A. Dimitrios Colevas

All Publications

• Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. The Journal of clinical investigation Nambiar, D. K., Aguilera, T., Cao, H., Kwok, S., Kong, C., Bloomstein, J., Wang, Z., Rangan, V. S., Jiang, D., von Eyben, R., Liang, R., Agarwal, S., Colevas, A. D., Korman, A., Allen, C. T., Uppaluri, R., Koong, A. C., Giaccia, A., Le, Q. T. 2019

  Abstract

  Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.

  View details for DOI 10.1172/JCI129025

  View details for PubMedID 31710313

• Optical molecular imaging can differentiate metastatic from benign lymph nodes in head and neck cancer. Nature communications Nishio, N., van den Berg, N. S., van Keulen, S., Martin, B. A., Fakurnejad, S., Teraphongphom, N., Chirita, S. U., Oberhelman, N. J., Lu, G., Horton, C. E., Kaplan, M. J., Divi, V., Colevas, A. D., Rosenthal, E. L. 2019; 10 (1): 5044

  Abstract

  Identification of lymph node (LN) metastasis is essential for staging of solid tumors, and as a result, surgeons focus on harvesting significant numbers of LNs during ablative procedures for pathological evaluation. Isolating those LNs most likely to harbor metastatic disease can allow for a more rigorous evaluation of fewer LNs. Here we evaluate the impact of a systemically injected, near-infrared fluorescently-labeled, tumor-targeting contrast agent, panitumumab-IRDye800CW, to facilitate the identification of metastatic LNs in the ex vivo setting for head and neck cancer patients. Molecular imaging demonstrates a significantly higher mean fluorescence signal in metastatic LNs compared to benign LNs in head and neck cancer patients undergoing an elective neck dissection. Molecular imaging to preselect at-risk LNs may thus allow a more rigorous examination of LNs and subsequently lead to improved prognostication than regular neck dissection.

  View details for DOI 10.1038/s41467-019-13076-7

  View details for PubMedID 31695030

• Assessing Care Value for Older Patients Receiving Radiotherapy With or Without Cisplatin or Cetuximab for Locoregionally Advanced Head and Neck Cancer. JAMA otolaryngology-- head & neck surgery Saraswathula, A., Chen, M. M., Colevas, A. D., Divi, V. 2019

  Abstract

  Importance: Clinicians frequently use radiotherapy with cetuximab over radiotherapy only or radiotherapy with cisplatin because of a perceived survival and tolerability advantage, but scant data are available to support this perception.Objective: To measure the 3 aspects of value (quality, outcomes, and cost) in older patients receiving radiotherapy only, radiotherapy with cisplatin, or radiotherapy with cetuximab for locoregionally advanced head and neck cancer.Design, Setting, and Participants: For this cohort study, patient records were obtained from the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare outcomes and claims database from January 1, 2004, to December 31, 2014. Participants were 65 years or older; received a diagnosis between 2006 and 2013 of stages III to IVB head and neck cancer; had only 1 cancer on record; and did not undergo surgical intervention. Data analysis was conducted from February 5, 2018, to March 27, 2019.Exposures: Patients were divided into exposure arms on the basis of their first-line therapy or identified chemoradiotherapy and radiotherapy regimen.Main Outcomes and Measures: Overall survival was analyzed by propensity score matching Cox proportional hazards regression models, quality by measuring 90-day emergency department (ED) visit and inpatient admission rates, and costs by assessing 90-day total Medicare spending.Results: The overall cohort included 1091 patients, of whom 815 (74.7%) were male; the mean (SD) age was 73.9 (6.6) years. Patients receiving radiotherapy with cisplatin had higher overall survival compared with those receiving radiotherapy only (adjusted hazard ratio [HR], 0.64; 95% CI, 0.47-0.87). This finding was not seen in patients receiving radiotherapy with cetuximab (adjusted HR, 0.95; 95% CI, 0.75-1.20), compared with the radiotherapy only group, and it persisted after stratifying patients by age. The ED visit (adjusted incidence rate ratio [IRR], 1.72; 95% CI, 1.30-2.30) and inpatient admission (adjusted IRR, 1.48; 95% CI, 1.12-1.98) rates in the 90 days after treatment start were higher in patients receiving radiotherapy with cisplatin compared with those treated with radiotherapy only. Patients receiving radiotherapy with cetuximab had a higher rate of ED visits (adjusted IRR, 1.38; 95% CI, 1.05-1.82) compared with those in the radiotherapy only group. The 90-day after-treatment spending for patients receiving radiotherapy with cetuximab was $48?620 (95% CI, $46?466-$50?775) compared with $33?009 (95% CI, $31?499-$34?519) for radiotherapy with cisplatin and $27?622 (95% CI, $25?118-$30?126) for radiotherapy only.Conclusions and Relevance: In this cohort study, no survival difference, a higher rate of ED visits but not of inpatient admissions, and higher spending were observed in patients receiving radiotherapy with cetuximab compared with patients receiving radiotherapy only. The findings suggest that radiotherapy alone should be maintained as a treatment arm in evaluation of novel therapeutics for locoregionally advanced head and neck cancer in older and sicker patients.

  View details for DOI 10.1001/jamaoto.2019.2381

  View details for PubMedID 31621810

• Probe-based fluorescence dosimetry of an antibody-dye conjugate to identify head and neck cancer as a first step to fluorescence-guided tissue preselection for pathological assessment. Head & neck Nishio, N., van Keulen, S., van den Berg, N. S., Lu, G., LaRochelle, E. P., Davis, S. C., Martin, B. A., Fakurnejad, S., Zhou, Q., Birkeland, A. C., Kaplan, M. J., Divi, V., Colevas, A. D., Pogue, B. W., Rosenthal, E. L. 2019

  Abstract

  BACKGROUND: Despite the rapid growth of fluorescence imaging, accurate sampling of tissue sections remains challenging. Development of novel technologies to improve intraoperative assessment of tissue is needed.METHODS: A novel contact probe-based fluorescence dosimeter device, optimized for IRDye800CW quantification, was developed. After evaluation of the device in a phantom setup, its clinical value was defined ex vivo in patients with head and neck squamous cell carcinoma who received panitumumab-IRDye800CW.RESULTS: Ten patients were enrolled with a total of 216 data points obtained. Final histopathology showed tumor in 119 spots and normal tissue in 97 spots. Fluorescence-to-excitation ratios in tumor tissue were more than three times higher than those in normal tissue. The area under the curve was 0.86 (95% CI: 0.81-0.91) for tumor detection.CONCLUSIONS: Fluorescence-guided tissue preselection using a fluorescence dosimeter could have substantial impact on tissue sampling for frozen section analysis and potentially reduce sampling errors.

  View details for DOI 10.1002/hed.25964

  View details for PubMedID 31571335

• Fluorescence molecular imaging for identification of high-grade dysplasia in patients with head and neck cancer. Oral oncology Fakurnejad, S., van Keulen, S., Nishio, N., Engelen, M., van den Berg, N. S., Lu, G., Birkeland, A., Baik, F., Colevas, A. D., Rosenthal, E. L., Martin, B. A. 2019; 97: 50?55

  Abstract

  OBJECTIVE: High-grade dysplasia is associated with a risk of malignant transformation, and it is necessary to distinguish from normal epithelium or low-grade dysplasia, especially in the intraoperative setting. We hypothesize that an anti-epidermal growth factor receptor (EGFR) contrast agent can be used to differentiate high-grade dysplasia from low-grade dysplasia and normal epithelium.MATERIALS AND METHODS: Patients with biopsy proven head and neck squamous cell carcinoma (HNSCC) were enrolled in a clinical trial using systemically injected fluorescently labeled anti-EGFR antibody (panitumumab-IRDye800CW) (NCT02415881). Paraffin embedded tumor specimens from 11 patients were evaluated by fluorescence histopathology. Hematoxylin and eosin (H&E) slides were reviewed by a board-certified pathologist, and regions of invasive squamous cell carcinoma, high-grade dysplasia and low-grade dysplasia were delineated. EGFR expression was assessed for each patient by way of immunohistochemistry.RESULTS: 11 patients were included in the study with a total of 219 areas on tissue sections analyzed; 68 normal epithelium, 53 low-grade dysplasia, 48 high-grade dysplasia, and 50 malignant regions. The signal-to-background ratio (SBR) increased proportionally with increasing grade of dysplasia; normal epithelium (1.5?±?0.1), low-grade dysplasia (1.8?±?0.1), high-grade dysplasia: (2.3?±?0.2). High-grade dysplasia had a significantly higher SBR when compared to normal or low-grade dysplasia (p?

  View details for DOI 10.1016/j.oraloncology.2019.08.008

  View details for PubMedID 31421471

• Cost comparison of treatment for oropharyngeal carcinoma LARYNGOSCOPE Tam, K., Orosco, R. K., Colevas, A., Bedi, N., Starmer, H. M., Beadle, B. M., Holsinger, F. 2019; 129 (7): 1604?9

  View details for DOI 10.1002/lary.27544

  View details for Web of Science ID 000471915700026

• Current Treatment Landscape of Nasopharyngeal Carcinoma and Potential Trials Evaluating the Value of Immunotherapy JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Le, Q., Colevas, A., OSullivan, B., Lee, A. M., Lee, N., Ma, B., Siu, L. L., Waldron, J., Lim, C., Riaz, N., Lynn, J., Malik, S. 2019; 111 (7): 655?63

  View details for DOI 10.1093/jnci/djz044

  View details for Web of Science ID 000484372900006

• Nivolumab treatment beyond RECIST-defined progression in recurrent or metastatic squamous cell carcinoma of the head and neck in CheckMate 141: A subgroup analysis of a randomized phase 3 clinical trial. Cancer Haddad, R., Concha-Benavente, F., Blumenschein, G. J., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Kasper, S., Vokes, E. E., Worden, F., Saba, N. F., Tahara, M., Jayaprakash, V., Lynch, M., Li, L., Gillison, M. L., Harrington, K. J., Ferris, R. L. 2019

  Abstract

  BACKGROUND: Response patterns with immune checkpoint inhibitors may be different from those with chemotherapy. Therefore, assessment of response to immunotherapy with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, could result in premature treatment termination. The randomized, open-label, phase 3 CheckMate 141 trial (NCT02105636), which evaluated nivolumab in recurrent/metastatic squamous cell carcinoma of the head and neck after platinum therapy, allowed treatment beyond first RECIST-defined progression (TBP) according to protocol-specified criteria.METHODS: In CheckMate 141, patients with RECIST-defined progression who had a stable performance status and demonstrated clinical benefit without rapid disease progression were permitted to receive TBP with nivolumab at 3 mg/kg every 2 weeks until further progression, which was defined as an additional ?10% increase in tumor volume. This post hoc analysis evaluated outcomes for patients who received TBP with nivolumab.RESULTS: Of 240 patients randomized to nivolumab, 146 experienced RECIST-defined progression. Sixty-two of these patients received TBP, and 84 discontinued treatment (no TBP). Among the 60 TBP patients evaluable for response, 15 (25%) had no change in their tumor burden, and 15 (25%) had reductions in target lesion size; 3 patients (5%) had reductions >30%. The median overall survival among TBP patients was 12.7 months (95% confidence interval, 9.7-14.6 months). No new safety signals were observed with TBP. Exploratory analyses of immune cell biomarkers suggested a potential relationship with initial and TBP responses.CONCLUSIONS: Tumor burden reduction was noted in a proportion of patients who received TBP with nivolumab in CheckMate 141. Additional research is warranted to identify factors predictive of a TBP benefit in this population.

  View details for DOI 10.1002/cncr.32190

  View details for PubMedID 31246283

• Nivolumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: Efficacy and Safety in CheckMate 141 by Prior Cetuximab Use. Clinical cancer research : an official journal of the American Association for Cancer Research Ferris, R. L., Licitra, L., Fayette, J., Even, C., Blumenschein, G. R., Harrington, K. J., Guigay, J., Vokes, E. E., Saba, N. F., Haddad, R. I., Ramkumar, S., Russell, J., Brossart, P., Tahara, M., Colevas, A. D., Concha-Benavente, F., Lynch, M., Li, L., Gillison, M. L. 2019

  Abstract

  PURPOSE: Cetuximab, which modulates immune responses, may affect the efficacy of subsequent immunotherapy. Here, we assessed outcomes with nivolumab, by prior cetuximab exposure, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) who had experienced progression within 6 months of platinum-containing chemotherapy.EXPERIMENTAL DESIGN: In the randomized, open-label, phase III CheckMate 141 trial, patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC) of single-agent chemotherapy, with stratification by prior cetuximab exposure. The primary endpoint was overall survival (OS); additional endpoints were progression-free survival, objective response rate, and safety.RESULTS: In patients with prior cetuximab exposure, the median OS was 7.1 months with nivolumab versus 5.1 months with IC (HR, 0.84; 95% CI, 0.62-1.15); OS benefit with nivolumab was maintained across most demographic subgroups. In patients without prior cetuximab exposure, the median OS was 8.2 months with nivolumab versus 4.9 months with IC (HR, 0.52; 95% CI, 0.35-0.77); OS benefit with nivolumab was maintained across patient baseline subgroups including tumor programmed death ligand 1 (PD-L1) expression (<1% or ?1%). Grade 3-4 treatment-related adverse event rates favored nivolumab versus IC in both subgroups.CONCLUSIONS: Nivolumab appeared to improve efficacy versus IC regardless of prior cetuximab use, supporting its use in patients with R/M SCCHN with or without prior cetuximab exposure. The reduction in risk of death with nivolumab compared with IC was greater in patients without prior cetuximab exposure versus with prior cetuximab exposure.

  View details for DOI 10.1158/1078-0432.CCR-18-3944

  View details for PubMedID 31239321

• The Clinical Application of Fluorescence-Guided Surgery in Head and Neck Cancer JOURNAL OF NUCLEAR MEDICINE van Keulen, S., Nishio, N., Fakurnejad, S., Birkeland, A., Martin, B. A., Lu, G., Zhou, Q., Chirita, S. U., Forouzanfar, T., Colevas, A., van den Berg, N. S., Rosenthal, E. L. 2019; 60 (6): 758?63

  View details for DOI 10.2967/jnumed.118.222810

  View details for Web of Science ID 000470084400020

• The Sentinel Margin: Intraoperative ex-vivo Specimen Mapping Using Relative Fluorescence Intensity. Clinical cancer research : an official journal of the American Association for Cancer Research van Keulen, S., Nishio, N., Birkeland, A., Fakurnejad, S., Martin, B. A., Forouzanfar, T., Cunanan, K., Colevas, A. D., van den Berg, N. S., Rosenthal, E. L. 2019

  Abstract

  PURPOSE: Despite major advancements in surgical oncology, the positive margin rate for primary head and neck cancer resection remains around 15-30%. In particular, the deep surface margin is the most challenging to adequately assess. Inadequate margins are directly correlated to poor survival, and as such, mitigation of these rates is critical to improve patient outcomes. We have developed an ex vivo imaging strategy that utilizes fluorescence intensity-peaks (relative to background signal) of an injected anti-epidermal growth factor receptor antibody conjugated to a fluorescent probe to locate potential close or positive margins on the deep surface of the resected tumor specimen.EXPERIMENTAL DESIGN: Twelve patients with head and neck cancer scheduled for surgery received systemic administration of a tumor-specific contrast-agent (panitumumab-IRDye800). After surgical resection, the tumor specimen was imaged using a fluorescence imager. The three highest fluorescence intensity-peaks on the deep surface of the specimen were isolated and correlated to histology to determine the margin distance at these regions.RESULTS: Relative fluorescence peak-intensities identified the closest margin on the deep surface of the specimen within 2.5 minutes. The highest intensity-peak consistently (100%) detected the closest margin to the tumor. The difference in tumor margin distance between the first and second highest fluorescence intensity-peak averaged 2.1±1.4mm. The tumor-margin difference between the second and third highest peak averaged 1.6±0.6mm.CONCLUSIONS: Fluorescence intensity-peaks can identify the region on the specimen where tumor is closest to specimen's edge on the deep surface. This technique could have broad applications in obtaining adequate margins in oncological surgery.

  View details for DOI 10.1158/1078-0432.CCR-19-0319

  View details for PubMedID 31142505

• Safety and disease control achieved with the addition of nivolumab (Nivo) to chemoradiotherapy (CRT) for intermediate (IR) and high-risk (HR) local-regionally advanced head and neck squamous cell carcinoma (HNSCC): RTOG Foundation 3504. Gillison, M. L., Ferris, R. L., Harris, J., Colevas, A., Mell, L. K., Kong, C., Jordan, R. C., Moore, K., Minh Tam Truong, Kirsch, C., Clump, D., Ohr, J., He, K., Blakaj, D., Deeken, J. F., Machtay, M., Curran, W., Quynh-Thu Le AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.6073

  View details for Web of Science ID 000487345806038

• Tabelecleucel in combination with pembrolizumab (Pembro) in platinum-pretreated, recurrent/metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (EBV plus NPC). Siu, L. L., Bauml, J., Adkins, D., Colevas, A., Perez, C., Choe, J., Zhang, Y., Shi, W., Navarro, W. H., Haigentz, M., Rabinowits, G., Pfister, D. G. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.TPS6092

  View details for Web of Science ID 000487345803410

• Optimal Dosing Strategy for Fluorescence-Guided Surgery with Panitumumab-IRDye800CW in Head and Neck Cancer. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Nishio, N., van den Berg, N. S., van Keulen, S., Martin, B. A., Fakurnejad, S., Zhou, Q., Lu, G., Chirita, S. U., Kaplan, M. J., Divi, V., Colevas, A. D., Rosenthal, E. L. 2019

  Abstract

  PURPOSE: To identify the optimal dosing strategy for fluorescence-guided surgery in patients with head and neck squamous cell carcinoma, we conducted a dose-ranging study evaluating the anti-epidermal growth factor receptor (EGFR) therapeutic antibody, panitumumab, that was fluorescently labeled with the near-infrared dye IRDye800CW.PROCEDURES: Patients (n=24) received either 0.5 or 1.0mg/kg panitumumab-IRDye800CW in the weight-based dosing group or 25 or 50mg panitumumab-IRDye800CW in the fixed dosing group. Following surgery, whole primary specimens were imaged in a closed-field device and the mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were assessed. Clinical variables, including dose, time of infusion-to-surgery, age, unlabeled dose, gender, primary tumor site, and tumor size, were analyzed to evaluate the factors affecting the fluorescence intensity in order to identify the optimal dose for intraoperative fluorescence imaging.RESULTS: A total of 24 primary tumor specimens were imaged and analyzed in this study. Although no correlations between TBR and dose of panitumumab-IRDye800CW were found, there were moderate-strong correlations between the primary tumor MFI and panitumumab-IRDye800CW dose for fixed dose (mg) (R2=0.42) and for dose/weight (mg/kg) (R2=0.54). Results indicated that the optimal MFI was at approximately 50mg for fixed dose and 0.75mg/kg for dose/weight. No significant differences were found for the primary tumor MFI and TBRs between the weight-based dosing and the fixed dosing groups. MFIs significantly increased when the infusion-to-surgery window was reduced to within 2days (vs. 3days or more, p<0.05).CONCLUSIONS: Antibody-based imaging for surgical resection is under investigation in multiple clinical trials. Our data suggests that a fixed dose of 50mg is an appropriate diagnostic dose for successful surgical fluorescence imaging.

  View details for PubMedID 31054001

• Pembrolizumab with or without vismodegib for advanced basal cell carcinoma: An investigator-initiated, proof-of-concept study Chang, A., Tran, D. C., Cannon, J., Li, S., Jeng, M., Rieger, K., Sarin, K. Y., Yost, K., Satpathy, A., Reddy, S., Colevas, A. ELSEVIER SCIENCE INC. 2019: S92

  View details for Web of Science ID 000465561503249

• First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers JOURNAL OF CLINICAL ONCOLOGY Sikic, B., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. 2019; 37 (12): 946-+

  View details for DOI 10.1200/JCO.18.02018

  View details for Web of Science ID 000466717700002

• Current Treatment Landscape of Nasopharyngeal Carcinoma and Potential Trials Evaluating the Value of Immunotherapy. Journal of the National Cancer Institute Thu Le, Q., Dimitrios Colevas, A., O'Sullivan, B., Lee, A. W., Lee, N., Ma, B., Siu, L. L., Waldron, J., Lim, C., Riaz, N., Lynn, J., Malik, S. 2019

  Abstract

  Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with a distinctive regional and racial prevalence. It is associated with Epstein Barr Virus infection and has a high propensity for regional and distant metastases, while at the same time it is very sensitive to radiation and chemotherapy. A common feature of Epstein Barr Virus-positive NPC is the dense infiltration of lymphocytes in the tumor stroma and positive PD-L1 expression in tumor cells, making it an attractive target for immunotherapy, especially immune checkpoint inhibitors. As new immunotherapeutic agents are being rapidly adopted in many cancers, including head and neck cancer, the National Cancer Institute sponsored a Clinical Trial Planning Meeting to identify opportunities for developing phase II and III trials testing immunotherapy in different stages of NPC. The meeting started with the summary of the biology of the disease, current standards of care and evidence of immunotherapy in this cancer. Three subcommittees were tasked to develop clinical trials: loco-regionally advanced, non-metastatic NPC; widely metastatic NPC; and either local-recurrence after initial treatment or presenting with oligometastatic disease. This article summarizes the proceedings of this Clinical Trial Planning Meeting and provides a roadmap for future trials incorporating immune checkpoint inhibitors for therapeutic management of NPC. This roadmap, though specific for NPC, may also be applicable to other virally-driven cancers that have similar ability to evade the host's immune system.

  View details for PubMedID 30912808

• First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Sikic, B. I., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A. D., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. 2019: JCO1802018

  Abstract

  PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis.PATIENTS AND METHODS: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort.RESULTS: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months.CONCLUSION: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

  View details for PubMedID 30811285

• The Clinical Application of Fluorescence-Guided Surgery in Head and Neck Cancer. Journal of nuclear medicine : official publication, Society of Nuclear Medicine van Keulen, S., Nishio, N., Fakurnejad, S., Birkeland, A., Martin, B. A., Lu, G., Zhou, Q., Chirita, S. U., Forouzanfar, T., Colevas, D., van den Berg, N. S., Rosenthal, E. L. 2019

  Abstract

  Although surgical resection has been the primary treatment modality of solid tumors for decades, surgeons still rely on visual cues and palpation to delineate healthy from cancerous tissue. This may contribute to the high rate (up to 30%) of positive margins in head and neck cancer resections. Margin status in these patients is the most important prognostic factor for overall survival. In addition, second primary lesions may be present at the time of surgery. Although often unnoticed by the medical team, these lesions can have significant survival ramifications. We hypothesize that real-time fluorescence imaging can enhance intraoperative decision-making by aiding the surgeon in detecting close or positive margins and visualizing unanticipated regions of primary disease. The purpose of this study was to assess the clinical utility of real-time fluorescence imaging for intraoperative decision-making. Methods: Head and neck cancer patients (n = 14) scheduled for curative resection were enrolled in a clinical trial evaluating panitumumab-IRDye800CW for surgical guidance (NCT02415881). Open-field fluorescence imaging was performed throughout the surgical procedure. The fluorescence signal was quantified as signal-to-background ratios to characterize the fluorescence contrast of regions of interest relative to background. Results: Fluorescence imaging was able to improve surgical decision-making in three cases (21.4%); identification of a close margin (n = 1) and unanticipated regions of primary disease (n = 2). Conclusion: This study demonstrates the clinical applications of fluorescence imaging on intraoperative decision-making. This information is required for designing phase III clinical trials using this technique. Furthermore, this study is the first to demonstrate this application for intraoperative decision-making during resection of primary tumors.

  View details for PubMedID 30733319

• Pembrolizumab for advanced basal cell carcinoma: An investigator-initiated, proof-of-concept study JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chang, A. S., Tran, D. C., Cannon, J. D., Li, S., Jeng, M., Patel, R., Van der Bokke, L., Pague, A., Brotherton, R., Rieger, K. E., Satpathy, A. T., Yost, K. E., Reddy, S., Sarin, K., Colevas, A. 2019; 80 (2): 564?66

  View details for DOI 10.1016/j.jaad.2018.08.017

  View details for Web of Science ID 000455473200042

• Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial LANCET Gillison, M. L., Trotti, A. M., Harris, J., Eisbruch, A., Harari, P. M., Adelstein, D. J., Sturgis, E. M., Burtness, B., Ridge, J. A., Ringash, J., Galvin, J., Yao, M., Koyfman, S. A., Blakaj, D. M., Razaq, M. A., Colevas, A., Beitler, J. J., Jones, C. U., Dunlap, N. E., Seaward, S. A., Spencer, S., Galloway, T. J., Phan, J., Dignam, J. J., Quynh Thu Le 2019; 393 (10166): 40?50

  View details for DOI 10.1016/S0140-6736(18)32779-X

  View details for Web of Science ID 000454925000031

• Rapid, non-invasive fluorescence margin assessment: Optical specimen mapping in oral squamous cell carcinoma. Oral oncology van Keulen, S., van den Berg, N. S., Nishio, N., Birkeland, A., Zhou, Q., Lu, G., Wang, H., Middendorf, L., Forouzanfar, T., Martin, B. A., Colevas, A. D., Rosenthal, E. L. 2019; 88: 58?65

  Abstract

  OBJECTIVE: Surgical resection remains the primary treatment for the majority of solid tumors. Despite efforts to obtain wide margins, close or positive surgical margins (<5?mm) are found in 15-30% of head and neck cancer patients. Obtaining negative margins requires immediate, intraoperative feedback of margin status. To this end, we propose optical specimen mapping of resected tumor specimens immediately after removal.MATERIALS AND METHODS: A first-in-human pilot study was performed in patients (n?=?8) after infusion of fluorescently labeled antibody, panitumumab-IRDye800 to allow surgical mapping of the tumor specimen. Patients underwent standard of care surgical resection for head and neck squamous cell carcinoma (HNSCC). Optical specimen mapping was performed on the primary tumor specimen and correlated with pathological findings after tissue processing.RESULTS: Optical mapping of the specimen had a 95% sensitivity and 89% specificity to detect cancer within 5?mm (n?=?160) of the cut surface. To detect tumor within 2?mm of the specimen surface, the sensitivity of optical specimen mapping was 100%. The maximal observed penetration depth of panitumumab-IRDye800 through human tissue in our study was 6.3?mm.CONCLUSION: Optical specimen mapping is a highly sensitive and specific method for evaluation of margins within <5?mm of the tumor mass in HNSCC specimens. This technology has potentially broad applications for ensuring adequate tumor resection and negative margins in head and neck cancers.

  View details for PubMedID 30616798

• Intraoperative Tumor Assessment Using Real-Time Molecular Imaging in Head and Neck Cancer Patients. Journal of the American College of Surgeons Keulen, S. v., Nishio, N., Fakurnejad, S., van den Berg, N. S., Lu, G., Birkeland, A., Martin, B. A., Forouzanfar, T., Dimitrios Colevas, A., Rosenthal, E. L. 2019

  Abstract

  In head and neck cancer, surgical resection using primarily visual and tactile feedback is considered gold standard for solid tumors. Due to high numbers of tumor-involved surgical margins which are directly correlated to poor clinical outcome, intraoperative optical imaging trials have rapidly proliferated over the past five years. However, few studies report on intraoperative in situ imaging data that could support surgical resection. To demonstrate the clinical application of in situ surgical imaging, we report on the imaging data that is directly (i.e. in real-time) available to the surgeon.Fluorescence intensities and tumor-to-background ratios (TBRs) were determined from the intraoperative imaging data - the view as seen by the surgeon during tumor resection - of 20 patients and correlated to patient and tumor characteristics including age, sex, tumor site, tumor size, histological differentiation and EGFR expression. Furthermore, different lighting conditions in regard to surgical workflow were evaluated.Under these circumstances, intraoperative TBRs of the primary tumors averaged 2.2±0.4 (range 1.5-2.9). Age, sex, tumor site, and tumor size did not have a significant effect on open-field intraoperative molecular imaging of the primary tumors (p>0.05). In addition, variation in EGFR expression levels or the presence of ambient light did not seem to alter TBRs.We present the results of successful in situ intraoperative imaging of primary tumors alongside the optimal conditions with respect to both molecular image acquisition and surgical workflow. This study illuminates the potentials of open-field molecular imaging to assist the surgeon in achieving successful cancer removal.

