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Simple Summary: Cisplatin-based chemoradiation is the standard of care for patients with squamous cell carcinomas of the head and neck area. Recent data from randomized phase 3 studies showed that weekly cisplatin has the same oncological outcomes as high-dose triweekly cisplatin when combined with definitive radiation. In this study, audiologic data were prospectively collected before, during, and after treatment completion. Standard audiogram evaluation was used in all cases. The primary endpoint was a hearing change grade of ≥3 (CTCAE v5.0) after completion of chemoradiation. The high-dose cisplatin regimen significantly increased the ≥grade 3 severe irreversible ototoxicity risk compared to the low-dose weekly regimen, irrespective of cumulative cisplatin dose, even with the use of cochlear-sparing intensity-modulated radiation therapy. No significant difference in oncologic outcomes was observed between the two schedules. These findings should be validated in a larger prospective multi-institutional study. Cisplatin, one of the most ototoxic anti-neoplastic agents, causes permanent hearing loss in up to 90% of patients. We assessed ototoxicity rates and prospectively collected audiologic outcomes of patients receiving low-dose or high-dose cisplatin with concurrent cochlear-sparing intensity-modulated radiation therapy (IMRT). Patients with head and neck squamous cell carcinoma (HNSCC) receiving definitive or adjuvant cisplatin-based chemoradiotherapy (CRT) were analyzed. Cisplatin was administered either in low doses weekly (40 mg/m2) for up to seven doses or in high doses triweekly (100 mg/m2) for up to three doses. Cochlear-sparing IMRT was delivered in all cases. Audiologic data were prospectively collected before, during, and after treatment completion. The primary endpoint was a hearing change grade of ≥3 after CRT completion. Of the 96 HNSCC patients evaluated, 69 received weekly cisplatin and 58 received definitive CRT. Of patients receiving weekly cisplatin, 13% developed ≥G3 ototoxicity vs. 56% of patients who received triweekly cisplatin (p < 0.001). In multivariable modeling, the cisplatin dose schedule remained significant (OR: 8.4, 95%CI: 2.8–27.8, p < 0.001) for risk of severe irreversible ototoxicity. Triweekly cisplatin CRT significantly increased the ≥G3 severe irreversible ototoxicity risk compared to low-dose weekly cisplatin, irrespective of the cumulative cisplatin dose, even with the use of cochlear-sparing IMRT. No significant difference in oncologic outcomes was observed between the two schedules. [ABSTRACT FROM AUTHOR]

No Food and Drug Administration-approved intervention exists for oral mucositis (OM) from chemoradiotherapy (CRT) used to treat head and neck cancers. RRx-001 is a hypoxia-activated, cysteine-directed molecule that affects key pathways involved in OM pathogenesis. This phase 2a, multi-institutional trial was designed to assess the safety and feasibility of 3 schedules of a fixed concentration of RRx-001; a standard-of-care arm was included to identify potential signals of efficacy for further study. This study enrolled patients with oral cavity and oropharynx squamous cell carcinoma receiving definitive or postoperative cisplatin-based CRT. Patients were randomized into 4 cohorts. In arms 1 to 3, RRx-001 was coinfused with patients' blood at differing intervals. Arm 4 was a control cohort of patients treated with CRT alone. Trained evaluators assessed OM using a standardized data collection instrument twice weekly during treatment and then until resolution. OM severity was scored centrally using World Health Organization criteria. Safety outcomes were assessed using National Cancer Institute - Common Terminology Criteriav4 benchmarks. Long-term tumor response was defined by Response evaluation criteria in solid tumors v1.1 criteria. Fifty-three patients were enrolled, with 46 and 45 individuals contributing safety and efficacy data, respectively. There were no severe adverse events attributed to the study drug. Across all 3 active arms, the study drug was infused fully per protocol in 86% of patients. All 3 RRx-001 treatment cohorts appeared to demonstrate a similar or lower OM duration relative to control; arm 1 had the lowest median duration of severe oral mucositis (SOM), 8.5 days versus 24 days in controls among patients who developed at least 1 day of SOM. There were no locoregional failures in any patient. Our results support the safety and feasibility of RRx-001 as an intervention to mitigate SOM. Additional studies are planned to confirm its efficacy. [ABSTRACT FROM AUTHOR]

Organ preservation versus total laryngectomy for advanced laryngeal cancer continues to be hotly debated. This review presents evidence-based decision making points for these patents. [ABSTRACT FROM AUTHOR]

Purpose. Transoral robotic surgery (TORS) has increased in popularity in the management of squamous cell carcinoma of the head and neck. However, TORS does not address the neck or retropharyngeal nodes (RPN). In the current report, we highlight the impact of the lack of adjuvant radiotherapy on RPN recurrence after TORS. Materials and Methods. A 58-year-old Caucasian male presented with squamous cell carcinoma of the head and neck of unknown primary. He was offered radiotherapy as a definitive management for clinical stage T0N2aM0, stage IVA, but he opted to left neck dissection. Follow-up PET-CT scan revealed recurrence in the left base of tongue and right level II lymph node. He was offered radiotherapy which he declined and opted to TORS and right neck dissection. Follow-up PET-CT scan showed recurrence in left RPN for which he underwent salvage concurrent chemoradiotherapy to 70 Gy. Results. After a followup of 9 months from the date of salvage chemoradiotherapy completion, the patient is with no evidence of disease. Conclusions. TORS followed by adjuvant radiotherapy seems reasonable in the context of squamous cell carcinoma of the head and neck due to the odds of RPN involvement. Further reports are warranted to optimize post-TORS adjuvant treatment. [ABSTRACT FROM AUTHOR]

The papillomavirus E2 proteins bind with high affinity to palindromic DNA sequences consisting of two highly conserved four base-pair sequences flanking a variable “spacer” of identical length (ACCG NNNN CGGT). While intimate contacts are observed between the bound proteins and conserved DNA in the available co-crystal structures, no contact is seen between the proteins and the spacer DNA. The ability of human papillomavirus strain 16 (HPV-16) E2 and bovine papillomavirus strain 1 (BPV-1) E2 to discriminate among binding sites with different spacer sequences is dependent on their sensitivity to the unique conformational and/or dynamic properties of the spacer DNA in a process termed “indirect readout”. Differential sequence-specific K+ uptake in low ionic strength solutions lacking Mg2+ is observed upon E2 protein binding to sites containing the AATT, TTAA or ACGT spacer sequences. In contrast, the cation displacement typical of protein–DNA complex formation is observed at high K+ concentrations or in the presence of Mg2+. These results are interpreted to reflect the sequence-specific stabilization of bent DNA conformations by cations localized within the narrowed minor grooves of the protein-bound DNA and the intrinsic structure and flexibility of the DNA target. Mg2+ differentially affects the binding of the HPV-16 E2 DNA binding domain (HPV16-E2/D) and the BPV-1 E2 DNA binding domain (BPV1-E2/D) to sites bearing different spacer sequences. This study suggests that monovalent and divalent cations contribute to the discrimination of DNA structure and flexibility that could in turn contribute to the specificity with which HPV16-E2/D and BPV1-E2/D mediate DNA replication and gene transcription. [Copyright &y& Elsevier]

Examines the molecular dynamics and thermodynamics of protein-RNA interactions. Mutation of a conserved aromatic residue; Arrangement of functional groups on the basic scaffold of the ribonucleoprotein domain; Importance of stacking interactions in RNA recognition.

The article analyzes various studies which explore the role of omega-3 essential fatty acids in the treatment of depression. It discusses a study by B. Hallahan and colleagues which uses self-harm as depression benchmark and a measure of depression's severity. It relates that the study by K. Su and colleagues showed improvements in terms of the Hamiltonian Rating Scale for Depression (HRDS) by about -15 for depressive patients treated with additional omega-3 fatty acids.

The number of older adults with head and neck squamous cell carcinoma (HNSCC) is increasing, and treatment of these patients is challenging. Although cisplatin-based chemotherapy concomitantly with radiation therapy is considered the standard regimen for patients with locoregionally advanced HNSCC, there is substantial real-world heterogeneity regarding concomitant chemotherapy in older patients with HNSCC. The SENIOR study is an international multicenter cohort study including older patients (≥65 years) with HNSCC treated with definitive radiation therapy at 13 academic centers in the United States and Europe. Patients with concomitant chemoradiation were analyzed regarding overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analyses. Fine‐Gray competing risk regressions were performed regarding the incidence of locoregional failures and distant metastases. Six hundred ninety-seven patients with a median age of 71 years were included in this analysis. Single-agent cisplatin was the most common chemotherapy regimen (n = 310; 44%), followed by cisplatin plus 5-fluorouracil (n = 137; 20%), carboplatin (n = 73; 10%), and mitomycin C plus 5-fluorouracil (n = 64; 9%). Carboplatin-based regimens were associated with diminished PFS (hazard ratio [HR], 1.39 [1.03-1.89]; P <.05) and a higher incidence of locoregional failures (subdistribution HR, 1.54 [1.00-2.38]; P =.05) compared with single-agent cisplatin, whereas OS (HR, 1.15 [0.80-1.65]; P =.46) was comparable. There were no oncological differences between single-agent and multiagent cisplatin regimens (all P >.05). The median cumulative dose of cisplatin was 180 mg/m2 (IQR, 120-200 mg/m2). Cumulative cisplatin doses ≥200 mg/m2 were associated with increased OS (HR, 0.71 [0.53-0.95]; P =.02), increased PFS (HR, 0.66 [0.51-0.87]; P =.003), and lower incidence of locoregional failures (subdistribution HR, 0.50 [0.31-0.80]; P =.004). Higher cumulative cisplatin doses remained an independent prognostic variable in the multivariate regression analysis for OS (HR, 0.996 [0.993-0.999]; P =.009). Single-agent cisplatin can be considered in the standard chemotherapy regimen for older patients with HNSCC who can tolerate cisplatin. Cumulative cisplatin doses are prognostically relevant in older patients with HNSCC. [ABSTRACT FROM AUTHOR]

The current standard for meningioma treatment planning involves magnetic resonance imaging–based guidance. Somatostatin receptor ligands such as 68Ga-DOTATATE are being explored for meningioma treatment planning due to near-universal expression of somatostatin receptors 1 and 2 in meningioma tissue. We hypothesized that 68Ga-DOTATATE positron emission tomography (PET)–guided treatment management for patients with meningiomas is safe and effective and can identify which patients benefit most from adjuvant radiation therapy. A single-institution prospective registry study was created for inclusion of patients with intracranial meningiomas who received a 68Ga-DOTATATE PET/CT to assist with radiation oncologist decision making. Patients who received a PET scan from January 1, 2018, to February 25, 2022, were eligible for inclusion. Of the 60 patients included, 40%, 47%, and 5% had World Health Organization grades 1, 2, and 3 meningiomas, respectively, and 8% (5 patients) had no grade assigned. According to Radiation Therapy Oncology Group 0539 criteria, 22%, 72%, and 7% were categorized as high, intermediate, and low risk, respectively. After completing their PET scans, 48 patients, 11 patients, and 1 patient proceeded with radiation therapy, observation, and redo craniotomy, respectively. The median follow-up for the entire cohort was 19.5 months. Of the 3 patients (5%) who experienced local failure between 9.2 and 28.5 months after diagnosis, 2 had PET-avid disease in their postoperative cavity and elected for observation before recurrence, and 1 high-risk patient with multifocal disease experienced local failure 2 years after a second radiation course and multiple previous recurrences. Notably, 5 patients did not have any local PET uptake and were observed; none of these patients experienced recurrence. Only 1 grade 3 toxicity was attributed to PET-guided radiation. This study examined one of the largest known populations of patients with intracranial meningiomas followed by physicians who used 68Ga-DOTATATE PET-guided therapy. Incorporating 68Ga-DOTATATE PET into future trials may assist with clinician decision making and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Salivary duct carcinomas (SDC) can present with distinct immunologic profiles similar to breast cancer, such as androgen receptor (AR) and HER-2/Neu-positivity, raising the hypothesis that these tumors may respond to hormonal signaling. No consensus exists on how to best manage this entity. The data evaluating the use of targeted therapies, such as androgen deprivation therapy and HER-2 receptor inhibitors, in the front-line setting when treating curatively is limited. We studied patients with AR+ SDC, demonstrating high rates of control and survival using an aggressive approach to treatment. Immunoprofiles were highly variable, highlighting the potential for future treatment individualization. We hope that this may allow for personalization of treatment in the future, using molecular profiling to determine whether the addition of biological agents in the definitive setting against specific targets, such as AR and HER-2/Neu, will further improve outcomes for these patients. Background: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. Methods: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan–Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). Results: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8–6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. Conclusion: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy represents the standard-of-care systemic therapy in patients with recurrent and metastatic head and neck cancer (HNC). However, these patients often present with local disease, which can affect quality of life, and local progression can lead to significant morbidity. Local response rates from immunotherapy alone are subpar. Thus, palliative radiation is often utilized in this scenario. 'QuadShot'(QS), a hypofractionated palliative radiation regimen, can provide symptomatic relief and local control and may potentiate the effects of immunotherapy. There have been no previous studies evaluating the combination of immunotherapy with QS. We found that the combination of QS with concurrent immunotherapy was well tolerated and significantly improved local control compared to QS alone. The median survival of 9.4 months compares favorably to historical controls for patients with HNC treated with QS. This approach represents a promising treatment option for patients with HNC unsuited for curative-intent treatment and warrants prospective evaluation. Objectives: Patients with recurrent and metastatic head and neck cancer (HNC) have limited treatment options. 'QuadShot' (QS), a hypofractionated palliative radiotherapy regimen, can provide symptomatic relief and local control and may potentiate the effects of immune checkpoint inhibitors (ICIs). We compared outcomes of QS ± concurrent ICIs in the palliative treatment of HNC. Materials and Methods: We identified patients who received ≥three cycles of QS from 2017 to 2022 and excluded patients without post-treatment clinical evaluation or imaging. Outcomes for patients who received QS alone were compared to those treated with ICI concurrent with QS, defined as receipt of ICI within 4 weeks of QS. Results: Seventy patients were included, of whom 57% received concurrent ICI. Median age was 65.5 years (interquartile range [IQR]: 57.9–77.8), and 50% patients had received prior radiation to a median dose of 66 Gy (IQR: 60–70). Median follow-up was 8.8 months. Local control was significantly higher with concurrent ICIs (12-month: 85% vs. 63%, p = 0.038). Distant control (12-month: 56% vs. 63%, p = 0.629) and median overall survival (9.0 vs. 10.0 months, p = 0.850) were similar between the two groups. On multivariable analysis, concurrent ICI was a significant predictor of local control (HR for local failure: 0.238; 95% CI: 0.073–0.778; p = 0.018). Overall, 23% patients experienced grade 3 toxicities, which was similar between the two groups. Conclusions: The combination of QS with concurrent ICIs was well tolerated and significantly improved local control compared to QS alone. The median OS of 9.4 months compares favorably to historical controls for patients with HNC treated with QS. This approach represents a promising treatment option for patients with HNC unsuited for curative-intent treatment and warrants prospective evaluation. [ABSTRACT FROM AUTHOR]

Background: Olfactory neuroblastoma (ONB) or esthesioneuroblastoma (ENB) is a rare malignancy of the nasal cavity believed to arise from the olfactory epithelium. The goal of this study was to systematically review the genomics, epigenetics, and cytogenetics of ONB and to understand the potential clinical implications of these studies. Methods: A systematic literature review was performed for articles published before May 2020 using Cochrane, Embase, Pubmed, and Scopus databases. Inclusion criteria included genomics, cytogenetics, and epigenetics studies on ONB. Exclusion criteria included studies not in English or systematic reviews. Articles and abstracts were reviewed by two independent reviewers to reduce bias during article selection and synthesis of results. Of the 36 studies included in this review, 24 were research articles and 12 were abstracts. Results: Although recurrent mutations among ONB tumors are uncommon, alterations in TP53, DMD, PIK3CA, NF1, CDKN2A, CDKN2C, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, SMAD4, FGFR3 and IDH2 genes have been reported in several recent studies. In addition, cytogenetic studies revealed that the landscape of chromosomal aberrations varies widely amongst ONB tumors. Conclusions: The rare character of ONB has limited the sample size available for cytogenetic, genomic, and epigenetic studies and contributes to the limitations of this systematic review. Comprehensive genomic and epigenomic studies with larger cohorts are warranted to validate the initial reports summarized in this review and to identify potential therapeutic targets for ONB. [ABSTRACT FROM AUTHOR]

Stereotactic radiosurgery (SRS) is the current standard of care in patients with brain metastases and controlled extracranial disease. Radiation necrosis (RN) is the dose-limiting side effect of SRS, but the dose constraints especially for fractionated SRS remain poorly defined. We assessed the risk of RN after 3-fraction SRS with a goal to identify specific dose-volume constraints associated with grade 3 or higher RN (G3RN). A single-institutional retrospective review of patients treated with 3-fraction SRS was performed. The primary endpoint was G3RN, which was defined as severe symptoms with evidence of necrosis on magnetic resonance imaging with perfusion and/or biopsy confirmation. Tissue volume around each target lesion was contoured, and volumetric doses per lesion were recorded. Logistic regression models were used to estimate the relationship between RN and each volumetric dose, and normal tissue complication probability modeling was performed using a modified Lyman-Kutcher-Burman model. From 2015 to 2021, 434 patients underwent 539 courses of linear accelerator–based SRS; 2518 lesions were treated. Median SRS dose was 24 Gy. Median follow-up after SRS was 7.9 months, and the median overall survival was 9 months. A total of 93 patients (17.2%) and 123 lesions (4.9%) developed any RN. Forty-two patients (7.8%) and 57 lesions (2.3%) developed G3RN. On logistic regression, V20 and V23 were best predictors of any grade RN and G3RN, respectively, with cutoff values of 4 cc, 10 cc, and 20 cc associated with <5%, <7.5%, and <10% risk of any RN, respectively, and V23 < 15 cc associated with <5% risk of G3RN. With constrained optimization of the normal tissue complication probability Lyman-Kutcher-Burman model for G3RN, we obtained a TD50 (uniform dose resulting in a 50% complication risk) of 31.4 Gy (95% CI, 27.8-35.1 Gy). In patients receiving 3-fraction SRS, G3RN was seen in 7.8% of patients, and 2.3% of the lesions were treated. V20 and V23 were the most robust dosimetric parameters associated with RN. Further studies evaluating the outcomes and RN in patients treated with fractionated SRS compared with single-fraction SRS are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: There is paucity of data on the optimal management of brain metastases in older women ≥65 years old with breast cancer. In this single-institutional retrospective study, we assessed the survival outcomes and treatment patterns of breast cancer patients ≥65 years old with brain metastases and compared them to younger patients. A total of 112 patients were included. Treatment-related adverse events were similar in both groups. Although older women had a poorer median overall survival compared to younger women (9.5 vs. 14.5 months), survival was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and leptomeningeal disease in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with brain metastases and personalized decision-making including a comprehensive geriatric assessment should be considered. Background: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution. Methods: An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan–Meier estimates and Cox proportional hazard regression method were used for survival analyses. Results: A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were <65 years old. Median age at RT was 72 years (range 65–84) compared to 52 years (31–64) in younger patients. There were significantly higher number of older women with ER/PR positive disease (75% vs. 49%, p = 0.036), while younger patients were more frequently triple negative (32% vs. 12%, p = 0.074) and HER2 positive (42% vs. 29%, p = 0.3). Treatment-related adverse events were similar in both groups. Overall, 14.3% patients had any grade radiation necrosis (RN) (older vs. young: 8.3% vs. 16%, p = 0.5) while 5.4% had grade 3 or higher RN (0% vs. 6.8%, p = 0.7). Median OS after RT was poorer in older patients compared to younger patients (9.5 months vs. 14.5 months, p = 0.037), while intracranial PFS from RT was similar between the two groups (9.7 months vs. 7.1 months, p = 0.580). On univariate analysis, significant predictors of OS were age ≥65 years old (hazard risk, HR = 1.70, p = 0.048), KPS ≤ 80 (HR = 2.24, p < 0.001), HER2 positive disease (HR = 0.46, p < 0.001), isolated CNS metastatic disease (HR = 0.29, p < 0.001), number of brain metastases treated with RT (HR = 1.06, p = 0.028), and fractionated SRS (HR = 0.53, p = 0.013). On multivariable analysis, KPS ≤ 80, HER2 negativity and higher number of brain metastases predicted for poorer survival, while age was not a significant factor for OS after adjusting for other variables. Patients who received systemic therapy after SRS had a significantly improved OS on univariate and multivariable analysis (HR = 0.32, p < 0.001). Number of brain metastases treated was the only factor predictive of worse PFS (HR = 1.06, p = 0.041), which implies a 6% additive risk of progression for every additional metastasis treated. Conclusions: Although older women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with BMs and personalized decision-making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in older patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Total laryngectomy (TL) with post-operative radiotherapy (PORT) is recommended for patients with clinically advanced (cT4a) laryngeal cancer and is associated with superior outcomes compared to non-operative treatment with chemoradiation. Despite this, many patients with a diagnosis of laryngeal cancer do not receive TL as part of their treatment course, which places them at risk for inferior oncologic outcomes, and the factors associated with the utilization of TL in this setting remain poorly understood. Thus, the aims of this observational cohort study utilizing the National Cancer Database (NCDB) were both to elucidate the patient and treatment facility characteristics associated with TL utilization in patients with cT4a laryngeal cancer and to evaluate how its usage has changes over time. Background: Despite recommendations for upfront total laryngectomy (TL), many patients with cT4a laryngeal cancer (LC) instead undergo definitive chemoradiation, which is associated with inferior survival. Sociodemographic and oncologic characteristics associated with TL utilization in this population are understudied. Methods: This retrospective cohort study utilized hospital registry data from the National Cancer Database to analyze patients diagnosed with cT4a LC from 2004 to 2017. Patients were stratified by receipt of TL, and patient and facility characteristics were compared between the two groups. Logistic regression analyses and Cox proportional hazards methodology were performed to determine variables associated with receipt of TL and with overall survival (OS), respectively. OS was estimated using the Kaplan–Meier method and compared between treatment groups using log-rank testing. TL usage over time was assessed. Results: There were 11,149 patients identified. TL utilization increased from 36% in 2004 to 55% in 2017. Treatment at an academic/research program (OR 3.06) or integrated network cancer program (OR 1.50), male sex (OR 1.19), and Medicaid insurance (OR 1.31) were associated with increased likelihood of undergoing TL on multivariate analysis (MVA), whereas age > 61 (OR 0.81), Charlson–Deyo comorbidity score ≥ 3 (OR 0.74), and clinically positive regional nodes (OR 0.78 [cN1], OR 0.67 [cN2], OR 0.21 [cN3]) were associated with decreased likelihood. Those undergoing TL with post-operative radiotherapy (+/− chemotherapy) had better survival than those receiving chemoradiation (median OS 121 vs. 97 months; p = 0.003), and TL + PORT was associated with lower risk of death compared to chemoradiation on MVA (HR 0.72; p = 0.024). Conclusions: Usage of TL for cT4a LC is increasing over time but remains below 60%. Patients seeking care at academic/research centers are significantly more likely to undergo TL, highlighting the importance of decreasing barriers to accessing these centers. Increased focus should be placed on understanding and addressing the additional patient-, physician-, and system-level factors that lead to decreased utilization of surgery. [ABSTRACT FROM AUTHOR]

