Evolutionary Action Score of TP53 Analysis in Pathologically High-Risk Human Papillomavirus-Negative Head and Neck Cancer From a Phase 2 Clinical Trial: NRG Oncology Radiation Therapy Oncology Group 0234.

Purpose: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing TP53 missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as TP53 wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods and Materials: Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to TP53 targeted sequencing and EAp53 scoring to correlate with clinical outcomes. Due to the limited sample size, patients were combined into 2 EAp53 groups: (1) wild-type or low-risk; and (2) high-risk or other. Results: At a median follow-up of 9.8 years, there was a significant interaction between EAp53 group and treatment for overall survival (P = .008), disease-free survival (P = .05), and distant metastasis (DM; P = .004). In wild-type or low-risk group, the docetaxel arm showed significantly better overall survival (hazard ratio [HR] 0.11, [0.03-0.36]), disease-free survival (HR 0.24, [0.09-0.61]), and less DM (HR 0.04, [0.01-0.31]) than the cisplatin arm. In high-risk or other group, differences between treatments were not statistically significant. Conclusions: The docetaxel arm was associated with better survival than the cisplatin arm for patients with wild-type or low-risk EAp53. These benefits appear to be largely driven by a reduction in DM.

Precision medicine: preliminary results from the Initiative for Molecular Profiling and Advanced Cancer Therapy 2 (IMPACT2) study.

Precision medicine is associated with favorable outcomes in selected patients with cancer. Herein, we report an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer. Patients with metastatic cancer underwent tumor genomic profiling (ClinialTrials.gov: NCT02152254), and 69 patients met the criteria for randomization. Tumor board and multidisciplinary review of molecular alterations optimized treatment selection. From 5/2014 to 4/2017, 320 patients (median age, 63 years; men, 47%) had tumor molecular aberrations, and 213 (66.56%) received anticancer therapy. The most frequently mutated genes were TP53 (42%), KRAS (16%), PIK3CA (12%), and CDKN2A (11%). The median OS was 10.9 months (95% CI, 8.8-12.9). OS was shorter in patients with higher tumor mutational burden. Independent factors associated with shorter OS were age ≥60 years, liver metastases, low albumin levels, high LDH levels, and KRAS and TP53 mutations. Outcomes for randomized patients will be reported after completion of the study.

A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma.

LESSONS LEARNED: Treatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or peritoneal mesothelioma. In a limited sample size, MYC copy-number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes. BACKGROUND: Malignant mesothelioma is an aggressive disease for which few effective therapies are available. The Aurora family kinases are critical for mitotic fidelity and highly expressed in mesothelioma, wherein their inhibition leads to growth arrest in vitro. We evaluated the efficacy of alisertib, an Aurora A kinase inhibitor, in relapsed malignant mesothelioma. METHODS: Twenty-six patients with previously treated, unresectable pleural or peritoneal mesothelioma were enrolled on a single-arm, single-institution phase II trial of alisertib at a dosage of 50 mg twice daily for 7 of every 21 days. The primary endpoint was 4-month disease control rate. Secondary endpoints included overall response rate, progression free survival, overall survival, safety/toxicity, and correlation of endpoints with MYC copy number. RESULTS: Of the 25 evaluable patients treated on study, 8 (32%) experienced 4-month disease control, surpassing the futility endpoint. There were no confirmed partial or complete responses. Median progression-free and overall survival were 2.8 months and 6.3 months, respectively. No associations between MYC copy number and outcomes were observed. CONCLUSION: Alisertib has modest activity in this unselected malignant mesothelioma population. Several patients achieved durable disease control. Although the study did meet its prespecified futility endpoint, the sponsor elected to close the trial at the interim analysis.

Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy.

BACKGROUND: Patients with advanced primary and recurrent salivary duct carcinoma (SDC), a rare and lethal malignancy, have limited therapeutic options. Novel small-molecule agents aimed at targeting critical signaling associated with SDC tumorigenesis may lead to new therapeutic options for patients with these tumors. The human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K) axis, an important oncogenic pathway, has been targeted for therapy in several solid tumors. Currently, little is known about the role and clinical implications of alterations of the HER2/PI3K pathway in patients with SDC. METHODS: The authors investigated the clinicopathologic features, genetic alterations, and expression of key members of the HER2/PI3K pathway in 43 primary tumors and conducted in vitro functional and targeted drug-response analyses on cell lines derived from salivary epithelial carcinomas. RESULTS: In primary tumors, loss of phosphatase and tensin homolog (PTEN) expression was identified in 22 of 43 tumors (51%), overexpression of HER2 was observed in 12 of 43 tumors (28%), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations were identified in 12 of 43 tumors (28%). Phosphorylated protein kinase B (p-AKT) was highly expressed in most tumors. Most tumors (70%) displayed mutually exclusive alterations of PI3K members, whereas 8 tumors (19%) had 2 or more concurrent abnormalities. In vitro studies demonstrated a direct association between PTEN loss and PI3K pathway activation and evidence of response to combined PI3Kα and PI3Kß and/or pan-PI3K inhibitors. CONCLUSIONS: The current analyses reveal frequent PTEN loss and mutually exclusive alterations of key PI3K pathway members in SDC and demonstrate in vitro evidence of a response to pan-PI3K inhibitors. These results provide a framework for a biomarker-based substratification of patients with SDC in future targeted therapy. Cancer 2018;124:3523-32. © 2018 American Cancer Society.

