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Importance: Mitotane (Lysodren, o,p'-DDD [1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane)] is currently the only United States Food and Drug Administration and European Medicines Agency-approved product for the treatment of adrenocortical carcinoma., Observations: Mitotane is challenging to administer; however, its toxicities (specifically adrenal insufficiency) are well known, and the management of adverse consequences has established approaches. While often viewed through the prism of a cytotoxic agent, it can also interfere with hormone production making it a valuable asset in managing functional ACC. A recently completed prospective trial has shed some light on its use in the adjuvant setting, but further clarity is needed. Many think mitotane has a role in the advanced or metastatic setting, although prospective data are lacking and retrospective analyses are often difficult to interpret., Conclusions and Relevance: When used carefully and thoughtfully, especially in patients with hormonal excess, mitotane is an important component of the treatment armamentarium for ACC., (Published by Oxford University Press 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Importance: Because unprofessional behaviors are associated with patient complications, malpractice claims, and well-being concerns, monitoring concerns requiring investigation and individuals identified in multiple reports may provide important opportunities for health care leaders to support all team members., Objective: To examine the distribution of physicians by specialty who demonstrate unprofessional behaviors measured through safety reports submitted by coworkers., Design, Setting, and Participants: This retrospective cohort study was conducted among physicians who practiced at the 193 hospitals in the Coworker Concern Observation Reporting System (CORS), administered by the Vanderbilt Center for Patient and Professional Advocacy. Data were collected from January 2018 to December 2022., Exposure: Submitted reports concerning communication, professional responsibility, medical care, and professional integrity., Main Outcomes and Measures: Physicians' total number and categories of CORS reports. The proportion of physicians in each specialty (nonsurgeon nonproceduralists, emergency medicine physicians, nonsurgeon proceduralists, and surgeons) who received at least 1 report and who qualified for intervention were calculated; logistic regression was used to calculate the odds of any CORS report., Results: The cohort included 35 120 physicians: 18 288 (52.1%) nonsurgeon nonproceduralists, 1876 (5.3%) emergency medicine physicians, 6743 (19.2%) nonsurgeon proceduralists, and 8213 (23.4%) surgeons. There were 3179 physicians (9.1%) with at least 1 CORS report. Nonsurgeon nonproceduralists had the lowest percentage of physicians with at least 1 report (1032 [5.6%]), followed by emergency medicine (204 [10.9%]), nonsurgeon proceduralists (809 [12.0%]), and surgeons (1134 [13.8%]). Nonsurgeon nonproceduralists were less likely to be named in a CORS report than other specialties (5.6% vs 12.8% for other specialties combined; difference in percentages, -7.1 percentage points; 95% CI, -7.7 to -6.5 percentage points; P < .001). Pediatric-focused nonsurgeon nonproceduralists (2897 physicians) were significantly less likely to be associated with a CORS report than nonpediatric nonsurgeon nonproceduralists (15 391 physicians) (105 [3.6%] vs 927 [6.0%]; difference in percentages, -2.4 percentage points, 95% CI, -3.2 to -1.6 percentage points; P < .001). Pediatric-focused emergency medicine physicians, nonsurgeon proceduralists, and surgeons had no significant differences in reporting compared with nonpediatric-focused physicians., Conclusions and Relevance: In this cohort study, less than 10% of physicians ever received a coworker report with a concern about unprofessional behavior. Monitoring reports of unprofessional behaviors provides important opportunities for health care organizations to identify and intervene as needed to support team members.

