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Mandibular dose constraints are designed to limit high dose to small volumes to avoid osteoradionecrosis (ORN). Based upon a published experience, intermediate-dose constraints were introduced but have not been independently validated. We hypothesize that these constraints lower ORN rate without compromising other organs at risk (OAR).Oropharyngeal cancer patients treated with standard fractionation adjuvant/definitive VMAT from 01/2014-08/2020 were included. In 09/2017, mandibular dose constraint was changed from historical constraint (HC) of D 0.1 cc 70 Gy to modified constraints (MC) of V 44 Gy 42%, V 58 Gy 25%, D 0.5 cc 70 Gy. OAR dosimetric changes and ORN development were evaluated. Regression modelling predicted long-term ORN cases in MC group.There were 174 patients, 71 in MC group. Seven cases of ORN in HC group at a median follow up (FU) of 39 months and 1 case of ORN in MC group at a median FU of 11 months were observed. More patients in the MC group met V 44 Gy (87% vs 62%, p 0.01) and V 58 Gy constraints (92% vs 73%, p 0.01). Mean doses to OARs did not rise. Mandible V 44 Gy and V 58 Gy were significantly associated with ORN (p 0.01 and p = 0.03, respectively) across all patients. In the HC group, V 44 Gy was independently associated with ORN (p = 0.01). To account for shorter FU in MC group, logistic regression of ORN based on V 44 Gy in HC patients was performed. This predicts 3.2 ORN cases in the MC group (95% CI: 0.00-6.4).Achieving V 44 Gy and V 58 Gy was successful in 87% of cases without sacrificing target coverage or OARs and resulted in non-significant ORN decrease.

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus–negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as considering signal-seeking trial designs. A fourth breakout group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other breakout groups prior to the meeting to aid in study development. A total of 4 concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the Clinical Trials Planning Meeting with the goal of developing clinical trials for patients with TP53-mutant HNSCC that can be conducted within the National Clinical Trials Network.

Retreatment of recurrent or second primary head and neck cancers occurring in a previously irradiated field is complex. Few guidelines exist to support practice. We performed an updated literature search of peer-reviewed journals in a systematic fashion. Search terms, key questions, and associated clinical case variants were formed by panel consensus. The literature search informed the committee during a blinded vote on the appropriateness of treatment options via the modified Delphi method. The final number of citations retained for review was 274. These informed 5 key questions, which focused on patient selection, adjuvant reirradiation, definitive reirradiation, stereotactic body radiation, and reirradiation to treat nonsquamous cancer. Results of the consensus voting are presented along with discussion of the most current evidence. This provides updated evidence-based recommendations and guidelines for the retreatment of recurrent or second primary cancer of the head and neck.

Cytokines and Chemokines

Oral mucositis (OM) causes significant detriment to patient quality of life. Despite advances in RT, chemotherapy, and surgery for HNC which have led to improved local control and survival, management of certain toxicities such as OM have not kept pace. Numerous strategies have emerged with demonstrable benefit in preventing severe OM. However, ones which are not only effective, but practical and affordable to implement are rare. For example, infusion of growth factors or free radical scavengers, and daily treatment of intra-oral sites with lasers are supported by high-quality evidence but have not become widely adopted. It falls to familiarity of the physician with the available preventative measures and ultimately, patient preference in accepting which strategies for OM amelioration are used. In this review, we present a pathophysiological-based review of prevention techniques available for reducing the incidence and duration of severe OM.

Purpose: CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin–radiotherapy in the treatment of HNSCC.Experimental Design: CUDC-101 monotherapy was administered intravenously three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m2 every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks.Results: Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-negative. The MTD of CUDC-101–based combination therapy was established at 275 mg/m2/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression.Conclusions: CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration. Clin Cancer Res; 21(7); 1566–73. ©2015 AACR.

Supplemental Figure 2. FISH analysis of EGFR and HER2 gene amplification in the archival tumor biopsies from 2 patients who received 275 mg/m2 of CUDC-101.

Purpose:Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti–PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC.Patients and Methods:This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling.Results:Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%–84%) and 75% (51%–88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells.Conclusions:Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.

T cell gating

Supplemental Figures Legend

Supplemental Figure 3. Ac-H3 induction in PBMCs from patients with evaluable clinical response.

PFS and OS by AJCC 8

Supplemental Figure 1. Pharmacodynamic effects of CUDC-101 in tumor, skin and PBMCs.