Comparing Intensity-Modulated Proton Therapy With Intensity-Modulated Photon Therapy for Oropharyngeal Cancer: The Journey From Clinical Trial Concept to Activation.

Intensity-modulated proton therapy minimizes the incidental irradiation of normal tissues in patients with head and neck cancer relative to intensity-modulated photon (x-ray) therapy and has been associated with lesser treatment-related toxicity and improved quality of life. A phase II/III randomized trial sponsored by the US National Cancer Institute is currently underway to compare deintensification treatment strategies with intensity-modulated proton therapy vs intensity-modulated photon (x-ray) therapy for patients with advanced-stage oropharyngeal tumors. After significant input from numerous stakeholders, the phase III portion of the randomized trial was redesigned as a noninferiority trial with progression-free survival as the primary endpoint. The process by which that redesign took place is described here.

Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase 2 clinical trial.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is a very common malignancy in which most patients present with localized disease. Recurrent and metastatic disease is rare, and there is no standard therapy. These tumors frequently overexpress the epidermal growth factor receptor (EGFR). We conducted a phase 2 trial to determine the response rate to therapy with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with locoregionally recurrent or metastatic CSCC that was not amenable to curative treatment (NCT01198028). METHODS: Eligible patients had CSCC not amenable to curative intent therapy. Patients who had previously received anti-EGFR targeted therapy were excluded. All patients received oral therapy with erlotinib 150 mg daily. Response was assessed every 8 weeks, and treatment continued until progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was overall response rate according to RECIST 1.1 criteria. RESULTS: A total of 39 patients received treatment during the trial; 29 of these patients were evaluable for response. The overall response rate was 10% (3/29); all responses were partial responses. The disease control rate (partial response + stable disease) was 72% (21/29). The median progression-free survival was 4.7 months (95% confidence interval, 3.5-6.2 months); the median overall survival was 13 months (95% confidence interval, 8.4-20.5 months). No unexpected toxicities were seen. CONCLUSION: Erlotinib therapy was feasible for most patients with incurable CSCC and was associated with expected toxicities. However, only a modest response rate of 10% was observed. Further study of EGFR tyrosine kinase inhibitors in this patient population is not warranted. Cancer 2018;124:2169-73. © 2018 American Cancer Society.

Poly ADP-ribose polymerase-1 as a potential therapeutic target in Merkel cell carcinoma.

BACKGROUND: Patients with metastatic Merkel cell carcinoma are treated similarly to small cell lung cancer (SCLC). Poly ADP-ribose polymerase-1 (PARP1) is overexpressed in SCLC and response to PARP inhibitors have been reported in patients with SCLC. Our study explores PARP as a therapeutic target in Merkel cell carcinoma. METHODS: We evaluated PARP1 expression and Merkel cell polyomavirus (MCPyV) in 19 patients with Merkel cell carcinoma. Target exome-sequencing was performed in 14 samples. Sensitivity to olaparib was tested in 4 Merkel cell carcinoma cell lines. RESULTS: Most Merkel cell carcinomas (74%) express PARP1 at high levels. Mutations in DNA-damage repair genes were identified in 9 samples (64%), occurred exclusively in head neck primaries, and correlated with TP53/RB1 mutations. The TP53/RB1 mutations were more frequent in MCPyV-negative tumors. Sensitivity to olaparib was seen in the Merkel cell carcinoma line with highest PARP1 expression. CONCLUSION: Based on PARP1 overexpression, DNA-damage repair gene mutations, platinum sensitivity, and activity of olaparib in a Merkel cell carcinoma line, clinical trials with PARP inhibitors are warranted in Merkel cell carcinoma.

Single Arm, Phase II Study of Cisplatin, Docetaxel, and Erlotinib in Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinomas.

