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Prior studies of conventional chemotherapy or epidermal growth factor receptor inhibitors for advanced (ie, locally advanced cutaneous squamous cell carcinoma [laCSCC] or metastatic [mCSCC]) cutaneous squamous cell cancer enrolled ≤ 40 patients. This retrospective, observational study assessed real‐world treatment patterns and clinical outcomes in patients with unresectable laCSCC or mCSCC using electronic health records of patients who initiated first‐line (1L) systemic treatment from 1 January 2008 to 31 December 2015, with follow‐up to 30 September 2017. The median duration of follow‐up from 1L treatment was 10.1 months (range 0.03‐67.6 months). Duration of therapy (DOT) and overall survival (OS) were assessed using Kaplan‐Meier analysis. Response rate was calculated as the proportion of patients who achieved physician‐assessed‐response. Eighty‐two patients were identified (17 laCSCC and 65 mCSCC). Median age at 1L treatment initiation was 75 years; 85% were male, 88% had an Eastern Cooperative Oncology Group performance status of 1, and 84% had received radiotherapy. The most common 1L regimens were carboplatin + paclitaxel (27%) and cetuximab monotherapy (24%). The median 1L DOT was 4.1 months for laCSCC and 2.3 months for mCSCC. The physician‐assessed response rate for 1L therapy was 17.6% for laCSCC, and 18.5% for mCSCC. The median OS from 1L treatment initiation was 16.2 months for laCSCC, and 15.3 months for mCSCC. Only 24 patients (29%) received second‐line therapy. This is the largest retrospective data set regarding patients with advanced CSCC treated with anticancer systemic therapy prior to approval of the anti‐programmed cell death‐1 antibody, cemiplimab. Efficacy was low in both laCSCC and mCSCC. These data provide historic benchmarks for outcomes in patients with advanced CSCC prior to Food and Drug Administration approval of cemiplimab‐rwlc. [ABSTRACT FROM AUTHOR]

Abstract: Background: The human papillomavirus (HPV) E6 oncoprotein enhances the oncogenic potential of ErbB proteins in HPV‐related malignancies. This phase I study evaluates the addition of afatinib, an ErbB family inhibitor, and ribavirin to paclitaxel and carboplatin induction chemotherapy in HPV‐associated, locally advanced oropharyngeal squamous cell carcinoma (SCC). Methods: This dose escalation study included 2 doses of oral afatinib: 30 and 40 mg daily. Ribavirin dosing was weight based. Paclitaxel (80 mg/m2) and carboplatin (area under the curve [AUC] 1.5) were administered on days 1 and 8 of each 21‐day cycle. After 3 cycles, patients were removed from protocol to receive definitive treatment. Results: Among 10 patients, there were no dose‐limiting toxicities. Six patients (67%) had unconfirmed objective partial responses. The 2‐year progression‐free survival rate was 75%. Conclusion: Afatinib, ribavirin, paclitaxel, and carboplatin induction chemotherapy is safe and well tolerated. The phase II recommended dose of afatinib is 40 mg oral daily in this combination regimen. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to evaluate the efficacy and tolerability of the addition of 2 monoclonal antibodies, bevacizumab and cetuximab, to 2 cycles of high-dose cisplatin administered concurrently with intensity-modulated radiation therapy (IMRT) for head and neck squamous cell carcinoma (HNSCC). Methods Patients with newly diagnosed stage III/IVB (M0) HNSCC received cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2 weekly), bevacizumab (15 mg/kg, days 1 and 22), and cisplatin (50 mg/m2, days 1, 2, 22, and 23) concurrently with IMRT (70 Gy). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety and tolerability. Results Among 30 patients enrolled in this study, the primary tumor site was the oropharynx in 24 patients (p16 immunohistochemistry was positive in 17, negative in 1, and not done in 6 of the oropharyngeal tumors). Median age was 57 years (range, 38-77 years) and 27 patients had clinical stage IVA disease. All patients completed the full planned dose of radiation therapy. The most common ≥ grade 3 adverse events were lymphopenia, mucositis (functional), and dysphagia. With a median follow-up of 33.8 months, 2-year PFS was 88.5% (95% confidence interval [CI] = 68.1-96.1) and 2-year OS was 92.8% (95% CI = 74.2-98.1). Conclusion The addition of bevacizumab and cetuximab to 2 cycles of cisplatin, given concurrently with IMRT, was well-tolerated and was associated with favorable efficacy outcomes in this patient population. © 2015 Wiley Periodicals, Inc. Head Neck 38: E566-E570, 2016 [ABSTRACT FROM AUTHOR]

