Publications by authors named "David Adelstein"

124 Publications

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma: A multi-site validation study.

J Clin Invest 2021 Mar 2. Epub 2021 Mar 2.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, United States of America.

Background: p16 positive oropharyngeal squamous cell carcinoma (OPSCC) patients are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure in p16 positive OPSCC. Pathologist-based visual assessment of tumor cell multinucleation has been shown to be independently prognostic of disease-free survival in p16 positive OPSCC. However, its quantification is time-intensive, subjective, and at risk of interobserver variability.

Methods: We present a deep learning-based metric, the multi-nucleation index (MuNI), for prognostication in p16 positive OPSCC. This approach quantifies tumor multi-nucleation from digitally scanned hematoxylin eosin (H&E)-stained slides. Representative H&E whole slide images from 1,094 previously untreated p16 positive OPSCC patients were acquired from six institutions for optimizing and validating MuNI.

Results: MuNI was prognostic for disease-free (DFS), overall (OS), or distant metastasis-free (DMFS) survival in p16 positive OPSCC with HRs of 1.78(95%CI:1.37-2.30), 1.94(1.44-2.60), and 1.88(1.43-2.47), respectively, independent of age, smoking status, treatment type, and T/N-categories in multivariable analyses. It was also prognostic for DFS, OS, and DMFS in OPSCC patients at stages I and III.

Conclusion: MuNI holds promise as a low-cost, tissue non-destructive, H&E stain based digital biomarker test for counseling, treatment, and surveillance of p16 positive OPSCC patients. These data support further confirmation of MuNI in prospective trials.

Funding: This work was supported by the National Cancer Institute of the National Institutes of Health (under award numbers 1U24CA199374-01, R01CA202752-01A, R01CA208236-01A1, R01CA216579-01A1, R01CA220581-01A1, 1U01CA239055-01), the National Institute for Biomedical Imaging and Bioengineering (1R43EB028736-01), the National Center for Research Resources (1C06RR12463-01), the VA Merit Review Award (IBX004121A) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DoD Breast Cancer Research Program Breakthrough Level 1 Award (W81XWH-19-1-0668), the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering, and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University, the Michael E. DeBakey VA Medical Center, an institutional pilot grant (1IK2CX001953) and Dan L Duncan Comprehensive Cancer Center Support Grant (NCI-CA125123). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, the Department of Defense, or the United States Government.
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http://dx.doi.org/10.1172/JCI145488DOI Listing
March 2021

Failure rate in the untreated contralateral node negative neck of small lateralized oral cavity cancers: A multi-institutional collaborative study.

Oral Oncol 2021 Feb 11;115:105190. Epub 2021 Feb 11.

Department of Cancer Services, Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, Queensland, Australia; Faculty of Medicine, University of Queensland, St. Lucia, Australia.

Objectives: The importance of treating the bilateral neck in lateralized small oral cavity squamous cell carcinoma (OCC) is unclear. We sought to define the incidence and predictors of contralateral neck failure (CLF) in patients who underwent unilateral treatment.

Materials And Methods: We performed a multi-institutional retrospective study of patients with pathologic T1-T2 (AJCC 7th edition) OCC with clinically node negative contralateral neck who underwent unilateral treatment with primary surgical resection ± adjuvant radiotherapy between 2005 and 2015. Incidence of CLF was estimated using the cumulative incidence method. Clinicopathological factors were analyzed by univariate (UVA) and multivariate analysis (MVA) for possible association with CLF. Kaplan-Meier analysis was used to estimate overall survival (OS).

Results: 176 patients were evaluated with a median of 65.9 months of follow-up. Predominant pathologic T-stage was T1 (68%), 8.5% of patients were N1, 2.8% were N2b. Adjuvant radiotherapy was delivered to 17% of patients. 5-year incidence of CLF was 4.3% (95% CI 1.2-7.4%). Depth of invasion (DOI) > 10 mm and positive ipsilateral neck node were significant predictors for CLF on UVA. DOI > 10 mm remained significant on MVA (HR = 6.7, 95% CI 1.4-32.3, p = 0.02). The 2- and 5-year OS was 90.6% (95% CI 86.2-95.0%) and 80.6% (95% CI 74.5-86.8%), respectively.

Conclusion: Observation of the clinically node negative contralateral neck in small lateralized OCC can be a suitable management approach in well selected patients, however caution should be applied when DOI upstages small but deeply invasive tumors to T3 on 8th edition AJCC staging.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105190DOI Listing
February 2021

Disease Progression in Cutaneous Squamous Cell Carcinoma Patients With Satellitosis and In-transit Metastasis.

Anticancer Res 2021 Jan;41(1):289-295

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, U.S.A.

Background/aim: Satellitosis/in-transit metastasis (S-ITM) has prognostic value in melanoma and Merkel cell carcinoma, but is not incorporated into cutaneous squamous cell carcinoma (cSCC) staging.

Patients And Methods: From our IRB-approved registry, patients with high-risk cSCC, including patients with S-ITM, were identified. Univariate (UVA) and multivariate (MVA) analyses were performed to compare disease progression (DP) and overall survival (OS). Cumulative incidence of DP and OS analyses were performed using Fine-Gray and Kaplan-Meier methods, respectively.

