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Background: Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors., Methods: Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high., Results: The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control., Conclusions: Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors., Trial Registration Number: NCT04510129., Competing Interests: Competing interests: KCF, JE, JH, RLW, MMP, DNM, JIG, and EJD are employed, have stock interests, and/or a financial relationship with Cofactor Genomics, maker of the OncoPrism-HNSCC test., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: VEGF, a key mediator of angiogenesis and resistance to immunotherapy, is overexpressed in head and neck squamous cell carcinoma (HNSCC). We aimed to determine the recommended phase 2 dose of ramucirumab, a selective VEGFR2 inhibitor, given with pembrolizumab and the objective response rate of this combination as first-line treatment for recurrent or metastatic HNSCC., Methods: In this single-centre, phase 1/2 trial, which was done at Washington University (St Louis, MO, USA), eligible patients were aged 18 years or older with incurable recurrent or metastatic HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. Patients in phase 2 were required to have had no previous systemic therapy for recurrent or metastatic disease. In a dose de-escalation phase 1 design, patients received ramucirumab (starting dose 10 mg/kg given intravenously) and pembrolizumab (200 mg intravenously) on day 1 of each 21-day cycle. The recommended phase 2 dose of ramucirumab was defined as the highest dose at which one or fewer of three patients had dose-limiting toxicity during cycle one (primary endpoint of phase 1). In a Simon's two-stage phase 2 design, patients received the recommended phase 2 dose of ramucirumab and pembrolizumab. Tumour response (primary endpoint of phase 2) was assessed by Response Evaluation Criteria in Solid Tumours (version 1.1). We hypothesised that there would be an objective response rate of 32% or higher (null ≤13%). Eight or more responses among 33 evaluable patients (those with at least one response assessment) was evidence for activity (80% power; one-sided α=0·05). Analyses were done per protocol. The trial is registered with ClinicalTrials.gov, NCT03650764, and is closed to enrolment., Findings: Between June 18, 2019, and Feb 11, 2021, three patients enrolled and were treated in phase 1 and 37 patients in phase 2. Median age of all patients was 64 years (IQR 59-72). 36 (90%) of 40 patients were men and four (10%) were women, and 36 (90%) patients were White, three (8%) were Black or African American, and one (3%) was Asian. In phase 1, no dose-limiting toxicity event occurred. The recommended phase 2 dose of ramucirumab was 10 mg/kg. Median follow-up for patients on phase 2 was 14·8 months (IQR 4·9-31·0). In phase 2, 18 (55%; 95% CI 38-70) of 33 evaluable patients had an objective response, including confirmed complete response in 11 patients, confirmed partial response in six patients, and unconfirmed partial response in one patient. The most common grade 3 or worse adverse events were dysphagia (14 [38%] of 37 patients), lung infection (11 [30%]), lymphocyte count decrease (ten [27%]), hypophosphataemia (nine [24%]), and hypertension (eight [22%]). No treatment-related deaths were recorded., Interpretation: Ramucirumab and pembrolizumab were safe to administer to patients with recurrent or metastatic HNSCC, and the objective response rate with this combination as first-line treatment for recurrent or metastatic HNSCC was favourable. Further studies of ramucirumab and pembrolizumab in patients with recurrent or metastatic HNSCC are warranted., Funding: Lilly and the Joseph Sanchez Foundation., Competing Interests: Declaration of interests DA reports research funding from Eli Lilly for the submitted work and consulting or scientific advisory board support from Washington University (St Louis, MO, USA), Merck, Cue Biopharma, Inhibrx, Blueprint Medicines, Exelixis, Immunitas, Kura Oncology, Vaccinex, Xilio, Boehringer Ingelheim, Eisai Europe, Coherus Biosciences, Gilead Biosciences, TargImmune Therapeutics, and Jazz Pharmaceuticals; travel support from Natco; leadership role on the NCCN practice guidelines and the Barnes Jewish Hospital Pharmacy and Therapeutics Committee; and institutional research support from Pfizer, Merck, Celgene/Bristol Myers Squibb, Novartis, AstraZeneca, Blueprint Medicine, Kura Oncology, Cue Biopharma, Cofactor Genomics, Debiopharm Group, ISA pharmaceuticals, Gilead Sciences, BeiGene, Roche, Vaccinex, Immutep, Hookpia Biotech, Epizyme, Adlai Nortye, BioAtla, Boehringer Ingelheim, Calliditas Therapeutics, Genmab, Natco Pharma, Tizona Therapeutics, Erasca, Alentis, Inhibrx, Seagen, Surface (now Coherus), Takeda, Xilio, Aveo, GSK, and Johnson & Johnson, outside the submitted work. JCL reports travel support from Natco, outside the submitted work. PO reports research funding from Merck and HiFiBio, payment for testimony, and travel support from Natco, outside the submitted work. JL declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed, but further insights into the mechanisms underlying resistance and approaches to improve responses are needed., Experimental Design: We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-sequencing data to explore the mechanism of aPD1 resistance. Tumors and tumor-draining lymph nodes (DLN) from MOC models were analyzed for antigen-specific priming. CCL5 expression was enforced in an aPD1-resistant model., Results: An aPD1-resistant mouse model showed poor priming in the tumor DLN due to type 1 conventional dendritic cell (cDC1) dysfunction, which correlated with exhausted and poorly responsive antigen-specific T cells. Tumor microenvironment analysis also showed decreased cDC1 in aPD1-resistant tumors compared with sensitive tumors. Following neoadjuvant aPD1 therapy, pathologic responses in patients also positively correlated with baseline transcriptomic cDC1 signatures. In an aPD1-resistant model, intratumoral cDC1 vaccine was sufficient to restore aPD1 response by enhancing T-cell infiltration and increasing antigen-specific responses with improved tumor control. Mechanistically, CCL5 expression significantly correlated with neoadjuvant aPD1 response and enforced expression of CCL5 in an aPD1-resistant model, enhanced cDC1 tumor infiltration, restored antigen-specific responses, and recovered sensitivity to aPD1 treatment., Conclusions: These data highlight the contribution of tumor-infiltrating cDC1 in HNSCC aPD1 response and approaches to enhance cDC1 infiltration and function that may circumvent aPD1 resistance in patients with HNSCC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objectives: Evaluate factors associated with adherence to ototoxicity monitoring among patients with head and neck cancer treated with cisplatin and radiation therapy at a tertiary care center., Methods: We performed a single-institution retrospective cohort study on adults with head and neck cancer treated with cisplatin and radiation therapy who participated in an ototoxicity monitoring program. The primary outcomes were rates of post-treatment audiograms at the following time points: one, three, six, 12, and greater than 12 months. Multivariable logistic regression was performed to identify risk factors associated with complete loss of follow-up after pre-treatment evaluation., Results: Two hundred ninety-four head and neck cancer patients were analyzed. Overall, 220 (74.8%) patients had at least one post-treatment audiogram; 58 (20.0%) patients had more than one audiogram. The time point with the highest follow-up rate was at 3 months (n = 170, 57.8%); rates at the remaining times ranged from 7.1% to 14.3%. When controlling for covariates, patients without insurance and those with stage IV cancers were associated with complete loss of audiologic follow-up (aOR = 7.18, 95% CI = 2.75-19.90; aOR = 1.96, 95% CI = 1.02-3.77, respectively). Among 156 patients recommended for a hearing aid, only 39 (24.8%) patients received one., Conclusions: Head and neck cancer patients enrolled in an ototoxicity monitoring program demonstrate moderately high follow-up rates for at least one post-treatment audiogram. However, follow-up tapers dramatically after 6 months, and overall hearing aid utilization is low. Further research is needed to understand barriers to long-term audiologic follow-up and hearing aid utilization to decrease untreated hearing loss in cancer survivorship., Level of Evidence: Level 3 Laryngoscope, 133:3161-3168, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy-refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC., Experimental Design: We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells., Results: Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets., Conclusions: These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC., (©2023 American Association for Cancer Research.)