Introduction: Small bowel adenocarcinomas (SBAs) are rare and frequently treated like large intestinal adenocarcinomas. However, SBAs have a very different microenvironment and could respond differently to the same therapies. Our previous data suggested that SBAs might benefit from targeting the PD-1/PD-L1 axis based on PD-L1 staining in almost 50% of SBA tissue samples tested. Thus, we designed a phase 2 study to explore safety and efficacy of avelumab in SBA., Patients and Methods: Patients with advanced or metastatic disease were enrolled; ampullary tumors were considered part of the duodenum and allowed. Prior PD-1/PD-L1 inhibition was not allowed. Avelumab (10 mg/kg) was given every 2 weeks, and imaging was performed every 8 weeks. Primary endpoint was response rate., Results: Eight patients (n = 5, small intestine; n = 3, ampullary) were enrolled, with a majority (88%) being male and a median age of 61 years. Of 7 efficacy-evaluable patients, 2 (29%) experienced partial responses; stable disease occurred in 3 additional patients (71%). Median progression-free survival was 3.35 months. Most frequent, related toxicities were anemia, fatigue, and infusion-related reaction (25% each), mostly grade ≤2; grade 3 hypokalemia and hyponatremia occurred in one patient, and another reported grade 4 diabetic ketoacidosis., Conclusions: Despite the observed benefit, accrual was slower than expected and the study was closed early due to feasibility. A general clinic observation was that patients were receiving immunotherapy off-label as the availability of these agents increased. Off-label availability and disease rarity were likely drivers of insufficient accrual., Competing Interests: Disclosure JB is an advisory board member of Insmed, Bayer, Mirati, Ipsen, QED, Oxford Biotherapeutics DSMB: Novocure, Pancreatic Cancer Action Network, Karyopharm, and his institution has received research funding from I-Mab, Dragonfly, Astellas, Atreca, AbbVie, Pfizer, Karyopharm, Boston biomedical, PsiOxus, EMD Serono, BMS. The other authors do not have any relevant conflicts to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Larotrectinib is a first-in-class, highly selective, and central nervous system-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer. We report the efficacy and safety of larotrectinib in patients with TRK fusion-positive salivary gland cancers., Patients and Methods: Patients with TRK fusion-positive salivary gland cancer treated with larotrectinib were identified from two clinical trials (NCT02122913 and NCT02576431). Patients received larotrectinib 100 mg twice daily (BID) except for one patient who received 150 mg BID in the phase I trial. The primary endpoint was objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1., Results: At the data cut-off (July 20, 2020), 24 patients with TRK fusion-positive salivary gland cancer had been treated. The most common histologies were secretory carcinoma (54%), adenocarcinoma (25%), and mucoepidermoid carcinoma (13%). All 24 patients had an ETV6-NTRK3 gene fusion. The ORR was 92% (95% confidence interval, 73-99). Best overall response was complete response in three (13%) patients, partial response in 19 (79%), and progressive disease in two (8%). The rate of progression-free survival at 24 months was 78% (median follow-up 30.9 months). Most treatment-related adverse events (AEs) were grade 1-2, and no patients discontinued treatment due to AEs., Conclusion: Larotrectinib demonstrated robust and durable efficacy in patients with TRK fusion-positive salivary gland tumors of various histologies, and a favorable safety profile. These findings support NTRK gene fusion testing in patients with advanced salivary gland cancers., Clinicaltrials.gov Numbers: NCT02122913 and NCT02576431., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: COVID-19 challenged medical practice and graduate medical education. Building on previous initiatives, we describe and reflect on the formative process and goals of the Hematology-Oncology Collaborative Videoconferencing Learning Initiative, a trainee-led multi-institutional virtual COVID-19 learning model., Methods: Clinical fellows and faculty from 13 US training institutions developed consensus needs, goals, and objectives, recruited presenters, and generated a multidisciplinary COVID-19 curriculum. Weekly Zoom conferences consisted of two trainee-led instructional segments and a trainee-moderated faculty Q&A panel. Hematology-oncology training program faculty and trainees were the targeted audience. Leadership evaluations consisted of anonymized baseline and concluding mixed methods surveys. Presenter evaluations consisted of session debriefs and two structured focus groups. Conference evaluations consisted of attendance, demographics, and pre- or postmultiple-choice questions on topic learning objectives., Results: In 6 weeks, the initiative produced five conferences: antivirals, anticoagulation, pulmonology, provider resilience, and resource scarcity ethics. The average attendance was 100 (range 57-185). Among attendees providing both pre- and postconference data, group-level knowledge appeared to increase: antiviral (n = 46) pre-/postcorrect 82.6%/97.8% and incorrect 10.9%/2.2%, anticoagulation (n = 60) pre-/postcorrect 75%/93.3% and incorrect 15%/6.7%, and pulmonary (n = 21) pre-/postcorrect 66.7%/95.2% and incorrect 33.3%/4.8%. Although pulmonary management comfort appeared to increase, comfort managing of antivirals and anticoagulation was unchanged. At the conclusion of the pilot, leadership trainees reported improved self-confidence organizing multi-institutional collaborations, median (interquartile range) 58.5 (50-64) compared with baseline 34 (26-39), but did not report improved confidence in other educational or leadership skills., Conclusion: During crisis, trainees built a multi-institutional virtual education platform for the purposes of sharing pandemic experiences and knowledge. Accomplishment of initiative goals was mixed. Lessons learned from the process and goals may improve future disaster educational initiatives., Competing Interests: Shonali MidhaStock and Other Ownership Interests: AbbVie, Moderna Therapeutics Jori MayStock and Other Ownership Interests: Roche, Novartis, Thermo Fisher Scientific Emily CollierResearch Funding: Mirati Therapeutics Nikesh ShahHonoraria: MJH Life Sciences Samuel RubinsteinHonoraria: SanofiConsulting or Advisory Role: Roche Jill GilbertLeadership: Tennessee OncologyHonoraria: UpToDate, Bayer, Loxo/Bayer, Exelixis, HRA PharmaConsulting or Advisory Role: Bayer, HRA Pharma, ExelixisResearch Funding: Pfizer, Exelixis Christine M. LovlyHonoraria: Novartis, Takeda, Pfizer, Cepheid, Foundation Medicine, AstraZeneca, Blueprint Medicines, Achilles Therapeutics, Lilly, Genentech, Syros Pharmaceuticals, Amgen, Roche, EMD SeronoConsulting or Advisory Role: Novartis, Foundation Medicine, Pfizer, Takeda, Cepheid, AstraZeneca, Blueprint Medicines, Achilles Therapeutics, Syros Pharmaceuticals, Genentech, Lilly, Amgen, EMD SeronoResearch Funding: Novartis, Xcovery, AstraZenecaTravel, Accommodations, Expenses: Pfizer, Takeda, Foundation Medicine, Novartis, Cepheid, Genentech Nagashree SeetharamuConsulting or Advisory Role: AstraZeneca, Genentech, Takeda, Amgen, Boehringer Ingelheim Deepa RangachariHonoraria: AstraZenecaConsulting or Advisory Role: Advance Medical, DynaMedResearch Funding: Bristol Myers Squibb, Novocure, AbbVie/StemcentrxOpen Payments Link: https://openpaymentsdata.cms.gov/physician/941245 Martina MurphyConsulting or Advisory Role: Pfizer Elizabeth HenryConsulting or Advisory Role: Seattle Genetics/AstellasResearch Funding: Seattle Genetics/Astellas, Bristol Myers Squibb, Nektar Frances CollichioResearch Funding: Amgen, Novartis, Merck, Replimune, NektarOther Relationship: ACGME Jennifer R. GreenHonoraria: Scripps HospitalTravel, Accommodations, Expenses: Scripps HospitalNo other potential conflicts of interest were reported.

Purpose: Lymphedema and fibrosis (LEF) are common yet overlooked late effects of head and neck cancer and its therapy. Lack of reliable and valid measures of head and neck LEF is a critical barrier to the timely identification and management of head and neck LEF. To fill this gap, we developed and pilot tested a 64-item patient-reported outcome measure ( Lymphedema Symptom Intensity and Distress Survey-Head and Neck, LSIDS-H&N). This article aims to report the process of further validation and refinement of the tool., Methods and Materials: A prospective, longitudinal study was conducted, and 120 patients with oral cavity and oropharyngeal cancer were recruited. Participants completed the LSIDS-H&N at pretreatment, end of treatment, and every 3 months up to 12 months after treatment. SAS PROC VARCLUS was used to generate preliminary clusters of item responses. Internal consistency of the item responses within each cluster was assessed using Cronbach's alpha., Results: A total of 117 patients completed the study. The participants reported that the LSIDS-H&N was easy to understand and captured their symptoms and medical conditions. However, >50% of participants indicated that the survey was burdensome due to length. Thus, we proceeded with item reduction, and the shortened tool (33-item) was named Head and Neck Lymphedema and Fibrosis Symptom Inventory (HN-LEF Symptom Inventory). The subsequent exploration of symptom clusters identified 7 symptom domain clusters (eg, soft tissue and neurologic toxicity), all of which demonstrated good internal consistency., Conclusions: The HN-LEF Symptom Inventory has been carefully developed and refined to allow clinicians and researchers to capture LEF-associated symptom burden and function impairments. Additional rigorous psychometric testing of the tool is ongoing to further validate the strength and internal validity of this tool., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Radiation for patients with head and neck cancer (HNC) is associated with painful mucositis that impacts the delivery of treatment and contributes to high symptom burden., Methods: This was a prospective, randomized pilot trial. Eligible patients received primary or adjuvant chemoradiation. Patients were randomized to usual care vs usual care plus gabapentin titrated to drug tolerance during radiation. Patients completed a symptom survey at baseline and weekly during therapy., Results: Seventy-nine patients were enrolled in the study (38 control, 41 treatment). At interim analysis, gabapentin use resulted in a decrease in pain (P = .004), with the biggest decreases being in the latter weeks of therapy. By week 7, the median pain score in the treatment group was below the 0.25 quantile of the control group., Conclusion: Prophylactic use of gabapentin during chemoradiation for HNC patients resulted in a decrease in pain, neurosensory symptoms, and general systemic symptoms., (© 2020 Wiley Periodicals LLC.)

