Daniel Chang

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

Abstract

OBJECTIVES/HYPOTHESIS: 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. STUDY DESIGN: Retrospective cohort study. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LEVEL OF EVIDENCE: 4. Laryngoscope, 2013.

View details for DOI 10.1002/lary.24081

View details for Web of Science ID 000326231200029

View details for PubMedID 23553253

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

Abstract

PURPOSE: To report outcomes in patients treated with postoperative radiotherapy for nonadenoid cystic carcinomas of the major salivary glands. MATERIALS AND METHODS: From 1998-2011, 37 patients with nonadenoid cystic carcinomas of the major salivary gland underwent postoperative radiotherapy. The median radiation dose was 60Gy (range, 45-70Gy). 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 4.7years for all patients (range, 0.3-14.1years) and 5.0years for living patients (range, 1.2-12.2years). RESULTS: 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 ≥65years 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 >60Gy 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. CONCLUSIONS: 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

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 Web of Science ID 000317308200032

View details for PubMedID 23149854

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

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 PubMedID 23800897

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 Web of Science ID 000313606800026

View details for PubMedID 23236018

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 PubMedID 23681075

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

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

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 Web of Science ID 000308712300008

View details for PubMedID 22168251

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 Web of Science ID 000306128100022

View details for PubMedID 22554582

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 Web of Science ID 000306128100047

View details for PubMedID 22270168

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

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 Web of Science ID 000307222200008

View details for PubMedID 22481281

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

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 Web of Science ID 000302814000013

View details for PubMedID 22314188

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 Web of Science ID 000301989100016

View details for PubMedID 22341260

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 Web of Science ID 000299834300031

View details for PubMedID 21773972

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 Web of Science ID 000298846500003

View details for PubMedID 21617522

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

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

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

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 Web of Science ID 000294924800030

View details for PubMedID 21432842

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 Web of Science ID 000293103800008

View details for PubMedID 21287530

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 Web of Science ID 000293207600020

View details for PubMedID 20675073

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

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

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 Web of Science ID 000286290400017

View details for PubMedID 20848427

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 Web of Science ID 000292117400021

View details for PubMedID 21625166

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 Web of Science ID 000284380900001

View details for PubMedID 21059255

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

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

View details for DOI 10.1111/j.1463-1318.2009.02013.x

View details for Web of Science ID 000208355900003

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 Web of Science ID 000276675300012

View details for PubMedID 19540068

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 Web of Science ID 000275897900012

View details for PubMedID 20189509

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 Web of Science ID 000274121500040

View details for PubMedID 19879062

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 Web of Science ID 000278109300005

View details for PubMedID 19732129

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 Web of Science ID 000272889900001

View details for PubMedID 20003342

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

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 Web of Science ID 000268761600007

View details for PubMedID 19398901

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 Web of Science ID 000268761600014

View details for PubMedID 19415029

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 Web of Science ID 000266733600002

View details for PubMedID 19433961

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 Web of Science ID 000264358900038

View details for PubMedID 19304719

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

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 Web of Science ID 000263075000012

View details for PubMedID 19019700

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 Web of Science ID 000263003400025

View details for PubMedID 19117351

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

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

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

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

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

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

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

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

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