B cell gating

BACKGROUND: Palliative care improves symptoms and coping in patients with advanced cancers, but has not been evaluated for patients with curable solid malignancies. Because of the tremendous symptom burden and high rates of psychological distress in head and neck cancer (HNC), we evaluated feasibility and acceptability of a palliative care intervention in patients with HNC receiving curative-intent chemoradiation therapy (CRT). METHODS: This was a prospective single-arm study in HNC patients receiving CRT at a single center in the United States. The intervention entailed weekly palliative care visits integrated with oncology care with a focus on symptoms and coping. The primary outcome was feasibility, defined as a >50% enrollment rate with >70% of patients attending at least half of the visits. To assess acceptability, we collected satisfaction ratings post-intervention. We also explored symptom burden, mood, and quality of life (QOL). RESULTS: We enrolled 91% (20/22) of eligible patients. Patients attended 133 of 138 palliative care visits (96%); all 20 attended >85% of visits. Eighteen of 19 (95%) found the intervention “very helpful” and would “definitely recommend” it. QOL and symptom burden worsened from baseline to week 5, but subsequently improved at one-month post-CRT. Overall, patients valued the one-on-one format of the intervention and receipt of additional care. CONCLUSIONS: Our palliative care intervention during highly morbid CRT was feasible and acceptable with high enrollment, excellent intervention compliance, and high patient satisfaction. Future randomized studies will further explore the impact on patient-reported outcomes and health care utilization.

Human papillomavirus-associated oropharyngeal cancer (HPV-OPC) is a distinct clinical entity with a favorable prognosis compared with non-HPV-OPC. Surgery and radiotherapy (RT) result in adverse effects, and negative quality of life or functional outcomes, which impact a significant proportion of HPV-OPC survivors. Ongoing studies aim to reduce these negative treatment effects while maintaining high cure rates through deintensified therapy typically use either a primary surgical or RT approach. A single-day curative surgery will remain relevant for many patients with early-stage disease. However, the average patient with HPV-OPC will have indications for adjuvant therapy. A primary RT approach to deintensified therapy has more available data from patients on prospective multi-institutional trials, provides broader patient selection, and may be more cost-effective. Anticipated results from an active phase II/III NCTN trial will help guide the standard of care using primary RT. Next generation trials will help further refine patient selection and/or radical deintensification (30-50 Gy).

BACKGROUND Management of hypopharynx cancer is often extrapolated from larynx cancer. This report analyses treatment patterns and survival limited to hypopharynx cancer using the National Cancer Database (NCDB). METHODS There are 9314 patients diagnosed with hypopharynx cancer between 2004 and 2016. The association between treatment modality and survival was analyzed using Kaplan-Meier survival curves and multivariable Cox regression. RESULTS Five-year overall survival ranged from 45% for stage I to 21% for stage IVB. Treatment modality did not influence survival in stage I/II. For stage III/IV, chemoradiation and surgery + adjuvant therapy were equivalent. Surgery yielded improved survival for T4 disease. Human papillomavirus (HPV)-positive tumors were present in 21% and were associated with improved hazard ratio of death (0.60, p =

Author(s): Margalit, Danielle N; Sacco, Assuntina G; Cooper, Jay S; Ridge, John A; Bakst, Richard L; Beadle, Beth M; Beitler, Jonathan J; Chang, Steven S; Chen, Allen M; Galloway, Tom J; Koyfman, Shlomo A; Mita, Carol; Robbins, Jared R; Tsai, C Jillian; Truong, Minh T; Yom, Sue S; Siddiqui, Farzan | Abstract: BackgroundThe aims of this systematic review are to (a) evaluate the current literature on the impact of postoperative therapy for resected squamous cell carcinoma of the head and neck (SCCHN) on oncologic and non-oncologic outcomes and (b) identify the optimal evidence-based postoperative therapy recommendations for commonly encountered clinical scenarios.MethodsAn analysis of the medical literature from peer-reviewed journals was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Prospective studies and methodology-based systematic reviews and meta-analyses of postoperative therapy for SCCHN were identified by searching Medline (OVID) and EMBASE (Elsevier) using controlled vocabulary terms (ie, National Library of Medicine Medical Subject Headings [MeSH], EMTREE). Study screening and selection was performed with Covidence software and full-text review. The RAND/UCLA appropriateness method was used by the expert panel to rate the appropriate use of postoperative therapy, and the modified Delphi method was used to come to consensus.ResultsA total of 5660 studies were identified and screened using the title and abstract, leading to 201 studies assessed for relevance using full-text review. After limitation to the eligibility criteria, 101 studies from 1977 to 2020 were identified, including 77 with oncologic endpoints and 24 with function and quality of life endpoints. All studies reported staging prior to the implementation of American Joint Committee on Cancer (AJCC-8).ConclusionsProspective clinical studies and systematic reviews identified through the PRISMA systematic review provided good evidence for consensus statements regarding the appropriate use of postoperative therapy for resected SCCHN. Further research is needed in domains where consensus by the expert panel could not be achieved for the appropriateness of specific postoperative therapeutic interventions.