  View details for DOI 10.1016/j.jamcollsurg.2019.09.007

  View details for PubMedID 31568855

• Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy ANNALS OF ONCOLOGY Chen, Y., Wang, Y., Lv, J., Li, Y., Chua, M. K., Le, Q., Lee, N., Colevas, A., Seiwert, T., Hayes, D. N., Riaz, N., Vermorken, J. B., O'Sullivan, B., He, Q., Yang, X., Tang, L., Mao, Y., Sun, Y., Liu, N., Ma, J. 2019; 30 (1): 68?75

  View details for DOI 10.1093/annonc/mdy470

  View details for Web of Science ID 000459677700011

• Rapid, non-invasive fluorescence margin assessment: Optical specimen mapping in oral squamous cell carcinoma ORAL ONCOLOGY van Keulen, S., van den Berg, N. S., Nishio, N., Birkeland, A., Zhou, Q., Lu, G., Wang, H., Middendorf, L., Forouzanfar, T., Martin, B. A., Colevas, A., Rosenthal, E. L. 2019; 88: 58?65

  View details for DOI 10.1016/j.oraloncology.2018.11.012

  View details for Web of Science ID 000454890700010

• PD-L1 Expression and Tumor-Infiltrating Lymphocytes in High-Risk and Metastatic Cutaneous Squamous Cell Carcinoma OTOLARYNGOLOGY-HEAD AND NECK SURGERY Amoils, M., Kim, J., Lee, C., Sunwoo, J. B., Colevas, A., Aasi, S. Z., Hollmig, S., Ma, Y., Divi, V. 2019; 160 (1): 93?99

  View details for DOI 10.1177/0194599818788057

  View details for Web of Science ID 000454870600012

• Survival After Definitive Chemoradiotherapy With Concurrent Cisplatin or Carboplatin for Head and Neck Cancer. Journal of the National Comprehensive Cancer Network : JNCCN Xiang, M., Colevas, A. D., Holsinger, F. C., Le, Q. X., Beadle, B. M. 2019; 17 (9): 1065?73

  Abstract

  For definitive chemoradiotherapy (chemoRT) of head and neck squamous cell carcinoma (HNSCC), cisplatin is the preferred concurrent agent, with superiority over cetuximab for HPV-associated oropharyngeal squamous carcinoma recently shown in 2 randomized trials (RTOG 1016 and De-ESCALaTE). Patients who are not candidates for cisplatin may be treated with carboplatin instead, but its comparative efficacy is unclear. We analyzed nationwide patterns of care and cancer-specific outcomes after cisplatin- versus carboplatin-based chemoRT.Patients with locoregionally advanced (stages III-IVB according to the 6th and 7th editions of the AJCC Cancer Staging Manual) squamous cell carcinoma of the oropharynx, larynx, or hypopharynx who received definitive radiotherapy (RT) were identified in the linked SEER-Medicare database. The concurrent chemotherapy regimen was determined through corresponding Medicare claims. Death caused by HNSCC (cancer-specific mortality [CSM]) was analyzed with competing risks. Propensity score analysis and multivariable Fine-Gray regression were used to adjust for baseline differences, including age and comorbidity.We identified 807 patients who received cisplatin-based chemoRT and 342 who received carboplatin-based chemoRT. Most carboplatin recipients (68%) had combination chemotherapy, predominantly with paclitaxel. Carboplatin- and cisplatin-based chemoRT had similar incidences of death attributable to HNSCC (3-year CSM, 29% vs 26%; P=.19), which persisted in propensity score-matched analysis. In addition, no significant difference in overall survival was seen in the matched cohorts. ChemoRT with either cisplatin or carboplatin was superior to RT alone and RT with concurrent cetuximab. In the multivariable model, the adjusted hazard ratio of CSM for carboplatin relative to cisplatin was 1.01 (95% CI, 0.79-1.28; P=.94).Definitive carboplatin-based chemoRT was equivalent to cisplatin-based therapy and superior to RT alone and RT with concurrent cetuximab. In light of recent results of the RTOG 1016 and De-ESCALaTE trials, our findings suggest that carboplatin-based regimens warrant prospective investigation as an alternative to cisplatin for patients who are not cisplatin candidates.

  View details for DOI 10.6004/jnccn.2019.7297

  View details for PubMedID 31487677

• Development and validation of radiomic signatures of head and neck squamous cell carcinoma molecular features and subtypes. EBioMedicine Huang, C., Cintra, M., Brennan, K., Zhou, M., Colevas, A. D., Fischbein, N., Zhu, S., Gevaert, O. 2019

  Abstract

  Radiomics-based non-invasive biomarkers are promising to facilitate the translation of therapeutically related molecular subtypes for treatment allocation of patients with head and neck squamous cell carcinoma (HNSCC).We included 113 HNSCC patients from The Cancer Genome Atlas (TCGA-HNSCC) project. Molecular phenotypes analyzed were RNA-defined HPV status, five DNA methylation subtypes, four gene expression subtypes and five somatic gene mutations. A total of 540 quantitative image features were extracted from pre-treatment CT scans. Features were selected and used in a regularized logistic regression model to build binary classifiers for each molecular subtype. Models were evaluated using the average area under the Receiver Operator Characteristic curve (AUC) of a stratified 10-fold cross-validation procedure repeated 10 times. Next, an HPV model was trained with the TCGA-HNSCC, and tested on a Stanford cohort (N?=?53).Our results show that quantitative image features are capable of distinguishing several molecular phenotypes. We obtained significant predictive performance for RNA-defined HPV+ (AUC?=?0.73), DNA methylation subtypes MethylMix HPV+ (AUC?=?0.79), non-CIMP-atypical (AUC?=?0.77) and Stem-like-Smoking (AUC?=?0.71), and mutation of NSD1 (AUC?=?0.73). We externally validated the HPV prediction model (AUC?=?0.76) on the Stanford cohort. When compared to clinical models, radiomic models were superior to subtypes such as NOTCH1 mutation and DNA methylation subtype non-CIMP-atypical while were inferior for DNA methylation subtype CIMP-atypical and NSD1 mutation.Our study demonstrates that radiomics can potentially serve as a non-invasive tool to identify treatment-relevant subtypes of HNSCC, opening up the possibility for patient stratification, treatment allocation and inclusion in clinical trials. FUND: Dr. Gevaert reports grants from National Institute of Dental & Craniofacial Research (NIDCR) U01 DE025188, grants from National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (NIBIB), R01 EB020527, grants from National Cancer Institute (NCI), U01 CA217851, during the conduct of the study; Dr. Huang and Dr. Zhu report grants from China Scholarship Council (Grant NO:201606320087), grants from China Medical Board Collaborating Program (Grant NO:15-216), the Cyrus Tang Foundation, and the Zhejiang University Education Foundation during the conduct of the study; Dr. Cintra reports grants from São Paulo State Foundation for Teaching and Research (FAPESP), during the conduct of the study.

  View details for DOI 10.1016/j.ebiom.2019.06.034

  View details for PubMedID 31255659

• NRG-RTOG 1016: Phase III Trial Comparing Radiation/Cetuximab to Radiation/Cisplatin in HPV-related Cancer of the Oropharynx Trotti, A., Harris, J., Gillison, M., Eisbruch, A., Harari, P. M., Adelstein, D. J., Sturgis, E. M., Galvin, J. M., Koyfman, S., Blakaj, D., Razaq, M. A., Colevas, A. D., Beitler, J. J., Jones, C. U., Dunlap, N. E., Seaward, S. A., Spencer, S. A., Ridge, J. A., Phan, J., Le, Q. T. ELSEVIER SCIENCE INC. 2018: 1604?5

  View details for DOI 10.1016/j.ijrobp.2018.08.051

  View details for Web of Science ID 000450453400047

• Survival of patients with head and neck cancer treated with definitive radiotherapy and concurrent cisplatin or concurrent cetuximab: A Surveillance, Epidemiology, and End Results-Medicare analysis CANCER Xiang, M., Holsinger, F., Colevas, A., Chen, M. M., Quynh-Thu Le, Beadle, B. M. 2018; 124 (23): 4486?94

  View details for DOI 10.1002/cncr.31708

  View details for Web of Science ID 000452622400012

• Cost comparison of treatment for oropharyngeal carcinoma. The Laryngoscope Tam, K., Orosco, R. K., Dimitrios Colevas, A., Bedi, N., Starmer, H. M., Beadle, B. M., Christopher Holsinger, F. 2018

  Abstract

  OBJECTIVES/HYPOTHESIS: Based on current guidelines, surgical and nonsurgical therapies are viable frontline treatment for patients with locoregional oropharyngeal carcinoma (OPC). We sought to compare financial parameters between chemoradiation and transoral robotic surgery (TORS) in this patient population.STUDY DESIGN: Case-control study.METHODS: In this study we identified patients with selected American Joint Committee on Cancer 7th Edition stage II to IVa OPC treated with TORS between January 2013 and December 2014. Fifteen patients who underwent TORS were stage matched with 15 patients treated with chemoradiation. Total charges and cost data for each patient were analyzed at 4-month and 1-year time points; functional and oncologic outcomes were assessed.RESULTS: There were no significant differences in functional and oncologic outcomes. Patients undergoing TORS had a longer inpatient hospital stay, and most required a nasogastric tube for an average of 3.5 days. There were no local or regional recurrences. Across all time points, the TORS group had lower charges and costs compared to the chemoradiation group, with 14% lower costs at 1 year. In the chemoradiation group, nearly two-thirds of costs came from radiation therapy and pharmacy expenses. Chemotherapy accounted for most pharmacy costs. The costs of operating the surgical robot accounted for a about half of surgical costs.CONCLUSIONS: Selected patients with stage II to IVa oropharyngeal carcinoma treated with TORS may incur lower costs than those treated nonsurgically. With rising healthcare spending, the financial impact of treatment might be considered for those patients eligible for treatment regimens with comparable functional and oncologic outcomes.LEVEL OF EVIDENCE: 3b Laryngoscope, 2018.

  View details for PubMedID 30485445

• Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet (London, England) Gillison, M. L., Trotti, A. M., Harris, J., Eisbruch, A., Harari, P. M., Adelstein, D. J., Sturgis, E. M., Burtness, B., Ridge, J. A., Ringash, J., Galvin, J., Yao, M., Koyfman, S. A., Blakaj, D. M., Razaq, M. A., Colevas, A. D., Beitler, J. J., Jones, C. U., Dunlap, N. E., Seaward, S. A., Spencer, S., Galloway, T. J., Phan, J., Dignam, J. J., Le, Q. T. 2018

  Abstract

  BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.METHODS: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (?10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834.FINDINGS: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups.INTERPRETATION: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.FUNDING: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.

  View details for PubMedID 30449625

• Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Annals of oncology : official journal of the European Society for Medical Oncology Chen, Y., Wang, Y., Lv, J., Li, Y., Chua, M. L., Le, Q., Lee, N., Colevas, A. D., Seiwert, T., Hayes, D. N., Riaz, N., Vermorken, J. B., O'Sullivan, B., He, Q., Yang, X., Tang, L., Mao, Y., Sun, Y., Liu, N., Ma, J. 2018

  Abstract

  Background: Targeting the immune checkpoint pathway has demonstrated anti-tumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its anti-tumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups.Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation.Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity and active interferon-gamma signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/TGF-beta signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes (TILs), high human papillomavirus (HPV) infection and favorable prognosis was associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to PD-1 blockade (P = 0.01).Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.

  View details for PubMedID 30407504

• Cisplatin or Carboplatin-Based Chemoradiation for Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck: A Population-Based Comparison Xiang, M., Holsinger, F. C., Colevas, A. D., Hara, W., Le, Q. T., Beadle, B. M. ELSEVIER SCIENCE INC. 2018: E371

  View details for DOI 10.1016/j.ijrobp.2018.07.1109

  View details for Web of Science ID 000447811601136

• Survival of patients with head and neck cancer treated with definitive radiotherapy and concurrent cisplatin or concurrent cetuximab: A Surveillance, Epidemiology, and End Results-Medicare analysis. Cancer Xiang, M., Holsinger, F. C., Colevas, A. D., Chen, M. M., Le, Q., Beadle, B. M. 2018

  Abstract

  BACKGROUND: Cisplatin and cetuximab are both systemic therapies commonly used in combination with radiation (RT) for the definitive treatment of head and neck cancers, but their comparative efficacy is unclear.METHODS: Patients with locoregionally advanced (American Joint Committee on Cancer stage III-IVB) squamous cell carcinomas of the oropharynx, larynx, or hypopharynx were identified in the Surveillance, Epidemiology, and End Results-Medicare database. Patients received either cisplatin or cetuximab concurrent with RT, as determined by Medicare claims. The primary study outcome was head and neck cancer-specific mortality (CSM) analyzed with competing risks. Filtering, propensity score matching, and multivariable Fine-Gray regression were used to adjust for differences between the cisplatin and cetuximab cohorts, including age, comorbidity, and cycles of systemic therapy received.RESULTS: The total cohort consisted of 1395 patients, of whom 786 (56%) received cisplatin and 609 (44%) received cetuximab; the median follow-up was 3.5 years in the patients who remained alive. In the cetuximab cohort, CSM was significantly higher than in the cisplatin cohort (39% vs 25% at 3 years; P < .0001). In the matched cohorts (n = 414), the adjusted hazard ratio of CSM for cetuximab was 1.65 (95% confidence interval, 1.30-2.09; P < .0001) relative to cisplatin, corresponding to an absolute difference of approximately 10% in both CSM and overall survival at 3 years. Cetuximab was associated with less dysphagia, more dermatitis, and a similar incidence of mucositis.CONCLUSIONS: In this sizeable, national patient population, treatment with cetuximab was associated with significantly higher CSM than cisplatin. These results suggest that cisplatin may be the preferred chemotherapeutic agent in this setting. Cancer 2018;124:000-000.

  View details for PubMedID 30332498

• Safety and Clinical Activity of Atezolizumab in Head and Neck Cancer: Results From a Phase I Trial. Annals of oncology : official journal of the European Society for Medical Oncology Colevas, A. D., Bahleda, R., Braiteh, F., Balmanoukian, A., Brana, I., Chau, N. G., Sarkar, I., Molinero, L., Grossman, W., Kabbinavar, F., Fasso, M., O'Hear, C., Powderly, J. 2018

  Abstract

  Background: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial.Patients and methods: Patients with previously-treated, advanced HNC received atezolizumab intravenously every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability, and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated.Results: Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ?2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with 3 experiencing grade 3 TRAEs and 1 experiencing a grade 4 TRAE. No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level.Conclusions: In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC.ClinicalTrials.gov number: NCT01375842.

  View details for DOI 10.1093/annonc/mdy411

  View details for PubMedID 30219915

• A case of combination PD-1 inhibitor and intralesional 5-fluorouracil for high-frequency nonmelanoma skin cancers in an immunocompromised patient Duy Tran, Lee, C., Colevas, A., Chang, A. MOSBY-ELSEVIER. 2018: AB6

  View details for Web of Science ID 000440565900023

• Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence CANCER RESEARCH Gao, R. W., Teraphongphom, N. T., van den Berg, N. S., Martin, B. A., Oberhelman, N. J., Divi, V., Kaplan, M. J., Hong, S. S., Lu, G., Ertsey, R., Tummers, W. J., Gomez, A. J., Holsinger, F., Kong, C. S., Colevas, A. D., Warram, J. M., Rosenthal, E. L. 2018; 78 (17): 5144?54

  View details for DOI 10.1158/0008-5472.CAN-18-0878

  View details for Web of Science ID 000443753700029

• CheckMate 141: 1-Year Update and Subgroup Analysis of Nivolumab as First-Line Therapy in Patients with Recurrent/Metastatic Head and Neck Cancer ONCOLOGIST Gillison, M. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A., Licitra, L., Harrington, K. J., Kasper, S., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Docampo, L., Haddad, R., Rordorf, T., Kiyota, N., Tahara, M., Monga, M., Lynch, M., Li, L., Ferris, R. L. 2018; 23 (9): 1079?82

  Abstract

  Nivolumab significantly improved overall survival (OS) vs investigator's choice (IC) of chemotherapy at the primary analysis of randomized, open-label, phase 3 CheckMate 141 in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Here, we report that OS benefit with nivolumab was maintained at a minimum follow-up of 11.4 months. Further, OS benefit with nivolumab vs IC was also noted among patients who received first-line treatment for R/M SCCHN after progressing on platinum therapy for locally advanced disease in the adjuvant or primary (i.e., with radiation) setting.

  View details for PubMedID 29866947

• Survival benefit of post-operative chemotherapy for intermediate-risk advanced stage head and neck cancer differs with patient age ORAL ONCOLOGY Chen, M. M., Colevas, A., Megwalu, U., Divi, V. 2018; 84: 71?75

  Abstract

  The National Comprehensive Cancer Network (NCCN) guidelines state that surgical patients with advanced-stage head and neck cancer (HNC) and risk factors other than extranodal extension (ENE) or positive margins should consider post-operative chemoradiation (POCRT). The goal of our study was to determine if POCRT is associated with overall survival (OS) compared with post-operative radiation therapy (PORT) and whether this varies with patient age.We conducted a retrospective study of 5319 adult patients with stage III-IV HNC who received primary surgical treatment with POCRT or PORT in the National Cancer Database (2010-2013). Patients with distant metastases, ENE, and positive margins were excluded. Intermediate risk features included pT3-T4, pN2-N3 disease, and lymphovascular invasion. Our main outcome was overall survival (OS). Statistical analysis included chi-squared tests and Cox proportional hazards regressions.On multivariable analysis for non-oropharyngeal cancer patients <70?years, POCRT was associated with improved OS for T1-4N2-3 disease (hazard ratio [HR], 0.73, 95% confidence interval [CI]; 0.58-0.93) but was not associated with OS for T3-4N0-1 disease (HR, 0.92; 95% CI, 0.71-1.19). For patients ?70?years, POCRT was not associated with improved OS for patients with T1-4N2-3 disease (HR, 1.21; 95% CI, 0.79-1.86) or T3-4N0-1 disease (HR, 1.08; 95% CI, 0.71-1.65). For oropharyngeal cancer patients with HPV-positive disease, POCRT was associated with decreased OS (HR, 9.52; 95% CI, 2.38-38.08).Chemoradiation may offer a survival benefit for non-oropharyngeal intermediate-risk advanced-stage HNC patients <70?years of age with T1-4N2-3 disease, but may not benefit those ?70?years of age or those with T3-4N0-1 disease.

  View details for PubMedID 30115479

• Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence. Cancer research Gao, R. W., Teraphongphom, N. T., van den Berg, N. S., Martin, B. A., Oberhelman, N. J., Divi, V., Kaplan, M. J., Hong, S. S., Lu, G., Ertsey, R., Tummers, W. S., Gomez, A. J., Holsinger, F. C., Kong, C. S., Colevas, A. D., Warram, J. M., Rosenthal, E. L. 2018

  Abstract

  For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for in situ imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor-mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. 21 adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 (n=3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A (n=5) received 0.5mg/kg, cohort 2B (n=7) received 1mg/kg, and cohort 3 (n=6) received 50 mg. Patients were followed 30 days post-infusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. In situ imaging demonstrated tumor-to-background ratio (TBR) of 2-3, compared to ex vivo specimen imaging TBR of 5-6. We obtained clear differentiation between tumor and normal tissue, with a three-fold signal difference between positive and negative specimens (p<0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy which are otherwise less amenable to image guidance.

  View details for PubMedID 29967260

• Weekly Docetaxel, Cisplatin, and Cetuximab in Palliative Treatment of Patients with Squamous Cell Carcinoma of the Head and Neck ONCOLOGIST Trieu, V., Pinto, H., Riess, J. W., Lira, R., Luciano, R., Coty, J., Boothroyd, D., Colevas, A. 2018; 23 (7): 764-+

  Abstract

  Chemotherapy for recurrent, metastatic squamous cell carcinoma of the head and neck need not be known for extreme toxicity.The weekly regimen studied here has been demonstrated to be tolerable and effective.The objective of this study was to establish the response rate, progression-free survival (PFS) and overall survival (OS), and safety profile of weekly docetaxel, platinum, and cetuximab (TPC) in patients with relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN).Twenty-nine patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group (ECOG) performance status <3 were enrolled in an institutional review board-approved phase II trial. This study permitted prior chemoradiation, radiation, and/or surgery, provided that 3 months had elapsed since the end of the potentially curative treatment. Patients received cisplatin 30 mg/m2 or carboplatin area under the curve (AUC) 2, docetaxel 30 mg/m2, and cetuximab 250 mg/m2 weekly for 3 weeks, followed by a break during the fourth week, for a 28-day cycle. Planned intrapatient dose modifications were based on individual toxicity.Twenty-seven patients received TPC and were evaluable for response and toxicity. Rates of complete response (CR), partial response (PR), and confirmed PR were 3%, 52%, and 30%, respectively. The overall objective response rate was 56%. Estimated median PFS and OS were 4.8 and 14.7 months, respectively. The rates of grade 3 and 4 worst-grade adverse events (AEs) per patient were 85% and 7%, respectively. Dose density through cycle 4 was preserved for all patients; however, treatment beyond cycle 6 with the TPC regimen proved unfeasible.Weekly docetaxel, cisplatin, and cetuximab is an effective regimen for patients with metastatic or recurrent SCCHN. Response rates, PFS, and OS compare favorably with other combination chemotherapy treatments. Grade 4 toxicity rates observed in this study were substantially lower than those described with regimens using less frequent, higher-dose chemotherapy schedules.

  View details for PubMedID 29540603

  View details for PubMedCentralID PMC6058339

• Nivolumab (Nivo) vs investigator's choice (IC) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): 2-yr outcomes in the overall population and PD-L1 subgroups of CheckMate 141 Ferris, R. L., Blumenschein, G. R., Fayette, J., Guigay, J., Colevas, A., Licitra, L., Harrington, K. J., Kasper, S., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Docampo, L., Haddad, R., Rordorf, T., Kiyota, N., Tahara, M., Lynch, M., Jayaprakash, V., Li, L., Gillison, M. L. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-CT116

  View details for Web of Science ID 000468818900107

• PD-L1 Expression and Tumor-Infiltrating Lymphocytes in High-Risk and Metastatic Cutaneous Squamous Cell Carcinoma. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Amoils, M., Kim, J., Lee, C., Sunwoo, J. B., Colevas, A. D., Aasi, S. Z., Hollmig, S. T., Ma, Y., Divi, A. V. 2018: 194599818788057

  Abstract

  Objective To characterize programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) positivity for locally aggressive or regionally metastatic cutaneous head and neck squamous cell carcinoma (cHNSCC). Study Design Retrospective chart review, followed by immunohistochemical staining of archived tumor specimens. Setting Tertiary academic medical center. Subjects and Methods After identification of 101 patients treated surgically for locally advanced or regionally metastatic cHNSCC, archived tissue was stained and graded for PD-L1 expression in addition to TIL presence. Cross-tabulation was performed to examine the association between either of these variables and clinicopathologic features and outcomes. Results A total of 101 patients met inclusion criteria, but archived tissue was available only for 83 (31 primaries, 52 metastases). The majority of primary tumors demonstrated grade 1 PD-L1 staining, while grade 2 staining was more likely for metastases. Neither high- nor low-grade PD-L1 expression correlated with any clinicopathologic variable for primary tumors. However, for metastases, high-grade staining was significantly associated with regional recurrence (15 of 19, P = .02). TILs were present for 65% of primary tumors and 90% of regional metastases but did not correlate with any clinicopathologic variables. Conclusion Diffuse expression of PD-L1 in this study highlights the possibility of using immunotherapy in the form of programmed death 1/PD-L1 blockade to improve treatment for this devastating disease. However, further studies are needed to clarify the significance of PD-L1 expression and TIL positivity for locally advanced or regionally metastatic cHNSCC.

  View details for PubMedID 30012051

• Comparative Effectiveness and Toxicity of Cetuximab or Cisplatin With Concurrent Radiation for Locoregionally Advanced Squamous Cell Carcinoma of The Head And Neck: A Population-Based Analysis Xiang, M., Holsinger, F., Chen, M., Colevas, A., Beadle, B. ELSEVIER SCIENCE INC. 2018: E16

  View details for Web of Science ID 000432447200037

• Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression ORAL ONCOLOGY Ferris, R. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A., Licitra, L., Harrington, K. J., Kasper, S., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Iglesias Docampo, L., Haddad, R., Rordorf, T., Kiyota, N., Tahara, M., Lynch, M., Jayaprakash, V., Li, L., Gillison, M. L. 2018; 81: 45?51

  Abstract

  We report 2-year results from CheckMate 141 to establish the long-term efficacy and safety profile of nivolumab and outcomes by tumor PD-L1 expression in patients with recurrent or metastatic (R/M),platinum-refractory squamous cell carcinoma of the head and neck (SCCHN).Patients with R/M SCCHN with tumor progression/recurrence within 6?months of platinum therapy were randomized 2:1 to nivolumab 3?mg/kg every 2?weeks or investigator's choice (IC). Primary endpoint: overall survival (OS). Data cutoff: September 2017.With 24.2?months' minimum follow-up, nivolumab (n?=?240) continued to improve OS vs IC (n?=?121), hazard ratio (HR)?=?0.68 (95% CI 0.54-0.86). Nivolumab nearly tripled the estimated 24-month OS rate (16.9%) vs IC (6.0%), and demonstrated OS benefit across patients with tumor PD-L1 expression ?1% (HR [95% CI]?=?0.55 [0.39-0.78]) and ?

  View details for PubMedID 29884413

• NCCN Guidelines (R) Insights Head and Neck Cancers, Version 1.2018 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Colevas, A., Yom, S. S., Pfister, D. G., Spencer, S., Adelstein, D., Adkins, D., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Eisele, D. W., Fenton, M., Foote, R. L., Gilbert, J., Gillison, M. L., Haddad, R. I., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Leizman, D., Maghami, E., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rocco, J., Rodriguez, C. P., Shah, J. P., Weber, R. S., Witek, M., Worden, F., Zhen, W., Burns, J. L., Darlow, S. D. 2018; 16 (5): 479?90

  Abstract

  The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

  View details for DOI 10.6004/jnccn.2018.0026

  View details for Web of Science ID 000431928700006

  View details for PubMedID 29752322

• Panitumumab-IRDye800 as an Optical Agent for Image-Guided Surgery in Patients With Squamous Cell Carcinoma Gao, R. W., Teraphongphom, N., van den Berg, N. S., Hong, S., Martin, B. A., Divi, V., Kaplan, M. J., Ertsey, R., Oberhelman, N. J., Lu, G., Kong, C. S., Colevas, A. D., Rosenthal, E. L. ELSEVIER SCIENCE INC. 2018: 1312?13

  View details for Web of Science ID 000428145600052

• Safety Evaluation of Nivolumab Concomitant With Platinum-Based Chemoradiation therapy for Intermediate and High-Risk Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma: RTOG Foundation 3504 Gillison, M., Ferris, R. L., Zhang, Q., Colevas, A. D., Mell, L. K., Kirsch, C., Moore, K. L., Truong, M. T., Kong, C. S., Jordan, R., Clump, D. A., Ohr, J., He, K., Blakaj, D., Deeken, J., Machtay, M., Curran, W. J., Harris, J., Le, Q. T. ELSEVIER SCIENCE INC. 2018: 1307?8

  View details for Web of Science ID 000428145600042

• Two-year Update From CheckMate 141: Outcomes With Nivolumab (Nivo) vs Investigator's Choice (IC) in Recurrent or Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN) in the Overall Population and PD-L1 Subgroups Ferris, R. L., Blumenschein, G. R., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Kasper, S., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Docampo, L. C., Haddad, R. I., Rordorf, T., Kiyota, N., Tahara, M., Lynch, M., Li, L., Gillison, M. ELSEVIER SCIENCE INC. 2018: 1317

  View details for Web of Science ID 000428145600062

• Survival Benefit of Postoperative Chemotherapy for Intermediate-Risk Advanced Stage Head and Neck Cancer Chen, M. M., Colevas, A. D., Megwalu, U., Divi, V. ELSEVIER SCIENCE INC. 2018: 1326

  View details for Web of Science ID 000428145600084

• Comparative Effectiveness of Cetuximab or Cisplatin With Concomitant Radiation for Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck: A Population-Based Analysis Xiang, M., Holsinger, F. C., Chen, M. M., Colevas, A. D., Beadle, B. M. ELSEVIER SCIENCE INC. 2018: 1322

  View details for Web of Science ID 000428145600074

• Pembrolizumab for advanced basal cell carcinoma: an investigator-initiated, proof-of-concept study. Journal of the American Academy of Dermatology Chang, A. L., Tran, D. C., Cannon, J. G., Li, S., Jeng, M., Patel, R., Van der Bokke, L., Pague, A., Brotherton, R., Rieger, K. E., Satpathy, A. T., Yost, K. E., Reddy, S., Sarin, K., Colevas, A. D. 2018

  View details for PubMedID 30145186

• Nivolumab (Nivo) vs Investigator's Choice (IC) for Platinum-Refractory (PR) Recurrent or Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN; CheckMate 141): Outcomes in First-line (1L) R/M Patients (Pts) and Updated Safety and Efficacy Kasper, S., Gillison, M. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Docampo, L. I., Haddad, R., Rordorf, T., Kiyota, N., Makoto, T., Lynch, M., Kopit, J., Ferris, R. L. KARGER. 2018: 96

  View details for Web of Science ID 000424914300256

• A pooled analysis of advanced nonsquamous non-small cell lung cancer patients with stable treated brain metastases in two phase II trials receiving bevacizumab and pemetrexed as second-line therapy JOURNAL OF THORACIC DISEASE Gubens, M. A., Chuang, J. C., Akerley, W., Langer, C. J., Clement-Duchene, C., San Pedro-Salcedo, M., Colevas, A., Dragnev, K., Socinski, M. A., Wakelee, H. A. 2018; 10 (1): 219?27

  Abstract

  Brain metastases are a common complication of advanced non-small cell lung cancer (NSCLC). Patients with brain metastases were excluded from the registration trials of bevacizumab that showed a survival benefit with the use of angiogenesis inhibition.In this study, we pooled data from two separate trials designed to evaluate the risk of central nervous system (CNS) hemorrhage in patients with stable treated brain metastases to look specifically at both the safety and efficacy of bevacizumab and pemetrexed when used as second-line treatment in NSCLC patients with stable treated brain metastases.We report acceptable safety and promising efficacy from our analysis.Our study adds further evidence of safety of administering pemetrexed and bevacizumab to patients with stable brain metastases. There is increasing roles for systemic therapies to treat stable brain metastases for patients with advanced NSCLC.