BACKGROUND Although obesity increases risk and negatively affects survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with prediagnosis weight loss, are unknown. METHODS Patients with T1-T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥ 30 kg/m2), overweight (25-29.9 kg/m2), or normal (18.5-24.9 kg/m2). Clinical outcomes, including disease-specific survival, recurrence-free survival, and overall survival, were compared by BMI group using Cox regression. RESULTS From 2000 to 2009, 155 patients (90 men, 65 women) of median age 57 years (range, 18-86 years) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse disease-specific survival compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI] = 1.07-6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI = 1.69-14.81; P = .004). A consistent association was seen between obesity and worse recurrence-free survival (HR = 1.87; 95% CI = 0.90-3.88) and between obesity and worse overall survival (HR = 2.03; 95% CI = 0.88-4.65) though without reaching statistical significance ( P = .09 and P = .10, respectively) in multivariable analyses. CONCLUSIONS In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including prediagnosis weight loss. Cancer 2014;120:983-991. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m2 weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins. [ABSTRACT FROM AUTHOR]

BACKGROUND: For patients with stage III through IVB head and neck squamous cell carcinoma (HNSCC), concurrent high-dose cisplatin plus radiation therapy is a widely accepted standard of care. HNSCC tumors that express high levels of vascular endothelial growth factor have been associated with a worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation. METHODS: Planned treatment consisted of definitive intensity-modulated radiation therapy (IMRT) (total, 70 grays) with concurrent cisplatin (50 mg/m2 on days 1, 2, 22, 23, 43, and 44) and bevacizumab (15 mg/kg on days 1, 22, and 43). The primary endpoint was 2-year progression-free survival (PFS), and overall survival (OS) was a secondary endpoint. RESULTS: Forty-two previously untreated patients (34 men and 8 women; median age, 55 years; range, 27-75 years) with stage III through IV HNSCC without distant metastasis (oropharyngeal carcinoma, 39 patients; laryngeal carcinoma, 3 patients) were treated. Human papillomavirus (HPV) status by was determined by in situ hybridization (HPV positive, 16 patients; HPV negative, 14 patients, unknown HPV status, 12 patients). The toxicities (determined according to version 3.0 of Common Terminology Criteria for Adverse Events Common) that were experienced by all patients (any grade) were mucositis, lymphopenia, leukopenia, throat pain, fatigue, and anemia. There were 2 treatment-related deaths, including 1 sudden death and 1 death from aspiration pneumonia. The median follow-up was approximately 31.8 months (range, <3 to 51 months). The 2-year PFS rate was 75.9% (95% confidence interval, 63.9%-90.1%), and the 2-year OS rate was 88% (95% confidence interval, 78.6%-98.4%). Among 32 patients for whom post-treatment Head and Neck Performance Status Scores were obtained (median, 5.6 months after completing radiation therapy), scores of 100 for eating, speech, and diet, respectively, were recorded among 75%, 84%, and 50% of patients. BACKGROUND: The addition of bevacizumab to high-dose cisplatin plus IMRT did not appear to increase toxicity to unacceptable levels among patients with HNSCC, and the efficacy results were encouraging. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background. Expression of p16 is a marker for human papillomavirus (HPV)-related carcinogenesis in head and neck cancer. The purpose of this study is to determine if p16 immunoreactivity is associated with aberrant expression of components of the PI3 kinase pathway. Methods. A tissue microarray (TMA) was constructed for 46 archived tonsillar squamous cell carcinoma specimens. Clinical demographics of these patients were analyzed, and the TMA was interrogated with antibodies directed against p16, phosphorylated AktSer473, phosphorylated S6Ser240/244, phosphorylated S6Ser235/236, phosphorylated 4E-BP1Thr37/46, phosphorylated eIF4ESer209, PTEN, p21, and p53. Results. There was a significant correlation between history of tobacco abuse (>10 pack/years) and absence of p16 expression ( p = .01). Expression of p16 was significantly associated with immunoreactivity of p21 ( p = .02), PTEN ( p = .02), and phosphorylated eIF4E ( p = .03). There was no evidence of association between p16 status and expression of phosphorylated S6, phosphorylated 4E-BP1, or p53. Conclusion. p16 positive tonsillar squamous cell carcinoma is characterized by expression of phosphorylated eIF4E that may occur via a mammalian target of rapamycin (mTOR)-independent mechanism. © 2010 Wiley Periodicals, Inc. Head Neck, 2010 [ABSTRACT FROM AUTHOR]

