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Background: Hybrid controlled trials with real-world data (RWD), where the control arm is composed of both trial and real-world patients, could facilitate research when the feasibility of randomized controlled trials (RCTs) is challenging and single-arm trials would provide insufficient information., Methods: We propose a frequentist two-step borrowing method to construct hybrid control arms. We use parameters informed by a completed randomized trial in metastatic triple-negative breast cancer to simulate the operating characteristics of dynamic and static borrowing methods, highlighting key trade-offs and analytic decisions in the design of hybrid studies., Results: Simulated data were generated under varying residual-bias assumptions (no bias: HR RWD  = 1) and experimental treatment effects (target trial scenario: HR Exp  = 0.78). Under the target scenario with no residual bias, all borrowing methods achieved the desired 88% power, an improvement over the reference model (74% power) that does not borrow information externally. The effective number of external events tended to decrease with higher bias between RWD and RCT (i.e. HR RWD away from 1), and with weaker experimental treatment effects (i.e. HR Exp closer to 1). All dynamic borrowing methods illustrated (but not the static power prior) cap the maximum Type 1 error over the residual-bias range considered. Our two-step model achieved comparable results for power, type 1 error, and effective number of external events borrowed compared to other borrowing methodologies., Conclusion: By pairing high-quality external data with rigorous simulations, researchers have the potential to design hybrid controlled trials that better meet the needs of patients and drug development., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: At the time of the study, BDS, MDC, SSB, WKT, SS, MS report employment in Flatiron Health, Inc., and stock ownership in Roche. BPH reports research fundings from Amgen, scientific advisor role and stock ownership in Presagia. RAH reports grant funding from 10.13039/100004319Pfizer. JZ and WBC report employment in Roche/Genentech and stock ownership in Roche. DSH reports research/grant funding from 10.13039/100006483AbbVie, Adaptimmune, Aldi-Norte, 10.13039/100002429Amgen, Astra-Zeneca, 10.13039/100004326Bayer, BMS, 10.13039/501100002973Daiichi-Sankyo, 10.13039/501100003769Eisai, Fate Therapeutics, 10.13039/100004328Genentech, Genmab, 10.13039/100014584Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, 10.13039/100004334Merck, 10.13039/501100004628MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, 10.13039/100004336Novartis, 10.13039/100004319Pfizer, 10.13039/100010293Seattle Genetics, Takeda, and Turning Point Therapeutics; travel and accommodation expenses from 10.13039/100004326Bayer, LOXO, miRNA, Genmab, 10.13039/100000043AACR, 10.13039/100006293ASCO, SITC; consulting or advisory roles with Alpha Insights, Acuta, 10.13039/100002429Amgen, Axiom, Adaptimmune, 10.13039/100004702Baxter, 10.13039/100004326Bayer, COG, Ecor1, 10.13039/100004328Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, 10.13039/100004319Pfizer, Prime Oncology, 10.13039/100010293Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD; and other ownership interests in Molecular Match, OncoResponse, and Presagia Inc. Other authors: nothing to disclose., (© 2022 Flatiron Health, Inc.)

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAF V600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF- mutant RAIR thyroid cancer. Methods: Patients with BRAF V600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 ( 124 I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124 I uptake on the second PET/CT then received therapeutic radioactive iodine ( 131 I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131 I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131 I. At 6 months, 2 patients achieved partial response after 131 I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Purpose To measure financial toxicity and explore its association with quality of life (QOL) in an emerging population of survivors: advanced melanoma patients treated with immunotherapy. Design Cross-sectional survey and medical record review. Sample 106 survivors (39% response). Median time since start of immunotherapy was 36.4 months (range: 14.2-133.9). Methods The Comprehensive Score for Financial Toxicity measured financial toxicity, and the EORTC-QLQ30 assessed QOL and functioning across five domains. Data were collected online, by phone, or in clinic. Findings : Younger patients (<65 years) reported higher financial toxicity ( p  < .001) than older patients. Controlling for age, financial toxicity was correlated with QOL ( p  < .001), financial difficulties ( p  < .001), and EORTC-QLQ30 functioning subscales. Conclusions Given the demonstrated association between financial toxicity and QOL, our study highlights the importance of addressing financial toxicity, particularly among patients receiving high-cost treatments. Implications for Psychosocial Providers : Providers should educate patients and their caregivers about cost-management techniques, link them with available resources, and provide psychosocial counseling to alleviate related distress.

Electronic health records (EHRs) can define real world patient populations with high levels of clinical specificity, potentially addressing some of the shortcomings of other types of real world data (RWD) when informing decisions about the comparative effectiveness of medical technologies. An important but under-recognized concern for EHR-derived RWD, however, is that the rich clinical data permits creation of very homogenous subpopulations from the larger group of eligible patients, thereby reducing the representativeness of the cohort relative to clinical practice. In this article, we discuss the tradeoffs between choosing clinical specificity versus representativeness in population sampling for comparative effectiveness research. Using EHR-derived RWD, we provide an example in non-small cell lung cancer to illustrate the concepts, showing wide variation in outcomes among potential comparator cohorts. We close with several recommendations for selecting comparator populations from EHRs that address the balance between matching clinical guidelines and capturing practice variability in comparative effectiveness research.

In this issue, Smyth and colleagues investigate the natural history of AKT1 -mutant metastatic breast cancer using the AACR Project GENIE, a novel research platform comprised of real-world, clinicogenomic data. A rare subset of tumors, AKT1 -mutant breast cancers demonstrated similar clinical and demographic characteristics and overall survival as AKT1 -wild-type tumors, but a longer duration of therapy on mTOR inhibitors. See related article by Smyth et al., p. 526 ., (©2020 American Association for Cancer Research.)