  View details for PubMedID 29600052

  View details for PubMedCentralID PMC5863135

• Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers THERANOSTICS Gao, R. W., Teraphongphom, N., de Boer, E., van den Berg, N. S., Divi, V., Kaplan, M. J., Oberhelman, N. J., Hong, S. S., Capes, E., Colevas, A., Warram, J. M., Rosenthal, E. L. 2018; 8 (9): 2488?95

  Abstract

  Purpose: To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. Procedures: We conducted two phase I trials for anti-epidermal growth factor receptor antibodies cetuximab-IRDye800CW (n=12) and panitumumab-IRDye800CW (n=15). Adults with biopsy-confirmed head and neck squamous cell carcinoma scheduled for standard-of-care surgery were eligible. For cetuximab-IRDye800CW, cohort 1 was intravenously infused with 2.5 mg/m2, cohort 2 received 25 mg/m2, and cohort 3 received 62.5 mg/m2. For panitumumab-IRDye800CW, cohorts received 0.06 mg/kg, 0.5 mg/kg, and 1 mg/kg, respectively. Electrocardiograms and blood samples were obtained, and patients were followed for 30 days post-study drug infusion. Results: Both fluorescently labeled antibodies had similar pharmacodynamic properties and minimal toxicities. Two infusion reactions occurred with cetuximab and none with panitumumab. There were no grade 2 or higher toxicities attributable to cetuximab-IRDye800CW or panitumumab-IRDye800CW; fifteen grade 1 adverse events occurred with cetuximab-IRDye800CW, and one grade 1 occurred with panitumumab-IRDye800CW. There were no significant differences in QTc prolongation between the two trials (p=0.8). Conclusions: Panitumumab-IRDye800CW and cetuximab-IRDye800CW have toxicity and pharmacodynamic profiles that match the parent compound, suggesting that other therapeutic antibodies may be repurposed as imaging agents with limited preclinical toxicology data.

  View details for PubMedID 29721094

• Nivolumab vs Investigator'S Choice (IC) in Patients With Recurrent or Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN): Efficacy and Safety in CheckMate 141 by Prior Cetuximab Use Ferris, R. L., Licitra, L., Fayette, J., Even, C., Blumenschein, G., Harrington, K. J., Guigay, J., Vokes, E. E., Saba, N. F., Haddad, R., Ramkumar, S., Russell, J., Brossart, P., Tahara, M., Monga, M., Zhu, J., Colevas, A., Gillison, M. L. WILEY. 2017: 143

  View details for Web of Science ID 000413954500207

• Characterisation of Potential Predictive Biomarkers of Response to Nivolumab in Checkmate 141 in Patients With Squamous Cell Carcinoma of the Head and Neck (SCCHN) Concha-Benavente, F., Gillison, M. L., Blumenschien, G., Harrington, K. J., Fayette, J., Colevas, A., Licitra, L., Kasper, S., Even, C., Worden, F., Saba, N. F., Haddad, R., Tahara, M., Hasegawa, Y., Yen, C., Lynch, M., Monga, M., Geese, W. J., Vokes, E. E., Ferris, R. L. WILEY. 2017: 141

  View details for Web of Science ID 000413954500203

• Nivolumab Versus Investigator'S Choice (IC) for Platinum-Refractory Recurrent or Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN; CHECKMATE 141): Outcomes in First-Line R/M Patients and Updated Safety and Efficacy Gillison, M. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A., Licitra, L., Harrington, K. J., Kasper, S., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Iglesias Docampo, L., Haddad, R., Rordorf, T., Kiyota, N., Tahara, M., Lynch, M., Kopit, J., Ferris, R. L. WILEY. 2017: 144

  View details for Web of Science ID 000413954500208

• Long-Term Safety and Clinical Outcomes of Atezolizumab in Head and Neck Cancer: Phase la Trial Results Bahleda, R., Braiteh, F. S., Balmanoukian, A. S., Brana, I., Hodi, F. S., Garbo, L., Liu, B., Molinero, L., O'Hear, C., Shen, X., Colevas, A. D. OXFORD UNIV PRESS. 2017

  View details for Web of Science ID 000411324002232

• Commentary on "Weekly Low-Dose Versus Three-Weekly High-Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta-Analysis of Aggregate Data" ONCOLOGIST Colevas, A. 2017; 22 (9): 1022?23

  View details for PubMedID 28751507

  View details for PubMedCentralID PMC5599207

• Treatment beyond progression with nivolumab (nivo) in patients with recurrent or metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN) in the phase 3 CheckMate 141 study Kasper, S., Haddad, R., Ferris, R. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Vokes, E. E., Worden, F., Saba, N. F., Tahara, M., Monga, M., Lynch, M., Zhu, J., Shaw, J. W., Gillison, M. L., Harrington, K. J. KARGER. 2017: 250-+

  View details for Web of Science ID 000411428400606

• Treatment beyond progression with nivolumab in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) in the phase 3 checkmate 141 study: A biomarker analysis and updated clinical outcomes Haddad, R., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Kasper, S., Vokes, E. E., Worden, F., Saba, N. F., Tahara, M., Concha-Benavente, F., Monga, M., Lynch, M., Li, L., Shaw, J. W., Gillison, M. L., Harrington, K. J., Ferris, R. L. OXFORD UNIV PRESS. 2017

  View details for Web of Science ID 000411324002231

• Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial LANCET ONCOLOGY Harrington, K. J., Ferris, R. L., Blumenschein, G., Colevas, A., Fayette, J., Licitra, L., Kasper, S., Even, C., Vokes, E. E., Worden, F., Saba, N. F., Kiyota, N., Haddad, R., Tahara, M., Gruenwald, V., Shaw, J. W., Monga, M., Lynch, M., Taylor, F., DeRosa, M., Morrissey, L., Cocks, K., Gillison, M. L., Guigay, J. 2017; 18 (8): 1104?15

  Abstract

  Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs).CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40-60 mg/m2 of body surface area), docetaxel (30-40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636.Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from -2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, -24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs -7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires.In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting.Bristol-Myers Squibb.

  View details for PubMedID 28651929

• NCCN Guidelines (R) Insights Head and Neck Cancers, Version 2.2017 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Adelstein, D., Gillison, M. L., Pfister, D. G., Spencer, S., Adkins, D., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A., Eisele, D. W., Fenton, M., Foote, R. L., Gilbert, J., Haddad, R. I., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Leizman, D., Lydiatt, W. M., Maghami, E., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rocco, J., Rodriguez, C. P., Shah, J. P., Weber, R. S., Witek, M., Worden, F., Yom, S. S., Zhen, W., Burns, J. L., Darlow, S. D. 2017; 15 (6): 761?70

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

  View details for DOI 10.6004/jnccn.2017.0101

  View details for Web of Science ID 000403152400004

  View details for PubMedID 28596256

• PD-1 inhibition for cutaneous squamous cell carcinoma: A study of six consecutive cases Duy Tran, Colevas, A., Chang, A. MOSBY-ELSEVIER. 2017: AB193

  View details for Web of Science ID 000403369301360

• An open-label, single-arm, multi-institutional phase II trial of avelumab for recurrent, metastatic nasopharyngeal carcinoma. Sacco, A., Messer, K., Leidner, R. S., Colevas, A., Nieva, J. J., Chau, N., Nangia, C., Pinsky, B., Gold, K. A., Daniels, G. A., Cohen, E. W. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.TPS6092

  View details for Web of Science ID 000411931705088

• Characterization of potential predictive biomarkers of response to nivolumab in CheckMate 141 in patients with squamous cell carcinoma of the head and neck (SCCHN). Concha-Benavente, F., Gillison, M. L., Blumenschein, G. R., Harrington, K., Fayette, J., Colevas, A., Licitra, L., Kasper, S., Even, C., Worden, F. P., Saba, N. F., Haddad, R. I., Tahara, M., Hasegawa, Y., Yen, C., Lynch, M., Monga, M., Geese, W. J., Vokes, E. E., Ferris, R. L. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.6050

  View details for Web of Science ID 000411931705048

• A randomized phase II study of chemoradiation (CRT) plus /- nivolumab (Nivo) with sequential safety evaluations of Nivo plus /- lirilumab (Liri) or ipilumumab (Ipi) concomitant with (C) RI in intermediate (IR) and high-risk (HR) head and neck squamous cell carcinoma (HNSCC) (RTOG 3504, NCT02764593). Gillison, M. L., Ferris, R. L., Zhang, Q., Colevas, A., Mell, L. K., Kong, C., Jordan, R., Moore, K., Truong, M., Kirsch, C., Machtay, M., Curran, W., Le, Q. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.TPS6097

  View details for Web of Science ID 000411931705093

• Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy. JAMA dermatology Freites-Martinez, A., Kwong, B. Y., Rieger, K. E., Coit, D. G., Colevas, A. D., Lacouture, M. E. 2017

  Abstract

  To our knowledge, there have been no previous reports of eruptive keratoacanthomas (KAs) in patients receiving pembrolizumab.To report the cases of 3 consecutive patients with pembrolizumab-induced eruptive KAs and their management.Case report study of 3 patients from 2 centers with pembrolizumab-treated cancer who all developed eruptive KAs.All 3 patients had AK treatment with clobetasol ointment and intralesional triamcinolone; 2 patients also underwent open superficial cryosurgery.Three consecutive patients with cancer, 2 men and 1 woman (median age, 83 years; range 77-91 years), experienced pembrolizumab-associated eruptive KAs. All patients presented with a sudden onset of multiple lesions on sun-exposed areas of their extremities after a median of 13 months (range, 4-18 months) of pembrolizumab therapy. On lesional biopsy, a lichenoid infiltrate was observed in the underlying dermis, predominantly composed of CD3+ T cells, scattered CD20+ B cells, and relatively few PD-1+ (programmed cell death 1-positive) T cells, an immunophenotypic pattern also observed in other cases of anti-PD-1-induced lichenoid dermatitis. Patients were treated with clobetasol ointment and intralesional triamcinolone, alone or in combination with open superficial cryosurgery. All KAs resolved in all patients, and no new lesions occurred during close follow-up. Pembrolizumab treatment was continued without disruption in all 3 cases, and all patients had complete responses of their primary cancers.Pembrolizumab is used in advanced melanoma, advanced non-small-cell lung cancer, and in head and neck cancer. A variety of dermatologic immune-related adverse events including maculopapular eruption, lichenoid reactions, pruritus, and vitiligo have been described. This case series demonstrates that pembrolizumab therapy may also be associated with eruptive KAs with characteristic dermal inflammation, which improved with corticosteroid treatment (topical and intralesional) alone or in combination with cryosurgery, allowing patients to continue therapy with pembrolizumab.

  View details for DOI 10.1001/jamadermatol.2017.0989

  View details for PubMedID 28467522

• E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx-ECOG-ACRIN Cancer Research Group AMERICAN JOURNAL OF PSYCHOLOGY Marur, S., Li, S., Cmelak, A. J., Gillison, M. L., Zhao, W. J., Ferris, R. L., Westra, W. H., Gilbert, J., Bauman, J. E., Wagner, L. I., Trevarthen, D. R., Balkrishna, J., Murphy, B. A., Agrawal, N., Colevas, A. D., Chung, C. H., Burtness, B. 2017; 130 (1): 490-U169

  View details for DOI 10.1200/JCO.2016.68.3300

  View details for Web of Science ID 000394365500016

• Node-positive cutaneous squamous cell carcinoma of the head and neck: Survival, high-risk features, and adjuvant chemoradiotherapy outcomes. Head & neck Amoils, M., Lee, C. S., Sunwoo, J., Aasi, S. Z., Hara, W., Kim, J., Sirjani, D., Colevas, A. D., Chang, A. L., Divi, V. 2017

  Abstract

  Data lacks to guide treatment of regionally metastatic cutaneous head and neck squamous cell carcinoma (HNSCC).We conducted a retrospective review of 80 patients treated for regionally metastatic cutaneous HNSCC. The effect of various clinicopathologic variables on overall survival (OS) was investigated, in addition to outcomes by treatment modality.On multivariate regression, cutaneous primary >2 cm (p = .03) and extracapsular spread (ECS; p = .01) were significantly associated with decreased OS. Location of regional metastasis (neck vs parotid vs both) had no effect on OS (p = .2), nor did the presence of a cutaneous primary at the time of presentation (p = .9). The 3-year survival was 43%, 52%, and 49% for surgery alone, adjuvant radiation, and adjuvant chemoradiation, respectively. Fifty-one percent of patients had a recurrence of their disease.Regionally metastatic cutaneous HNSCC is an aggressive disease associated with high recurrence rates. Patients with tumors >2 cm and ECS have poorer OS despite adjuvant therapy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 881-885, 2017.

  View details for DOI 10.1002/hed.24692

  View details for PubMedID 28252823

• Characterization of potential predictive biomarkers of response to nivolumab in CheckMate-141 in patients with squamous cell carcinoma of the head and neck (SCCHN). Ferris, R. L., Concha-Benavente, F., Blumenschein, G. R., Harrington, K. J., Fayette, J., Colevas, A., Licitra, L. F., Kasper, S., Even, C., Gillison, M. L., Worden, F., Saba, N. F., Haddad, R. I., Tahara, M., Hasegawa, Y., Yen, C., Lynch, M., Monga, M., Geese, W. J., Vokes, E. E. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for Web of Science ID 000443282900006

• Characterizing CD137 upregulation on NK cells in patients receiving monoclonal antibody therapy ANNALS OF ONCOLOGY MAKKOUK, A., Sundaram, V., Chester, C., Chang, S., Colevas, A. D., Sunwoo, J. B., Maecker, H., Desai, M., Kohrt, H. E. 2017; 28 (2): 415-420

  Abstract

  In the era of personalized cancer medicine, identifying techniques for effectively matching patients to efficacious treatments is a critical step in the treatment process. The advent of anti-cancer immunotherapies necessitates novel approaches to biomarker identification beyond traditional genomic profiling. One promising approach is incorporation of nomograms into treatment decisions. Nomograms are prediction tools, based on statistical modeling, designed to predict treatment outcomes. As a first step toward developing a nomogram, we conducted analyses to predict CD137 expression of natural killer cells after monoclonal antibody (mAb) treatment.Patient, tumor and immune characteristics were collected from 199 patients with breast cancer (N?=?62), head/neck cancers (N?=?46) and non-Hodgkin's lymphoma (NHL) (N?=?91), who were receiving mAb therapy as part of clinical trials. The difference in CD137 expression before and after mAb therapy was assessed by flow cytometry. To evaluate those who respond to mAb therapy via increased CD137 expression, we applied classification and regression trees (CART), multivariable lasso regression tools and Random Forest.The CD137 expression was significantly different for each cancer type [mean (SD): Breast: 6.6 (6.5); Head/Neck: 11.0 (7.0); NHL: 7.5 (7.1), P?

  View details for DOI 10.1093/annonc/mdw570

  View details for Web of Science ID 000397278300032

• E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group. Journal of clinical oncology Marur, S., Li, S., Cmelak, A. J., Gillison, M. L., Zhao, W. J., Ferris, R. L., Westra, W. H., Gilbert, J., Bauman, J. E., Wagner, L. I., Trevarthen, D. R., Balkrishna, J., Murphy, B. A., Agrawal, N., Colevas, A. D., Chung, C. H., Burtness, B. 2016: JCO2016683300-?

  Abstract

  Purpose Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of ? 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with < T4, < N2c, and ? 10 pack-year smoking history who were treated with ? 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose ? 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.

  View details for DOI 10.1200/JCO.2016.68.3300

  View details for PubMedID 28029303

• Prognostic nomogram for refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer Pan, J. J., Ng, W. T., Zong, J. F., Lee, S. W., Choi, H. C., Chan, L. L., Lin, S. J., Guo, Q. J., Sze, H. C., Chen, Y. B., Xiao, Y. P., Kan, W. K., O'Sullivan, B., Xu, W., Le, Q. T., Glastonbury, C. M., Colevas, A. D., Weber, R. S., Lydiatt, W., Shah, J. P., Lee, A. W. 2016; 122 (21): 3307-3315

  Abstract

  The objective of this study was to develop a nomogram for refining prognostication for patients with nondisseminated nasopharyngeal cancer (NPC) staged with the proposed 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system.Consecutive patients who had been investigated with magnetic resonance imaging, staged with the proposed 8th edition of the AJCC/UICC staging system, and irradiated with intensity-modulated radiotherapy from June 2005 to December 2010 were analyzed. A cohort of 1197 patients treated at Fujian Provincial Cancer Hospital was used as the training set, and the results were validated with 412 patients from Pamela Youde Nethersole Eastern Hospital. Cox regression analyses were performed to identify significant prognostic factors for developing a nomogram to predict overall survival (OS). The discriminative ability was assessed with the concordance index (c-index). A recursive partitioning algorithm was applied to the survival scores of the combined set to categorize the patients into 3 risk groups.A multivariate analysis showed that age, gross primary tumor volume, and lactate dehydrogenase were independent prognostic factors for OS in addition to the stage group. The OS nomogram based on all these factors had a statistically higher bias-corrected c-index than prognostication based on the stage group alone (0.712 vs 0.622, P <.01). These results were consistent for both the training cohort and the validation cohort. Patients with <135 points were categorized as low-risk, patients with 135 to <160 points were categorized as intermediate-risk, and patients with ?160 points were categorized as high-risk. Their 5-year OS rates were 92%, 84%, and 58%, respectively.The proposed nomogram could improve prognostication in comparison with the TNM stage group. This could aid in risk stratification for individual NPC patients. Cancer 2016;122:3307-3315. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30198

  View details for PubMedID 27434142

• Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck NEW ENGLAND JOURNAL OF MEDICINE Ferris, R. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Kasper, S., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Iglesias Docampo, L. C., Haddad, R., Rordorf, T., Kiyota, N., Tahara, M., Monga, M., Lynch, M., Geese, W. J., Kopit, J., Shaw, J. W., Gillison, M. L. 2016; 375 (19): 1856-1867

  Abstract

  Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

  View details for DOI 10.1056/NEJMoa1602252

  View details for Web of Science ID 000387534200009

  View details for PubMedID 27718784

• Characterizing CD137 Upregulation on NK cells in Patients Receiving Monoclonal Antibody Therapy. Annals of oncology MAKKOUK, A., Sundaram, V., Chester, C., Chang, S., Colevas, A. D., Sunwoo, J. B., Maecker, H., Desai, M., Kohrt, H. E. 2016

  Abstract

  In the era of personalized cancer medicine, identifying techniques for effectively matching patients to efficacious treatments is a critical step in the treatment process. The advent of anti-cancer immunotherapies necessitates novel approaches to biomarker identification beyond traditional genomic profiling. One promising approach is incorporation of nomograms into treatment decisions. Nomograms are prediction tools, based on statistical modeling, designed to predict treatment outcomes. As a first step toward developing a nomogram, we conducted analyses to predict CD137 expression of natural killer cells after monoclonal antibody (mAb) treatment.Patient, tumor and immune characteristics were collected from 199 patients with breast cancer (N?=?62), head/neck cancers (N?=?46) and non-Hodgkin's lymphoma (NHL) (N?=?91), who were receiving mAb therapy as part of clinical trials. The difference in CD137 expression before and after mAb therapy was assessed by flow cytometry. To evaluate those who respond to mAb therapy via increased CD137 expression, we applied classification and regression trees (CART), multivariable lasso regression tools and Random Forest.The CD137 expression was significantly different for each cancer type [mean (SD): Breast: 6.6 (6.5); Head/Neck: 11.0 (7.0); NHL: 7.5 (7.1), P?

  View details for PubMedID 27831501

• Follow-up on Programmed Cell Death 1 Inhibitor for Cutaneous Squamous Cell Carcinoma. JAMA dermatology Tran, D. C., Colevas, A. D., Chang, A. L. 2016

  View details for DOI 10.1001/jamadermatol.2016.3884

  View details for PubMedID 27784038

• A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Investigational new drugs Rosen, L. S., LoRusso, P., Ma, W. W., Goldman, J. W., Weise, A., Colevas, A. D., Adjei, A., Yazji, S., Shen, A., Johnston, S., Hsieh, H., Chan, I. T., Sikic, B. I. 2016; 34 (5): 604-613

  Abstract

  Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

  View details for DOI 10.1007/s10637-016-0374-3

  View details for PubMedID 27424159

• BRAF inhibitor therapy of primary ameloblastoma ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY Tan, S., Pollack, J. R., Kaplan, M. J., Colevas, A., West, R. B. 2016; 122 (4): 518?19

  View details for PubMedID 27651290

• Design and rationale of a prospective, multi-institutional registry for patients with sinonasal malignancy. Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W., Colevas, A. D., Le, Q., Berry, G. J., Hwang, P. H. 2016; 126 (9): 1977-1980

  Abstract

  Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

  View details for DOI 10.1002/lary.25996

  View details for PubMedID 27283472

• Ameloblastoma: a clinical review and trends in management EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY McClary, A. C., West, R. B., McClary, A. C., Pollack, J. R., Fischbein, N. J., Holsinger, C. F., Sunwoo, J., Colevas, A. D., Sirjani, D. 2016; 273 (7): 1649-1661

  Abstract

  Ameloblastoma is a rare odontogenic neoplasm of the mandible and maxilla, with multiple histologic variants, and high recurrence rates if improperly treated. The current mainstay of treatment is wide local excision with appropriate margins and immediate reconstruction. Here we review the ameloblastoma literature, using the available evidence to highlight the change in management over the past several decades. In addition, we explore the recent molecular characterization of these tumors which may point towards new potential avenues of personalized treatment.

  View details for DOI 10.1007/s00405-015-3631-8

  View details for PubMedID 25926124

• BRAF inhibitor treatment of primary BRAF-mutant ameloblastoma with pathologic assessment of response ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY Tan, S., Pollack, J. R., Kaplan, M. J., Colevas, A. D., West, R. B. 2016; 122 (1): E5-E7

  Abstract

  Molecular characterization of ameloblastoma has indicated a high frequency of driver mutations in BRAF and SMO. Preclinical data suggest that Food and Drug Administration-approved BRAF-targeted therapies may be immediately relevant for patients with ameloblastoma positive for the BRAF V600E mutation.A neoadjuvant treatment regime of dabrafenib was given to a patient with recurrent BRAF-mutant mandibular ameloblastoma. The patient subsequently underwent left mandible composite resection of the tumor and pathologic evaluation of treatment response.The ameloblastoma had a slow but dramatic response with >90% tumor volume reduction. The inner areas of the tumor underwent degeneration and squamous differentiation, and intact ameloblastoma was present in the outer areas associated with bone.Targeted neoadjuvant therapy for ameloblastoma may be useful in certain clinical settings of primary ameloblastoma. These might include tumors of advanced local stage when a neoadjuvant reduction could alter the extent of surgery and instances of local recurrence when surgical options are limited.

  View details for DOI 10.1016/j.oooo.2015.12.016

  View details for Web of Science ID 000377426600002

  View details for PubMedID 27209484

• Third party assessment of resection margin status in head and neck cancer. Oral oncology Ransohoff, A., Wood, D., Solomon Henry, A., Divi, V., Colevas, A. 2016; 57: 27-31

  Abstract

  Definitive assessment of primary site margin status following resection of head and neck cancer is necessary for prognostication, treatment determination and qualification for clinical trials. This retrospective analysis determined how often an independent reviewer can assess primary tumor margin status of head and neck cancer resections based on review of the pathology report, surgical operative report, and first follow-up note alone.We extracted from the electronic medical record pathology reports, operative reports, and follow-up notes from head and neck cancer resections performed at Stanford Hospital. We classified margin status as definitive or not. We labeled any pathology report clearly indicating a positive, negative, or close (<5mm) margin as definitive. For each non-definitive pathology report, we reviewed the operative report and then the first follow-up note in an attempt to clarify margin status. We also looked for associations between non-definitive status and surgeon, year, and primary site.743 unique cases of head and neck cancer resection were extracted. We discarded 255 as non-head and neck cancer cases, or cases that did not involve a definitive resection of a primary tumor site. We could not definitively establish margin status in 20% of resections by independent review of the medical record. There was no correlation between margin determination and surgeon, site, or year of surgery.A substantial fraction (20%) of primary site surgical margins could not be definitively determined via independent EMR review. This could have implications for subsequent patient care decisions and clinical trial options.

  View details for DOI 10.1016/j.oraloncology.2016.03.009

  View details for PubMedID 27208841

• Third party assessment of resection margin status in head and neck cancer ORAL ONCOLOGY Ransohoff, A., Wood, D., Henry, A. S., Divi, V., Colevas, A. 2016; 57: 27-31

  Abstract

  Definitive assessment of primary site margin status following resection of head and neck cancer is necessary for prognostication, treatment determination and qualification for clinical trials. This retrospective analysis determined how often an independent reviewer can assess primary tumor margin status of head and neck cancer resections based on review of the pathology report, surgical operative report, and first follow-up note alone.We extracted from the electronic medical record pathology reports, operative reports, and follow-up notes from head and neck cancer resections performed at Stanford Hospital. We classified margin status as definitive or not. We labeled any pathology report clearly indicating a positive, negative, or close (<5mm) margin as definitive. For each non-definitive pathology report, we reviewed the operative report and then the first follow-up note in an attempt to clarify margin status. We also looked for associations between non-definitive status and surgeon, year, and primary site.743 unique cases of head and neck cancer resection were extracted. We discarded 255 as non-head and neck cancer cases, or cases that did not involve a definitive resection of a primary tumor site. We could not definitively establish margin status in 20% of resections by independent review of the medical record. There was no correlation between margin determination and surgeon, site, or year of surgery.A substantial fraction (20%) of primary site surgical margins could not be definitively determined via independent EMR review. This could have implications for subsequent patient care decisions and clinical trial options.