Background: Programmed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study (NCT01375842) of atezolizumab, in a cohort of patients with relapsed/refractory SCLC., Patients and Methods: Eligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed., Results: Seventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS., Conclusion: Atezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)., Patients and Methods: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved., Results: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy ( P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy ( P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P < .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy., Conclusion: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.

Background: Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid cancer expressing programmed death ligand 1 (PD-L1)., Methods: Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1., Results: Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7-34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1-29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2-14 months); median overall survival was not reached (95% CI, 22 months to not reached)., Conclusions: Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings., Trial Registration: Clinicaltrials.gov identifier: NCT02054806 . Registered 4 February 2014.

Importance: Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression., Objective: To assess safety and objective response rate of durvalumab combined with tremelimumab., Design, Setting, and Participants: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific., Interventions: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy., Main Outcomes and Measures: Safety and tolerability and efficacy measured by objective response rate., Results: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively., Conclusions and Relevance: In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way., Trial Registration: clinicaltrials.gov Identifier: NCT02319044.

Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC., Patients and Methods: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS)., Results: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up., Conclusion: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Treatment options for patients with unresectable or metastatic salivary gland carcinoma (SGC) are limited. Safety and efficacy of pembrolizumab for SGC expressing programmed death ligand 1 (PD-L1) were explored., Materials and Methods: A cohort of patients with advanced, PD-L1-positive SGC was enrolled in the nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors (KEYNOTE-028; NCT02054806). Key inclusion criteria included recurrent or metastatic disease, failure of prior systemic therapy, and PD-L1 expression on ≥1% of tumor or stroma cells (per a prototype immunohistochemistry assay). Patients received pembrolizumab 10 mg/kg every 2 weeks for ≥2 years or until confirmed disease progression or unacceptable toxicity. Primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator review., Results: Twenty-six patients with PD-L1-positive SGC were enrolled and treated; median age was 57 years, 88% were men, and 74% had received prior therapy for recurrent/metastatic disease. Confirmed objective response rate after median follow-up of 20 months was 12% (95% confidence interval, 2%-30%), with 3 patients achieving partial response; there were no complete responses. Median duration of response was 4 months (range, 4 to 21 mo). Treatment-related adverse events occurred in 22 patients (85%), resulting in discontinuation in 2 patients and death in 1 (interstitial lung disease); those occurring in ≥15% of patients were diarrhea, decreased appetite, pruritus, and fatigue., Conclusions: Pembrolizumab demonstrated promising antitumor activity and a manageable safety profile in patients with advanced, PD-L1-positive SGC.

Objective: This study was designed to assess the feasibility of using the Jaw Dynasplint System as an adjunct to conventional stretching exercises as a preventative measure against trismus in patients undergoing radiotherapy., Methods: Study participants (n = 40) were randomized using a permuted block design to conventional stretching or stretching plus use of the Jaw Dynasplint 3 times per day for 30 minutes. Patients were instructed to record maximum interincisal opening each day as well as logging use of the Jaw Dynasplint., Results: At 6 months after initiation of the preventative regimen, 50% of patients in the Dynasplint arm and 75% in the conventional stretching arm remained on their assigned therapy. Trismus was diagnosed in 2 patients in the control arm and in 4 patients in the Dynasplint arm. Only 25% (95% confidence interval = 11.1, 46.9) of patients in the Dynasplint arm used the device as prescribed., Conclusions: The addition of the Jaw Dynasplint decreased compliance compared with conventional stretching. It is unlikely that the prescribed regimen will prove efficacious as a preventative measure due to low compliance.

Background: Although induction studies of TPF in SCCHN have not improved outcomes compared to chemoradiotherapy alone, phase II studies of weekly carboplatin (CbP), paclitaxel and cetuximab (C225) have shown promising results. Nano-albumin-paclitaxel (nab-paclitaxel) based chemotherapy has demonstrated a higher response rate (RR) than solvent-based paclitaxel in squamous cell carcinoma of the lung with favorable toxicity., Materials and Methods: Patients with treatment naïve SCCHN of any site with ≥N2b disease or that was unresectable by strict criteria were eligible. Patients were treated with nab-paclitaxel 100 mg/m 2 , CbP area under the curve (AUC) 2 and C225 400 mg/m 2 week 1 then 250 mg/m 2 for six weeks, followed by standard of care chemoradiotherapy (CRT). The primary endpoint was clinical response rate to induction therapy as defined by RECIST version 1.1. Secondary measures included toxicity, progression-free survival, overall survival and quality of life as measured by FACT-HN., Results: 38 eligible subjects were treated. Primary sites were: oropharynx (OPX) (25), larynx (3) oral cavity (OC) (9), hypopharynx (1). The most common grade 3 or 4 toxicity during induction was acneiform rash (26%) followed by neutropenia (16%). RR was 76.3%. Median PFS and OS have not been reached (median follow-up of 3.3 years); they were superior in patients with response., Conclusions: The combination of nab-paclitaxel, CbP and C225 is feasible, tolerable and active against locally advanced SCCHN., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Adrenocortical carcinoma (ACC) is rare within the adult population. Ectopic ACC proves even rarer. This variant is formed by cortical fragments arrested during embryologic migration. ACC is also known to be associated with several genetic syndromes and has recently been linked to Lynch syndrome in 3% of cases. We present the case of a 68-year-old male with a confirmed diagnosis of Lynch syndrome secondary to a germline MSH2 mismatch-repair gene-mutation who presented with 2 months history of non-specific abdominal pain. After imaging work-up, the patient was found to have a right upper quadrant, retroperitoneal mass. Biochemical tests were without any evidence of a hormonally active process. Fine needle aspiration of the mass revealed a poorly differentiated carcinoma of unknown etiology. The lesion was resected and found to be consistent with ectopic ACC with an associated MSH2 mutation.