Purpose: Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC., Methods and Materials: This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m 2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m 2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design., Results: Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans., Conclusions: The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (CIs) have revolutionized treatment of advanced melanoma, leading to an emerging population of long-term survivors. Survivors' quality of life (QOL) and symptom burden are poorly understood. We set out to evaluate symptom burden and QOL in patients with advanced melanoma alive more than 1 year after initiating CI therapy., Methods: Cross-sectional surveys, accompanied by chart review of patients with advanced melanoma treated with CIs at Memorial Sloan Kettering Cancer Center, completed therapy, and were alive >1 year after treatment initiation. Surveys were administered between February and August 2018. Surveys included: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, EuroQOL, items from Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events and Fatigue Severity Scale., Results: We included 90 patients. The most common CI regimens were ipilimumab plus nivolumab (53%) and pembrolizumab (41%); most patients (71%) were not treated in clinical trials. Median time from CI therapy initiation was 40 months and from last dose was 28 months. Fatigue was reported by 28%, with higher fatigue scores in women than men; 12% reported difficulty sleeping. Aching joints (17%) and muscles (12%) were fairly common. Level of functioning was generally high. Overall QOL was excellent though 40% reported 'some or moderate' problems with anxiety/depression and 31% with pain/discomfort., Conclusions: After CI therapy, long-surviving advanced melanoma patients commonly report fatigue but otherwise have moderate symptom burden and good QOL. Ensuring appropriate symptom management will optimize clinical outcomes for these patients., Competing Interests: Competing interests: SSB is an employee of Flatiron Health which is a subsidiary of Roche. JW is a consultant for: Adaptive Biotech; Advaxis; Amgen; Apricity; Array BioPharma; Ascentage Pharma; Astellas; Bayer; Beigene; Bristol Myers Squibb; Celgene; Chugai; Elucida; Eli Lilly; F Star; Genentech; Imvaq; Janssen; Kleo Pharma; Kyowa Hakko Kirin; Linneaus; MedImmune; Merck; Neon Therapuetics; Northern Biologics; Ono; Polaris Pharma; Polynoma; Psioxus; Puretech; Recepta; Takara Bio; Trieza; Sellas Life Sciences; Serametrix; Surface Oncology; Syndax; Syntalogic. Research support: Bristol Myers Squibb; Medimmune; Merck Pharmaceuticals; Genentech. Equity in: Potenza Therapeutics; Tizona Pharmaceuticals; Adaptive Biotechnologies; Elucida; Imvaq; Beigene; Trieza; Linneaus; Honoraium: EsanexMP is a consultant for: BMS; Merck; Array BioPharma; Novartis; Aduro; Incyte; NewLink Genetics. Institutional support for: BMS; Merck; RGenix; Infinity; AstraZeneca; Novartis; Array BioPharma. Honoraria: BMS and Merck. DK’s spouse serves on the scientific advisory board of Vedanta Biosciences and is a consultant for Takeda. JAL discloses salary support for Project Genomics Evidence Neoplasia Information Exchange (GENIE) through the American Association for Cancer Research., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim:  Standard first-line treatment of advanced urothelial cell carcinoma involves cisplatin-based chemotherapy, with carboplatin or immune checkpoint inhibitor therapy (ICI) reserved for cisplatin-ineligible individuals. Methods: Using a large de-identified electronic health record-derived database of patients with advanced urothelial cell carcinoma in the USA, we examined trends in utilization of first-line systemic therapies in cisplatin-eligible patients from 1 January 2015 to 31 March 2018. Results: Among 1181 cisplatin-eligible patients, the quarterly proportion who received first-line ICI increased from 1 to 42% (p trend  <0.001), while the proportion who received cisplatin-based chemotherapy decreased from 53 to 33% (p trend  = 0.018). Patients receiving ICI were older than those receiving cisplatin (median age: 75 vs 68). Conclusion: Our analysis suggests rising off-label ICI use in cisplatin-eligible individuals, potentially because of ICI's favorable toxicity profile.

Background: Several multitargeted tyrosine kinase inhibitors (TKIs) have demonstrated activity in patients with thyroid cancer that is refractory to radioactive iodine (RAI). The antitumor effect is attributed at least in part to the ability of these TKIs to inhibit angiogenesis in these vascular tumors. Vascular endothelial growth factor (VEGF) Trap (VT) is a recombinantly produced fusion protein consisting solely of human sequences for VEGF receptors 1 and 2 extracellular domains and human immunoglobulin 1. Evaluating VT in patients with thyroid cancer is reasonable considering the activity observed with TKIs targeting VEGF., Methods: The current study was a single-institution, phase 2, Simon 2-stage design (21 to >41 patients) study based on the objective response rate and/or 6-month progression-free survival as the primary endpoints. Eligible patients were required to have progressive, RAI-refractory and/or [ 18 F]fludeoxyglucose-avid, recurrent and/or metastatic, nonmedullary, nonanaplastic thyroid cancer; disease that was measurable using Response Evaluation Criteria In Solid Tumors (RECIST) criteria; and adequate organ and bone marrow function. VT at a dose of 4 mg/kg intravenously was administered every 14 days., Results: A total of 40 patients were included in the analysis. Of these patients, 24 had papillary thyroid cancer, 2 had follicular thyroid cancer, and 11 had Hurthle cell thyroid cancer. The final 3 tumors were classified as poorly differentiated. There were no complete and/or partial responses noted; 34 patients achieved stable disease and 6 patients experienced disease progression as their best response. Of the 34 patients with stable disease, 16 remained on the study for >6 months and 6 patients remained on the study for >12 months. The median duration on treatment was 4.1 months (range, 0.6-30.8 months)., Conclusions: Unlike TKIs, which have shown responses in this setting, to the authors' knowledge there have been no responses observed with the use of single-agent VT to date. It does not appear to be a promising drug for the treatment of patients with thyroid cancer., (© 2019 American Cancer Society.)

Context: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI)., Objectives: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR)., Design: This was a pilot trial that enrolled from June 2014 to January 2016., Setting: Academic cancer center., Patients: Patients with RAIR, BRAF mutant thyroid cancer., Intervention: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation., Main Outcome Measure: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I., Results: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048)., Conclusions: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit., (Copyright © 2019 Endocrine Society.)

Purpose: Although the provision of a treatment summary (TS) is a quality indicator in oncology, routine delivery of TSs remains challenging. Automatic TS generation could facilitate use, but data on accuracy are lacking in complex cancers such as head and neck cancer (HNC). We developed and evaluated an electronic platform to automate TS generation for HNC., Methods: The algorithms autopopulated TSs using data from billing records and an institutional cancer registry. A nurse practitioner used the medical record to verify the accuracy of the information and made corrections electronically. Inaccurate and missing data were considered errors. We described and investigated reasons for errors in the automatically generated TSs., Results: We enrolled a heterogeneous population of 43 survivors of HNC. Using billing data, the information on primary site, lymph node status, radiation, and chemotherapy use was accurate in 93%, 95%, 93%, and 95% of patients, respectively. Billing data captured surgery accurately in 77% of patients; once an omitted billing code was identified, accuracy increased to 98%. Chemotherapies were captured in 90% of patients. Using the cancer registry, month and year of diagnosis were accurate in 91% of cases; stage was accurate in 28% of cases. Reprogramming the algorithm to ascertain clinical stage when pathologic stage was unavailable resulted in 100% accuracy. The algorithms inconsistently identified radiation receipt and treating physicians from billing data., Conclusion: It is feasible to automatically and accurately generate most components of TSs for HNC using billing and cancer registry data, although clinical review is necessary in some cases.