Background Rapid recurrence, defined as gross tumor recurrence after primary operation but prior to initiating postoperative radiation therapy (PORT), is underappreciated in head and neck cancer (HNC). Methods CT simulation images in patients with HNC managed surgically with adjuvant therapy at a single center between 2010 and 2017 were retrospectively reviewed. Results A total of 194 patients with HNC were included. Rapid recurrence occurred in 39 patients (20%) with a median time from operation to CT simulation of 37 days. On multivariable analysis (MVA), extranodal extension (ENE) was the only predictor of rapid recurrence (P = .03). While rapid recurrence, ENE, and perineural invasion were all associated with poor overall survival (OS) on MVA, rapid recurrence was the strongest predictor (hazard ratio [HR] 5.47). Conclusion Rapid recurrence occurs at an underappreciated rate and is associated with poor survival outcomes. Patients with ENE are at highest risk and may benefit from diagnostic imaging evaluations immediately prior to PORT.

Purpose: Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti–PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC. Patients and Methods: This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling. Results: Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%–84%) and 75% (51%–88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells. Conclusions: Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.

Background The objective of this study was to compare the cosmesis and recurrence rates of conventional excision (CE), Mohs micrographic surgery (MMS), external-beam radiation therapy (EBRT), or brachytherapy (BT), for basal cell carcinoma and squamous cell carcinoma of the skin. Methods Population, Intervention, Control, Outcome, Study Design (PICOS), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) methods were used to identify studies on PubMed (from 1985 to 2018), including patients with American Joint Committee on Cancer (AJCC) T1-T2N0 basal cell carcinomas and squamous cell carcinomas and ≥10 months follow-up who received CE, MMS, EBRT, or BT. The primary endpoint was cosmesis, classified as "good," "fair," or "poor." The secondary endpoint was 1-year recurrence. Fixed-effects and random-effects meta-analyses were performed to evaluate primary and secondary outcomes with respect to treatment modality. Results In total, 18,095 studies met initial search criteria. There were 24 CE, 13 MMS, 19 EBRT, and 7 BT studies included with a total of 21,371 patients. The summary effect size for "good" cosmesis was 81% (95% CI, 70.6%-89.6%), 74.6% (95% CI, 63%-84.6%), and 97.6% (95% CI, 91.3%-100%) for CE, EBRT, and BT, respectively. Good cosmesis was 96.0% in the only MMS study that reported cosmesis. BT had improved "good" cosmesis over EBRT (P = .0025) and was similar to CE and MMS. No significant differences were seen for "fair" or "poor" cosmesis. One-year recurrence rates were low throughout at 0.8% (95% CI, 0.3%-1.6%), 0.2% (95% CI, 0%-0.6%), 2% (95% CI, 1.3%-2.7%), and 0% (95% CI, 0%-0.5%) for CE, MMS, EBRT, and BT, respectively. Conclusions For T1-T2N0 skin cancers, BT and MMS have improved cosmesis over EBRT and CE. It is unclear whether this is because of treatment superiority or selection and reporting bias. Local control is similar among all modalities at 1 year.