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., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Progress in the treatment of advanced medullary thyroid cancer (MTC) has resulted from the approval of 2 drugs within the past 5 years, vandetanib and cabozantinib. These multikinase inhibitors (MKIs) possess overlapping specificities for multiple kinase targets implicated in the progression of MTC. Both drugs are associated with toxicities, including hypertension, hemorrhage/perforation, diarrhea and other gastrointestinal events, several dermatologic events, and hypothyroidism. In addition, vandetanib is uniquely associated with QTc prolongation through interaction with myocardial potassium channels, and cabozantinib is uniquely associated with hand-foot skin reaction. Treatment-related toxicities occur frequently and can be severe or life-threatening, and patients undergoing long-term treatment will likely experience adverse events (AEs). Here we offer specific practical recommendations for managing AEs commonly occurring with vandetanib and cabozantinib. The recommended approach relies on early recognition and palliation of symptoms, dose interruption, and dose reduction as necessary in order for the patient to maintain the highest tolerable dose for as long as possible and optimal quality of life. Treatment guidelines do not specify a recommended sequence for treating with vandetanib and cabozantinib; however, most patients will receive both drugs during their lifetime. The choice for first-line therapy is individualized after a risk-benefit assessment and depends on physician preference and patient-related factors, such as comorbid conditions. Because most generalist practices may not be familiar with the intricacies of agents such as vandetanib and cabozantinib, we commend that patients with advanced MTC be managed and treated by a thyroid cancer specialist with coordination of care within a multidisciplinary team., (Copyright © 2018. Published by Elsevier Ltd.)

PET/CT imaging is frequently used for cancer diagnosis and restaging as metabolically active cells, including cancer, utilize glucose for proliferation. F-FDG is the most commonly utilized radiopharmaceutical in PET/CT imaging. Limitations of F-FDG imaging include intense physiologic uptake in benign tissues such as the brain and myocardium. We present a case of non-small cell lung cancer with myocardial and pericardial metastases obscured by physiologic F-FDG cardiac uptake but detected with the investigational PET radiotracer (4S)-4-(3-F-fluoropropyl)-L-glutamate (F-FSPG), which targets a pathway associated with glutathione biosynthesis. This case demonstrates the added value of F-FSPG PET/CT imaging.

Recurrent and/or metastatic head and neck cancer portends a poor prognosis with traditional treatments, but current immunotherapy with immune checkpoint inhibitors has the potential to improve these clinical outcomes. This review focuses on the major breakthroughs that have led to the current understanding of immunotherapy in head and neck cancer as well as the future direction of the field. Ultimately, this understanding will guide clinicians on the selection of patients with head and neck cancer and practical considerations before starting immunotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: This study aims to describe the types of musculoskeletal impairment in head and neck cancer survivors and to evaluate objective and subjective measures of musculoskeletal impairment and identify areas of need in future studies., Methods: This is a cross-sectional pilot study of 29 head and neck cancer patients who were treated with resection and reconstruction. Subjective measures of musculoskeletal impairment (Neck Disability Index, Shoulder Pain and Disability Index, Vanderbilt Head and Neck Symptom Survey, General Symptom Survey) were collected and compared to objective measures (Cervical Range of Motion Device, Inter-incisal Distance). Digital photography was used to assess the severity of postural abnormalities. Findings were summarized using descriptive statistical and graphical methods., Results: The majority of patients in this cohort suffered from neck disability (69%). Thirty-five percent of patients had shoulder pain and disability. Cervical range of motion deficits were observed in all directions. Inter-incisal distance averaged 33.4 mm and inversely correlated with self-reported jaw and trismus symptoms. Digital photography identified shoulder misalignment in 93% of subjects, head tilt in 89% of subjects, and postural deviation in 68% of subjects., Conclusion: Musculoskeletal impairment is a significant side effect in head and neck cancer survivors that results in chronic neck pain, shoulder disability, trismus, and postural deficits. Tools to describe postural deficits are needed.

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., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.

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.

Advanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX. This was a single-institution phase Ib study that enrolled adult patients with unresectable or metastatic biliary tract, pancreas, duodenal, or ampullary carcinomas that have not received any prior treatment for their disease. Dose escalation followed a standard 3 + 3 design, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity, except nausea/vomiting, or grade 4 hematologic toxicity. A dose expansion cohort in ABTC was treated at the MTD. Twenty-eight patients were enrolled and 4 dose levels were explored. The MTD was erlotinib 150 mg + GEM 800 mg/m 2  + OX 85 mg/m 2 . DLTs were diarrhea and anemia. Most frequent toxicities were nausea (78 %), fatigue (71 %), neuropathy (68 %), and diarrhea (61 %), predominantly grade 1-2. In the ABTC patients, the objective response and disease control rates were 29 % and 94 %, respectively, and median overall survival was 18 months. Erlotinib plus GEMOX was well tolerated. Encouraging anti-tumor activity was seen as evidenced by a high disease control rate and longer median OS than standard chemotherapy in the patients with ABTC., Competing Interests: Compliance with ethical standards Conflicts of interest LWG has served as a consultant for Celgene and has institutional research funding from Astellas Pharma, Pfizer, Onxy, SunPharma, Lilly, and Bristol-Myers Squibb. DBC has served as a consultant for Merrimack and has institutional research funding from Synta, Incyte, Celgene, Hoffman-LaRoxhe, EMD-Serono, and Oncolytics Biotech. KBD has an immediate family member who is employed by Ardent Health Services. KKC has institutional research funding from Pfizer, Boston Biomedical, MedImmune, Onyx, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb. JG has institutional research funding from AstraZeneca. EC has served on advisory boards for Castle Biosciences, Taiho, EMD-Serono, Amgen, Lilly, Advaxis, Bayer and Merrimack. JB has served as a consultant for Celgene, Genentech, Aduro, Boston Biomedical, Janssen, Cornerstone, Symphogen, and Bayer and has institutional research funding from Genentech, Abbvie, Taiho, Bayer, 5Prime, Phoenix, Incyte, and Vertex. Funding This study was supported in part by Astellas Pharmaceutics, Inc. and the Vanderbilt-Ingram Cancer Center Support Grant (2P30 CA068485–14). Erlotinib was supplied for the study by Astellas Pharmaceutics, Inc. The ITR is supported by the Vanderbilt-Ingram Cancer Center, the TJ Martell Foundation, and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained for all individual participants included in the study.

