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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.

Purpose: Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood. Experimental Design: All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR ≤ 3 lesions of disease progression) or systemic (sAR). We analyzed the relationships between patient characteristics, burden/location of disease, outcomes, and efficacy of therapeutic interventions. Results: Of 1,536 patients, 312 (20%) had an initial response and 143 developed AR (9% overall, 46% of responders). OligoAR was the most common pattern (80/143, 56%). Baseline tumor mutational burden, depth of response, and duration of response were significantly increased in oligoAR compared with sAR (P < 0.001, P = 0.03, P = 0.04, respectively), whereas baseline PD-L1 and tumor burden were similar. Post-progression, oligoAR was associated with improved overall survival (median 28 months vs. 10 months, P < 0.001) compared with sAR. Within oligoAR, post-progression survival was greater among patients treated with locally-directed therapy (e.g., radiation, surgery; HR, 0.41; P = 0.039). Fifty-eight percent of patients with oligoAR treated with locally-directed therapy alone are progression-free at last follow-up (median 16 months), including 13 patients who are progression-free more than 2 years after local therapy. Conclusions: OligoAR is a common and distinct pattern of acquired resistance to PD-(L)1 blockade compared with sAR. OligoAR is associated with improved post-progression survival and some cases can be effectively managed with local therapies with durable benefit.

Supplementary Figure S1. Association between age, number of mutations and smoking status.

Purpose: Epidemiologic studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients.Experimental Design: DNA isolated from tongue tumors of young (45 years) patients at was subjected to whole-exome sequencing and copy-number analysis. These data were compared with data from similar patients in the TCGA (The Cancer Genome Atlas) project.Results: In this study, we found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site–specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.Conclusions: Overall, tumors from young patients with SCCOT appear genomically similar to those of older patients with SCCOT, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood. Clin Cancer Res; 20(14); 3842–8. ©2014 AACR.

For patients with oligometastatic cancer, radiotherapy presents a promising avenue for achieving meaningful symptom relief and durable disease control. Data from recently published and ongoing randomized studies are helping to define the appropriate contexts for effective intervention with stereotactic ablative body radiotherapy (SABR) in the oligometastatic setting. Importantly, older adults represent a significant portion of patients with oligometastatic disease, yet often comprise a minority of patients in clinical trials. Moreover, older adults of the same chronologic age may have variable degrees of fitness and frailty. In this review, we highlight the specific challenges and considerations for the use of radiotherapy for older adults with oligometastatic disease-noting the importance of geriatric assessments in clinical decision-making about the appropriateness of SABR and other metastasis-directed therapies in this population. We then review data from existing trials, including a subset analysis of adverse events and survival estimates among older adults enrolled in the landmark SABR-COMET trial. Finally, we discuss future directions for research, including the need for focused clinical trials in older adult cohorts. Ultimately, a multidisciplinary approach is critical when carefully balancing the potential risks and benefits of this emerging treatment paradigm in the older adult population.

ImportanceDespite federal initiatives encouraging the enrollment of individuals from racial and ethnic minority groups in US clinical trials, no studies to date have specifically examined demographic disparities among participants in phase 1 drug development trials for patients with metastatic cancer.ObjectiveTo assess trends in the enrollment of patients from racial and ethnic minority groups in US phase 1 therapeutic drug trials for metastatic cancer from 2000 to 2018.Design, Setting, and ParticipantsIn this cross-sectional study, ClinicalTrials.gov was queried in July 2021 to identify completed phase 1 drug trials for metastatic cancer in the US from January 1, 2000, to December 31, 2018, with published results, yielding 221 phase 1 trials with 8309 participants aged 18 years or older with metastatic solid tumors. Proportions of each racial and ethnic group of trial participants were compared with that from the North American Association of Central Cancer Registries’ Cancer in North America (CiNA) database. Statistical analysis was performed from July 12, 2021, to March 15, 2022.Main Outcomes and MeasuresFor each racial and ethnic group, the difference between trial and CiNA proportions was examined using a 2-sample test for equality of proportions with continuity correction.ResultsThe 8309 phase 1 trial participants (4198 men [50.5%]; median age, 59 years) included 23 American Indian or Alaska Native participants (0.3%), 371 Asian or Pacific Islander participants (4.5%), 514 Black participants (6.2%), 401 of 5076 Hispanic or Latinx participants (7.9%), and 7154 White participants (86.1%). Industry funded 165 of the 221 trials (74.7%). White patients were overrepresented overall compared with the corresponding CiNA cohort (7154 of 8309 [86.1%] vs 4 113 096 of 4 891 486 [84.1%]; difference, 2.0 percentage points; P P = .23) to 2012-2018 (trials, 4374 of 5063 [86.4%]; CiNA, 1 735 077 of 2 090 775 [82.9%]; difference, 3.5 percentage points; P Conclusions and RelevanceIn this cross-sectional study of participants in phase 1 clinical trials of drugs for metastatic cancer, worsening disparities were observed over time in the accrual of patients from racial and ethnic minority groups. These findings may represent widening inequalities in access to trial sites and worsening systemic biases. More efforts are needed to diversify phase 1 cancer drug trials to improve equity in access to new treatments and to ensure that safety and efficacy findings from early drug trials are generalizable across populations.