Evaluation of distant metastasis (DM) is part of every new cancer evaluation. Understanding DM presentation patterns may impact the imaging workup of Head and Neck Squamous Cell Carcinoma (HNSCC).Examine the frequency and location of DM at presentation in HNSCC. We hypothesize that DM are rare, and the lung is the most common site for DM. Secondary evaluation includes identifying patient and tumor factors predictive of DM, and the implications for selection of workup imaging.Data from the National Cancer Data Base (NCDB) from 2010 to 2015 were analyzed. Subsites evaluated included oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx. Sites of distant metastasis were evaluated in available cases and analyzed.Population based database study.151,730 cases were available for analysis. Nasopharynx had the highest percentage of M1 disease (9.1%) followed by hypopharynx (7.3%). Excluding the nasopharynx (NP), 3.1% of cases were reported as M1. Advanced T-stage, positive N-stage, and N3 status were all predictors of M1 status on univariate and multivariate analysis for all subsites (P 0.05). Where site of metastasis was available, most (53.1%) DM cases presented with at least lung involvement. In nasopharynx cancers, only 32.8% of DM included the lung.Distant metastasis in HNSCC are rare events. PET/CT offers many advantages, but for routine distant metastasis evaluation in HNSCC, CT scan of the chest may be more cost-effective.

Positive margins are known to impact survival in oral cavity squamous cell carcinoma (OCSCC). We aimed to determine the impact of positive margins on survival and whether radiation improves survival following positive margins.Data was obtained from the National Cancer Database and included patients with cT1T2N0 OCSCC. Survival outcomes were assessed via log-rank test. Cox-regression analysis was performed to determine if positive margins or radiation, when applicable, correlated with survival after accounting for covariates.Positive margin patients had worse overall survival compared to negative margin control (HR = 1.76, p 0.001) and reduced survival by 13%. On multivariate analysis, positive margins correlated with survival (HR = 1.60, p 0.001). Radiation did not improve survival in positive margin patients (HR = 0.99, p = 0.55).Patients with positive margins have an 11-15% worse overall survival. Radiation does not appear to impact survival in patients with a positive margin.

BACKGROUND Identifying and treating late dysfunction in survivors of head and neck cancer (HNC) is important; however, an effective way to do so is not established. METHODS A quality improvement initiative altering our HNC survivorship clinic to include surveillance by rehabilitation providers was undertaken. The nature of dysfunction identified, along with the number and type of referrals to ancillary/support services were collected and compared to baseline. RESULTS The baseline, single-provider, clinic evaluated 61 patients and referred 2 (3%) to ancillary/support services. Fifty-seven patients were evaluated in the interdisciplinary clinic, with 36 (63%) referred to at least one ancillary/support service for new/progressive dysfunction. Of 59 referrals made, 22 (37%) were for dysphagia, 17(29%) were for neck/shoulder dysfunction, and 28 (47%) were attended by the patient. CONCLUSION Many HNC survivors exhibit late dysfunction appropriate for referral to ancillary/support services. A survivorship clinic including surveillance by rehabilitation specialists may optimize identification of dysfunction.

Background We conducted the current systemic review to provide up-to-date literature summary and optimal evidence-based recommendations for ipsilateral radiation for squamous cell carcinoma of the tonsil. Methods We performed literature search of peer-reviewed journals through PubMed. The search strategy and subject-specific keywords were developed based on the expert panel's consensus. Articles published from January 2000 to May 2020 with full text available on PubMed and restricted to the English language and human subjects were included. Several prespecified search terms were used to identify relevant publications and additional evidence published since the initial American College of Radiology Appropriateness Criteria Ipsilateral Tonsil Radiation recommendation was finalized in 2012. The full bibliographies of identified articles were reviewed and irrelevant studies were removed. Results The initial search and review returned 46 citations. The authors added three citations from bibliographies, websites, or books not found in the literature search. Of the 49 citations, 30 citations were retained for further detailed review, and 14 of them were added to the evidence table. Articles were removed from the bibliography if they were not relevant or generalizable to the topic, or focused on unknown primary disease. Several commonly encountered clinical case variants were created and panelists anonymously rated each treatment recommendation. The results were reviewed and disagreements discussed. Conclusions The panel provided updated evidence and recommendations for ipsilateral radiation for squamous cell carcinoma of the tonsil in the setting of primary radiation-based therapy and postoperative adjuvant radiotherapy. This committee did not reach agreements for some case variants due to a lack of strong evidence supporting specific treatment decisions, indicating a further need for research in these topics.