Background: We explored if age affects quality of life (QOL) in survivors of locally advanced human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC)., Methods: In a cross-sectional survey of 185 patients, at least 12 months from radiation, we evaluated generic (EuroQOL-5D questionnaire [EQ-5D]) and head and neck specific (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35-questions [EORTC-QLQ-H&N35]) QOL questionnaires and compared differences between younger (<65) and older (≥65) patients., Results: The median age was 57.0 years (range 25-77 years), and 31 patients (16.8%) were ≥65 years old. There was no significant difference in EQ-5D global QOL scores by age (P = .53). Patients ≥65 years reported more immobility (P < .01), problems with social eating (P < .0001), and coughing (P < .01). Patients ≥65 years were not more likely to ever require a gastrostomy (P = .24) but were more likely to remain gastrostomy-dependent at the time of the survey (P = .02)., Conclusion: Despite similar generic QOL, older survivors may have more mobility problems and issues with social eating compared with younger survivors deserving of further evaluation., (© 2018 Wiley Periodicals, Inc.)

Background: Patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited treatment options. Sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results., Methods: In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate., Results: The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis., Conclusions: Sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Activating events along the PI3K/mTOR pathway are common in head and neck squamous cell carcinomas (HNSCC), and preclinical studies suggest additive or synergistic effects when combining mTORC1 inhibitors with carboplatin and paclitaxel chemotherapy., Patients and Methods: In this single-institution phase II study, the combination of temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m2 administered on days 1 and 8 of a 21-day cycle was evaluated in 36 patients with recurrent and/or metastatic (R/M) HNSCC. The primary end point was objective response rate after two cycles of treatment. Secondary end points include the safety and tolerability profile and overall survival. Correlative studies with exome mutational analysis were performed in pre-treatment biopsy samples from 21 patients., Results: Fifteen (41.7%) patients had an objective response, which were all partial responses, and 19 (52.3%) patients had stable disease as best response. The two patients who were designated as 'non-responders' were removed from study prior to two cycles of treatment, but are included in the efficacy and safety analyses. The median duration on study was 5.3 months and the median progression-free survival and overall survival were 5.9 months (95% confidence interval, 4.8-7.1) and 12.8 months (95% confidence interval, 9.8-15.8), respectively. The most common grade 3 and 4 adverse events were hematologic toxicities. Three (3.8%) patients developed neutropenic fever on study. Three of four patients with PIK3CA mutations experienced tumor regressions, and responses were also seen in patients with other genetic alterations in the PI3K/mTOR pathway., Conclusion: The combination of temsirolimus with low-dose weekly carboplatin and paclitaxel appears to have meaningful clinical efficacy in the treatment of R/M HNSCC. This regimen has a relatively high response rate compared to other treatments evaluated in R/M HNSCC, and potential associations with genetic alterations in the PI3K/mTOR pathway should be further explored., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Objectives: Primary surgical treatment of patients with early T-classification (T1-T2) oropharyngeal squamous cell carcinoma (OPSCC) has increased. We sought to determine how often these patients receive postoperative chemoradiation (CRT)., Methods: Patients with T1-T2 OPSCC in the National Cancer Database who underwent primary surgery were evaluated for receipt of postoperative CRT. Postoperative CRT use was examined among patients with high risk factors (positive margins and/or extracapsular spread [ECS]), intermediate risk factors (negative margins, no ECS, and either pT3-4 and/or N2-N3), and no apparent risk factors., Results: Of 4833 patients with T1-T2 OPSCC who underwent primary surgery, 43% had high risk pathologic factors, of whom only 63% received postoperative CRT. Another 31% had no apparent risk factors, of whom 16% nonetheless received postoperative CRT. On multivariable analysis, in addition to tumor and demographic factors, patients treated at community hospitals were more likely to receive postoperative CRT (O.R. 1.41 C.I. 1.18-1.87, P = 0.001)., Conclusions: Variation in postoperative CRT use indicates a lack of consensus and/or knowledge about its benefits and indications. Usage of postoperative CRT regardless of pathologic risk factors suggests an area where future efforts at implementation of best practices may be targeted., (© 2017 Wiley Periodicals, Inc.)

Purpose: With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base., Methods: OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature., Results: To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers., Conclusion: OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions., Competing Interests: Disclosures: Feras M. Hantash and Andrew Grupe are employees of Quest Diagnostics and have some equity interest in the company. All other authors have no pertinent conflicts for the purposes of this paper.

Background: Overuse, the provision of health services for which harms outweigh the benefits, results in suboptimal patient care and may contribute to the rising costs of cancer care. We performed a systematic review of the evidence on overuse in oncology., Methods: We searched Medline, EMBASE, the Cochrane Library, Web of Science, SCOPUS databases, and 2 grey literature sources, for articles published between December 1, 2011 and March 10, 2017. We included publications from December 2011 to evaluate the literature since the inception of the ABIM Foundation's Choosing Wisely initiative in 2012. We included original research articles quantifying overuse of any medical service in patients with a cancer diagnosis when utilizing an acceptable standard to define care appropriateness, excluding studies of cancer screening. One of 4 investigator reviewed titles and abstracts and 2 of 4 reviewed each full-text article and extracted data. Methodology used PRISMA guidelines., Results: We identified 59 articles measuring overuse of 154 services related to imaging, procedures, and therapeutics in cancer management. The majority of studies addressed adult or geriatric patients (98%) and focused on US populations (76%); the most studied services were diagnostic imaging in low-risk prostate and breast cancer. Few studies evaluated active cancer therapeutics or interventions aimed at reducing overuse. Rates of overuse varied widely among services and among studies of the same service., Conclusions: Despite recent attention to overuse in cancer, evidence identifying areas of overuse remains limited. Broader investigation, including assessment of active cancer treatment, is critical for identifying improvement targets to optimize value in cancer care.