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.

OBJECTIVE: Gaps in access to appropriate cancer care, and associated cancer mortality, have widened across socioeconomic groups. We examined whether demographic and socioeconomic factors influenced receipt of adjuvant radiation therapy (RT) in patients with high-risk, early-stage endometrial cancer. METHODS: A retrospective study cohort was selected from 349,404 endometrial carcinoma patients from the National Cancer Database in whom adjuvant RT would be recommended per national guidelines. The study included surgically treated patients with endometrioid endometrial cancer with one of the following criteria: 1) FIGO 2009 stage IB, grade 1/2 disease, age ≥60 years; 2) stage IB, grade 3 disease; or 3) stage II disease. Logistic regression analysis was performed to identify factors associated with omission of adjuvant RT. Association between adjuvant RT, covariables, and overall survival (OS) was assessed with multivariable Cox proportional hazards models. RESULTS: 19,594 patients were eligible for analysis; 47% did not receive adjuvant RT. Omission of adjuvant RT was more prevalent among African-American, Hispanic, and Asian compared to non-Hispanic white patients (OR 0.79, 95%CI: 0.69–0.91; OR 0.75, 95%CI: 0.64–0.87; OR 0.75, 95%CI: 0.60–0.94, respectively). Lower median household income of patient’s area of residence, lack of health insurance, treatment at non-academic hospitals, farther distance to treatment facilities, and residence in metropolitan counties were associated with omission of adjuvant RT (OR≤0.81, p≤0.01). Such omission was independently associated with worse OS (HR1.43, p

The concept of oligometastatic disease has evolved substantially over the past decade. During this time, there has been a transition from retrospective and single-arm prospective studies to randomized evidence suggesting a benefit of local consolidative therapy (LCT) in the setting of limited metastatic non-small cell lung cancer. These trials had constraints and were thus limited in the strength of their conclusions, but led to several other ongoing randomized trials examining the role of LCT. These studies span various disease states (synchronous oligometastatic vs oligoprogressive), the scope of histologies included, and in how they define oligometastases. In addition, parallel biologic work is attempting to integrate relevant biomarkers and molecular classifications, with the ultimate goal of more precisely defining oligometastases and triaging patients to appropriate care. Finally, consensus guidelines have been initiated that provide a framework for designing future studies and for maintaining consistency across analyses that will facilitate the interpretation of results. This review describes the prior randomized data, the limitations therein, and future directions of clinical and preclinical studies that highlight the emerging paradigms for treatment of this select patient cohort.