Purpose: Cancer and cancer therapy-related neurocognitive changes negatively affect quality of life, yet few studies have examined neurocognitive changes in patients with head and neck cancer. The purpose of this study was to evaluate neurocognitive performance in patients with head and neck cancer at baseline before starting treatment and 3 months after treatment completion to assess treatment-associated changes in performance., Methods: Patients with head and neck cancer who were to receive primary or adjuvant chemoradiation (N = 55) underwent neuropsychological testing before and 3 months posttreatment. Changes in neurocognitive performance were assessed using a practice effect adjusted Reliable Change Index., Results: At baseline, 38 % of patients exhibited global neurocognitive impairment. Posttreatment, 21.8 % demonstrated declines in neurocognitive performance in at least one domain. Declines in domain-specific performance ranged from 1.8 to 12.7 % with the greatest decline in language, specifically verb retrieval. Domain-specific improvements ranged from 0 to 7.3 %., Conclusions: Patients had a high prevalence of baseline neurocognitive impairment. While neurocognitive performance posttreatment remained unchanged in the majority, almost 13 % suffered declines in language. Small percentages of patients exhibited improvements in their performance. Long-term effects and risk factors for neurocognitive decline in this population should be studied on a larger scale.

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies., Competing Interests: JBe received research support to Karolinska Institutet and University Hospital from Amgen, AstraZeneca, Bayer, Merck, Roche and Sanofi-Aventis. JBu received travel accommodations from Genentech/Roche. FC received a consultant honoraria in Astellas/Medivation, AstraZeneca, Celgene, Daiitchi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline (GSK), Merck-Scharp, Merus BV, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Teva. HC has worked in a consulting or advisory role in Amgen received speakers’ bureau in Baxalta, Celgene and received research funding from Celgene. PC received honoraria for consultancy/advisory role and/or for lectures from Bayer, Blueprint Medicines, Eisai, Eli Lilly, Glaxo SK, Merck SD, Merck Serono, Nektar Ther., Novartis, Pfizer, PharmaMar. AC received honoraria from MerckSerono, Roche, Amgen, Bayer, Lilly and speakers’ bureau from Roche and MerckSerono. RC received research funding from Genentech/Roche, Puma Biotechnology, Novartis and travel, accommodations, expenses from Novartis. LDP received fees as consultant or for lectures (no speakers’ bureau) from F. Hoffmann-La Roche, Pfizer, Bristol Meyer Squibb, AstraZeneca, Qiagen, Boehringer Ingelheim. All fees were paid to Institution. MDS received honoraria and consultation fees from Amgen, Astellas, Bayer, Celgene, Dendreon, Eisai Inc, ESSA, Ferring, GSK, Janssen Cilag, Merck, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, Sanofi Aventis, Shionogi, Synthon, Takeda, Teva/OncoGenex; received research grant from Pierre Fabre Oncologie. EGEdV received research grants to the institute from Roche/Genentech, Amgen, Novartis, Pieris, Servier, is part of data monitoring committee in Biomarin and of advisory board in Synthon. CD received (un)restricted research grants donated to the research institute from Amgen, AstraZeneca, Bayer, Celgene, Eisai, Boehringer Ingelheim, Merck, MSD, Mundipharma, Novartis, Pfizer Corporation, PharmaMar, Pierre Fabre, Roche Austria, Sanofi-aventis, Takeda; received honoraria for consulting from AstraZeneca, Eli Lilly, Merck, Novartis Pharma, Roche Austria. DSD has worked in a consulting or advisory role for UpToDate and received research funding from Aeterna Zentaris (to Institution). LRD received research funding from GlaxoSmithKline (to Institution), Millennium (to Institution), Bristol-Myers Squibb (to Institution), Aeterna Zentaris (to Institution), Millenuim (to Institution) and has other relationship with Genentech. NES received honoraria from Roche, Novartis, MSD Oncology; received research funding from GlaxoSmithKline, Roche; received travel, accommodations, expenses from Novartis, Roche, Celgene. AE conduct research sponsored by Roche, GSK, Novartis, AstraZeneca, Celltrion, Apotex Inc. ME has stock and other ownership interests with Bristol-Myers Squibb, GE Healthcare, Nestle SA, Pfizer, CVS CAREMARK; has worked in a consulting or advisory role from Merck, Bristol-Myers Squibb, ALKERMES; received research funding from Altor BioScience, Bristol-Myers Squibb, Merck, Alkermes, Polynoma; received travel, accommodations, expenses from Myriad Genetics, Bristol-Myers Squibb, Merck. EF has worked as a consultant for Boehringer Ingelheim, Eli Lilly, Pfizer, Roche, BMS, MSD, Novartis; received speaker's bureau from Eli Lilly, BMS, Novartis. MFF has owned stock from Novartis. PKG research funding from Abbvie (to Institution) and Onyx (to Institution). AG has worked in a consulting or advisory role for Genentech/Roche (to Institution), Bayer (to Institution), Sanofi (to Institution), Bristol-Myers Squibb (to Institution), Lilly (to Institution), Boston Biomedical (to Institution), Amgen (to Institution); received research funding from Genentech/Roche (to Institution), Bayer (to Institution), Pfizer (to Institution), Eisai (to Institution), Sanofi (to Institution), Lilly (to Institution), Boston Biomedical (to Institution); received travel, accommodations, expenses from Genentech/Roche, Bayer, Bristol-Myers Squibb, Boston Biomedical, Amgen. SMH has stock and other ownership interests with Liquid Biotech, USA; has patents, royalties, other intellectual property with Liquid Biotech, USA. JH received advisory board and speaker fee from Tesaro and honorarium from SOBI. DVJ has worked in a consulting or advisory role for Bayer. UK received honoraria from Amgen, BMS, GSK, Glycotope, MerckSerono, Merck/MSD, Pfizer; received research support from Pfizer, MerckSerono, Innate, Sirtec. RK conduct research supported by Roche; a member of speaker's bureau of Roche, Meda, Novartis. SK received research funding from Novartis (to Institution), Merck (to Institution), Threshold Pharmaceuticals (to Institution), Gilead Sciences (to Institution), Bayer/Onyx (to Institution); received travel, accommodation, expenses from Novartis. C-HK received honoraria from Merck/Darmstadt, Amgen. MK is on speakers’ bureau for Astellas Pharma, Genentech/Roche, Sanofi, Lilly, Bayer; received research funding from Genentech/Roche (to Institution) and Merck Serono (to Institution). H-JL has received honoraria from Merck Serono, Roche, Celgene, Bayer, Boehringer Ingelheim; has served in a consulting or advisory role for Merck Serono, Roche, Bayer; received travel, accommodations, expenses from Merck Serono, Bayer, Roche. LL has served as a consultant/advisory for EISAI, BMS, MSD, Merck-Serono, Boehringer Ingelheim, DEBIOPHARM, SOBI, Novartis, AstraZeneca, Bayer and Roche; received research funds to institute for clinical studies from EISAI, MSD, Merck-Serono, Boehringer Ingelheim, Novartis, AstraZeneca and Roche; received travel coverage for medical meetings from Merck-Serono, DEBIOPHARM, SOBI, Bayer. PJL received research funding from Novartis (to Institution), Celgene (to Institution), ImClone Systems (to Institution), Taiho Pharmaceutical (to Institution); has patents, royalties, other intellectual property US PPA/61/499,988 Gene Expression Analysis of Thymic Neoplasms Inventors Sunil Badve, Yesim Gokmen-Polar, Patrick Loehrer (to Institution). RIL has served in consulting or advisory role for Roche, Novartis, Janssen; received speakers’ bureau from Roche, Novartis, Janssen. MJM received research funding from Astex Pharmaceuticals (to Institution). TN has ownership interest with Bioclassifier LLC; has role for invention of PAM50 breast cancer assay, which has been licensed to NanoString technologies and being marketed as Prosigna; has served as a consultant for NanoString. KÖ received speaker bureau from Novartis, Ipsen. PÖ received consulting fees, honoraria, travel grants or lecturing fees from Amgen, Bayer, Baxalta, Celgene, EliLilly, Merck, Nordic Drugs, Prime Oncology, Sanofi Oncology. AP received honoraria and consultancy fee from Amgen, Novartis, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Sanofi Aventis. MR received honoraria from AstraZeneca; has served in a consulting or advisory role for Bayer, Pfizer, McKesson; received research funding from AstraZeneca (to Institution), AbbVie (to Institution), Myriad Genetics (to Institution), Biomarin (to Institution); received travel, accommodations, expenses from AstraZeneca, Biomarin. LS has served in a consulting or advisory role for bioTheranostics. MS conduct research sponsored by AstraZeneca, Bayer, Eisai, Exelixis, Genzyme. H-JS is an advisor for Roche, Bayer. LS has served in leadership for Eviti; has served in a consulting or advisory role for Merck; has patents, royalties, other intellectual property; as Co-Editor-in-Chief of UpToDate, Oncology. JS is an employee of Genentech; received honoraria, speakers’ bureau, travel, accommodations, expenses from Genentech. CNS received honoraria or research grant from Novartis, GSK, Pfizer, Merck, Lilly, BMS, Astellas, Bayer, Janssen, Sanofi. FS received unrestricted industry grants for clinical research from Celgene, Fresenius, Helsinn; FS participates in Novartis-lead clinical trials and received punctual advisorship (boards, expert meetings) from Acacia, ACRAF, Amgen, Baxter, Celgene, Danone, Fresenius, GlaxoSmithKline, Grünenthal, Helsinn, ISIS Global, Millennium/Takeda, Mundipharma, Novartis, Novelpharm, Nycomed, Obexia, Otsuka, Ono, Pharm-Olam, Pfizer, Psioxus, PrIME, Santhera, Sunstone, Teva, Vifor. RS received honoraria or consulting fee (paid to institution) from Roche, Merck KGaA/EMD-Serono, MSD/Merck & Co, Pfizer, Ipsen Pharma, Novartis. JT has worked in a consultant/advisory role for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho and Takeda. EV has stock and other ownership interests with McKesson; has worked in a consulting or advisory role for Abbvie, AstraZeneca, Boehringer Ingelheim, Celgene, Clovis Oncology, GeneCentric, Genentech, Merck, Synta, VentiRx, Eisai, Lilly, Transgene; received speakers’ bureau for Amgen; received research funding from Abbvie (to Institution), Bristol-Myers Squibb (to Institution), Gen Vec Inc, (to Institution), Sanofi (to Institution), Monsanto (to Institution), Cyclacel (to Institution); received travel, accommodations, expenses from Amgen. JSW has stock and other ownership interests with Altor BioScience, Celldex, cCam Biotherapeutics; received honoraria from Bristol-Myers Squibb, Merck, Genentech, Abbvie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Lion Biotechnologies, Amgen, Roche, Ichor Medical Systems, Celldex, cCam Biotherapeutics, Pieris; has worked in a consulting or advisory role for Celldex, Ichor Medical Systems, cCam Biotherapeutics, Lion Biotechnologies, Pieris, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Abbvie, Eisai; received research funding from Bristol-Myers Squibb (to Institution), Merck (to Institution), GlaxoSmithKline (to Institution), Genentech (to Institution), Astellas Pharma (to Institution), Incyte (to Institution), Roche (to Institution), Novartis (to Institution); received travel, accommodations, expenses from Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Pieris, cCam Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech.