Purpose: To identify the proportion of Emergency Department (ED) visits in cancer patients associated with a mental and substance use disorder (MSUD) and the subsequent healthcare costs. Methods: Nationally representative data on ED visits from 2009 to 2018 was obtained from the Nationwide Emergency Department Sample (NEDS). We identified cancer‐related visits with or without a MSUD using the Clinical Classifications Software diagnoses documented during the ED visit. Survey‐adjusted frequencies and proportions of ED visits among adult cancer patients with or without a MSUD was evaluated. Survey‐adjusted multivariable logistic regression models were used to examine demographic and clinical predictors of the presence of an MSUD and the likelihood of hospital admission for patients with a primary MSUD. Results: Among 54,004,462 ED visits with a cancer diagnosis between 2009 and 2018, 11,803,966 (22%) were associated with a MSUD. Compared to a primary diagnosis of cancer, patients who presented to the ED with a chief complaint of MSUD were more likely to be female (54% vs. 49%), younger (median: 58 vs. 66), more likely to have Medicaid insurance, and more likely to be discharged home. The three most common MSUD diagnoses among cancer patients were alcohol‐related disorders, anxiety disorders, and depressive disorders. The total costs associated with a primary MSUD from 2009 to 2018 was $3,133,432,103, of which alcohol‐related disorders claimed the largest majority. Younger age (OR per 10‐year increase: 0.86, 95% CI: 0.85, 0.86) and female sex (OR: 1.34, 95% CI: 1.33–1.35) were associated with higher odds of having an MSUD. Conclusions: Our findings demonstrate a high burden of psychiatric and substance use illness in the cancer population and provide the rationale for early psychosocial intervention to support these patients. These findings demonstrate a high rate of mental and substance use disorder (MSUD) in cancer patients with one in five cancer‐related visits to the ED presenting with a MSUD. Younger age and female gender were more likely associated with mental or substance use disorders. Healthcare costs for MSUD were 3 billion dollars over 10 years. [ABSTRACT FROM AUTHOR]