PURPOSE: Guidelines recommend short-course (≤10 fractions) external-beam radiotherapy (EBRT) for bone metastases. Stereotactic body radiotherapy (SBRT) may also improve outcomes; however, routine use is not recommended outside clinical trials. We assess national radiotherapy trends in complex techniques for bone metastases and associated expenditures. METHODS: Using a claims-based Medicare dataset covering 84% of beneficiaries, we assessed the relative proportion of all radiation episodes represented by bone metastases. We then evaluated use of short-course and long-course (>10 fractions) EBRT, intensity-modulated radiotherapy (IMRT), and SBRT for bone metastases in hospital-affiliated outpatient (OPD) or freestanding (FREE) facilities. We assessed differences using chi-squared or Wilcoxon rank-sum tests for categorical and continuous variables, respectively. We identified associations with modality, fractionation, and expenditures using multivariable logistic/linear regression. RESULTS: Among 467,781 radiation episodes for 17 cancer diagnoses, the overall proportion of episodes dedicated to bone metastases (9.4%) was stable from 2015–2017, though treatments were increasing in the hospital-affiliated outpatient setting (P

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

Background Proton beam radiation therapy (PBRT) has dosimetric advantages compared to photon radiation therapy for the treatment of major salivary gland tumors (MSGTs). Methods Patients with non-metastatic MSGTs treated at a single proton therapy center from October 2013 to October 2018 were retrospectively reviewed. Results Sixty-eight patients with MSGTs were included and the most common site and histology were the parotid gland (75.0%) and adenoid cystic carcinoma (22.1%), respectively. The 3-year rates of locoregional control, progression-free survival, and overall survival were 95.1% (95% CI: 89.9%-100.0%), 80.7% (70.2%-92.7%), and 96.1% (95% CI: 90.9%-100.0%), respectively. Conclusion In a large cohort of MSGTs treated with PBRT, the rates of locoregional control were high in short-term follow-up and treatment was well tolerated.

PURPOSE The objective response rate (ORR) for single-agent anti–programmed death receptor 1 (anti–PD-1) therapy is modest in patients with metastatic or recurrent head and neck squamous cell carcinoma (HNSCC). We aimed to test whether radiotherapy may act synergistically with anti–PD-1 therapy to improve response through the abscopal effect. PATIENTS AND METHODS We conducted a single-center, randomized, phase II trial of nivolumab (anti–PD-1 therapy) versus nivolumab plus stereotactic body radiotherapy (SBRT) in patients with metastatic HNSCC. Patients had at least two metastatic lesions: one that could be safely irradiated and one measurable by RECIST version 1.1. Patients were randomly assigned (1:1), stratified by human papillomavirus status, to nivolumab (3 mg/kg intravenously every 2 weeks) or nivolumab (same dose) plus SBRT (9 Gy × 3) to 1 lesion. The primary end point was ORR in nonirradiated lesions, which was assessed by RECIST in patients with at least one available set of on-treatment images; safety was assessed in a per-protocol population. RESULTS Between March 11, 2016, and June 22, 2018, 62 patients were randomly assigned to nivolumab (n = 30) or nivolumab plus SBRT (n = 32). There was no statistically significant ORR difference between arms (34.5% [95% CI, 19.9% to 52.7%] v 29.0% [95% CI, 16.1% to 46.6%]; P = .86). There was no significant difference in overall survival ( P = .75), progression-free survival ( P = .79), or response duration ( P = .26). Grade 3-5 toxicities were similar (13.3% v 9.7%; P = .70). CONCLUSION We found no improvement in response and no evidence of an abscopal effect with the addition of SBRT to nivolumab in unselected patients with metastatic HNSCC.

The purpose of this systematic review was to examine whether dental intervention involving bone or soft-tissue manipulation preradiotherapy (pre-RT) is associated with lower rates of osteoradionecrosis of the jaw (ORNJ) in patients with head and neck cancer (HNC).The authors included relevant studies from MEDLINE, Embase, and Cochrane Library, including observational studies published from 2007 through 2021 and involving adults who underwent dental intervention pre-RT for HNC. Authors assessed evidence certainty by using the Grading of Recommendations Assessment, Development, and Evaluation approach. Random-effects models were used to calculate pooled relative risk estimates and hazard ratios. When meta-analysis was not possible, study-level measures of association and narrative summaries of the evidence were reported.Twenty-two studies were included. From the pooled, unadjusted analysis, patients undergoing pre-RT extractions may have a 55% increased risk of experiencing ORNJ (relative risk, 1.55; 95% CI, 0.85 to 2.86; very low certainty); the unadjusted pooled hazard ratio was 3.19 (95% CI, 0.99 to 10.31; very low certainty), corresponding to a possible increased hazard of developing ORNJ (very low certainty). Findings for other pre-RT procedures manipulating bone or tissue relied on limited, observational studies with low or very low certainty evidence.Mostly very low certainty evidence suggests that patients with HNC who need pre-RT dental intervention may have an increased risk of developing ORNJ compared with those who do not.Maintaining optimal oral health may help reduce the need for urgent pre-RT dental treatment, potentially reducing ORNJ risk and minimizing delay of oncologic treatment in patients with HNC.