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility., Significance: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162., (©2023 The Authors; Published by the American Association for Cancer Research.)

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8 + T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8 + tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX + ) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX + ZNF683 + CD8 + TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103 + PD-1 + CD8 + T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683 + CTX + TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683 + CTX + TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Objective: To explore whether deintensification of adjuvant therapy reduces ototoxicity among patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC)., Study Design: Retrospective cohort study., Setting: Single academic center., Methods: The ototoxicity rate among adult patients with HPV-related OPSCC enrolled in the Minimalist Trial (MINT), a prospective phase 2 trial of surgery followed by risk-adjusted deintensified adjuvant therapy (42 Gy radiation given alone or with a single 100 mg/m 2 dose of cisplatin), was compared to that among a historical cohort treated with standard adjuvant therapy (60-66 Gy radiation with up to three 100 mg/m 2 doses of cisplatin). Ototoxicity was defined as Common Terminology Criteria for Adverse Events v5.0 ≥ Grade 2. Mixed model analysis was performed to investigate the association between deintensified adjuvant therapy and treatment-related hearing loss., Results: A total of 29 patients (58 ears) were analyzed in the MINT cohort, and 27 patients (54 ears) in the historical cohort. The ototoxicity rate was 5% (n = 3/58 ears) in the MINT cohort and 46% (n = 25/54 ears) in the historical cohort (difference, 41%; 95% confidence interval [CI] = 27%-56%). Patients in the MINT cohort demonstrated a 95% decrease in risk of ototoxicity compared to those in the historical cohort (adjusted odds ratio: 0.05, 95% CI = 0.01-0.31). Differences in estimated marginal mean threshold shifts were statistically and clinically significant at frequencies ≥ 3 kHz., Conclusion: The deintensified adjuvant therapy given in MINT led to less ototoxicity than standard adjuvant therapy among patients with HPV-related OPSCC., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objective: Chemoradiation for patients with laryngeal squamous cell carcinoma (SCC) may achieve organ preservation, but appropriate patient selection remains unknown. This study investigates pre-treatment risk factors associated with functional and survival outcomes after radiation-based therapy in patients with advanced laryngeal SCC., Methods: A retrospective cohort study was performed on 75 adult patients with stage III or IV laryngeal SCC receiving definitive radiation-based therapy from 1997 to 2016 at a tertiary care center. Tracheostomy and gastrostomy dependence were the primary functional outcomes. Multivariable logistic regressions were performed to evaluate relationships between pre-treatment factors and tracheostomy and gastrostomy dependence. Time-to-event analyses were performed to determine risk factors associated with overall survival., Results: Among 75 patients included in the analysis, 30 (40%) patients were tracheostomy dependent and 31 (41%) were gastrostomy tube dependent. The median length of follow-up was 31 months (range = 1 to 142 months). Pre-treatment tracheostomy was a significant predictor of post-treatment tracheostomy (aOR = 13.9, 95% CI = 3.35 to 57.5) and moderate-severe comorbidity was a significant predictor of post-treatment gastrostomy dependence (aOR = 2.96, 95% CI = 1.04 to 8.43). The five-year overall survival was 51% (95% CI = 38 to 64%). Pre-treatment gastrostomy tube dependence was associated with an increased risk of death (aHR = 2.45, 95% CI = 1.09 to 5.53)., Conclusions: Baseline laryngeal functional status and overall health in advanced laryngeal SCC are associated with poor functional outcomes after radiation-based therapy, highlighting the importance of patient selection when deciding between surgical and non-surgical treatment plans. Laryngoscope, 133:594-600, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Abstract: Preclinical data support investigation of selective CDK4/6 inhibition as a therapeutic strategy for human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC). Phase 1 clinical trials established the feasibility of combining palbociclib with cetuximab in patients with recurrent or metastatic HNSCC. Nonrandomized phase II trials showed that palbociclib plus cetuximab resulted in efficacy outcomes better than cetuximab in biomarker-unselected, platinum-resistant or cetuximab-resistant, HPV-unrelated HNSCC. A double-blind, randomized phase II trial (PALATINUS) evaluated the efficacy of palbociclib or placebo and cetuximab in patients with biomarker-unselected, platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC. Palbociclib and cetuximab did not significantly prolong overall survival compared with placebo and cetuximab. However, correlative biomarker analyses identified that trends for better overall survival with palbociclib and cetuximab were observed in certain prespecified subsets; the largest reduction in risk of death with palbociclib versus placebo and cetuximab occurred in the subset with CDKN2A mutations. Several phase II-III trials are underway investigating palbociclib in biomarker-selected patients with HPV-unrelated locally advanced or recurrent or metastatic HNSCC., Competing Interests: Conflicts of Interest and Source of Funding: D.A. has received research funding as principal investigator from Pfizer, Eli Lilly, Merck, Celgene/BMS, Astra Zeneca, Blueprint Medicine, Kura Oncology, Exelixis, Aduro Biotech, Cue Biopharma, Cofactor Genomics, Shanghai Denovo, Hookipa, Debio, Adlai Nortye, Beigene, Conjupro, Epizyme, Gilead, ISA, Roche, Rubius, Immutep, Tizona, Vaccinex, Genmab, Tacti, Boehringer Ingelheim, and Kymab and is a consultant for Merck, Cue Biopharma, Blueprint Medicine, Exelixis, Immunitas, Kura Oncology, Targimmune Therapeutics, TwoXAR, Vaccinex, Xilio Therapeutics, and Boehringer Ingelheim. P.O. has received research funding as principal investigator from Merck and Enzychem and is on the advisory board for Eisai. For the remaining authors, none were declared. No funding support was received for the publication of this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Anti-programmed cell death receptor-1 (PD-1) therapy is standard of care for incurable recurrent or metastatic non-nasopharyngeal head and neck cancer. In contrast, there are no regulatory agency-approved anti-PD-1 agents indicated for the treatment of recurrent or metastatic nasopharyngeal carcinomas (RM-NPC) in the Western hemisphere, and no standard treatment option exists beyond first-line chemotherapy for RM-NPC. The pace of development of novel systemic therapy regimens for RM-NPC has been slow compared to many other advanced tumor types, leaving an unmet clinical need for these patients with a poor prognosis., Observations: Recent clinical trials have documented the clinical activity of anti-PD-1 therapy in RM-NPC. In particular, randomized clinical trials in the first-line setting have demonstrated significant improvements in progression-free survival (PFS) with the addition of anti-PD-1 therapy to standard chemotherapy. Whether the observed PFS benefits require combination chemoimmunotherapy or can be achieved with chemotherapy followed by crossover to immunotherapy upon progression remains unknown. Ongoing clinical trials are exploring novel anti-PD-1 therapy-based combinations, which may further solidify a role for these agents in RM-NPC., Conclusions and Relevance: Among patients with RM-NPC, anti-PD-1 therapy added to first-line standard-of-care gemcitabine plus cisplatin provides significantly better efficacy outcomes compared to chemotherapy alone, and anti-PD-1 monotherapy appears to have comparable clinical activity and better tolerability than chemotherapy in previously treated disease. Thus, anti-PD-1 therapy is poised to advance standard of care for the treatment of RM-NPC., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC., Patients and Methods: Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival., Results: Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size., Conclusions: Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC., (©2021 The Authors; Published by the American Association for Cancer Research.)