  View details for DOI 10.1016/j.oraloncology.2016.03.009

  View details for Web of Science ID 000376084500010

  View details for PubMedID 27208841

• Current Standards in Treatment of Radioiodine Refractory Thyroid Cancer CURRENT TREATMENT OPTIONS IN ONCOLOGY Narayanan, S., Colevas, A. D. 2016; 17 (6)

  Abstract

  Radioiodine refractory differentiated thyroid cancer (RAI-R DTC) is a challenging malignancy with limited prognosis and treatment options. Recently, clinical trials with targeted therapies have advanced the outlook of these patients, and inhibition of the vascular endothelial growth factor (VEGF) axis has led to the approval of small-molecule tyrosine kinase inhibitors (TKIs) for first-line treatment of radioiodine refractory disease. In addition to approved therapies (sorafenib and lenvatinib), other multi-targeted tyrosine kinase inhibitors that are commercially available have been recognized as viable treatment options for RAI-R DTC. Our preference is to initially use lenvatinib, given the dramatic progression-free survival (PFS) improvement versus placebo, with the caveat that 24 mg daily is not often tolerated and lower doses often used. In patients with BRAF V600E mutation, BRAF inhibitors are now considered for treatment, especially if patients are at high risk from antiangiogenic therapy. Research is continuing to evolve in identifying mechanisms related to radioiodine refractoriness, and trials are evaluating therapeutic molecules to overcome this resistance. Clinical care of patients with RAI-R DTC requires careful consideration of both patient and disease characteristics. Many patients with asymptomatic and indolent disease can be followed for years without treatment while others with high volume or rapidly progressive disease merit early intervention.

  View details for DOI 10.1007/s11864-016-0404-6

  View details for Web of Science ID 000377809200004

  View details for PubMedID 27139457

• A first-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers Sikic, B. I., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.3019

  View details for Web of Science ID 000404665404058

• A phase 2 study of tarloxotinib bromide (TRLX) in patients (Pts) with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Rischin, D., Boyer, M. J., Brzezniak, C. E., Colevas, A., Doebele, R., Gilbert, J., Gitlitz, B., Khan, S. A., Mehra, R., Seiwert, T. Y., Kroll, S., Pearce, T. E., Liu, S. V. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.TPS6105

  View details for Web of Science ID 000404711502231

• Further evaluations of nivolumab (nivo) versus investigator's choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. Ferris, R. L., Blumenschein, G. R., Fayette, J., Guigay, J., Colevas, A., Licitra, L. F., Harrington, K. J., Kasper, S., Vokes, E. E., Even, C., Worden, F. P., Haddad, R. I., Kiyota, N., Tahara, M., Monga, M., Lynch, M., Geese, W. J., Kopit, J., Shaw, J. W., Gillison, M. L. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.6009

  View details for Web of Science ID 000404711502137

• Number of positive nodes is superior to the lymph node ratio and American Joint Committee on Cancer N staging for the prognosis of surgically treated head and neck squamous cell carcinomas CANCER Roberts, T. J., Colevas, A. D., Hara, W., Holsinger, F. C., Oakley-Girvan, I., Divi, V. 2016; 122 (9): 1388-1397

  Abstract

  Recent changes in head and neck cancer epidemiology have created a need for improved lymph node prognostics. This article compares the prognostic value of the number of positive nodes (pN) with the value of the lymph node ratio (LNR) and American Joint Committee on Cancer (AJCC) N staging in surgical patients.The Surveillance, Epidemiology, and End Results database was used to identify cases of head and neck squamous cell carcinomas from 2004 to 2012. The sample was grouped by the AJCC N stage, LNR, and pN and was analyzed with Kaplan-Meier and multivariate Cox proportional hazards models. The sample was also analyzed by the site of the primary tumor.This study identified 12,437 patients. Kaplan-Meier survival curves showed superior prognostic ability for LNR and pN staging in comparison with AJCC staging. Patients with a pN value > 5 had the worst overall survival (5-year survival rate, 16%). Patients with oropharyngeal tumors had better outcomes for all groupings, and a pN value > 5 for oropharyngeal cancers was associated with decreased survival. Multivariate regressions demonstrated larger hazard ratios (HRs) and a lower Akaike information criterion for the pN model versus the AJCC stage and LNR models. The HRs were 1.78 (95% confidence interval, 1.62-1.95) for a pN value of 1, 2.53 (95% confidence interval, 2.32-2.75) for a pN value of 2 to 5, and 4.64 (95% confidence interval, 4.18-5.14) for a pN value > 5.The pN models demonstrated superior prognostic value in comparison with the LNR and AJCC N staging. Future modifications of the nodal staging system should be based on the pN with a separate system for oropharyngeal cancers. Future trials should consider examining adjuvant treatment escalation in patients with >5 lymph nodes. Cancer 2016;122:1388-1397. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.29932

  View details for Web of Science ID 000374706500010

  View details for PubMedID 26969807

• Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma. JAMA dermatology Ally, M. S., Ransohoff, K., Sarin, K., Atwood, S. X., Rezaee, M., Bailey-Healy, I., Kim, J., Beachy, P. A., Chang, A. L., Oro, A., Tang, J. Y., Colevas, A. D. 2016; 152 (4): 452-456

  Abstract

  Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P?

  View details for DOI 10.1001/jamadermatol.2015.5473

  View details for PubMedID 26765315

• A Pilot Study of Electronic Quality of Life Assessments Using Tablet Devices During and After Treatment of Head and Neck Cancers Wang, E., Pollom, E., Bui, T., Ognibene, G., von Eyben, R., Divi, V., Sunwoo, J., Kaplan, M., Colevas, A. D., Le, Q. T., Hara, W. ELSEVIER SCIENCE INC. 2016: 969

  View details for DOI 10.1016/j.ijrobp.2015.12.343

  View details for Web of Science ID 000371581900289

• Regionally Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck: Survival and High-Risk Features Amoils, M., Lee, C. S., Sunwoo, J., Aasi, S. Z., Hara, W., Kim, J., Sirjani, D., Colevas, A. D., Chang, A. S., Divi, V. ELSEVIER SCIENCE INC. 2016: 954

  View details for DOI 10.1016/j.ijrobp.2015.12.304

  View details for Web of Science ID 000371581900251

• Prognostic Value of Lymph Node Status Is Greater Than Lymph Node Ratio and AJCC N Staging for Head and Neck Squamous Cell Carcinomas Roberts, T., Colevas, A. D., Hara, W., Holsinger, F. C., Oakley-Girvan, I., Divi, V. ELSEVIER SCIENCE INC. 2016: 911?12

  View details for DOI 10.1016/j.ijrobp.2015.12.140

  View details for Web of Science ID 000371581900144

• Proposal for the 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer Pan, J. J., Ng, W. T., Zong, J. F., Chan, L. L., O'Sullivan, B., Lin, S. J., Sze, H. C., Chen, Y. B., Choi, H. C., Guo, Q. J., Kan, W. K., Xiao, Y. P., Wei, X., Le, Q. T., Glastonbury, C. M., Colevas, A. D., Weber, R. S., Shah, J. P., Lee, A. W. 2016; 122 (4): 546-558

  Abstract

  An accurate staging system is crucial for cancer management. Evaluations for continual suitability and improvement are needed as staging and treatment methods evolve.This was a retrospective study of 1609 patients with nasopharyngeal carcinoma investigated by magnetic resonance imaging, staged with the 7th edition of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system, and irradiated by intensity-modulated radiotherapy at 2 centers in Hong Kong and mainland China.Among the patients without other T3/T4 involvement, there were no significant differences in overall survival (OS) between medial pterygoid muscle (MP)?±?lateral pterygoid muscle (LP), prevertebral muscle, and parapharyngeal space involvement. Patients with extensive soft tissue involvement beyond the aforementioned structures had poor OS similar to that of patients with intracranial extension and/or cranial nerve palsy. Only 2% of the patients had lymph nodes?>?6?cm above the supraclavicular fossa (SCF), and their outcomes resembled the outcomes of those with low extension. Replacing SCF with the lower neck (extension below the caudal border of the cricoid cartilage) did not affect the hazard distinction between different N categories. With the proposed T and N categories, there were no significant differences in outcome between T4N0-2 and T1-4N3 disease.After a review by AJCC/UICC preparatory committees, the changes recommended for the 8th edition include changing MP/LP involvement from T4 to T2, adding prevertebral muscle involvement as T2, replacing SCF with the lower neck and merging this with a maximum nodal diameter?>?6?cm as N3, and merging T4 and N3 as stage IVA criteria. These changes will lead not only to a better distinction of hazards between adjacent stages/categories but also to optimal balance in clinical practicability and global applicability. Cancer 2016;122:546-558. © 2015 American Cancer Society.

  View details for DOI 10.1002/cncr.29795

  View details for PubMedID 26588425

• Discordance in routine second opinion pathology review of head and neck oncology specimens: A single-center five year retrospective review ORAL ONCOLOGY Zhu, G. A., Lira, R., Colevas, A. D. 2016; 53: 36-41

  Abstract

  Second opinion review of pathology specimens is a common institutional practice, supported by large retrospective studies demonstrating significant histologic discordance. Since the most recent study of head and neck-specific pathology review was conducted, routine HPV and EBV testing is now recommended for certain specimens. We describe the frequency of and reasons for discordant reports and their potential impact on treatment recommendations and prognosis in a five-year retrospective cohort study at a single academic referral institution from 2005 to 2010.Following institutional review board review, 1003 cases referred to the Head and Neck Oncology Service were identified using a retrospective database search. Discordance between outside and second review pathology report was assessed by a board-certified medical oncologist.667 cases were included, of which 22% were discordant. Discordance was associated with adenocarcinomas (AOR [adjusted odds ratio] 0.09, 95% CI 0.03-0.31; p<0.001), poorly differentiated carcinomas (AOR 0.14, 95% CI 0.06-0.39; p<0.001), and specimens of uncommon histology (AOR 0.18, 95% CI 0.07-0.45; p<0.001) but not biopsy site in a multivariate model. The most common reasons for discordance included histology (61%), followed by the results of special studies (36%), and the presence or absence of stromal invasion (14%). Differences in tumor HPV status comprised 16% of discordant cases and were associated with better prognosis (p<0.001) following second opinion review.Routine second opinion pathology review may lead to clinically significant differences in treatment recommendations and prognosis.

  View details for DOI 10.1016/j.oraloncology.2015.11.018

  View details for Web of Science ID 000367523100006

• Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma JAMA Dermatology Sarin, K. Y., Ally, M. S., Ransohoff, K. J., Atwood, S. X., Rezaee, M. 2016: 1?5

  Abstract

  Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P?

  View details for DOI 10.1001/jamadermatol.2015.5473

• Discordance in routine second opinion pathology review of head and neck oncology specimens: A single-center five year retrospective review. Oral oncology Zhu, G. A., Lira, R., Colevas, A. D. 2016; 53: 36?41

  Abstract

  Second opinion review of pathology specimens is a common institutional practice, supported by large retrospective studies demonstrating significant histologic discordance. Since the most recent study of head and neck-specific pathology review was conducted, routine HPV and EBV testing is now recommended for certain specimens. We describe the frequency of and reasons for discordant reports and their potential impact on treatment recommendations and prognosis in a five-year retrospective cohort study at a single academic referral institution from 2005 to 2010.Following institutional review board review, 1003 cases referred to the Head and Neck Oncology Service were identified using a retrospective database search. Discordance between outside and second review pathology report was assessed by a board-certified medical oncologist.667 cases were included, of which 22% were discordant. Discordance was associated with adenocarcinomas (AOR [adjusted odds ratio] 0.09, 95% CI 0.03-0.31; p<0.001), poorly differentiated carcinomas (AOR 0.14, 95% CI 0.06-0.39; p<0.001), and specimens of uncommon histology (AOR 0.18, 95% CI 0.07-0.45; p<0.001) but not biopsy site in a multivariate model. The most common reasons for discordance included histology (61%), followed by the results of special studies (36%), and the presence or absence of stromal invasion (14%). Differences in tumor HPV status comprised 16% of discordant cases and were associated with better prognosis (p<0.001) following second opinion review.Routine second opinion pathology review may lead to clinically significant differences in treatment recommendations and prognosis.

  View details for PubMedID 26684543

• A Case Report of Unresectable Cutaneous Squamous Cell Carcinoma Responsive to Pembrolizumab, a Programmed Cell Death Protein 1 Inhibitor JAMA DERMATOLOGY Chang, A. S., Kim, J., Luciano, R., Sullivan-Chang, L., Colevas, A. D. 2016; 152 (1): 106?8

  View details for PubMedID 26422398

• Design and rationale of a prospective multi-institutional registry for patients with sinosodal malignancy The Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W. Y., Colevas, A. D., Le, Q. T., Berry, G. J., Hwang, P. H. 2016

  Abstract

  Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

  View details for DOI 10.1002/lary.25996

• Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck ONCOLOGIST Iberri, D. J., Colevas, A. D. 2015; 20 (12): 1393-1403

  Abstract

  : The epidermal growth factor receptor (EGFR) is overexpressed in more than 80% of squamous cell cancers of the head and neck (SCCHN). An evolving understanding of the role of EGFR in tumorigenesis has made the receptor an important therapeutic target in SCCHN. Several EGFR inhibitors (EGFRIs) are active in SCCHN, and their use is associated with improvement in progression-free survival and overall survival in various treatment settings. Nevertheless, EGFR inhibition is associated with significant mucocutaneous toxicity that must be balanced against its anticipated efficacy. This review summarizes the relevant clinical trial experience with EGFRIs, with attention to efficacy, toxicity, and methods of selecting patients most likely to benefit from therapy.Cetuximab and other inhibitors of the epidermal growth factor receptor (EGFR) have entered the medical oncologist's arsenal against squamous cell carcinoma of the head and neck (SCCHN). They are modestly active as single agents and in combination with chemotherapy and radiotherapy. Despite their efficacy across multiple treatment settings, cetuximab and other EGFR inhibitors (EGFRIs) have not supplanted platinum-based therapies, which remain a standard of care for SCCHN. The modest benefits of EGFRI therapy must take into consideration patient, disease, and treatment characteristics and must be balanced against potential treatment toxicity.

  View details for DOI 10.1634/theoncologist.2015-0177

  View details for Web of Science ID 000368416400007

• New Diseases and New Treatments-Head and Neck Cancer Updates Preface HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Colevas, A. 2015; 29 (6): XIII-XIV

  View details for PubMedID 26568555

• A prospective study of electronic quality of life assessment using tablet devices during and after treatment of head and neck cancers. Oral oncology Pollom, E. L., Wang, E., Bui, T. T., Ognibene, G., von Eyben, R., Divi, V., Sunwoo, J., Kaplan, M., Dimitri Colevas, A., Le, Q., Hara, W. Y. 2015; 51 (12): 1132-1137

  Abstract

  Electronic data collection is increasingly used for quality of life (QOL) assessments in the field of oncology. It is important to assess the feasibility of these new data capture technologies.Patients at our institution who were 18years or older with a pathological diagnosis of head and neck cancer were prospectively enrolled. Each patient completed two questionnaires [EORTC-QLQ-C30 and EORTC-QLQ-H&N35] administered on a touch-screen tablet device (iPad?) at initial consult, during treatment, at the completion of treatment and at each subsequent follow up visit for one year after treatment.A total of 50 patients were included in this study. Although all patients completed the surveys at the initial consult, 86% of initially enrolled patients completed surveys at the end of radiation treatment, and 48% of initially enrolled patients completed surveys by the fourth follow-up visit. Average time to complete the survey for all patients over all time points was 9.8min (standard deviation 6.1). Age as a continuous variable was significantly associated with time for survey completion (p<0.001), with older age associated with longer survey completion times.QOL assessment using tablet devices in head and neck cancer patients is feasible, but may be more challenging in elderly patients. Patients ?70years old may benefit from more assistance with electronic forms and should be allotted more time for completing tablet-based QOL surveys.

  View details for DOI 10.1016/j.oraloncology.2015.10.003

  View details for PubMedID 26475062

• NCCN Oncology Research Program's Investigator Steering Committee and NCCN Best Practices Committee Molecular Profiling Surveys JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Kurzrock, R., Colevas, A. D., Olszanski, A., Akerley, W., Arteaga, C. L., Carson, W. E., Clark, J. W., DiPersio, J. F., Ettinger, D. S., Morgan, R. J., Schwartzberg, L. S., Venook, A. P., Gocke, C. D., Tait, J., Stewart, F. M. 2015; 13 (11): 1337-1346

  Abstract

  This article summarizes the systemic treatment options for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, with an emphasis on recommendations based on phase II and III comparison trials of commercially available agents. Many single-agent and combination regimens have activity against these cancers, but improvement in overall survival remains a challenge, and median survivals in this population with best available therapy remain less than 1 year. The major recent advancement has been the introduction of epidermal growth factor receptor inhibitors, with mixed success. Although single-agent treatment with methotrexate, paclitaxel, docetaxel, or 5-fluorouracil remains one standard for many patients, the use of cisplatin- or carboplatin-based multidrug regimens that include cetuximab has become more popular, primarily based on one randomized study demonstrating a modest survival improvement of approximately 3 months associated with the addition of cetuximab. The burdensome adverse event profile of multidrug regimens makes appropriate patient selection for such aggressive treatment challenging, and consideration should include factors such as need for palliation, performance status of the patients, history of prior treatment, convenience, and cost. Genetically targeted and immunologically mediated treatments are promising but remain experimental. Given the worrisome prognosis for these patients, innovative clinical trials are a good option for many patients and deserve support.

  View details for Web of Science ID 000364277500006

  View details for PubMedID 26553764

• Outcomes of Young Patients With Oral Cavity Squamous Cell Carcinoma Shah, J. L., Bui, T., Kaplan, M., Colevas, A. D., Le, Q. T., Hara, W. ELSEVIER SCIENCE INC. 2015: S214

  View details for DOI 10.1016/j.ijrobp.2015.07.515

  View details for Web of Science ID 000373215302193

• Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase I trial in patients with advanced solid tumors: a California Cancer Consortium trial CANCER CHEMOTHERAPY AND PHARMACOLOGY Morgan, R. J., Synold, T. W., Longmate, J. A., Quinn, D. I., Gandara, D., Lenz, H., Ruel, C., Xi, B., Lewis, M. D., Colevas, A. D., Doroshow, J., Newman, E. M. 2015; 76 (5): 897-907

  Abstract

  The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four.This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m(2), and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay.Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m(2)/week. The second phase ended at 2.0 mg/m(2)/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m(2)/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]).E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of ?-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for >72 h.

  View details for DOI 10.1007/s00280-015-2868-7

  View details for Web of Science ID 000363245800002

  View details for PubMedID 26362045

  View details for PubMedCentralID PMC4694049

• Concurrent Vismodegib and Radiotherapy for Recurrent, Advanced Basal Cell Carcinoma. JAMA dermatology Pollom, E. L., Bui, T. T., Chang, A. L., Colevas, A. D., Hara, W. Y. 2015; 151 (9): 998-1001

  View details for DOI 10.1001/jamadermatol.2015.0326

  View details for PubMedID 25874733

• Concurrent Vismodegib and Radiotherapy for Recurrent, Advanced Basal Cell Carcinoma. JAMA dermatology Pollom, E. L., Bui, T. T., Chang, A. L., Colevas, A. D., Hara, W. Y. 2015; 151 (9): 998-1001

  Abstract

  Vismodegib is a targeted agent recently approved for treating patients who develop recurrent or locally advanced basal cell carcinoma (BCC), and will inevitably be integrated into existing therapy for advanced BCC as it becomes increasingly used. Improved understanding of how vismodegib interacts with other treatment modalities, including radiotherapy, would help optimize multidisciplinary therapy and clinical outcomes.We report 2 cases of recurrent, advanced BCC treated from April 1, 2012, through October 31, 2014, with concurrent radiotherapy and vismodegib. Concurrent treatment appeared to be well tolerated and efficacious, with both patients having no evidence of progressive disease at last follow-up.We found that the combination of vismodegib and radiotherapy is feasible for patients with recurrent or locally advanced BCC and that combined use of currently available therapies for advanced BCC warrants further prospective study.

  View details for DOI 10.1001/jamadermatol.2015.0326

  View details for PubMedID 25874733

• Hearing evaluation of patients with head and neck cancer: Comparison of Common Terminology Criteria for Adverse Events, Brock and Chang adverse event criteria in patients receiving cisplatin. Head & neck Colevas, A. D., Lira, R. R., Colevas, E. A., Lavori, P. W., Chan, C., Shultz, D. B., Chang, K. W. 2015; 37 (8): 1102-1107

  Abstract

  The purpose of this study was to compare Common Terminology Criteria for Adverse Events (CTCAE), Brock and Chang hearing loss grading in patients with head and neck cancer receiving cis-diamminedichloroplatinum (CDDP). Endpoints were baseline distribution of hearing loss, interobserver consistency, and sensitivity to hearing loss after CDDP treatment.Four hundred sixty single ear audiograms in 110 patients with head and neck cancer were graded. Hearing loss at baseline, interobserver agreement rates, and changes in hearing loss after CDDP were evaluated.The Chang and Brock tools' baseline hearing loss distribution was concentrated at grade 0 (57% and 41%, respectively), whereas 47%, per the CTCAE, had grade 3 baseline hearing loss. Interobserver agreement was highest for the Brock scale (?90%) followed by the Chang (?89%) and CTCAE (?75%) scales. Detection of change after CDDP was highest for Chang (48%) followed by Brock (45%) and the CTCAE (32%).The Brock and Chang tools may be superior to the CTCAE in patients with head and neck cancer receiving CDDP using baseline hearing loss distribution, interobserver agreement, and detection of hearing loss grade change as performance indicators. © 2014 Wiley Periodicals, Inc. Head Neck, 2014.

  View details for DOI 10.1002/hed.23714

  View details for PubMedID 24737682

• Head and Neck Cancers, Version 1.2015. Journal of the National Comprehensive Cancer Network Pfister, D. G., Spencer, S., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Foote, R. L., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Kies, M. S., Lydiatt, W. M., Maghami, E., McCaffrey, T., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rodriguez, C. P., Samant, S., Shah, J. P., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N., Hughes, M. 2015; 13 (7): 847-856

  Abstract

  These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

  View details for PubMedID 26150579

• Head and Neck Cancers, Version 1.2015 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Spencer, S., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Foote, R. L., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Kies, M. S., Lydiatt, W. M., Maghami, E., McCaffrey, T., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rodriguez, C. R., Samant, S., Shah, J. R., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N., Hughes, M. 2015; 13 (7): 847-856

  Abstract

  These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

  View details for Web of Science ID 000357901600005

• Outcomes of elderly patients treated for oral cavity squamous cell carcinoma Shah, J., Kaplan, M., Colevas, A., Quynh-Thu Le, Hara, W. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901393

• Third party assessment of resection margin status in head and neck cancer. Ransohoff, A., Wood, D., Henry, S., Divi, V., Colevas, A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.e17011

  View details for Web of Science ID 000358036903396

• Low pre-operative absolute monocyte count to predict overall survival benefit for oral cavity squamous cell carcinoma Bui, T., Shah, J., Kaplan, M., Colevas, A., Quynh-Thu Le, Hara, W. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901394

• A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma CLINICAL CANCER RESEARCH Galloway, T. J., Wirth, L. J., Colevas, A. D., Gilbert, J., Bauman, J. E., Saba, N. F., Raben, D., Mehra, R., Ma, A. W., Atoyan, R., Wang, J., Burtness, B., Jimeno, A. 2015; 21 (7): 1566-1573

  Abstract

  CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin-radiotherapy in the treatment of HNSCC.CUDC-101 monotherapy was administered intravenously three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m(2) every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks.Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-negative. The MTD of CUDC-101-based combination therapy was established at 275 mg/m(2)/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression.CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration.

  View details for DOI 10.1158/1078-0432.CCR-14-2820

  View details for Web of Science ID 000352076700011

  View details for PubMedID 25573383

• Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer. Head & neck Tang, C., Chan, C., Jiang, W., Murphy, J. D., von Eyben, R., Colevas, A. D., Pinto, H., Lee-Enriquez, N., Kong, C., Le, Q. 2015; 37 (3): 386-392

  Abstract

  The purpose of this study was to present our experience utilizing cetuximab and platinum-based concurrent chemoradiotherapy for the definitive treatment of head and neck squamous cell carcinoma (HNSCC).Patients (n = 177) who received definitive concurrent chemoradiotherapy for HNSCC were stratified into 3 groups: receiving cetuximab monotherapy (n = 24), cetuximab and chemotherapy combination (n = 33), or platinum-based chemotherapy without cetuximab (n = 120). Primary endpoints were freedom from relapse, event-free survival, and overall survival (OS).Patients receiving cetuximab monotherapy were older with lower Karnofsky performance status (KPS) and higher Charlson comorbidity scores compared with those treated with combination cetuximab and chemotherapy or platinum-based concurrent chemoradiotherapy. Patients treated with platinum-based concurrent chemoradiotherapy exhibited significantly better freedom from relapse, event-free survival, and OS compared with those receiving cetuximab monotherapy or cetuximab and chemotherapy combination therapies (all p < .05). Differences between patients receiving cetuximab monotherapy and platinum-based concurrent chemoradiotherapy held on multivariate Cox regression.This study suggests that platinum-based concurrent chemoradiotherapy is superior to cetuximab-based monotherapy for the definitive treatment of HNSCC. © 2014 Wiley Periodicals, Inc. Head Neck 37: 386-392, 2015.

  View details for DOI 10.1002/hed.23609

  View details for PubMedID 24431011

• Differentiated Thyroid Cancer: Focus on Emerging Treatments for Radioactive Iodine-Refractory Patients ONCOLOGIST Gruber, J. J., Colevas, A. D. 2015; 20 (2): 113-126

  Abstract

  The treatment of differentiated thyroid cancer refractory to radioactive iodine (RAI) had been hampered by few effective therapies. Recently, tyrosine kinase inhibitors (TKIs) have shown activity in this disease. Clinical guidance on the use of these agents in RAI-refractory thyroid cancer is warranted.Molecular mutations found in RAI-refractory thyroid cancer are summarized. Recent phase II and III clinical trial data for TKIs axitinib, lenvatinib, motesanib, pazopanib, sorafenib, sunitinib, and vandetinib are reviewed including efficacy and side effect profiles. Molecular targets and potencies of these agents are compared. Inhibitors of BRAF, mammalian target of rapamycin, and MEK are considered.Routine testing for molecular alterations prior to therapy is not yet recommended. TKIs produce progression-free survival of approximately 1 year (range: 7.7-19.6 months) and partial response rates of up to 50% by Response Evaluation Criteria in Solid Tumors. Pazopanib and lenvatinib are the most active agents. The majority of patients experienced tumor shrinkage with TKIs. Common adverse toxicities affect dermatologic, gastrointestinal, and cardiovascular systems.Multiple TKIs have activity in RAI-refractory differentiated thyroid cancer. Selection of a targeted agent should depend on disease trajectory, side effect profile, and goals of therapy.

  View details for DOI 10.1634/theoncologist.2014-0313

  View details for Web of Science ID 000351915500007

  View details for PubMedID 25616432

  View details for PubMedCentralID PMC4319630

• Advances in Nanotechnology and Microfluidics for Human Papillomavirus Diagnostics PROCEEDINGS OF THE IEEE Tasoglu, S., Tekin, H. C., Inci, F., Knowlton, S., Wang, S., Wang-Johanning, F., Johanning, G., Colevas, D., Demirci, U. 2015; 103 (2): 161-178

  View details for DOI 10.1109/JPROC.2014.2384836

  View details for Web of Science ID 000352156900004

• Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck. The oncologist Iberri, D. J., Colevas, A. D. 2015

  Abstract

  : The epidermal growth factor receptor (EGFR) is overexpressed in more than 80% of squamous cell cancers of the head and neck (SCCHN). An evolving understanding of the role of EGFR in tumorigenesis has made the receptor an important therapeutic target in SCCHN. Several EGFR inhibitors (EGFRIs) are active in SCCHN, and their use is associated with improvement in progression-free survival and overall survival in various treatment settings. Nevertheless, EGFR inhibition is associated with significant mucocutaneous toxicity that must be balanced against its anticipated efficacy. This review summarizes the relevant clinical trial experience with EGFRIs, with attention to efficacy, toxicity, and methods of selecting patients most likely to benefit from therapy.Cetuximab and other inhibitors of the epidermal growth factor receptor (EGFR) have entered the medical oncologist's arsenal against squamous cell carcinoma of the head and neck (SCCHN). They are modestly active as single agents and in combination with chemotherapy and radiotherapy. Despite their efficacy across multiple treatment settings, cetuximab and other EGFR inhibitors (EGFRIs) have not supplanted platinum-based therapies, which remain a standard of care for SCCHN. The modest benefits of EGFRI therapy must take into consideration patient, disease, and treatment characteristics and must be balanced against potential treatment toxicity.

  View details for PubMedID 26446236

• Phase I Trial of Bortezomib (PS-341; NSC 681239) and "Nonhybrid" (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms CLINICAL CANCER RESEARCH Holkova, B., Kmieciak, M., Perkins, E. B., Bose, P., Baz, R. C., Roodman, G. D., Stuart, R. K., Ramakrishnan, V., Wan, W., Peer, C. J., Dawson, J., Kang, L., Honeycutt, C., Tombes, M. B., Shrader, E., Weir-Wiggins, C., Wellons, M., Sankala, H., Hogan, K. T., Colevas, A. D., Doyle, L. A., Figg, W. D., Coppola, D., Roberts, J. D., Sullivan, D., Grant, S. 2014; 20 (22): 5652-5662

  Abstract

  This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma).Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted.A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses.The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies.

  View details for DOI 10.1158/1078-0432.CCR-14-0805

  View details for Web of Science ID 000345130800011

  View details for PubMedID 25248382

• Head and Neck Cancers, Version 2.2014 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Spencer, S., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rodriguez, C. P., Samant, S., Schuller, D. E., Shah, J. P., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N. R., Hughes, M. 2014; 12 (10): 1454-1487

  Abstract

  This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

  View details for Web of Science ID 000343275600010

• Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Pfister, D. G., Spencer, S., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rodriguez, C. P., Samant, S., Schuller, D. E., Shah, J. P., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N. R., Hughes, M. 2014; 12 (10): 1454-1487

  Abstract

  This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

  View details for PubMedID 25313184

• CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma. Oncotarget Murillo-Sauca, O., Chung, M. K., Shin, J. H., Karamboulas, C., Kwok, S., Jung, Y. H., Oakley, R., Tysome, J. R., Farnebo, L. O., Kaplan, M. J., Sirjani, D., Divi, V., Holsinger, F. C., Tomeh, C., Nichols, A., Le, Q. T., Colevas, A. D., Kong, C. S., Uppaluri, R., Lewis, J. S., Ailles, L. E., Sunwoo, J. B. 2014; 5 (16): 6854-6866

  Abstract

  Tumor-initiating cells (TICs) in squamous cell carcinoma of the head and neck (SCCHN) are best characterized by their surface expression of CD44. Although there is great interest in identifying strategies to target this population, no marker of these cells has been found to be functionally active. Here, we examined the expression of the purported marker of normal human oral epithelial stem cells, CD271. We show that CD271 expression is restricted to a subset of the CD44+ cells. Using xenograft assays, we show that the CD44+CD271+ subpopulation contains the most tumorigenic cells. Loss of CD271 function results in a block in the G2-M phase of the cell cycle and a profound negative impact on the capacity of these cells to initiate tumor formation in vivo. Incubation with recombinant NGF results in enhanced phosphorylation of Erk, providing additional evidence that CD271 is functionally active. Finally, incubation of SCCHN cells with antibody to CD271 results in decreased Erk phosphorylation and decreased tumor formation in vivo. Thus, our data are the first to demonstrate that CD271 more specifically identifies the TIC subpopulation within the CD44+ compartment in SCCHN and that this receptor is a functionally active and targetable molecule.

  View details for PubMedID 25149537

• E1308: Reduced-dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC). Cmelak, A., Li, S., Marur, S., Zhao, W., Westra, W. H., Chung, C. H., Gillison, M. L., Gilbert, J., Bauman, J. E., Wagner, L. I., Ferris, R. L., Trevarthen, D. R., Colevas, A., Jahagirdar, B. N., Burtriess, B. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358244900009

• Targeting CD137 enhances the efficacy of cetuximab. journal of clinical investigation Kohrt, H. E., Colevas, A. D., Houot, R., Weiskopf, K., Goldstein, M. J., Lund, P., Mueller, A., Sagiv-Barfi, I., Marabelle, A., Lira, R., Troutner, E., Richards, L., Rajapaska, A., Hebb, J., Chester, C., Waller, E., Ostashko, A., Weng, W., Chen, L., Czerwinski, D., Fu, Y., Sunwoo, J., Levy, R. 2014; 124 (6): 2668-2682

  Abstract

  Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.

  View details for DOI 10.1172/JCI73014

  View details for PubMedID 24837434

• Targeting CD137 enhances the efficacy of cetuximab. journal of clinical investigation Kohrt, H. E., Colevas, A. D., Houot, R., Weiskopf, K., Goldstein, M. J., Lund, P., Mueller, A., Sagiv-Barfi, I., Marabelle, A., Lira, R., Troutner, E., Richards, L., Rajapaska, A., Hebb, J., Chester, C., Waller, E., Ostashko, A., Weng, W., Chen, L., Czerwinski, D., Fu, Y., Sunwoo, J., Levy, R. 2014; 124 (6): 2668-2682

  Abstract

  Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.

  View details for DOI 10.1172/JCI73014

  View details for PubMedID 24837434

• Review of pathologic diagnosis in head and neck cancer patients: Why do it? Zhu, G., Lira, R. R., Colevas, A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613203624

• E1308: Reduced-dose INERT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC). Cmelak, A., Li, S., Marur, S., Zhao, W., Westra, W. H., Chung, C. H., Gillison, M. L., Gilbert, J., Bauman, J. E., Wagner, L. I., Ferris, R. L., Trevarthen, D. R., Colevas, A., Jahagirdar, B. N., Burtness, B. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613201960

• Population-based evaluation of incidence trends in oropharyngeal cancer focusing on socioeconomic status, sex, and race/ethnicity HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Colevas, A. D. 2014; 36 (1): 34-42

  Abstract

  BACKGROUND: The influences of socioeconomic status (SES) on the incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) are unclear. METHODS: Data from the California Cancer Registry and U.S. Census were used to compare incidence rates and trends of OPSCC and other human papillomavirus-related and -unrelated cancer sites by neighborhood SES, race/ethnicity, and sex. RESULTS: The incidence of OPSCC rose in both higher and lower SES neighborhoods. Absolute rates were greater in the latter. Only non-Hispanic white males with OPSCC demonstrated a significant increase in the incidence rate of squamous cell carcinoma of the head and neck (SCCHN). The incidence rate for this group increased from 4.5/100,000 person-years between 1988 and 1992 to 7.1 between 2003 and 2009. Regression analysis demonstrated an annual percentage change of 1% from 1988 to 1997 and 4% thereafter. CONCLUSIONS: Increases in incidence rates are SES independent. Incidence rates are higher in lower-SES groups. The rise in OPSCC incidence is limited to non-Hispanic white males. © 2013 Wiley Periodicals, Inc. Head Neck, 2013.

  View details for DOI 10.1002/hed.23253

  View details for Web of Science ID 000328217300010

  View details for PubMedID 23633438

• Phase 1b, Multicenter, Single Blinded, Placebo-Controlled, Sequential Dose Escalation Study to Assess the Safety and Tolerability of Topically Applied AG013 in Subjects With Locally Advanced Head and Neck Cancer Receiving Induction Chemotherapy CANCER Limaye, S. A., Haddad, R. I., Cilli, F., Sonis, S. T., Colevas, A. D., Brennan, M. T., Hu, K. S., Murphy, B. A. 2013; 119 (24): 4268-4276

  Abstract

  Oral mucositis (OM) is a significant toxicity of induction chemotherapy for locally advanced head and neck cancer (LAHNC). The safety and tolerability of AG013, an oral rinse containing recombinant Lactococcus lactis secreting mucosal protectant human trefoil factor 1 (hTFF1), was evaluated in a phase 1b study in LAHNC subjects who received induction with cisplatin, 5-fluorouracil, with or without docetaxel. Preliminary efficacy data were also obtained.A total of 25 of 52 LAHNC subjects who were followed during induction cycle 1 developed ulcerative oral mucositis (UOM; World Health Organization grade > 2) and were randomized to AG013:placebo (5:2 ratio) for cycle 2. Dosing schedules of 1, 3, or 6 times daily were evaluated (2 × 10(11) , 6 × 10(11) , and 1.2 × 10(12) colony forming units per day, respectively). OM was evaluated daily from cycle 2, day 1 through 14, using World Health Organization criteria. Pharmacokinetic assessment was also conducted.AG013 bacteria were not detected in blood. Oral live AG013 bacterial and hTFF1 levels in saliva and oral mucosa were equivalent among treatment groups. The most frequently occurring adverse events were nausea, oral pain, fatigue, diarrhea, and mucosal inflammation. Only 12% (3 of 25 adverse events), mainly nausea, were attributed to the investigational medicinal product: AG013 or placebo. Efficacy analysis showed a 35% reduction in percentage of days with UOM in AG013-subjects versus placebo. All placebo subjects experienced ? 2 days of UOM, whereas 29% of AG013 subjects had UOM for 0 or 1 day. AG013 use resulted in fewer unscheduled office and emergency room visits. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement.AG013 was safe and well tolerated. Preliminary efficacy data support further study.

  View details for DOI 10.1002/cncr.28365

  View details for Web of Science ID 000330091900010

  View details for PubMedID 24114811

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

  Abstract

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

  View details for DOI 10.1002/lary.24081

  View details for PubMedID 23553253

• Markedly improved overall survival in 10 consecutive patients with metastatic basal cell carcinoma. British journal of dermatology Danial, C., Lingala, B., Balise, R., Oro, A. E., Reddy, S., Colevas, A., Chang, A. L. 2013; 169 (3): 673-676

  Abstract

  BACKGROUND: Metastatic basal cell carcinoma (BCC) is a rare but life-threatening condition. Prior estimates of overall survival (OS) from time of diagnosis of distant metastasis to death are approximately 8-14 months. However, these estimates are based on analyses of case reports published prior to 1984. OBJECTIVES: To assess a more updated OS in metastatic BCC patients at a single academic institution. METHODS: Using patients from 1997 to 2011, a retrospective chart review was performed on biopsy-confirmed cases of distant metastatic BCC at Stanford University School of Medicine. Kaplan-Meier analysis was used to determine OS and progression free survival (PFS). RESULTS: Ten consecutive cases of distant metastatic BCC were identified. Median OS was 7.3 (95% confidence interval, CI; 1.6, ?) years; median PFS was 3.4 (95% CI; 1.1, 5.2) years. CONCLUSION: Our findings suggest that OS in patients with distant metastaticBCC may be more favorable than previously reported.

  View details for DOI 10.1111/bjd.12333

  View details for PubMedID 23521172

• Markedly improved overall survival in 10 consecutive patients with metastatic basal cell carcinoma BRITISH JOURNAL OF DERMATOLOGY Danial, C., Lingala, B., Balise, R., Oro, A. E., Reddy, S., Colevas, A., Chang, A. L. 2013; 169 (3): 673-676

  Abstract

  BACKGROUND: Metastatic basal cell carcinoma (BCC) is a rare but life-threatening condition. Prior estimates of overall survival (OS) from time of diagnosis of distant metastasis to death are approximately 8-14 months. However, these estimates are based on analyses of case reports published prior to 1984. OBJECTIVES: To assess a more updated OS in metastatic BCC patients at a single academic institution. METHODS: Using patients from 1997 to 2011, a retrospective chart review was performed on biopsy-confirmed cases of distant metastatic BCC at Stanford University School of Medicine. Kaplan-Meier analysis was used to determine OS and progression free survival (PFS). RESULTS: Ten consecutive cases of distant metastatic BCC were identified. Median OS was 7.3 (95% confidence interval, CI; 1.6, ?) years; median PFS was 3.4 (95% CI; 1.1, 5.2) years. CONCLUSION: Our findings suggest that OS in patients with distant metastaticBCC may be more favorable than previously reported.

  View details for DOI 10.1111/bjd.12333

  View details for Web of Science ID 000323700000027

• Head and Neck Cancers, Version 2.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B. A., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Schuller, D. E., Shah, J. P., Spencer, S., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N. R., Hughes, M. 2013; 11 (8): 917-923

  Abstract

  These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

  View details for Web of Science ID 000323156900003

• Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B. A., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Schuller, D. E., Shah, J. P., Spencer, S., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N. R., Hughes, M. 2013; 11 (8): 917-923

  Abstract

  These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

  View details for PubMedID 23946171

• Stereotactic radiosurgery for retreatment of gross perineural invasion in recurrent cutaneous squamous cell carcinoma of the head and neck. American journal of clinical oncology Tang, C., Fischbein, N. J., Murphy, J. D., Chu, K. P., Bavan, B., Dieterich, S., Hara, W., Kaplan, M. J., Colevas, A. D., Le, Q. 2013; 36 (3): 293-298

  Abstract

  : To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma with gross perineural invasion (GPNI).: Ten patients who received SRS as part of retreatment for recurrent head and neck cutaneous squamous cell carcinoma with GPNI were included. All patients exhibited clinical and radiologic evidence of GPNI before SRS. Previous treatments included surgery alone in 3 patients and surgery with adjuvant external beam radiotherapy (EBRT) in 7 patients. Retreatment included SRS alone in 2 and EBRT boosted with SRS in 8 patients. Magnetic resonance images were obtained every 3 to 6 months after SRS to track failure patterns.: At a median 22-month follow-up, the 2-year progression-free and overall survival rates were 20% and 50%, respectively. Seven patients exhibited local failures, all of which occurred outside both SRS and EBRT fields. Five local failures occurred in previously clinically uninvolved cranial nerves (CNs). CN disease spreads through 3 distinct patterns: among different branches of CN V; between CNs V and VII; and between V1 and CNs III, IV, and/or VI. Five patients experienced side effects potentially attributable to radiation.: Although there is excellent in-field control with this approach, the rate of out-of-field failures remains unacceptably high. We found that the majority of failures occurred in previously clinically uninvolved CNs often just outside treatment fields. Novel treatment strategies targeting this mode of perineural spread are needed.

  View details for DOI 10.1097/COC.0b013e3182468019

  View details for PubMedID 22547009

• E 1308: A phase II trial of induction chemotherapy (IC) followed by cetuximab with low dose versus standard dose IMRT in patients with human papilloma virus (HPV)-associated resectable squamous cell carcinoma of the oropharynx (OPSCC) Marur, S., Li, S., Cmelak, A., Gillison, M. L., Ferris, R. L., Bauman, J. E., Zhao, W., Westra, W. H., Chung, C. H., Wagner, L. I., Trevarthen, D. R., Jahagirdar, B. N., Colevas, A., Barbara Burtness Eastern Cooperati AMER SOC CLINICAL ONCOLOGY. 2013

  View details for Web of Science ID 000335419602130

• Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence. Cancer Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Le, Q., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356

  Abstract

  In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

  View details for DOI 10.1002/cncr.27892

  View details for PubMedID 23225544

• Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence CANCER Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Quynh-Thu Le, Q. T., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356

  Abstract

  In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

  View details for DOI 10.1002/cncr.27892

  View details for Web of Science ID 000316811900010

• Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug-drug interaction potential CANCER CHEMOTHERAPY AND PHARMACOLOGY LoRusso, P. M., Piha-Paul, S. A., Mita, M., Colevas, A. D., Malhi, V., Colburn, D., Yin, M., Low, J. A., Graham, R. A. 2013; 71 (1): 193-202

  Abstract

  Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs).This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 ?g; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8).The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 ?M (range 7.93-62.4 ?M). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [?8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (?5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib.This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.

  View details for DOI 10.1007/s00280-012-1996-6

  View details for Web of Science ID 000313004900021

  View details for PubMedID 23064958

• Biased View of the Role of Site-Specific Therapy in Carcinoma of Unknown Primary. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Percival, M. E., Colevas, A. D. 2013

  View details for DOI 10.1200/JCO.2013.49.5036

  View details for PubMedID 23733770

• Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors INVESTIGATIONAL NEW DRUGS Kunz, P. L., He, A. R., Colevas, A. D., Pishvaian, M. J., Hwang, J. J., Clemens, P. L., Messina, M., Kaleta, R., Abrahao, F., Sikic, B. I., Marshall, J. L. 2012; 30 (6): 2364-2370

  Abstract

  Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or ?III-tubulin.This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements.Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90-100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT.On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely.

  View details for DOI 10.1007/s10637-012-9800-3

  View details for PubMedID 22331549

• Postoperative Radiation Therapy for Minor Salivary Gland Carcinomas of the Head and Neck: Long-term Outcomes Zeidan, Y., Murphy, J. D., Chan, C., An, Y., Kaplan, M., Colevas, A., Kong, C., Le, Q. ELSEVIER SCIENCE INC. 2012: S500

  View details for DOI 10.1016/j.ijrobp.2012.07.1332

  View details for Web of Science ID 000310542901465

• A Phase 2 Trial of Flavopiridol (Alvocidib) and Cisplatin in Platin-Resistant Ovarian and Primary Peritoneal Carcinoma: MC0261 GYNECOLOGIC ONCOLOGY Bible, K. C., Peethambaram, P. P., Oberg, A. L., Maples, W., Groteluschen, D. L., Boente, M., Burton, J. K., Dahl, L. C., Tibodeau, J. D., Isham, C. R., Maguire, J. L., Shridhar, V., Kukla, A. K., Voll, K. J., Mauer, M. J., Colevas, A. D., Wright, J., Doyle, L. A., Erlichman, C. 2012; 127 (1): 55-62

  Abstract

  Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers.A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) immediately followed by flavopiridol (100 mg/m2 IV, 24 h infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression>vs. ?6 months following prior platin-based therapy). Measurable disease (RECIST)--or evaluable disease plus CA125>2X post-treatment nadir--and ECOG performance?2 were required.Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118 days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3 months; overall survival was 16.1 months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8 months and median overall survival 20.6 months) the cohort was closed due to poor accrual.The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study.

  View details for DOI 10.1016/j.ygyno.2012.05.030

  View details for Web of Science ID 000308783800012

  View details for PubMedID 22664059

• Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Trakul, N., Chang, C. N., Harris, J., Chapman, C., Rao, A., Shen, J., Quinlan-Davidson, S., Filion, E. J., Wakelee, H. A., Colevas, A. D., Whyte, R. I., Dieterich, S., Maxim, P. G., Hristov, D., Tran, P., Quynh-Thu Le, Q. T., Loo, B. W., Diehn, M. 2012; 84 (1): 231-237

  Abstract

  Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy.We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ?12 mL) received multifraction regimens with BED ?100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2).The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02).A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

  View details for DOI 10.1016/j.ijrobp.2011.10.071

  View details for PubMedID 22381907

• A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours BRITISH JOURNAL OF CANCER Diaz-Padilla, I., Siu, L. L., San Pedro-Salcedo, M., Razak, A. R., Colevas, A. D., Shepherd, F. A., Leighl, N. B., Neal, J. W., Thibault, A., Liu, L., Lisano, J., Gao, B., Lawson, E. B., Wakelee, H. A. 2012; 107 (4): 604-611

  Abstract

  To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75?mg?m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ? 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

  View details for DOI 10.1038/bjc.2012.319

  View details for Web of Science ID 000307770300005

  View details for PubMedID 22805331

  View details for PubMedCentralID PMC3419963

• Validation that metabolic tumor volume predicts outcome in head-and-neck cancer. International journal of radiation oncology, biology, physics Tang, C., Murphy, J. D., Khong, B., La, T. H., Kong, C., Fischbein, N. J., Colevas, A. D., Iagaru, A. H., Graves, E. E., Loo, B. W., Le, Q. 2012; 83 (5): 1514-1520

  Abstract

  We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment (18)F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16(INK4a) status as a surrogate marker for human papillomavirus (HPV).The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV(max)) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV.Similarly to our prior findings, an increase in total MTV of 17 cm(3) (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV(max) was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16(INK4a)-positive oropharyngeal cancer.This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

  View details for DOI 10.1016/j.ijrobp.2011.10.023

  View details for PubMedID 22270174

• A randomized phase II study of cilengitide (EMD 121974) in patients with metastatic melanoma MELANOMA RESEARCH Kim, K. B., Prieto, V., Joseph, R. W., Diwan, A. H., Gallick, G. E., Papadopoulos, N. E., Bedikian, A. Y., Camacho, L. H., Hwu, P., Ng, C. S., Wei, W., Johnson, M. M., Wittemer, S. M., Vardeleon, A., Reckeweg, A., Colevas, A. D. 2012; 22 (4): 294-301

  Abstract

  Cilengitide (EMD 121974) is a selective inhibitor of integrins ?v?3 and ?v?5. The ?v?3 promotes the proliferation of tumor-associated endothelial cells and potentially the survival of melanoma cells. We conducted a randomized phase II trial in patients with metastatic melanoma to evaluate the clinical efficacy of cilengitide. Patients with stage IV or unresectable stage III melanoma who were either chemonaive or who had previously received one systemic therapy were enrolled. Patients were randomly assigned to either 500 or 2000 mg of cilengitide administered intravenously twice weekly. The primary aim of this study was to determine the progression-free survival rate at 8 weeks. Tumor samples and blood samples were collected for pharmacodynamic and pharmacokinetic studies. Twenty-nine patients were enrolled, of whom 26 were treated (14 at 500 mg and 12 at 2000 mg). Among those treated, only three were progression free at 8 weeks: two in the 500 mg arm and one in the 2000 mg arm. One patient in the 2000 mg arm showed a prolonged partial response after an initial 28% enlargement of her target lesions. The treatment was well tolerated without clinically significant adverse events. The sole responder and one of two patients with stable disease had no ?v?3 expression at baseline. Overall, ?v?3 expression was decreased by day 8 of the treatment (P=0.05). Cilengitide was well tolerated by patients in both the treatment arms but had minimal clinical efficacy as a single-agent therapy for metastatic melanoma, and the efficacy was not related to baseline ?v?3 expression.

  View details for DOI 10.1097/CMR.0b013e32835312e4

  View details for Web of Science ID 000306278300002

  View details for PubMedID 22668797

• Validation that Metabolic Tumor Volume Predicts Outcome in Head-and-Neck Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Tang, C., Murphy, J. D., Khong, B., La, T. H., Kong, C., Fischbein, N. J., Colevas, A. D., Iagaru, A. H., Graves, E. E., Loo, B. W., Quynh-Thu Le, Q. T. 2012; 83 (5): 1514-1520

  Abstract

  We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment (18)F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16(INK4a) status as a surrogate marker for human papillomavirus (HPV).The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV(max)) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV.Similarly to our prior findings, an increase in total MTV of 17 cm(3) (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV(max) was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16(INK4a)-positive oropharyngeal cancer.This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

  View details for DOI 10.1016/j.ijrobp.2011.10.023

  View details for Web of Science ID 000306128100046

  View details for PubMedCentralID PMC3337958

• Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl(+) hematological malignancies CANCER CHEMOTHERAPY AND PHARMACOLOGY Bose, P., Perkins, E. B., Honeycut, C., Wellons, M. D., Stefan, T., Jacobberger, J. W., Kontopodis, E., Beumer, J. H., Egorin, M. J., Imamura, C. K., Figg, W. D., Karp, J. E., Koc, O. N., Cooper, B. W., Luger, S. M., Colevas, A. D., Roberts, J. D., Grant, S. 2012; 69 (6): 1657-1667

  Abstract

  Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl(+) malignancies.In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed.A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed.This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease.

  View details for DOI 10.1007/s00280-012-1839-5

  View details for Web of Science ID 000304622600028

  View details for PubMedID 22349810

  View details for PubMedCentralID PMC3365614

• ECOG 1308: A phase II trial of induction chemotherapy followed by cetuximab with low dose versus standard dose IMRT in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx (OP). 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Marur, S., Lee, J., Cmelak, A., Zhao, W., Westra, W. H., Chung, C. H., Gillison, M. L., Gilbert, J., Bauman, J. E., Wagner, L. I., Ferris, R. L., Trevarthen, D. R., Colevas, A. D., Jahagirdar, B. N., Burtness, B. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009800120

• Hearing evaluation of head and neck cancer patients (HNCP): Comparison of adverse event (AE) criteria Colevas, A., Lira, R. R., Colevas, E. A., Lavori, P. W., Chang, K. W. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009801570

• Phase Ib, multicenter, single-blinded, placebo-controlled, sequential dose-escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer (LAHNC) receiving induction chemotherapy (ICT). 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Limaye, S. A., Sonis, S. T., Cilli, F., Colevas, A. D., Brennan, M., Hu, K., Haddad, R. I., Murphy, B. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009802371

• Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M., Lund, P., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Sunwoo, J., Tedder, T., Chen, L., Levy, R. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009801791

• Intensity-Modulated Radiotherapy for Tumors of the Nasal Cavity and Paranasal Sinuses: Clinical Outcomes and Patterns of Failure 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Wiegner, E. A., Daly, M. E., Murphy, J. D., Abelson, J., Chapman, C. H., Chung, M., Yu, Y., Colevas, A. D., Kaplan, M. J., Fischbein, N., Quynh-Thu Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 243?51

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2011.05.044

  View details for PubMedID 22019239

• A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors CANCER CHEMOTHERAPY AND PHARMACOLOGY Padda, S. K., Krupitskaya, Y., Chhatwani, L., Fisher, G. A., Colevas, A. D., Pedro-Salcedo, M. S., Decker, R., Latz, J. E., Wakelee, H. A. 2012; 69 (4): 1013-1020

  Abstract

  Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated.This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with advanced solid malignancies including non-small-cell lung cancer (NSCLC). Two dose levels of enzastaurin (with loading doses) were explored: 250 mg daily and 500 mg daily. Erlotinib was given at 150 mg daily.Sixteen patients were enrolled in this study (median age, 64 years). Most patients were heavily pre-treated, female, and Caucasian and had NSCLC. The highest dose of enzastaurin, 500 mg daily, was tolerated with no unexpected adverse events and no alteration in the pharmacokinetics of either drug at this dose level. The mean clearance was 5.75 L/h for erlotinib and 53.8 L/h for enzastaurin. The most common possibly drug-related grade 3-4 adverse events included diarrhea (25.0%), neurologic symptoms (18.8%), and vomiting (18.8%). Activity was noted, with a partial response in one patient and prolonged disease stability for >12 cycles in three patients.The combination of enzastaurin 500 mg daily and erlotinib 150 mg daily is well tolerated and does not alter the pharmacokinetics of the individual drugs, with clinical activity seen. A phase II trial of this combination has been initiated in patients with advanced-stage NSCLC.

  View details for DOI 10.1007/s00280-011-1792-8

  View details for PubMedID 22160298

• Quantitation of Human Papillomavirus DNA in Plasma of Oropharyngeal Carcinoma Patients INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Cao, H., Banh, A., Kwok, S., Shi, X., Wu, S., Krakow, T., Khong, B., Bavan, B., Bala, R., Pinsky, B. A., Colevas, D., Pourmand, N., Koong, A. C., Kong, C. S., Quynh-Thu Le, Q. T. 2012; 82 (3): E351-E358

  Abstract

  To determine whether human papillomavirus (HPV) DNA can be detected in the plasma of patients with HPV-positive oropharyngeal carcinoma (OPC) and to monitor its temporal change during radiotherapy.We used polymerase chain reaction to detect HPV DNA in the culture media of HPV-positive SCC90 and VU147T cells and the plasma of SCC90 and HeLa tumor-bearing mice, non-tumor-bearing controls, and those with HPV-negative tumors. We used real-time quantitative polymerase chain reaction to quantify the plasma HPV DNA in 40 HPV-positive OPC, 24 HPV-negative head-and-neck cancer patients and 10 non-cancer volunteers. The tumor HPV status was confirmed by p16(INK4a) staining and HPV16/18 polymerase chain reaction or HPV in situ hybridization. A total of 14 patients had serial plasma samples for HPV DNA quantification during radiotherapy.HPV DNA was detectable in the plasma samples of SCC90- and HeLa-bearing mice but not in the controls. It was detected in 65% of the pretreatment plasma samples from HPV-positive OPC patients using E6/7 quantitative polymerase chain reaction. None of the HPV-negative head-and-neck cancer patients or non-cancer controls had detectable HPV DNA. The pretreatment plasma HPV DNA copy number correlated significantly with the nodal metabolic tumor volume (assessed using (18)F-deoxyglucose positron emission tomography). The serial measurements in 14 patients showed a rapid decline in HPV DNA that had become undetectable at radiotherapy completion. In 3 patients, the HPV DNA level had increased to a discernable level at metastasis.Xenograft studies indicated that plasma HPV DNA is released from HPV-positive tumors. Circulating HPV DNA was detectable in most HPV-positive OPC patients. Thus, plasma HPV DNA might be a valuable tool for identifying relapse.