Importance: Primary care clinicians, who are increasingly responsible for caring for the growing population of cancer survivors, may be unfamiliar with appropriate cancer surveillance strategies. Clinical practice guidelines can inform cancer follow-up care and surveillance testing. Vague recommendations and inconsistencies among guidelines can lead to overuse and underuse of health care resources and have a negative impact on cost and quality of survivorship care., Objective: To examine the specificity and consistency of recommendations for surveillance after active treatment across cancer guidelines., Design, Setting, and Participants: Retrospective cross-sectional analysis of national cancer guidelines from North America and Europe published since 2010 addressing posttreatment care for survivors of the 9 most common cancers. We categorized surveillance modalities into history and physical examinations, tumor markers, diagnostic procedures (eg, colonoscopy), and imaging. Within each guideline, we classified individual recommendations into 5 categories: (1) risk-based recommendation, (2) recommendation for surveillance, (3) addressed but no clear recommendation, (4) recommendation against surveillance, or (5) cases in which surveillance was not addressed. We reviewed each surveillance recommendation for frequency and a stop date, evaluated consistency among guidelines, and analyzed associations between the organizations proposing the guidelines and recommendation characteristics., Main Outcomes and Measures: Description of guideline recommendations for cancer surveillance., Results: We identified 41 guidelines published between January 1, 2010, and March 1, 2016. Eighty-five percent of guidelines (35) were from professional organizations. Ambiguous recommendations (ie, modality not discussed or discussed without a clear recommendation) were present in 83% of guidelines (34), and 44% (18) recommended against at least 1 test. European guidelines were more likely than North American guidelines to contain ambiguous recommendations (100% vs 68%; P < .01). Recommendations commonly specified testing frequency (from 88% [14 of 16] for tumor markers to 92% [24 of 26] for procedures and/or imaging) but infrequently provided a definitive stop time. Cross-sectional imaging recommendations varied among guidelines for each cancer. For example, among breast cancer guidelines, surveillance computed tomographic scans were recommended against in 2, discussed without a clear recommendation in 1, and not addressed in 3 guidelines., Conclusions and Relevance: Guidelines addressing the care of cancer survivors have low specificity and consistency. As guidelines continue to be revised, developers should clarify recommendations with simple, nonambiguous, definitive language for or against the use of specific tests to optimize care quality and resource utilization.

Background: Despite controversy surrounding its benefit, the use of concomitant chemoradiotherapy (CCRT) in patients with oropharyngeal squamous cell carcinoma (OPSCC) who are aged > 70 years is increasing. However, to the authors' knowledge, few studies to date have compared the outcomes of different systemic treatments in this population., Methods: Records from 74 patients aged ≥ 70 years with stage III to stage IVB OPSCC who were undergoing CCRT from 2002 to 2013 at a single institution were reviewed. Patients were stratified according to the systemic therapy received, including cisplatin, carboplatin with either 5-fluorouracil or paclitaxel (CARB), or cetuximab to compare oncologic outcome and toxicity., Results: The median follow-up was 36 months. The median age of the patients was 75.3 years (range, 70-91 years), with significantly older patients receiving cetuximab (P = .03). A total of 28, 20, and 26 patients, respectively, received CCRT with cisplatin, CARB, and cetuximab. RT interruptions of > 1 day were needed in 4% of patients receiving cisplatin, 20% of patients receiving CARB, and 15% of patients receiving cetuximab (P = .19). Unplanned hospitalizations during CCRT occurred in 25%, 55%, and 58%, respectively, of patients receiving cisplatin, CARB, and cetuximab (P = .03). There were 2 treatment-related deaths, both of which occurred among the patients who were treated with cetuximab. At 5 years, locoregional control was achieved in 100%, 88%, and 60% (P<.001), respectively, and the overall survival rate was 87%, 61%, and 47% (P = .03), respectively, among patients treated with cisplatin, CARB, and cetuximab., Conclusions: Toxicity from CCRT remains a challenge for older adults with OPSCC. Herein, the authors found no evidence that this toxicity was mitigated by treatment with cetuximab. Nevertheless, a subset of patients aged ≥70 years appear to tolerate cisplatin-based treatment with acceptable toxicity and excellent outcomes. Further identification of this patient subgroup is crucial to optimize therapy for older patients with OPSCC. Cancer 2017;123:1345-1353. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background : The Thyroid Cancer Care Collaborative developed a web-based clinical decision-making module (CDMM) to inform risk-adjusted decisions on post-thyroidectomy radioactive iodine (RAI) use in papillary thyroid cancer (PTC). Methods : In a pilot study, we evaluated the CDMM in 19 PTC cases representing low- (five), intermediate- (seven) and high-risk (seven) disease. Two PTC experts and 10 PTC physicians reviewed cases and assigned risk level and RAI recommendation. The experts used a standard approach while the others used the CDMM. We assessed agreement between responses using a weighted Kappa. Results : Between experts, risk-assignment was concordant in 100%, 57% and 86% of low-, intermediate- and high-risk cases, respectively. Between CDMM users, risk-assignment was concordant in 100%, 29% and 14% in low-, intermediate- and high-risk cases, respectively (p=0.01). CDMM-assigned risk agreed with the expert-assigned risk in 100%, 25% and 0% of low-, intermediate- and high-risk cases, respectively (Kappa=0.69). For RAI use, the experts agreed in 15 cases while CDMM users agreed in eight. On further analysis, interpretation of extrathyroidal extension and lymph node staging led to discrepancies with the CDMM. Conclusions : For a web-based CDMM to accurately inform appropriate use of RAI in PTC, standard pathological and surgical reports are necessary., Competing Interests: Disclosure: Shrujal S Baxi has a consulting role with BMS and serves on an advisory board for AstraZeneca. Leonard Wartofsky has been a consultant for Asuragen, Eisei, IBSA and Interpace Diagnostics. He has received speaker honoraria from Genzyme. R Michael Tuttle is a consultant for AstraZeneca, Bayer/Onyx, Genzyme, Novo Nordisk and Veracyte. Rachel Kurtzman, Anne Eaton, Eliza Dewey, Craig Bickford and Stephanie Fish have nothing to disclose in relation to this paper.

Importance: Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies., Objective: To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease., Design, Setting, and Participants: After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis., Interventions: Next-generation sequencing of tumors and matched normal DNA., Main Outcomes and Measures: Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease., Results: Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%])., Conclusions and Relevance: These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.