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

Purpose: In a head and neck squamous cell carcinoma (HNSCC) "window of opportunity" clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples., Experimental Design: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing., Results: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity., Conclusions: These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response., (©2021 American Association for Cancer Research.)

Objectives: This study examined whether palbociclib and cetuximab prolonged overall survival (OS) versus placebo and cetuximab., Materials and Methods: In this double-blind, randomized, phase 2 trial (PALATINUS), patients with platinum-resistant, cetuximab-naïve, human papillomavirus-unrelated recurrent/metastatic head and neck squamous-cell carcinoma received cetuximab and either palbociclib (arm A) or placebo (arm B). The primary endpoint was OS; 120 patients were required to have ≥80% power to detect a hazard ratio (HR) of 0.6 (median OS of 10 months in arm A and 6 months in arm B) using a one-sided, log-rank test (P = 0.10)., Results: 125 patients were randomized (arm A: 65, arm B: 60). Median follow-up was 15.9 months (IQR, 11.3-22.7). Median OS was 9.7 months in arm A and 7.8 months in arm B (HR, 0.82; 95% CI, 0.54-1.25; P = 0.18). Median progression-free survival was 3.9 months in arm A and 4.6 months in arm B (HR, 1.00; 95% CI, 0.67-1.5; P = 0.50). The most common treatment-related adverse events in arm A were rash (39 patients, 60.9%) and neutropenia (26, 40.6%; three febrile) and in arm B was rash (32, 53.3%)., Conclusion: There was no significant difference in median OS with palbociclib and cetuximab versus placebo and cetuximab., Funding: Pfizer Inc (NCT02499120)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Macropinocytosis promotes internalization of albumin into cells to serve as a nutrient supply and is constitutively driven by signaling pathways frequently hyperactivated in head and neck squamous-cell carcinoma (HNSCC). In this way, drugs bound to albumin may selectively target HNSCC. nab-paclitaxel is a nanoparticle albumin-bound formulation of paclitaxel that improves drug delivery into tumor compared to paclitaxel. The primary aim of this single-arm, multicenter, phase 2 trial was to determine if nab-paclitaxel, cetuximab, and carboplatin (CACTUX regimen) would result in longer progression-free survival (PFS) than the historical regimen (EXTREME: 5-fluorouracil, cetuximab, and a platinum)., Materials and Methods: Patients with untreated recurrent or metastatic HNSCC received six, three-week cycles of nab-paclitaxel, cetuximab, and carboplatin, followed by maintenance nab-paclitaxel and cetuximab until progression. We hypothesized the median PFS with CACTUX would be 35% longer than with EXTREME (corresponding to 7.6 vs 5.6 months; power 0.80, α = 0.05, one-sided test, n = 70). Secondary outcomes included objective response rate (ORR) and overall survival (OS)., Results: Seventy-four patients enrolled into the trial; seventy were evaluable. The median PFS was 6.1 months (95% CI, 4.1-7.4). The ORR was 60%. Median follow-up was 18 months (IQR: 4.7-23). The median OS was 17.8 months (95% CI, 8.5-21.7) for all patients, and 19.8 months (95% CI, 10.9-22.0) for human papillomavirus (HPV)-related oropharynx SCC and 14.0 months (95% CI, 4.6-23.3) for HPV-unrelated HNSCC., Conclusion: Among patients with recurrent or metastatic HNSCC, CACTUX did not result in a longer PFS than historical EXTREME. However, CACTUX did result in a more favorable ORR and OS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In locally advanced head and neck squamous-cell carcinoma (LA-HNSCC), clinical complete response (cCR) at the primary site, assessed by clinical examination, after induction chemotherapy predicts for a low relapse risk after subsequent chemoradiotherapy. Prior studies showed a cCR rate of 77% with induction nanoparticle albumin-bound (nab)-paclitaxel given with cisplatin and 5-fluorouracil (APF). The primary aims of this non-randomized phase 2 trial were to determine the cCR rate after induction nab-paclitaxel and cisplatin (Arm 1) and after nab-paclitaxel monotherapy (Arm 2). Eligibility required LA-HNSCC, T2-T4 stage classification, and suitable (Arm 1) or unsuitable (Arm 2) candidates for cisplatin. Arm 1 patients received nab-paclitaxel and cisplatin, then cisplatin with radiation. Arm 2 patients received nab-paclitaxel, then cetuximab with radiation. The primary endpoint was cCR after two cycles of induction chemotherapy. Each arm enrolled forty patients. cCR at the primary site occurred in 28 patients (70%) after nab-paclitaxel and cisplatin and in 8 patients (20%) after nab-paclitaxel monotherapy. The overall clinical response rate was 98% after nab-paclitaxel and cisplatin and 90% after nab-paclitaxel monotherapy. In subset analyses, cCR rates by T stage classifications (T2, T3, T4) were 54, 86, and 69% after nab-paclitaxel and cisplatin, and 14, 11, and 26% after nab-paclitaxel. cCR rates by human papillomavirus status (p16 positive oropharynx vs other) were 72 and 64% after nab-paclitaxel and cisplatin and 35 and 9% after nab-paclitaxel. The cCR rate after nab-paclitaxel and cisplatin was similar to APF; however, the cCR rate after nab-paclitaxel monotherapy was lower. The trial was registered at ClinicalTrials.gov NCT02573493 on October 9, 2015.

Introduction: Delays in radiation are multifactorial, frequent, and associated with poor outcomes. This study investigates the effect of both primary and adjuvant radiation therapy duration and their interaction with other measures of treatment delay on survival in head and neck squamous cell carcinoma (HNSCC)., Methods: We built a retrospective cohort using the National Cancer Database, consisting of primary oral cavity, hypopharynx, larynx and oropharynx squamous cell carcinoma without distant metastasis and with at least six weeks of radiation. The primary exposure was the duration of radiation therapy (DRT), and the primary outcome was death. We estimated the association between DRT and 5-year overall survival (OS) using Kaplan-Meier curves and hazard ratios (HRs) with Cox proportional hazard regression., Results: In both primary (definitive) and adjuvant (post-surgical) radiation settings, increased DRT results in decreased survival. In the primary radiation cohort, 5-year OS was 59.7% [59.1%-60.3%] among those with 47-53 days DRT, which decreased significantly with each subsequent week to completion (81+ days: 38.4% [36.2%-40.7%]). In the surgical cohort, survival decreased 16.5% when DRT extended beyond 75 days (40-46 days: 68.2% [67.3%-69.1%] vs. 75+ days: 53.3% [50.1%-56.7%]). Multivariate analyses showed increased hazard of death with increased DRT (primary radiation: 81+ days HR: 1.69 [1.58-1.81]); surgical: 75+ days HR: 1.61 [1.37-1.88]), with effects intensifying when restricting to those receiving full-dose radiation., Conclusion: A prolonged DRT was associated with worse OS in head and neck cancer. Radiation treatment delays of even a week lead to a significant survival disadvantage. DRT had a stronger association with survival than time to initiation of postoperative adjuvant radiotherapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance., Methods: In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m 2 weekly (TC) or single-agent temsirolimus (T). The primary outcome was progression-free survival (PFS) in the TC arm versus the T arm. Response rates, overall survival, and toxicity were secondary outcomes., Results: Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms., Conclusions: The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation., (© 2020 American Cancer Society.)

