoradiotherapy by either intensity-modulated radiation therapy (IMRT) or conventional radiotherapy (CRT).Forty-six patients who received definitive chemoradiotherapy from January 1993 to August 2009 were included. Forty-five patients received 5-fluorouracil with mitomycin C (n = 39) or cisplatin (n = 6). Seventeen (37%) were treated with CRT and 29 (63%) with IMRT. The median dose was 54 Gy in both groups. Median follow-up was 26 months (CRT) and 32 months (IMRT). T3-T4 stage (P = .18) and lymph node-positive disease (P = .6) were similar between groups.The CRT group required longer treatment duration (57 days vs 40 days, P < .0001), more treatment breaks (88% vs 34.5%, P = .001), and longer breaks (12 days vs 1.5 days, P < .0001) than patients treated with IMRT. Eleven (65%) patients in the CRT group experienced grade >2 nonhematologic toxicity compared with 6 (21%) patients in the IMRT group (P = .003). The 3-year overall survival (OS), locoregional control (LRC), and progression-free survival were 87.8%, 91.9%, and 84.2%, respectively, for the IMRT groups and 51.8%, 56.7%, and 56.7%, respectively, for the CRT group (all P < .01). On multivariate analysis, T stage, use of IMRT, and treatment duration were associated with OS, and T stage and use of IMRT were associated with LRC.The use of IMRT was associated with less toxicity, reduced need for treatment breaks, and excellent LRC and OS compared with CRT in patients with SCCA of the anal canal.

View details for DOI 10.1002/cncr.25901

View details for PubMedID 21287530
INTENSITY-MODULATED RADIOTHERAPY FOR ORAL CAVITY SQUAMOUS CELL CARCINOMA: PATTERNS OF FAILURE AND PREDICTORS OF LOCAL CONTROL INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Daly, M. E., Quynh-Thu Le, Q. T., Kozak, M. M., Maxim, P. G., Murphy, J. D., Hsu, A., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Chang, D. T. 2011; 80 (5): 1412-1422
Abstract

Few studies have evaluated the use of intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma (SCC) of the oral cavity (OC). We report clinical outcomes and failure patterns for these patients.Between October 2002 and June 2009, 37 patients with newly diagnosed SCC of the OC underwent postoperative (30) or definitive (7) IMRT. Twenty-five patients (66%) received systemic therapy. The median follow-up was 38 months (range, 10-87 months). The median interval from surgery to RT was 5.9 weeks (range, 2.1-10.7 weeks).Thirteen patients experienced local-regional failure at a median of 8.1 months (range, 2.4-31.9 months), and 2 additional patients experienced local recurrence between surgery and RT. Seven local failures occurred in-field (one with simultaneous nodal and distant disease) and two at the margin. Four regional failures occurred, two in-field and two out-of-field, one with synchronous metastases. Six patients experienced distant failure. The 3-year actuarial estimates of local control, local-regional control, freedom from distant metastasis, and overall survival were 67%, 53%, 81%, and 60% among postoperative patients, respectively, and 60%, 60%, 71%, and 57% among definitive patients. Four patients developed Grade ≥ 2 chronic toxicity. Increased surgery to RT interval predicted for decreased LRC (p = 0.04).Local-regional control for SCC of the OC treated with IMRT with or without surgery remains unsatisfactory. Definitive and postoperative IMRT have favorable toxicity profiles. A surgery-to-RT interval of < 6 weeks improves local-regional control. The predominant failure pattern was local, suggesting that both improvements in target delineation and radiosensitization and/or dose escalation are needed.

View details for DOI 10.1016/j.ijrobp.2010.04.031

View details for PubMedID 20675073
How radiation damages teeth: Getting to the root of the problem PRACTICAL RADIATION ONCOLOGY Chang, D. T., Sandow, P. L. 2011; 1 (3): 149–51
View details for PubMedID 24673943
Rectal and bladder deformation and displacement during preoperative radiotherapy for rectal cancer: Are current margin guidelines adequate for conformal therapy? Practical radiation oncology Daly, M. E., Murphy, J. D., Mok, E., Christman-Skieller, C., Koong, A. C., Chang, D. T. 2011; 1 (2): 85-94
Abstract

To evaluate rectal motion and estimate an appropriate target volume for preoperative radiotherapy (RT) for rectal cancer.Between January 2006 and December 2009, 17 rectal cancer patients undergoing preoperative RT underwent 39 cone-beam computed tomographic scans (CBCTs). CBCTs were fused to treatment planning CT scans by bony anatomy. The rectum and bladder were contoured on each scan. Margins of 2, 5, 10, and 15 mm were added to the rectum, and the volume and percent rectum on CBCT outside each of these margins were determined. The clinical target volume (CTV) was examined to determine the necessary margin beyond the posterior bladder edge to ensure coverage of the mesorectum at all time points.Median percentage rectum on CBCT outside the planning rectum was 7.77% (range, 0.19%-42.91%). Two patients had 1 or more CBCT with 1% or greater rectum outside a 1.5 cm margin. Five patients had 1 or more CBCT with 1% or greater rectum outside a 1.0 cm margin. A CTV extending 1 cm into the posterior bladder edge (CTV1.0) was adequate at all time points for 79% of evaluable patients, and a CTV with a 1.5 cm anterior margin was adequate for 93% of patients. For 2 patients, the rectum extended outside the CTV1.0 on CBCT.With a limited number of CBCT scans, we found that the rectum tended to remain within 1.5 cm of the initial location on treatment planning CT. However, an anterior margin of 1.5 cm beyond the posterior bladder edge provides better coverage of the mesorectum than 1 cm for the initial CTV.

View details for DOI 10.1016/j.prro.2010.11.006

View details for PubMedID 24673921
PROSPECTIVE RANDOMIZED DOUBLE-BLIND PILOT STUDY OF SITE-SPECIFIC CONSENSUS ATLAS IMPLEMENTATION FOR RECTAL CANCER TARGET VOLUME DELINEATION IN THE COOPERATIVE GROUP SETTING INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Fuller, C. D., Nijkamp, J., Duppen, J. C., Rasch, C. R., Thomas, C. R., Wang, S. J., Okunieff, P., Jones, W. E., Baseman, D., Patel, S., Demandante, C. G., Harris, A. M., Smith, B. D., Katz, A. W., McGann, C., Harper, J. L., Chang, D. T., Smalley, S., Marshall, D. T., Goodman, K. A., Papanikolaou, N., Kachnic, L. A. 2011; 79 (2): 481-489
Abstract

Variations in target volume delineation represent a significant hurdle in clinical trials involving conformal radiotherapy. We sought to determine the effect of a consensus guideline-based visual atlas on contouring the target volumes.A representative case was contoured (Scan 1) by 14 physician observers and a reference expert with and without target volume delineation instructions derived from a proposed rectal cancer clinical trial involving conformal radiotherapy. The gross tumor volume (GTV), and two clinical target volumes (CTVA, including the internal iliac, presacral, and perirectal nodes, and CTVB, which included the external iliac nodes) were contoured. The observers were randomly assigned to receipt (Group A) or nonreceipt (Group B) of a consensus guideline and atlas for anorectal cancers and then instructed to recontour the same case/images (Scan 2). Observer variation was analyzed volumetrically using the conformation number (CN, where CN = 1 equals total agreement).Of 14 evaluable contour sets (1 expert and 7 Group A and 6 Group B observers), greater agreement was found for the GTV (mean CN, 0.75) than for the CTVs (mean CN, 0.46-0.65). Atlas exposure for Group A led to significantly increased interobserver agreement for CTVA (mean initial CN, 0.68, after atlas use, 0.76; p = .03) and increased agreement with the expert reference (initial mean CN, 0.58; after atlas use, 0.69; p = .02). For the GTV and CTVB, neither the interobserver nor the expert agreement was altered after atlas exposure.Consensus guideline atlas implementation resulted in a detectable difference in interobserver agreement and a greater approximation of expert volumes for the CTVA but not for the GTV or CTVB in the specified case. Visual atlas inclusion should be considered as a feature in future clinical trials incorporating conformal RT.

View details for DOI 10.1016/j.ijrobp.2009.11.012

View details for Web of Science ID 000286451000023

View details for PubMedID 20400244

View details for PubMedCentralID PMC2929319
Pattern of Lymph Node Involvement and Prognosis in Pancreatic Adenocarcinoma: Direct Lymph Node Invasion Has Similar Survival to Node-Negative Disease AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Beck, A. H., Mitchem, J., Linehan, D. C., Chang, D. T., Norton, J. A., Pai, R. K. 2011; 35 (2): 228-234
Abstract

Lymph node status is one of the most important predictors of survival in pancreatic ductal adenocarcinoma. Surgically resected pancreatic adenocarcinoma is often locally invasive and may invade directly into peripancreatic lymph nodes. The significance of direct invasion into lymph nodes in the absence of true lymphatic metastases is unclear. The purpose of this study was to retrospectively compare clinical outcome in patients with pancreatic ductal adenocarcinoma with direct invasion into peripancreatic lymph nodes with patients with node-negative adenocarcinomas and patients with true lymphatic lymph node metastasis. A total of 380 patients with invasive pancreatic ductal adenocarcinoma classified as pT3, were evaluated: ductal adenocarcinoma with true lymphatic metastasis to regional lymph nodes (248 cases), ductal adenocarcinoma without lymph node involvement (97 cases), and ductal adenocarcinoma with regional lymph nodes involved only by direct invasion from the main tumor mass (35 cases). Isolated lymph node involvement by direct invasion occurred in 35 of 380 (9%) patients. Overall survival for patients with direct invasion of lymph nodes (median survival, 21 mo; 5-year overall survival, 36%) was not statistically different from patients with node-negative adenocarcinomas (median survival, 30 mo; 5-year overall survival, 31%) (P=0.609). Patients with node-negative adenocarcinomas had an improved survival compared with patients with lymph node involvement by true lymphatic metastasis (median survival, 15 mo; 5-year overall survival, 8%) (P<0.001) regardless of the number of lymph nodes involved by adenocarcinoma. There was a trend toward decreased overall survival for patients with 1 or 2 lymph nodes involved by true lymphatic metastasis compared with patients with direct invasion of tumor into lymph nodes (P=0.056). However, this did not reach statistical significance. Our results indicate that patients with isolated direct lymph node invasion have a comparable overall survival with patients with node-negative adenocarcinomas as opposed to true lymphatic lymph node metastasis.