Background: There is a known gender gap in oncology publishing with worse disparities within specialty fields such as radiation oncology. There has been a significant increase in the number of manuscripts submitted to academic journals during the pandemic. Several analyses have suggested that the pandemic has had a disproportionate effect on academic productivity of women in academia, as measured by manuscript publication rates. Materials and Methods: The gender of first/co-first and corresponding/co-corresponding authors, as well as non-senior versus senior status and manuscript type, for all papers published by Advances from its inception in December 2015 to the end of February 2020 was compared to those published between March 1, 2020, and May 31, 2020 – the months during which the onset of the COVID-19 pandemic in North America began. Results: This examination of papers published during COVID-19 did not indicate a statistically significant decrease in the overall proportion of women publishing in Advances (P=0.76). For non-senior female authors, this proportion fell just short of statistical significance (39% vs. 19%, P=0.051). When only scientific manuscripts were considered, there was a statistically significant decrease in publications by non-senior female first authors during the early months of the pandemic (37% vs. 11%, P=0.02) Conclusions: During the early months of the COVID-19 pandemic, non-senior female researchers participated less in manuscript publishing in radiation oncology.

Highlights • Contemporary trends in radiation technique and fractionation for bone metastases at a large academic center with a specialized metastatic program. • Stereotactic body radiation therapy (SBRT) is replacing long-course conventional RT for bone metastases. • Complexity of RT is increasing, particularly in the community-based regional clinic setting. • Single-fraction conventional RT is preferentially employed at the end of life, but prognostic algorithms are needed to further optimize use., Background Bone metastases cause significant morbidity in patients with cancer, and radiation therapy (RT) is an effective treatment approach. Indications for more complex ablative techniques are emerging. We sought to evaluate RT trends at a large multi-site tertiary cancer center. Methods Patients who received RT for bone metastases at a single institution (including regional outpatient clinics) from 2016 to 2018 were identified. Patients were grouped by RT regimen: single-fraction conventional RT (8 Gy × 1), 30 Gy in 10 fractions, SBRT, and “other”. Multinomial logistic regression was performed to assess trends in regimens over time. Binary logistic regression was performed to evaluate factors associated with receipt of SBRT. Results Between 2016 and 2018, 5,952 RT episodes were received by 2,969 patients with bone metastases. Overall, 76% of episodes were ≤ 5 fractions. The median number of fractions planned for SBRT and non-SBRT episodes was 3 (IQR 3–3) and 5 (IQR 5–10), respectively. Use of SBRT increased from 2016 to 2018 (39% to 53%, 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.

Because of the national emergency triggered by the coronavirus disease 2019 (COVID‐19) pandemic, government‐mandated public health directives have drastically changed not only social norms but also the practice of oncologic medicine. Timely head and neck cancer (HNC) treatment must be prioritized, even during emergencies. Because severe acute respiratory syndrome coronavirus 2 predominantly resides in the sinonasal/oral/oropharyngeal tracts, nonessential mucosal procedures are restricted, and HNCs are being triaged toward nonsurgical treatments when cures are comparable. Consequently, radiation utilization will likely increase during this pandemic. Even in radiation oncology, standard in‐person and endoscopic evaluations are being restrained to limit exposure risks and preserve personal protective equipment for other frontline workers. The authors have implemented telemedicine and multidisciplinary conferences to continue to offer standard‐of‐care HNC treatments during this uniquely challenging time. Because of the lack of feasibility data on telemedicine for HNC, they report their early experience at a high‐volume cancer center at the domestic epicenter of the COVID‐19 crisis., Cancer care is undeniably affected by the coronavirus disease 2019 (COVID‐19) public health emergency, but quality cancer care must persist. A high‐volume cancer center from the domestic epicenter of the COVID‐19 crisis shares its multidisciplinary approach to integrating current public health restrictions and adopting telemedicine to optimize the care of patients with head and neck cancer; it is hoped that this center's experience will provide helpful insights to oncology colleagues.