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.

Background: MET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC., Methods: In total, 78 evaluable patients with cetuximab-naive, platinum-refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus [HPV] status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m 2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression-free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional., Results: The response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different [NS]). The median progression-free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV-positive/p16-positive patients was 0% in both arms, whereas the response rate in HPV-negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed., Conclusions: Combined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV-negative HNSCC. MET-aberration-focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest., (© 2020 American Cancer Society.)

We performed a prospective trial to assess the clinical benefit of a tailored gene set built on a next-generation sequencing (NGS) platform in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Archived tumor tissue obtained from patients with recurrent or metastatic HNSCC was analyzed for variants by a tailored Comprehensive Cancer Gene set of 40 genes (CCG-40) performed on a NGS platform. These data were provided to clinicians to inform treatment decisions. The primary endpoint was clinical benefit (disease control) that resulted from selection and administration of a targeted therapy based on results of the CCG-40. Barriers to performance and implementation of the assay were recorded. Forty patients enrolled. Primary tumor sites included oropharynx (14), larynx/hypopharynx (14), oral cavity (9), and nasopharynx (3). The CCG-40 assay was performed in 23 patients (57.5%), but not in 17 patients due inadequate financial coverage (12) or insufficient tumor tissue (5). Potentially actionable tumor variants were identified in 3 patients (7.5%); all were PIK3CA variants. Due to inability to obtain access to candidate drugs (2) or rapid decline in performance status (1), none of these patients received targeted therapy informed by the CCG-40 results. The CCG-40 assay did not provide clinical benefit to the patients on this trial. Identification of limitations of the assay and barriers to the test's performance and application may be used to optimize this strategy in future trials.

In patients with locally advanced human papillomavirus (HPV)-unrelated head and neck squamous-cell carcinoma (HNSCC), cisplatin and radiation therapy (CisRT) resulted in a local-regional recurrence (LRR) rate of 35%, progression-free survival (PFS) of 49%, and overall survival (OS) of 60%. We, and others, showed that nab-paclitaxel is an active agent in metastatic and locally advanced HNSCC. The aim of this report was to assess the efficacy of nab-paclitaxel-based induction chemotherapy and CisRT in HPV-unrelated HNSCC. We performed a retrospective single-institution analysis of patients treated with nab-paclitaxel-based chemotherapy and CisRT. Key inclusion criteria included stage III-IV HPV-unrelated HNSCC. Induction chemotherapy included nab-paclitaxel and cisplatin (AP), AP + 5-fluorouracil (APF), or APF + Cetuximab (APF-C). Endpoints included LRR, overall relapse, PFS, and OS. Thirty-eight patients were the subject of this analysis. Patient characteristics included median age 59 years (IQR: 54-64) and smoking history in 36 patients (95%). Primary tumor sites included larynx/hypopharynx (27), p16 negative oropharynx (10), and oral cavity (1). Most patients had bulky disease: 82% T 3-4 (n = 31) and 74% N 2b-3 (n = 28). Median follow-up was 44 months (IQR: 23-59). The three-year LRR rate was 16% (95% confidence interval [CI] 7-34) and the overall relapse rate was 22% (95% CI 11-41). The three-year PFS was 64% (95% CI 46-77) and OS was 72% (95% CI 54-84). Among patients with HPV-unrelated HNSCC, nab-paclitaxel-based induction chemotherapy and CisRT resulted in a lower-than-expected rate of LRR and more favorable PFS and OS compared to historical results with CisRT.

Purpose: The volume treated with postoperative radiation therapy (PORT) is a mediator of toxicity, and reduced volumes result in improved quality of life (QOL). In this phase II trial, treatment volumes were reduced by omitting PORT to the pathologically negative (PN0) neck in patients with primary head and neck squamous cell carcinoma., Methods: Patients with head and neck squamous cell carcinoma who underwent surgical resection and neck dissection with a PN0 neck and high-risk features mandating PORT to the primary and/or involved neck were eligible. The primary end point was greater than 90% disease control in the unirradiated neck. QOL was evaluated using the MD Anderson Dysphagia Inventory and the University of Michigan patient-reported xerostomia questionnaire., Results: Seventy-three patients were enrolled, and 72 were evaluable. Median age was 56 years (range, 31 to 81 years); 58 patients were male, and 47 (65%) had a smoking history. Sites included oral cavity (n = 14), oropharynx (n = 37), hypopharynx (n = 4), larynx (n = 16), and unknown primary tumor (n = 1). According to the American Joint Committee on Cancer Staging Manual (7 th edition), 67 patients (93%) had stage III/IV disease, and 71% of tumors involved or crossed midline. No patient had contralateral neck PORT. In 17 patients (24%), only the primary site was treated. At a median follow-up of 53 months, two patients experienced treatment failure of the PN0 unirradiated neck; they also experienced treatment failure locally. Unirradiated neck control was 97% (95% CI, 93.4% to 100.0%). Five-year rates of local control, regional control, progression-free survival, and overall survival were 84%, 93%, 60%, and 64%, respectively. QOL measures were not significantly different from baseline at 12 and 24 months post-PORT ( P > .05)., Conclusion: Eliminating PORT to the PN0 neck resulted in excellent control rates in the unirradiated neck without long-term adverse effects on global QOL.

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma., (Copyright © 2018 by the National Comprehensive Cancer Network.)

The clinical benefit of immunotherapy in recurrent, metastatic head and neck squamous cell carcinoma has fueled interest in revisiting neoadjuvant approaches to complement definitive treatment. Neoadjuvant strategies incorporating immune checkpoint inhibitors and other novel immune-based therapies in head and neck cancer are reviewed here, with particular attention paid to the rationale for these approaches from both a clinical and biologic discovery standpoint. The potential benefits of neoadjuvant immunotherapy include reduction of extent of surgery and the intensity of adjuvant therapy by tumor downstaging, reduction of the risk of distant metastatic spread by early introduction of systemic therapy, conversion of unresectable to resectable disease, and early evaluation of biomarkers of tumor response. We await early trial results utilizing these approaches to confirm both safety and initial efficacy in head and neck cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Determine if highly proliferative head and neck squamous cell carcinomas, assessed by pretreatment Ki-67 expression, respond more robustly to induction chemotherapy (IC) that is selectively toxic to cycling cells. Retrospective analysis of 59 patients treated with IC and chemoradiation. IC included either nab-paclitaxel, cisplatin, 5-FU and cetuximab (APF-C, n = 27) or docetaxel, cisplatin, 5-FU +/- cetuximab (TPF+/-C, n = 32). Ki-67 expression was assessed by immunohistochemistry. Tumor response (complete/partial/stable/progressive) at the primary site after two IC cycles was evaluated by visual examination in all patients. In the APF-C sub-group, tumor response (primary site and neck nodes) after two IC cycles was evaluated by computed tomography (CT) and fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT. Ki-67 expression (median 66%, range: 16-97) did not differ across the tumor response categories assessed by visual examination (p = 0.95), CT (p = 0.30), or FDG-PET/CT (p = 0.65). Median decrease in summed SUV max of measured lesions was 71.6% (range: 8.3-100%). The Pearson correlation coefficient between Ki-67 expression and the percent decrease in summed SUV max was 0.48 (p = 0.02). Ki-67 expression was not different between those with or without a relapse (median: 60 and 71%, p = 0.10). In multivariate regression analysis (MVA) controlling for p16 positive oropharyngeal SCC status and smoking status, Ki-67 expression was not significantly associated with tumor response by visual examination (coefficient estimate -0.002, standard error 0.010, p = 0.84), CT (coefficient estimate -0.007, standard error 0.011, p = 0.54), FDG-PET/CT (coefficient estimate 0.006, standard error 0.008, p = 0.51), the percent decrease in summed SUV max (coefficient estimate 0.389, standard error 0.222, p = 0.09), or relapse events (OR = 1.02(95%CI:0.99-1.05), p = 0.28). No significant relationships were found in MVA between pretreatment Ki-67 expression and tumor response to IC or to relapse.