View details for DOI 10.1097/PAS.0b013e318206c37a

View details for Web of Science ID 000286581700007

View details for PubMedID 21263243
INTENSITY-MODULATED RADIOTHERAPY FOR LOCALLY ADVANCED CANCERS OF THE LARYNX AND HYPOPHARYNX HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Daly, M. E., Le, Q., Jain, A. K., Maxim, P. G., Hsu, A., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Colevas, A. D., Pinto, H., Chang, D. T. 2011; 33 (1): 103-111
Abstract

Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.Between September 2001 and December 2007, 42 patients with squamous cell carcinoma (SCC) of the hypopharynx (n = 23) and larynx (n = 19) underwent IMRT, 11 postoperatively and 31 definitively. Thirty-six received systemic therapy. Median follow-up was 30 months among surviving patients.Three local failures occurred within the high-dose region and 3 occurred in regional nodes. Seven patients developed distant metastasis as the initial failure. Three-year actuarial estimates of locoregional control, freedom from distant metastasis, and overall survival rates were, respectively, 80%, 72%, and 46%.IMRT provides good locoregional control for SCC of the hypopharynx and larynx compared with historical controls. Locoregional relapses occurred in the high-dose volumes, suggesting adequate target volume delineation. Hypopharyngeal tumors, which fare worse than laryngeal tumors, warrant investigation of more aggressive treatment.

View details for DOI 10.1002/hed.21406

View details for PubMedID 20848427
Postchemoradiotherapy Positron Emission Tomography for Predicting Survival in Patients with Esophageal Cancer Jayachandran, P., Krakow, T., La, T., Loo, B. W., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S310
View details for DOI 10.1016/j.ijrobp.2011.06.500

View details for Web of Science ID 000296411700633
Intrafraction Verification using Beam Level kV Images for Gated RapidArc Li, R., Mok, E., Chang, D., Koong, A., Daly, M. E., Xing, L. ELSEVIER SCIENCE INC. 2011: S152–S153
View details for DOI 10.1016/j.ijrobp.2011.06.313

View details for Web of Science ID 000296411700307
Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Patients with Squamous Cell Carcinoma of the Anal Canal Treated with Definitive Chemoradiotherapy Bazan, J. G., Luxton, G., Mok, E. C., Kunz, P. A., Fisher, G. A., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S126
View details for DOI 10.1016/j.ijrobp.2011.06.260

View details for Web of Science ID 000296411700254
Effect of Chemoradiotherapy before and after Surgery for Esophageal Cancer: A SEER-Medicare Analysis Hong, J. C., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S314
View details for DOI 10.1016/j.ijrobp.2011.06.509

View details for Web of Science ID 000296411700642
Gastrointestinal Normal Tissue Toxicity Prediction In Stereotactic Body Radiotherapy Murphy, J. D., Abelson, J., Chung, M. P., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2011: S378–S378
View details for Web of Science ID 000296411700781
Multimodality Therapy for Esophageal Cancer: The Benefit of Chemoradiation Vossler, S. R., Bavan, B., Kunz, P., Ford, J. M., Fisher, G. A., Whyte, R., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S309–S309
View details for Web of Science ID 000296411700630
Radiotherapy For Adenoid Cystic Carcinomas Of The Head and Neck: Clinical Outcomes And Patterns Of Failure Shultz, D. B., Murphy, J. D., Daly, M. E., Hara, W., Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S528–S528
View details for Web of Science ID 000296411701162
Dosimetric Comparison of RapidArc versus CyberKnife for Stereotactic Body Radiation Therapy for Pancreatic Cancer Atwood, T. F., Mok, E., Lo, A., Xing, L., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S345–S346
View details for Web of Science ID 000296411700708
Stereotactic Body Radiation Therapy for Gastrointestinal Malignancies IMRT IGRT SBRT- ADVANCES IN THE TREATMENT PLANNING AND DELIVERY OF RADIOTHERAPY Minn, A. Y., Koong, A. C., Chang, D. T. 2011; 43: 412-427
Abstract

Stereotactic body radiotherapy (SBRT) is an emerging treatment for pancreas cancer and liver tumors. Early data suggest excellent control rates for locally advanced pancreas cancer. However, due to the close proximity of the duodenum and stomach, steps to effectively minimize toxicities must be taken through image guidance of treatments. SBRT for liver tumors has also shown high rates of local control with low risks for hepatic toxicity. Careful selection of cases for SBRT is essential to achieve disease control and to minimize toxicity for patients. In treatment, attention must be paid to minimizing exposure of nearby normal tissues, including ribs, skin and bowel as well as the functioning organs surrounding the tumors. There is no accepted standard for the SBRT dose/fractionation schedule for these cases and the optimal strategy will likely depend on the size, number and location of lesions for each patient. However, the published data seem to suggest an overall dose-response effect. To realize the clinical potential of SBRT for these tumors, investigations are needed to determine optimum fractionation schedules and to integrate its use with systemic chemotherapy programs.

View details for PubMedID 21625166
A DOSIMETRIC MODEL OF DUODENAL TOXICITY AFTER STEREOTACTIC BODY RADIOTHERAPY FOR PANCREATIC CANCER 51st Annual Meeting of the American-Society-for-Therapeutic-Radiology-and Oncology (ASTRO) Murphy, J. D., Christman-Skieller, C., Kim, J., Dieterich, S., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2010: 1420–26
Abstract

Dose escalation for pancreas cancer is limited by the tolerance of adjacent normal tissues, especially with stereotactic body radiotherapy (SBRT). The duodenum is generally considered to be the organ at greatest risk. This study reports on the dosimetric determinants of duodenal toxicity with single-fraction SBRT.Seventy-three patients with locally advanced unresectable pancreatic adenocarcinoma received 25 Gy in a single fraction. Dose-volume histogram (DVH) endpoints evaluated include V(5) (volume of duodenum that received 5 Gy), V(10), V(15), V(20), V(25), and D(max) (maximum dose to 1 cm(3)). Normal tissue complication probability (NTCP) was evaluated with a Lyman model. Univariate and multivariate analyses were conducted with Kaplan-Meier and Cox regression models.The median time to Grade 2-4 duodenal toxicity was 6.3 months (range, 1.6-11.8 months). The 6- and 12-month actuarial rates of toxicity were 11% and 29%, respectively. V(10)-V(25) and D(max) all correlated significantly with duodenal toxicity (p<0.05). In particular, V(15)≥9.1 cm(3) and V(15)<9.1 cm(3) yielded duodenal toxicity rates of 52% and 11%, respectively (p=0.002); V(20)≥3.3 cm(3) and V(20)<3.3 cm(3) gave toxicity rates of 52% and 11%, respectively (p=0.002); and D(max)≥23 Gy and D(max)<23 Gy gave toxicity rates of 49% and 12%, respectively (p=0.004). Lyman NTCP model optimization generated the coefficients m=0.23, n=0.12, and TD(50)=24.6 Gy. Only the Lyman NTCP model remained significant in multivariate analysis (p=0.001).Multiple DVH endpoints and a Lyman NTCP model are strongly predictive of duodenal toxicity after SBRT for pancreatic cancer. These dose constraints will be valuable in future abdominal SBRT studies.

View details for DOI 10.1016/j.ijrobp.2009.09.075

View details for PubMedID 20399033
Expression of p16(INK4A) But Not Hypoxia Markers or Poly Adenosine Diphosphate-Ribose Polymerase Is Associated With Improved Survival in Patients With Pancreatic Adenocarcinoma 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Chang, D. T., Chapman, C. H., Norton, J. A., Visser, B., Fisher, G. A., Kunz, P., Ford, J. M., Koong, A. C., Pai, R. K. WILEY-BLACKWELL. 2010: 5179–87
Abstract

Pancreatic cancer is associated with mutations in the tumor suppressor gene cyclin-dependent kinase inhibitor 2A (p16(INK4A) ), a regulator of the cell cycle and apoptosis. This study investigates whether immunohistochemical expression of p16(INK4A) as well as hypoxia markers and poly adenosine diphosphate-ribose polymerase (PARP) correlates with survival in patients with resected pancreatic adenocarcinoma.Seventy-three patients with pancreatic adenocarcinoma who underwent curative resection at Stanford University were included. From the surgical specimens, a tissue microarray was constructed using triplicate tissue cores from the primary tumor and used for immunohistochemical staining for the following markers: carbonic anhydrase IX, dihydrofolate reductase, p16(INK4A) , and PARP1/2. Staining was scored as either positive or negative and percentage positive staining. Staining score was correlated with overall survival (OS) and progression-free survival (PFS).Of the markers tested, only immunohistochemical expression of p16(INK4A) correlated with clinical outcome. On univariate analysis, p16(INK4A) expression in the tumor was associated with improved OS (P = .038) but not PFS (P = .28). The median survival for patients with positive versus negative p16(INK4A) staining was 28.8 months versus 18 months. On multivariate analysis, p16(INK4A) expression was associated with improved OS (P = .026) but not PFS (P = .25). Age (P = .0019) and number of nodes involved (P = .025) were also significant for OS. Adjuvant chemotherapy and margin status did not correlate with OS or PFS.Expression of p16(INK4A) is associated with improved OS in patients with resected pancreatic adenocarcinoma. Further investigation is needed for validation, given conflicting data in the published literature. .