Purpose: The rapid spread of the SARS-CoV-2 pandemic around the world caused most healthcare services to turn substantial attention to treatment of these patients and also to alter the structure of healthcare systems to address an infectious disease. As a result, many cancer patients had their treatment deferred during the pandemic, increasing the time to treatment initiation, the number of untreated patients (which will alter the dynamics of healthcare delivery in the post-pandemic era) and increasing their risk of death. Hence, we analyzed the impact on global cancer mortality considering the decline in oncology care during the COVID-19 outbreak using head and neck cancer, a known time-dependent disease, as a model. Methods: An online practical tool capable of predicting the risk of cancer patients dying due to the COVID-19 outbreak and also useful for mitigation strategies after the peak of the pandemic has been developed, based on a mathematical model. The scenarios were estimated by information of 15 oncological services worldwide, given a perspective from the five continents and also some simulations were conducted at world demographic data. Results: The model demonstrates that the more that cancer care was maintained during the outbreak and also the more it is increased during the mitigation period, the shorter will be the recovery, lessening the additional risk of dying due to time to treatment initiation. Conclusions: This impact of COVID-19 pandemic on cancer patients is inevitable, but it is possible to minimize it with an effort measured by the proposed model.

Multidisciplinary care (MDC) yields proven benefits for patients with cancer, although it may be underused in the complex management of head and neck squamous cell carcinoma (HNSCC).To characterize the patterns of MDC in the treatment of HNSCC among elderly patients in the US.This nationwide, population-based, retrospective cohort study used Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from January 1, 1991, to December 31, 2011, to identify patients 66 years or older diagnosed with head and neck cancer and determine the dates of diagnosis, oncology consultations, treatment initiation, and speech therapy evaluation in addition to MDC completion. Multidisciplinary care was defined in a stage-dependent manner: localized disease necessitated consultations with radiation and surgical oncologists, and advanced-stage disease also included a medical oncology consultation, all before definitive treatment. Data were analyzed between December 2016 and September 2020.Rates of MDC across all subsites of head and neck cancer as measured by the presence of an evaluation for each oncologist on the MDC team and its effect on treatment initiation.This cohort study assessed 28 293 patients with HNSCC (mean [SD] age, 75.1 [6.6] years; 67% male; 87% White) from the SEER-Medicare linked database. The HNSCC subsites included larynx (40%), oral cavity (30%), oropharynx (21%), hypopharynx (7%), and nasopharynx (2%). Overall, the practice of MDC significantly increased over time, from 24% in 1991 to 52% in 2011 (P .001). For patients with localized (stage 0-II) tumors, 60% received care in the multidisciplinary setting, whereas 28% of those with advanced-stage disease did. A total of 18 181 patients (64%) were treated with initial definitive nonsurgical therapy across all stages. Regardless of stage and subsite, few patients (2%) underwent evaluation by a speech-language pathologist before definitive therapy. Multidisciplinary care prolonged the time to initiation of definitive treatment by 11 days for localized disease and 10 days for advanced disease.This cohort study found that most elderly patients with localized HNSCC received MDC, whereas few patients with advanced-stage disease received such care, although a significant proportion received adjuvant therapy. Multidisciplinary care may prolong time to initiation of definitive treatment with an uncertain impact. Consultation with a speech-language pathologist before definitive therapy was rare.

Purpose The rapid spread of the SARS-CoV-2 pandemic around the world caused most healthcare services to turn substantial attention to treatment of these patients and also to alter the structure of healthcare systems to address an infectious disease. As a result, many cancer patients had their treatment deferred during the pandemic, increasing the time-to-treatment initiation, the number of untreated patients (which will alter the dynamics of healthcare delivery in the post-pandemic era) and increasing their risk of death. Hence, we analyzed the impact on global cancer mortality considering the decline in oncology care during the COVID-19 outbreak using head and neck cancer, a known time-dependent disease, as a model. Methods An online practical tool capable of predicting the risk of cancer patients dying due to the COVID-19 outbreak and also useful for mitigation strategies after the peak of the pandemic has been developed, based on a mathematical model. The scenarios were estimated by information of 15 oncological services worldwide, given a perspective from the five continents and also some simulations were conducted at world demographic data. Results The model demonstrates that the more that cancer care was maintained during the outbreak and also the more it is increased during the mitigation period, the shorter will be the recovery, lessening the additional risk of dying due to time-to-treatment initiation. Conclusions This impact of COVID-19 pandemic on cancer patients is inevitable, but it is possible to minimize it with an effort measured by the proposed model. Supplementary Information The online version contains supplementary material available at 10.1007/s10552-021-01411-7.