Purpose: Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown.Methods and Materials: We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms.Results: Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol.Conclusions: Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593). [ABSTRACT FROM AUTHOR]

Simple Summary: Racial disparities in head and neck cancers contribute to mortality in racial/ethnic (R/E) minorities, but the specific risk factors associated with inferior survival are poorly understood. The aim of our retrospective study was to describe and report clinical and treatment-related survival outcomes by specific racial and ethnic groups, and determine if specific demographic, clinical, and socioeconomic factors could be associated with inferior outcomes among R/E minorities. In this study, we demonstrated that Black race was independently associated with worse overall survival rates across multiple head and neck disease subsites. We also showed that Black patients presented with more advanced stage of disease and had longer total treatment package times compared to White patients. We conclude that more research is needed to understand the biological basis for the worse outcomes identified in our results, after controlling for the social determinants of health. Background: Racial/ethnic (R/E) minorities with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared to White patients. While disparities in patient outcomes for R/E minorities have been well documented, the specific drivers of the inferior outcomes remain poorly understood. Patients and Methods: This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database (NCDB) from 2000–2016. Patient outcomes were stratified by R/E groups including White, Black, Hispanic, Native American/Other, and Asian. The main outcome in this study was overall survival (OS). Univariate time-to-event survival analyses were performed using the Kaplan–Meier product limit estimates and the log-rank test to evaluate the differences between strata. Results: There were 304,138 patients with HNSCC identified in this study, of which 262,762 (86.3%) were White, 32,528 (10.6%) were Black, 6191 were Asian (2.0%), and 2657 were Native American/Other (0.9%). Black R/E minorities were more likely to be uninsured (9% vs. 5%, p < 0.0001), have Medicaid insurance (22% vs. 8%, p < 0.0001), be in a lower income quartile (<30,000, 42% vs. 13%, p < 0.0001), have metastatic disease (5% vs. 2%, p < 0.001), and have a total treatment time 6 days longer than White patients (median 107 vs. 101 days, p < 0.001). The 5-year OS for White, Black, Native American/Other, and Asian patients was 50.8%, 38.6%, 51.1%, and 55.8%, respectively. Among the oropharynx HNSCC patients, the 5-year OS rates in p16+ White, Black, and Asian patients were 65.7%, 39.4%%, and 55%, respectively. After a multivariate analysis, Black race was still associated with an inferior OS (HR:1.09, 95% CI: 1.03–1.15, p = 0.002). Conclusions: This large cohort study of HNSCC patients demonstrates that Black race is independently associated with worse OS, in part due to socioeconomic, clinical, and treatment-related factors. [ABSTRACT FROM AUTHOR]

Purpose/Objective(s): Microbiome has been shown to affect tumorigenesis by promoting inflammation. However, the association between the upper aerodigestive microbiome and head and neck squamous cell carcinoma (HNSCC) is not well established. Hypoxia is a modifiable factor associated with poor radiation response. Our study analyzed the HNSCC tumor samples from The Cancer Genome Atlas (TCGA) to investigate the relationship between different HNSCC tumor subsites, hypoxia, and local tumor microbiome composition. Results: A total of 357 patients were included [Oral cavity (OC) = 226, Oropharynx (OPx) = 53, and Larynx/Hypopharynx (LHPx) = 78], of which 12.8%, 71.7%, and 10.3%, respectively, were HPV positive. The mean (SD) hypoxia scores were 30.18 (11.10), 24.31 (14.13), and 29.53 (12.61) in OC, OPx, and LHPx tumors, respectively, with higher values indicating greater hypoxia. The hypoxia score was significantly higher for OC tumors compared to OPx (p = 0.044) and LHPx (p = 0.002). There was no significant correlation between hypoxia and HPV status. Pseudomonas sp. in OC, Actinomyces sp. and Sulfurimonas sp. in OPx, and Filifactor, Pseudomonas and Actinomyces sp. in LHPx had the strongest association with the hypoxia score. Materials/Methods: Tumor RNAseq samples from TCGA were processed, and the R package "tmesig" was used to calculate gene expression signature, including the Buffa hypoxia (BH) score, a validated hypoxia signature using 52 hypoxia-regulated genes. Microbe relative abundances were modeled with primary tumor location and a high vs. low tertile BH score applying a gamma-distributed generalized linear regression using the "stats" package in R, with adjusted p-value < 0.05 considered significant. Conclusions: In our study, oral cavity tumors were found to be more hypoxic compared to other head and neck subsites, which could potentially contribute to their radiation resistance. For each subsite, distinct microbial populations were over-represented in hypoxic tumors in a subsite-specific manner. Further studies focusing on an association between microbiome, hypoxia, and patient outcomes are warranted. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model.Methods: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction.Results: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79.Conclusions: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis typically featuring lower extremity osteosclerosis (96%) from Langerin-negative histiocytes with fibrosis. Central nervous system (CNS)-only disease is extremely rare, and particularly difficult to diagnose and manage. Neurologic complaints may be refractory to systemic therapy (ST), and the role of radiation therapy (RT) is undefined. We present a patient with ECD of the medulla complicated by respiratory failure and strength deficits with disseminated leptomeningeal disease (LMD) but not systemic disease, representing the first report of CNS-limited ECD with LMD. He received upfront craniospinal irradiation (CSI), representing a rare account of CSI for ESD, with marked clinical improvement resulting in extubation and improved strength. CSI facilitated excellent preservation of quality of life, and no treatment-related toxicity was observed prior to eventual, unrelated cardiopulmonary arrest. Thus, palliative CSI may augment ST by safely offering improved local control and symptomatic relief for CNS ECD. [ABSTRACT FROM AUTHOR]