Background: Tumor/treatment-related internal lymphedema (IL) and/or external lymphedema (EL) are associated with functional deficits and increased symptom burden in head and neck cancer patients (HNCP). Previously, we noted association between EL/IL and patient-reported dysphagia using the Vanderbilt Head and Neck Symptom Survey (VHNSS) version 1.0., Objective: To determine the relationship between IL/EL and subjective and objective measures of swallowing function., Methods: Eighty-one HNCP completed: (1) VHNSS version 2.0, including 13 swallowing/nutrition-related questions grouped into three clusters: swallow solids (ss), swallow liquids (sl), and nutrition(nt); (2) physical assessment of EL using Foldi scale; (3) endoscopic assessment of IL using Patterson scale (n = 56); and (4) modified barium swallow study rated by dysphagia outcome and severity scale (DOSS) and in conjunction with a swallow evaluation by National Outcomes Measurement System (NOMS). Examinations were performed at varied time points to assess lymphedema spectrum, from baseline (n = 15, 18.1%) to 18 months post-therapy (n = 20, 24.1%)., Results: VHNSS swallow/nutrition items scores correlated with NOMS/DOSS ratings (p < 0.001). Highest correlation was with NOMS: ss (-0.73); sl (-0.61); nt (-0.56). VHNSS swallow/nutrition scores correlated with maximum grade of swelling for any single structure on Patterson scale: ss (0.43; p = 0.001); sl (0.38; p = 0.004); nt (0.41; p = 0.002). IL of aryepiglottic/pharyngoepiglottic folds, epiglottis, and pyriform sinus were most strongly correlated with VHNSS and NOMS ratings. NOMS/DOSS ratings correlated with EL (> = -0.34; p < 0.01). No meaningful correlations exist between VHNSS swallow/nutrition items and EL (< ± 0.15, p > 0.20)., Conclusions: IL correlated with subjective and objective measures of swallow dysfunction. Longitudinal analysis of trajectory and impact of IL/EL on dysphagia is ongoing.