Results: A total of 18 S-ITM subjects were compared to 247 high risk subjects including T3N0 (n=143), N1-N3 without extranodal extension (ENE) (n=56), N1-N3 with ENE (n=26) and M1 disease (n=22). Median follow up was 16.5 months. Three-year rates of DP were 22% for T3N0, 42% for S-ITM, 48% for T4 bone invasion, 50% for N1-N3 without extranodal extension (ENE), 53% for N1-N3 with ENE, and 66% for M1. Patients with S-ITM did not experience significantly worse DP compared to those with T3N0 (HR=1.96, 95%CI=0.8-4.9; p=0.14).

Conclusion: Cutaneous SCC patients with S-ITM experienced outcomes similar to locally advanced non-metastatic cSCC patients. Larger studies are needed to guide incorporation into staging systems.
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http://dx.doi.org/10.21873/anticanres.14775DOI Listing
January 2021

Identifying an oligometastatic phenotype in HPV-associated oropharyngeal squamous cell cancer: Implications for clinical trial design.

Oral Oncol 2021 Jan 28;112:105046. Epub 2020 Oct 28.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States.

Objectives: Patients with human papillomavirus (HPV) associated squamous cell carcinoma of the oropharynx (SCC-OP) have improved overall survival (OS) after distant metastasis (DM) compared to HPV negative patients. These patients may be appropriate candidates for enrollment on clinical trials evaluating the efficacy of metastasis-directed therapy (MDT). This study seeks to identify prognostic factors associated with OS after DM, which could serve as enrollment criteria for such trials.

Materials And Methods: From an IRB approved multi-institutional database, we retrospectively identified patients with HPV/p16 positive SCC-OP diagnosed between 2001 and 2018. Patterns of distant failure were assessed, including number of lesions at diagnosis and sites of involvement. The primary outcome was OS after DM. Prognostic factors for OS after DM were identified with Cox proportional hazards. Stepwise approach was used for multivariable analysis.

Results: We identified 621 patients with HPV-associated SCC-OP, of whom 82 (13.2%) were diagnosed with DM. Median OS after DM was 14.6 months. On multivariable analysis, smoking history and number of lesions were significantly associated with prolonged OS. Median OS after DM by smoking (never vs ever) was 37.6 vs 11.2 months (p = 0.006), and by lesion number (1 vs 2-4 vs 5 or more) was 41.2 vs 17.2 vs 10.8 months (p = 0.007).

Conclusion: Among patients with newly diagnosed metastatic HPV-associated SCC-OP, lesion number and smoking status were associated with significantly prolonged overall survival. These factors should be incorporated into the design of clinical trials investigating the utility of MDT, with or without systemic therapy, in this population.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105046DOI Listing
January 2021

Locoregional and distant recurrence for HPV-associated oropharyngeal cancer using AJCC 8 staging.

Oral Oncol 2020 12 7;111:105030. Epub 2020 Oct 7.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, United States.

Introduction: The objective of this study is to evaluate locoregional and distant failure for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) using American Joint Committee on Cancer eighth edition (AJCC 8) staging.

Materials And Methods: Retrospective cohort study of 457 patients with HPV + OPSCC, treated with platinum-based chemoradiation from 2002 to 2018, followed for a median of 4.3 years. Time to locoregional failure (TTLRF) and distant failure (TTDF) were estimated by Kaplan-Meier method. Log-rank, recursive partitioning analysis (RPA), and multivariable Cox proportional hazards were used to evaluate associated factors and stratify risk.

Results: Rates of five-year locoregional control (LRC) and distant control (DC) were 92% (95% CI, 90-95%) and 89% (95% CI, 85-92%), respectively. Smoking, T4, N3, and stage III were associated with significantly worse TTLRF. RPA identified three distinct locoregional failure groups: cT1-3 and <19 pack-years vs. cT1-3 with ≥19 pack-years vs. cT4 (five-year LRC: 97% vs. 90% vs. 82%, P < .0001). The only factor associated with significantly worse TTDF was smoking status, while stage was not correlated. RPA identified two prognostic groups: former or never smokers vs. current smokers (five-year DC: 92% vs. 77%, P = .0003).

Discussion: In the largest evaluation of HPV + OPSCC after platinum-based chemoradiation using AJCC 8, risk for locoregional recurrence was stratified by smoking, T category, N category, and overall stage. Risk of distant recurrence was only stratified by smoking status and not related to stage. This has implications for surveillance and clinical trial design.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105030DOI Listing
December 2020

Evaluating compliance with process-related quality metrics and survival in oral cavity squamous cell carcinoma: Multi-institutional oral cavity collaboration study.

Head Neck 2021 Jan 12;43(1):60-69. Epub 2020 Sep 12.

Head and Neck Institute, Cleveland Clinic, Cleveland, OH, USA.

Background: Process-related measures have been proposed as quality metrics in head and neck cancer care. A recent single-institution study identified four key metrics associated with increased survival. This study sought to validate the association of these quality metrics with survival in a multi-institutional cohort.

Methods: Multicenter retrospective study of patients with oral cavity squamous cell (1/2005-1/2015). Baseline patient and disease characteristics and compliance with quality metrics was evaluated. Association between compliance with quality metrics with overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) was evaluated using Cox proportional hazards models.