View details for DOI 10.1002/cncr.25481

View details for PubMedID 20665497
Orthovoltage intraoperative radiation therapy for pancreatic adenocarcinoma RADIATION ONCOLOGY Bachireddy, P., Tseng, D., Horoschak, M., Chang, D. T., Koong, A. C., Kapp, D. S., Tran, P. T. 2010; 5
Abstract

To analyze the outcomes of patients from a single institution treated with surgery and orthovoltage intraoperative radiotherapy (IORT) for pancreatic adenocarcinoma.We retrospectively reviewed 23 consecutive patients from 1990-2001 treated with IORT to 23 discrete sites with median and mean follow up of 6.5 and 21 months, respectively. Most tumors were located in the head of the pancreas (83%) and sites irradiated included: tumor bed (57%), vessels (26%), both the tumor bed/vessels (13%) and other (4%). The majority of patients (83%) had IORT at the time of their definitive surgery. Three patients had preoperative chemoradiation (13%). Orthovoltage X-rays (200-250 kVp) were employed via individually sized and beveled cone applicators. Additional mean clinical characteristics include: age 64 (range 41-81); tumor size 4 cm (range 1.4-11); and IORT dose 1106 cGy (range 600-1500). Post-operative external beam radiation (EBRT) or chemotherapy was given to 65% and 76% of the assessable patients, respectively. Outcomes measured were infield control (IFC), loco-regional control (LRC), distant metastasis free survival (DMFS), overall survival (OS) and treatment-related complications.Kaplan-Meier (KM) 2-year IFC, LRC, DMFS and OS probabilities for the whole group were 83%, 61%, 26%, and 27%, respectively. Our cohort had three grade 3-5 complications associated with treatment (surgery and IORT).Orthovoltage IORT following tumor reductive surgery is reasonably well tolerated and seems to confer in-field control in carefully selected patients. However, distant metastases remain the major problem for patients with pancreatic adenocarcinoma.

View details for DOI 10.1186/1748-717X-5-105

View details for PubMedID 21059255
Comparison of Intensity-Modulated Radiotherapy and 3-Dimensional Conformal Radiotherapy as Adjuvant Therapy for Gastric Cancer 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Minn, A. Y., Hsu, A., La, T., Kunz, P., Fisher, G. A., Ford, J. M., Norton, J. A., Visser, B., Goodman, K. A., Koong, A. C., Chang, D. T. JOHN WILEY & SONS INC. 2010: 3943–52
Abstract

The current study was performed to compare the clinical outcomes and toxicity in patients treated with postoperative chemoradiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT).Fifty-seven patients with gastric or gastroesophageal junction cancer were treated postoperatively: 26 with 3D CRT and 31 with IMRT. Concurrent chemotherapy was capecitabine (n=31), 5-fluorouracil (5-FU) (n=25), or none (n=1). The median radiation dose was 45 Gy. Dose volume histogram parameters for kidney and liver were compared between treatment groups.The 2-year overall survival rates for 3D CRT versus IMRT were 51% and 65%, respectively (P=.5). Four locoregional failures occurred each in the 3D CRT (15%) and the IMRT (13%) patients. Grade>or=2 acute gastrointestinal toxicity was found to be similar between the 3D CRT and IMRT patients (61.5% vs 61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively). The median serum creatinine from before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P=.02). The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gy vs 11.1 Gy; P=.05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5% vs 22%; P=.17). The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6 Gy, respectively (P=.19). The median liver V30 was 16.1% and 28%, respectively (P<.001).Adjuvant chemoradiotherapy was well tolerated. IMRT was found to provide sparing to the liver and possibly renal function.

View details for DOI 10.1002/cncr.25246

View details for PubMedID 20564136
(18)FLUORODEOXYGLUCOSE PET IS PROGNOSTIC OF PROGRESSION-FREE AND OVERALL SURVIVAL IN LOCALLY ADVANCED PANCREAS CANCER TREATED WITH STEREOTACTIC RADIOTHERAPY INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Schellenberg, D., Quon, A., Minn, A. Y., Graves, E. E., Kunz, P., Ford, J. M., Fisher, G. A., Goodman, K. A., Koong, A. C., Chang, D. T. 2010; 77 (5): 1420-1425
Abstract

This study analyzed the prognostic value of positron emission tomography (PET) for locally advanced pancreas cancer patients undergoing stereotactic body radiotherapy (SBRT).Fifty-five previously untreated, unresectable pancreas cancer patients received a single fraction of 25-Gy SBRT sequentially with gemcitabine-based chemotherapy. On the preradiation PET-CT, the tumor was contoured and the maximum standardized uptake value (SUVmax) and metabolic tumor burden (MTB) were calculated using an in-house software application. High-SUVmax and low-SUVmax subgroups were created by categorizing patients above or below the median SUVmax. The analysis was repeated to form high-MTB and low-MTB subgroups as well as clinically relevant subgroups with SUVmax values of <5, 5-10, or >10. Multivariate analysis analyzing SUVmax, MTB, age, chemotherapy cycles, and pretreatment carbohydrate antigen (CA)19-9 was performed.For the entire population, median survival was 12.7 months. Median survival was 9.8 vs.15.3 months for the high- and low- SUVmax subgroups (p <0.01). Similarly, median survival was 10.1 vs. 18.0 months for the high MTB and low MTB subgroups (p <0.01). When clinical SUVmax cutoffs were used, median survival was 6.4 months in those with SUVmax >10, 9.5 months with SUVmax 5.0-10.0, and 17.7 months in those with SUVmax <5 (p <0.01). On multivariate analysis, clinical SUVmax was an independent predictor for overall survival (p = 0.03) and progression-free survival (p = 0.03).PET scan parameters can predict for length of survival in locally advanced pancreas cancer patients.

View details for DOI 10.1016/j.ijrobp.2009.06.049

View details for Web of Science ID 000280459700020

View details for PubMedID 20056345
Pathological response after chemoradiation for T3 rectal cancer. Colorectal disease Chennupati, S. K., Kamaya, A., Fisher, G. A., Ford, J. M., Kunz, P., Itakura, H., Welton, M. L., Shelton, A., Van Dam, J., Koong, A. C., Chang, D. T. 2010; 12 (7 Online): e24-30
Abstract

The aim of this study was to investigate the effect of preoperative chemoradiotherapy (CRT) on nodal disease in locally advanced rectal adenocarcinoma.Thirty-two patients staged uT3N0 and 27 patients staged uT3N1 rectal adenocarcinoma who underwent pre-CRT staging using endoscopic ultrasound or rectal protocol CT were included. The median radiation dose was 50.4 Gy (range: 45-50.4 Gy) at 1.8 Gy per fraction and all patients received concurrent 5-FU or capecitabine-based chemotherapy. Low anterior resection or abdomino-perineal resection occurred at a median of 46 days (range: 27-112 days) after CRT.Eleven of 32 uT3N0 patients (34.4%) and 13 of 26 uT3N1 patients (50.0%) had ypN+ (P = 0.29). For patients with uT3N0, 10 of 20 (50.0%) with ypT2-3 and 1 of 12 (8.3%) with ypT0-1 were ypN+ (P = 0.02). For patients with uT3N1, 12 of 20 (60.0%) with ypT2-3 and 1 of 6 (16.7%) with ypT0-1 were ypN+ (P = 0.16). Overall, the ypN+ rate was 11.1% in the ypT0-yT1 group compared with 55.0% in the ypT2-yT3 group (P = 003). Among patients with uT3N0 disease, the ypN+ rate in patients who had surgery > 46 days vs 46 days vs 46 days vs
View details for DOI 10.1111/j.1463-1318.2009.02013.x

View details for PubMedID 19614668
Pathological response after chemoradiation for T3 rectal cancer COLORECTAL DISEASE Chennupati, S. K., Kamaya, A., Fisher, G. A., Ford, J. M., Kunz, P., Itakura, H., Welton, M. L., Shelton, A., Van Dam, J., Koong, A. C., Chang, D. T. 2010; 12 (7): E24-E30
Abstract