Objective To describe the reflections of patients treated for laryngeal cancer with regard to treatment-related decision making. Study Design Cross-sectional survey-based pilot study. Setting Single-institution tertiary care cancer center. Subjects/Methods Adults with laryngeal carcinoma were eligible to participate (N = 57; 46% treated surgically, 54% nonsurgically). Validated surveys measuring decisional conflict and regret explored patients' reflections on their preferences and priorities regarding treatment-related decision making for laryngeal cancer and how patient-reported functional outcomes, professional referral patterns, and desired provider input influenced these reflections. Results When considering the level of involvement of surgeons, radiation oncologists, and medical oncologists in their care, patients were more likely to believe that the specialist whom they saw first was the most important factor in deciding how to treat their cancer (Fisher's exact, ~χ 2 = 16.2, df = 6, P = .02). Patients who were treated for laryngeal cancer who reported worse voice-related quality of life recalled more decisional conflict ( P = .01) and experienced more decisional regret ( P < .001). Of the patients for whom speech was a top priority prior to treatment, better voice-related quality of life overall scores were correlated with less decision regret about treatment decisions ( P < .02). Of the patients for whom eating and drinking were top priorities prior to treatment, better MD Anderson Dysphagia Inventory global scores were correlated with less decision regret about treatment decisions ( P < .002). Conclusion Patient priorities and attitudes, coupled with functional outcomes and professional referral patterns, influence how patients reflect on their choices regarding management of laryngeal cancer. Better understanding of these variables may assist in ensuring that patients' voices are integrated into individualized laryngeal cancer treatment planning.

Background: Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC., Patients and Methods: This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients., Results: Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months)., Conclusions: Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Concurrent chemotherapy and radiation (CTRT) improves disease-free survival in locally advanced head and neck cancer but is associated with numerous acute and chronic toxicities resulting in substantial alterations in body mass and composition. We aim to summarize the current evidence on body composition changes experienced by patients undergoing CTRT, examine the impact of these changes on clinical outcomes and address potential interventions aimed at mitigating the loss., Main Body: Loss of 20 % of pre-CTRT weight predicts poorer treatment tolerance and 30-day mortality. While clinical practice focuses on body weight, emerging data indicates that CTRT causes profound adverse changes in lean body mass (sarcopenia). Higher prevalence of sarcopenia predicts poorer disease-free survival as well as overall survival, lower quality of life and functional performance. The magnitude of CTRT-induced sarcopenia is the equivalent to that observed in a decade of aging in a healthy adult. Alterations in body composition are only explained, in part, by decreased caloric intake; other significant predictors include body mass index, stage, and dysphagia. Lifestyle interventions aimed at preventing loss of whole-body and especially lean mass include nutritional counseling, nutritional supplements, dietary supplements and exercise training. Personalized nutritional counseling has been associated with improvement in quality of life, while the benefits of feeding tube placement are inconsistent. There are inconsistently reported benefits of resistance training in this population., Conclusion: Patients with head and neck cancer undergoing CTRT therapy experience dramatic shifts in body composition, including sarcopenia, which can negatively impact clinical outcomes. Efforts to understand the magnitude, clinical importance and mechanisms of sarcopenia are needed to inform a more personalized approach to mitigating the body composition changes associated with CTRT., Competing Interests: The authors declare that they have no competing interests however SSB does serve on an advisory board for AstraZeneca and Lilly Oncology and serves as a consultant for Bristol Myers Squibb.

Background: Human papillomavirus (HPV)-positive oropharyngeal cancer primarily affects working-age adults. Chemotherapy and radiation (CTRT) used to treat this disease may adversely impact a survivors' ability to work after treatment., Methods: We surveyed participants with HPV-positive oropharyngeal cancer who completed CTRT regarding employment. We examined the associations between 1) sociodemographic and clinical factors and employment outcomes, and 2) health-related quality of life and satisfaction with ability to work., Results: 102 participants were employed full-time at diagnosis for pay and surveyed at a median of 23 months post-CTRT (range 12-57 months). The median age at diagnosis was 57 years (range 25-76 years). During CTRT, 8 % stopped working permanently, 89 % took time off or reduced responsibility but later returned, and 3 % reported no change. For those who took time off but returned, median time to return to work was 14.5 weeks. In multivariable analysis, younger age predicted for needing more than the median time off. At time of survey, 85 % participants were working, 7 % had retired, and 8 % were not working for other reasons. Seventeen percent of participants were not satisfied with their current ability to work, which was associated with poorer health-related quality of life and persistent treatment toxicities ( p  < 0.001)., Conclusions: CTRT interrupts employment in the majority of working patients with HPV-positive oropharyngeal cancer but most return. However, treatment-related toxicities might lead to dissatisfaction with ability to work., Competing Interests: Authors HX, TS, CA, SSM, NL, and EE declares that they have no competing interests. SB receives consulting fees from Bristol-Myers Squibb. ES receives consulting fees from Bayer and Eisai. AH has research grants from Genentech-Roche, Lilly, Bayer, AstraZeneca, Koltan Pharm, and Kura Oncology, received a speaker honorarium from Novartis and is a member of the Alliance Experimental therapeutics, and chair of the International Rare Cancers Initiative head and neck cancer subgroup. DP is a member of the National Comprehensive Cancer Network Guidelines Steering Committee.