  View details for DOI 10.1016/j.ijrobp.2011.05.061

  View details for PubMedID 21985946

• Mucosal Melanoma of the Head and Neck JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B., Cmelak, A. J., Dimitrios Colevas, A., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Sanguineti, G., Schuller, D. E. 2012; 10 (3): 320-338

  View details for Web of Science ID 000301222300006

  View details for PubMedID 22393194

• Maintenance Bevacizumab is Associated With Increased Hemoglobin in Patients With Advanced, Nonsquamous, Non-Small Cell Lung Cancer CANCER INVESTIGATION Riess, J. W., Logan, A. C., Krupitskaya, Y., Padda, S., Clement-Duchene, C., Ganjoo, K., Colevas, A. D., San Pedro-Salcedo, M., Kuo, C. J., Wakelee, H. A. 2012; 30 (3): 231-235

  Abstract

  We retrospectively analyzed hematologic parameters in 22 patients with advanced, nonsquamous, NSCLC undergoing VEGF inhibition on a phase II clinical trial of bevacizumab, carboplatin, and gemcitabine. We also examined TTP in relation to hemoglobin changes. Median hemoglobin increased significantly from a 12.9 g/dL pretreatment to 13.8 g/dL (p =.01) after the second cycle of maintenance bevacizumab until the first off cycle measurement. There was no difference in TTP in patients who achieved a rise in hemoglobin compared with patients who did not (median 238 days vs. 268 days, p =.38.) Maintenance bevacizumab is associated with increased hemoglobin in advanced, nonsquamous, NSCLC patients.

  View details for DOI 10.3109/07357907.2012.656862

  View details for PubMedID 22360362

• Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer JOURNAL OF CLINICAL INVESTIGATION Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M. J., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Stockdale, F. E., Mollick, J. A., Chen, L., Levy, R. 2012; 122 (3): 1066-1075

  Abstract

  Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the Fc?RIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors.

  View details for DOI 10.1172/JCI61226

  View details for Web of Science ID 000301021500029

  View details for PubMedID 22326955

  View details for PubMedCentralID PMC3287235

• Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial LANCET ONCOLOGY Lee, N. Y., Zhang, Q., Pfister, D. G., Kim, J., Garden, A. S., Mechalakos, J., Hu, K., Le, Q. T., Colevas, A. D., Glisson, B. S., Chan, A. T., Ang, K. K. 2012; 13 (2): 172-180

  Abstract

  We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy.We enrolled patients older than 18 years with stage IIB-IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m(2)) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m(2)), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m(2) per day), given on days 64-67, 85-88, and 106-109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694.From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3-4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1-2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3-4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2·5 years (IQR 2·1-2·9), the estimated 2 year locoregional progression-free interval was 83·7% (95% CI 72·6-94·9), the 2 year distant metastasis-free interval was 90·8% (82·2-99·5), the 2 year progression-free survival was 74·7% (61·8-87·6), and 2 year overall survival was 90·9% (82·3-99·4).The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease.National Cancer Institute, USA.

  View details for DOI 10.1016/S1470-2045(11)70303-5

  View details for Web of Science ID 000300197400042

  View details for PubMedID 22178121

  View details for PubMedCentralID PMC4985181

• The use of epidermal growth factor receptor monoclonal antibodies in squamous cell carcinoma of the head and neck. Chemotherapy research and practice Russell, J. S., Colevas, A. D. 2012; 2012: 761518-?

  Abstract

  Targeting of the EGF receptor (EGFR) has become a standard of care in several tumor types. In squamous cell carcinoma of the head and neck, monoclonal antibodies directed against EGFR have become a regular component of therapy for curative as well as palliative treatment strategies. These agents have anti-tumor efficacy as a single modality and have demonstrated synergistic tumor killing when combined with radiation and/or chemotherapy. While cetuximab has been the primary anti-EGFR monoclonal antibody used in the US, variant anti-EGFR monoclonal antibodies have been used in several clinical studies and shown benefit with improved toxicity profiles. Next generation anti-EGFR monoclonal antibodies may demonstrate multi-target epitope recognition, enhanced immune cell stimulation, or conjugation with radioisotopes in order to improve clinical outcomes. Identification of the specific patient subset that would optimally benefit from anti-EGFR monoclonal antibodies remains an elusive goal.

  View details for DOI 10.1155/2012/761518

  View details for PubMedID 23150825

  View details for PubMedCentralID PMC3488396

• Evaluation of patients with disseminated or locoregionally advanced thyroid cancer: a primer for medical oncologists. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Colevas, A. D., Shah, M. H. 2012: 384?88

  Abstract

  Historically, patients with thyroid cancers are managed by endocrinologists, surgeons and radiation oncologists. Due to recent progress in this field with advances in treatment of thyroid cancer, medical oncologists are now commonly involved in care of patients with advanced thyroid cancers. In this manuscript, we describe general principles in management of patients with various types of thyroid cancers including differentiated, medullary and anaplastic thyroid cancers.

  View details for PubMedID 24451768

• Transsphenoidal Resection of Sellar Tumors Using High-Field Intraoperative Magnetic Resonance Imaging SKULL BASE-AN INTERDISCIPLINARY APPROACH Szerlip, N. J., Zhang, Y., Placantonakis, D. G., Goldman, M., Colevas, K. B., Rubin, D. G., Kobylarz, E. J., Karimi, S., Girotra, M., Tabar, V. 2011; 21 (4): 223-232

  Abstract

  There has been increasing experience in the utilization of intraoperative magnetic resonance imaging (iMRI) for intracranial surgery. Despite this trend, only a few U.S centers have examined the use of this technology for transsphenoidal resection of tumors of the sella. We present the largest series in North America examining the role of iMRI for pituitary adenoma resection. We retrospectively reviewed our institutional experience of 59-patients who underwent transsphenoidal procedures for sellar and suprasellar tumors with iMRI guidance. Of these, 52 patients had a histological diagnosis of pituitary adenoma. The technical results of this subgroup were examined. A 1.5-T iMRI was integrated with the BrainLAB (Feldkirchen, Germany) neuronavigation system. The majority (94%) of tumors in our series were macroadenomas. Seventeen percent of tumors were confined to the sella, 49% had suprasellar extensions without involvement of the cavernous sinus, 34% had frank cavernous sinus invasion. All patients underwent at least one iMRI, and 19% required one or more additional sets of intraoperative imaging. In 58% of patients, iMRI led to the surgeon attempting more resection. A gross total resection was obtained in 67% of the patients with planned total resections. There was one case of permanent postoperative diabetes insipidus and no other instances of new hormone replacement. In summary, iMRI was most useful for tumors of the sella with and without suprasellar extension where the information from the iMRI extended the complete resection rate from 40 to 72% and 55 to 88%, respectively. As one would expect, it did not substantially increase the rate of resection of tumors with cavernous sinus invasion. Overall, iMRI was particularly useful in guiding resection safely, aiding in clinical decision making, and allowing identification and preservation of the pituitary stalk and normal pituitary gland. Limitations of the iMRI include a need for additional personnel and training as well as additional operative time, which diminishes over time as personnel learn to optimize workflow efficiency. Additional costs are mitigated in part by using the iMRI as an immediate postoperative scan. Other data emerging from our experience suggest that preservation of normal gland and thus avoidance of hypopituitarism may be improved by iMRI use, but longer follow-up periods are required to test this conclusion. iMRI can detect unsuspected complications sooner than routine postoperative imaging, potentially leading to improved outcomes. However, larger studies are needed.

  View details for DOI 10.1055/s-0031-1277262

  View details for Web of Science ID 000292876600003

  View details for PubMedID 22470265

• Head and Neck Cancers JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B. A., Cmelak, A. J., Colevas, D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Sanguineti, G., Schuller, D. E., Shah, J. P., Spencer, S., Trotti, A., Weber, R. S., Wolf, G. T., Worden, F. 2011; 9 (6): 596-649

  View details for Web of Science ID 000291282100002

  View details for PubMedID 21636536

• A POOLED ANALYSIS OF ADVANCED NONSQUAMOUS NSCLC PATIENTS WITH STABLE TREATED BRAIN METASTASES IN TWO PHASE II TRIALS RECEIVING BEVACIZUMAB AND PEMETREXED AS SECOND-LINE THERAPY Gubens, M., Akerley, W., Lynch, T., Langer, C. J., Socinski, M. A., Colevas, A., Clement-Duchene, C., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: S1224?S1225

  View details for Web of Science ID 000291769801052

• Controversies in the Locoregional Management of Head and Neck Cancer JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Brizel, D. M., Lydiatt, W., Colevas, A. D. 2011; 9 (6): 653-662

  Abstract

  Head and neck cancer (HNC) is a heterogeneous combination of various sites and types of disease. This manuscript elaborates on 3 important and current issues: the emerging role of human papilloma virus (HPV) in oropharyngeal cancer (OPC), current considerations in systemic therapy for advanced disease, and evolving treatment of the neck. Exogenous carcinogens, most notably tobacco, have classically been implicated in the development of HNC. A large increase in the incidence of OPC has occurred in the past few decades, predominantly in nontobacco users, and is caused by HPV. This disease is unique in many respects and presents an opportunity for novel therapeutic approaches. Because the prognosis for HPV-related HNC is better, regardless of whether surgery or radiation is used as the primary therapy, the reduction of treatment-related morbidity has assumed increasing importance and provides unique opportunities and challenges for de-escalation of therapies. Radiotherapy (RT) and concurrent cisplatin is the most commonly used nonsurgical platform for locally advanced disease. New data suggest that viable alternatives exist to the typical 3 cycles of bolus high-dose cisplatin. The role of RT and concurrent taxanes remains less understood. Similarly, the value of integrating epidermal growth factor inhibition and concurrent chemoradiation is under continuing investigation. The use of PET scanning is changing the traditional use of adjuvant neck dissection after RT or chemoradiation. Recent data support the use of surgery in the presence of a positive posttreatment PET, and observation in the setting of a negative posttreatment scan.

  View details for Web of Science ID 000291282100003

  View details for PubMedID 21636537

• Safety, pharmacokinetics (PK), and pharmacodynamics (PD) of HGS1029, an inhibitor of apoptosis protein (IAP) inhibitor, in patients (Pts) with advanced solid tumors: Results of a phase I study. Sikic, B. I., Eckhardt, S. G., Gallant, G., Burris, H. A., Camidge, D. R., Colevas, A. D., Jones, S. F., Messersmith, W. A., Wakelee, H. A., Li, H., Kaminker, P. G., Morris, S., Infante, J. R. AMER SOC CLINICAL ONCOLOGY. 2011

  View details for DOI 10.1200/jco.2011.29.15_suppl.3008

  View details for Web of Science ID 000208880301437

• Chemoradiation for nasopharyngeal carcinoma (NPC) with pilot hypoxia imaging with F18 misonidazole PET scanning. Colevas, A. D., Quon, A., McMillan, A., Le, Q. AMER SOC CLINICAL ONCOLOGY. 2011

  View details for DOI 10.1200/jco.2011.29.15_suppl.5556

  View details for Web of Science ID 000208880301700

• A first-in-human phase 1 study to evaluate the MEK1/2 inhibitor GDC-0973 administered daily in patients with advanced solid tumors Rosen, L., LoRusso, P., Ma, W., Goldman, J., Weise, A., Colevas, A., Adjei, A., Yazji, S., Shen, A., Johnston, S., Gates, M. R., Jones, C., Musib, L., De Crespigny, A., Chan, I., Sikic, B. AMER ASSOC CANCER RESEARCH. 2011

  View details for DOI 10.1158/1538-7445.AM2011-4716

  View details for Web of Science ID 000209701404368

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

  Abstract

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

  View details for DOI 10.1002/hed.21406

  View details for PubMedID 20848427

• A Phase II First-Line Study of Gemcitabine, Carboplatin, and Bevacizumab in Advanced Stage Nonsquamous Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Clement-Duchene, C., Krupitskaya, Y., Ganjoo, K., Lavori, P., McMillan, A., Kumar, A., Zhao, G., Padda, S., Zhou, L., San Pedro-Salcedo, M., Colevas, A. D., Wakelee, H. A. 2010; 5 (11): 1821-1825

  Abstract

  Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab.Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity.From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1-42) with 37 patients (78.7%) completing ?4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8-7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0-16.5). The OS is 57% at 1 year and 10% at 2 years.Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.

  View details for DOI 10.1097/JTO.0b013e3181f1d23c

  View details for PubMedID 20881641

• HIGHER INCIDENCE OF HEAD AND NECK CANCERS AMONG VIETNAMESE AMERICAN MEN IN CALIFORNIA HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Filion, E. J., McClure, L. A., Huang, D., Seng, K., Kaplan, M. J., Colevas, A. D., Gomez, S. L., Chang, E. T., Le, Q. 2010; 32 (10): 1336-1344

  Abstract

  Our aim was to determine the incidence rates of head and neck cancer in Vietnamese Californians compared with other Asian and non-Asian Californians.Age-adjusted incidence rates of head and neck cancer between 1988 and 2004 were computed for Vietnamese Californians compared with other racial/ethnic groups by time period, ethnicity, neighborhood-level socioeconomic status (SES), and sex using data from the population-based California Cancer Registry (CCR). Data by smoking and alcohol status were tabulated from the California Health Interview Survey.Vietnamese men had a higher incidence rate of head and neck cancer than other Asian men. Specifically, the laryngeal cancer rate was significantly higher for Vietnamese men (6.5/100,000; 95% confidence interval [CI], 5.0-8.2) than all other Asian men (range, 2.6-3.8/100,000), except Korean men (5.1/100,000; 95% CI, 3.9-6.4). Both Vietnamese and Korean men had the highest percentage of current smokers. Neighborhood SES was inversely related to head and neck cancer rates among Vietnamese men and women.The higher incidence rate of head and neck cancer in Vietnamese men may correspond to the higher smoking prevalence in this group. Individual-level data are needed to establish the link of tobacco, alcohol, and other risk factors with head and neck cancer in these patients.

  View details for DOI 10.1002/hed.21330

  View details for Web of Science ID 000282707500008

  View details for PubMedID 20091688

  View details for PubMedCentralID PMC4349526

• MOLECULAR AND CLINICAL RESPONSES IN A PILOT STUDY OF GEFITINIB WITH PACLITAXEL AND RADIATION IN LOCALLY ADVANCED HEAD-AND-NECK CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Van Waes, C., Allen, C. T., Citrin, D., Gius, D., Colevas, A. D., Harold, N. A., Rudy, S., Nottingham, L., Muir, C., Chen, Z., Singh, A. K., Dancey, J., Morris, J. C. 2010; 77 (2): 447-454

  Abstract

  Epidermal growth factor receptor (EGFR) overexpression in head-and-neck squamous cell carcinoma (HNSCC) stimulates tumor cell proliferation, inhibits apoptosis, and increases chemotherapy and radiation resistance. We examined the toxicity, safety and the effects on EGFR signaling in tumor biopsy samples from patients with locally advanced HNSCC treated with the EGFR signaling inhibitor gefitinib (GEF) combined with weekly intravenous paclitaxel (PAC) and radiation therapy (RT).This was a pilot Phase I dose-escalation study. Eligibility included Stage III to IVB HNSCC, age >or=18 years, no prior RT or chemotherapy, adequate organ function, and informed consent. Endpoints included determination of maximum tolerated dose (MTD) and analysis of treatment effect on EGFR signaling, tumor cell proliferation, and apoptosis in biopsy samples.Ten patients were treated. The MTD of this combination was GEF 250 mg/d with PAC 36 mg/m(2) intravenously weekly x 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 weeks) stomatitis (7 patients), infection (2 patients), and interstitial pneumonitis (1 patient). There were five complete responses (CR) and two partial responses (PR). Of 7 patients undergoing serial biopsies, only 1 patient demonstrated a reduction in phosphorylated EGFR, decreased downstream signaling, and reduced cellular proliferation after initiating GEF.Inhibition of EGFR by GEF was observed in only one of seven tumors studied. The addition of GEF to PAC and RT did not appear to improve the response of locally advanced HNSCC compared with our prior experience with PAC and RT alone. This treatment appeared to delay recovery from stomatitis.

  View details for DOI 10.1016/j.ijrobp.2009.05.037

  View details for Web of Science ID 000278167500018

  View details for PubMedID 19879702

• Phase I study evaluating the safety, tolerability, and pharmacokinetics (PK) of HGS1029, a small-molecule inhibitor of apoptosis protein (IAP), in patients (pts) with advanced solid tumors. Eckhardt, S. G., Gallant, G., Sikic, B. I., Camidge, D. R., Burris, H. A., Wakelee, H. A., Messersmith, W. A., Jones, S. F., Colevas, A. D., Infante, J. R. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for Web of Science ID 000208852003171

• A phase I study of an oral formulation of ixabepilone (ixa) in patients with advanced cancer He, A. R., Kunz, P. L., Pishvaian, M. J., Colevas, A. D., Hwang, J. J., Clemens, P. L., Messina, M., Kaleta, R., Abrahao, F., Sikic, B. I. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.e13090

  View details for Web of Science ID 000208852000315

• Nano-immunoassay profiling of ERK and MEK isoforms in fine-needle aspirates of solid tumors Fan, A. C., Dermody, J., Kong, C., Zhang, N., Colevas, A. D., Felsher, D. W. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.2564

  View details for Web of Science ID 000208852003155

• Plasma human papillomavirus (HPV) DNA as a potential tool for tumor detection and monitoring response in HPV-related oropharyngeal carcinoma (OP) Cao, H., Kwok, S., Shi, X., Bala, R., Pinsky, B., Colevas, A. D., Pourmand, N., Koong, A., Kong, C., Le, Q. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.5529

  View details for Web of Science ID 000208852004206

• A population-based evaluation of incidence trends in oropharynx cancer (OP) focusing on socioeconomic status (SES), sex, and race/ethnicity Colevas, A. D., Clarke, C. A., Lichtensztajn, D., Chang, E. T. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.5526

  View details for Web of Science ID 000208852004203

• Toxicity Monitoring: Why, What, When.? ONCOLOGY CLINICAL TRIALS Colevas, A., Kelly, W. K., Halabi, S. 2010: 151?61

  View details for Web of Science ID 000273577900018

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

  View details for DOI 10.1016/j.ijrobp.2010.07.1086

  View details for Web of Science ID 000288775701081

• Quantification of pre-treatment metabolic tumor growth rate in lung cancer Eastham, D., Chapman, C. H., Rao, A. K., Balasubramanian, N., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, D. A., Maxim, P. A., Graves, E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S733?S733

  View details for Web of Science ID 000269496002262

• Excellent early local control with tumor volume adapted dosing of stereotactic body radiation therapy for pulmonary tumors Chang, C. N., Zhou, L. Y., MacFarlane, G., Tran, P., Rao, A., Chapman, C., Le, Q., Wakelee, H., Colevas, A. D., Whyte, R., Hristov, D., Dieterich, S., Maxim, P., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S938?S939

  View details for Web of Science ID 000269496002720

• LONG-TERM OUTCOMES AND TOXICITY OF CONCURRENT PACLITAXEL AND RADIOTHERAPY FOR LOCALLY ADVANCED HEAD-AND-NECK CANCER 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Citrin, D., Mansueti, J., Likhacheva, A., Sciuto, L., Albert, P. S., Rudy, S. F., Cooley-Zgela, T., Cotrim, A., Solomon, B., Colevas, A. D., Russo, A., Morris, J. C., Herscher, L., Smith, S., Van Waes, C. ELSEVIER SCIENCE INC. 2009: 1040?46

  Abstract

  To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m(2)/cycle, and the subsequent 19 patients received 120 mg/m(2)/cycle. External beam radiotherapy was delivered to a dose of 70.2-72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen.The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%).The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.

  View details for DOI 10.1016/j.ijrobp.2008.09.053

  View details for Web of Science ID 000267505000010

  View details for PubMedID 19117692

  View details for PubMedCentralID PMC2720824

• Does Pre-treatment Metabolic Tumor Growth Rate (MTGR) Predict Progression in Lung Cancer? 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Eastham, D. V., Chapman, C. H., Rao, A. K., Narasimhan, B., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, A. D., Loo, B. W. ELSEVIER SCIENCE INC. 2009: S446?S446

  View details for Web of Science ID 000270573601456

• Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms Grant, S., Sullivan, D., Roodman, D., Stuart, R. K., Perkins, E., Kolla, S., Rarnakrishnan, V., Wright, J., Colevas, A., Tombes, M. B., Roberts, J. D. AMER SOC HEMATOLOGY. 2008: 558

  View details for Web of Science ID 000262104701794

• A multicentre phase II clinical experience with the novel aza-epothilone Ixabepilone (BMS247550) in patients with relapsed or refractory indolent non-Hodgkin lymphoma and mantle cell lymphoma BRITISH JOURNAL OF HAEMATOLOGY O'Connor, O. A., Portlock, C., Moskowitz, C., Straus, D., Hamlin, P., Stubblefield, M., Dumetrescu, O., Colevas, A. D., Grant, B., Zelenetz, A. 2008; 143 (2): 201-209

  Abstract

  The epothilones represent a novel group of microtubule stabilization agents that appear to retain activity even in chemotherapy-resistant cell lines and animal models. Because of their ability to overcome chemotherapy resistance, we conducted a phase II study of Ixabepilone in patients with indolent non-Hodgkin lymphoma and mantle cell lymphoma (MCL). Ixabepilone was given at a dose of 25 mg/m(2) weekly for three of four consecutive weeks. Patients were required to have received < or =4 prior chemotherapy regimens, with an interval of at least one month since the last treatment, 3 months from prior rituximab, and 7 d from prior steroids, an absolute neutrophil count >1 x 10(9)/l and a platelet count >50 x 10(9)/l. Dose reductions were allowed. The overall response rate in assessable patients was 27% in this otherwise heavily treated population. One patient with chemotherapy-refractory follicular lymphoma attained a complete remission that lasted approximately 8 months. Three responses were also seen in refractory MCL and one in small lymphocytic lymphoma. The duration of response ranged from 2 to 8 months. Major toxicities included fatigue, myelosuppression and neuropathy. These data suggest that Ixabepilone has activity in chemotherapy-refractory lymphoma.

  View details for DOI 10.1111/j.1365-2141.2008.07271.x

  View details for Web of Science ID 000259505900005

  View details for PubMedID 18691173

• Head and neck cancers. Journal of the National Comprehensive Cancer Network Forastiere, A. A., Ang, K., Brizel, D., Brockstein, B. E., Burtness, B. A., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Goepfert, H., Hicks, W. L., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pfister, D. G., Pinto, H. A., Posner, M. R., Ridge, J. A., Samant, S., Schuller, D. E., Shah, J. P., Spencer, S., Trotti, A., Weber, R. S., Wolf, G. T., Worden, F. 2008; 6 (7): 646-695

  View details for PubMedID 18691457

• Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck 31st Congress of the European-Society-for-Medical-Oncology Tang, P. A., Siu, L. L., Chen, E. X., Hotte, S. J., Chia, S., Schwarz, J. K., Pond, G. R., Johnson, C., Colevas, A. D., Synold, T. W., Vasist, L. S., Winquist, E. SPRINGER. 2008: 257?64

  Abstract

  Ispinesib (SB-715992) inhibits the mitotic kinesin spindle protein (KSP), a novel target for anticancer therapy. A phase II study was conducted to examine the efficacy of ispinesib in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSC). Patients with up to one prior line of chemotherapy for RMHNSC were treated with ispinesib 18 mg/m2 IV over 1 hour every 21 days. Twenty-one patients were enrolled onto this study with a target stage I sample size of 19. Of 20 evaluable patients, no objective responses were seen and stable disease > 2 cycles was observed in five patients (25%). The median time to progression was 1.4 (95% CI 1.3-2.3) months, median survival was 3.5 (95% CI 2.8-7.8) months, and 1 year overall survival was 20% (95% CI 8.3-48.1%). The most frequent attributable grades III-V adverse events were neutropenia (60% of patients) and leukopenia (55%). The pharmacokinetic profile was consistent with results from phase I studies. Archival tissues (n = 14) demonstrated low to moderate KSP expression by immunohistochemistry. In addition, no pharmacodynamic changes were observed in peripheral blood mononuclear cells. We detected no antitumor activity of ispinesib in RMHNSC on this dosing schedule.

  View details for DOI 10.1007/s10637-007-9098-8

  View details for Web of Science ID 000255194000008

  View details for PubMedID 18038218

• Intensity modulated radiotherapy for squamous cell carcinoma of the hypopharynx and larynx: Clinical outcomes and patterns of failure Daly, M. E., Le, Q. T., Loo, B. W., Maxim, P. G., Pinto, H. A., Colevas, A. D., Fee, W. E., Kaplan, M. J., Chang, D. T. ELSEVIER SCIENCE INC. 2008: S405?S406

  View details for DOI 10.1016/j.ijrobp.2008.06.1296

  View details for Web of Science ID 000258805301382

• High incidence of larynx cancers in Vietnamese population in the bay area Huang, D. D., Filion, E. J., Chang, E., Colevas, A. D., Kaplan, M. J., Le, Q. ELSEVIER SCIENCE INC. 2008: S484

  View details for DOI 10.1016/j.ijrobp.2008.06.1426

  View details for Web of Science ID 000258805301558

• A phase 2 trial of flavopiridol and cisplatin in platinum-resistant ovarian cancer Peethambaram, P. P., Burton, J. K., Oberg, A. L., Gomez-Dahl, L. C., Isham, C. R., Tibodeau, J. D., Chomjak, T. L., Colevas, A., Wright, J. J., Erlichman, C., Bible, K. C. AMER ASSOC CANCER RESEARCH. 2007: 3380S?3381S

  View details for Web of Science ID 000251969000150

• Patient-reported outcomes and the evolution of adverse event reporting in oncology JOURNAL OF CLINICAL ONCOLOGY Trotti, A., Colevas, A. D., Setser, A., Basch, E. 2007; 25 (32): 5121-5127

  Abstract

  Adverse event (AE) reporting in oncology has evolved from informal descriptions to a highly systematized process. The Common Terminology Criteria for Adverse Events (CTCAE) is the predominant system for describing the severity of AEs commonly encountered in oncology clinical trials. CTCAE clinical descriptors have been developed empirically during more than 30 years of use. The method of data collection is clinician based. Limitations of the CTC system include potential for incomplete reporting and limited guidance on data analysis and presentation methods. The Medical Dictionary for Regulatory Activities (MedDRA) is a comprehensive medical terminology system used for regulatory reporting and drug labeling. MedDRA does not provide for severity ranking of AEs. CTC-based data presentations are the primary method of AE data reporting used in scientific journals and oncology meetings. Patient-reported outcome instruments (PROs) cover the subjective domain of AEs. Exploratory work suggests PROs can be used with a high degree of patient engagement and compliance. Additional studies are needed to determine how PROs can be used to complement current AE reporting systems. Potential models for integrating PROs into AE reporting are described in this review. AE reporting methods will continue to evolve in response to changing therapies and growing interest in measuring the impact of cancer treatment on health status. Although integration of PROs into AE reporting may ultimately improve the comprehensiveness and quality of collected data, it may also increase the administrative burden and cost of conducting trials. Therefore, care must be used when developing health outcomes and safety data collection plans.

  View details for DOI 10.1200/JCO.2007.12.4784

  View details for Web of Science ID 000251074200013

  View details for PubMedID 17991931

• Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer NEW ENGLAND JOURNAL OF MEDICINE Posner, M. R., Hershock, D. M., Blajman, C. R., Mickiewicz, E., Winquist, E., Gorbounova, V., Tjulandin, S., Shin, D. M., Cullen, K., Ervin, T. J., Murphy, B. A., Raez, L. E., Cohen, R. B., Spaulding, M., Tishler, R. B., Roth, B., del Carmen Viroglio, R., Venkatesan, V., Romanov, I., Agarwala, S., Harter, K. W., Dugan, M., Cmelak, A., Markoe, A. M., Read, P. W., Steinbrenner, L., Colevas, A. D., Norris, C. M., Haddad, R. I. 2007; 357 (17): 1705-1715

  Abstract

  A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy.We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival.With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group.Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).