Results: Failure to comply with two or more of the quality metrics was associated with worse OS, DFS, and DSS. Adherence to all or all but one of the quality metrics was found to be associated with improved survival.

Conclusions: Process-related quality metrics are associated with increased survival in patients with oral cavity squamous cell carcinoma in a multi-institutional cohort.
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http://dx.doi.org/10.1002/hed.26454DOI Listing
January 2021

Detection and Oncologic Outcomes of Head and Neck Squamous Cell Carcinoma of Unknown Primary Origin.

Anticancer Res 2020 Aug;40(8):4207-4214

Head and Neck Institute, Cleveland Clinic, Cleveland, OH, U.S.A.

Background/aim: To assess factors that predict detection of tumors and oncologic outcomes in head and neck squamous cell carcinoma of unknown primary (SCCUP).

Patients And Methods: This was a retrospective cohort study at a single tertiary care institution.

Results: The primary site was detected at examination under anesthesia (EUA) in 92 (51.1%) patients. The primary site was detected by directed biopsies in 60 (65%), palatine tonsillectomy in 28 (30.4%), and lingual tonsillectomy in 4 patients (4.3%). Four of eight lingual tonsillectomies were positive (50%). Primary locations included: palatine tonsils (51, 28.3%), base of tongue (37, 20.6%), larynx (4, 2.2%), oral cavity (3, 1.67%) and nasopharynx (1, 0.6%). Human papillomavirus (HPV) positive status (HR=0.26, p=0.004) and treatment with chemoradiation (CRT) (HR=0.38, p=0.004) were associated with better disease free survival (DFS).

Conclusion: A primary site was located after aggressive investigation in approximately half of the patients. More research is warranted towards the use of lingual tonsillectomy. Predictors of favorable prognosis included HPV positive status and treatment with CRT.
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http://dx.doi.org/10.21873/anticanres.14421DOI Listing
August 2020

Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 Jul;18(7):873-898

29National Comprehensive Cancer Network.

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.
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http://dx.doi.org/10.6004/jnccn.2020.0031DOI Listing
July 2020

Rethinking the 10-pack-year rule for favorable human papillomavirus-associated oropharynx carcinoma: A multi-institution analysis.

Cancer 2020 Jun 13;126(12):2784-2790. Epub 2020 Mar 13.

Department of Radiation Oncology, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina.

Background: De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved.

Methods: From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation).

Results: Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%.

Conclusions: The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established.
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http://dx.doi.org/10.1002/cncr.32849DOI Listing
June 2020

Impact of routine surveillance imaging on detecting recurrence in human papillomavirus associated oropharyngeal cancer.

Oral Oncol 2020 04 7;103:104585. Epub 2020 Feb 7.

Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, United States.

Objectives: This study examines the utility of surveillance imaging in detecting locoregional failures (LRF), distant failures (DF) and second primary tumors (SPT) in patients with human papillomavirus (HPV) associated oropharyngeal cancer (OPC) after definitive chemoradiotherapy (CRT).

Methods And Materials: An institutional database identified 225 patients with biopsy proven, non- metastatic HPV+ OPC treated with definitive CRT between 2004 and 2015, whose initial post-treatment imaging was negative for disease recurrence (DR). Two groups were defined: patients with <2 scans/year Group 1 and patients with ≥2 scans/year Group 2. The Mann-Whitney test or Chi-square was used to determine differences in baseline characteristics between groups. Fine & Gray regression was used to detect an association between imaging frequency, DR and diagnosis of SPT.

Results: Median follow up was 40.8 months. 30% of patients had ≥T3 disease and 90% had ≥ N2 disease (AJCC 7th edition). Twenty one failures (9.3%) were observed, 7 LRF and 15 DF. Six LRF occurred within 24 months and 14 DF occurred within 36 months of treatment completion. Regression analysis showed Group 2 had increased risk of DR compared to Group1 (HR 10.3; p = 0.002) albeit with more advanced disease at baseline. Five SPT were found (2 lung, 2 esophagus, and 1 oropharynx) between 4.5 and 159 months post-CRT.

Conclusion: Surveillance imaging seems most useful in the first 2-3 years post treatment, and is particularly important in detecting DF. Surveillance scans for SPT has a low yield, but should be considered for those meeting lung cancer screening guidelines.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104585DOI Listing
April 2020

Chemotherapy in the definitive management of oral cancers: Where do we stand today?

Oral Oncol 2020 03 4;102:104584. Epub 2020 Feb 4.

Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, United States.

The treatment of locally advanced oral cavity cancer is often multimodal, involving surgical resection, radiotherapy (RT), and chemotherapy. Systemic therapy is the mainstay of treatment for recurrent/metastatic disease. While the concurrent use of cisplatin with post-operative RT is well established in patients with high risk features of extranodal extension and/or positive surgical margins following resection, the role of chemotherapy in other curative settings is not clear. Studies reporting success of induction chemotherapy or definitive chemoradiotherapy in absence of primary resection include all anatomic sites of head and neck cancer, and oral cavity cancer subset is rarely reported as a separate analysis, thus limiting the interpretation of results. This article will focus on the use of systemic therapy for locoregionally advanced oral cavity cancer.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104584DOI Listing
March 2020

Impact of active smoking on outcomes in HPV+ oropharyngeal cancer.

Head Neck 2020 02 26;42(2):269-280. Epub 2019 Nov 26.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.

Background: The role of smoking among patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is unclear.

Methods: A retrospective cohort study of patients with HPV(+) OPSCC from 2001 to 2015 at a tertiary-care institution was conducted. The primary outcome was overall survival (OS).

Results: Among 484 included patients, 94 (19.4%) were active smokers, 226 (46.7%) were former smokers, and 164 (33.9%) never smoked. Among active smokers, 82 patients (87.2%) had a ≥10 pack-year and 69 (73.4%) had a ≥20 pack-year smoking history. After adjusting for covariates, active smoking was a significant predictor of inferior OS (HR 2.28, P < .001) and PFS (HR 2.26, P < .001). When including pack-years as the covariate, ≥20 pack-years predicted a decreased effect-size for inferior OS and PFS.

Conclusions: For patients with HPV(+) OPSCC, active smoking at diagnosis is the most powerful covariate capturing smoking history to predict OS and PFS.
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http://dx.doi.org/10.1002/hed.26001DOI Listing
February 2020

Tumor Volume Useful Beyond Classic Criteria in Selecting Larynx Cancers For Preservation Therapy.

Laryngoscope 2020 10 13;130(10):2372-2377. Epub 2019 Nov 13.

Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

Objective: To investigate the association between tumor volume and locoregional failure (LRF) after concurrent chemoradiation (CCRT) for locally advanced larynx cancer (LC).

Methods: This is a retrospective cohort study from 2009 to 2014 identified from an institutional review board-approved registry. Fifty-nine of 68 patients with locally advanced larynx cancer treated with definitive CCRT who had available imaging for review were identified. The main endpoint to be assessed was the association between gross tumor volumes (GTV; T = total, P = primary, N = nodal) and LRF. Receiver operative characteristic (ROC) curves were used to investigate diagnostic accuracy.

Results: Twenty LRFs were observed, resulting in a 2-year LRF rate of 39% (95% CI, 23-52%). On UVA, the GTV-T (P = .01), GTV-P (P = .05), and GTV-N (P = .04) were statistically significant predictors of LRF. Furthermore, age, smoking status, N-stage, larynx subsite, and tracheostomy/feeding tube dependence were potentially associated with LRF (P < .3), whereas T-stage (T3-4 vs. T2) was not (HR 1.05, 95% CI, 0.38-2.91, P = .92). In the multivariable model, GTV-P (HR 1.022, 95% CI, 0.999-1.046, P = .07) and GTV-N (HR 1.053, 95% CI, 1.0004-1.108, P = .05) were the two most impactful covariates on the model's R . ROC analysis suggested an optimal cut point of 12 cc in the GTV-T. The 2-year LRF for GTV-T > 12 cc was 64.2% and ≤ 12 cc was 16.4%, P = .006.

Conclusion: GTV is associated with LRF after definitive CCRT for LC. Patients with bulky primary and/or nodal tumors may be better served with upfront surgical resection regardless of T-stage. Further investigation into the safety of larynx preservation for low-volume T4 tumors can be considered.

Level Of Evidence: 4 Laryngoscope, 130:2372-2377, 2020.
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http://dx.doi.org/10.1002/lary.28396DOI Listing
October 2020

The prognostic impact of level I lymph node involvement in oropharyngeal squamous cell carcinoma.

Head Neck 2019 11 30;41(11):3895-3905. Epub 2019 Aug 30.

Head and Neck Institute, Cleveland Clinic, Cleveland, Ohio.

Background: We investigated the impact of level I lymph node involvement (LNI) on survival for patients with oropharyngeal squamous cell carcinoma (OPSCC).

Methods: We performed a cohort study of patients with OPSCC who underwent resection with known human papillomavirus (HPV) status in the National Cancer Database (2010-2014).

Results: Among 5591 patients with OPSCC, 599 (10.7%) had level I LNI. Predictors of level I LNI included pT classification (pT3 vs pT1; odds ratio [OR], 1.95; P < 0.001), pN classification (pN3 vs pN1; OR, 1.63; P = 0.05), and level III LNI (OR, 6.05; P < 0.001). Among included patients, 4035 had known survival status. Level I LNI predicted inferior overall survival (OS) while adjusting for covariates (HR, 1.64; P < 0.001). Subset analyses revealed association between level I LNI and inferior OS among patients with base of tongue cancer, pT/pN classification greater than 1, and HPV-negative cancer.

Conclusions: Level I LNI predicts inferior OS, particular among patients with at least pT2 or pN2 OPSCC.
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http://dx.doi.org/10.1002/hed.25927DOI Listing
November 2019

Role of Treatment Deintensification in the Management of p16+ Oropharyngeal Cancer: ASCO Provisional Clinical Opinion.

J Clin Oncol 2019 06 25;37(18):1578-1589. Epub 2019 Apr 25.

13 Fox Chase Cancer Center, Philadelphia, PA.

Purpose: An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership after publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the role of treatment deintensification in the management of p16+ oropharyngeal cancer (OPC).

Clinical Context: For patients with p16+ OPC, current treatment approaches are well established. In the good-prognosis subset of nonsmoking p16+ patients with early-stage disease, these treatments have been highly successful, albeit with significant associated acute and late toxicity. Deintensification of surgical, radiation, and medical treatment in an effort to reduce toxicity while preserving high survival rates is an appropriate therapeutic objective currently being explored in patients who are experiencing the best treatment results. However, careful delineation of this good-risk subset is essential. While the current eighth edition of the American Joint Committee on Cancer staging system is prognostically robust, it should not be interpreted as reason to alter therapeutic decisions or justify treatment deintensification. The development of transoral surgical techniques and the adoption of intensity-modulated radiation therapy planning have been transformative in disease management and suggest potentially beneficial approaches. Recent advances in systemic treatments have been notable. The optimal integration and modification of these modalities to ameliorate toxicity has not been defined and remains an important focus of current investigation.

Provisional Clinical Opinion: The hypothesis that de-escalation of treatment intensity for patients with p16+ OPC can reduce long-term toxicity without compromising survival is compelling and necessitates careful study and the analysis of well-designed clinical trials before changing current treatment standards. Treatment deintensification for these patients should only be undertaken in a clinical trial. Additional information is available at www.asco.org/head-neck-cancer-guidelines .
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http://dx.doi.org/10.1200/JCO.19.00441DOI Listing
June 2019

Clinical Factors Associated With Cost in Head and Neck Cancer: Implications for a Bundled Payment Model.

J Oncol Pract 2019 06 22;15(6):e560-e567. Epub 2019 Apr 22.

3 Levine Cancer Institute, Atrium Health, Charlotte, NC.

Purpose: To determine which factors influence cost in head and neck cancer (HNC) to inform the development of a bundled payment model (BPM).

Methods: Patients with stages 0 to IVB (by American Joint Commission on Cancer, 7th edition) HNC of various sites and histology treated definitively at a single tertiary care center during 2013 were included. Clinical variables and direct cost data were obtained, and their associations were investigated using χ, , Wilcoxon rank sum, and analysis of variance testing. Results were used to develop a BPM.

Results: One hundred fifty patients were included; 87% were white, 74% were men, 48% had oropharyngeal cancer, and 58% had stage IVA disease. Treatment consisted of surgery alone (17%), radiation alone (11%), surgery plus radiation (14%), chemoradiation (45%), and surgery plus chemoradiation (13%). On multivariable analysis, both increasing group stage and number of treatment modalities used were significantly associated with higher cost. Given that stage often dictates treatment, we developed three cost tiers that were based on overall treatment modality. Tier A, the least costly, consisted of single-modality therapy with either surgery alone or radiation alone (median cost divided by the median overall cost of treatment, 0.54; 25th to 75th percentile range, 0.29 to 1.02), followed by tier B, which consisted of bimodality therapy with either chemoradiation or surgery plus radiation (1.03; range, 0.81 to 1.35), followed by tier C, which consisted of trimodality therapy with surgery plus chemoradiation (1.43; range, 1.10 to 1.96).

Conclusion: The number of treatment modalities required is the primary driver of cost in HNC. These data can simplify development of a comprehensive HNC BPM.
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http://dx.doi.org/10.1200/JOP.18.00665DOI Listing
June 2019

Low-Dose vs. High-Dose Cisplatin: Lessons Learned From 59 Chemoradiotherapy Trials in Head and Neck Cancer.

Front Oncol 2019 21;9:86. Epub 2019 Feb 21.

Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

In locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN), concurrent chemoradiotherapy is an integral part of multimodality management both in the adjuvant and in the definitive settings. Although de-intensification strategies have been propelled to the forefront of clinical research in human papillomavirus (HPV) positive oropharyngeal cancer, three cycles of 100 mg/m cisplatin given every 3 weeks concurrently with conventionally fractionated external beam radiotherapy represent a cost-effective and globally accessible treatment option for the majority of LA-SCCHN cases. Based on four large randomized trials, this regimen has become the non-surgical standard of care for cisplatin-eligible patients. Nevertheless, the outcomes in terms of efficacy, toxicity, and compliance have been rather disappointing. Therefore, there is an unmet need to find a better alternative. With limited support from randomized trials, weekly low-dose cisplatin regimens have replaced the standard high-dose schedule at some institutions. Four prospective trials exploring radiotherapy with and without weekly low-dose cisplatin have been published. Two of them were conducted in the 1980s, one of which had a negative outcome, the third study provided insufficient information on toxicity, and the fourth trial had to be prematurely terminated due to poor accrual. Moreover, the findings of two phase III trials comparing the two concurrent cisplatin regimens favored the high-dose protocol. We performed a composite meta-analysis of 59 prospective trials enrolling a total of 5,582 patients. The primary endpoint was overall survival. Reflecting different radiotherapy fractionation schemes and treatment intents, three meta-analyses were carried out, one for postoperative conventional chemoradiotherapy, one for definitive conventional chemoradiotherapy, and one for definitive altered fractionation chemoradiotherapy. In the former two settings, both high- and low-dose regimens yielded similar survival outcomes, thus, the primary objective was not met. When given concurrently with altered fractionation radiotherapy, patients treated with high-dose cisplatin had significantly longer overall survival than those who received low-dose cisplatin. In this article we provide a synthetic view of the results, discuss the issue of cumulative dose, compare two vs. three cycles of high-dose cisplatin, and present our three-step recommendations for use of the current standard of care, high-dose cisplatin, in clinical practice.
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http://dx.doi.org/10.3389/fonc.2019.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394212PMC
February 2019

Case Report: Primary Orbital Squamous Cell Carcinoma.

Ocul Oncol Pathol 2019 Jan 29;5(1):60-65. Epub 2018 Jun 29.

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Squamous cell carcinoma (SCC) of the orbit is almost uniformly the result of local invasion from a cutaneous primary, extension by perineural invasion, or the result of metastasis. This is owed to the lack of native squamous epithelium in the orbit. After review of the literature, to date, only 6 reports of 8 patients with primary orbital SCC exist. Of those cases, only 2 reported non-apical orbital SCC. There are 2 reports of orbital SCC after retina surgery with proposed transplanted conjunctival epithelium and subsequent malignant transformation of a conjunctival cyst. The initial signs and symptoms can be vague and lead to delay in diagnosis. We present a case of primary orbital SCC and discuss the workup, imaging, and multidisciplinary management of this rare condition.
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http://dx.doi.org/10.1159/000490060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341336PMC
January 2019

Data Set for the Reporting of Carcinomas of the Nasopharynx and Oropharynx: Explanations and Recommendations of the Guidelines From the International Collaboration on Cancer Reporting.

Arch Pathol Lab Med 2019 04 30;143(4):447-451. Epub 2018 Nov 30.

From the Departments of Otolaryngology, and Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Department of Otorhinolaryngology, Cleveland Clinic, Cleveland, Ohio (Dr Adelstein); the Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital, Erlangen, Germany (Dr Agaimy); the Department of Pathology, Cleveland Clinic Florida, Weston (Dr Carlson); the Department of Pathology, Massachusetts General Hospital, Boston (Dr Faquin); the Department of Cellular Pathology, University of Liverpool, Liverpool, United Kingdom (Dr Helliwell); the Department of Oral & Maxillofacial Pathology, University of the Western Cape & Tygerberg Laboratories, Cape Town, South Africa (Dr Hille); the Department of Pathology, Vancouver General Hospital, and the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada (Dr Ng); the Department of Pathology, Queen Mary Hospital, Hong Kong (Dr Nicholls); the Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada (Dr O'Sullivan); and the Department of Pathology, Woodland Hills Medical Center, Woodland Hills, California (Dr Thompson).

The International Collaboration on Cancer Reporting was established to internationally unify and standardize the pathologic reporting of cancers based on collected evidence, as well as to allow systematic data collection across institutions and countries to guide cancer care in the future. An expert panel was convened to identify the minimum data set of elements that should be included in cancer reporting from tumors of the nasopharynx and oropharynx. Specifically, there has been a significant change in practice as a result of identifying oncogenic viruses, including human papillomavirus and Epstein-Barr virus, because they preferentially affect the oropharynx and nasopharynx, respectively. For these anatomic sites, when viral association is taken into account, usually reported elements of in situ versus invasive tumor, depth of invasion, and degree of differentiation are no longer applicable. Thus, guidance about human papillomavirus testing in oropharyngeal carcinomas and Epstein-Barr virus testing in nasopharyngeal carcinomas is highlighted. Further, the clinical and the pathologic differences in staging as proposed by the 8th edition of the Union for International Cancer Control are incorporated into the discussion, pointing out several areas of continued study and further elaboration. A summary of the International Collaboration on Cancer Reporting guidelines for oropharyngeal and nasopharyngeal carcinomas is presented, along with discussion of the salient evidence and practical issues.
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http://dx.doi.org/10.5858/arpa.2018-0405-SADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404548PMC
April 2019

Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.

Lancet 2019 01 15;393(10166):40-50. Epub 2018 Nov 15.

Department of Radiation Oncology, Stanford University, Stanford, CA, USA.

Background: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.

Methods: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m weekly for seven doses (total 2150 mg/m), or cisplatin 100 mg/m on days 1 and 22 of radiotherapy (total 200 mg/m). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834.

Findings: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups.

Interpretation: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.

Funding: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.
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http://dx.doi.org/10.1016/S0140-6736(18)32779-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541928PMC
January 2019

Suboptimal Outcomes in Cutaneous Squamous Cell Cancer of the Head and Neck with Nodal Metastases.

Anticancer Res 2018 Oct;38(10):5825-5830

Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, U.S.A.

Background/aim: There are limited data regarding survival, failure patterns, and factors associated with disease recurrence in patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) with nodal metastases.

Patients And Methods: A retrospective analysis of patients with cSCC-HN metastatic to cervical and/or parotid lymph nodes treated with surgery and post-operative radiation therapy was performed.

Results: This study included 76 patients (57 immunocompetent and 18 immunosuppressed) with a median follow-up of 18 months. Overall survival, disease-free survival (DFS), and disease recurrence (DR) at 2 years was 60%, 49%, and 40%, respectively. Immunosuppressed patients had significantly lower 2-year DFS (28% vs. 55%; p=0.003) and higher DR (61% vs. 34%; p=0.04) compared to immunocompetent patients. Analysis of immunocompetent patients demonstrated extracapsular extension (ECE) as the only factor associated with DR (p<0.0001).

Conclusion: Patients with nodal metastases from cSCC-HN have suboptimal outcomes. ECE and immunosuppression were significantly associated with DR.
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http://dx.doi.org/10.21873/anticanres.12923DOI Listing
October 2018

Definitive Chemoradiation in Locally Advanced Squamous Cell Carcinoma of the Hypopharynx: Long-term Outcomes and Toxicity.

Anticancer Res 2018 Jun;38(6):3543-3549

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, U.S.A.

Background/aim: Definitive chemoradiation (CRT) is a common approach for locally advanced hypopharyngeal squamous cell carcinoma (SCC) with the goal of organ preservation. Reports on long-term oncologic and functional outcomes have been limited. This study reports on outcomes utilizing this approach at a single institution over 30 years.

Materials And Methods: Medical records for patients with stage III-IVB SCC of the hypopharynx were retrospectively reviewed. Patient and disease-related factors were identified and analyzed for impact on overall survival (OS), cancer-specific survival (CSS), disease-free survival, distant failure, and locoregional failure.

Results: A total of 54 patients were identified who were treated with definitive CRT to a mean dose of 72 Gy. With a median follow-up period of 49.8 months, 5- and 10-year OS was 62% and 43% respectively. Five and 10-year CSS were 74% and 72% respectively. Ten-year local control was 78%. Of the 37 patients with no treatment failure, 29% experienced a grade 3 or higher late toxicity, with the majority resolving during continued long-term follow-up.

Conclusion: This study demonstrates good outcomes with long-term follow-up with acceptable rates of late toxicities. The findings here represent the longest published median follow-up in this population and validate the strategy of organ preservation.
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http://dx.doi.org/10.21873/anticanres.12626DOI Listing
June 2018

NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018.

J Natl Compr Canc Netw 2018 05;16(5):479-490

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.
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http://dx.doi.org/10.6004/jnccn.2018.0026DOI Listing
May 2018

Reply to A. Piccardo et al, E. Hindié et al, M.C. Kreissl et al, M. Doss, J. Buscombe, R. Fisher, M. Sollini et al, M. Lichtenstein, and M. Tulchinsky et al.

J Clin Oncol 2018 06 3;36(18):1889-1892. Epub 2018 May 3.

Remco J. Molenaar, Cleveland Clinic, Cleveland, Ohio, and University of Amsterdam, Amsterdam, the Netherlands; Surbhi Sidana, Cleveland Clinic, Cleveland, Ohio, and Mayo Clinic, Rochester, MN; and Tomas Radivoyevitch, Aaron T. Gerds, Hetty E. Carraway, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneed S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, Ohio.

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http://dx.doi.org/10.1200/JCO.2018.78.4074DOI Listing
June 2018

Increased pathologic upstaging with rising time to treatment initiation for head and neck cancer: A mechanism for increased mortality.

Cancer 2018 04 9;124(7):1400-1414. Epub 2018 Jan 9.

Section of Head and Neck Surgery and Oncology, Head and Neck Institute, Cleveland Clinic, Cleveland, Ohio.

Background: Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical-to-pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC).

Methods: Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively.

Results: Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P = .038) or ≥ 70 days (odds ratio, 2.04; P < .001) were found to predict T upstaging, a finding that is consistent for N and stage group upstaging. Using restricted cubic splines, relative odds of T and stage group upstaging escalated to 2.25 and 1.93, respectively, at a TTI of 365 days. In survival analyses, T (hazard ratio [HR], 1.53), N (HR, 1.88), and stage group (HR, 1.69) upstaging all predicted mortality (P < .001), whereas TTI only predicted mortality after 70 days (HR, 1.11; P = .023).

Conclusions: Tumor progression, measured by clinical-to-pathologic upstaging, increases mortality for patients with HNSCC experiencing treatment delays. Cancer 2018;124:1400-14. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31213DOI Listing
April 2018

Altered fractionation radiotherapy combined with concurrent low-dose or high-dose cisplatin in head and neck cancer: A systematic review of literature and meta-analysis.

Oral Oncol 2018 01 8;76:52-60. Epub 2017 Dec 8.

Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium.

Objectives: Altered fractionation radiotherapy and concomitant chemoradiotherapy represent commonly used intensification strategies in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). This meta-analysis compares compliance, safety, and efficacy between two single-agent cisplatin schedules given concurrently with altered fractionation radiotherapy.

Methods: We systematically searched for prospective trials of patients with LA-SCCHN who received post-operative or definitive altered fractionation concurrent chemoradiotherapy. High-dose cisplatin once every three to four weeks (100 mg/m, 2 doses) was compared with a weekly low-dose protocol (≤50 mg/m, ≥4 doses). The primary outcome was overall survival. The secondary endpoints comprised treatment adherence, acute and late toxicities, and objective response rate.

Results: Twelve studies with 1373 patients treated with definitive chemoradiotherapy were included. Compared to the weekly low-dose cisplatin regimen, the three- to four-weekly high-dose cisplatin regimen improved overall survival (p=.0185), was more compliant with respect to receiving all planned cycles of cisplatin (71% versus 95%, p=.0353), and demonstrated less complications in terms of severe (grade 3-4) acute mucositis and/or stomatitis (75% versus 40%, p=.0202) and constipation (8% versus 1%, p=.0066), toxic deaths (4%, versus 1%, p=.0168), 30-day mortality (8% versus 3%, p=.0154), and severe late subcutaneous fibrosis (21% versus 2%, p<.0001). Overall and complete response rates were similar between both chemotherapy schedules.