This article presents an effort toward building an artificial intelligence (AI) assisted framework, coined ReconGAN, for creating a realistic digital twin of the human vertebra and predicting the risk of vertebral fracture (VF). ReconGAN consists of a deep convolutional generative adversarial network (DCGAN), image‐processing steps, and finite element (FE) based shape optimization to reconstruct the vertebra model. This DCGAN model is trained using a set of quantitative micro‐computed tomography (micro‐QCT) images of the trabecular bone obtained from cadaveric samples. The quality of synthetic trabecular models generated using DCGAN are verified by comparing a set of its statistical microstructural descriptors with those of the imaging data. The synthesized trabecular microstructure is then infused into the vertebra cortical shell extracted from the patient's diagnostic CT scans using an FE‐based shape optimization approach to achieve a smooth transition between trabecular to cortical regions. The final geometrical model of the vertebra is converted into a high‐fidelity FE model to simulate the VF response using a continuum damage model under compression and flexion loading conditions. A feasibility study is presented to demonstrate the applicability of digital twins generated using this AI‐assisted framework to predict the risk of VF in a cancer patient with spinal metastasis. [ABSTRACT FROM AUTHOR]

We present the application of ReconGAN, introduced in a previous study, for simulating the vertebroplasty (VP) operation and its impact on the fracture response of a vertebral body. ReconGAN consists of a Deep Convolutional Generative Adversarial Network (DCGAN) and a finite element based shape optimization algorithm to virtually reconstruct the trabecular bone microstructure. The VP procedure involves injecting shear‐thinning liquid bone cement through a needle in the trabecular region to reinforce a diseased or fractured vertebra. To simulate this treatment modality, computational fluid dynamics (CFD) is employed to predict the morphology of the injected cement within the bone microstructure. A power‐law equation is utilized to characterize the non‐Newtonian shear‐thinning behavior of the polymethyl methacrylate (PMMA) bone cement during injection simulations. The CFD model is coupled with the level‐set method to simulate the motion of the interface separating bone cement and bone marrow. After predicting the cement morphology, a data co‐registration algorithm is employed to transform the CFD model to a high‐fidelity continuum damage mechanics (CDM) finite element model of the augmented vertebra for predicting the fracture response. A feasibility study is presented to demonstrate the ability of this CFD‐CDM framework to investigate the effect of VP on the mechanical integrity of the vertebral body in a cancer patient with a lytic metastatic tumor. [ABSTRACT FROM AUTHOR]

Adequate dose homogeneity and full prescription dose delivery to the scalp still remains a dosimetric problem during scalp irradiation due to the anatomical shape of the cranium. Confounding variables such as gravity, the irregular and convex shape of the cranium, air gaps between scalp surface and commercial bolus, and potential inconsistencies in a 3D printed bolus can negatively impact the dose delivered to the scalp surface during scalp irradiation. The purpose of this retrospective case study was to implement the use of a 3D milled rigid bolus technique combined with volumetric modulated arc therapy (VMAT) treatment planning and evaluate the dosimetric efficacy in delivering dose to the surface of the scalp. The 8-patient retrospective case study consisted of patients with a scalp lesion treated using a 3D milled bolus, VMAT, 6 megavoltage (MV) photon beams, and aligned for treatment using daily conebeam computed tomography (CT) and 6° of freedom couch positioning. Dose volume histograms (DVHs) were used to evaluate maximum dose delivered to the planning target volumes (PTVs) while the dose homogeneity index (DHI) was calculated and compared to that of an ideal value of 1. The researchers evaluated the minimum dose delivered to the individual PTVs after plan normalization. The researchers found that the 3D milled bolus coupled with volumetric modulated arc therapy increased surface dose homogeneity, while also increasing the percentage of planning target volumes receiving full prescription dose. With statistically significant results, patient specific 3D milled rigid bolus offers a viable bolus option for treatment of superficial scalp lesions when combined with volumetric modulated arc therapy treatment planning. However, a larger sample size used in a scientific research study across multiple institutions would be desirable to validate these case study findings. [ABSTRACT FROM AUTHOR]

Oral Mucositis (OM) continues to be an oncologic challenge in the context of antineoplastic therapy for head and neck cancer (HNC) treatment. It is a dose-limiting toxicity of chemotherapy and radiation treatment and negatively impacts quality of life and cancer treatment efficacy. Significant effort in the field of OM has been made to help alleviate its symptoms and its subsequent clinical and economic impact. Despite these advances, the treatment of oral mucositis remains difficult and focuses on palliative measures. There are, however, many promising new biological targets currently undergoing investigation to ameliorate or help prevent the toxicity of OM in HNC. Some of these targets undergoing investigation in phase 2 and 3 clinical trials are further highlighted along with the pathobiology of OM, clinical course, prevention, and management measures. [ABSTRACT FROM AUTHOR]