Background: There has been increasing interest in the primary surgical treatment of patients with early T classification (T1-T2) oropharyngeal squamous cell carcinoma (OPSCC), with the stated goal of de-escalating or avoiding adjuvant treatment. Herein, the authors sought to determine the degree to which this interest has translated into changes in practice patterns, and the rates of adverse postoperative pathologic features., Methods: Patients with T1 to T2 OPSCC in the National Cancer Data Base who were treated from 2004 through 2013 were categorized as receiving primary surgical or primary radiation-based treatment. Trends in treatment selection and factors related to the selection of primary surgery were examined. The rates of adverse pathologic features including positive surgical margins, extracapsular spread (ECS), and advanced T and N classifications after surgery were analyzed., Results: Of 8768 patients with T1 to T2 OPSCC, 68% underwent primary surgical treatment, increasing from 56% in 2004 to 82% in 2013 (P<.0001). The highest versus lowest volume hospitals treated 78% versus 59% of patients with primary surgery (odds ratio, 2.23; 95% confidence interval, 1.55-3.22 [P<.0001]). Higher lymph node classification was found to be predictive of lower rates of primary surgery, but the majority of patients with clinical N2/N3 disease underwent primary surgery. Among patients treated with surgery, positive surgical margins were present in 24% and ECS in 25% of patients. The rate of positive surgical margins decreased over time (P<.0001) and was observed less often at high-volume centers (P<.0001). Among candidates for single-modality therapy (those with clinical T1-T2/N0-N1 disease), 33% had positive surgical margins and/or ECS and 47% had at least 1 adverse feature (T3-T4 disease, N2-N3 disease, positive surgical margins, and/or ECS)., Conclusions: Primary surgical treatment among patients with early T classification OPSCC has become more widespread. Cancer 2016;122:1523-32. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: Head and neck cancer survivors commonly experience severe long-term toxicities, late-occurring symptoms, and significant risks of the second primary malignancy and comorbid illnesses. With multiple simultaneous health issues, these complex cancer survivors often do not receive comprehensive health care that addresses their needs. A tool is needed to streamline and standardize comprehensive care for this cohort., Methods/design: We designed the Head and Neck Survivorship Tool: Assessment and Recommendations (HN-STAR) to address health care challenges for head and neck cancer survivors. HN-STAR is an electronic platform that aims to simplify the provision of personalized care in cancer survivorship clinics. It uses an algorithmic approach to integrate patient-reported outcomes, clinical details, and evidence-based guidelines to standardize comprehensive care provided in routine survivorship visits. It has four integrated components: (1) a simplified treatment summary , which pulls treatment details from a clinical database or can be completed manually using a streamlined form; (2) an online self-assessment for patients to report their own symptoms; (3) an interactive discussion guide presenting all relevant information to the provider during the clinic visit; and (4) a survivorship care plan generated at the end of each visit that reflects decisions made during the visit. By using a modifiable electronic platform, HN-STAR provides a method for incorporating survivorship care plans into clinical practice and for disseminating evidence on symptom management and preventive care. This is a study to assess the feasibility of a future multi-site, randomized clinical trial of HN-STAR. We will enroll head and neck cancer survivors who are followed in one of two nurse practitioner-led survivorship clinics. We will implement HN-STAR for one routine survivorship visits. We will assess (1) usability and feasibility outcomes of HN-STAR from the perspective of key stakeholders and (2) the planned outcomes intended for the larger trial. We will collect usability and feasibility data from online surveys of survivors and their providers. Our findings will inform whether it is feasible to advance HN-STAR to trial. If so, we will adapt HN-STAR and the study design of the trial in response to feedback from survivors and providers. The long-term goal is to determine if such an intervention will lead to improved and simplified comprehensive survivorship care., Discussion: This feasibility study will evaluate implementation of HN-STAR into clinical practice in terms of usability, practicality, and clinical flow in two distinct clinical settings. This study will also provide critical baseline data to characterize this vulnerable population. Findings from this study will inform a multicenter randomized trial of HN-STAR, aimed at standardizing and streamlining the delivery of evidence-guided comprehensive care for head and neck cancer survivors. Ultimately, if found effective, the modular structure of HN-STAR could permit its expansion to survivors of other complex cancers., Trial Registration: ClinicalTrials.gov, NCT02571673.

Background: Cetuximab was approved for use in chemoradiation therapy (CRT) for locally advanced head and neck squamous cell carcinoma (HNSCC) in 2006., Methods: Among 3705 patients with locally advanced HNSCC identified in the linked Surveillance Epidemiology and End Results (SEER) Medicare database, we assessed treatment trends, including surgery, radiation therapy (RT), CRT, and specific agents used in CRT. We examined the influence of demographic and clinical characteristics on the likelihood of receiving CRT before and after 2006., Results: Chemoradiation use increased from 29% of patients diagnosed in 2001 to 61% in 2009 (p < .0001). Compared to before 2006, neither age nor comorbidity score was associated with receipt of CRT after 2006. Platinum combinations were the most commonly used concurrent chemotherapies before 2006, but, since then, cetuximab has become the most commonly used agent., Conclusion: The use of CRT has increased substantially and cetuximab may have increased CRT use, especially in older and sicker patients. © 2015 Wiley Periodicals, Inc. Head Neck 38: E165-E171, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: Despite advantages in terms of cancer control and organ preservation, the benefits of chemotherapy and radiation therapy (CTRT) may be offset by potentially severe treatment-related toxicities, particularly in older patients. The objectives of this study were to assess the types and frequencies of toxicities in older adults with locally or regionally advanced head and neck squamous cell carcinoma (HNSCC) who were receiving either primary CTRT or radiation therapy (RT) alone., Methods: With Surveillance, Epidemiology, and End Results cancer registry data linked with Medicare claims, patients who were 66 years old or older with locally advanced HNSCC, were diagnosed from 2001 to 2009, and received CTRT or RT alone were identified. Differences in the frequency of toxicity-related hospital admissions and emergency room visits as well as feeding tube use were examined, and controlling for demographic and disease characteristics, this study estimated the impact of chemotherapy on the likelihood of toxicity., Results: Among patients who received CTRT (n = 1502), 62% had a treatment-related toxicity, whereas 46% of patients who received RT alone (n = 775) did. When the study controlled for demographic and disease characteristics, CTRT patients were twice as likely to experience an acute toxicity in comparison with their RT-only peers. Fifty-five percent of CTRT patients had a feeding tube placed during or after treatment, whereas 28% of the RT-only group did., Conclusions: In this population-based cohort of older adults with HNSCC, the rates of acute toxicities and feeding tube use in patients receiving CTRT were considerable. It is possible that for certain older patients, the potential benefit of adding chemotherapy to RT does not outweigh the harms of this combined-modality therapy., (© 2015 American Cancer Society.)