ImportanceUse of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret.ObjectiveTo evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma.Design, Setting, and ParticipantsThis retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and grade early and late toxic effects.ExposuresProton therapy reirradiation.Main Outcomes and MeasuresFollow-up was defined from the start of PT-ReRT. The Kaplan-Meier method was used for outcomes of interest, including local control (LC), locoregional control, distant metastatic control, progression-free survival, and overall survival (OS). Cox proportional hazards regression modeling was used to assess associations of covariates with OS.ResultsA total of 242 patients (median [range] age, 63 [21-96] years; 183 [75.6%] male) were included. Of these patients, 231 (95.9%) had a Karnofsky performance status score of 70 or higher, and 145 (59.9%) had at least a 10–pack-year smoking history. Median (range) follow-up was 12.0 (5.8-26.0) months for all patients and 24.5 (13.8-37.8) months for living patients. A total of 206 patients (85.1%) had recurrent disease vs second primary or residual disease. The median (range) interval between radiation courses was 22 (1-669) months. Median PT-ReRT dose was 70 cobalt gray equivalents (CGE) for the fractionated cohort and 44.4 CGE for the quad shot cohort. For the fractionated cohort, the 1-year LC was 71.8% (95% CI, 62.8%-79.0%) and the 1-year OS was 66.6% (95% CI, 58.1%-73.8%). For the quad shot cohort, the 1-year LC was 61.6% (95% CI, 46.4%-73.6%) and the 1-year OS was 28.5% (95% CI, 19.4%-38.3%). Higher Karnofsky performance status scores (hazard ratio [HR], 0.50; 95% CI, 0.25-0.99; P = .046) and receipt of salvage surgery prior to PT-ReRT (HR, 0.57; 95% CI, 0.39-0.84; P = .005) were associated with improved OS, whereas receipt of quad shot (HR, 1.97; 95% CI, 1.36-2.86; P Conclusions and RelevanceThe findings of this cohort study suggest that, compared with previous reports with photon-based reirradiation, patients are living longer with aggressive PT-ReRT; however, surviving patients remain at risk of early and late complications.

Background Numerous studies and guidelines suggest an outcome detriment from radiation treatment breaks (rTBs) and the need for compensatory dosing in patients with head and neck cancer. Methods In a consecutive cohort of 521 patients with oropharyngeal squamous cell carcinoma (OPSCC), we investigated the impact of rTBs and prolongation of overall treatment time (OTT) on OS, DFS, LRC, and cancer recurrence using competing risk and multivariate analyses. Results Neither OTT prolongation by ≤2 days nor rTBs of ≤3 days were associated with detriments to clinical outcomes. Consecutive breaks of ≥3 days were also not significantly associated with detriment to clinical outcomes. There was significantly increased competing mortality in those with longer breaks. Conclusions In OPSCC patients treated with definitive concurrent chemoradiotherapy, there is no significant association between disease failure and total rTBs of ≤3 consecutive or scattered days. Further investigation is needed for longer breaks.