Objectives: To explore the effect of incorporating cetuximab into induction chemotherapy in locally advanced head and neck squamous cell carcinoma (HNSCC)., Materials and Methods: Retrospective comparative analysis of two consecutive prospective phase II trials was performed: trial 1 with nab-paclitaxel/cisplatin/5-FU and cetuximab (APF-C; n=30) and trial 2 with APF (n=30). Patients were scheduled to receive chemoradiation therapy (CRT) with cisplatin. T 2-4 classification oropharynx (OP)/larynx/hypopharynx SCC were included. Cumulative incidence of death of disease (CIDD), overall survival (OS), and cumulative incidence of relapse were compared between APF-C and APF., Results: No significant differences in patient or tumor characteristics were noted between the groups. Median follow-up of surviving patients was 52 (25-95) months. Relapse occurred in 5 (17%) patients treated with APF-C and in 2 (7%) treated with APF (p=0.37). In human papillomavirus (HPV)-related OPSCC (n=34), the CIDD at 52months was 3.4% with APF-C and 2.6% with APF and the two-year OSs were 94%. In HPV-unrelated HNSCC (n=25), the CIDD at 52months was 4.4% with APF-C and 3.3% with APF and two-year OSs were 83% and 92%, respectively. CIDD or OS did not differ when stratified by treatment group and HPV status (CIDD: p=0.80; OS: p=0.30)., Conclusion: This exploratory retrospective comparative analysis demonstrated no significant difference in CIDD, OS, or cumulative incidence of relapse between patients treated with APF-C or APF., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer., (Copyright © 2017 by the National Comprehensive Cancer Network.)

The clinical benefit of nab-paclitaxel monotherapy for recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC) that progressed on other taxanes (cremophor-based paclitaxel or docetaxel) is unknown. A retrospective analysis of patients treated at a single institution with nab-paclitaxel for taxane-resistant RM-HNSCC. The exploratory hypothesis was that nab-paclitaxel would result in clinical benefit (tumor response) in patients with taxane-resistant RM-HNSCC. Twelve patients who were treated with nab-paclitaxel monotherapy for taxane-resistant RM-HNSCC and met all eligibility criteria were identified. The majority of patients (n = 9; 75%) received three or more lines of therapy for RM-HNSCC. All patients had platin-resistant, and ten patients (83%) had cetuximab-resistant disease. Patients had RM-HNSCC that progressed on cremophor-based paclitaxel (8), docetaxel (1), or both (3). With prior taxane, the best tumor response was partial (PR) in 4 patients (33%), stable (SD) in 3 (25%), and progression in 5 (42%). The median time-to-progression (TTP) with prior taxane was 1.7 (range 0.7-9.0) months. The median interval from last dose of taxane to first dose of nab-paclitaxel was 3 (0.7-31.3) months. With nab-paclitaxel, tumor response occurred in two patients (17%; PR in both) and disease control (PR and SD) occurred in five (42%). Median TTP with nab-paclitaxel was 2.1 months (range 0.6-6.2), and median overall survival was 4.9 months (range 1.9-13.5). nab-Paclitaxel provided clinical benefit in some patients with taxane-resistant RM-HNSCC. The median TTP with nab-paclitaxel and with prior taxane were similar. This exploratory observation warrants further investigation in prospective studies.

Objective: This phase 2 estimation study evaluated docetaxel/cisplatin with/without panitumumab, an anti-epidermal growth factor receptor monoclonal antibody, as first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN)., Patients and Methods: Randomized patients received docetaxel/cisplatin (75mg/m(2) each) with/without panitumumab (9mg/kg) in 21-day cycles. Patients randomized to panitumumab+chemotherapy could continue panitumumab monotherapy after completing six chemotherapy cycles without progression; patients randomized to chemotherapy alone could receive second-line panitumumab after progression. Progression-free survival (PFS) was the primary endpoint. Secondary endpoints included overall survival (OS), overall response rate (ORR), time to response (TTR), duration of response (DOR), and safety. A protocol amendment limited enrollment to patients <70years owing to excess toxicity in older patients and added mandatory pegfilgrastim/filgrastim support. Outcomes were also analyzed by human papillomavirus status., Results: 103 of the 113 enrolled patients were evaluable and randomized to receive ⩾1 dose of first-line treatment. Median PFS for panitumumab+chemotherapy was 6.9 (95% CI=4.7-8.3) months versus 5.5 (95% CI=4.1-6.8) months for chemotherapy alone (hazard ratio [HR]=0.629; 95% CI=0.395-1.002; P=0.048). ORR for panitumumab+chemotherapy was 44% (95% CI=31-58%) versus 37% (95% CI=24-51%) for chemotherapy alone (odds ratio [OR]=1.37; 95% CI=0.57-3.33). Median OS for panitumumab+chemotherapy was 12.9 (95% CI=9.4-18.5) months versus 13.8 (95% CI=11.8-22.9) months for chemotherapy alone (HR=1.103; 95% CI=0.709-1.717). Median TTR for panitumumab+chemotherapy treatment was 6.9weeks versus 11.0weeks for chemotherapy alone. Median DOR was 8.0 (95% CI=5.7-11.1) months with panitumumab+chemotherapy versus 5.1 (95% CI=4.4-7.2) months with chemotherapy alone. Grade 3/4 adverse event incidence was 73% with panitumumab+chemotherapy versus 56% with chemotherapy alone. 41% and 55% of patients in the panitumumab+chemotherapy and chemotherapy-alone arms, respectively, received panitumumab monotherapy., Conclusion: The addition of panitumumab to docetaxel/cisplatin may improve PFS in recurrent/metastatic SCCHN and has the potential to improve outcomes in these fully, or mostly, active patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: We previously reported the efficacy of nab-paclitaxel added to cisplatin, 5-FU, and cetuximab (APF-C) followed by concurrent high dose bolus cisplatin and radiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). In this phase II trial, we determined the efficacy of APF (without cetuximab) followed by CRT in similar patients., Materials and Methods: Eligible patients had stage III-IV oropharynx (OP), larynx, or hypopharynx SCC and adequate organ function and performance status. T1 tumors were excluded. Patients were treated with three cycles of APF followed by CRT. Efficacy endpoints included two-year disease-specific survival (DSS), progression-free survival (PFS), overall survival (OS), and relapse rate., Results: Thirty patients were enrolled. Most patients were smokers (77%) with bulky T3/4 (73%) and N2/3 (83%) tumors. Analyses were stratified for human papilloma virus (HPV) status: HPV-related OPSCC (n=17; 57%) and HPV-unrelated HNSCC (n=13; 43%). With a minimum follow-up of 21months, relapse occurred in 1 (3%) patient. Two-year DSS was 94% in HPV-related OPSCC and 100% in HPV-unrelated HNSCC. Two-year PFS was 94% in HPV-related OPSCC and 100% in HPV-unrelated HNSCC. Two-year OS was 94% in HPV-related OPSCC and 92% in HPV-unrelated HNSCC. Causes of death were relapse (1), treatment-related mortality (1), and co-morbidity (1). Two patients with HPV-unrelated HNSCC treated with APF declined CRT and remained free of relapse at 36 and 28months of follow-up., Conclusion: This phase II trial demonstrated favorable two-year DSS, PFS, and OS and a low relapse rate in HPV-unrelated HNSCC and HPV-related OPSCC treated with APF followed by CRT., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis. As a result, de-escalation clinical trials are under way. However, approximately 10% of patients will experience distant recurrence even with standard-of-care treatment. Here, we sought to identify novel biomarkers to better risk-stratify HPV-positive patients with OPSCC., Methods and Materials: Gene expression profiling by RNA sequencing (RNA-seq) and quantitative polymerase chain reaction was performed on HPV-positive OPSCC primary tumor specimens from patients with and without distant metastasis (DM)., Results: RNA-seq analysis of 39 HPV-positive OPSCC specimens revealed that patients with DM had 2-fold higher E6 gene expression levels than did patients without DM (P=.029). This observation was confirmed in a validation cohort comprising 93 patients with HPV-positive OPSCC. The mean normalized E6 expression level in the 17 recurring primary specimens was 13 ± 2 compared with 8 ± 1 in the remaining 76 nonrecurring primaries (P=.001). Receiver operating characteristic analysis established an E6 expression level of 7.3 as a cutoff for worse recurrence-free survival (RFS). Patients from this cohort with high E6 gene expression (E6-high) (n=51, 55%) had more cancer-related deaths (23% vs 2%, P<.001) and DM (26% vs 5%, P<.001) than did patients with low E6 gene expression (E6-low) (n=42, 45%). Kaplan-Meier survival analysis revealed that E6-high had worse RFS (95% vs 69%, P=.004) and cancer-specific survival (97% vs 79%, P=.007). E6-high maintained statistical significance in multivariate regression models balancing surgery, chemotherapy, nodal stage, and smoking status. Gene set enrichment analysis demonstrated that tumors with high E6 expression were associated with P53, epidermal growth factor receptor, activating transcription factor-2, and transforming growth factor-β signaling pathways., Conclusion: High E6 gene expression level identifies HPV-positive OPSCC patients with 5-fold greater risk of distant disease recurrence and worse cancer-specific survival. Validation in a multi-institutional prospective clinical trial is required to assess the utility of E6 gene expression as a clinically useful prognostic biomarker., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To test the safety of the CDK4/6 inhibitor palbociclib with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)., Materials and Methods: A phase I trial using 3+3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of palbociclib with standard dose weekly cetuximab. Palbociclib was administered orally days 1-21 every 28days: dose level 1 (100mg/d) and 2 (125mg/d; approved monotherapy dose). Pharmacokinetic assessments were performed on cycle 2, day 15. Cyclin D1, p16(INK4a), and Rb protein expression were measured on pre-treatment tumor. Tumor response was assessed using RECIST1.1., Results: Nine patients (five p16(INK4a) negative; four positive) were enrolled across dose levels 1 (n=3) and 2 (n=6) and none experienced a DLT. A MTD of palbociclib was not reached. Myelosuppression was the most common adverse event. Six of nine patients had cetuximab-resistant and 4/9 had platin-resistant disease. Disease control (DC) occurred in 89%, including partial response (PR) in two (22%) and stable disease in six (67%) patients. PRs occurred in p16(INK4a) negative HNSCC. Five patients (56%) had measurable decreases in tumor target lesions. In cetuximab-resistant HNSCC, best tumor response was PR in 1 and DC in 5 and median TTP was 112days (range: 28-168). In platin-resistant HNSCC, best tumor response: PR in 1, DC in 3 and median TTP was 112days (range: 28-112). The Cmax and AUC0-24h appeared comparable in patients receiving 125 vs 100mg dose of palbociclib., Conclusion: This trial, the first to evaluate a CDK4/6 inhibitor in HNSCC, determined that palbociclib 125mg/day on days 1-21 every 28days with cetuximab was safe. Tumor responses were observed, even in cetuximab- or platin-resistant disease., Competing Interests: Conflict of Interest/Disclosures Disclosures: Research Support – Pfizer, (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Panitumumab Regimen In Second-line Monotherapy of Head and Neck Cancer (PRISM) trial evaluated the safety and efficacy of panitumumab as second-line monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)., Methods: This was an open-label, single-arm, multicenter trial that enrolled patients with progressive disease or intolerance to first-line systemic chemotherapy for recurrent or metastatic SCCHN. Patients received panitumumab 9 mg/kg Q3W. The primary endpoint was overall response rate; secondary endpoints included disease control rate, overall survival (OS), progression-free survival (PFS), and safety., Results: The overall response rate was 4% (2 of 51 patients) and the disease control rate was 39% (20 of 51 patients). Median PFS was 1.4 months (95% confidence interval [CI] = 1.3-2.4 months). Median OS was 5.1 months (95% CI = 4.3-8.3 months). The most common adverse events were rash/dermatitis acneiform (69%), fatigue (33%), dry skin (21%), and hypomagnesemia (21%). There was one treatment-related death (angioedema)., Conclusion: Panitumumab monotherapy had limited activity in previously treated patients with recurrent or metastatic SCCHN. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1756-E1761, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: Cetuximab, in combination with platinum chemotherapy plus 5-fluoruracil (5-FU), is approved for the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Cetuximab manufactured by ImClone (US commercial cetuximab) potentially results in higher systemic exposures than cetuximab manufactured by Boehringer Ingelheim (BI-manufactured cetuximab). This prospective, randomized, double-blind study compared the safety profiles of the two cetuximab formulations., Methods: Patients with previously untreated locoregionally recurrent and/or metastatic SCCHN were randomly assigned to receive the same dose of US commercial cetuximab (Arm A) or BI-manufactured cetuximab (Arm B), each in combination with cisplatin or carboplatin plus 5-FU. The primary outcome was all-grade, all-cause treatment-emergent adverse events (TEAEs)., Results: The majority of patients experienced ≥ 1 TEAE, regardless of causality (Arm A: 75/77 patients, 97.4%; Arm B: 68/71 patients, 95.8%). TEAEs with the highest incidence included nausea, fatigue, and hypomagnesemia in both arms. The absolute risk difference between the two arms for patients experiencing at least one adverse event (AE) was 0.029 (p = 0.281, 95% confidence interval [CI]: -0.024, 0.082) for AEs regardless of causality and 0.005 (p = 0.915, 95% CI: -0.092, 0.103) for AEs possibly related to study drug. There were no significant differences between the two arms in the incidence of acneiform rash, cardiac events, infusion reactions, or hypomagnesemia. Overall survival, progression-free survival, and overall response rates were similar in the two arms., Conclusions: There were no clinically meaningful differences in safety between US commercial cetuximab and BI-manufactured cetuximab in combination with platinum-based therapy with 5-FU in patients with locoregionally recurrent and/or metastatic SCCHN. The use of US commercial cetuximab in this combination chemotherapy regimen did not result in any unexpected safety signals. The efficacy results of this study are consistent with the efficacy results of the cetuximab arm of the EXTREME study., Trial Registration: ClinicalTrials.gov NCT01081041 ; date of registration: March 3, 2010).