Background: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.Methods: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834.Findings: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups.Interpretation: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.Funding: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Intraoperative resection of positive margins operation improves local control in oral tongue cancer. • Patients that underwent immediate re-resection of a positive margin had similar rates of local control as those who with negative margins. • Technology that enhances intraoperative margin analysis has significant potential to improve local control in oral tongue cancer. This study investigates the impact of immediate resection of positive margins on local control of oral tongue cancer. We analyzed 273 consecutive oral tongue cancers resected from 2013 to 2018. Additional resection was performed in cases during the initial operation based on surgeon inspection of the specimen and/or frozen margins. Positive margins were defined as invasive carcinoma/high-grade dysplasia < 1 mm from the inked edge. Patients were grouped as follows: negative margin (Group 1); positive margin with immediate additional tissue resection (Group 2); and positive margin without additional tissue resection (Group 3). Overall, the rate of local recurrence was 7.7 % (21/273), and the rate of positive main specimen margin was 17.9 %. Of these patients, 38.8 % (19/49) underwent immediate additional resection of the presumed positive margin. Group 3 had higher local recurrence rates than Group 1 after adjustment for T -stage (aHR 2.8 [95 % CI 1.0–7.7], p = 0.04). Group 2 had similar rates of local recurrence (aHR 0.45 [95 % CI 0.06–3.6], p = 0.45). Three year local recurrence free survival for Groups 1, 2, and 3 were 91 %, 92 % and 73 %, respectively. Compared to the main specimen margin, sensitivity of intraoperative frozen tumor bed margins was 17.4 %, and specificity was 95 %. In patients with positive main specimen margins, anticipation and detection in real-time with immediate additional tissue resection reduced local recurrence to rates similar to those with negative main specimen margins. These findings support the use of technology to provide real-time intraoperative margin data and guide additional resection for improved local control. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Radiation induced cranial nerve palsy (RICNP) involving the lower cranial nerves (CNs) is a serious complication of head and neck radiotherapy (RT). Recommendations for delineating the lower CNs on RT planning studies do not exist. The aim of the current study is to develop a standardized methodology for contouring CNs IX–XII, which would help in establishing RT limiting doses for organs at risk (OAR). Methods: Using anatomic texts, radiologic data, and guidance from experts in head and neck anatomy, we developed step-by-step instructions for delineating CNs IX–XII on computed tomography (CT) imaging. These structures were then contoured on five consecutive patients who underwent definitive RT for locally-advanced head and neck cancer (LAHNC). RT doses delivered to the lower CNs were calculated. Results: We successfully developed a contouring atlas for CNs IX–XII. The median total dose to the planning target volume (PTV) was 70Gy (range: 66–70Gy). The median CN (IX–XI) and (XII) volumes were 10c.c (range: 8–12c.c) and 8c.c (range: 7–10c.c), respectively. The median V50, V60, V66, and V70 of the CN (IX–XI) and (XII) volumes were (85, 77, 71, 65) and (88, 80, 74, 64) respectively. The median maximal dose to the CN (IX–XI) and (XII) were 72Gy (range: 66–77) and 71Gy (range: 64–78), respectively. Conclusions: We have generated simple instructions for delineating the lower CNs on RT planning imaging. Further analyses to explore the relationship between lower CN dosing and the risk of RICNP are recommended in order to establish limiting doses for these OARs. [ABSTRACT FROM AUTHOR]

Simple Summary: The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma. Patients with locoregional, pathologically high-risk disease recur frequently despite adjuvant cisplatin–radiation therapy. Targeting PD1 may reverse immunosuppression induced by cancer, chemotherapy, or radiation therapy. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule for adding fixed-dose pembrolizumab to standard adjuvant cisplatin–radiation therapy. Eligible patients had resected, human papillomavirus-negative, stage III–IV oral cavity, pharynx, or larynx cancer with extracapsular nodal extension or positive margin. A total of four dose-limiting toxicities were observed in 34 patients (fever, wound infection, diverticulitis, nausea). Three of four were successfully rechallenged with pembrolizumab. The recommended phase II schedule was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before adjuvant CRT. The regimen was safe and feasible in the cooperative group setting. Further development is warranted. The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin–radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III–IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted. [ABSTRACT FROM AUTHOR]

Laryngeal squamous cell carcinoma is the second most common head and neck cancer. Its pathogenesis is strongly associated with smoking. The management of this disease is challenging and mandates multidisciplinary care. Currently, accepted treatment modalities include surgery, radiation therapy, and chemotherapy—all focused on improving survival while preserving organ function. Despite changes in smoking patterns resulting in a declining incidence of laryngeal cancer, the overall outcomes for this disease have not improved in the recent past, likely due to changes in treatment patterns and treatment-related toxicities. Here, we review emerging concepts and novel strategies in the use of radiation therapy in the management of laryngeal squamous cell carcinoma that could improve the relationship between tumor control and normal tissue damage (therapeutic ratio). [ABSTRACT FROM AUTHOR]