Patients undergoing radiation treatment for head and neck cancer experience significant side-effects that can impact a wide range of daily activities. Patients often report receiving insufficient information during and after treatment, which could impede rehabilitation efforts; they may also encounter practical and logistical barriers to receipt of supportive care. Thus, we developed a web-based program, My Journey Ahead, to provide information and strategies for managing symptom-focused concerns, which may be easily accessed from the patient’s home. The purpose of this study was to evaluate patient acceptability and satisfaction with the My Journey Ahead program. In Phase 1, five patients with head and neck squamous cell carcinoma (HNSCC) reviewed the web-based program and provided initial feedback, which informed program modifications. In Phase 2, 55 patients were recruited to evaluate the program. Patient assessments were obtained prior to and after use of the web-based program, and included measures of psychological distress, self-efficacy in coping with cancer-related issues, and satisfaction with the website. Among the 55 patients enrolled, 44 logged in and viewed the web-based program. Participants reported high levels of satisfaction with the information received, and indicated that the website was interesting and easy to use. Older age and higher levels of self-efficacy in coping were each associated with higher levels of satisfaction with the website. In summary, the web-based program was well-received by patients, the majority of whom found it to be informative and useful. An easy-to-use web-based program, particularly for older patients who may have difficulty locating reliable evidence-based information on the internet, may be helpful in addressing survivors’ needs in symptom management and coping with cancer.Clinical Trial Registrationhttps://clinicaltrials.gov/, NCT02442336

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.

OBJECTIVE Prognostic factors and optimal treatment approaches for Merkel cell carcinoma (MCC) remain uncertain. This study evaluated the influences of sentinel lymph node (SLN) biopsy and lymphovascular invasion (LVI) on treatment planning and prognosis. STUDY DESIGN Retrospective cohort study. METHODS Stage 1 to 3 MCC patients treated 2005 to 2018. Predictors of nodal radiation were tested using logistic regression. Predictors of recurrence-free, disease-specific, and overall survival were tested in Cox proportional hazard models. RESULTS Of 122 patients, 99 were without clinically apparent nodal metastases. Of these, 76 (77%) underwent excision and SLN biopsy; 29% had metastasis in SLNs, including 20% of MCCs 1 cm or less. Primary tumor diameter, site, patient age, gender, and immunosuppressed status were not significantly associated with an involved SLN. Among patients who underwent SLN biopsy, 13 of 21 (62%) MCCs with LVI had cancer in SLNs compared with 14 of 44 (25.5%) without LVI (P = .003). Although local radiation was common, nodal radiation was infrequently employed in SLN negative (pathologic N0) patients (21.8% vs. 76.2% for patients with SLN metastases, P = .0001). Survival of patients with positive SLNs was unfavorable, regardless of completion lymphadenectomy and/or adjuvant radiation. After accounting for tumor (T) and node (N) classification, age, immunosuppression, and primary site, a positive SLN and LVI were independently associated with worse survival (LVI/recurrence-free survival [RFS]: hazard ratio [HR] 2.3 (1.04-5, P = .04; LVI/disease-specific survival [DSS]: HR 5.2 (1.8-15, P = .007); N1a vs. pN0/RFS HR 3.6 (1.42-9.3, P = .007); DSS HR5.0 (1.3-19, P = .17). CONCLUSION SLN biopsy assists in risk stratification and radiation treatment planning in MCC. LVI and disease in SLNs, independently associated with worse survival, constitute markers of high-risk disease warranting consideration for investigational studies. LEVEL OF EVIDENCE III Laryngoscope, 131:E828-E835, 2021.