Background: Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-α-1,3-galactose in serum can predict anaphylaxis in response to cetuximab., Methods: Sixty patients were prospectively screened as part of the entry criteria for a phase 2 study of neoadjuvant carboplatin, nab-paclitaxel, and cetuximab. Patients were recruited at 2 academic medical centers known to have high anaphylaxis rates: the University of North Carolina and Vanderbilt. Only patients with a negative laboratory result were treated on the clinical protocol., Results: No patient experienced anaphylaxis; the negative predictive value was thus 100%. Other than smoking history, the demographics were similar for assay-positive subjects and assay-negative subjects., Conclusions: Subjects with a negative test result can be safely treated with cetuximab. Further research is required regarding the optimal cutoff for positivity and the positive predictive value. Cancer 2016;122:1697-701. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Objective: We describe development and preliminary testing of Vanderbilt Head and Neck Symptom Survey-Recurrent/Metastatic (VHNSS-RM) to assess residual symptoms, tumor-related symptoms, and side effects from therapy., Methods: Items were identified through patient and provider interviews. Card sort selected high-yield and high-impact items. The VHNSS-RM was administered to 50 patients with recurrent/metastatic head and neck cancer (RMHNC)., Results: The VHNSS-RM includes 12 unique symptoms (diet change, tongue movement affecting speech/swallowing, face/neck swelling, neck/jaw cramping, bad breath, drooling, wound drainage/pain/odor, nasal congestion/drainage, eyes watering, face/tongue/ear/scalp numbness, headaches, and confusion) and 7 unique psychosocial issues (burden to family/friends, lost independence, fear, embarrassment, mood swings, stress, and boredom)., Conclusions: The VHNSS-RM contains 35 physical and 12 psychosocial issues. The VHNSS-RM is feasible and not overly burdensome. Nineteen unique items may improve palliation to patients with RMHNC., (© The Author(s) 2015.)

Introduction: Afatinib is an ErbB family receptor inhibitor with efficacy in head and neck squamous cell carcinoma (HNSCC). A phase I trial was conducted to determine the maximally tolerated dose (MTD) of afatinib in combination with carboplatin and paclitaxel as induction chemotherapy (IC)., Material and Methods: Patients with newly diagnosed, locally advanced HPV-negative or HPV-positive HNSCC with a significant smoking history were enrolled. Afatinib alone was given daily for two weeks as lead-in and subsequently given with carboplatin AUC 6mg/mlmin and paclitaxel 175mg/m(2) every 21days as IC. Afatinib was started at a dose of 20mg daily and dose escalated using a modified Fibonacci design. After completion of IC, afatinib was discontinued and patients received concurrent cisplatin 40mg/m(2) weekly and standard radiation. Toxicity was assessed using CTCAE version 4.0., Results: Seven of nine patients completed afatinib lead-in and IC. Five patients had partial response and two patients had stable disease after IC. Dose level 1 (afatinib 20mg) was well tolerated with one grade 3 (ALT elevation) and one grade 4 (neutropenia) toxicities. However, dose level 2 (afatinib 30mg) was not well tolerated with nine grade 3 (pneumonia, abdominal pain, diarrhea, pancytopenia, and UTI), two grade 4 (sepsis) and one grade 5 (death) toxicities., Conclusions: The MTD of afatinib given with carboplatin AUC 6mg/mlmin and paclitaxel 175mg/m(2) is 20mg daily. Combination of afatinib at doses higher than 20mg with carboplatin and paclitaxel should be administered with caution due to the toxicities., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 by the National Comprehensive Cancer Network.)

Purpose: 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., Experimental Design: 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., Results: 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., Conclusions: 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., (©2015 American Association for Cancer Research.)

Introduction: A combination of cetuximab and sorafenib in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) were assessed for potential benefit., Material and Methods: In a randomized phase II study, R/M HNSCC patients were treated with cetuximab 400mg/m(2) IV on day 1 followed by 250mg/m(2) IV weekly (Arm A), or cetuximab at the same dose/schedule plus sorafenib 400mg PO twice-a-day (Arm B). Each cycle was 21days. Tumor p16 and HPV status, and plasma immunomodulatory cytokine levels were assessed., Results: Of 55 patients enrolled (Arm A-27, Arm B-28), 52 patients received assigned treatments and 43 were evaluable for response. Overall response rate was 8% for both arms. Median overall survival (OS) and progression-free survival (PFS) were 9.0 and 3.0months in Arm A, and 5.7 and 3.2months in Arm B, respectively. Forty-four patients had tumors available for p16 staining (35-negative, 9-positive). Three of nine p16-positive tumors were also HPV positive. The p16-negative patients had significantly better PFS compared to the p16-positive patients (3.7 vs. 1.6months; p-value: 0.03), regardless of study arms. Twenty-four plasma samples were tested for 12 cytokine levels and patients with higher TGFβ1 levels had inferior PFS compared to lower levels (1.9 vs. 4.7months; adjusted p-value: 0.015), regardless of study arms., Conclusions: A subset of R/M patients with p16-negative tumors or lower plasma TGFβ1 levels had longer PFS given the cetuximab-based therapy. However, both arms showed only modest response and sorafenib given with cetuximab did not demonstrate clinical benefit., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma., Methods: In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989., Findings: Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0·94 [95% CI 0·61-1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related., Interpretation: Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma., Funding: Astellas., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors., Patients and Methods: This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules., Results: Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified., Conclusions: At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors., (©2014 American Association for Cancer Research.)

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.", (Copyright © 2014 by the National Comprehensive Cancer Network.)