The aim of this study was to investigate the effect of preoperative chemoradiotherapy (CRT) on nodal disease in locally advanced rectal adenocarcinoma.Thirty-two patients staged uT3N0 and 27 patients staged uT3N1 rectal adenocarcinoma who underwent pre-CRT staging using endoscopic ultrasound or rectal protocol CT were included. The median radiation dose was 50.4 Gy (range: 45-50.4 Gy) at 1.8 Gy per fraction and all patients received concurrent 5-FU or capecitabine-based chemotherapy. Low anterior resection or abdomino-perineal resection occurred at a median of 46 days (range: 27-112 days) after CRT.Eleven of 32 uT3N0 patients (34.4%) and 13 of 26 uT3N1 patients (50.0%) had ypN+ (P = 0.29). For patients with uT3N0, 10 of 20 (50.0%) with ypT2-3 and 1 of 12 (8.3%) with ypT0-1 were ypN+ (P = 0.02). For patients with uT3N1, 12 of 20 (60.0%) with ypT2-3 and 1 of 6 (16.7%) with ypT0-1 were ypN+ (P = 0.16). Overall, the ypN+ rate was 11.1% in the ypT0-yT1 group compared with 55.0% in the ypT2-yT3 group (P = 003). Among patients with uT3N0 disease, the ypN+ rate in patients who had surgery > 46 days vs 46 days vs 46 days vs
View details for DOI 10.1111/j.1463-1318.2009.02013.x

View details for Web of Science ID 000208355900003
Treatment of pancreatic cancer in patients age 70 or older Christman-Skieller, C., Heestand, G. M., Fisher, G. A., Kunz, P. L., Ford, J. M., Columbo, L. A., Chang, D. T., Koong, A. AMER SOC CLINICAL ONCOLOGY. 2010
View details for DOI 10.1200/jco.2010.28.15_suppl.e14590

View details for Web of Science ID 000208852000715
INTENSITY-MODULATED RADIOTHERAPY IN THE TREATMENT OF OROPHARYNGEAL CANCER: CLINICAL OUTCOMES AND PATTERNS OF FAILURE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Daly, M. E., Le, Q., Maxim, P. G., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Pinto, H., Chang, D. T. 2010; 76 (5): 1339-1346
Abstract

To report outcomes, failures, and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma of the oropharynx.Between Aug 2001 and Oct 2007, 107 patients were treated with IMRT with curative intent at Stanford University. Twenty-two patients were treated postoperatively, and 85 were treated definitively. Concurrent platinum-based chemotherapy was administered to 86 patients (80%) and cetuximab to 8 patients (7%). The prescribed dose was 66 Gy at 2.2 Gy/fraction for definitively treated cases and 60 Gy at 2 Gy/fraction for postoperative cases. Median follow-up was 29 months among surviving patients (range, 4-105 months).Eight patients had persistent disease or local-regional failure at a median of 6.5 months (range, 0-9.9 months). Six local failures occurred entirely within the high-risk clinical target volume (CTV) (one with simultaneous distant metastasis). One patient relapsed within the high- and intermediate-risk CTV. One patient had a recurrence at the junction between the IMRT and low-neck fields. Seven patients developed distant metastasis as the first site of failure. The 3-year local-regional control (LRC), freedom from distant metastasis, overall survival, and disease-free survival rates were 92%, 92%, 83%, and 81%, respectively. T stage (T4 vs. T1-T3) was predictive of poorer LRC (p = 0.001), overall survival (p = 0.001), and disease-free survival (p < 0.001) rates. Acute toxicity consisted of 58% grade 3 mucosal and 5% grade 3 skin reactions. Six patients (6%) developed grade >or=3 late complications.IMRT provides excellent LRC for oropharyngeal squamous cell carcinoma. Distant metastases are a major failure pattern. No marginal failures were observed.

View details for DOI 10.1016/j.ijrobp.2009.04.006

View details for PubMedID 19540068
EUS-guided gold fiducial insertion for image-guided radiation therapy of pancreatic cancer: 50 successful cases without fluoroscopy GASTROINTESTINAL ENDOSCOPY Park, W. G., Yan, B. M., Schellenberg, D., Kim, J., Chang, D. T., Koong, A., Patalano, C., Van Dam, J. 2010; 71 (3): 513-518
Abstract

Image-guided radiation therapy (IGRT) accurately delivers a high dose of potentially tumoricidal radiation to its target while sparing adjacent healthy tissue. Application of IGRT to unresectable pancreatic cancer requires the use of fiducials to track the precise location of the tumor. Fiducial markers have been successfully placed endoscopically.To determine the feasibility of EUS-guided gold fiducial placement for IGRT.Prospective case series.Tertiary medical center.Consecutively referred patients with locally advanced unresectable pancreatic adenocarcinoma for EUS-guided insertion of gold fiducials from December 2006 to February 2009.Under only EUS guidance, fiducial markers were deployed into or near the tumor by using a 19-gauge needle. In most cases, a sterile water injection technique was used to insert the fiducials. Fluoroscopy was not used in any case.Successful placement of an adequate number of fiducials to proceed with IGRT as determined by CT.Fifty-seven consecutive patients were included. Fifty cases (88%) were successful. Of the cases in which fiducial placement was attempted and follow-up was adequate, 94% (50 of 53) of cases were successful.Single-center, nonrandomized study.EUS-guided fine-needle insertion was safe and effective in delivering gold fiducial markers for image-guided radiation therapy. Fluoroscopy was not required for successful fiducial placement.

View details for DOI 10.1016/j.gie.2009.10.030

View details for PubMedID 20189509
INTERFRACTIONAL UNCERTAINTY IN THE TREATMENT OF PANCREATIC CANCER WITH RADIATION INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Jayachandran, P., Minn, A. Y., Van Dam, J., Norton, J. A., Koong, A. C., Chang, D. T. 2010; 76 (2): 603-607
Abstract

To compare the interfractional variation in pancreatic tumor position using bony anatomy and implanted fiducial markers.Five consecutively treated patients with pancreatic adenocarcinoma who received definitive intensity-modulated radiation therapy at Stanford University (Stanford, CA) underwent fiducial seed placement and treatment on the Varian Trilogy system (Varian, Palo Alto, CA) with respiratory gating. Daily orthogonal kilovoltage imaging was performed to verify patient positioning, and isocenter shifts were made initially to match bony anatomy. Next, a final shift to the fiducial seeds was made under fluoroscopic guidance to confirm the location of the pancreatic tumor during the respiratory gated phase. All shifts were measured along three axes, left (+)-right (-), anterior (-)-posterior (+), and superior (+)-inferior (-), and the overall interfractional tumor movement was calculated based on these values.A total of 140 fractions were analyzed. The mean absolute shift to fiducial markers after shifting to bony anatomy was 1.6 mm (95th percentile, 7 mm; range, 0-9 mm), 1.8 mm (95th percentile, 7 mm; range, 0-13 mm), and 4.1 mm (95th percentile, 12 mm; range, 0-19 mm) in the anterior-posterior, left-right, and superior-inferior directions, respectively. The mean interfractional vector shift distance was 5.5 mm (95th percentile, 14.5 mm; range, 0-19.3 mm). In 28 of 140 fractions (20%) no fiducial shift was required after alignment to bony anatomy.There is substantial residual uncertainty after alignment to bony anatomy when radiating pancreatic tumors using respiratory gating. Bony anatomy matched tumor position in only 20% of the radiation treatments. If bony alignment is used in conjunction with respiratory gating without implanted fiducials, treatment margins need to account for this uncertainty.

View details for DOI 10.1016/j.ijrobp.2009.06.029

View details for PubMedID 19879062
Multimodality treatment with intensity modulated radiation therapy for esophageal cancer DISEASES OF THE ESOPHAGUS La, T. H., Minn, A. Y., Su, Z., Fisher, G. A., Ford, J. M., Kunz, P., Goodman, K. A., Koong, A. C., Chang, D. T. 2010; 23 (4): 300-308
Abstract

The objective of this study is to determine the feasibility and report the outcome of patients with locally advanced esophageal cancer treated with preoperative or definitive chemoradiotherapy (CRT) using intensity-modulated radiation therapy (IMRT). Between 2003 and 2007, 30 patients with non-cervical esophageal cancer received concurrent chemotherapy and IMRT at Stanford University. Eighteen patients were planned for definitive CRT and 12 were planned for preoperative CRT. All patients had computed tomography-based treatment planning and received IMRT. The median dose delivered was 50.4 Gy. Patients planned for preoperative CRT underwent surgery 4-13 weeks (median 8.3 weeks) following completion of CRT. Median follow-up of surviving patients from start of RT was 24.2 months (range 8.2-38.3 months). The majority of tumors were adenocarcinomas (67%) and poorly differentiated (57%). Tumor location was 7% upper, 20% mid, 47% lower, and 27% gastroesophageal junction. Actuarial 2-year local-regional control (LRC) was 64%. High tumor grade was an adverse prognostic factor for LRC and overall survival (OS) (P= 0.015 and 0.012, respectively). The 2-year LRC was 83% vs. 51% for patients treated preoperatively vs. definitively (P= 0.32). The 2-year disease-free and OS were 38% and 56%, respectively. Twelve patients (40%) required feeding tube placement, and the average weight loss from baseline was 4.8%. Twelve (40%) patients experienced grade 3+ acute complications and one patient died of complications following feeding tube placement. Three patients (10%) required a treatment break. Eight patients (27%) experienced grade 3 late complications. No grade 4 complications were seen. IMRT was effective and well tolerated. Disease recurrence remains a challenge and further investigation with dose escalation to improve LRC and OS is warranted.

View details for DOI 10.1111/j.1442-2050.2009.01004.x

View details for PubMedID 19732129
Intensity Modulated Radiotherapy for Tumors of the Nasal Cavity and Paranasal Sinuses: Clinical Outcomes and Patterns of Failure Wiegner, E. A., Daly, M. E., Chapman, C. H., Yu, Y., Colevas, A. D., Kaplan, M. J., Fischbein, N., Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2010: S463
View details for DOI 10.1016/j.ijrobp.2010.07.1086

View details for Web of Science ID 000288775701081
Liver Tumor Motion using Different Fiducial Landmarks Smedra, B. J., Hong, J. C., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2010: S308
View details for DOI 10.1016/j.ijrobp.2010.07.731

View details for Web of Science ID 000288775700667
Management of T1/T2 Rectal Cancers with Transanal Excision and Radiation Therapy LOWER GASTROINTESTINAL MALIGNANCIES Mehta, N., Chang, D. T., Lee, P., Ben Josef, E., Koong, A. 2010; 1 (2): 323–33
View details for DOI 10.5003/2151-4208.1.2.323

View details for Web of Science ID 000281785700006
Rectal Deformation and Displacement during Pre-operative Radiotherapy for Rectal Cancer: Insights from Mid-treatment Cone-beam Computed Tomography Daly, M. E., Murphy, J. D., Mok, E., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2010: S310
View details for DOI 10.1016/j.ijrobp.2010.07.736

View details for Web of Science ID 000288775700672
Cost Effectiveness of Radiotherapy in Locally Advanced Pancreatic Cancer Murphy, J. D., Chang, D. T., Abelson, J., Daly, M. E., Yeung, H. N., Nelson, L. M., Koong, A. C. ELSEVIER SCIENCE INC. 2010: S576
View details for DOI 10.1016/j.ijrobp.2010.07.1343

View details for Web of Science ID 000288775701330
Stereotactic Body Radiotherapy for Colorectal Liver Metastases: A Pooled Analysis 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Chang, D. T., Swaminath, A., Kozak, M., Weintraub, J., Koong, A. C., Kim, J., Dawson, L. A., Kavanagh, B. D., Schefter, T. E. ELSEVIER SCIENCE INC. 2010: S56–S57
View details for Web of Science ID 000288775700120
Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head and Neck Cancer Outcomes 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Chu, K. P., Murphy, J., La, T. H., Loo, B. W., Krakow, T. E., Hsu, A., Maxim, P. G., Graves, E., Chang, D., Le, Q. ELSEVIER SCIENCE INC. 2010: S460–S460
View details for Web of Science ID 000288775701074
Combined Modality Therapy for Rectal Cancer: Analysis of Potential Differences in Disease Presentation, Treatment Adherence, and Treatment Outcome According to Race 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Liauw, S., Song, S., Tonlaar, N., Hong, J. C., Minsky, B. D., Chang, D. T., Polite, B. ELSEVIER SCIENCE INC. 2010: S198–S198
View details for Web of Science ID 000288775700424
Significant Duodenal Dose Variation within the Respiratory Cycle during Stereotactic Body Radiotherapy for Pancreatic Cancer 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Taniguchi, C. M., Kielar, K. N., Murphy, J. D., Atwood, T. F., Christman-Skieller, C., Dieterich, S., Xing, L., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2010: S329–S329
View details for Web of Science ID 000288775700714
Comparison of RapidArc vs. Conventional Intensity Modulated Radiation Therapy for Stereotactic Body Radiation Therapy for Pancreatic Cancer 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Kielar, K. N., Atwood, T. F., Taniguchi, C. M., Christman-Skieller, C., Xing, L., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2010: S785–S785
View details for Web of Science ID 000288775701789
Intensity Modulated Radiation Therapy vs. Conventional Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Bazan, J. G., Hara, W., Kunz, P., Fisher, G. A., Ford, J. M., Welton, M. L., Koong, A., Shelton, A., Goodman, K. A., Chang, D. T. ELSEVIER SCIENCE INC. 2010: S300–S301
View details for Web of Science ID 000288775700650
Identification of a biomarker panel using a multiplex proximity ligation assay improves accuracy of pancreatic cancer diagnosis JOURNAL OF TRANSLATIONAL MEDICINE Chang, S. T., Zahn, J. M., Horecka, J., Kunz, P. L., Ford, J. M., Fisher, G. A., Le, Q. T., Chang, D. T., Ji, H., Koong, A. C. 2009; 7
Abstract

Pancreatic cancer continues to prove difficult to clinically diagnose. Multiple simultaneous measurements of plasma biomarkers can increase sensitivity and selectivity of diagnosis. Proximity ligation assay (PLA) is a highly sensitive technique for multiplex detection of biomarkers in plasma with little or no interfering background signal.We examined the plasma levels of 21 biomarkers in a clinically defined cohort of 52 locally advanced (Stage II/III) pancreatic ductal adenocarcinoma cases and 43 age-matched controls using a multiplex proximity ligation assay. The optimal biomarker panel for diagnosis was computed using a combination of the PAM algorithm and logistic regression modeling. Biomarkers that were significantly prognostic for survival in combination were determined using univariate and multivariate Cox survival models.Three markers, CA19-9, OPN and CHI3L1, measured in multiplex were found to have superior sensitivity for pancreatic cancer vs. CA19-9 alone (93% vs. 80%). In addition, we identified two markers, CEA and CA125, that when measured simultaneously have prognostic significance for survival for this clinical stage of pancreatic cancer (p < 0.003).A multiplex panel assaying CA19-9, OPN and CHI3L1 in plasma improves accuracy of pancreatic cancer diagnosis. A panel assaying CEA and CA125 in plasma can predict survival for this clinical cohort of pancreatic cancer patients.

View details for DOI 10.1186/1479-5876-7-105

View details for PubMedID 20003342
Pharmacologically Increased Tumor Hypoxia Can Be Measured by F-18-Fluoroazomycin Arabinoside Positron Emission Tomography and Enhances Tumor Response to Hypoxic Cytotoxin PR-104 CLINICAL CANCER RESEARCH Cairns, R. A., Bennewith, K. L., Graves, E. E., Giaccia, A. J., Chang, D. T., Denko, N. C. 2009; 15 (23): 7170-7174
Abstract

Solid tumors contain microenvironmental regions of hypoxia that present a barrier to traditional radiotherapy and chemotherapy, and this work describes a novel approach to circumvent hypoxia. We propose to overcome hypoxia by augmenting the effectiveness of drugs that are designed to specifically kill hypoxic tumor cells.We have constructed RKO colorectal tumor cells that express a small RNA hairpin that specifically knocks down the hypoxia-inducible factor 1a (HIF1a) transcription factor. We have used these cells in vitro to determine the effect of HIF1 on cellular sensitivity to the hypoxic cytotoxin PR-104, and its role in cellular oxygen consumption in response to the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA). We have further used these cells in vivo in xenografted tumors to determine the role of HIF1 in regulating tumor hypoxia in response to DCA using (18)F-fluoroazomycin arabinoside positron emission tomography, and its role in regulating tumor sensitivity to the combination of DCA and PR-104.HIF1 does not affect cellular sensitivity to PR-104 in vitro. DCA transiently increases cellular oxygen consumption in vitro and increases the extent of tumor hypoxia in vivo as measured with (18)F-fluoroazomycin arabinoside positron emission tomography. Furthermore, we show that DCA-dependent alterations in hypoxia increase the antitumor activity of the next-generation hypoxic cytotoxin PR-104.DCA interferes with the HIF-dependent "adaptive response," which limits mitochondrial oxygen consumption. This approach transiently increases tumor hypoxia and represents an important method to improve antitumor efficacy of hypoxia-targeted agents, without increasing toxicity to oxygenated normal tissue.

View details for DOI 10.1158/1078-0432.CCR-09-1676

View details for Web of Science ID 000272363700011

View details for PubMedID 19920111

View details for PubMedCentralID PMC2810128
SINGLE FRACTION STEREOTACTIC BODY RADIATION THERAPY (SBRT) AND SEQUENTIAL GEMCITABINE FOR THE TREATMENT OF LOCALLY ADVANCED PANCREATIC CANCER Schellenberg, D., Kim, J., Columbo, L., Fisher, G., Quon, A., Desser, T., Maxim, P., Goodman, K., Chang, D., Koong, A. ELSEVIER IRELAND LTD. 2009: S20
View details for DOI 10.1016/S0167-8140(12)72449-0

View details for Web of Science ID 000433337800063
Treatment of Esophageal Cancer Based on Histology A Surveillance Epidemiology and End Results Analysis AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Chang, D. T., Chapman, C., Shen, J., Su, Z., Koong, A. C. 2009; 32 (4): 405-410
Abstract

The majority of esophageal cancer is either adenocarcinoma (ACA) or squamous cell carcinoma (SCCA). Recent randomized trials suggest that definitive chemoradiotherapy may be equally effective as surgery. However, the responsiveness of ACA versus SCCA to radiotherapy (RT) has never been compared. This Surveillance Epidemiology and End Results registry analysis investigates whether survival differed between ACA and SCCA based on the treatment modality.Patients with T2-4N0 or N+ SCCA and ACA in the cervical or thoracic esophagus diagnosed from 1983 to 2004 were obtained from the Surveillance Epidemiology and End Results database. Patients with multiple primary cancers, underwent a surgical procedure other than partial or total esophagectomy, had metastatic or T1N0 disease, or received RT that did not include external beam radiation were excluded. Patients were grouped according to treatment received: RT alone, preoperative RT, any surgery (regardless of use of RT), and surgery alone.A total of 4752 patients were included, 2680 (56%) had ACA and 2072 (44%) had SCCA. After adjusting for age, marital status, cost of living, and race, the overall survival (OS) and cause-specific survival was similar for all treatment groups except the RT-alone group where OS and SCC were superior for ACA. However, no difference in 3- and 5-year OS and cause-specific survival rates for all groups.No difference in survival was seen between patients with ACA and SCCA across any of the major treatment modalities for esophageal cancer, suggesting that both histologies respond to treatment similarly.