  View details for Web of Science ID 000250355100006

  View details for PubMedID 17960013

• A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors INVESTIGATIONAL NEW DRUGS Hensley, M. L., Dizon, D., Derosa, F., Venkatraman, E., Sabbatini, P., Chi, D. S., Dupont, J., Colevas, A. D., Spriggs, D., Aghajanian, C. 2007; 25 (4): 335-341

  Abstract

  The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received or=7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m2 plus BMS-247550 30 mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m2 plus BMS-247550 30 mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicities included neutropenia, thrombocytopenia, neutropenic fever, hypophosphatemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m2 over 90 min days 1 and 8 plus BMS-247550 20 mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.

  View details for DOI 10.1007/s10637-007-9035-x

  View details for Web of Science ID 000247275600006

  View details for PubMedID 17364235

• Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: A phase II trial in adults with poor-risk acute myelogenous leukemia CLINICAL CANCER RESEARCH Karp, J. E., Smith, B. D., Levis, M. J., Gore, S. D., Greer, J., Hattenburg, C., Briel, J., Jones, R. J., Wright, J. J., Colevas, A. D. 2007; 13 (15): 4467-4473

  Abstract

  Flavopiridol is a cyclin-dependent kinase inhibitor that is cytotoxic to leukemic blasts. In a phase I study of flavopiridol followed by 1-beta-d-arabinofuranosylcytosine (ara-C) and mitoxantrone, overall response rate for adults with relapsed and refractory acute myelogenous leukemias (AML) was 31%. We have now completed a phase II study of sequential flavopiridol, ara-C, and mitoxantrone in 62 adults with poor-risk AML.Flavopiridol (50 mg/m(2)) was given by 1-h infusion daily x 3 beginning day 1 followed by 2 gm/m(2)/72 h ara-C beginning day 6 and 40 mg/m(2) mitoxantrone on day 9.Flavopiridol caused a > or =50% decrease in peripheral blood blasts in 44% by median day 2 and > or =80% decrease in 26% by day 3. Self-limited tumor lysis occurred in 53%. Three (5%) died during therapy (2 multiorgan failure and 1 fungal pneumonia). Complete remissions (CR) were achieved in 12 of 15 (75%) newly diagnosed secondary AML, 18 of 24 (75%) first relapse after short CR (median CR, 9 months, including prior allotransplant), and 2 of 13 (15%) primary refractory but 0 of 10 multiply refractory AML. Disease-free survival for all CR patients is 40% at 2 years, with newly diagnosed patients having a 2-year disease-free survival of 50%.Flavopiridol has anti-AML activity directly and in combination with ara-C and mitoxantrone. This timed sequential regimen induces durable CRs in a significant proportion of adults with newly diagnosed secondary AML (including complex cytogenetics) and adults with AML in first relapse after short first CR.

  View details for DOI 10.1158/1078-0432.CCR-07-0381

  View details for Web of Science ID 000248525100024

  View details for PubMedID 17671131

• Inhibition of poly (ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models CLINICAL CANCER RESEARCH Albert, J. M., Cao, C., Kim, K. W., Willey, C. D., Geng, L., Xiao, D., Wang, H., Sandler, A., Johnson, D. H., Colevas, A. D., Low, J., Rothenberg, M. L., Lu, B. 2007; 13 (10): 3033-3042

  Abstract

  Poly(ADP-ribose) polymerase-1 (PARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation.We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1 inhibition on irradiated tumors and tumor vasculature.ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone gamma-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated doses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1 day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase-mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis.We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.

  View details for DOI 10.1158/1078-0432.CCR-06-2872

  View details for Web of Science ID 000246572600029

  View details for PubMedID 17505006

• Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma 9th Annual Meeting of the Society-for-Neuro-Oncology Nabors, L. B., Mikkelsen, T., Rosenfeld, S. S., Hochberg, F., Akella, N. S., Fisher, J. D., Cloud, G. A., Zhang, Y., Carson, K., Wittemer, S. M., Colevas, A. D., Grossman, S. A. AMER SOC CLINICAL ONCOLOGY. 2007: 1651?57

  Abstract

  This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma.Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration.A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy.Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.

  View details for DOI 10.1200/JCO.2006.06.6514

  View details for Web of Science ID 000246299500006

  View details for PubMedID 17470857

• A phase II study of ixabepilone (BMS-247550) in metastatic renal-cell carcinoma CANCER BIOLOGY & THERAPY Posadas, E. M., Undevia, S., Manchen, E., Wade, J. L., Colevas, A. D., Karrison, T., Vokes, E. E., Stadler, W. M. 2007; 6 (4): 490-493

  Abstract

  Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has been seen in early clinical studies.Eligible patients had metastatic RCC as well as ECOG performance status 0-2 and normal organ function. Patients received ixabepilone at a dose of 40 mg/m2 intravenously over three hours every 21 days. There was no restriction on RCC histology or prior treatment type, but prior treatment with tubule inhibitors was not allowed. The primary endpoint was RECIST defined response and radiographic evaluations were performed every three cycles. Toxicity evaluations utilized CTCAE v3.0 and were performed every cycle. Using a Simon two-stage optimal design with alpha = 0.1, beta = 0.1, a null hypothesized response rate of 0.05 and an alternative response rate of 0.2, an initial 12 patients were to be accrued with full accrual of 37 patients if at least one response were observed.A median of five cycles were administered. No objective responses were observed in the first 12 evaluable patients, and six patients showed stable disease for more than 18 weeks on therapy. Median time to progression among those with objective progression was nine weeks. One patient experienced grade 4 anemia and lymphopenia. Grade 3 adverse events included lymphopenia, neutropenia, leukopenia, diarrhea, and infection. Common grade 2 toxicities included alopecia, fatigue and anemia.Ixabepilone administered at a dose of 40 mg/m2 every 21 days should not be advanced for further study in metastatic RCC. Given previous results, however, other dosing schedules may be worthy of further investigation.

  View details for Web of Science ID 000248102700009

  View details for PubMedID 17457044

• Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia BLOOD Byrd, J. C., Lin, T. S., Dalton, J. T., Wu, D., Phelps, M. A., Fischer, B., Moran, M., Blum, K. A., Rovin, B., Brooker-McEldowney, M., Broering, S., Schaaf, L. J., Johnson, A. J., Lucas, D. M., Heerema, N. A., Lozanski, G., Young, D. C., Suarez, J., Colevas, A. D., Grever, M. R. 2007; 109 (2): 399-404

  Abstract

  Despite promising preclinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic-derived schedule of administration of this agent. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m2 loading dose followed by 30 mg/m2 4-hour infusion; cohort 2, 40 mg/m2 loading dose followed by 40 mg/m2 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m2 loading dose followed by a 50 mg/m2 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200x10(9)/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, 19 (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high-risk disease, including 5 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases.

  View details for DOI 10.1182/blood-2006-05-020735

  View details for Web of Science ID 000243416600008

  View details for PubMedID 17003373

• Long term followup of a phase I study of concurrent paclitaxel and radiation for locally advanced squamous cell carcinoma of the head and neck 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Mansueti, J., Likhacheva, A., Albert, P., Scuito, L., Harold, N., Rudy, S., Colevas, D., Morris, J. C., Van Waes, C., Citrin, D. ELSEVIER SCIENCE INC. 2007: S444?S444

  View details for Web of Science ID 000249950201123

• Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone ANNALS OF ONCOLOGY Mani, S., McDaid, H. M., Grossman, A., Muggia, F., Goel, S., Griffin, T., Colevas, D., Horwitz, S. B., Egorin, M. J. 2007; 18 (1): 190-195

  Abstract

  We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken.Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m2 administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK.Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n=27) and tumor cells (n=9), peak MBF occurred at the end of infusion; however, at 24-72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50=109.65 ng/ml; r2=0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P=0.050).Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents.

  View details for DOI 10.1093/annonc/mdl315

  View details for Web of Science ID 000243593700032

  View details for PubMedID 17018704

• Phase I study of continuous weekly dosing of dimethylamino benzoylphenylurea (BPU) in patients with solid tumours EUROPEAN JOURNAL OF CANCER Messersmith, W. A., Rudek, M. A., Baker, S. D., Zhao, M., Collins, C., Colevas, A. D., Donehower, R. C., Carducci, M. A., Wolff, A. C. 2007; 43 (1): 78-86

  Abstract

  A phase I study of dimethylamino benzoylphenylurea (BPU), a tubulin inhibitor, was performed using a weekly continuous schedule. Patients with refractory solid tumours received oral BPU once weekly without interruption at doses ranging from 5 to 320mg using an accelerated titration design. Nineteen subjects received 54 cycles of BPU. Early pharmacokinetic findings of decreased clearance with increasing dose and plasma accumulation led to the expansion of the 320mg dose level. Two subjects then developed late haematologic dose-limiting toxicities (DLTs) that were associated with the highest plasma exposure to BPU and metabolites. Study enrollment resumed at dose 150mg with real-time pharmacokinetic monitoring. Seven additional subjects (6 evaluable) were treated for a median of 2 cycles (range 1.5-4) without further myelotoxicity. A long half-life and accumulation of BPU and active metabolites were observed, recommending against a continuous administration. Weekly oral BPU therapy should be further tested using an interrupted schedule.

  View details for DOI 10.1016/j.ejca.2006.09.006

  View details for Web of Science ID 000244311000019

  View details for PubMedID 17084620

• Adverse event reporting in publications compared with sponsor database for cancer clinical trials JOURNAL OF CLINICAL ONCOLOGY Scharf, O., Colevas, A. D. 2006; 24 (24): 3933-3938

  Abstract

  Prospectively planned collection and analysis of adverse event (AE) data are essential parts of well-conducted clinical trials. The AE data in a trial sponsor's database should be comparable with what is stipulated in the protocol and with the AE data published. We examined whether the published AE data differ from those in the sponsor's database and from the data collection requirements stated in study protocols.We searched the National Cancer Institute (NCI) Clinical Data Update System (CDUS) for studies that used the Common Toxicity Criteria version 2.0 and for which a final study publication was available. We extracted from the protocols information pertaining to AE collection and reporting methods and compared it with the methods cited in the article. We also compared the AE data in the trial publication with the AE data submitted by the investigators to CDUS.We identified 22 studies meeting the criteria for this review. There was considerable inconsistency between AE collection and reporting methods cited in the protocols versus final publications. AE data in the article and CDUS were not identical. Twenty-seven percent of article high-grade AEs could not be matched to agent-attributable AEs in the CDUS. Twenty-eight percent of CDUS high-grade AEs could not be matched to AEs in the corresponding article. In 14 of 22 articles, the number of high-grade AEs in CDUS differed from the number in the articles by 20% or more.Lack of consistency in and reporting of AEs are associated with NCI database and trial publication AE data discrepancy.

  View details for DOI 10.1200/JCO.2005.05.3959

  View details for Web of Science ID 000240052300020

  View details for PubMedID 16921045

• Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck JOURNAL OF CLINICAL ONCOLOGY Colevas, A. D. 2006; 24 (17): 2644-2652

  Abstract

  The purpose of this review is to provide readers with guidance concerning treatment of patients with advanced, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in the context of clinical trial data. We discuss issues surrounding the treatment of patients with SCCHN, with an emphasis on recommendations based on results from phase II and III clinical trials published since 1980. Many options exist for the treatment of patients with SCCHN. The most important decisions involve determining which patients are in need of treatment and which are most likely to benefit from treatment. Although many chemotherapy treatments have been shown to induce responses, survival improvement remains an unfulfilled goal. Definitive data do not exist on the effects of chemotherapy on quality of life or progression-free survival as measures of clinical benefit in this setting. Performance status, history of prior treatment, extent of tumor, and need for palliation are the most important factors in the decision to treat a patient with chemotherapy for incurable SCCHN. Single-agent treatment with conventional doses of methotrexate remains a standard for most patients with advanced, recurrent or metastatic SCCHN. Cisplatin plus fluorouracil, cisplatin plus a taxane, and single-agent taxane are the most widely studied alternatives. There is a need for further trials with end points other than overall survival or tumor response in this patient population. Guidelines for patient selection and treatment options are provided.

  View details for DOI 10.1200/JCO.2005.05.3348

  View details for Web of Science ID 000238379900008

  View details for PubMedID 16763278

• Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: Scientific rationale and study design CLINICAL GENITOURINARY CANCER Beekman, K. W., Colevas, A. D., Cooney, K., DiPaola, R., Dunn, R. L., Gross, M., Keller, E. T., Pienta, K. J., Ryan, C. J., Smith, D., Hussain, M. 2006; 4 (4): 299-302

  Abstract

  Two randomized trials demonstrated an improvement in survival with docetaxel-based chemotherapy for patients with metastatic, androgen-independent prostate disease. However, the effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential. Cilengitide (EMD121974; NSC 707544), is a potent selective alphavbeta3 and alphavbeta5 integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities including endothelial cell proliferation and migration. Blocking the ligation of integrins by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In prostate cancer specifically, integrins are known to be involved in metastases with differential expression on tumor cells. Tumors and vascular endothelial cells produce factors, such as vascular endothelial growth factor and basic fibroblast growth factor, that promote neovascularization, which has been implicated in prostate cancer progression. Cilengitide has been shown to inhibit alphavbeta3- and alphavbeta5-mediated cell adhesion and block in vitro endothelial cell migration. In vivo experiments demonstrated that cilengitide inhibited cytokine-induced basic fibroblast growth factor- and vascular endothelial growth factor-mediated angiogenesis in a dose-dependent manner. Cilengitide also inhibited tumor growth in various in vivo systems. Two Cancer Therapy Evaluation Program-sponsored, multicenter, phase II trials are designed to evaluate the safety and efficacy of this agent in patients with androgen-independent prostate cancer. National Cancer Institute trial 6735 is evaluating cilengitide at 2000 mg in patients with nonmetastatic androgen-independent prostate cancer, and National Cancer Institute trial 6372 is evaluating 2 dose levels of cilengitide, 500 mg or 2000 mg, intravenously twice weekly in patients with metastatic prostate cancer.

  View details for Web of Science ID 000242526800012

  View details for PubMedID 16729916

• Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: A southwest oncology group trial S0111 40th Annual Meeting of the American-Society-of-Clinical-Oncology Hussain, M., Tangen, C. M., Lara, P. N., Vaishampayan, U. N., Petrylak, D. P., Colevas, A. D., Sakr, W. A., Crawford, E. D. AMER SOC CLINICAL ONCOLOGY. 2005: 8724?29

  Abstract

  The epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC).Eligible patients had chemotherapy-naive metastatic HRPC, a Zubrod performance status of 0 to 2, and adequate organ function. All patients received BMS-247550 at 40 mg/m2 over 3 hours every 3 weeks. The primary end point was proportion of patients achieving a prostate-specific antigen (PSA) response.Forty-eight patients with metastatic HRPC were registered. Forty-two patients were eligible, with a median age of 73 years and a median PSA level of 111 ng/mL; 78% had bone-only or bone and soft tissue metastases, and 88% had objective radiologic disease progression at registration. Grade 3 and 4 adverse events (AEs) occurred in 16 and three patients, respectively. All grade 4 toxicities were neutropenia or leukopenia. The most frequent grade 3 AEs were neuropathy (eight patients), hematologic toxicity (seven patients), flu-like symptoms, and infection (five patients each). There were no grade 3/4 thrombocytopenia or grade 5 AEs. There were 14 confirmed PSA responses (33%; 95% CI, 20% to 50%); 72% of PSA responders had declines greater than 80%, and two patients achieved an undetectable PSA. The estimated median progression-free survival is 6 months (95% CI, 4 to 8 months), and the median survival is 18 months (95% CI, 13 to 24 months).Ixabepilone has demonstrated activity in patients with chemotherapy-naive metastatic HRPC. Major toxicities were neutropenia and neuropathy. Further testing to define its activity relative to standard therapy is warranted.

  View details for DOI 10.1200/JCO.2005.02.4448

  View details for Web of Science ID 000233690200026

  View details for PubMedID 16314632

• In vitro and in vivo clinical pharmacology of dimethyl benzoylphenylurea, a novel oral tubulin-interactive agent CLINICAL CANCER RESEARCH Rudek, M. A., Zhao, M., Smith, N. F., Robey, R. W., He, P., Hallur, G., Khan, S., Hidalgo, M., Jimeno, A., Colevas, A. D., Messersmith, W. A., Wolff, A. C., Baker, S. D. 2005; 11 (23): 8503-8511

  Abstract

  Dimethyl benzoylphenylurea (BPU) is a novel tubulin-interactive agent with poor and highly variable oral bioavailability. In a phase I clinical trial of BPU, higher plasma exposure to BPU and metabolites was observed in patients who experienced dose-limiting toxicity. The elucidation of the clinical pharmacology of BPU was sought. BPU, monomethylBPU, and aminoBPU were metabolized by human liver microsomes. Studies with cDNA-expressed human cytochrome P450 enzymes revealed that BPU was metabolized predominantly by CYP3A4 and CYP1A1 but was also a substrate for CYP2C8, CYP2D6, CYP3A5, and CYP3A7. BPU was not a substrate for the efflux transporter ABCG2. Using simultaneous high-performance liquid chromatography/diode array and tandem mass spectrometry detection, we identified six metabolites in human liver microsomes, plasma, or urine: monomethylBPU, aminoBPU, G280, G308, G322, and G373. In patient urine, aminoBPU, G280, G308, and G322 collectively represented <2% of the given BPU dose. G280, G308, G322, and G373 showed minimal cytotoxicity. When BPU was given p.o. to mice in the presence and absence of the CYP3A and ABCG2 inhibitor, ritonavir, there was an increase in BPU plasma exposure and decrease in metabolite exposure but no overall change in cumulative exposure to BPU and the cytotoxic metabolites. Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites.

  View details for DOI 10.1158/1078-0432.CCR-05-1037

  View details for Web of Science ID 000233701300038

  View details for PubMedID 16322314

• Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias CLINICAL CANCER RESEARCH Karp, J. E., Passaniti, A., Gojo, I., Kaufmann, S., Bible, K., Garimella, T. S., Greer, J., Briel, J., Smith, B. D., Gore, S. D., Tidwell, M. L., Ross, D. D., Wright, J. J., Colevas, A. D., Bauer, K. S. 2005; 11 (23): 8403-8412

  Abstract

  The serine/threonine kinase inhibitor flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation. We designed a phase I clinical trial using a timed sequential therapy approach where flavopiridol was given for the dual purpose of initial cytoreduction and enhancing cell cycle progression of the remaining leukemia cell cohort followed by cycle-dependent drugs 1-beta-D-arabinofuranosylcytosine (ara-C) and mitoxantrone.Flavopiridol was given by 1-hour infusion daily for 3 days beginning day 1 followed by 2 g/m2/72 h ara-C beginning day 6 and 40 mg/m2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels.Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with > or =50% drop in peripheral blast counts and tumor lysis in 9 (26%). Four (12%) died during therapy (two fungal infections and two sudden death). Dose-limiting toxicity occurred at 60 mg/m2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m2/d. Overall response rate was 31% in 26 acute myelogenous leukemia and 12.5% in acute lymphoblastic leukemia. Pharmacokinetics showed that a linear two-compartment model with first-order elimination provided the best fit of the observed concentration versus time data. Flavopiridol down-regulated one or more target proteins in marrow blasts in vivo. Vascular endothelial growth factor was detected in sera and marrow supernatant pretreatment, and sera obtained on day 3 inhibited bovine aortic endothelial cell proliferation by a mean of 32% (range, 10-80%).Our data suggest that flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. These findings warrant continuing development of flavopiridol at 50 mg/m2/d x 3 days in combination with cytotoxic and biological agents for acute leukemias.

  View details for DOI 10.1158/1078-0432.CCR-05-1201

  View details for Web of Science ID 000233701300026

  View details for PubMedID 16322302

• Phase I trial and pharmacokinetics of escalating doses of paclitaxel and concurrent hyperfractionated radiotherapy with or without amifostine in patients with advanced head and neck carcinoma 37th Annual Meeting of the American-Society-of-Clinical-Oncology Amrein, P. C., Clark, J. R., Supko, J. G., Fabian, R. L., Wang, C. C., Colevas, A. D., Posner, M. R., Deschler, D. G., Rocco, J. W., Finkelstein, D. M., McIntyre, J. F. JOHN WILEY & SONS INC. 2005: 1418?27

  Abstract

  Amifostine was developed to protect normal tissues from radiation exposure. The current study was undertaken to determine whether amifostine would allow the delivery of greater numbers of weekly paclitaxel treatments with concomitant, hyperfractionated radiotherapy in patients with advanced head and neck carcinoma.Patients received radiation therapy twice daily using 1.6-gray (Gy) fractions up to a total of 70.4 Gy over an elapsed time of 6.5 weeks. All patients received paclitaxel 60 mg/m(2) once weekly starting on Day 1. The number of doses of paclitaxel was escalated from three to a maximum of six in groups of three patients. For the patients who received amifostine, a dose of 400 mg/m(2) was given intravenously over 15 minutes on Days 1-5, 8, 29-33, and 36. Patients underwent surgery for persistent tumor after radiotherapy. The plasma pharmacokinetics of paclitaxel were characterized during treatment with the first weekly dose to determine the effect of concurrently administered amifostine.Thirty-six patients were evaluable for this study. In the absence of amifostine, a maximum of four doses of paclitaxel were tolerated in combination with the radiotherapy. With amifostine, up to five doses of paclitaxel could be given. Generally, the treatment resulted in Grade 2 and 3 stomatitis. Overall, 69% of patients had a complete remission, and 29% had a partial remission. Both progression-free survival and overall survival were 66% at 30 months. Amifostine had no effect on the pharmacokinetics of paclitaxel.The administration of amifostine allowed the authors to give an additional dose of paclitaxel to patients who were undergoing hyperfractionated radiotherapy for head and neck carcinoma. This treatment regimen resulted in a high frequency of complete remissions and an excellent progression-free survival pattern without compromising the plasma kinetics of paclitaxel.

  View details for DOI 10.1002/cncr.21312

  View details for Web of Science ID 000232001200011

  View details for PubMedID 16116597

• Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 213 design CLINICAL CANCER RESEARCH Gadgeel, S. M., Wozniak, A., Boinpally, R. R., Wiegand, R., Heilbrun, L. K., Jain, V., Parchment, R., Colevas, D., Cohen, M. B., LoRusso, P. M. 2005; 11 (17): 6233-6239

  Abstract

  BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated titration "2B" design, of BMS-247550 given as a 1-hour infusion every 3 weeks.Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles (1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m2. All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists.First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m2. Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m2. Grade 1 to 2 peripheral neuropathy was also observed. Other grade 1 to 2 toxicities were myalgias, arthralgias, rash, hand/foot syndrome, and mucositis. AUC and C(max) seemed proportional to the dose and the DLT. Development of neutropenia with BMS-247550 is related to the duration of drug exposure above a threshold.The maximum tolerated dose (MTD) of BMS-247550 is 40 mg/m2 given every 3 weeks. Neutropenia is the DLT. The accelerated titration "2B" design may help in determining MTD with fewer patients enrolled and more being treated closer to the MTD. However, the accelerated titration design did not seem to shorten the study duration.

  View details for DOI 10.1158/1078-0432.CCR-05-0127

  View details for Web of Science ID 000231723600021

  View details for PubMedID 16144926

• Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer 40th Annual Meeting of the American-Society-of-Clinical-Oncology Galsky, M. D., Small, E. J., Oh, W. K., Chen, I., Smith, D. C., Colevas, A. D., Martone, L., Curley, T., Delacruz, A., Scher, H. I., Kelly, W. K. AMER SOC CLINICAL ONCOLOGY. 2005: 1439?46

  Abstract

  To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer.Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

  View details for DOI 10.1200/JCO.2005.09.042

  View details for Web of Science ID 000227367900015

  View details for PubMedID 15735119

• Current clinical trials of cilengitide, an alpha(v) antagonist in clinical development as an anticancer agent ONCOLOGY-NEW YORK Colevas, A. D., Scharf, O., Schoenfeldt, M. 2004; 18 (14): 1778-?

  View details for Web of Science ID 000238212800012

• Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma INVESTIGATIONAL NEW DRUGS Burdette-Radoux, S., Tozer, R. G., Lohmann, R. C., Quirt, I., Ernst, D. S., Walsh, W., Wainman, N., Colevas, A. D., Eisenhauer, E. A. 2004; 22 (3): 315-322

  Abstract

  To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system.Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles.17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity.Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.

  View details for Web of Science ID 000221132400012

  View details for PubMedID 15122079

• The clinical development of new mitotic inhibitors that stabilize the microtubule ANTI-CANCER DRUGS Mani, S., Macapinlac, M., Goel, S., Verdier-Pinard, D., Fojo, T., Rothenberg, M., Colevas, D. 2004; 15 (6): 553-558

  Abstract

  Microtubule-stabilizing agents are increasingly studied for cancer treatment based largely on the prior success of paclitaxel and docetaxel. In this review, we focus on the clinical development of epothilones and discodermolide, and we discuss salient preclinical and clinical highlights of these two novel natural products. These agents are distinguished by their biochemical features making them poor P-glycoprotein substrates and capable of inducing cytotoxicity in cell lines or in vivo tumor models harboring mutations in tubulin. There is now considerable data regarding the efficacy of the epothilones in human beings and discodermolide holds such promise, as well.

  View details for DOI 10.1097/01.cad.0000131681.21637.b2

  View details for Web of Science ID 000222792600002

  View details for PubMedID 15205596

• HER2 expression in salivary gland carcinomas: Dependence on histological subtype CLINICAL CANCER RESEARCH Glisson, B., Colevas, A. D., Haddad, R., Krane, J., El-Naggar, A., Kies, M., Costello, R., Summey, C., Arquette, M., Langer, C., Amrein, P. C., Posner, M. 2004; 10 (3): 944-946

  Abstract

  Previous evaluation of HER2 overexpression in salivary gland cancers indicated an incidence varying between 7 and 56%, with no clear difference among three histologically different subtypes. As part of a Phase II trial of trastuzumab for treatment of incurable salivary gland cancer, we screened 137 tumors for HER2 expression.Unstained sections of paraffin-embedded tumor samples were stained with p185/HER2 receptor antibody. Tumors with moderate (2+) to strong (3+) complete membrane staining in at least 10% of the tumor cells were scored as positive for overexpression.The overall frequency of overexpression for HER2 was 17% (23 of 137), whereas it was only 8% in the three most common histological subtypes screened. Overexpression was distinctly rare in the most common subtype screened, adenoid cystic carcinoma (4%, 3 of 70). Overexpression was very common in salivary duct cancers; 10 (83%) of 12 were positive for HER2. This observation is consistent with the typical high-grade histological features and aggressive behavior of this subtype as well as with its histogenetic similarity to breast cancer. Analysis based on histogenesis (intercalated duct versus excretory duct) indicated a higher frequency of overexpression in the latter (55%) than in the former (7%).Our overall results suggest that trastuzumab will not have a major role in treatment of salivary gland cancers of intercalated duct origin. Further systematic evaluation of trastuzumab in subtypes of excretory duct origin could be supported.

  View details for Web of Science ID 000188982700017

  View details for PubMedID 14871971

• Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study ORAL ONCOLOGY Haddad, R., Colevas, A. D., Krane, J. F., Cooper, D., Glisson, B., Amrein, P. C., Weeks, L., Costello, R., Posner, M. 2003; 39 (7): 724-727

  Abstract

  Phase II study of Herceptin (Trastuzumab) in patients with advanced salivary gland tumors overexpressing Her2/neu. Patients with advanced, incurable salivary gland tumors and 2(+) or 3(+) Her2/neu expression in their tumors were enrolled in the study. After an initial dose of 4 mg/kg, patients received 2 mg/kg weekly. Patients were treated until they experienced progression of disease or unacceptable toxicity. The study was closed early when it has become clear that the majority of tumors screened did not overexpress Her2/neu. Fourteen patients were enrolled in the study. A total of 86 cycles of Herceptin were delivered with a median of three cycles per patient (range 1-40). Median time to progression was 4.2 months. One patient with metastatic mucoepidermoid carcinoma has received 40 cycles of Herceptin to date with a documented partial response. Herceptin given as a single agent has a low activity in salivary gland tumors overexpressing Her2/neu. New agents are still needed.

