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Purpose: The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response. Patients and Methods: A phase II study of cetuximab and durvalumab in metastatic HNSCC was conducted. Eligible patients had measurable disease. Patients who had received both cetuximab and an ICI were excluded. The primary endpoint was objective response rate (ORR) by RECIST 1.1 at 6 months. Results: As of April 2022, 35 patients enrolled, of whom 33 received at least 1 dose of durvalumab and were included in the response analysis. Eleven patients (33%) had received prior platinum-based chemotherapy, 10 an ICI (30%), and 1 patient (3%) cetuximab. ORR was 39% (13/33) with a median duration of response of 8.6 months [95% confidence interval (CI): 6.5–16.8]. Median progression-free and overall survivals were 5.8 months (95% CI: 3.7–14.1) and 9.6 months (95% CI: 4.8–16.3), respectively. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE, with no treatment-related deaths. Overall and progression-free survival did not correlate with PD-L1 status. NK cell cytotoxic activity was increased by cetuximab and further increased with the addition of durvalumab in responders. Conclusions: The combination of cetuximab and durvalumab demonstrated durable activity with a tolerable safety profile in metastatic HNSCC and warrants further investigation.

Purpose/ObjectivesDetermining the optimal postoperative reirradiation volume following salvage surgery for recurrent head and neck squamous cell cancer (HNSCC) is critical given the significant risk of severe reirradiation toxicity and need to provide durable local control. The purpose of this study was to evaluate patterns of locoregional recurrence (LRR) after surgical salvage and adjuvant reirradiation with IMRT.Materials/MethodsPatterns of LRR for 61 patients treated consecutively between 2003-2014 who received post-operative IMRT reirradiation to ≥60 Gy for recurrent HNSCC were determined by 2 methods: 1) physician classification via visual comparison of post-radiotherapy imaging to reirradiation plans; and 2) using deformable image registration (DIR). Those without evaluable CT planning image data were excluded. All recurrences were verified by biopsy or radiological progression. Failures were defined as in-field, marginal, or out-of-field. Logistic regression analyses were performed to identify predictors for LRR.ResultsA total of 55 patients were eligible for analysis and 23 (42%) had documented LRR after reirradiation. Location of recurrent disease prior to salvage surgery (lymphatic vs. mucosal) was the only significant predictor of LRR after post-operative reirradiation (p = 0.037). Physician classification of LRR yielded 14 (61%) in-field failures, 3 (13%) marginal failures, and 6 (26%) out-of-field failures, while DIR yielded 10 (44%) in-field failures, 4 (17%) marginal failures, and 9 (39%) out-of-field failures. Most failures (57%) occurred within the original site of recurrence or first echelon lymphatic drainage. Of patients who had a free flap placed during salvage surgery, 56% of failures occurred within 1 cm of the surgical flap.ConclusionThe majority of locoregional recurrences after surgical salvage and adjuvant reirradiation for recurrent HNSCC occurred marginally or in-field, often in or near the anastomotic site.

Supplementary Figure 5. Comparison of outcomes between patients that were PD-L1 positive vs. negative A) Progression-free survival and B) Overall survival comparison

Purpose:The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response.Patients and Methods:A phase II study of cetuximab and durvalumab in metastatic HNSCC was conducted. Eligible patients had measurable disease. Patients who had received both cetuximab and an ICI were excluded. The primary endpoint was objective response rate (ORR) by RECIST 1.1 at 6 months.Results:As of April 2022, 35 patients enrolled, of whom 33 received at least 1 dose of durvalumab and were included in the response analysis. Eleven patients (33%) had received prior platinum-based chemotherapy, 10 an ICI (30%), and 1 patient (3%) cetuximab. ORR was 39% (13/33) with a median duration of response of 8.6 months [95% confidence interval (CI): 6.5–16.8]. Median progression-free and overall survivals were 5.8 months (95% CI: 3.7–14.1) and 9.6 months (95% CI: 4.8–16.3), respectively. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE, with no treatment-related deaths. Overall and progression-free survival did not correlate with PD-L1 status. NK cell cytotoxic activity was increased by cetuximab and further increased with the addition of durvalumab in responders.Conclusions:The combination of cetuximab and durvalumab demonstrated durable activity with a tolerable safety profile in metastatic HNSCC and warrants further investigation.

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Study protocol

Purpose: Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection. Patients and Methods: This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery. Results: Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8–88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58–91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)–positive and PD-L1–negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083). Conclusions: Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.

Financial toxicity due to cancer treatment is a significant concern for patients. To increase transparency related to treatment costs, the Hospital Price Transparency Final Rule (HPTFR) was passed on January 1, 2021. We used hospital pricing documentation to explore the costs of head and neck cancer (HNC) radiotherapy in Ohio, hypothesizing a large variance in cost based on geography.Radiation oncology facilities were identified using the Ohio Hospital Association (OHA) website. The reported technical charges for Current Procedural Terminology (CPT) codes commonly billed in the definitive management of HNC with radiotherapy were recorded, and total treatment costs (TTCs) were calculated.Of 254 OHA-listed hospitals, 102 had radiation oncology facilities. Seven facilities were excluded due to a lack of pricing data, leaving 95 facilities in 40 of 88 counties. Median TTC was $176,496. Average TTC was $184,831 (SD: $83,982). The 22 rural hospitals charged less compared with nonrural hospitals, with a difference in medians of $72,084.38 (P0.001). No difference was found between the TTCs of nonprofit and public hospitals (P=0.348) nor between academically affiliated and nonacademically affiliated hospitals (P=0.247). There is no correlation between county median household income and TTC (R2=0.0007). Rather, TTCs varied drastically across counties, regardless of income levels.There is a wide range of treatment costs for HNC patients receiving definitive radiotherapy in Ohio, and no variables fully explain this variance. Further policies are needed to improve the quality, quantity, and accessibility of health care data to address financial toxicity.

This study compare dosimetric parameters and secondary malignancy risk (SMN) using intensity modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) plans for the treatment of sinonasal cancer (SC). After IRB-approval, 10 patients previously treated with IMPT for cancers of the ethmoid, sphenoid, maxillary, or frontal sinuses were identified. Dosimetrists blinded to the IMPT plans generated VMAT plans for comparison. Volume coverage and dose to organs at risk (OAR) were recorded and compared. Organ equivalent dose (OED) of tissues outside of the treatment volume was used to define the excess absolute and relative risk of SMNs. In all cases, both VMAT and IMPT provided acceptable target volume coverage and were able to meet OAR constraints. IMPT was superior for brain V10, V30, and mean, brainstem D0.01 ipsilateral cochlea V30, contralateral cochlea mean, contralateral lacrimal gland mean, contralateral parotid mean, spinal cord D0.01 and body outside of the CTV V10, V20, and V30. VMAT was superior for ipsilateral eye mean, ipsilateral lens mean, CTV V100 and maximum hotspot. The relative risk of SMNs with VMAT compared to IMPT is 3.35 (95% CI, 1.92-5.89). For the treatment of SC, IMPT spares OARs that are not immediately adjacent to the treatment volume and reduces the risk of SMNs when compared to VMAT. VMAT spares OARs abutting the target volume better than IMPT and has more homogenous target coverage. Tumors of the ethmoid sinus, benefit more from IMPT, while tumors located elsewhere require application of our findings on a case by case basis.

Supplementary Figure from Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck

Supplementary Figure from Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local–Regionally Advanced Head and Neck Squamous Cell Carcinoma

Supplementary Data from Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local–Regionally Advanced Head and Neck Squamous Cell Carcinoma

Purpose:Patients with resected, local–regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%–69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear.Patients and Methods:Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1–3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60–66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0.Results:From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27–80), 30% were female, 86% had stage T3–T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%–90%) in the intermediate-risk group and 66% (95% CI, 55%–84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%–77%). No new safety signals were identified.Conclusions:Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.

Supplementary Table from Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local–Regionally Advanced Head and Neck Squamous Cell Carcinoma

Purpose:Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection.Patients and Methods:This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery.Results:Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8–88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58–91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)–positive and PD-L1–negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083).Conclusions:Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.

Correlative studies’ methodology

BackgroundMetformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401,NCT02083692).MethodsPeripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses.ResultsIncreased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1.ConclusionsOur data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC.

Introduction Head and neck reconstructive surgery using a flap is increasingly common. Best practices and outcomes for postoperative radiotherapy (poRT) with flaps have not been specified. We aimed to provide consensus recommendations to assist clinical decision-making highlighting areas of uncertainty in the presence of flaps. Material and methods Radiation, medical, and surgical oncologists were assembled from GORTEC and internationally with the Head and Neck Cancer International Group (HNCIG). The consensus-building approach covered 59 topics across four domains: (1) identification of postoperative tissue changes on imaging for flap delineation, (2) understanding of tumor relapse risks and target volume definitions, (3) functional radiation-induced deterioration, (4) feasibility of flap avoidance. Results Across the 4 domains, international consensus (median score ≥ 7/9) was achieved only for functional deterioration (73.3%); other consensus rates were 55.6% for poRT avoidance of flap structures, 41.2% for flap definition and 11.1% for tumor spread patterns. Radiation-induced flap fibrosis or atrophy and their functional impact was well recognized while flap necrosis was not, suggesting dose-volume adaptation for the former. Flap avoidance was recommended to minimize bone flap osteoradionecrosis but not soft-tissue toxicity. The need for identification (CT planning, fiducials, accurate operative report) and targeting of the junction area at risk between native tissues and flap was well recognized. Experts variably considered flaps as prone to tumor dissemination or not. Discrepancies in rating of 11 items among international reviewing participants are shown. Conclusion International GORTEC and HNCIG-endorsed recommendations were generated for the management of flaps in head and neck radiotherapy. Considerable knowledge gaps hinder further consensus, in particular with respect to tumor spread patterns.

Unilateral radiation to cervical nodes has been used as a de-escalation strategy in well-lateralized tonsil cancers. The efficacy of this approach with multiple ipsilateral nodes is not established. The study hypothesis was that unilateral radiation for American Joint Committee on Cancer (AJCC)-7 T1-2N2b tonsillar cancer results in a low rate of contralateral nodal failure.This study was a retrospective chart review of patients with AJCC-7 T1-2N2b tonsillar cancer from 2 academic institutions who were treated with unilateral radiation. The primary endpoint was the contralateral nodal failure rate. Locoregional control, overall survival, and the need for gastrostomy tube placement were additional endpoints.The study cohort included 66 patients treated between 2005 and 2016. The median follow-up time was 80.9 months; contralateral nodal failure occurred in 2/66 (3.0%) patients at 4.1 and 20.9 months, respectively. Both patients underwent salvage treatment with long-term subsequent survival. Overall locoregional control at both 2 and 5 years was 93.9% and the median duration of control was not reached. Overall survival at 5 years was 92.4%.The use of unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer resulted in low rates of contralateral nodal failure. This outcome demonstrates the safety of considering unilateral radiation treatment in patients with a relatively high ipsilateral nodal burden.

OBJECTIVES/HYPOTHESIS Dysphagia is a treatment-related complication of head and neck cancer (HNCA). We demonstrate the predictive value of a modified head and neck swallow scale (m-HNSW) adapted from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35 (EORTC-QLQ-H&N35). STUDY DESIGN Retrospective Cohort Study. METHODS Retrospective, single-center cohort study utilizing a prospectively collected database of HNCA patients in a high-volume tertiary referral center. 736 HNCA patients more than 2 years from completion of treatment were identified. EORTC-QLQ-H&N35 data collected from at least one of three defined episodes of care were used. The m-HNSW uses three questions to form a 9-point dysphagia scale. A Cox proportional hazards model was used to determine the effect of the m-HNSW while controlling for demographics, tumor staging, site, and treatment. RESULTS Using data from 3, 6, 12 months from treatment, we analyzed a subset that included 328 patients. Three months after the completion of therapy, the m-HNSW score had a significant association with 1 (HR = 1.24, P = .0005) and 5 year survival (HR = 1.19, P = .0002) after accounting for body mass index. Six (HR = 1.14, P = .014) and 12 month (hazard ratio (HR) = 1.33, P

Osteoradionecrosis is a relatively rare but potentially morbid and costly complication of radiation therapy for head and neck cancer. Multidisciplinary diagnosis and treatment are essential. Despite evidence guiding individual aspects of care for osteoradionecrosis, there is a lack of broad consensus on the overall diagnosis and management of this condition. This study comprehensively reviews the literature, with a focus on the past 10 years, to guide evaluation and treatment.

Current frontline chemotherapy and radiotherapy for head and neck cancer (HNC) is insufficient as ~60% of patients relapse within two years, indicating a need to identify novel targeted therapies to improve survival outcomes for HNC patients. Human papilloma virus (HPV) incidence is a major cause of head and neck squamous cell carcinoma (HNSCC) in addition to tobacco use. HPV- HNSCC patients are less responsive to frontline treatment than HPV+ HNSCC patients. However, HPV- and HPV+ HNSCC patients are treated similarly. The cell cycle serine-threonine kinase polo-like kinase 1 (Plk1) is known to be overexpressed in HNC. The Cancer Genome Atlas (TCGA) revealed that high expression of Plk1 correlates with worse survival in HNSCC patients (p Citation Format: Julianna Korns, Samuel Thompson, Trisha Wise-Draper, Vinita Takiar. Plk1 signaling as a therapeutic target for HPV- head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2832.

Background: Although the epidermal growth factor receptor (EGFR) is overexpressed in 80-90% of Head and Neck Squamous Cell Carcinomas (HNSCCs), response to anti-EGFR targeted therapy remains low. Trans-activation of other receptor tyrosine kinases is a common mechanism of resistance to EGFR directed therapy. The RON receptor tyrosine kinase (Macrophage stimulating 1-receptor/MST1R) is a member of the c-MET oncogene family. While limited, prior studies by our group and others have reported elevated RON expression in over 60% of primary HNSCC samples and that receptor cross talk exists with RON and EGFR. Based on this information, we hypothesize that the pro-tumorigeneic role of RON and its crosstalk with EGFR contributes to HNSCC growth and to anti-EGFR therapeutic failure. To test this hypothesis, we examined the expression level of RON and EGFR in human and mouse HNSCC cell lines and in HNSCC patient samples from publicly available databases. Further, we investigated the role of RON in radiation resistance as radiation is a primary treatment modality for HNSCC. Results: Immunoblotting demonstrated strong RON expression in eight of nine human HNSCC cell lines tested and strong EGFR expression in six HNSCC cell lines. In exploring mRNA expression of RON using the Kaplan-Meier Plotter HNSCC RNA-seq dataset, high RON expression was associated with poorer overall survival (P = 0.054) in patients with Stage 3 HNSCC and low mutation burden. To assess the relationship between RON and EGFR, mRNA expression was mined in the GSE6631 dataset from the NCBI gene expression omnibus (GEO). Our analysis found RON to be significantly overexpressed in HNSCC samples compared to normal matched controls (P = 0.029). Interestingly, EGFR mRNA expression was negatively correlated (r = -0.2) with RON mRNA expression from the same patients. This inverse correlation between RON and EGFR expression was corroborated by immunoblotting data of HNSCC lines, UM-SCC-090 and 93-UV-147T which demonstrated low levels of EGFR and high levels of RON. As ionizing radiation is a pillar of HNSCC treatment and is often delivered concurrent with anti-EGFR therapy, we next examined the relative radiosensitivity in multiple murine and human cancer cell lines with and without RON expression using colony formation assays. Preliminary studies demonstrated significantly increased colony formation in high RON-expressing cells relative to low RON-expressing cells. Conclusion: RON is expressed at high levels in multiple HNSCC cell lines and in human samples. Protein expression data and in silica analyses support an inverse association between EGFR and RON. RON expression is associated with radiation resistance. Future studies will investigate interactions between RON and EGFR, and whether RON inhibition can increase anti-EGFR treatment and radiation sensitivity in HNSCC cells. Citation Format: Zhixin Lu, Vinita Takiar, Susan E. Waltz. RON receptor tyrosine kinase in head and neck cancer: a potential target for overcoming resistance to anti-EGFR therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 377.

Purpose: Patients with resected, local–regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%–69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear. Patients and Methods: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1–3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60–66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0. Results: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27–80), 30% were female, 86% had stage T3–T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%–90%) in the intermediate-risk group and 66% (95% CI, 55%–84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%–77%). No new safety signals were identified. Conclusions: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.