PURPOSE/OBJECTIVE(S) Dose constraint recommendations to limit mandible (MN) osteoradionecrosis (ORN) are largely unchanged since the advent of head and neck intensity modulated radiotherapy (IMRT). Updated MN dose volume histogram (DVH) constraints have been proposed but not validated in a prospective dataset. We hypothesize that after adopting more stringent MN constraints at our institution, we lowered the estimated ORN rate without compromising target coverage / organ at risk (OAR) avoidance. MATERIALS/METHODS This is a single institution retrospective study of a prospective database of non-metastatic oropharynx cancer (OPC) patients ≥ 18 years treated with standard fractionation adjuvant or definitive IMRT from 01 / 2014 - 08 / 2020. In 09 / 2017, MN dose constraint was changed from 0.1 cm3 < 70 Gy - historical constraints (HC) - to V44 < 42%, V58 < 25%, 0.5cc < 70 Gy - modified constraints (MC). No other target / OAR criteria were altered. ORN was defined as having exposed MN bone for ≥ 3 months without recurrence. Impact on ORN rate and resulting dosimetric changes in MN and other OARs (parotid and submandibular glands, oral cavity, pharyngeal constrictors) between HC and MC groups were evaluated. Continuous variables were compared via the Wilcoxon test, discrete variables via Fisher's exact test. Due to shorter follow-up (FU), regression modeling was used to estimate ORN cases in MC group. RESULTS There were 174 patients total, 71 in MC group. The mean prescription dose was 67.7 Gy and 68.5 Gy in HC and MC groups, respectively. More of the HC group (37%) had clinical T3 - T4 tumors compared to MC group (25%). More patients in the MC group met both the V44 < 42% (62 v 87%, P < 0.01) and the V58 < 25% constraints (73 v 92%, P < 0.01). Percent of patients meeting neither, one, or both MN constraints in the HC group was 23%, 13%, and 63%, versus 8%, 4%, and 87% in the MC group, respectively (P < 0.01). Mandible V44 and V58 were significantly associated with ORN (P < 0.01 and P = 0.03, respectively) across entire patient cohort. In HC group, mean MN V44 was significantly associated with ORN (62% in ORN cases vs 38%, P = 0.01) while mean MN V58 was approaching significance (P < 0.06). There were too few ORN cases in the MC group for similar analysis. Mean dose to OARs was not increased in MC group. There were 7 cases (76%) of ORN in the HC group at median FU 39 months (range: 2 - 78 months) and 2 cases (33%) of ORN in the MC group at median FU 11 months (range: 2 - 39 months). To account for shorter FU in MC group, logistic regression of ORN based on V44 in HC patients resulted in a model to predict ORN cases in MC group. This model estimates a total of 3.2 ORN cases (55%) in MC group (95% CI: 0.00 - 6.4). CONCLUSION We confirm MN V44 and V58 are predictive of ORN development. The goals of MN V44 < 42% and V58 < 25% were achievable in 87% of cases without sacrificing target coverage or other OAR constraints. Regression modeling estimates fewer ORN cases in MC group.

Purpose To characterize the cosmetic outcomes and local recurrence (LR) rates of various hypofractionated radiation therapy (RT) regimens for skin basal and squamous cell cancers (BCCs/SCCs). Methods A PICOS/PRISMA/MOOSE selection protocol was performed to identify 344 articles published between 1985–2016 evaluating patients with T1–2 N0 SCCs/BCCs treated with definitive RT. Biologically equivalent doses with α/β = 3 (BED 3 s) were calculated. The primary endpoint was post-treatment cosmesis. Mixed effects regression models were used to estimate weighted linear relationships between BED 3 and cosmetic outcomes. Results A total of 21 studies were identified detailing the treatment of 9729 skin BCC/SCC patients, across seven countries, with external beam RT (n = 9255) or brachytherapy (n = 474). Median follow-up was 36 months (range: 12–77). Median dose was 45 Gy/11 fractions (interquartile range: 37.5 Gy/6–55 Gy/18) at 4 Gy/fraction (interquartile range: 2.5–6 Gy); most hypofractionated 18.75 Gy/1. There was a trend to decreased “good” cosmesis with higher total dose: −3.4% “good” cosmesis/10 Gy BED 3 , p = 0.01. Similarly, there was a trend to increased “fair” cosmesis with higher dose: +3.8% “fair” cosmesis/10 Gy BED 3, p = 0.006. At a BED 3 of 100 Gy, the expected rate of “good” cosmesis is 79% (95% confidence interval: 70%, 88%). Hypofractionated schedules produced similar cosmesis to conventionally fractionated schedules, at the same BED 3 . Fewer than 8% of patients experienced “poor” cosmesis, independent of dose or fractionation regimen. Conclusion Hypofractionated RT has favorable cosmesis for patients with skin BCCs/SCCs. We recommend clinicians consider these commonly-used regimens, which all have BED 3 of ∼100 Gy: 50 Gy/15 fractions, 36.75 Gy/7 fractions, or 35 Gy/5 fractions, as they result in “good” cosmesis in 80% of patients.