PURPOSE Telomerase reverse transcriptase ( TERT) promoter mutations are prognostic in many cancers and have been observed in human papillomavirus (HPV)–negative head and neck squamous cell carcinomas (HNSCCs). However, the role of TERT promoter mutations in HPV-negative HNSCCs remains poorly understood in these cancers, which have increased risk for locoregional failure (LRF). PATIENTS AND METHODS We retrospectively identified patients who were diagnosed with HNSCC between July 1, 2004, and October 12, 2017, at Memorial Sloan Kettering Cancer Center and whose tumors underwent next-generation sequencing using the MSK-IMPACT panel. Patients with HPV-positive oropharyngeal squamous cell carcinoma (SCC) were excluded. Cumulative incidence of LRF, patterns of failure, and overall survival were measured. RESULTS We identified 117 patients with SCC of the oral cavity (OSCC), larynx, hypopharynx, or HPV-negative oropharynx whose tumors underwent next-generation sequencing. Sequencing was performed on 95 tumors that were obtained after recurrence and 22 that were obtained before recurrence. TERT promoter mutations were enriched in OSCC compared with laryngopharyngeal cancers (81.1% v 7.0%; P < .001), which was the largest genetic difference between these anatomic disease subsites. TERT promoter mutations were associated with LRF in OSCCs (Gray's test, P < .001) and in the overall cohort (Gray's test, P < .001). On multivariate analysis, TERT promoter mutations were associated with an increased risk for LRF (subdistribution hazard ratio, 2.82; 95% CI, 1.47 to 5.42; P = .0019), independent of oral cavity primary site and TP53 mutation status. CONCLUSION TERT promoter status is associated with the cumulative incidence of LRF and patterns of failure. TERT promoter mutations may define a subset of OSCCs with unique pathogenesis that is associated with an increased risk of LRF. Validation in prospective cohorts is warranted.

Background Our objective was to evaluate the outcomes of metastatic head and neck squamous cell carcinoma (HNSCC) by disease burden with an emphasis on metastasis-directed therapy (MDT) in patients with limited metastatic disease burden. Methods In total, 186 patients who developed metastatic disease after definitive therapy for HNSCC were included. Clinically and radiographically apparent metastases were enumerated. Kaplan–Meier methods were used to estimate survival. Cox regression was used to assess the association between clinical variables. Results Patients with a single metastasis had a 5-year overall survival (OS) of 35% (95% CI 16–54%) in contrast to patients with multiple metastases with a 5-year OS of 4% (95% CI 2–9%). Thirty patients (16.1%) underwent MDT. On multivariable analysis, oral cavity or sinonasal primary (HR 2.22 95% CI 1.16–4.25, p = 0.015; HR 4.88, 95% CI 1.10–21.70, p = 0.037, respectively) were associated with higher risk of death, whereas receipt of MDT (HR 0.36, 95% CI 0.17–0.74, p = 0.006) was associated with lower hazard of death. Median subsequent metastasis-free survival and 5-year survival after MDT (n = 30) were estimated at 26.4 months (95% CI: 9.8–54.0) and 31%, (95% CI: 15–48%). Conclusions HNSCC patients with limited metastatic disease may derive significant benefit from MDT. Prospective trials evaluating MDT in HNSCC are warranted.

Objectives/hypothesis We used the National Cancer Database to identify the patterns of care and prognostic factors in adult patients with head and neck soft-tissue sarcoma (HNSTS). Study design Retrospective cohort analysis. Methods Using the National Cancer Database, we identified patients age ≥ 18 years who were diagnosed with HNSTS between 2004 and 2013. Both χ2 and multivariate logistic regression were used to identify factors associated with radiation therapy (RT) utilization. Kaplan-Meier methods were used to estimate overall survival (OS) and Cox proportional regression was used to determine significant contributors to OS. Results Our final cohort included 1,282 patients (682 treated with surgery only, 199 treated with RT only, and 401 treated with surgery and RT). Patients with younger age, poor tumor grade, rhabdomyosarcoma histology, and chemotherapy treatment were more likely to receive RT alone without surgery. Among the 1,083 surgical patients, RT utilization was associated with positive margins (odds ratio [OR]: 2.18, 95% confidence interval [CI]: 1.36-3.48), poor grade (OR: 2.92, 95% CI: 1.95-4.38), and chemotherapy use (OR: 1.78, 95% CI: 1.15-2.76). Radiotherapy utilization among surgical patients was not affected by demographic factors (age, sex, or ethnicity) or treatment institution (academic or community). For surgical patients, poor grade, large tumor size, and rhabdomyosarcoma histology were associated with worse OS on multivariate analysis. Conclusions In this analysis of HNSTS, younger patients with poor tumor grade and rhabdomyosarcoma histology were more likely to receive RT without surgery. Among surgical patients, adjuvant RT was more likely to be used for positive margins and poor grade, with no demographic disparities identified. Poor grade and rhabdomyosarcoma histology were negative prognostic factors for surgical patients. Level of evidence NA Laryngoscope, 130:120-127, 2020.