View details for DOI 10.1097/COC.0b013e3181917158

View details for PubMedID 19415029
Pancreatic Tumor Motion on a Single Planning 4D-CT Does Not Correlate With Intrafraction Tumor Motion During Treatment AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Minn, A. Y., Schellenberg, D., Maxim, P., Suh, Y., McKenna, S., Cox, B., Dieterich, S., Xing, L., Graves, E., Goodman, K. A., Chang, D., Koong, A. C. 2009; 32 (4): 364-368
Abstract

To quantify pancreas tumor motion on both a planning 4D-CT and during a single fraction treatment using the CyberKnife linear accelerator and Synchrony respiratory tracking software, and to investigate whether a single 4D-CT study is reliable for determining radiation treatment margins for patients with locally advanced pancreas cancer.Twenty patients underwent fiducial placement, biphasic pancreatic protocol CT scan and 4D-CT scan in the treatment position while free-breathing. Patients were then treated with a single 25 Gy fraction of stereotactic body radiotherapy. Predicted pancreas motion in the superior-inferior (SI), left-right (LR), and anterior-posterior (AP) directions was calculated from the maximum inspiration and maximum expiration 4D-CT scan. For CyberKnife treatments, mean respiratory cycle motion and maximum respiratory cycle motion was determined in the SI, LR, and AP directions.The range of centroid movement based on 4D-CT in the SI, LR, and AP directions were 0.9 to 28.8 mm, 0.1 to 13.7 mm, and 0.2 to 7.6 mm, respectively. During CyberKnife treatment, in the SI direction, the mean motion of the centroid ranged from 0.5 to 12.7 mm. In the LR direction, the mean motion range was 0.4 to 9.4 mm. In the AP direction, the mean motion range was 0.6 to 5.5 mm. The maximum range of movement (mean) during CyberKnife treatment in the SI, LR, and AP directions were 4.5 to 48.8 mm (mean 20.8 mm), 1.5 to 41.3 mm (mean 11.3 mm), and 1.6 to 68.1 mm (mean 13.4 mm), respectively. Neither the maximum or mean motion correlated with the 4D-CT movement.There is substantial respiratory associated motion of pancreatic tumors. The 4D-CT planning scans cannot accurately predict the movement of pancreatic tumors during actual treatment on CyberKnife.

View details for DOI 10.1097/COC.0b013e31818da9e0

View details for PubMedID 19398901
Long-term Outcomes for Stage I-II Aggressive Non-Hodgkin Lymphoma of Waldeyer's Ring AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Chang, D. T., Mendenhall, N. P., Lynch, J. W., Morris, C. G., Olivier, K. R. 2009; 32 (3): 233-237
Abstract

To determine the long-term outcome of patients treated at the University of Florida for aggressive non-Hodgkin lymphoma (NHL) of Waldeyer's ring.Forty-six patients treated with radiotherapy (RT) at the University of Florida from 1964 to 2006 for biopsy-proven aggressive NHL of Waldeyer's ring were included in this study. Of this group, 20 patients were treated with RT alone and 26 with combined-modality therapy (CMT) with the addition of chemotherapy: 24 patients with induction and 2 with concurrent or adjuvant chemotherapy.The 5-year and 10-year in-field control rates were 95% and 85%, respectively, and the out-of-field control rates were 67% and 63%, respectively. The 10-year disease-free survival (DFS), cause-specific survival, and overall survival (OS) rates were 47%, 50%, and 37%, respectively. The CMT group had superior 10-year DFS compared with the RT-alone group (57% vs. 37%), but this difference was not statistically significant. No difference in 10-year OS was seen between the CMT group and the RT-alone group.Similar to other sites, out-of-field recurrences are the primary pattern of failure for NHL of Waldeyer's ring. DFS was superior with CMT compared with RT alone and remains the standard of care.

View details for DOI 10.1097/COC.0b013e318187ddbb

View details for PubMedID 19433961
Adjuvant chemoradiotherapy with carboplatin and a fluoropyrimidine for resectable gastric and gastroesophageal junction cancer: A retrospective review of the Stanford experience de Bruin, M. A., Kunz, P. L., Sharma, V. B., Norton, J. A., Bastidas, J., Chang, D. T., Koong, A. C., Koong, A. C., Balise, R. R., Ford, J. M., Fisher, G. A. AMER SOC CLINICAL ONCOLOGY. 2009
View details for Web of Science ID 000276606603390
Percutaneous Implantation of Fiducial Markers for Imaging-Guided Radiation Therapy AMERICAN JOURNAL OF ROENTGENOLOGY Kothary, N., Dieterich, S., Louie, J. D., Chang, D. T., Hofmann, L. V., Sze, D. Y. 2009; 192 (4): 1090-1096
Abstract

The use of imaging-guided radiation therapy (IGRT) to treat thoracic and abdominal tumors is increasing. In this article, we review the process of IGRT and describe techniques to implant fiducial markers in the optimal geometry.Implantation of fiducial markers can be challenging. A better understanding of the physics of IGRT can help optimize fiducial marker placement for precise tumor targeting.

View details for DOI 10.2214/AJR.08.1399

View details for PubMedID 19304719
Xerostomia in Long-term Survivors of Aggressive Non-Hodgkin's Lymphoma of Waldeyer's Ring A Potential Role for Parotid-Sparing Techniques? AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Chang, D. T., Amdur, R. J., Pacholke, H., Mendenhall, N. P., Morris, C. G., Byer, G. A., Olivier, K. R. 2009; 32 (2): 145-149
Abstract

The degree of xerostomia in patients treated for intermediate-and high-grade non-Hodgkin lymphoma (NHL) of Waldeyer's ring (WR) is unknown.Fifteen patients treated for stage I-IV NHL of WR with radiotherapy (RT) were administered a xerostomia questionnaire. Numerical responses (0 = no xerostomia; 100 = maximum xerostomia) were compared with responses from 5 sets of patients treated for head and neck squamous cell carcinoma who were grouped by amount of parotid in RT field: larynx-only, ipsilateral parotid, bilateral-partial parotid, bilateral-total parotid, parotid-sparing intensity-modulated radiotherapy.Waldeyer's patients' median xerostomia questionnaire score was 31, which was significantly different from the larynx-only group, bilateral-partial parotid group, and bilateral-total parotid group, but not significantly different from the ipsilateral parotid group or parotid-sparing intensity-modulated radiotherapy group.Xerostomia in survivors WR NHL is a detectable toxicity with severity like that in head and neck squamous cell carcinoma patients who receive ipsilateral parotid irradiation, and warrants parotid-sparing RT techniques.

View details for DOI 10.1097/COC.0b013e3181841f42

View details for Web of Science ID 000265056900007

View details for PubMedID 19307951
Safety and Efficacy of Percutaneous Fiducial Marker Implantation for Image-guided Radiation Therapy JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Kothary, N., Heit, J. J., Louie, J. D., Kuo, W. T., Loo, B. W., Koong, A., Chang, D. T., Hovsepian, D., Sze, D. Y., Hofmann, L. V. 2009; 20 (2): 235-239
Abstract

To evaluate the safety and technical success rate of percutaneous fiducial marker implantation in preparation for image-guided radiation therapy.From January 2003 to January 2008, we retrospectively reviewed 139 percutaneous fiducial marker implantations in 132 patients. Of the 139 implantations, 44 were in the lung, 61 were in the pancreas, and 34 were in the liver. Procedure-related major and minor complications were documented. Technical success was defined as implantation enabling adequate treatment planning and computed tomographic simulation.The major and minor complication rates were 5% and 17.3%, respectively. Pneumothorax after lung implantation was the most common complication. Pneumothoraces were seen in 20 of the 44 lung implantations (45%); a chest tube was required in only seven of the 44 lung transplantations (16%). Of the 139 implantations, 133 were successful; in six implantations (4.3%) the fiducial markers migrated and required additional procedures or alternate methods of implantation.Percutaneous implantation of fiducial marker is a safe and effective procedure with risks that are similar to those of conventional percutaneous organ biopsy.

View details for DOI 10.1016/j.jvir.2008.09.026

View details for PubMedID 19019700
Stereotactic Radiotherapy for Unresectable Adenocarcinoma of the Pancreas CANCER Chang, D. T., Schellenberg, D., Shen, J., Kim, J., Goodman, K. A., Fisher, G. A., Ford, J. M., Desser, T., Quon, A., Koong, A. C. 2009; 115 (3): 665-672
Abstract

The authors report on the local control and toxicity of stereotactic body radiotherapy (SBRT) for patients with unresectable pancreatic adenocarcinoma.Seventy-seven patients with unresectable adenocarcinoma of the pancreas received 25 gray (Gy) in 1 fraction. Forty-five patients (58%) had locally advanced disease, 11 patients (14%) had medically inoperable disease, 15 patients (19%) had metastatic disease, and 6 patients (8%) had locally recurrent disease. Nine patients (12%) had received prior chemoradiotherapy. Sixteen patients (21%) received between 45 to 54 Gy of fractionated radiotherapy and SBRT. Various gemcitabine-based chemotherapy regimens were received by 74 patients (96%), but 3 patients (4%) did not receive chemotherapy until they had distant failure.The median follow-up was 6 months (range, 3-31 months) and, among surviving patients, it was 12 months (range, 3-31 months). The overall rates of freedom from local progression (FFLP) at 6 months and 12 months were 91% and 84%, respectively. The 6- and 12-month isolated local recurrence rates were 5% and 5%, respectively. There was no difference in the 12-month FFLP rate based on tumor location (head/uncinate, 91% vs body/tail, 86%; P = .52). The progression-free survival (PFS) rates at 6 months and 12 months were 26% and 9%, respectively. The PFS rate at 6 months was superior for patients who had nonmetastatic disease versus patients who had metastatic disease (28% vs 15%; P = .05). The overall survival (OS) rates at 6 months and 12 months from SBRT were 56% and 21%, respectively. Four patients (5%) experienced grade > or = 2 acute toxicity. Three patients (4%) experienced grade 2 late toxicity, and 7 patients (9%) experienced grade > or = 3 late toxicity. At 6 months and 12 months, the rates of grade > or = 2 late toxicity were 11% and 25%, respectively.SBRT for pancreatic adenocarcinoma was effective for local control with associated risk of toxicity and should be used with rigorous attention to quality assurance. Efforts to reduce complications are warranted. Distant metastases account for the vast majority of disease-related mortality.