Objectives To characterize the recognized but poorly understood long-term toxicities of radiation therapy (RT) for head and neck cancer (HNC). Materials and methods We retrospectively evaluated patients treated with curative-intent RT for HNC between 1990 and 2005 at a single institution with systematic multidisciplinary follow-up ≥10 years. Long-term toxicities of the upper aerodigestive tract were recorded and assigned to two broad categories: pharyngeal-laryngeal and oral cavity toxicity. Kaplan-Meier estimates and Chi-square tests were used for univariable analysis (UVA). Cox model and logistic regression were used for multivariable analysis (MVA). Results We identified 112 patients with follow-up ≥10 years (median 12.2). The primary tumor sites were pharynx (42%), oral cavity (34%), larynx (13%), and other (11%). Forty-four percent received postoperative RT, 24% had post-RT neck dissection, and 47% received chemotherapy. Twenty-eight (25%) patients developed pharyngeal-laryngeal toxicity, including 23 (21%) requiring permanent G-tube placed at median of 5.6 years (0–20.3) post-RT. Fifty-three (47%) developed oral cavity toxicity, including osteoradionecrosis in 25 (22%) at a median of 7.2 years (0.5–15.3) post-RT. On MVA, pharyngeal-laryngeal toxicity was significantly associated with chemotherapy (HR 3.24, CI 1.10–9.49) and age (HR 1.04, CI 1.00–1.08); oral cavity toxicity was significantly associated with chemotherapy (OR 4.40, CI 1.51–12.9), oral cavity primary (OR 5.03, CI 1.57–16.1), and age (OR 0.96, CI 0.92–1.00). Conclusion Among irradiated HNC patients, pharyngeal-laryngeal and oral cavity toxicity commonly occur years after radiation, especially in those treated with chemotherapy. Follow-up for more than five years is essential because these significant problems afflict patients who have been cured.

Angiosarcoma of the adrenal gland is an extremely rare malignancy. We report a case of a 59-year-old female who presented with abdominal pain and profound anemia. A 7 cm enhancing, lipid-poor adrenal mass with calcifications that extended posterior to the vena cava was identified on imaging. Patient underwent right adrenalectomy with retroperitoneal lymph node dissection. Pathology demonstrated angiosarcoma of the adrenal gland. Consolidative treatment included adjuvant radiation and chemotherapy. Patient remains disease free 1.5 years following treatment. Prior reported literature on the diagnosis and management of adrenal angiosarcoma is reviewed.

OBJECTIVES To investigate the prognostic impact of primary tumor-specific growth rate (TSGR) on treatment outcomes after definitive radiation therapy (RT) for nonoropharyngeal squamous cell carcinoma (non-OPSCC). METHODS The diagnostic tumor and nodal volumes of 39 non-OPSCC patients were contoured and compared to corresponding RT planning scan volumes to determine TSGR. Overall survival (OS), disease-free survival (DFS), and local recurrence-free survival were evaluated according to the Kaplan-Meier method; and hazard ratios (HR) were estimated using Cox regression. Based on the 75th percentile TSGR of 2.18%, we stratified patients into a high TSGR group (≥ 2.18% per day) and low TSGR group (

Objective: To report T1-2N0 tongue cancer recurrences initially treated with surgery alone. Methods: Between 1990 and 2010, 27 patients at tertiary hospital referral center institution were treated with curative intent for locoregional recurrence after initial glossectomy with or without neck dissection for T1-2N0 tongue cancer. None had received adjuvant postoperative radiation as a component of the original treatment. Results: Median time to locoregional recurrence was 12 months (range 5â39 months) and 78% of failures occurred in the first 2 years. Most treatment failures were local (63%). Salvage strategy was risk-adapted by individual patient. The 5-year disease specific survival (DSS) was 61%. Patients with local recurrences alone fared significantly better than those with regional recurrences (5-yr DSS: 86% vs. 22%, PÂ =Â 0.0018). Local recurrences were usually treated by surgery alone, while regional recurrences were more commonly treated with combined modality treatment (PÂ =Â 0.005). Conclusions: Recurrence of early stage oral tongue cancer can be successfully salvaged in a majority of cases. Patients developing regional recurrence have significantly worse prognosis than those with local failures. Keywords: Oral cancer, Head and neck cancer, Tongue neoplasms, Salvage therapy

Purpose To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). Methods Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds. Results A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days. Conclusion TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival.