Search

Objectives: To describe swallowing and feeding-tube outcomes in patients with high-risk oropharyngeal cancer treated with trimodality therapy (TMT), including transoral robotic surgery (TORS) and adjuvant chemoradiotherapy., Methods: A chart review was conducted on patients with HPV+ OPSCC receiving TMT with TORS at an academic medical center from March 2010 to March 2021. Data collected included demographics, treatment, feeding tube placement, functional oral intake scale (FOIS) scores, and swallowing-language pathology (SLP) evaluations., Results: A total of 255 patients met selection criteria (mean age 61 years, 88% male). Following intraoperative nasogastric tube (NG) placement, 31% remained NG tube dependent after 3 weeks. A gastrostomy tube was placed in 19% of patients, and at 1 year after end-of-treatment (EOT), 3.5% overall remained tube-dependent. Mean FOIS scores were 6.9 (SD = 0.3) at pre-operative visit, 2.6 (1.8) at first post-operative visit, and 5.5 (1.5) after EOT. In the subset of patients with follow-up longer than 2 years (n = 118), the mean FOIS was 6.1 (SD = 1.3) at most recent visit. Clinical signs of aspiration/penetration were suspected on SLP evaluation in 18% of patients. These patients were subsequently evaluated with fiberoptic endoscopic evaluation of swallowing (FEES) and/or barium swallow study, which confirmed signs of aspiration in 2.7% of patients overall. Delayed NG tube removal after 3 weeks was predictive of (1) gastrostomy tube requirement and (2) clinical signs of aspiration on an SLP visit after EOT., Conclusions: Favorable functional and feeding-tube outcomes are demonstrated in patients with HPV-associated OPSCC undergoing TMT. In this single-institution study, we found low rates of long-term feeding tube dependence and high median FOIS following treatment. Review of routine SLP visits provides a detailed and easily accessible means for assessing swallowing function in this cohort., Level of Evidence: 4 Laryngoscope, 133:3013-3020, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Importance: Cetuximab-based and carboplatin-based chemoradiotherapy (CRT) are often used for patients with locally advanced head and neck cancer who are ineligible for cisplatin. There are no prospective head-to-head data comparing cetuximab-based and carboplatin-based regimens for radiosensitization., Objective: To compare survival with cetuximab-based and carboplatin-based CRT in locally advanced head and neck squamous cell carcinoma (HNSCC)., Design, Setting, and Participants: This cohort study included US veterans who received a diagnosis of HNSCC between January 2006 and December 2020 and were treated with systemic therapy and radiation. Data cutoff was March 1, 2022 and data analysis was conducted from April-May 2022., Exposures: Cisplatin, cetuximab, or carboplatin-based systemic therapy as captured in VA medication data and cancer registry., Main Outcomes and Measures: Overall survival by systemic therapy was estimated using Kaplan-Meier methods. We used propensity score and inverse probability weighting to achieve covariate balance between cetuximab-treated and carboplatin-treated patients and used Cox regression to estimate cause-specific hazard ratios of death associated with carboplatin vs cetuximab. We also performed subgroup analyses of patients with oropharynx vs nonoropharynx primary sites., Results: A total of 8290 patients (median [IQR] age, 63 [58-68] years; 8201 men [98.9%]; 1225 [15.8%] Black or African American and 6424 [82.6%] White individuals) with nonmetastatic HNSCC were treated with CRT with cisplatin (5566 [67%]), carboplatin (1231 [15%]), or cetuximab (1493 [18%]). Compared with cisplatin-treated patients, patients treated with carboplatin and cetuximab were older with worse performance status scores and higher comorbidity burden. Median (IQR) overall survival was 74.4 (22.3-162.2) months in patients treated with cisplatin radiotherapy (RT), 43.4 (15.3-123.8) months in patients treated with carboplatin RT, and 31.1 (12.4-87.8) months in patients treated with cetuximab RT. After propensity score and inverse probability weighting, carboplatin was associated with improved overall survival compared with cetuximab (cause-specific hazard ratio, 0.85; 95% CI, 0.78-0.93; P = .001). This difference was prominent in the oropharynx subgroup., Conclusions and Relevance: In this cohort study of a US veteran population with HNSCC undergoing treatment with CRT, almost a third of patients were ineligible to receive treatment with cisplatin and received cetuximab-based or carboplatin-based radiosensitization. After propensity score matching, carboplatin-based systemic therapy was associated with 15% improvement in overall survival compared with cetuximab, suggesting that carboplatin may be the preferred radiosensitizer, particularly in oropharynx cancers.

Importance: Cardiovascular events are an important cause of morbidity in patients with oropharyngeal squamous cell carcinoma (OPSCC). Radiation and chemotherapy have been associated with increased risk of stroke; up-front surgery allows the opportunity for (chemo)radiotherapy de-escalation., Objective: To evaluate whether up-front surgery was associated with decreased stroke risk compared to nonsurgical treatment for OPSCC., Design, Setting, and Participants: This cohort study was conducted at the US Veterans Health Administration and examined US veterans diagnosed with nonmetastatic OPSCC from 2000 to 2020. Data cutoff was September 17, 2021, and data analysis was performed from October 2021 to February 2022., Exposures: Up-front surgical treatment or definitive (chemo)radiotherapy as captured in cancer registry., Main Outcomes and Measures: Cumulative incidence of stroke, accounting for death as a competing risk; and association between up-front surgery and stroke risk. After generating propensity scores for the probability of receiving surgical treatment and using inverse probability weighting (IPW) to construct balanced pseudo-populations, Cox regression was used to estimate a cause-specific hazard ratio (csHR) of stroke associated with surgical vs nonsurgical treatment., Results: Of 10 436 patients, median (IQR) age was 61 (56-67) years; 10 329 (99%) were male; 1319 (13%) were Black, and 7823 (75%) were White; 2717 received up-front surgery, and 7719 received nonsurgical therapy with definitive (chemo)radiotherapy. The 10-year cumulative incidence of stroke was 12.5% (95% CI, 11.8%-13.3%) and death was 57.3% (95% CI, 56.2%-58.4%). Surgical patients who also received (chemo)radiotherapy had shorter radiation and chemotherapy courses than nonsurgical patients. After propensity score and IPW, the csHR of stroke for surgical treatment was 0.77 (95% CI, 0.66-0.91). This association was consistent across subgroups defined by age and baseline cardiovascular risk factors., Conclusions and Relevance: In this cohort study, up-front surgical treatment was associated with a 23% reduced risk of stroke compared with definitive (chemo)radiotherapy. These findings present an important additional risk-benefit consideration to factor into treatment decisions and patient counseling and should motivate future studies to examine cardiovascular events in this high-risk population.