Background Human papillomavirus has been implicated in the carcinogenesis of squamous cell carcinoma of the anal canal. p16 expression and the presence of human papillomavirus DNA have been used to define human papillomavirus-positive patients, but neither approach has been validated against the standard of human papillomavirus E6/7 mRNA expression at this disease site. Objective This study aimed to evaluate the acceptability of p16 immunohistochemistry as a surrogate to E6/7 mRNA expression in identifying human papillomavirus-mediated squamous cell carcinoma of the anal canal. Design This was a retrospective analysis of a previously constructed tissue microarray. Settings This study was conducted at a tertiary academic center. Patients Biopsies and resection specimens from patients diagnosed with squamous cell carcinoma of the anal canal at the study institution from 2005 to 2015 were reviewed for sample adequacy. Main outcome measures Concordance between p16 positivity by immunohistochemistry and E6/7 mRNA expression by in situ hybridization was evaluated. Sensitivity, specificity, and positive predictive value were assessed. Results Among the 25 patients evaluated, p16 and E6/7 mRNA results were concordant in 24 of 25 specimens (96%). Of the 24 concordant samples, there were 23 true positives (p16+ and E6/7+) and 1 true negative (p16- and E6/7-). One specimen was discordant (p16- and E6/7+) between p16 and E6/7 mRNA (4%). This resulted in a sensitivity of 96% and a specificity of 100%. Positive predictive value of p16 immunohistochemistry for E6/7 mRNA expression was 100%. Limitations This study was limited by its retrospective nature and small sample size. It only assessed diagnostic parameters rather than prognostic implications. Conclusions In this study, the clinically prevalent method of p16 immunohistochemistry showed excellent concordance with the standard of E6/7 mRNA expression and demonstrated its potential to serve as a surrogate for identifying human papillomavirus-induced squamous cell carcinoma of the anal canal. See Video Abstract at http://links.lww.com/DCR/B448. Evaluando la confiabilidad y el valor predictivo positivo de p, como sustituto de la expresin de arnm de e / , mediada por el virus del papiloma humano, en carcinoma de clulas escamosas del canal anal ANTECEDENTES:El virus del papiloma humano se ha relacionado en la carcinogenesis del carcinoma de celulas escamosas del canal anal. La expresion de p16 y la presencia de ADN del virus del papiloma humano, se han utilizado para definir a los pacientes positivos al virus del papiloma humano. Pero ninguno de estos enfoques, han sido validados frente al estandar de oro de la expresion del ARNm del virus del papiloma humano E6 / 7, en este sitio de la enfermedad.OBJETIVO:El estudio tuvo como objetivo, evaluar la aceptabilidad de la inmunohistoquimica del p16, como sustituto de la expresion de ARNm de E6 / 7, en la identificacion del carcinoma de celulas escamosas del canal anal, mediada por virus del papiloma humano.DISENO:Fue un analisis retrospectivo de un microarreglo de tejido previamente construido.AJUSTE:El estudio se realizo en un centro academico terciario.PACIENTES:Se revisaron biopsias y muestras de reseccion de pacientes diagnosticados con carcinoma de celulas escamosas del canal anal, en la institucion del estudio, entre 2005 y 2015 para determinar la idoneidad de la muestra.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluo la concordancia entre la positividad de p16 por inmunohistoquimica y la expresion de ARNm de E6 / 7 por hibridacion in situ. Se evaluaron la sensibilidad, especificidad y valor predictivo positivo.RESULTADOS:Entre los 25 pacientes evaluados, los resultados del ARNm de p16 y E6 / 7 fueron concordantes en 24/25 muestras (96%). De las 24 muestras concordantes, hubo 23 positivos verdaderos (p16 + y E6 / 7 +) y un negativo verdadero (p16- y E6 / 7-). Una muestra fue discordante (p16- y E6 / 7 +) entre p16 y ARNm de E6 / 7 (4%). Esto resulto en una sensibilidad del 96% y una especificidad del 100%. El valor predictivo positivo de la inmunohistoquimica de p16 para la expresion de ARNm de E6 / 7 fue del 100%.LIMITACIONES:El estudio estuvo limitado por su naturaleza retrospectiva y por el tamano pequeno de la muestra. Solamente evaluo los parametros de diagnostico, en lugar de las implicaciones pronosticas.CONCLUSIONES:En este estudio, el metodo clinico prevalente de inmunohistoquimica p16, mostro una excelente concordancia con el estandar de oro de la expresion de ARNm de E6 / 7 y demostro su potencial para servir, como sustituto para identificar el carcinoma de celulas escamosas del canal anal, inducido por el virus del papiloma humano. Consulte Video Resumen en http://links.lww.com/DCR/B448.