Purpose: The purpose of this study was to analyze national trends and disparities in proton therapy use among patients with head and neck cancer receiving radiotherapy to primary disease sites. Patients and Methods: Using the National Cancer Database, we identified patients diagnosed with any nonmetastatic head and neck primary malignancy between 2005 and 2014 who were treated with radiation therapy or proton therapy directed specifically at the primary disease site. Distributions of patient and clinical factors between the two groups were evaluated. Multivariable logistic regression was used to correlate factors associated with proton therapy use compared with other modalities of radiation therapy. Results: There were 220 491 patients who received any radiation therapy as part of their initial treatment course, only 417 (0.2%) of whom received proton therapy. The use of protons underwent a small increase from 0.13% in 2005-06 to 0.41% by 2013-14 (P $63 000; OR, 2.52; P = .002) were associated with an increased likelihood of receiving proton therapy. Conclusion: Proton use has undergone an incremental increase in the United States but remains an uncommon modality for the treatment of primary head and neck cancer.

Data on the biology and radiosensitivity of human papillomavirus–related cancers have led many expert radiation oncologists to decrease the radiation dose to target areas in selected situations. At Memorial Sloan Kettering Cancer Center, we have altered our radiation guidelines to allow substantial dose reduction to elective treatment regions and to omit radiation completely in other regions that have historically been included in the elective treatment volume. Here we summarize our current dose prescriptions and briefly explain the rationale behind these choices, which we anticipate will change when additional data mature. These recommendations are based on the American Joint Committee on Cancer seventh edition TNM Staging System and applicable only to patients who receive concurrent platinum-based chemotherapy and in whom both p16 immunohistochemistry and human papillomavirus RNA in situ hybridization tests are positive.

The aim of the present study was to identify whether the quantitative metrics from pre-treatment (TX) non-Gaussian intravoxel incoherent motion (NGIVIM) diffusion weighted (DW-) and fast exchange regime (FXR) dynamic contrast enhanced (DCE)-MRI can predict patients with locoregional failure (LRF) in nasopharyngeal carcinoma (NPC). Twenty-nine NPC patients underwent pre-TX DW- and DCE-MRI on a 3T MR scanner. DW imaging data from primary tumors were fitted to monoexponential (ADC) and NGIVIM (D, D*, f, and K) models. The metrics Ktrans, ve, and τi were estimated using the FXR model. Cumulative incidence (CI) analysis and Fine-Gray (FG) modeling were performed considering death as a competing risk. Mean ve values were significantly different between patients with and without LRF (p = 0.03). Mean f values showed a trend towards the difference between the groups (p = 0.08). Histograms exhibited inter primary tumor heterogeneity. The CI curves showed significant differences for the dichotomized cutoff value of ADC ≤ 0.68 × 10−3 (mm2/s), D ≤ 0.74 × 10−3 (mm2/s), and f ≤ 0.18 (p &lt, 0.05). τi ≤ 0.89 (s) cutoff value showed borderline significance (p = 0.098). FG’s modeling showed a significant difference for the K cutoff value of ≤0.86 (p = 0.034). Results suggest that the role of pre-TX NGIVIM DW- and FXR DCE-MRI-derived metrics for predicting LRF in NPC than alone.