View details for DOI 10.1002/cncr.24059

View details for PubMedID 19117351
A Prospective Randomized Pilot Study of Site-specific Atlas Incorporation into Target Volume Delineation Instructions in the Cooperative Group Setting: Preliminary Results from a Southwest Oncology Group Pilot using Big Brother 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Fuller, C. D., Duppen, J., Rasch, C. R., Kachnic, L., Wang, S. J., Chang, D., Goodman, K. A., Katz, A. W., OKUNIEFF, P., Thomas, C. R. ELSEVIER SCIENCE INC. 2009: S136–S137
View details for Web of Science ID 000270573600292
Cyclin-dependent Kinase Inhibitor 2A (p16ink4a) Expression is Associated with Improved Survival in Patients with Pancreatic Adenocarcinoma Chang, D. T., Pai, R., Chapman, C. H., Norton, J. A., Visser, B., Fisher, G. A., Ford, J. M., Koong, A. C. ELSEVIER SCIENCE INC. 2009: S57
View details for DOI 10.1016/j.ijrobp.2009.07.150

View details for Web of Science ID 000270573600121
Comparison of IMRT and 3D Conformal Radiotherapy for Adjuvant Therapy for Gastric Cancer Minn, A., Fisher, G., Ford, J., Kunz, P., Norton, J., Koong, A., Chang, D. ELSEVIER SCIENCE INC. 2009: S259
View details for DOI 10.1016/j.ijrobp.2009.07.597

View details for Web of Science ID 000270573601043
Intensity Modulated Radiotherapy for Adenocarcinoma of the Pancreas Abelson, J. A., Fisher, G. A., Ford, J. M., Kunz, P., Notion, J. A., Visser, B., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2009: S272–S273
View details for DOI 10.1016/j.ijrobp.2009.07.628

View details for Web of Science ID 000270573601072
Duodenal Toxicity in Single-fraction Stereotactic Body Radiotherapy Murphy, J. D., Dieterich, S., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2009: S29–S30
View details for DOI 10.1016/j.ijrobp.2009.07.090

View details for Web of Science ID 000270573600062
Stereotactic body radiotherapy for unresectable adenocarcinoma of the pancreas 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Chang, D. T., Schellenberg, D., Shen, J., Kim, J., Goodman, K., Fisher, G., Ford, J., Desser, T., Quon, A., Koong, A. ELSEVIER SCIENCE INC. 2008: S249–S249
View details for Web of Science ID 000258805301032
Salvage re-irradiation using intensity-modulated radiotherapy for squamous cell carcinoma of the head and neck Chin, R. K., Daly, M. E., Maxim, P. G., Loo, B. W., Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2008: S420
View details for DOI 10.1016/j.ijrobp.2008.06.1329

View details for Web of Science ID 000258805301414
Intensity modulated radiotherapy for squamous cell carcinoma of the hypopharynx and larynx: Clinical outcomes and patterns of failure Daly, M. E., Le, Q. T., Loo, B. W., Maxim, P. G., Pinto, H. A., Colevas, A. D., Fee, W. E., Kaplan, M. J., Chang, D. T. ELSEVIER SCIENCE INC. 2008: S405–S406
View details for DOI 10.1016/j.ijrobp.2008.06.1296

View details for Web of Science ID 000258805301382
Intensity modulated radiotherapy for gastric cancers: Toxicity and clinical outcome Minn, Y., Ford, J., Fisher, G. A., Norton, J., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2008: S264
View details for DOI 10.1016/j.ijrobp.2008.06.1700

View details for Web of Science ID 000258805301066
Positron emission tomography for predicting pathologic response following neoadjuvant chemoradiotherapy for locally advanced rectal cancer Chennupati, S. K., Welton, M., Shelton, A., Fisher, G. A., Ford, J. M., Pai, R. K., Quon, A., Kamaya, A., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2008: S268–S269
View details for DOI 10.1016/j.ijrobp.2008.06.1710

View details for Web of Science ID 000258805301076
Phase II trial of single fraction stereotactic body radiotherapy delivered by trilogy linear accelerator for the treatment of locally advanced adenocarcinoma of the pancreas Schellenberg, D., Kim, J., Columbo, L., Lee, C., Fisher, G. A., Kunz, P., Maxim, P. G., Goodman, K. A., Chang, D. T., Koong, A. C. ELSEVIER SCIENCE INC. 2008: S127
View details for DOI 10.1016/j.ijrobp.2008.06.428

View details for Web of Science ID 000258805300283
Do pre-irradiation dental extractions reduce the risk of osteoradionecrosis of the mandible? HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Chang, D. T., Sandow, P. R., Morris, C. G., Hollander, R., Scarborough, L., Amdur, R. J., Mendenhall, W. M. 2007; 29 (6): 528-536
Abstract

This study was done to determine if pre-radiotherapy (pre-RT) dental extractions reduce the risk of osteoradionecrosis (ORN).Between 1987 and 2004, 413 patients with oropharyngeal carcinomas were treated with definitive RT at the University of Florida. Dentate patients underwent pretreatment dental evaluation. Teeth in the RT field were usually extracted if thought to have poor long-term prognosis from dental disease. The endpoint was > or = grade 2 ORN using a modified staging system. Patients were excluded for local recurrence, additional RT above the clavicles, or head and neck surgery besides neck dissection.ORN rates were as follows: edentulous, <1%; teeth in-field with pre-RT extractions, 15%; and teeth in-field without pre-RT extractions, 9%. Patients with poor in-field teeth and pre-RT extractions had a higher 5-year incidence of ORN than those who did not have pre-RT extractions (16% vs 6%, p = .48). Likewise, for those with in-field teeth in good condition and pre-RT extractions, the 5-year ORN incidence was higher than for those who did not undergo extractions (15% vs 2%, p = .42). Multivariate analysis revealed increased ORN risk with doses of >70 Gy, once-daily fractionation, or brachytherapy.Pre-RT extractions do not appear to reduce the risk of ORN.

View details for DOI 10.1002/hed.20538

View details for Web of Science ID 000246958600002

View details for PubMedID 17230555
Long-term outcomes in breast cancer patients with ten or more positive axillary nodes treated with combined-modality therapy: The importance of radiation field selection INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chang, D. T., Feigenberg, S. J., Indelicato, D. J., Morris, C. G., Lightsey, J., Grobmyer, S. R., Copeland, E. M., Mendenhall, N. P. 2007; 67 (4): 1043-1051
Abstract

To determine the long-term outcome of a consistent treatment approach with electron beam postmastectomy radiation therapy (PMRT) in breast cancer patients with > or =10 positive nodes treated with combined-modality therapy.TSixty-three breast cancer patients with > or =10 positive lymph nodes were treated with combined-modality therapy using an electron beam en face technique for PMRT at the University of Florida. Patterns of recurrence were studied for correlation with radiation fields. Potential clinical and treatment variables were tested for possible association with local-regional control (LRC), disease-free survival (DFS), and overall survival (OS).TAt 5, 10, and 15 years, OS rates were 57%, 36%, and 27%, respectively; DFS rates were 46%, 37%, and 34%; and LRC rates were 87%, 87%, and 87%. No clinical or treatment variables were associated with OS or DFS. The use of supplemental axillary radiation (SART) (p = 0.012) and pathologic N stage (p = 0.053) were associated with improved LRC. Patients who received SART had a higher rate of LRC than those who did not. Moderate to severe arm edema developed in 17% of patients receiving SART compared with 7% in patients not treated with SART (p = 0.28).TA substantial percentage of patients with > or =10 positive lymph nodes survive breast cancer. The 10-year overall survival in these patients was 36%. The addition of SART was associated with better LRC.