Objectives: Sex differences in surgically treated HPV-associated oropharyngeal squamous cell carcinoma are not defined due to the low number of affected women. We explored the oncologic outcomes of men and women with p16-positive oropharyngeal squamous cell carinoma treated with primary surgery., Materials and Methods: Retrospective analysis of patients with HPV-related oropharyngeal cancer treated with surgery and pathology guided adjuvant therapy from 2007 to 2017. Primary end point was recurrence-free and overall survival., Results: Of 468 men (86.7%) and 72 women (13.3%), women presented more often with clinical N0 nodal disease (25% vs 12.2%). There were no differences in adverse pathologic features or T stage, although women were more likely to present with N0 disease (16.7% vs 10%), less N2 disease (6.9% vs 17.7%, p = 0.03), and more stage I disease (88.9% vs 75%). As a result, women were more likely to undergo surgery alone (30.6% vs 14.1%) while men were more likely to require adjuvant radiation therapy (47.2% vs 36.1%). Four women (5.6%) and 30 men (6.4%, p = 0.8) died during follow-up. Multivariate analysis controlling for age, sex, treatment, and pathologic stage demonstrated no differences in overall survival between men and women. There were no differences in recurrence-free or overall survival between men and women at two and five years., Conclusions: Although women undergoing transoral robotic surgery for HPV+ oropharyngeal squamous cell carcinoma may have less advanced disease, upfront surgery with pathology-guided adjuvant therapy produces similar oncologic results in men and women while accounting for disease burden., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Patients with oropharyngeal cancer who undergo transoral robotic surgery (TORS) and have high-risk features generally receive adjuvant chemoradiotherapy or trimodality therapy (TMT). The notion that TMT leads to high toxicity is largely based on studies that included human papilloma virus (HPV)-negative cancers and/or nonrobotic surgery; we sought to describe outcomes in HPV-associated oropharyngeal squamous cell cancer (HPV + OPSCC) undergoing TORS-TMT., Methods: In consecutive patients with HPV + OPSCC receiving TMT at an academic center from 2010 to 2017, survival was estimated using Kaplan-Meier methodology, and toxicities were ascertained via chart review., Results: In our cohort of 178 patients, 5-year survival was 93.6%. Feeding tube rates were 25.8% at therapy completion and 0.7% at 1 year. Rates of grade ≥ 3 kidney injury, anemia, and neutropenia in cisplatin-treated patients were 2.7%, 3.4%, and 11.0%, respectively., Conclusions: Patients with HPV + OPSCC who underwent TORS-TMT had excellent survival and low rates of toxicity and feeding tube dependence. These outcomes compare favorably to historical cohorts treated with definitive chemoradiotherapy., (© 2021 Wiley Periodicals LLC.)

Background: Patients with human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) continue to experience disappointing outcomes following chemoradiotherapy (CRT) and appreciable morbidity following historical surgical approaches. We aimed to investigate the oncologic outcomes and perioperative morbidity of a transoral robotic surgery (TORS) approach to surgically resectable HPV-negative OPSCC., Methods: Retrospective analysis HPV-negative OPSCC patients who underwent TORS, neck dissection and pathology-guided adjuvant therapy (2005-2017)., Results: Fifty-six patients (91.1% stage III/IV) were included. Three-year overall survival, locoregional control, and disease-free survival were 85.5%, 84.4%, and 73.6%, respectively (median follow-up 30.6 months, interquartile range 18.4-66.6). Eighteen (32.1%) patients underwent adjuvant radiotherapy and 20 (39.3%) underwent adjuvant CRT. Perioperative mortality occurred in one (1.8%) patient and hemorrhage occurred in two (3.6%) patients. Long-term gastrostomy and tracheostomy rates were 5.4% and 0.0%, respectively., Conclusion: The TORS approach for resectable HPV-negative OPSCC can achieve encouraging oncologic outcomes with infrequent morbidity., (© 2021 Wiley Periodicals LLC.)

Background: Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS)., Methods: Three-hundred and sixty-four patients with treatment-naïve, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared., Results: The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P < .001). Despite increased LRF, avoiding PORT was not associated with increased 3-year distant metastasis rates (8% vs 4%, P = .56) or worse 3-year survival (95% vs 98%, P = .34). Recurrences in the surgery alone cohort varied between local and regional sites and were often successfully salvaged., Conclusions: Patients with HPV-associated OPSCC who do not receive indicated PORT have an increased risk of LRF but similar survival due to high salvage rates., (© 2020 Wiley Periodicals LLC.)

Background: Patients with metastatic non-small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited., Patients and Methods: We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation., Results: Between Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy., Conclusions: Patients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: While early epidemiologic studies ascribed increases in the incidence of human papillomavirus-associated oropharyngeal cancers to middle-aged patients, recent analyses have demonstrated an increasing median age of diagnosis. Treatment of patients older than 70 years is controversial as their inclusion in the practice-defining clinical trials has been limited and the survival benefit conferred by chemotherapy may be outweighed by treatment toxic effects., Objective: To assess the oncologic outcomes of older adults with human papillomavirus-associated oropharyngeal cancer who underwent upfront transoral robotic surgery and pathologic characteristics-guided adjuvant therapy in a large cohort of patients with close follow-up., Design, Setting, and Participants: A retrospective cohort analysis was conducted in a tertiary care academic medical center between January 1, 2010, and December 30, 2017. Patients aged 70 years or older at time of diagnosis with biopsy-proven and surgically resectable p16-positive oropharyngeal cancers were included. Data analysis was conducted from March 1 to June 1, 2020., Exposures: Transoral robotic surgery oropharyngeal resection and neck dissection with pathologic characteristic-guided adjuvant therapy., Main Outcomes and Measures: Three-year estimates of disease-specific survival, overall survival, and disease-free survival, as well as rates of adjuvant therapy (radiotherapy and chemoradiotherapy) and perioperative complications., Results: Seventy-seven patients were included (median age, 73.0; interquartile range, 71.0-76.0; range, 70-89 years); of these, 58 were men (75.3%). Perioperative mortality was 1.3% and the rate of oropharyngeal hemorrhage was 2.6%. Twenty-seven patients (35.1%) underwent postoperative radiotherapy and 20 patients (26.0%) underwent postoperative chemoradiotherapy. The median length of follow-up was 39.6 (range, 0.1-96.2) months, and the 3-year estimates of survival were 92.4% (95% CI, 82.4%-96.9%) for disease-specific survival, 90.0% (95% CI, 79.4%-95.0%) for overall survival, and 84.3% (95% CI, 73.4%-91.0%) for disease-free survival., Conclusions and Relevance: The findings of this cohort study suggest that transoral robotic surgery and pathologic characteristic-guided adjuvant therapy can provide beneficial survival outcomes, infrequent perioperative mortality, and, for most carefully selected older adults, obviate the need for chemotherapy.

Purpose: This trial tested the safety and efficacy of a novel, deintensified radiation therapy (RT) approach after initial surgical resection for patients with human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC)., Methods and Materials: This single-arm phase 2 prospective clinical trial enrolled 60 patients with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection at a single institution between May 2014 and September 2017. Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high-volume head and neck cancer center with expertise in TORS. Patients received postoperative RT to at-risk areas in the involved neck (60-66 Gy) and uninvolved neck (54 Gy). The resected primary site was treated as an active avoidance structure in the treatment planning of postoperative RT. Concurrent chemotherapy was administered for patients with extranodal extension., Results: Median follow-up of the 60 patients enrolled was 2.4 years (range, 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and 2 patients (3.3%) developed distant metastases. Measured 2-year local recurrence-free survival was 97.9% (95% confidence interval, 86.1%-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy (standard deviation, 10.3 Gy). Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up., Conclusions: Deintensified postoperative RT that avoids the resected primary tumor site and targets only the at-risk neck after TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: One approach to reduce treatment-related morbidity for human papilloma virus (HPV)-associated tonsil cancer is omitting radiotherapy to the contralateral neck. Pathologic risk factors for early contralateral neck disease, however, are poorly understood. We report on the risk contralateral neck failures from the time of pre-operative diagnostic imaging to time of planning for adjuvant radiation in a single institution series of HPV-associated tonsillar cancer patients undergoing surgery followed by radiotherapy (RT)., Methods: Retrospective analysis of 123 patients with T1 - T3 HPV-positive tonsillar squamous cell carcinoma treated between 2010 and 2016 with transoral robotic surgery and selective ipsilateral neck dissection followed by adjuvant RT. Contralateral neck recurrence was classified as the detection of a pathologic node in the contralateral neck prior to initiation of adjuvant RT., Results: Seven patients (5.7%) developed contralateral neck disease/failure between the time of pre-operative diagnostic neck imaging and time of planning of adjuvant radiation. Increased ratio of positive/resected nodes [odds ratio (OR) 1.073, p = 0.005] was significantly associated with increased risk of contralateral neck recurrence, with a trend found for close/positive margins (OR 5.355, p = 0.06), tumor size (OR 2.046, p = 0.09), and total number of nodes positive (OR 1.179, p = 0.062)., Conclusions: Patients who develop very early contralateral neck disease, between completion of ipsilateral neck dissection and the initiation of radiotherapy, have a higher ratio of positive nodes to total nodes resected in the ipsilateral neck. These findings suggest that proper selection of patients for omission of treatment of the contralateral, node-negative neck should be made with this in mind, with future studies needed to document the impact on toxicity and disease outcomes from such an approach., Advances in Knowledge: Pathologic risk factors in the dissected, ipsilateral neck in patients with tonsil cancer may inform the risk of contralateral neck failure. Patient selection for future, prospective efforts to examine sparing of the contralateral neck need to be based with these risk factors in mind.

Background: For patients with head and neck squamous cell carcinoma (SCC) undergoing surgery followed by postoperative radiotherapy (PORT), time from surgery to completion of adjuvant therapy, "package time" impacts locoregional control (LRC). However, the significance of package time in HPV+ oropharyngeal SCC (OPSCC) is unknown., Methods: We examined patients undergoing TORS resection with PORT for HPV+ OPSCC from January 2010 to December 2015 with ≥18 months follow-up (n = 267). A cutoff of 15 weeks was used to delineate patients into short and long package time groups. LRC loss was defined as any recurrence after surgery., Results: Prolonged package time >15 weeks was associated with inferior LRC in this HPV+ OPSCC cohort, driven primarily by interval from surgery to PORT initiation. Multivariate analysis showed that package time and T classification are both independently associated with LRC., Conclusions: Among HPV+ OPSCC, prolongation of package time appears to compromise LRC, but not survival., (© 2019 Wiley Periodicals, Inc.)

HIV-positive people are at increased risk for malignancies associated with human papillomavirus (HPV) infection, including oropharyngeal squamous cell carcinoma (OPSCC). The purpose of this study was to determine whether cancer treatment disparities exist between HIV-positive and HIV-negative people with OPSCC. We conducted a retrospective cohort study comparing OPSCC treatment adequacy and treatment outcomes in HIV-positive and HIV-negative people in the post-antiretroviral therapy era. Treatment adequacy was determined by measuring two primary endpoints associated with OPSCC survival: time to therapy and total radiation dose. Treatment outcomes were assessed by measuring disease-free and overall survival. We identified a total of 37 HIV-positive and 149 HIV-negative people with OPSCC. HIV-positive people experienced a median delay of 10 days from time of OPSCC diagnosis to start of therapy compared with HIV-negative people [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.38-0.98]. Total post-radiation dose in HIV-positive people was lower than that in HIV-negative people [58.5 Gray (Gy) versus 64.4 Gy, p  = .04]. HIV-positive people also experienced greater hazards for disease recurrence (HR 3.43, 95% CI 1.39-8.46) and death (HR 4.21, 95% CI 1.29-13.80) compared with HIV-negative people. In conclusion, we detected a clinically important delay in time to therapy as well as worse disease-free and overall survival in HIV-positive people with OPSCC compared with their HIV-negative counterparts. These findings are relevant to understanding how HIV-positive people are diagnosed and undergo therapy for HPV-associated malignancies and highlight the need to address cancer treatment disparities in this group.

Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8 + T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8 + T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: We examine whether induction chemotherapy response predicts thoracic radiotherapy response in locally advanced or oligometastatic non-small cell lung cancer., Materials and Methods: Between January 2001 to August 2010, 25 consecutive patients were identified who received systemic dose chemotherapy followed by definitive thoracic radiotherapy alone. All patients had measurable disease after chemotherapy that was evaluable for response to radiotherapy. Response to each modality was scored by RECIST as stable disease (SD), progressive disease (PD), partial response (PR), or complete response (CR)., Results: Patients had adenocarcinoma (n=13), squamous cell carcinoma (n=8), or other histologies (n=4). They had stage IIIA (n=6), IIIB (n=14), and IV (n=5) disease. Patients received 2 to 6 cycles (median 4) of platinum-based chemotherapy followed by radiotherapy (median 66.6/1.8 Gy [range 50 to 84 Gy]). Median time between chemotherapy end and radiotherapy start was 6.7 weeks (range, 1.6 to 53.4 wk). Twelve patients responded to chemotherapy (all were PRs) and 13 did not (SD+PD). Fifteen patients responded to radiotherapy (7 CR, 8 PR) and 10 did not (SD+PD). Of the 12 patients who responded to chemotherapy, 8 also responded to radiotherapy (4 CR, 4 PR). Of the 13 chemotherapy nonresponders, 7 responded to radiotherapy (3 CR, 4 PR). χ analysis did not find any association between chemotherapy and radiotherapy response (P=0.513). Regression analysis also failed to identify any correlation between chemotherapy and radiotherapy response (r=0.008)., Conclusions: This study suggests that response to chemotherapy does not predict response to radiotherapy in locally advanced or oligometastatic non-small cell lung cancer. Lack of response to chemotherapy, therefore, should not preclude treatment with definitive radiotherapy.

Purpose To examine recent utilization and survival outcomes associated with use of adjuvant chemoradiotherapy (CRT) for patients with resected locally advanced head and neck cancer (LAHNC) with negative surgical margins (SM negative) and no extracapsular extension (ECE). Materials and Methods We conducted a retrospective observational cohort study using the National Cancer Database evaluating patients diagnosed in 2004 to 2012 with AJCC stage III to IVB squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx treated with definitive surgery and adjuvant radiotherapy (RT) or CRT. We identified a subset of patients with SM negative and no ECE (n = 10,870). We determined factors associated with CRT use and examined overall survival of patients receiving CRT versus RT. We further evaluated survival outcomes by number of lymph nodes involved to assess whether this was associated with benefit from CRT. Results Among patients with resected LAHNC with SM negative and no ECE, 47% received adjuvant CRT. The use of CRT varied substantially according to several factors, including patient age, contralateral/bulky neck disease, increasing number of positive lymph nodes, and lower neck disease. CRT was associated with a statistically significant improvement in overall survival compared with RT alone (hazard ratio, 0.90; 95% CI, 0.86 to 0.94; P < .001). Survival benefits of CRT versus RT alone increased in patients with multiple positive lymph nodes. Conclusion The use of adjuvant CRT in patients with resected LAHNC with SM negative and no ECE is common. Substantial practice variation as well as the survival differences observed in this study support the conduct of additional research to guide personalized treatment approaches in this setting. The number of positive lymph nodes seems to be an appropriate selection factor for further investigation of CRT in such patients.

Importance: Management of cervical lymph node metastasis without a known primary tumor is a diagnostic and treatment challenge for head and neck oncologists. Identification of the occult mucosal primary tumor minimizes the morbidity of treatment., Objective: To analyze the role of transoral robotic surgery (TORS) in facilitating the identification of a primary tumor site for patients presenting with squamous cell carcinoma of unknown primary (CUP). In addition, we assessed treatment deintensification by determining the number of patients who did not undergo definitive radiation therapy and chemotherapy., Design, Setting, and Participants: In this retrospective case series from January 2011 to September 2015, 60 consecutive patients with squamous cell CUP who underwent TORS-assisted endoscopy and ipsilateral neck dissection were included from an academic medical center and studied to study the rate success rate of TORS identifying occult mucosal malignancy., Main Outcomes and Measures: Success rate of identifying occult mucosal malignancy; usage of radiation therapy and chemotherapy., Results: Overall, 60 patients (mean [SD] age, 55.5 [8.9] years) were identified; 48 of the 60 patients (80.0%) had a mucosal primary identified during their TORS-assisted endoscopic procedure. The mean (SD) size of the identified mucosal primary lesions was 1.3 (0.1) cm. All mucosal primaries, when found, originated in the oropharynx including the base of tongue in 28 patients (58%), palatine tonsil in 18 patients (38%), and glossotonsillar sulcus in 2 patients (4%). Among patients in this study, 40 (67%) did not receive chemotherapy, and 15 (25%) did not receive radiation therapy., Conclusions and Relevance: Advances in transoral surgical techniques have helped identify occult oropharyngeal malignancies that traditionally have been treated with comprehensive radiation to the entire pharyngeal axis. We demonstrate the efficacy of a TORS-assisted approach to identify and surgically treat the primary tumor in patients presenting with CUP. In addition, patients managed with the TORS-assisted endoscopic approach benefit from surgical and pathological triage, which in turn results in deintensification of treatment by eliminating the need for chemotherapy in the majority of patients, as well as avoiding radiation therapy in select patients.

Background: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM-SCCHN., Methods: Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments., Results: Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia., Conclusions: In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016;122:3641-9. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Objectives: Comparisons of induction chemotherapy (IC) against upfront chemoradiation (CRT) for locally advanced head and neck cancer (LA-HNSCC) have demonstrated no differences except greater toxicity with IC. Effective induction regimens that are less toxic are therefore warranted. To inform future efforts with IC, we present our institutional experience comparing a less toxic IC regimen to CRT., Methods: We included patients with LA-HNSCC treated with organ-preservation CRT (+/-induction) between 2008 and 2011. Patients were of age above 18 years, ECOG performance status 0-1, and had minimum 6 months follow-up. IC consisted of 8 weekly cycles of cetuximab, carboplatin, and paclitaxel followed by CRT. The CRT regimen was platinum based, with cetuximab reserved for patients contraindicated to receive platinum., Results: Of 118 patients, 24 (20%) received IC and 94 (80%) received CRT. Median follow-up was 17 (IC) and 19 (CRT) months (P=0.05). There were no differences in toxicity between the groups. IC patients were more likely male, with more advanced tumor and nodal stage. Even when controlling for these factors, IC was still associated with worse locoregional control (HR=3.6, P=0.02), distant metastasis-free survival (HR=5.3, P=0.02), and overall survival (HR=5.1, P<0.01)., Conclusions: IC patients had greater disease burden than those receiving CRT. IC was well tolerated, but with significant rates of locoregional and systemic failures. Given the retrospective nature of the study, our findings are not meant to be definitive or conclusive, but rather suggestive in directing future efforts with IC. For now, we favor CRT as the standard option for treatment of inoperable LA-HNSCC., Competing Interests: notification: For the remaining authors, none were declared.

Background: Risk of nodal involvement in patients with squamous cell carcinomas (SCC) of the nasal cavity and maxillary sinus has not been well defined, especially by risk factors beyond local T-stage. Additional criteria defining patients at highest risk, as well as specific nodal levels at highest risk, has been limited in small retrospective series. We describe a population-based assessment of specific nodal involvement in this group., Material and Methods: The Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2010 identified 1283 eligible patients with SCC of the nasal cavity or maxillary sinus. Neck involvement and individual nodal level involvement at presentation were assessed, and comparison made with a contemporaneous cohort of patients with a borderline clinically significant risk of nodal involvement and recurrence., Results: Among 1283 patients, 182 (14.2%) had nodal involvement at presentation (4-27% by site and local extension). T-stage alone was associated with higher rates of nodal involvement in maxillary sinus SCC, while higher T-stage and size >2 cm were associated with higher rates of nodal involvement in nasal cavity SCC on multivariable analysis. Facial nodes and cervical nodes at levels 1 and 2 have the highest rates of involvement in T4a nasal cavity SCC, whereas nodal levels 1, 2, and/or 3 have the highest rates of involvement in T2 or higher maxillary sinus SCC when compared with a clinical reference standard., Conclusion: In this population-based study, there are high rates of initial nodal involvement when stratified by local extent determined by T-stage in nasal cavity SCC and maxillary sinus SCC, and independently by size in nasal cavity SCC. Involvement of the facial and nodal levels 1-3 varies depending on site and local extent of tumor involvement. These observations may help guide treatment decision making in the inclusion of and extent of elective nodal treatment fields.

Background: The combination of cisplatin, 5-fluorouracil, and cetuximab is a standard treatment for patients with recurrent/metastatic head and neck cancer, with a high rate of toxicity. Identifying less toxic, equally effective regimens is imperative. Therefore, in the current study, the authors investigated first-line treatment with an all-oral regimen of capecitabine and lapatinib., Methods: Patients were required to have incurable head and neck cancer of any primary site other than the nasopharynx, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, and no prior exposure to capecitabine or lapatinib. Subjects were treated with capecitabine at a dose of 1000 mg/m(2) twice daily and lapatinib at a dose of 1250 mg daily. Capecitabine was administered for 14 days of each 21-day cycle for 4 cycles. Lapatinib was administered daily until disease progression. The primary outcome was overall survival., Results: A total of 44 subjects were accrued between November 13, 2009 and April 29, 2014. Approximately 38.6% of the sample had an ECOG PS of 0, 52.3% had an ECOG PS of 1, and 9.1% had an ECOG PS of 2. Approximately 81.8% were male and the median age of the patients was 62 years. Prior attempts at curative treatment with chemotherapy had been used in 68.2% of patients (platinum was used in 55.8%). There was no grade 5 toxicity noted (toxicity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). The most common adverse events were diarrhea (18.2% of patients with grade 3) and rash (13.6% of patients with grade 3). The primary objective was met; the median overall survival was 10.7 months (90% confidence interval [90% CI], 8.7-12.9 months). The overall response rate was 25% (90% CI, 15%-38%). The median progression-free survival was 4.2 months (90% CI, 3.6-5.1 months). The results were not substantially different when subdivided by p16 status. Only 2 patients were positive for human epidermal growth factor receptor 2 by immunohistochemistry., Conclusions: The current study met its primary objective of survival comparable to the combination of cisplatin, 5-FU and cetuximab regimen, and the toxicity of this all-oral regimen was tolerable. Cancer 2016;122:2350-2355. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: The purpose of this study was to determine clinical factors that predict locoregional recurrence or distant metastasis in patients with human papillomavirus (HPV)-positive oropharyngeal cancer treated with surgery and guideline-indicated adjuvant therapy., Methods: We identified all presumed HPV-positive patients with oropharyngeal cancer in our health system from January 2010 to August 2012 treated with surgery and guideline-indicated adjuvant therapy. Statistical analysis was performed to identify clinical predictors associated with treatment failure., Results: One hundred fourteen p16+ oropharyngeal cancers managed with initial surgical resection were identified. Median follow-up was 17 months. Two-year locoregional failure was 3.3% and distant failure was 8.4%. Statistical analysis found that conventional poor prognostic features did not predict treatment failure., Conclusion: Locoregional recurrence and development of distant metastatic disease are uncommon in patients who are appropriately selected for surgical management of p16+ oropharyngeal cancer regardless of the presence or absence of conventional poor prognostic features., (© 2015 Wiley Periodicals, Inc.)

Purpose: To examine practice patterns and compare survival outcomes between total laryngectomy (TL) and larynx preservation chemoradiation (LP-CRT) in the setting of T4a larynx cancer, using a large national cancer registry., Methods and Materials: Using the National Cancer Database, we identified 969 patients from 2003 to 2006 with T4a squamous cell larynx cancer receiving definitive treatment with either initial TL plus adjuvant therapy or LP-CRT. Univariate and multivariable logistic regression were used to assess predictors of undergoing surgery. Survival outcomes were compared using Kaplan-Meier and propensity score-adjusted and inverse probability of treatment-weighted Cox proportional hazards methods. Sensitivity analyses were performed to account for unmeasured confounders., Results: A total of 616 patients (64%) received LP-CRT, and 353 (36%) received TL. On multivariable logistic regression, patients with advanced nodal disease were less likely to receive TL (N2 vs N0, 26.6% vs 43.4%, odds ratio [OR] 0.52, 95% confidence interval [CI] 0.37-0.73; N3 vs N0, 19.1% vs 43.4%, OR 0.23, 95% CI 0.07-0.77), whereas patients treated in high case-volume facilities were more likely to receive TL (46.1% vs 31.5%, OR 1.78, 95% CI 1.27-2.48). Median survival for TL versus LP was 61 versus 39 months (P<.001). After controlling for potential confounders, LP-CRT had inferior overall survival compared with TL (hazard ratio 1.31, 95% CI 1.10-1.57), and with the inverse probability of treatment-weighted model (hazard ratio 1.25, 95% CI 1.05-1.49). This survival difference was shown to be robust on additional sensitivity analyses., Conclusions: Most patients with T4a larynx cancer receive LP-CRT, despite guidelines suggesting TL as the preferred initial approach. Patients receiving LP-CRT had more advanced nodal disease and worse overall survival. Previous studies of (non-T4a) locally advanced larynx cancer showing no difference in survival between LP-CRT and TL may not apply to T4a disease, and patients should be counseled accordingly., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and antitumor activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with cetuximab in patients with incurable colorectal cancer or squamous cell carcinoma of the head and neck., Methods: PX-866 was administered at escalating doses (6-8 mg daily) combined with cetuximab given at a 400 mg/m(2) loading dose followed by 250 mg/m(2) weekly. A "3 + 3" study design was used. Prior therapy with anti-EGFR therapies, including cetuximab, was allowed., Results: Eleven patients were enrolled. The most frequent treatment-emergent adverse event was diarrhea (90.1%), followed by hypomagnesemia (72.2%), vomiting (72.2%), fatigue (54.5%), nausea (54.5%), rash (45.5%) and peripheral edema (40%). No dose limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. Best responses in 9 evaluable patients were: 4 partial responses (44.4%), 4 stable disease (44.4%), and 1 disease progression (11.1%). The median progression free survival was 106 days (range: 1-271)., Conclusion: Treatment with PX-866 and cetuximab was tolerated with signs of anti-tumor activity. Further development of this combination is warranted.