Purpose To determine the optimal dose‐volume constraint for laryngeal sparing using three commonly employed intensity modulated radiation therapy (IMRT) approaches in patients with oropharyngeal cancer treated to the bilateral neck. Materials and methods Thirty patients with stage II‐IVA oropharynx cancers received definitive radiotherapy with split‐field IMRT (SF‐IMRT) to the bilateral neck between 2008 and 2013. Each case was re‐planned using whole‐field IMRT (WF‐IMRT) and volumetric modulated arc therapy (VMAT) and plan quality metrics and dose to laryngeal structures was evaluated. Two larynx volumes were defined and compared on the current study: the Radiation Therapy Oncology Group (RTOG) larynx as defined per the RTOG 1016 protocol and the MDACC larynx defined as the components of the larynx bounded by the superior and inferior extent of the thyroid cartilage. Results Target coverage, conformity, and heterogeneity indices were similar in all techniques. The RTOG larynx mean dose was lower with WF‐IMRT than SF‐IMRT (22.1 vs 25.8 Gy; P

Background Human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than HNSCC due to other risk factors. However, there is significant heterogeneity within HPV-associated HNSCC and 25% of these patients still do poorly despite receiving aggressive therapy. We currently have no good molecular tools to differentiate and exclude this “high-risk” sub-population and focus on “low-risk” patients for clinical trials. This has been a potential barrier to identifying successful de-escalation treatment strategies in HPV-associated HNSCC. We conducted an analysis of molecular markers with a well-known role in the pathogenesis of HPV-associated HNSCC and hypothesized that these markers could help independently predict recurrence and prognosis in these patients and therefore help identify at the molecular level “low-risk” patients suitable for de-escalation trials. Methods We analyzed 24 tumor specimens of patients with p16+ HNSCC who underwent definitive resection as primary treatment. Tissue microarray (TMA) was generated from the 24 pathology blocks and immunohistochemistry (IHC) was performed using highly specific antibodies for our chosen biomarkers (PI3K-PTEN, AKT pathway, mTOR, 4EBP1, S6, and pAMPK, ERCC-1). Transcriptome data was also obtained for 7 p16+ HNSCC patients from The Cancer Genome Atlas (TCGA). Data from the TMA and TCGA were analyzed for association of relapse-free survival (RFS) and overall survival (OS) with protein and gene expression of the chosen biomarkers. Results Increased pAMPK protein activity by IHC and AMPK gene expression by TCGA gene expression data was correlated with improved RFS with a trend towards statistical significance. Conclusions This data suggests that increased pAMPK activity and expression may portend a better prognosis in HPV-associated HNSCC undergoing primary definitive resection. However, these findings require validation in larger studies.

Although radiation therapy (RT) is one of the mainstays of head and neck cancer (HNC) treatment, innovative approaches are needed to further improve treatment outcomes. A significant challenge has been to design delivery strategies that focus high doses of radiation on the tumor tissue while minimizing damage to surrounding structures. In the last decade, there has been increasing interest in harnessing high atomic number materials (Z-elements) as nanoparticle radiosensitizers that can also be specifically directed to the tumor bed. Metallic nanoparticles typically display chemical inertness in cellular and subcellular systems but serve as significant radioenhancers for synergistic tumor cell killing in the presence of ionizing radiation. In this review, we discuss the current research and therapeutic efficacy of metal nanoparticle (MNP)-based radiosensitizers, specifically in the treatment of HNC with an emphasis on gold- (AuNPs), gadolinium- (AGdIX), and silver- (Ag) based nanoparticles together with the metallic oxide-based hafnium (Hf), zinc (ZnO) and iron (SPION) nanoparticles. Both in vitro and in vivo systems for different ionizing radiations including photons and protons were reviewed. Finally, the current status of preclinical and clinical studies using MNP-enhanced radiation therapy is discussed.

The polo-like kinase (Plk) family is comprised of five different members (Plk1-5), each with their own distinct functions. Plk family members participate in pivotal cell division processes as well as in non-mitotic roles. Importantly, Plk expression has been correlated with various disease states, including cancer. Multiples therapies, which primarily target Plk1, are currently being investigated alone or in combination with other agents for clinical use in different cancers. As the role of Plks in disease progression becomes more prominent, it is important to outline their functions as cell cycle regulators and more. This review summarizes the structure and both mitotic and non-mitotic functions of each of the five Plk family members, sequentially. Additionally, the proposed mechanisms for how Plks contribute to tumorigenesis and the therapeutics currently under investigation are outlined.

IntroductionSurgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection.Methods and MaterialsFindings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts—surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)—were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated.ResultsForty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years.ConclusionsAmong patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts.Clinical Trial RegistrationClinicalTrials.gov, identifiers NCT02794675 and NCT02467738.

Recurrent and second primary head and neck cancers represent a clinical challenge due to frequently unresectable and/or locally advanced disease. Given that many of these patients have received definitive doses of radiation previously, reirradiation is associated with significant morbidity. Use of modern approaches such as conformal photon-based planning and charged particle therapy using protons or carbon ions allows for greater sparing of normal tissues while maintaining or escalating doses to tumor volumes. While the reirradiation data has consistently shown benefits to local control and even survival from escalation of radiotherapy dose, excessive cumulative doses can result in severe toxicities, including fatal carotid blowout syndrome. For all modalities, appropriate patient selection is of utmost importance. Large-scale trials and multi-institutional registry data are needed to standardize treatment modalities, and to determine optimal doses and volumes for reirradiation.

Simple Summary Human papillomavirus (HPV) has been associated with multiple cancers in the anogenital and upper aerodigestive tracts. In the head and neck region, HPV-positive cancers are common in oropharynx, with rising incidence and a well-established association with more favorable patient outcomes. However, the relationship with prognosis of sinonasal squamous cell carcinoma (SNSCC) has been much less often studied and is presently unclear. To better elucidate this relationship, we performed a systematic review and meta-analysis of the biomedical literature to determine the aggregate effect across studies. In doing so, we observed significantly better overall survival associated with HPV-positive SNSCC. Therefore, we conclude that HPV testing may be useful for determining patient prognosis and potentially guiding treatment decisions. Abstract Human papillomavirus (HPV) is detectable in a subset of sinonasal squamous cell carcinoma (SNSCC), but the impact on patient outcomes is presently unclear due to a modest number of studies with limited statistical power. Therefore, we conducted a systematic review and meta-analysis to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on overall (OS) or disease-free survival (DFS) for SNSCC by HPV status. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or, when not provided, indirectly estimated from each manuscript. Summary survival curves for 5-year OS and estimating survival probability by HPV status at pre-specified time intervals from study-specific Kaplan-Meier curves generated 2-year DFS. Log HRs and log CIs were combined across studies to generate summary estimates and a corresponding 95% CIs for OS and DFS. We identified ten unique studies reporting on OS and four for DFS. We observed a significant association between HPV and OS (summary HR = 0.51, 95% CI: 0.38–0.70) with relatively low heterogeneity between studies. These results indicate that HPV is a significant predictor of more favorable survival for SNSCC, and thus may be a useful biomarker for prognostication and, potentially, treatment modulation.

Background The 5-year overall survival (OS) rate remains at 50% for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), thereby underscoring the need for improved treatments. An antidiabetic agent, metformin, was found in retrospective studies to improve survival in patients with HNSCC. Therefore, the authors conducted a phase 1 dose escalation study combining metformin with chemoradiotherapy in patients with LAHNSCC. Methods Nondiabetic patients with LAHNSCC were enrolled in the current study to receive escalating doses of metformin and CRT based on the modified toxicity probability interval design. Metformin cohort doses included 2000 mg, 2550 mg, and 3000 mg daily in divided doses in addition to cisplatin (at a dose of 100 mg/m2 on days 1, 22, and 43) and standard radiotherapy (70 grays). Adverse events were categorized as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Results Twenty patients were enrolled, 2 of whom withdrew consent. The median age of the patients was 56 years and the majority were male (83%), were white (88%), had p16-positive disease (72%), and were tobacco users (61%). The median length of metformin exposure was 28.5 days. The most common grade ≥3 toxicities were nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Dose-limiting toxicities included diarrhea and acute kidney injury. After a median follow-up of 19 months, the 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No hypoglycemia events or lactic acidosis were observed. Cisplatin administration did not appear to affect metformin pharmacokinetics. The maximum tolerated dose for metformin could not be determined given the limited number of patients who tolerated metformin during chemoradiotherapy. Conclusions To the authors' knowledge, the current study is the first phase 1 trial combining metformin with chemoradiotherapy. Rates of overall survival and progression-free survival were encouraging in this limited patient population, and warrant further investigation in a phase 2 trial.