BACKGROUND: Preclinical studies suggest that additive or synergistic effects are achieved with the combination of pemetrexed plus gemcitabine. A phase 1 study of pemetrexed plus gemcitabine given every 2 weeks demonstrated encouraging preliminary efficacy against head and neck squamous cell cancer (HNSCC). METHODS: This was an open-label, single-institution, single-arm, phase 2 study for patients who had received no more than 2 cytotoxic regimens for recurrent and/or metastatic HNSCC. All patients received pemetrexed 500 mg/m² intravenously plus gemcitabine 1250 mg/m² intravenously every 2 weeks with vitamin B12 and folate support. The primary endpoint was the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST); secondary endpoints were to estimate overall survival and to evaluate safety and tolerability. RESULTS: Twenty-five patients received therapy. All patients had received prior radiotherapy, and half had received prior cytotoxic chemotherapy for recurrent and/or metastatic disease. Neutropenia (grade ≥3) occurred in 24% of patients. Four patients (16%) had a partial response (PR) according to RECIST, and 5 additional patients (20%) had objective tumor reductions of >20 but <30% did not meet RECIST criteria for a PR. The median overall survival for all treated patients was 8.8 months. CONCLUSIONS: Treatment with pemetrexed plus gemcitabine every 2 weeks with vitamin support generally was well tolerated. The results of this study provided further evidence that pemetrexed may have significant palliative activity against advanced HNSCC. Cancer 2011;117:795-801. [ABSTRACT FROM AUTHOR]

In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study. Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1–16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy. Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77–13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08–12.62; P < 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations. Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain. [Display omitted] [Display omitted] • This study examined patient-reported outcomes for cervical cancer treatments. • Patient-reported outcomes generally were stable/improved with cemiplimab and worsened with chemotherapy. • Quality of life and physical functioning significantly favoured cemiplimab in patients with squamous cell carcinoma. • Many other functioning and symptom scales also favoured cemiplimab versus chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Introduction Durvalumab selectively blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1. Encouraging clinical activity and manageable safety were reported in urothelial carcinoma, non–small-cell lung cancer (NSCLC), hepatocellular carcinoma (HC) and small-cell lung cancer (SCLC) in a multicenter phase I/II study. Safety and clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) were evaluated in the expansion phase. Methods Patients received 10 mg/kg of durvalumab intravenously every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. The primary objective was safety; clinical activity was a secondary objective. Results Sixty-two patients were enrolled and evaluable (received first dose ≥24 weeks before data cutoff). Median age was 57 years; 40.3% were human papillomavirus (HPV)-positive; 32.3% had tumour cell PD-L1 expression ≥25%, and 62.9% were current/former smokers. They had a median of 2 prior systemic treatments (range, 1–13). All-causality adverse events (AEs) occurred in 98.4%; drug-related AEs occurred in 59.7% and were grade III–IV in 9.7%. There were no drug-related discontinuations or deaths. Objective response rate (blinded independent central review) was 6.5% (15.0% for PD-L1 ≥25%, 2.6% for <25%). Median time to response was 2.7 months (range, 1.2–5.5); median duration was 12.4 months (range, 3.5–20.5+). Median progression-free survival was 1.4 months; median overall survival (OS) was 8.4 months. OS rate was 62% at 6 months and 38% at 12 months (42% for PD-L1 ≥25%, 36% for <25%). Conclusions Durvalumab safety in HNSCC was manageable and consistent with other cohorts of the study. Early, durable responses in these heavily pretreated patients warrant further investigation; phase III monotherapy and combination therapy studies are ongoing. Clinical trial registry clinicaltrials.gov NCT01693562; MedImmune study 1108. Highlights • Durvalumab monotherapy was safe in previously treated recurrent/metastatic head and neck squamous cell carcinoma. • Durable antitumour responses were observed, similar to other tumour cohorts. • Objective response rate and disease control rate were greater in patients with ≥25% vs <25% tumoural PD-L1 expression. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the effect of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) on treatment outcomes in patients treated with definitive intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC). Methods and Materials: Between September 1998 and April 2009, a total of 442 patients with squamous cell carcinoma of the oropharynx were treated with IMRT with curative intent at our center. Thirty patients treated postoperatively and 2 additional patients who started treatment more than 6 months after diagnosis were excluded. A total of 340 patients with restorable treatment plans were included in this present study. The majority of the patients underwent concurrent platinum-based chemotherapy. The pGTV and nGTV were calculated using the original clinical treatment plans. Cox proportional hazards models and log-rank tests were used to evaluate the correlation between tumor volumes and overall survival (OS), and competing risks analysis tools were used to evaluate the correlation between local failure (LF), regional failure (RF), distant metastatic failure (DMF) vs. tumor volumes with death as a competing risk. Results: Median follow-up among surviving patients was 34 months (range, 5-67). The 2-year cumulative incidence of LF, RF and DF in this cohort of patients was 6.1%, 5.2%, and 12.2%, respectively. The 2-year OS rate was 88.6%. Univariate analysis determined pGTV and T-stage correlated with LF (p < 0.0001 and p = 0.004, respectively), whereas nGTV was not associated with RF. On multivariate analysis, pGTV and N-stage were independent risk factors for overall survival (p = 0.0003 and p = 0.0073, respectively) and distant control (p = 0.0008 and p = 0.002, respectively). Conclusions: In this cohort of patients with OPC treated with IMRT, pGTV was found to be associated with overall survival, local failure, and distant metastatic failure. [ABSTRACT FROM AUTHOR]