Background: After completing treatment for cancer, survivors may experience late effects: consequences of treatment that persist or arise after a latent period., Purpose: To identify and describe all models that predict the risk of late effects and could be used in clinical practice., Data Sources: We searched Medline through April 2014., Study Selection: Studies describing models that (1) predicted the absolute risk of a late effect present at least 1 year post-treatment, and (2) could be used in a clinical setting., Data Extraction: Three authors independently extracted data pertaining to patient characteristics, late effects, the prediction model and model evaluation., Data Synthesis: Across 14 studies identified for review, nine late effects were predicted: erectile dysfunction and urinary incontinence after prostate cancer; arm lymphoedema, psychological morbidity, cardiomyopathy or heart failure and cardiac event after breast cancer; swallowing dysfunction after head and neck cancer; breast cancer after Hodgkin lymphoma and thyroid cancer after childhood cancer. Of these, four late effects are persistent effects of treatment and five appear after a latent period. Two studies were externally validated. Six studies were designed to inform decisions about treatment rather than survivorship care. Nomograms were the most common clinical output., Conclusion: Despite the call among survivorship experts for risk stratification, few published models are useful for risk-stratifying prevention, early detection or management of late effects. Few models address serious, modifiable late effects, limiting their utility. Cancer survivors would benefit from models focused on long-term, modifiable and serious late effects to inform the management of survivorship care., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives/hypothesis: Primary curative treatment of advanced laryngeal cancer may include surgery or chemoradiation, although recommendations vary and both are associated with complications. We evaluated predictors and trends in the use of these modalities and compared rates of complications and overall survival in a population-based cohort of older adults., Study Design: Retrospective population-based cohort study., Methods: Using Surveillance Epidemiology and End Results (SEER) cancer registry data linked with Medicare claims, we identified patients over 65 with advanced laryngeal cancer diagnosed 1999 to 2007 who had total laryngectomy (TL) or chemoradiation (CTRT) within 6 months following diagnosis. We identified complications and estimated the impact of treatment on overall survival, using propensity score methods., Results: The proportion of patients receiving TL declined from 74% in 1999 to 26% in 2007 (P < 0.0001). Almost 20% of the CTRT patients had a tracheostomy following treatment, and 57% had a feeding tube. TL was associated with an 18% lower risk of death, adjusting for patient and disease characteristics. The benefit of TL was greatest in patients with the highest propensity to receive surgery., Conclusion: TL remains an important treatment option in well selected older patients. However, treatment selection is complex; and factors such as functional status, patient preference, surgeon expertise, and post-treatment support services should play a role in treatment decisions., Level of Evidence: 2b. Laryngoscope, 124:2707-2713, 2014., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Before developing a survivorship care plan (SCP) that colorectal cancer (CRC) survivors will value, understanding the informational needs of CRC survivors is critical., Methods: We surveyed survivors treated for nonmetastatic CRC at two hospitals in New York about their needs and preferences for survivorship information. Participants completed treatment 6 to 24 months before the interview and had not received an SCP. We evaluated whether survivors knew their treatment history (10 topics), whether they understood ongoing risks (four topics), and their preferences for receiving 16 topics of survivorship information., Results: One hundred seventy-five survivors completed the survey. Most survivors remembered information about past treatment (98% to 99% for each treatment). Fewer survivors knew their risks of local recurrence, distant recurrence, or developing a new CRC (69%, 77%, and 40%, respectively). Most participants reported receiving information about their cancer history and ongoing oncology visits (77% to 86% across topics). Across all topics, 93% to 99% of those who reported receiving information found the information useful. A minority of survivors reported they received information about symptoms to report to doctors, returning to work, or financial or legal issues (5% to 48% across topics), but those who did found the information useful (89% to 100% across topics)., Conclusions: In the absence of an SCP, CRC survivors still generally understood their cancer history. However, many lacked knowledge of ongoing risks and prevention. Most survivors stated that they found the survivorship information they received useful. SCPs for CRC survivors should focus less on past care and more on helping survivors understand their risks and plan for the future., (Copyright © 2014 by American Society of Clinical Oncology.)

Background: Survivors of head and neck squamous cell carcinoma (HNSCC) face excess mortality from multiple causes., Methods: We used the population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry data to evaluate the causes of death in patients with nonmetastatic HNSCC diagnosed between 1992 and 2005 who survived at least 3 years from diagnosis (long-term survivors). We used competing-risks proportional hazards regression to estimate probabilities of death from causes: HNSCC, second primary malignancy (SPM) excluding HNSCC, cardiovascular disease, and other causes., Results: We identified 35,958 three-year survivors of HNSCC with a median age at diagnosis of 60 years (range = 18-100 years) and a median follow-up of 7.7 years (range = 3-18 years). There were 13,120 deaths during the study period. Death from any cause at 5 and 10 years was 15.4% (95% confidence interval [CI] = 15.0%-15.8%) and 41.0% (95% CI = 40.4%-41.6%), respectively. There were 3852 HNSCC deaths including both primary and subsequent head and neck tumors. The risk of death from HNSCC was greater in patients with nasopharynx or hypopharynx cancer and in patients with locally advanced disease. SPM was the leading cause of non-HNSCC death, and the most common sites of SPM death were lung (53%), esophagus (10%), and colorectal (5%) cancer., Conclusions: Many long-term HNSCC survivors die from cancers other than HNSCC and from noncancer causes. Routine follow-up care for HNSCC survivors should expand beyond surveillance for recurrent and new head and neck cancers., (© 2014 American Cancer Society.)

Background: The Institute of Medicine recommended that survivors of cancer and their primary care providers receive survivorship care plans (SCPs) to summarize cancer treatment and plan ongoing care. However, the use of SCPs remains limited., Methods: Oncology providers at 14 National Cancer Institute Community Cancer Centers Program hospitals completed a survey regarding their perceptions of SCPs, including barriers to implementation, strategies for implementation, the role of oncology providers, and the importance of topics in SCPs (diagnosis, treatment, recommended ongoing care, and the aspects of ongoing care that the oncology practice will provide)., Results: Among 245 providers (response rate of 70%), 52% reported ever providing any component of an SCP to patients. The most widely reported barriers were lack of personnel and time to create SCPs (69% and 64% of respondents, respectively). The most widely endorsed strategy among those using SCPs was the use of a template with prespecified fields; 94% of those who used templates found them helpful. For each topic of an SCP, although 87% to 89% of oncology providers believed it was very important for primary care providers to receive the information, only 58% to 65% of respondents believed it was very important for patients to receive the information. Furthermore, 33% to 38% of respondents reported mixed feelings regarding whether it was the responsibility of oncology providers to provide SCPs., Conclusions: Practices need additional resources to overcome barriers to implementing SCPs. We found resistance toward SCPs, particularly the perceived value for the survivor and the idea that oncology providers are responsible for SCP dissemination., (© 2013 American Cancer Society.)

The management of head and neck cancer has advanced in many areas, including but not limited to diagnostic imaging and response assessment, radiation delivery, surgical approaches, combined-modality therapy, as well as new drug discovery. These advances have become widely used, however, the associated improvements in outcomes of interest compared with other options may at times be modest in magnitude or supported by limited data. In addition, the price tag of these advancements is often high. There is a growing mandate to look at existing data to identify insights into how to improve the value of care and to better understand the comparative effectiveness of one intervention versus another with regard to tumor control, quality of life, and other important outcomes; such insights become particularly important when considerable disparities exist in related costs. We review selected issues in radiotherapy, chemotherapy and supportive care applicable to the management of head and neck cancer and relevant to ascertaining the value of care.