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 With multiple phase 2 trials supporting the use of stereotactic body radiation therapy (SBRT) in oligo-metastatic disease, we evaluated practices that could inform effective implementation of an oligo-metastasis SBRT program. Methods and Materials Using a context-focused realist methodology, an advisory committee of interprofessional clinicians met over a series of semistructured teleconference meetings to identify challenges in implementing an oligo-metastasis SBRT program. Consideration was given to 2 models of care: a subspecialist anatomic expertise model versus a single-practitioner “quarterback” model. Results The advisory committee structured recommendations within a context-mechanism-outcome framework. In summary, the committee recommends that during patient workup, a single practitioner arranges the minimum number of necessary tests, with case presentation at an appropriate multidisciplinary tumor board, including careful review of all previous treatments, and enrollment on clinical trials when possible. At simulation, common patient positions and immobilization on a single simulation scan for multiple sites is recommended. During radiation planning, dose-fractionation regimens should safely facilitate cumulative dose calculations, a single isocenter should be considered for multiple close targets to reduce treatment time, and adherence to strict quality assurance protocols is strongly recommended. Treatment duration should be minimized by treating multiple sites on the same day or choosing shorter dose fractionations. Team communication, thorough documentation, and standardized nomenclature can reduce system errors. Follow-up should aim to minimize redundant clinical appointments and imaging scans. Expert radiology review may be required to interpret post-SBRT imaging. Conclusions These guidelines inform best clinical practices for implementing an oligo-metastasis SBRT program. Iterations using a realist approach may further expand on local contexts.

Several de-escalation strategies for human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC) have focused on deintensifying gross disease treatment. Reduction of radiotherapy dose and target volume to subclinical regions may achieve good clinical outcomes with favorable patient quality of life (QOL).To determine outcomes from a systematic approach of reducing radiotherapy dose and target volume to the elective treatment regions in patients with HPV-associated OPC undergoing concurrent chemoradiotherapy (CCRT).This retrospective cohort study included 276 consecutive patients with HPV-positive OPC receiving CCRT from March 1, 2017, to July 31, 2019. Data were analyzed from February 23 to September 13, 2021.Elective nodal and subclinical regions received 30 Gy of radiotherapy in 15 fractions, followed by a cone down of 40 Gy in 20 fractions to gross disease for a total dose of 70 Gy. The high retropharyngeal nodal basins in the node-negative neck and bilateral levels IB and V basins were omitted.Patients were followed up to evaluate locoregional control as the primary outcome and distant metastasis-free survival, progression-free survival, and overall survival as secondary outcomes. Quality-of-life data were obtained at each visit when feasible.Among the 276 patients included in the analysis, the median age was 61 (range, 36-87) years; 247 (89.5%) were men; and 183 (66.3%) had less than 10 pack-years of smoking history. Most patients (251 [90.9%]) were White. Overall, 87 (31.5%) had cT3-cT4 disease and 65 (23.5%) had cN2-cN3 disease per the 8th edition of the American Joint Committee on Cancer Staging Manual. One hundred seventy-two patients (62.3%) completed 300-mg/m2 high-dose cisplatin therapy. During a median follow-up of 26 (range, 21-32) months, 8 patients developed locoregional recurrence, including 7 at the primary site or gross nodes that received a total dose of 70 Gy and 1 with a persistent node not previously identified as gross disease that received a total dose of only 30 Gy. The 24-month locoregional control was 97.0%; progression-free survival, 88.0%; distant metastasis-free survival, 95.2%; and overall survival, 95.1%. During treatment, 17 patients (6.2%) required a feeding tube. At 24 months, most of the QOL composite scores (jaw-related problems, pain, social contact, eating, speech, and swallow) were comparable or superior to baseline measures except for senses, dry mouth, muscular tension, and cognitive functioning, which improved over time but remained marginally worse than baseline.This cohort study found that the evaluated de-escalation strategy for elective regions showed favorable clinical outcomes and QOL profiles. Long-term follow-up data will help affirm the efficacy of this strategy as a care option for treating HPV-associated OPC with primary CCRT.

The speed at which the COVID-19 pandemic spread across the globe and the accompanying need to rapidly disseminate knowledge have highlighted the inadequacies of the traditional research/publication cycle, particularly the slowness and the fragmentary access globally to manuscripts and their findings. Scholarly communication has slowly been undergoing transformational changes since the introduction of the Internet in the 1990s. The pandemic response has created an urgency that has accelerated these trends in some areas. The magnitude of the global emergency has strongly bolstered calls to make the entire research and publishing lifecycle transparent and open. The global scientific community has collaborated in rapid, open, and transparent means that are unprecedented. The general public has been reminded of the important of science, and trusted communication of scientific findings, in everyday life. In addition to COVID-19-driven innovation in scholarly communication, alternative bibliometrics and artificial intelligence tools will further transform academic publishing in the near future.