Purpose: Dynamic contrast-enhanced MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of this study was to assess the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery. Methods and Materials: Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE-MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using the Tofts model. DCE-MRI parameters were related to treatment outcome (progression-free survival [PFS] and overall survival [OS]). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD), or dead of other causes (DOC). Prognostic significance was assessed using the log-rank test for single variables and Cox proportional hazards regression for combinations of variables. Results: At last clinical follow-up, for Stage III, all 12 patients were NED. For Stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. Ktrans is volume transfer constant. In a stepwise Cox regression, skewness of Ktrans (volume transfer constant) was the strongest predictor for Stage IV patients (PFS and OS: p <0.001). Conclusion: Our study shows that skewness of Ktrans was the strongest predictor of PFS and OS in Stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter Ktrans as a predictor of outcome in these patients. [ABSTRACT FROM AUTHOR]

Purpose: To correlate proton magnetic resonance spectroscopy (1H-MRS), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and 18F-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET) of nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) for assessment of tumor biology. Additionally, pretreatment multimodality imaging was evaluated for its efficacy in predicting short-term response to treatment. Methods and Materials: Metastatic neck nodes were imaged with 1H-MRS, DCE-MRI, and [18F]FDG PET in 16 patients with newly diagnosed HNSCC, before treatment. Short-term patient radiological response was evaluated at 3 to 4 months. Correlations among 1H-MRS (choline concentration relative to water [Cho/W]), DCE-MRI (volume transfer constant [K trans]; volume fraction of the extravascular extracellular space [v e]; and redistribution rate constant [k ep]), and [18F]FDG PET (standard uptake value [SUV] and total lesion glycolysis [TLG]) were calculated using nonparametric Spearman rank correlation. To predict short-term responses, logistic regression analysis was performed. Results: A significant positive correlation was found between Cho/W and TLG (ρ = 0.599; p = 0.031). Cho/W correlated negatively with heterogeneity measures of standard deviation std(v e) (ρ = −0.691; p = 0.004) and std(k ep) (ρ = −0.704; p = 0.003). Maximum SUV (SUVmax) values correlated strongly with MRI tumor volume (ρ = 0.643; p = 0.007). Logistic regression indicated that std(K trans) and SUVmean were significant predictors of short-term response (p < 0.07). Conclusion: Pretreatment multimodality imaging using 1H-MRS, DCE-MRI, and [18F]FDG PET is feasible in HNSCC patients with nodal metastases. Additionally, combined DCE-MRI and [18F]FDG PET parameters were predictive of short-term response to treatment. [ABSTRACT FROM AUTHOR]