  View details for DOI 10.1016/S1368-8375(03)00097-6

  View details for Web of Science ID 000185296300012

  View details for PubMedID 12907212

• CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment SEMINARS IN RADIATION ONCOLOGY Trotti, A., Colevas, A. D., SETSER, A., Rusch, V., Jaques, D., Budach, V., Langer, C., Murphy, B., Cumberlin, R., Coleman, C. N., Rubin, P. 2003; 13 (3): 176-181

  Abstract

  Multiple systems have been developed for grading the adverse effects (AEs) of cancer treatment. The National Cancer Institute Common Toxicity Criteria (CTC) system has substantially evolved since its inception in 1983. The most recent version, CTCAE v3.0 (Common Terminology Criteria for Adverse Events version 3.0) represents the first comprehensive, multimodality grading system for reporting the acute and late effects of cancer treatment. The new CTC requires changes in the application of AE criteria including new guidelines regarding late effects, surgical and pediatric effects, multimodality issues, and for reporting the duration of an effect. It builds on the strengths of previous systems, represents a considerable effort among hundreds of participants, and signifies an international collaboration and consensus of the oncology research community. This article updates recent progress in the evolution of adverse effects grading systems and reviews the development of CTCAE v3.0.

  View details for DOI 10.1016/S01053-4296(03)00031-6

  View details for Web of Science ID 000184670300002

  View details for PubMedID 12903007

• Development of investigational radiation modifiers JOURNAL OF THE NATIONAL CANCER INSTITUTE Colevas, A. D., Brown, J. M., Hahn, S., Mitchell, J., Camphausen, K., Coleman, C. N. 2003; 95 (9): 646-651

  View details for Web of Science ID 000182672800007

  View details for PubMedID 12734315

• Docetaxel, cisplatin, and 5-fluorouracil-based induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck - The Dana Farber Cancer Institute experience CANCER Haddad, R., Colevas, A. D., Tishler, R., Busse, P., Goguen, L., Sullivan, C., Norris, C. M., Lake-Willcutt, B., Case, M. A., Costello, R., Posner, M. 2003; 97 (2): 412-418

  Abstract

  The authors conducted a series of four Phase I-II trials of high-dose and intermediate-dose docetaxel, cisplatin, and 5-fluorouracil (TPF)-based induction chemotherapy for patients with advanced squamous cell carcinoma of the head and neck (SCCHN). The chemotherapy regimens and response rates for each trial were published previously. In the current analysis, the authors report the data on long-term survival, patterns of failure, and morbidity among the patients who were treated at their institution.A total of 101 patients with previously untreated, locally advanced, curable SCCHN were entered onto the studies. Overall, 68 patients (67%) had N2-N3 disease, and 86 patients (85%) had Stage IV disease. Patients were treated with combinations of TPF with or without leucovorin. Cycles were repeated every 21-28 days for a total of 3 cycles followed by hyperfractionated radiotherapy.After a median follow-up of 49 months, 65 patients (64%) remain alive with no evidence of disease (NED), and 3 patients remain alive with disease, for an overall survival rate of 67% (68 patients). Twenty-six patients had locoregional recurrences (LRR), and 5 patients had both LRR and distant metastasis (DM). Only five patients had DM as the sole site of failure. Four patients underwent salvage surgery at the primary site and remain alive with NED. Excluding 17 patients with nasopharyngeal carcinoma, of 84 patients, 55 patients remain alive with NED (65%). Notably, 43 of 84 patients (51%) had oropharyngeal primary tumors, and 30 of those patients remain alive with NED (70%). Significant morbidity was low, with two treatment-related deaths. All but two of the surviving patients are able to swallow and had their feeding tubes removed.These data suggest that docetaxel adds incrementally to the efficacy of cisplatin and fluorouracil. Local-regional failures continue to be the major impediment to cure in these patients. Given the increase in local-regional dose intensity with chemoradiation, sequential treatment plans that integrate induction chemotherapy and chemoradiotherapy seem to be the logical next step.

  View details for DOI 10.1002/cncr.11063

  View details for Web of Science ID 000180401600009

  View details for PubMedID 12518365

• Organ preservation-induction chemotherapy. Cancer treatment and research Colevas, A. D. 2003; 114: 213-234

  View details for PubMedID 12619543

• Timed sequential therapy of acute leukemia with flavopiridol: In vitro model for a phase I clinical trial CLINICAL CANCER RESEARCH Karp, J. E., Ross, D. D., Yang, W. D., Tidwell, M. L., Wei, Y. T., Greer, J., Mann, D. L., Nakanishi, T., Wright, J. J., Colevas, A. D. 2003; 9 (1): 307-315

  Abstract

  The survival of adults with acute leukemias remains unsatisfactory and requires new treatment approaches. Flavopiridol modulates cell cycle progression, inhibits transcription, and induces apoptosis. We designed an in vitro model of timed sequential therapy for acute leukemia to determine whether flavopiridol can: (a). trigger apoptosis in fresh acute leukemia; and (b). recruit surviving leukemic cells to a proliferative state, thereby priming such cells for the S-phase-related cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C).Bone marrow cells from 20 adults with relapsed and refractory acute leukemias were enriched for blasts by Ficoll Hypaque sedimentation. Blasts were cultured on day 0 in flavopiridol 250 nM for 24 h, removed from flavopiridol for 24 h, and then cultured in ara-C 1 microM for an additional 72 h (F(250)A(1)). Apoptosis and cell cycle phase distribution were estimated from cells stained with propidium iodide. Cell survival was determined after the 72 h ara-C exposure by double cytofluorescence assay with fluorescein diacetate and propidium iodide.Flavopiridol induced a 4.3-fold increase in apoptosis in human leukemia samples within the first 24 h of culture. Subsequent removal of flavopiridol led to a 1.7-fold increase in the proportion of cells in S phase by day 2. Mean survival in F(250)A(1) cultures after 72 h exposure to ara-C was 35.6% compared with flavopiridol alone (F(250)A(0), 56.1%; P = 0.0003) and ara-C alone (F(0)A(1), 65.2%; P < 0.00001).Flavopiridol induces apoptosis in marrow blasts from patients with refractory acute leukemias. Furthermore, flavopiridol pretreatment increases the proapoptotic and cytotoxic effects of ara-C. The advantage of sequential FP(250)A(1) over either agent alone is seen for both acute myelogenous leukemia and acute lymphoblastic leukemia. These findings support a clinical trial of timed sequential therapy where flavopiridol is given for cytoreduction and subsequent priming of remaining leukemic cells for enhanced cycle-dependent drug cytotoxicity.

  View details for Web of Science ID 000180430600039

  View details for PubMedID 12538483

• A Phase I/II trial of concurrent docetaxel and radiation after induction chemotherapy in patients with poor prognosis squamous cell carcinoma of the head and neck 37th Annual Meeting of the American-Society-of-Clinical-Oncology Tishler, R. B., Norris, C. M., Colevas, A. D., Lamb, C. C., Karp, D., Busse, P. M., Nixon, A., Frankenthaler, R., Lake-Willcutt, B., Costello, R., Case, M., Posner, M. R. JOHN WILEY & SONS INC. 2002: 1472?81

  Abstract

  The authors conducted a Phase I/II study in patients with a poor prognosis who had locally advanced squamous cell carcinoma of the head and neck (SCCHN) and who were treated initially with induction chemotherapy. Patients were treated with weekly docetaxel and concurrent daily fractionated radiation therapy to determine the maximum tolerated dose (MTD) of docetaxel and the efficacy of the regimen.Twenty-two patients were enrolled, and 21 patients were treated. Eight patients had Stage III SCCHN, and 13 patients had Stage IV SCCHN without distant metastases and were treated first with 2-3 cycles of induction chemotherapy, which consisted of cisplatin plus 5-fluorouracil with or without leucovorin. Patients with a poor prognosis were identified as those who achieved a partial response to induction treatment, achieved a complete response with a positive biopsy, or were at high risk for developing recurrent disease. Patients were treated subsequently with concurrent, escalating doses of docetaxel (given weekly x 6) and once daily 200-centigray radiation fractions.Three patients were treated with a weekly docetaxel dose of 20 mg/m(2) without dose-limiting toxicity (DLT). Both patients who were treated at the next dose level of 30 mg/m(2) experienced DLT. A dose of 25 mg/m(2) was studied without DLT in the 16 patients who were treated, establishing this as the MTD. Sixty-seven percent of the patients are alive without disease at a median follow-up of 35 months (range, 12-59 months) after the initiation of chemoradiotherapy.The MTD of weekly docetaxel with concurrent daily radiation therapy in the postinduction setting was 25 mg/m(2). Disease free survival data from this study were good and indicated that this regimen was effective in the treatment of patients with SCCHN who had a poor prognosis.

  View details for DOI 10.1002/cncr.10873

  View details for Web of Science ID 000178128600010

  View details for PubMedID 12237916

• Phase I/II trial of outpatient docetaxel, cisplatin, 5-fluorouracil, leucovorin (opTPFL) as induction for squamous cell carcinoma of the head and neck (SCCHN) AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Colevas, A. D., Norris, C. M., Tishler, R. B., Lamb, C. C., Fried, M. P., Goguen, L. A., Gopal, H. V., Costello, R., Read, R., Adak, S., Posner, M. R. 2002; 25 (2): 153-159

  Abstract

  The purpose of this study was to establish the maximum tolerated dose (MTD) of docetaxel in an outpatient docetaxel (T), cisplatin (P), 5-fluorouracil (5-FU) (F), and leucovorin (L) (opTPFL) regimen and to obtain preliminary assessment of opTPFL efficacy. Thirty-four patients with stage III or IV squamous cell carcinoma of the head and neck were treated with opTPFL. Docetaxel was escalated from 60 to 95 mg/m(2) in combination with 100 mg/m(2) cisplatin intravenous bolus, and 2,800 mg/m(2) 5-FU continuous infusion and 2,000 mg/m(2) leucovorin continuous infusion with prophylactic growth factors and antibiotics. Patients who achieved a complete (CR) or partial (PR) response to three cycles received definitive twice-daily radiation therapy. A total of 97 cycles were administered to 34 patients. The major acute toxicities were neutropenia and mucositis. The MTD of docetaxel was 90 mg/m(2) . Seventy-seven of 97 cycles of were administered on an outpatient basis. The overall clinical response rate to opTPFL was 94%, with 44% CRs and 50% PRs. The MTD of opTPFL is 90 mg/m(2) docetaxel. Outpatient administration of opTPFL is tolerable, feasible, and does not alter the ability to administer definitive radiation therapy on schedule.

  View details for Web of Science ID 000174906300010

  View details for PubMedID 11943893

• Hypothyroidism incidence after multimodality treatment for stage III and IV squamous cell carcinomas of the head and neck INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Colevas, A. D., Read, R., Thornhill, J., Adak, S., Tishler, R., Busse, P., Li, Y., Posner, M. 2001; 51 (3): 599-604

  Abstract

  Treatment of head-and-neck cancer patients with surgery, radiotherapy (RT), and chemotherapy has been associated with posttherapy hypothyroidism (HT). We evaluated the rate of posttherapy HT in patients with locally advanced squamous cell carcinoma of the head and neck, treated with multimodality therapy to determine which factors might predict this condition and at what interval the condition developed.We reviewed the prospectively collected thyroid function data of patients treated with sequential chemotherapy, RT, and neck dissection. The incidence of posttherapy HT was estimated. The patient, tumor, and treatment factors possibly associated with HT were evaluated.Of 203 patients, 118 had data adequate for evaluation. HT developed in 45% at a median of 24.4 months after therapy. HT occurred in 14% and 27% of patients at 6 months and 1 year after treatment, respectively. Univariate and multivariate analyses of sex, age, RT dose, RT fractionation, T and N stage, tumor site, and neck dissection failed to identify a clinically relevant risk factor.A high number of patients undergoing aggressive organ-sparing multimodality therapy for advanced squamous cell carcinoma of the head and neck are at risk for subsequent HT. We recommend that all patients definitively irradiated to the head and neck region undergo frequent serum thyroid-stimulating hormone screening for HT, beginning 6 months after RT.

  View details for Web of Science ID 000171892800004

  View details for PubMedID 11597798

• Clinical trials referral resource: Current clinical trials of epothilone B analog (BMS-247550) ONCOLOGY-NEW YORK Colevas, A. D., West, P. J., Cheson, B. D. 2001; 15 (9): 1168-?

  View details for Web of Science ID 000174070500015

  View details for PubMedID 11589064

• A Phase II study of combined oral uracil and ftorafur with leucovorin for patients with squamous cell carcinoma of the head and neck 36th Annual Meeting of the American-Society-of-Clinical-Oncology Colevas, A. D., Amrein, P. C., Gomolin, H., Barton, J. J., Read, R. R., Adak, S., Benner, S., Costello, R., Posner, M. R. JOHN WILEY & SONS INC. 2001: 326?31

  Abstract

  The objective of this Phase II study was to define the response rate, safety profile, and toxicity of oral uracil and ftorafur (UFT) with leucovorin (UFT/LV) as a palliative treatment for patients with squamous cell carcinoma of the head and neck (SCCHN).Patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group performance status < 2 and adequate organ function were enrolled in an institutional review board-approved trial. Prior induction or adjuvant chemotherapy was permitted provided 6 months had elapsed since the last chemotherapy. Patients were treated with UFT 300 mg/m(2) per day and leucovorin 90 mg per day administered in three doses daily for 28 days followed by a 7-day break for a 35-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Patients were removed from the study for progression of disease or unacceptable toxicity.One hundred six cycles of UFT/LV had been administered to 42 patients as of January 1, 2000. The most common toxicities, in descending order of incidence, were anemia, pain, fatigue, diarrhea, nausea, mucositis, and anorexia. Clinically significant toxicities attributable to UFT/ LV were primarily gastrointestinal. On an intent-to-treat basis, three patients (7%) achieved a complete response, and six patients (14%) achieved a partial response. The overall response rate was 21% (95% confidence interval, 10--37%).UFT/LV therapy is feasible in this patient population and is generally well tolerated. Response rates are similar to the rates expected with continuous-infusion 5-fluorouracil. UFT/LV should be studied further both alone and in combination therapy for patients with SCCHN.

  View details for Web of Science ID 000169943900016

  View details for PubMedID 11466686

• Multicenter phase I-II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck JOURNAL OF CLINICAL ONCOLOGY Posner, M. R., Glisson, B., Frenette, G., al-Sarraf, M., Colevas, A. D., Norris, C. M., Seroskie, J. D., Shin, D. M., Olivares, R., Garay, C. A. 2001; 19 (4): 1096-1104

  Abstract

  We conducted a phase I-II, multi-institutional trial to determine the maximum-tolerated dose (MTD) of cisplatin in an induction chemotherapy regimen of docetaxel, cisplatin, and fluorouracil for squamous cell cancer of the head and neck (SCCHN) and to determine the safety, tolerability, and efficacy of the regimen at MTD.A total of 43 patients with previously untreated, locally advanced, curable SCCHN were entered. Overall, 29 patients (67%) had N2 or N3 nodal disease and nine (21%) had T4 primary tumors. All patients received docetaxel 75 mg/m(2) on day 1; cisplatin at 75 (level I) or 100 (level II) mg/m(2) on day 1; and a continuous fluorouracil infusion at 1,000 mg/m(2)/d on days 1 through 4. Patients were treated with prophylactic antibiotics on days 5 through 15. Cycles were repeated every 21 days for a total of three cycles. Patients then received definitive therapy based on institutional preferences.Thirteen patients were treated at level I, and 30 patients were treated at level II. All 43 patients were assessable for toxicity. There were no major differences in toxicity between level I and level II. Cisplatin-associated grade 3 or 4 hypomagnesemia or hypocalcemia occurred in 13 (30%) and hearing loss in two patients (5%). Grade 3 or 4 neutropenia was observed in 41 patients (95%) and febrile neutropenia occurred in eight (19%). There was one serious infection (2%). There were 17 (40% [95% confidence interval [CI], 25% to 56%]) clinical complete responders (CR), 23 (54% [95% CI, 39% to 69%]) partial responders (PR), one (2%) with no change, and two (5%) unassessable patients. Major responses (CR, PR) were observed in 40 (93% [95% CI, 81% to 99%]) patients. Primary site CR was documented in 24 (54%) of patients. Postchemotherapy primary site biopsies were performed in 25 patients (58%) and pathologically negative biopsy was obtained in 11 (92%) of 12 primary site clinical CRs and seven (54%) of 13 with PR or no change. Overall, negative biopsies were obtained in 18 patients (72%).TPF induction chemotherapy can be delivered safely with a cisplatin dose of 100 mg/m(2) in previously untreated patients with SCCHN. The regimen is associated with a high rate of primary site clinical and pathologic CRs. Phase III comparison with cisplatinum and fluorouracil chemotherapy is warranted.

  View details for Web of Science ID 000167219400023

  View details for PubMedID 11181674

• NCCN Practice Guidelines for head and neck cancers ONCOLOGY-NEW YORK Forastiere, A. A., Pfister, D. G., Ang, K., Brockstein, B., Colevas, A. D., Ellenhorn, J., Goepfert, H., Hicks, W. L., Hong, W. K., Kies, M. S., Lydiatt, W., McCaffrey, T., Mittal, B. B., Ridge, J. A., Schuller, D. E., Shah, J. P., Spencer, S., Trotti, A., Urba, S., Weymuller, E. A., Wheeler, R. H., Wolf, G. T. 2000; 14 (11A): 163-194

  View details for Web of Science ID 000166713700017

  View details for PubMedID 11195409

• The role of induction chemotherapy in the curative treatment of squamous cell cancer of the head and neck SEMINARS IN ONCOLOGY Posner, M. R., Colevas, A. D., Tishler, R. B. 2000; 27 (4): 13-24

  Abstract

  Induction chemotherapy is appropriate for the treatment of locally advanced squamous cell carcinoma of the head and neck because it allows organ preservation without compromising survival and improves survival in unresectable disease. Radiation therapy, not surgery, should immediately follow induction chemotherapy in potentially resectable patients to prevent tumor repopulation. The results of three phase II studies of docetaxel-based regimens as induction therapy of patients with locally advanced squamous cell carcinoma of the head and neck are reviewed and reported. Overall response rates ranged from 93% to 100%, with complete response rates of 40% to 63%. The primary toxicities were neutropenia and febrile neutropenia. A North American phase III trial, randomizing patients to docetaxel/cisplatin/fluorouracil or cisplatin/fluorouracil sequentially followed by chemoradiotherapy is being performed to determine whether docetaxel improves the complete response rate, organ preservation rate, and survival of patients treated with induction chemotherapy.

  View details for Web of Science ID 000089136200003

  View details for PubMedID 10952434

• A phase II trial of palliative docetaxel plus 5-fluorouracil for squamous-cell cancer of the head and neck ANNALS OF ONCOLOGY Colevas, A. D., Adak, S., Amrein, P. C., Barton, J. J., Costello, R., Posner, M. R. 2000; 11 (5): 535-539

  Abstract

  A phase II study to determine the response rate and toxicity of docetaxel and 5-fluorouracil (5-FU) every four weeks ('TF'), in patients with incurable SCCHN.Patients with metastatic or recurrent SCCHN with an ECOG PS < 3 were enrolled in an institutional review board approved trial. Prior induction or adjuvant chemotherapy was permitted provided six months had elapsed. The regimen was docetaxel 70 mg/m2 i.v., day 1 and 5-FU 800 mg/m2/d x 5 days, days 1-5, as a continuous intravenous infusion, repeated every 28 days. Planned intra-patient dose modifications were based on hematological, cutaneous, and gastrointestinal toxicities. Patients were removed from the study for progression of disease or unacceptable toxicity.Seventeen patients were enrolled. Fourty-six cycles of TF were administered. Reasons for discontinuance of TF included: progressive disease, 12 patients; toxicity, 3 patients; concomitant illness, 1 patient; death, 1 patient. The most common toxicities were neutropenia, mucositis, anemia, fatigue, alopecia, pain, diarrhea and nausea. Evaluation of responses to TF showed that there were four patients of seventeen (24%, 95% exact CI: 6.8-49.9) who achieved a PR or CR. Accrual was terminated after interim analysis of the response rate of the first 17 patients failed to exceed 4 of 17.The response rate to TF in patients with SCCHN was lower than expected. Trials of other regimens should take precedence over further exploration of the TF regimen.

  View details for Web of Science ID 000087581500012

  View details for PubMedID 10907945

• Phase II trial of docetaxel, cisplatin, fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and neck JOURNAL OF CLINICAL ONCOLOGY Colevas, A. D., Norris, C. M., Tishler, R. B., Fried, M. P., Gomolin, H. I., Amrein, P., Nixon, A., Lamb, C., Costello, R., Barton, J., Read, R., Adak, S., Posner, M. R. 1999; 17 (11): 3503-3511

  Abstract

  To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN).Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4.Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively.TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.

  View details for Web of Science ID 000083473700020

  View details for PubMedID 10550148

• Re: "Sialadenosis: a presenting sign in Bulemia" (Head and Neck 20: 758-762, 1998) Head & neck Colevas, A. D. 1999; 21 (6): 582-?

  View details for PubMedID 10449677

• An initial experience using concurrent paclitaxel and radiation in the treatment of head and neck malignancies 33rd Annual Meeting of the American-Society-of-Clinical-Oncology Tishler, R. B., Busse, P. M., Norris, C. M., Rossi, R., Poulin, M., Thornhill, L., Costello, R., Peters, E. S., Colevas, A. D., Posner, M. R. ELSEVIER SCIENCE INC. 1999: 1001?8

  Abstract

  Combined modality therapy plays a central role in the management of head and neck malignancies. This study examined the feasibility and preliminary results of treating a group of patients using concurrent bolus paclitaxel (Taxol) and radiation therapy.Fourteen patients with a median age of 56 years (range 42-81) were treated. Paclitaxel was given every 3 weeks at a dose of 100 mg/m2 concurrently with external beam radiation. The patients treated included those who had failed to achieve a complete response (CR) to induction chemotherapy with cisplatin, 5-fluorouracil, and leucovorin (PFL), or who had locally advanced disease not previously treated.Median follow-up from the initiation of treatment is 40 months (range 23-48). The majority of patients (13/14) achieved clinical CRs at the primary site. The development of responses was characterized by a long time course. Three patients who were nonresponders (NRs) to induction PFL chemotherapy were treated. One was a clinical CR at the primary site, one did not achieve a CR, and the other had residual disease in the neck. Four patients have failed, one with local-regional disease, one with a marginal failure, one with distant metastases, and one was not rendered disease-free by the treatment. As expected, significant local toxicity was observed. Most patients were managed with the aid of a percutaneous endoscopic gastrostomy (PEG). Two patients experienced significant moist desquamation and required treatment breaks of greater than 1 week.Paclitaxel can be given on a 3-week schedule at 100 mg/m2 concurrently with radiation. The preliminary results indicate good local responses and acceptable toxicity. This treatment approach merits further study in the treatment of head and neck malignancies, and should be considered as an option in other sites.

  View details for Web of Science ID 000079279100010

  View details for PubMedID 10192347

• Intramucosal spread of malignant melanoma of the oral cavity OTOLARYNGOLOGY-HEAD AND NECK SURGERY Bhattacharyya, N., Norris, C. M., Colevas, A. D., Chasse, T. A. 1998; 119 (6): 711-711

  View details for Web of Science ID 000077409400033

  View details for PubMedID 9852557

• Docetaxel in head and neck cancer - A review AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Colevas, A. D., Posner, M. R. 1998; 21 (5): 482-486

  Abstract

  Docetaxel has been shown to have significant antitumor activity. The mechanism of action is through stabilization of tubulin, arresting cells in the G2M phase of the cell cycle. The maximum tolerated dose of docetaxel is 100 mg/m2 every 21 days. Short-lasting neutropenia is the dose-limiting toxicity. Other significant toxicities include alopecia, mucositis, fatigue, sensory neuropathy, fluid retention, rash, and hypersensitivity reactions. Phase II studies of docetaxel as a single agent in patients with squamous cell carcinoma of the head and neck (SCCHN) have documented response rates of 27% to 43%. Studies of docetaxel combined with cisplatin, and docetaxel, cisplatin, and 5-fluorouracil (TPF) as induction therapy for patients with SCCHN demonstrate that these regimens are highly active. An early trial of induction TPF with leucovorin (TPFL) has yielded an overall response rate of 100% and complete response rate of 61%. In vitro studies have shown docetaxel to be a potent radiation sensitizer for squamous cell carcinoma cell lines, and phase I trials using concurrent docetaxel and radiotherapy are ongoing.

  View details for Web of Science ID 000076339300013

  View details for PubMedID 9781605

• Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: A phase I/II trial JOURNAL OF CLINICAL ONCOLOGY Colevas, A. D., Busse, P. M., Norris, C. M., Fried, M., Tishler, R. B., Poulin, M., Fabian, R. L., Fitzgerald, T. J., Dreyfuss, A., Peters, E. S., Adak, S., Costello, R., Barton, J. J., Posner, M. R. 1998; 16 (4): 1331-1339

  Abstract

  A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed.Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor.TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.

  View details for Web of Science ID 000072875700015

  View details for PubMedID 9552034

• The Prognostic Value of Thymidylate Synthase and p53 Expression in Patients Treated with Induction Chemotherapy for Squamous Cell Carcinoma of the Head and Neck. oncologist Posner, Johnston, Tishler, ANDERSEN, Fiorentino, Busse, Cavacini, Colevas, Clark, NORRIS 1998; 3 (6): 424-431

  Abstract

  Thymidylate synthase (TS) and p53 are central molecules in the regulation of cell growth. Differences in the intracellular expression of these proteins by tumor cells may have predictive value for response to chemotherapy and early failure in patients with squamous cell cancer of the head and neck (SCCHN). Immunohistochemistry was used to assess the tumor cell expression of TS and p53 in pre-therapy biopsies from patients with advanced SCCHN treated with an induction chemotherapy protocol, PFL. Samples were available from 11 of 16 nonresponders, 13 of 19 early failures with progression within 24 months of treatment, and a random selection of 13 from 45 long-term, disease-free survivors (LTS). High TS expression was seen in the majority of samples from all three groups, 67% versus 78% versus 93%, respectively; however, only one of seven (14%) samples with low TS was from a LTS patient. TS expression did not differ in patients by sex, age, site of primary tumor, differentiation or stage. p53 was expressed in 33% of patient samples and did not predict response or correlate with sex, age, site of primary tumor, differentiation, or stage. Small primary tumors with extensive nodal disease were less likely to express p53 than larger primary tumors with or without nodal involvement. The data suggest that TS and p53 content have a limited prognostic value in patients treated with PFL, although tumors with lower TS expression appeared to be less likely to respond. Differences between this study and other investigations of TS and p53 may be disease site- and regimen-specific. Statistically significant differences between response groups may emerge from larger, site-specific, protocol-driven studies of TS and p53.

  View details for PubMedID 10388134

• Future directions in the treatment of squamous cell carcinoma of the head and neck: the role of UFT. Oncology (Williston Park, N.Y.) Colevas, A. D. 1997; 11 (9): 86-89

  Abstract

  Squamous cell carcinoma of the head and neck is a potentially curable neoplasm. Historically, the standard approach to treatment has been either surgery or radiation therapy, or a combination of the two. Over the past two decades, the role of chemotherapy in the curative approach to head and neck cancer has been evolving. Drugs like fluorouracil (5-FU), cisplatin (Platinol), methotrexate, paclitaxel (Taxol), docetaxel (Taxotere), and bleomycin (Blenoxane) have been investigated in both the palliative and curative settings. Multiple combination regimens have been used as neoadjuvant or induction regimens, but to date the original combination of cisplatin and fluorouracil is still the standard of therapy. UFT, a combination of uracil and tegafur (a fluorinated pyridine analogue), has been available in Japan as an oral form of treatment for squamous cell head and neck cancers. This article describes the rationale behind the use of UFT as an agent for the treatment of squamous cell carcinoma of the head and neck as well as data from ongoing investigations exploring its use in this disease.

  View details for PubMedID 9348576