View details for DOI 10.1016/j.ijrobp.2006.10.049

View details for Web of Science ID 000245021100012

View details for PubMedID 17336214
Predicting changes in dose distribution to tumor and normal tissue when correcting for heterogeneity in radiotherapy for lung cancer AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Chang, D., Liu, C., Dempsey, J. F., Palta, J. R., Kopea, J., Louis, D., Morris, C., Chopra, R., Olivier, K. R. 2007; 30 (1): 57-62
Abstract

The purposes of this study were to examine dose alterations to gross tumor volume (GTV) and lung using heterogeneity corrections and to predict the magnitude of these changes.Three separate conformal plans were generated for 37 patients with lung cancer: plan 1 corrected for heterogeneity, plan 2 did not correct for heterogeneity, and plan 3 used identical beams and monitor units from plan 2 but with heterogeneous calculations. Plans 1 and 2 were normalized to the 95% isodose line. Mean dose (MeanDGTV), maximum dose (MaxDGTV), and minimum dose (MinDGTV) to GTV and V20 were compared between plans 1 and 3. For each patient, the amount of lung in all beam paths of plan 3 was quantified by a density correction factor and correlated with the percent change.The median percent change in MeanDGTV, MaxDGTV, and MinDGTV between plan 3 and plan 1 was -4.7% (-0.1% to -19.1%, P < 0.0001), -5.59% (0.16% to -31.86%, P < 0.0001), and -4.88% (2.90% to -24.88%, P < 0.0001), respectively. The median V20 difference was -1% (1% to -8%). The density correction factor correlated with larger differences in MeanDGTV on univariate analysis.Heterogeneity correction lowers the dose to GTV by 5%. This difference can be correlated with the density correction factor.

View details for DOI 10.1097/01.coc.0000251222.36417.3b

View details for Web of Science ID 000244196300011

View details for PubMedID 17278896
Adjuvant radiotherapy for cutaneous melanoma: Comparing hypofractionation to conventional fractionation INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chang, D. T., Amdur, R. J., Morris, C. G., Mendenhall, W. M. 2006; 66 (4): 1051-1055
Abstract

To examine locoregional control after adjuvant radiotherapy (RT) for cutaneous melanoma and compare outcomes between conventional fractionation and hypofractionation.Between January 1980 and June 2004, 56 patients with high-risk disease were treated with adjuvant RT. Indications for RT included: recurrent disease, cervical lymph node involvement, lymph nodes >3 cm, more than three lymph nodes involved, extracapsular extension, gross residual disease, close or positive margins, or satellitosis. Hypofractionation was used in 41 patients (73%) and conventional fractionation was used in 15 patients (27%).The median age was 61 years (21->90). The median follow-up among living patients was 4.4 years (range, 0.6-14.4 years). The primary site was located in the head and neck in 49 patients (87%) and below the clavicles in 7 patients (13%). There were 7 in-field locoregional failures (12%), 3 out-of-field regional failures (5%), and 24 (43%) distant failures. The 5-year in-field locoregional control (ifLRC) and freedom from distant metastases (FFDM) rates were 87% and 43%, respectively. The 5-year cause-specific (CSS) and overall survival (OS) was 57% and 46%, respectively. The only factor associated with ifLRC was satellitosis (p = 0.0002). Nodal involvement was the only factor associated with FFDM (p = 0.0007), CSS (p = 0.0065), and OS (p = 0.016). Two patients (4%) who experienced severe late complications, osteoradionecrosis of the temporal bone and radiation plexopathy, and both received hypofractionation (5%).Although surgery and adjuvant RT provides excellent locoregional control, distant metastases remain the major cause of mortality. Hypofractionation and conventional fractionation are equally efficacious.

View details for DOI 10.1016/j.ijrobp.2006.05.056

View details for Web of Science ID 000241598600013

View details for PubMedID 16973303
The impact of heterogeneity correction on dosimetric parameters that predict for radiation pneumonitis INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chang, D. T., Olivier, K. R., Morris, C. G., Liu, C., Dempsey, J. F., Benda, R. K., Palta, J. R. 2006; 65 (1): 125-131
Abstract

To determine if heterogeneity correction significantly affects commonly measured dosimetric parameters predicting pulmonary toxicity in patients receiving radiation for lung cancer.Sixty-eight patients treated for lung cancer were evaluated. The conformal treatment technique mostly employed anteroposterior/posterior-anterior fields and off-cord obliques. The percent total lung volume receiving 20 Gy or higher (V20) and mean lung dose (MLD) were correlated with the incidence of radiation pneumonitis. Parameters from both heterogeneity-corrected and heterogeneity-uncorrected plans were used to assess this risk.Univariate analysis revealed a significant correlation between the development of radiation pneumonitis and both V20 and MLD. A best-fit line to a plot of V20 from the homogeneous plan against the corresponding V20 heterogeneous value produced a slope of 1.00 and zero offset, indicating no difference between the two parameters. For MLD, a similarly significant correlation is seen between the heterogeneous and homogeneous parameters, indicating a 4% difference when correcting for heterogeneity. A significant correlation was also observed between the MLD and V20 parameters (p < 0.0001).A high degree of correlation exists between heterogeneity-corrected and heterogeneity-uncorrected dosimetric parameters for lung and the risk of developing pneumonitis. Either V20 or MLD predicts the pneumonitis risk with similar effect.

View details for DOI 10.1016/j.ijrobp.2005.09.047

View details for Web of Science ID 000238162600018

View details for PubMedID 16427214
Re-examining the role of elective nodal irradiation - Finding ways to maximize the therapeutic ratio AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Chang, D. T., Zlotecki, R. A., Olivier, K. R. 2005; 28 (6): 597-602
Abstract

Elective nodal irradiation (ENI) of regional lymphatics has been a foundational paradigm for radiation oncologists in the treatment of nonsmall-cell lung cancer (NSCLC), but its utility has recently been called into question. This review summarizes the controversies surrounding ENI and reviews the therapeutic options available to treat regional lymphatics in NSCLC.Local failure after conventional radiotherapy (RT) occurs in 40% to 80% of patients fueling the investigation of more aggressive RT regimens. As the dose is increased and accelerated the volume of normal lung tissue treated becomes a limiting factor. Thus elimination of ENI followed by further dose escalation has become a commonly pursued solution. When ENI is excluded, treatment is restricted to clinically positive disease and negative lymph node stations are left untreated.Radiographic and surgical data suggest our ability to determine the true extent of disease is imperfect and therefore the elimination of ENI likely leaves microscopic NSCLC untreated.At our institution we have concluded that the prophylactic treatment of regional lymph nodes is best reserved for patients most likely to achieve local control and are designing treatment protocols including chemotherapy to take advantage of this improvement in local control.

View details for DOI 10.1097/01.coc.0000187927.06051.ec

View details for Web of Science ID 000233811900012

View details for PubMedID 16317271
Merkel cell carcinoma of the skin with leptomeningeal metastases AMERICAN JOURNAL OF OTOLARYNGOLOGY Chang, D. T., Mancuso, A. A., Riggs, C. E., Mendenhall, W. M. 2005; 26 (3): 210-213
Abstract

Merkel cell carcinoma is a rare skin tumor that is thought to arise from epithelial cells that have undergone neuroendocrine differentiation. It usually presents in older adults and has a slight male predominance. The most frequent site of occurrence is in the head and neck. It is an aggressive disease that has a high rate of local-regional and distant recurrence. Optimal treatment is controversial but generally consists of surgery and adjuvant radiotherapy. The role of chemotherapy is less defined. This report documents the first known case of Merkel cell carcinoma with perineural spread to the central nervous system with leptomeningeal dissemination. Whether this represents a more aggressive variant is unknown. Regardless, this pattern of spread is likely a rare event.

View details for DOI 10.1016/j.amjoto.2004.11.013

View details for Web of Science ID 000229206000013

View details for PubMedID 15858780
Role of p53 in cell cycle regulation and apoptosis following exposure to proteasome inhibitors CELL GROWTH & DIFFERENTIATION Chen, F., Chang, D., Goh, M., Klibanov, S. A., Ljungman, M. 2000; 11 (5): 239-246
Abstract

In this study, we explored what effect inhibitors of the 26S proteasome have on cell cycle distribution and induction of apoptosis in human skin fibroblasts and colon cancer cells differing in their p53 status. We found that proteasome inhibition resulted in nuclear accumulation of p53. This was surprising because it is thought that the degradation of p53 is mediated by cytoplasmic 26S proteasomes. Nuclear accumulation of p53 was accompanied by the induction of both p21WAF1 mRNA and protein as well as a decrease in cells entering S phase. Interestingly, cells with compromised p53 function showed a marked increase in the proportion of cells in the G2-M phase of the cell cycle and an attenuated induction of apoptosis after proteasome inhibition. Taken together, our results suggest that proteasome inhibition results in nuclear accumulation of p53 and a p53-stimulated induction of both G1 arrest and apoptosis.

View details for Web of Science ID 000087482700002

View details for PubMedID 10845424
Dose-dependent effects of DNA-damaging agents on p53-mediated cell cycle arrest CELL GROWTH & DIFFERENTIATION Chang, D., Chen, F., Zhang, F. F., McKay, B. C., Ljungman, M. 1999; 10 (3): 155-162
Abstract

We examined the dose-dependent effects of DNA-damaging agents on G1 arrest in isogenic human cell lines differing in their p53 status. As expected, 5 or 20 Gy of ionizing radiation induced a p53-dependent G1 arrest. In contrast, UV light or actinomycin D induced a modest G1 arrest that was p53-dependent only at lower doses. At higher doses, cells were arrested in G1 in a p53-independent manner coinciding with inhibition of RNA synthesis and abolished cyclin E expression. Interestingly, expression of cyclin E was enhanced after exposure to moderate doses of UV light and actinomycin D, and this enhancement was suppressed by wild-type p53. We propose that agents inducing transcription-blocking DNA lesions will at higher doses inhibit the progression of cells into S phase by a p53-independent mechanism involving the attenuation of E2F-mediated transcription of genes, such as cyclin E.

View details for Web of Science ID 000079180000003

View details for PubMedID 10099829

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