Eighteen percent of incident malignancies in the United States are a second (or subsequent) cancer. Second primary neoplasms (SPNs), particularly solid tumors, are a major cause of mortality and serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer survivor subsequently being diagnosed with an SPN, including radiotherapy for the first cancer, unhealthy lifestyle behaviors, genetic factors, aging, or an interaction between any of these factors. In this article, we discuss these factors and synthesize this information for use in clinical practice, including preventive strategies and screening recommendations for SPNs., (© 2013 Elsevier Inc. All rights reserved.)

Background: Oropharyngeal cancers are increasingly associated with human papillomavirus (HPV). Little is known about the experience of patients receiving this diagnosis., Methods: Semistructured interviews were conducted with ten survivors of HPV-related oropharyngeal cancer. The interviews were transcribed, and recurring themes were identified., Results: Physicians were a trusted source of information regarding HPV. Framing the diagnosis in terms of prognosis resonated with patients. The uncertainty about transmission, latency, and communicability colored the dialogue about HPV. Despite some understanding of prevalence and transmission, patients worried about their partner's risk. Patients sought information about HPV on the Internet, but it was not easily navigable. Emotional reactions to the diagnosis remained mostly cancer-centric rather than HPV-centric. A patient-education handout was developed in response to patient questions., Conclusions: Additional educational resources explaining the facts about HPV in HNSCC in a consistent way including content of highest priority to patients may improve understanding of HPV., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Second primary malignancies (SPMs) are the leading cause of death in survivors of head and neck squamous cell carcinoma (HNSCC). Synchronous SPMs are of significant clinical interest because they potentially can be identified by screening procedures at the time of diagnosis of the index cancer. Recently, human papillomavirus (HPV) has emerged as a distinct risk factor for oropharyngeal head and neck squamous cell carcinoma (HNSCC), differing from classic tobacco/alcohol-associated HNSCC, suggesting that there also may be distinct patterns of synchronous SPMs., Methods: The authors performed a population-based cohort study in 64,673 patients in the National Cancer Institute Surveillance, Epidemiology, and End Results registry (1979-2008), defining risks of synchronous SPM in patients with HNSCC who were diagnosed before and after the emergence of prevalent HPV-associated oropharyngeal HNSCC. Excess risk was calculated using standardized incidence ratios (SIR) and excess absolute risk per 100 patients., Results: Among patients with HNSCC, the SIR of synchronous SPM was 5.0, corresponding to 2.62 excess cases per 100 patients. The site with the highest excess risk of a second cancer was the head and neck (SIR, 41.4), followed by the esophagus (SIR, 21.8), and lung (SIR, 7.4). The risk of synchronous SPM changed markedly over time for patients with oropharyngeal HNSCC. In the 1970s and 1980s, oropharyngeal cancers carried the highest risk of SPM. Risk began to dramatically decline in the 1990s; and currently, oropharyngeal cancers carry the lowest risk of synchronous SPM., Conclusions: The current data are consistent with the etiologic shift of oropharyngeal HNSCC, from a primarily tobacco-associated malignancy associated with significant field cancerization of the upper aerodigestive mucosa, to a malignancy primarily caused by oncogenic human papillomavirus., (Copyright © 2013 American Cancer Society.)

Background: Agents such as aflibercept, which target the angiogenic pathway, are of great interest as candidates for the management of metastatic differentiated thyroid cancer. Here, we report a patient who developed a hemorrhagic abdominal pseudoaneurysm shortly after being started on this drug., Patient Findings: The patient was a 67-year-old woman being treated with single agent aflibercept (VEGF-Trap) for metastatic thyroid cancer. She had no history of intra-abdominal pathology or vascular disease but had been previously treated with sorafenib. Twelve days after receiving her second dose of aflibercept, she developed vague abdominal pain, which increased in severity and was accompanied by nausea and vomiting. Her symptoms progressed along with a decline in her hematocrit and signs of internal hemorrhaging. An angiogram identified an occluded celiac artery with increased collaterals and a bleeding pseudoaneurysm in the inferior pancreaticoduodenal artery. After the pseudoaneurysm was coiled, the patient stabilized., Summary and Conclusions: Anti-angiogenic agents, usually well tolerated, can disrupt the delicate balance of normal endothelium, leading to hemorrhagic and thrombotic complications. The hemorrhage of aberrant vasculature should be included in the differential diagnosis in patients presenting with vague complaints while being treated with anti-angiogenic agents.

The prognosis of Hodgkin's lymphoma (HL) has markedly improved as management strategies evolved. In the modern era, less than 15% of patients with early-stage, non-bulky HL will relapse, and less than one third of those with advanced disease will relapse. As therapy for HL intensified, and as disease-related outcomes improved, the impact of the late effects of therapy has become increasingly important. There is a growing body of literature describing the late morbidity experienced by survivors of HL, including risks of second primary malignancy, cardiac disease, pulmonary disease, and endocrine dysfunction. Additionally, the impact of disease and treatment on psychosocial function and quality of life has been a subject of investigation, with survivors often suffering from impairment. An understanding of these risks and the management implications inherent to them is central to the care of survivors of HL.

Objective: The objective of our study was to assess the experiences and preferences of radiology residents with respect to breast imaging., Materials and Methods: We surveyed radiology residents at 26 programs in New York and New Jersey. Survey topics included plans for subspecialty training, beliefs, and attitudes toward breast imaging and breast cancer screening and the likelihood of interpreting mammography in the future., Results: Three hundred forty-four residents completed the survey (response rate, 62%). The length of time spent training in breast imaging varied from no dedicated time (37%) to 1-8 weeks (40%) to more than 9 weeks (23%). Most respondents (97%) agreed that mammography is important to women's health. More than 85% of residents believed that mammography should be interpreted by breast imaging specialists. Respondents shared negative views about mammography, agreeing with statements that the field was associated with a high risk of malpractice (99%), stress (94%), and low reimbursement (68%). Respondents endorsed several positive attributes of mammography, including job availability (97%), flexible work schedules (94%), and few calls or emergencies (93%). Most radiology residents (93%) said that they were likely to pursue subspecialty training, and 7% expressed interest in breast imaging fellowships., Conclusion: Radiology residents' negative and positive views about mammography seem to be independent of time spent training in mammography and of future plans to pursue fellowship training in breast imaging. Systematic assessment of the plans and preferences of radiology residents can facilitate the development of strategies to attract trainees to careers in breast imaging.