Purpose: A subset of patients with oropharyngeal squamous cell carcinoma (OP-SCC) managed with transoral robotic surgery (TORS) and postoperative radiation therapy (PORT) developed soft tissue necrosis (STN) in the surgical bed months after completion of PORT. We investigated the frequency and risk factors., Materials and Methods: This retrospective analysis included 170 consecutive OP-SCC patients treated with TORS and PORT between 2006 and 2012, with >6 months' of follow-up. STN was defined as ulceration of the surgical bed >6 weeks after completion of PORT, requiring opioids, biopsy, or hyperbaric oxygen therapy., Results: A total of 47 of 170 patients (28%) had a diagnosis of STN. Tonsillar patients were more susceptible than base-of-tongue (BOT) patients, 39% (41 of 104) versus 9% (6 of 66), respectively. For patients with STN, median tumor size was 3.0 cm (range 1.0-5.6 cm), and depth of resection was 2.2 cm (range 1.0-5.1 cm). Median radiation dose and dose of fraction to the surgical bed were 6600 cGy and 220 cGy, respectively. Thirty-one patients (66%) received concurrent chemotherapy. Median time to STN was 2.5 months after PORT. All patients had resolution of STN after a median of 3.7 months. Multivariate analysis identified tonsillar primary (odds ratio [OR] 4.73, P=.01), depth of resection (OR 3.12, P=.001), total radiation dose to the resection bed (OR 1.51 per Gy, P<.01), and grade 3 acute mucositis (OR 3.47, P=.02) as risk factors for STN. Beginning May 2011, after implementing aggressive avoidance of delivering >2 Gy/day to the resection bed mucosa, only 8% (2 of 26 patients) experienced STN (all grade 2)., Conclusions: A subset of OP-SCC patients treated with TORS and PORT are at risk for developing late consequential surgical bed STN. Risk factors include tonsillar location, depth of resection, radiation dose to the surgical bed, and severe mucositis. STN risk is significantly decreased with carefully avoiding a radiation dosage of >2 Gy/day to the surgical bed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Overexpression of the epidermal growth factor receptor (EGFR) is a common characteristic of head and neck squamous cell carcinomas (HNSCC). Cetuximab is a chimeric anti-EGFR monoclonal antibody (mAb) with multiple approved indications in HNSCC, including with radiation therapy (RT) for locoregionally advanced disease, as monotherapy after platinum progression, and with platinum/5-fluorouracil for recurrent or metastatic disease. There remain, however, numerous unanswered questions regarding the optimal use of cetuximab in HNSCC, including patient selection, its mechanisms of action and resistance, the effect of human papillomavirus status on outcomes, its role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions. In addition, a variety of other anti-EGFR agents (the multitargeted small molecule tyrosine kinase inhibitors [TKIs] lapatinib, dacomitinib, and afatinib and the anti-EGFR mAbs zalutumumab, nimotuzumab, and panitumumab) are currently under investigation in phase II and III clinical trials in different HNSCC therapeutic settings. The anti-EGFR TKI erlotinib is currently in phase III development for oral cancer prevention. Numerous other drugs are in earlier stages of development for HNSCC treatment, including novel anti-EGFR mAbs (MEHD7945A, necitumumab, and RO5083945), small-molecule TKIs (vandetanib, icotinib, and CUDC-101), EGFR antisense, various add-on therapies to radiation and chemotherapy (bevacizumab, interleukin-12, lenalidomide, alisertib, and VTX-2337), and drugs (temsirolimus, everolimus, OSI-906, dasatinib, and PX-866) intended to overcome resistance to anti-EGFR agents. Overall, a wealth of clinical trial data is expected in the coming years, with the potential to modify significantly the approach to anti-EGFR therapy for HNSCC., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To determine the pattern of failures following intensity modulated radiation therapy for head and neck cancer., Material and Methods: A retrospective single institution study. Between May 2001 and June 2008, 176 patients with head and neck cancer were treated with intensity modulated radiation therapy at Fox Chase Cancer Center. Ninety-five (54%) were squamous cell carcinoma treated with curative intent. Tumor and nodal stage, tobacco history, definitive versus postoperative therapy (PORT), addition of chemotherapy and RT duration were analyzed for association with patterns of failure. In patients treated with definitive radiation, high-risk PTV (PTV1) was prescribed to 70 Gy and low-risk PTV (PTV2) to 56 Gy. In the PORT setting, PTV1 was prescribed to 60 to 66 Gy and PTV2 to 54 Gy. Patterns of failure were assessed. Local failure (LF) was defined as the persistence of disease or recurrence within PTV1, marginal failure as recurrence at the region of high-dose falloff, and regional failure as nodal recurrence within PTV2., Results: Median follow-up was 20 months (range: 1-117). Median age was 60 years (range: 28-88), with 80% smokers and 81% stage III or IV. PORT was given to 29% and 71% were treated definitively, with concurrent Cisplatin used in the majority. Three-year local and locoregional (LR) failure rates were 9% and 16%, respectively. Failures occurred in 14 patients: 8 local, 3 regional, 1 LR, and 2 distant. Five of the 8 LF and all 3 marginal failures were observed in PORT cohort. On univariate analysis, the only predictor of LF was the use of PORT (P = 0.06). LR control was 66% for PORT versus 87%, 97% for definitive RT and chemoRT., Conclusions: Local, regional failures were more common following PORT related to an increased risk of marginal failures.

Purpose: To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC)., Methods and Materials: Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinib started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days., Results: Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis., Conclusions: Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy of mitogen-activated protein kinase/extracellular signal-related kinase kinase inhibitor PD-0325901 in advanced non-small cell lung cancer patients who had experienced treatment failure after, or were refractory to, standard systemic therapy., Experimental Design: This open-label, phase II study initially evaluated 15 mg PD-0325901 twice daily administered intermittently (3 weeks on/1 week off; schedule A). As this schedule was not well tolerated, a second schedule was introduced as follows: 5 days on/2 days off for 3 weeks, followed by 1 week off (schedule B). The primary end point was objective response., Results: All patients had received prior systemic therapy (median of two regimens, including epidermal growth factor receptor inhibitors in 26%). Of 13 patients treated on schedule A, three discontinued due to adverse events (blurred vision, fatigue, and hallucinations, respectively). Twenty-one patients received schedule B. Main toxicities included diarrhea, fatigue, rash, vomiting, nausea, and reversible visual disturbances. Hematologic toxicity consisted mainly of mild-to-moderate anemia, without neutropenia. Chemistry abnormalities were rare. Mean (coefficient of variation) PD-0325901 trough plasma concentrations were 100 ng/mL (52%) and 173 ng/mL (73%) for schedules A and B, respectively, above the minimum target concentration established in preclinical studies (16.5 ng/mL). There were no objective responses. Seven patients had stable disease. Median (95% confidence interval) progression-free survival was 1.8 months (1.5-1.9) and overall survival was 7.8 months (4.5-13.9)., Conclusions: PD-0325901 did not meet its primary efficacy end point. Future studies should focus on PD-0325901 schedule, rational combination strategies, and enrichment of patient selection based on mode of action.

Background: The impact of posttreatment neck dissection on prolonged feeding tube dependence in patients with head and neck squamous cell cancer (HNSCC) treated with primary radiation or chemoradiation remains unknown., Methods: We conducted a retrospective cohort study using propensity score adjustment to investigate the effect of neck dissection on prolonged feeding tube dependence., Results: A review of 67 patients with node-positive HNSCC (T1-4N1-3), treated with primary radiation or chemoradiation, with no evidence of tumor recurrence and follow-up of at least 24 months, was performed. Following adjustment for covariates, the relative risk (RR) of feeding tube dependence at 18 months was significantly increased in patients treated with posttreatment neck dissection (RR 4.74, 95% confidence interval [CI] 2.07-10.89). At 24 months, the relative risk of feeding tube dependence in the patients having undergone neck dissection increased further (RR 7.66, 95% CI 2.07-10.89). Of patients with feeding tubes 2 years after completing treatment, 75% remained feeding tube dependent., Conclusion: Neck dissection may contribute to chronic oropharyngeal dysphagia in HNSCC patients treated with primary radiation or chemoradiation.

Background: Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival., Methods: Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227., Findings: Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002)., Interpretation: For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash., Funding: ImClone Systems, Merck KGaA, and Bristol-Myers Squibb., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Squamous cell carcinoma of the head and neck (HNSCC), while curable in many cases with surgery, radiation, and chemotherapy, remains a disease that is associated with significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated beneficial effects in this disease. The Food and Drug Administration approved cetuximab-a monoclonal antibody-in conjunction with radiation, for locally advanced, potentially curable disease, and also as a single agent for incurable recurrent/metastatic disease. In addition, there are more recent data showing a survival benefit for patients with recurrent/metastatic disease who were treated with a first-line regimen of platinum, fluorouracil and cetuximab. These promising results have had a significant impact on the standard of care for HNSCC, and have prompted further research on the role of EGFR inhibitors in the treatment of HNSCC. In the following review, we will discuss the history, mechanism, and clinical trials that pertain to the role of cetuximab in the treatment of HNSCC.