Background: Oncogenic genetic alterations "drive" neoplastic cell proliferation. Small molecule inhibitors and antibodies are being developed that target an increasing number of these altered gene products. Next-generation sequencing (NGS) is a powerful tool to identify tumor-specific genetic changes. To determine the clinical impact of extensive genetic analysis, we reviewed our experience using a targeted NGS platform (FoundationOne) in advanced cancer patients., Patients and Methods: We retrospectively assessed demographics, NGS results, and therapies received for patients undergoing targeted NGS (exonic sequencing of 236 genes and selective intronic sequencing from 19 genes) between April 2012 and August 2013. Coprimary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage who received genotype-directed therapy., Results: Samples from 103 patients were tested, most frequently breast carcinoma (26%), head and neck cancers (23%), and melanoma (10%). Most patients (83%) were found to harbor potentially actionable genetic alterations, involving cell-cycle regulation (44%), phosphatidylinositol 3-kinase-AKT (31%), and mitogen-activated protein kinase (19%) pathways. With median follow-up of 4.1 months, 21% received genotype-directed treatments, most in clinical trials (61%), leading to significant benefit in several cases. The most common reasons for not receiving genotype-directed therapy were selection of standard therapy (35%) and clinical deterioration (13%)., Conclusion: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in a majority of advanced cancer patients. The assay identified additional therapeutic options and facilitated clinical trial enrollment. As time progresses, NGS results will be used to guide therapy in an increasing proportion of patients., (©AlphaMed Press.)

Sixty-six attending physicians at academic medical centers completed a 43-question self-assessment evaluating communication skills, comfort with clinical trial enrollment, and knowledge of patient-related barriers to enrollment on clinical trials. Responses and demographic information were analyzed for trends and for association with estimated trial enrollment. Physician-described enrollment of patients onto trials varied widely, with estimated enrollment varying from less than 5 patients to well over 125 enrolled during the previous year. Participants perceived themselves to have excellent communication skills and were comfortable with the trial enrollment process, though did not consistently identify patient-related barriers to enrollment. Physician knowledge of clinical trials currently enrolling within their field was associated with increased patient enrollment on study (p = 0.03). Academic physicians expressed confidence in their skills related to clinical trial enrollment despite less than ideal reported enrollment. Knowledge of clinical trials currently enrolling within a physician's specialty was associated with estimated patient enrollment, and may represent a correctable barrier to trial enrollment.

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).

Background: Constitutive activation of nuclear factor κB (NF-κB) is associated with poor prognosis. Irinotecan demonstrates single-agent activity in head and neck cancer but activates NF-κB, promoting cell survival and resistance. Bortezomib is a proteasome inhibitor that inactivates NF-κB., Patients and Methods: We performed a randomized phase II trial of bortezomib on days 1, 4, 8, and 11 and irinotecan on days 1 and 8 of each 21-day cycle or single-agent bortezomib on days 1, 4, 8, and 11 on a 21-day cycle. The addition of irinotecan to bortezomib was allowed in patients who progressed on bortezomib alone., Results: The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with addition of irinotecan at time of progression on bortezomib., Conclusions: The bortezomib-based regimens evaluated in this study have minimal activity in recurrent or metastatic head and neck cancer., (Published 2012 Wiley Periodicals, Inc.)

Background: Lymphedema may disrupt local function and affect quality of life (QOL) in patients with head and neck cancer. The purpose of this study was to examine the associations among severity of internal and external lymphedema, symptoms, functional status, and QOL in patients with head and neck cancer., Methods: The sample included 103 patients who were ≥ 3 months after head and neck cancer treatment. Variables assessed included severity of internal and external lymphedema, physical/psychological symptoms, functional status, and QOL., Results: Severity of internal and external lymphedema was associated with physical symptoms and psychological symptoms. Patients with more severe external lymphedema were more likely to have a decrease in neck left/right rotation. The combined effects of external and internal lymphedema severity were associated with hearing impairment and decreased QOL., Conclusions: Lymphedema severity correlates with symptom burden, functional status, and QOL in patients after head and neck cancer treatment., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN)., Patients and Methods: Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing., Results: Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response., Conclusion: The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.

Purpose: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors., Experimental Design: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab., Results: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses., Conclusions: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents., (©2012 AACR.)

Background: The prevalence, severity, and functional implications of adverse oral health outcomes attributed to head and neck cancer therapy are largely undefined. We report development of an oral health outcome subscale for the Vanderbilt Head and Neck Symptom Survey (VHNSS)., Methods: Oral health outcome questions were formulated through literature review and consultation with an expert panel. Questions were incorporated into the VHNSS resulting in a 50-item survey, scored 0 (none) to 10 (severe). The tool was administered to 70 subjects who completed radiation to assess for feasibility., Results: Patient acceptance was high with a completion time <10 minutes. A full range of scores was noted for 46 of 50 questions. Oral health symptom burden was high early and late posttreatment., Conclusions: The VHNSS version 2.0 was feasible and could be completed in a timely manner. Validation studies are ongoing. The high prevalence of adverse oral health outcomes warrants further study., (Copyright © 2011 Wiley Periodicals, Inc.)

Purpose: A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC)., Experimental Design: Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed., Results: Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug., Conclusions: Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome., Competing Interests: of Potential Confiicts of Interest No potential conflicts of interest were disclosed., (©2012 AACR.)

Purpose: Erlotinib, an orally active selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, has synergistic activity with radiation and with cisplatin. The EGFR is overexpressed in the majority of head and neck cancers. The primary objective of this phase I study was to determine the maximum-tolerated dose (MTD) of erlotinib in combination with low-dose daily cisplatin and radiotherapy. We also sought evidence of biologic activity of erlotinib alone using serial 18-FDG positron emission tomography (PET) imaging., Experimental Design: Oral erlotinib was taken daily starting with a 14-day run-in and continued until radiation therapy (RT) was completed. Low-dose daily cisplatin, 6 mg/m(2) i.v. was given concurrently with standard fractionation RT to a total dose of 66 to 70 Gy. Dose escalation followed a modified Fibonacci dose escalation design., Results: Twenty-two patients were enrolled and 18 patients received therapy on protocol. MTD of the combination of erlotinib, cisplatin, and RT was not reached. The recommended phase II dose of erlotinib is 150 mg per day in combination with cisplatin and RT, the highest dose of erlotinib evaluated in this study. 18F-FDG PET showed evidence for metabolic response to single-agent erlotinib. Per PERCIST criteria, the overall metabolic response rate at day 14 was 38.8% (95% CI: 17.3-64.3). On completion of concurrent chemoradiotherapy, overall response rate derived from tumor measurements based on imaging studies was 83% for all dose levels combined., Conclusions: Erlotinib in combination with low-dose daily cisplatin and RT is well tolerated and shows evidence of clinical efficacy. The combination should be evaluated further.