Introduction: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC., Methods: Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75mg/m(2) IV every 21days) with or without PX-866 (8mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes., Results: 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P=0.13). Median PFS was 92days in Arm A and 82days in Arm B (P=0.42). There was no difference in OS between the two arms (263 vs. 195days; P=0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed., Conclusion: The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We previously reported that nab-paclitaxel-based induction chemotherapy (IC) and concurrent chemoradiotherapy resulted in low relapse rates (13%) and excellent survival in head and neck squamous cell carcinoma (HNSCC). We compare the disease-specific survival (DSS) and overall survival (OS) between patients given nab-paclitaxel, cisplatin, and fluorouracil with cetuximab (APF-C) and historical controls given docetaxel, cisplatin, and fluorouracil with cetuximab (TPF-C). Patients with locally advanced HNSCC were treated with APF-C (n = 30) or TPF-C (n = 38). After 3 cycles of IC, patients were scheduled to receive cisplatin concurrent with definitive radiotherapy. T and N classification and smoking history were similar between the two groups and within p16-positive and p16-negative subsets. The median duration of follow-up for living patients in the APF-C group was 43.5 (range: 30-58) months versus 52 (range: 13-84) months for TPF-C. The 2-year DSS for patients treated with APF-C was 96.7% [95% Confidence Interval (CI): 85.2%, 99.8%] and with TPF-C was 77.6% (CI: 62.6%, 89.7%) (P = 0.0004). Disease progression that resulted in death was more frequent in the TPF-C group (39%) compared with the APF-C group (3%) when adjusted for competing risks of death from other causes (Gray's test, P = 0.0004). In p16 positive OPSCC, the 2-year DSS for APF-C was 100% and for TPF-C was 74.6% (CI: 47.4%, 94.6%) (P = 0.0019) and the 2-year OS for APF-C was 94.1% (CI: 65.0%, 99.2%) and for TPF-C was 74.6% (CI: 39.8%, 91.1%) (P = 0.013). In p16 negative HNSCC, the 2-year DSS for APF-C was 91.7% (CI: 67.6%, 99.6%) and for TPF-C was 82.6% (CI: 64.4%, 94.8%) (P = 0.092). A 2-year DSS and OS were significantly better with a nab-paclitaxel-based IC regimen (APF-C) compared to a docetaxel-based IC regimen (TPF-C) in p16-positive OPSCC., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Radiation treatment volumes in head and neck squamous cell carcinoma (HNSCC) are controversial. The authors report the outcomes, patterns of failure, and quality of life (QOL) of patients who received treatment for HNSCC using intensity-modulated radiation therapy (IMRT) that eliminated the treatment of contralateral retropharyngeal lymph nodes (RPLNs) in the clinically uninvolved neck., Methods: A prospective institutional database was used to identify patients who had primary oral cavity, oropharyngeal, hypopharyngeal, laryngeal, and unknown primary HNSCC for which they received IMRT. There were 3 temporal groups (generations 1-3). Generation 1 received comprehensive neck IMRT with parotid sparing, generation 2 eliminated the contralateral high level II (HLII) lymph nodes, and generation 3 further eliminated the contralateral RPLNs in the clinically uninvolved neck. Patterns of failure and survival analyses were completed, and QOL data measured using the MD Anderson Dysphagia Inventory were compared in a subset of patients from generations 1 and 3., Results: In total, 748 patients were identified. Of the 488 patients who received treatment in generation 2 or 3, 406 had a clinically uninvolved contralateral neck. There were no failures in the spared RPLNs (95% confidence interval, 0%-1.3%) or in the high contralateral neck (95% confidence interval, 0%-0.7%). QOL data were compared between 44 patients in generation 1 and 51 patients in generation 3. QOL improved both globally and in all domains assessed for generation 3, in which reduced radiotherapy volumes were used (P < .007)., Conclusions: For patients with locally advanced HNSCC, eliminating coverage to the contralateral HLII lymph nodes and contralateral RPLNs in the clinically uninvolved side of the neck is associated with minimal risk of failure in these regions and significantly improved patient-reported QOL., (© 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Computed tomography (CT), the standard method to assess tumor response to cetuximab in incurable squamous cell carcinoma of the head and neck (SCCHN), performs poorly as judged by the disparity between high disease control rate (46%) and short time to progression (TTP) (70 days). F-18 fluorodeoxyglucose positron emission tomography (FDG-PET)/CT is an alternative method to assess tumor response. The primary objective of this prospective trial was to evaluate the metabolic response of target lesions, assessed as the change in maximum standardized uptake value (SUV(max)) on FDG-PET/CT before and after 8 weeks (cycle 1) of cetuximab. Secondary objectives were to compare tumor response by CT (RECIST 1.0) and FDG-PET/CT (EORTC criteria) following cycle 1, and determine TTP with continued cetuximab administration in patients with disease control by CT after cycle 1 but stratified for disease control or progression by FDG-PET/CT. Among 27 patients, the mean percent change of SUV(max) of target lesions after cycle 1 was -21% (range: +72% to -81%); by FDG-PET/CT, partial response (PR)/stable disease (SD) occurred in 15 patients (56%) and progression in 12 (44%), whereas by CT, PR/SD occurred in 20 (74%) and progression in 7 (26%). FDG-PET/CT and CT assessments were discordant in 14 patients (P = 0.0029) and had low agreement (κ = 0.30; 95% confidence interval [CI]: 0.12, 0.48). With disease control by CT after cycle 1, median TTP was 166 days (CI: 86, 217) if the FDG-PET/CT showed disease control and 105 days (CI: 66, 159) if the FDG-PET/CT showed progression (P < 0.0001). Median TTP of the seven patients whose post cycle 1 CT showed progression compared to the 12 whose FDG-PET/CT showed progression were similar (53 [CI: 49, 56] vs. 61 [CI: 50, 105] days, respectively). FDG-PET/CT may be better than CT in assessing benefit of cetuximab in incurable SCCHN., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

In head and neck squamous cell cancer (HNSCC), four intrinsic subtypes (or groups) have been identified, and each one possesses a unique biology that will require specific treatment strategies. We previously reported that mesenchymal (group 2) tumors exhibit reduced levels of Trop2 expression. In this study, we investigated the functional role of Trop2 in HNSCC and find that loss results in autocrine activation of the EGFR family member ErbB3 via neuregulin-1. Trop2 localizes to both the cell surface and cytosol of HNSCC cells and forms a complex with neuregulin-1, which is predominantly cytosolic. Inactivation of Trop2 increases the concentration of neuregulin-1 at the cell surface where it is cleaved to activate ErbB3. In primary HNSCC, detection of ErbB3 activation was limited to Trop2 negative tumors. An analysis of the Cancer Genome Atlas (TCGA) HNSCC dataset confirms enrichment for ErbB3 activity in mesenchymal tumors. Notably, Trop2 loss triggers sensitivity to anti-ErbB3 antibodies, which results in reduced proliferation and tumorigenic growth of Trop2 negative HNSCC cancer cells. These results uncover a molecular mechanism by which tumor cells control the amount of cell-surface neuregulin-1 available for cleavage and ErbB3 activation. Moreover, we demonstrate that Trop2 is a potential surrogate biomarker to identify tumors with ErbB3 activation and may therefore respond to anti-ErbB3 therapeutics.