Squamous cell carcinoma of the head and neck (SCCHN) continues to be a source of significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR), including monoclonal antibodies and small molecule tyrosine kinase inhibitors, have demonstrated activity in this disease. The US Food and Drug Administration has approved the monoclonal antibody cetuximab in conjunction with radiation for locally advanced disease, and as a single agent for recurrent/metastatic disease. In addition, recent data have shown a survival benefit for patients with recurrent/metastatic disease who are treated with platinum, fluorouracil, and cetuximab. These promising results have prompted further study of EGFR inhibitors with radiation and cytotoxic chemotherapy to further increase the benefit of treatment for SCCHN.

The epidermal growth factor (EGFR) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, profoundly radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides a reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.

Background: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy., Methods: We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival., Results: With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group., Conclusions: Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

Purpose: In this randomized, phase III study, quality of life (QoL) was assessed in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) after high-dose radiotherapy alone or in combination with cetuximab., Patients and Methods: Patients with stage III or IV nonmetastatic and measurable squamous cell carcinoma of the oropharynx, hypopharynx, or larynx were eligible. QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC QLQ Head and Neck Cancer-Specific Module at baseline, week 4, and at months 4, 8, and 12 postbaseline., Results: In this study, one of the largest conducted in a population of patients with locoregionally advanced SCCHN, 424 patients received radiotherapy alone (213 patients) or radiotherapy plus cetuximab (211 patients). Radiotherapy/cetuximab significantly improved locoregional control (P = .005) and overall survival (P = .03) compared with radiotherapy alone, without significantly increasing radiotherapy-associated adverse events. The current analysis focused on the impact of cetuximab on the QoL. Compliance with completion of QoL questionnaires was high in both arms. QoL worsened during treatment and improved after cessation of treatment, reaching baseline levels at 12 months. There were no significant differences in QoL scores between the treatment arms. This was particularly notable for global health status/QoL, social functioning, social eating, and social contact. Pretreatment global health status/QoL was identified as a significant prognostic variable in these patients., Conclusion: The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting QoL.

The epidermal growth factor (EGF) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides the reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locoregionally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.

Background: We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck., Methods: Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety., Results: The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P=0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P=0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P=0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups., Conclusions: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.), (Copyright 2006 Massachusetts Medical Society.)

Background: Patients with local recurrences or new head and neck primary tumors in previously irradiated tissues have few options for salvage treatment. One option for select patients is to undergo reirradiation with concurrent chemotherapy. The purpose of this study is to report the initial clinical results of the Fox Chase phase I and II prospective reirradiation and chemotherapy studies., Methods: Between July 1996 and January 2002, 38 patients with locally recurrent unresectable squamous cell carcinoma of the head and neck were treated with concurrent chemotherapy and reirradiation on two prospective trials. All patients had received prior radiation therapy to the head and neck region (median dose, 64.2 Gy). Patients received cisplatin and paclitaxel along with hyperfractionated external beam radiation therapy to the site of recurrence., Results: The median follow-up was 10 months. The median survival was 12.4 months, with actuarial rates of overall survival of 50% and 35% at 1 and 2 years, respectively. During follow-up, 63% of patients experienced local progression of disease, all in the irradiated field. Actuarial progression-free survival at 1 year was 33%, with a median time to progression of 7.3 months. Acute grade 3 to 4 toxicity included neutropenia, nausea, emesis, and mucositis., Conclusions: Hyperfractionated split-course reirradiation and concurrent cisplatin and paclitaxel chemotherapy demonstrates durable locoregional control in select patients, although late toxicity may occasionally be significant. Only sites of disease recurrence need to be covered in the reirradiation fields., (2005 Wiley Periodicals, Inc.)

Background: Paclitaxel (24-hour infusion) has yielded activity in advanced squamous cell carcinoma of the head and neck (SCCHN). Protracted exposure to paclitaxel may overcome resistance observed by using shorter infusions. Therefore we sought to evaluate paclitaxel by 96-hour infusion in both treatment-naïve and previously treated patients with SCCHN., Materials and Methods: Eligibility stipulated bi-dimensionally measurable, biopsy-documented, incurable SCCHN, Eastern Cooperative Oncology Group performance status (PS) 0-1, and adequate physiological indices. Patients were divided into three cohorts: 1) chemotherapy-naïve; 2) chemotherapy-exposed, paclitaxel-naïve; and 3) chemotherapy and paclitaxel exposed. Paclitaxel was dosed at 140 mg/m2 (96-hour infusion) every 3 weeks in treatment-naïve patients and at 120 mg/m2 (96 hours) every 3 weeks in previously treated patients., Results: Fifty patients were accrued between February 1997 and July 2000. The study was terminated because of low response rate. Eighty percent of patients were male, 75% PS 1. Nearly half the patients had oropharyngeal or hypopharyngeal primary sites. There was one treatment-related death due to neutropenic fever/pneumonia. Grade 4 toxicities included granulocytopenia in eight patients (20%), thrombocytopenia, and stomatitis in one patient each. Grade 3 or greater anemia occurred in 10 patients. There was no grade 2 or 3 peripheral sensory neuropathy. In 15 chemotherapy-naïve patients, two responses (13%) were observed. There were no responses in treatment-exposed patients. The overall median survival was 5.5 months, and 1-year survival rate 10%. Treatment-naïve patients had a median survival of 8.2 months and 1-year survival rate of 20%., Conclusions: Paclitaxel by 96-hour infusion at a dose of 120-140 mg/m2/96 hours is only marginally active in the treatment of SCCHN. This dose and schedule cannot be recommended for further evaluation.