Conclusion: In chemoradiotherapy incorporating altered fractionation, two cycles of high-dose cisplatin with a three to four week interval are superior to weekly low-dose schedules. Further studies should identify those who might derive the greatest benefit from this intensified approach.
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http://dx.doi.org/10.1016/j.oraloncology.2017.11.025DOI Listing
January 2018

Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer.

J Clin Oncol 2018 06 18;36(18):1831-1839. Epub 2017 Dec 18.

Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.

Purpose To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with radioactive iodine (RAI). Methods Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed. Results Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P < .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06). Conclusion Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance.
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http://dx.doi.org/10.1200/JCO.2017.75.0232DOI Listing
June 2018

Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update.

J Clin Oncol 2018 04 27;36(11):1143-1169. Epub 2017 Nov 27.

Arlene A. Forastiere, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Jan S. Lewin and Randy Weber, The University of Texas MD Anderson Cancer Center, Houston, TX; Cherie Ann Nathan, LSU Health, Shreveport, LA; David J. Adelstein, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Avraham Eisbruch and Gregory T. Wolf, University of Michigan, Ann Arbor, MI; Gail Fass, Support for People With Oral Head and Neck Cancer, Locust Valley; Bernard O'Malley, Snehal Patel, and David G. Pfister, Memorial Sloan Kettering Cancer Center; Anthony F. Provenzano, New York-Presbyterian Lawrence Hospital, New York, NY; Susan G. Fisher, Temple University; Gregory S. Weinstein, University of Pennsylvania School of Medicine, Philadelphia, PA; Scott A. Laurie, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; Quynh-Thu Le, Stanford University, Stanford, CA; and William M. Mendenhall, University of Florida, Gainesville, FL.

Purpose To update the guideline recommendations on the use of larynx-preservation strategies in the treatment of laryngeal cancer. Methods An Expert Panel updated the systematic review of the literature for the period from January 2005 to May 2017. Results The panel confirmed that the use of a larynx-preservation approach for appropriately selected patients does not compromise survival. No larynx-preservation approach offered a survival advantage compared with total laryngectomy and adjuvant therapy as indicated. Changes were supported for the use of endoscopic surgical resection in patients with limited disease (T1, T2) and for initial total laryngectomy in patients with T4a disease or with severe pretreatment laryngeal dysfunction. New recommendations for positron emission tomography imaging for the evaluation of regional nodes after treatment and best measures for evaluating voice and swallowing function were added. Recommendations Patients with T1, T2 laryngeal cancer should be treated initially with intent to preserve the larynx by using endoscopic resection or radiation therapy, with either leading to similar outcomes. For patients with locally advanced (T3, T4) disease, organ-preservation surgery, combined chemotherapy and radiation, or radiation alone offer the potential for larynx preservation without compromising overall survival. For selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy. Patients with clinically involved regional cervical nodes (N+) who have a complete clinical and radiologic imaging response after chemoradiation do not require elective neck dissection. All patients should undergo a pretreatment baseline assessment of voice and swallowing function and receive counseling with regard to the potential impact of treatment options on voice, swallowing, and quality of life. Additional information is available at www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .
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http://dx.doi.org/10.1200/JCO.2017.75.7385DOI Listing
April 2018

Cost-effectiveness of nivolumab for recurrent or metastatic head and neck cancer☆.

Oral Oncol 2017 11 23;74:49-55. Epub 2017 Sep 23.

Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. Electronic address:

Objective: Nivolumab is the first drug to demonstrate a survival benefit for platinum-refractory recurrent or metastatic head and neck cancer. We performed a cost-utility analysis to assess the economic value of nivolumab as compared to alternative standard agents in this context.

Materials And Methods: Using data from the CheckMate 141 trial, we constructed a Markov simulation model from the US payer's perspective to evaluate the cost-effectiveness of nivolumab compared to physician choice of either cetuximab, methotrexate or docetaxel. Alternative strategies considered included: single-agent cetuximab, methotrexate or docetaxel, or first testing for PD-L1 to select for nivolumab. Costs were extracted from Medicare and utilities from the literature and CheckMate. Probabilistic sensitivity analysis (PSA) was used to evaluate parameter uncertainty. $100,000/QALY was the primary threshold for cost-effectiveness.

Results: When comparing nivolumab to the standard arm of CheckMate, nivolumab demonstrated an incremental cost-effectiveness ratio (ICER) of $140,672/QALY. When comparing standard therapies, methotrexate was the most cost-effective with similar results for docetaxel. Nivolumab was cost-effective compared to single-agent cetuximab (ICER $89,786/QALY). Treatment selection by PD-L1 immunohistochemistry did not markedly improve the cost-effectiveness of nivolumab. Factors likely to positively impact the cost-effectiveness of nivolumab include better baseline quality-of-life, poor tolerability of standard treatments and/or a lower cost of nivolumab.

Conclusions: Nivolumab is preferred to single-agent cetuximab but requires a willingness-to-pay of at least $150,000/QALY to be considered cost-effective when compared to docetaxel or methotrexate. Selection by PD-L1 does not markedly improve the cost-effectiveness of nivolumab. This informs patient selection and clinical care-path development.
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http://dx.doi.org/10.1016/j.oraloncology.2017.09.017DOI Listing
November 2017