Objectives: Cetuximab, a chimeric monoclonal antibody, is the only targeted therapy approved for squamous cell carcinoma of the head and neck (SCCHN). Infusion reactions (IRs) occur in 6-18% of patients pre-medicated with diphenhydramine. Evidence for clinical risk factors for IRs is limited and the benefit of additional pre-medication to prevent IRs is unclear., Materials and Methods: A retrospective, single institution study of 243 SCCHN patients treated with cetuximab to evaluate potential risk factors for IRs and to assess the efficacy of additional pre-medications (nebulized albuterol and intravenous (IV) corticosteroids and/or H2-blockers) to decrease the risk of IR., Results: IR (grades 1-4) and high grade (grades 3-4 only) IR occurred in 47 (19.3%) and 16 (6.6%) patients, respectively. Multivariate analysis identified Caucasian race (OR7.11, p=0.003), medication allergy (OR3.74, p=0.002), and blood eosinophils >3% (OR2.75, p=0.01) independently increased the risk of IR; Caucasian race (OR5.57, p=0.007) and medication allergy (OR4.10, p=0.0007) increased the risk of high grade IR. IR (grades 1-4) and high grade IR occurred in 31.8% and 22.7% pre-medicated with diphenhydramine alone. Univariate analysis identified albuterol, famotidine, and corticosteroids decreased the risk of high grade IR. Furthermore, there was a significant difference between the possible combinations of the pre-medications and the risk of high grade IR by Fisher Exact test (p=0.003) whereby the combination of albuterol, famotidine and corticosteroids was effective in preventing high grade IR. Thirty (64%) of the 47 patients who developed an IR were re-challenged and did not experience a recurrence of an IR., Conclusion: These data may be used to identify patients at higher risk for cetuximab-induced IR who may be advised to not receive cetuximab or who may benefit from additional pre-medications to decrease the risk of a high grade IR., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: There are limited chemotherapeutic options for advanced recurrent or metastatic SCCHN. The efficacy and toxicity of docetaxel with or without vandetanib was investigated in these patients., Materials and Methods: Patients with pathologically confirmed, recurrent or metastatic SCCHN who had progressed on platinum based therapy given as definitive or palliative treatment, were randomized in this open label, multicenter phase II study of docetaxel (75 mg/m2 IV Q3 weeks) with or without vandetanib (100 mg PO daily). The primary objective was response rate (RR) and secondary objectives were progression free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DOR)., Results: 29 analyzable patients were enrolled, 14 in docetaxel arm and 15 in combined arm. PR was achieved in 1 patient in the docetaxel arm and 2 patients in the combined arm. The objective RR was 7% (1/14) (95% CI 0.2-33.8%) in the single and 13% (2/15) (95% CI 1.6-40.4%) combined arm. The median PFS was 3.21 (95% CI 3.0-22.0) and 9 (95% CI (5.86-18.1) weeks; median OS was 26.8(95% CI 17.7-100.7+) and 24.1 (95% CI, 16.4-171.1+) weeks. Most common adverse events were fatigue, dysphagia, diarrhea or constipation, cytopenias and alopecia., Conclusions: Although an initial benefit in response was noted and statistical criteria met there was only a minor trend towards improved PFS for the combined arm. The study was designed with low threshold for activity in each arm and results were deemed not to be of enough clinical significance in this group of patients to continue accrual., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear. The PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel, cisplatin, and fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer., Methods: Adult patients with previously untreated, non-metastatic, newly diagnosed head and neck cancer were eligible. Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage (3 or 4) or regional-node stage (2 or 3, except T1N2), or if they were a candidate for organ preservation. Patients were randomly assigned (in a 1:1 ratio) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin. A computer-generated randomisation schedule using minimisation was prepared and the treatment assignment was done centrally at one of the study sites. Patients, study staff, and investigators were not masked to group assignment. Stratification factors were WHO performance status, primary disease site, and stage. The primary endpoint was overall survival. Analysis was by intention to treat. Patient accrual was terminated in December, 2008, because of slow enrolment. The trial is registered with ClinicalTrials.gov, number NCT00095875., Findings: Between Aug 24, 2004, and Dec 29, 2008, we enrolled 145 patients across 16 sites. After a median follow-up of 49 months (IQR 39-63), 41 patients had died-20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy alone group. 3-year overall survival was 73% (95% CI 60-82) in the induction therapy followed by chemoradiotherapy group and 78% (66-86) in the chemoradiotherapy alone group (hazard ratio 1·09, 95% CI 0·59-2·03; p=0·77). More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group (16 patients) than in the chemoradiotherapy alone group (one patient)., Interpretation: Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone. We cannot rule out the possibility of a difference in survival going undetected due to early termination of the trial. Clinicians should still use their best judgment, based on the available data, in the decision of how to best treat patients. The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure., Funding: Sanofi-Aventis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Complete response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisplatin and 5-fluorouracil [5-FU]) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20% to 30%. This study evaluated the efficacy and feasibility of induction nab-paclitaxel and cetuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase 2 trial., Methods: Patients with squamous cell carcinoma of the head and neck were treated with ACPF (nab-paclitaxel 100 mg/m(2) /week; cetuximab 250 mg/m(2) /week; cisplatin 75 mg/m(2) on day 1; 5-FU 750 mg/m(2) /day on days 1 through 3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m(2) on days 1, 22, and 43 of radiation therapy [RT]). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint., Results: Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty-nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive RT per protocol, and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2-year overall and progression-free survival rates were 84% and 65%, respectively., Conclusions: Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is warranted., (Copyright © 2012 American Cancer Society.)

Objective: Whether or not cisplatin and cetuximab are similarly effective in improving outcomes when added to radiation therapy (RT) in squamous cell carcinoma of the head and neck is unknown., Methods: Retrospective analysis was performed of patients treated with definitive RT and cisplatin (n = 18) or cetuximab (n = 29)., Results: T and N classifications, stage, human papillomavirus status and smoking history were balanced in the two groups; however, patients in the cisplatin group were younger and had a better performance status. Delivery of RT was similar between the two groups. Median follow-up was 23 (4-64) months. Disease-specific survival (DSS) at 3 years was 83% in the cisplatin group and 31% in the cetuximab group. Recurrent disease was more common in the cetuximab group compared with the cisplatin group (17 vs. 4 patients). Propensity score analysis to adjust for differences in patient characteristics which influenced treatment selection showed that DSS was indeed longer with cisplatin than with cetuximab (DSS hazard ratio 0.15, confidence interval 0.033, 0.66; p = 0.012)., Conclusions: DSS was superior in the patients given cisplatin with definitive RT compared to cetuximab with definitive RT due to a lower risk of recurrent disease in the cisplatin group. These observations could not be explained by differences between the two groups in the patient and tumor characteristics or in treatment delivery., (© 2013 S. Karger AG, Basel.)