LESSONS LEARNED: The combination of cisplatin, docetaxel, and erlotinib as frontline treatment for recurrent and/or metastatic head and neck squamous cell carcinomas led to a response rate of 62%.This result exceeded the prespecified target response rate of 50% and represented an improvement compared with historical controls.This regimen warrants further investigation. BACKGROUND: The epidermal growth factor receptor (EGFR) plays a key role in the carcinogenesis of head and neck squamous cell carcinomas (HNSCC). We conducted this clinical study to test the hypothesis that the addition of erlotinib to first-line cisplatin and docetaxel for patients with recurrent and/or metastatic HNSCC would yield a response rate of at least 50%, representing an improvement from historical controls. METHODS: Patients with recurrent and/or metastatic HNSCC, with at least one measurable lesion, no prior chemotherapy for recurrent and/or metastatic disease, prior combined modality therapy completed >6 months before enrollment, and performance status ≤2 were treated with cisplatin, docetaxel, and erlotinib for up to six cycles, followed by maintenance erlotinib until disease progression. The primary endpoint was response rate. RESULTS: Fifty patients were enrolled (42 male, 12 never smokers, 19 with oropharynx cancer). The median number of cycles was five; 31 patients initiated maintenance erlotinib; 14 patients required erlotinib dose reductions. The objective response rate was 62%, and the median progression-free and overall survival were 6.1 and 11.0 months, respectively. Toxicity profiles were consistent with the known side effects of the study drugs. CONCLUSION: The study met its primary endpoint and improved response rates compared with historical controls. The findings support further evaluation of the regimen for recurrent and/or metastatic HNSCCs.

Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson Precision Medicine Study.

PURPOSE: Genomic profiling is increasingly used in the management of cancer. We have previously reported preliminary results of our precision medicine program. Here, we present response and survival outcomes for 637 additional patients who were referred for phase I trials and were treated with matched targeted therapy (MTT) when available. PATIENTS AND METHODS: Patients with advanced cancer who underwent tumor genomic analyses were treated with MTT when available. RESULTS: Overall, 1,179 (82.1%) of 1,436 patients had one or more alterations (median age, 59.7 years; men, 41.2%); 637 had one or more actionable aberrations and were treated with MTT (n = 390) or non-MTT (n = 247). Patients who were treated with MTT had higher rates of complete and partial response (11% v 5%; P = .0099), longer failure-free survival (FFS; 3.4 v 2.9 months; P = .0015), and longer overall survival (OS; 8.4 v 7.3 months; P = .041) than did unmatched patients. Two-month landmark analyses showed that, for MTT patients, FFS for responders versus nonresponders was 7.6 versus 4.3 months (P < .001) and OS was 23.4 versus 8.5 months (P < .001), whereas for non-MTT patients (responders v nonresponders), FFS was 6.6 versus 4.1 months (P = .001) and OS was 15.2 versus 7.5 months (P = .43). Patients with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase pathway alterations matched to PI3K/Akt/mammalian target of rapamycin axis inhibitors alone demonstrated outcomes comparable to unmatched patients. CONCLUSION: Our results support the use of genomic matching. Subset analyses indicate that matching patients who harbor a PI3K and mitogen-activated protein kinase pathway alteration to only a PI3K pathway inhibitor does not improve outcome. We have initiated IMPACT2, a randomized trial to compare treatment with and without genomic selection.

Nasopharyngeal carcinoma presenting as an inconspicuous primary lesion with extensive cavernous sinus involvement and temporal lobe extension: a case report and review of literature.

Detection of nodal metastasis in the neck or adjacent structures is common in nasopharyngeal carcinoma (NPC) when there is frank primary disease. Intracranial extension without obvious nasopharyngeal disease is not common. Here, we discuss a patient with NPC that presented with extensive intracranial disease with subtle findings in the nasopharynx.

Outcomes for olfactory neuroblastoma treated with induction chemotherapy.

BACKGROUND: Oncologic outcomes for induction chemotherapy and its role in patients with advanced olfactory neuroblastoma (ONB) remain unclear. METHODS: A retrospective review of 15 consecutive patients with extensive local invasion and/or nodal disease treated with induction chemotherapy with curative intent followed by definitive local therapy. RESULTS: The majority of patients were treated with cisplatin and etoposide. The response to chemotherapy was 68% (10/15). Response was 78% (7/9) in the high Hyams high-grade group and 50% (3/6) in the Hyams low-grade group. Seven patients had complete response (CR) and 3 patients were able to avoid orbital exenteration. The 5-year disease-free survival (DFS) and overall survival (OS) were 71% and 78%, respectively, with a trend toward improved survival in patients with CR. CONCLUSION: ONB is a chemosensitive tumor and induction chemotherapy is an acceptable strategy for aggressive and locoregional advanced disease. Hyams grade may predict chemosensitivity and CR may be associated with improved survival.

Delayed lower cranial neuropathy after oropharyngeal intensity-modulated radiotherapy: A cohort analysis and literature review.

BACKGROUND: The purpose of this study was to examine swallowing-related lower cranial nerve palsy (LCNP) in oropharyngeal cancer (OPC) survivors after intensity-modulated radiotherapy (IMRT). METHODS: Patients treated with definitive IMRT (66-72 Gy) were pooled from institutional trial databases. Prospective analyses on parent trials included videofluoroscopy, clinical LCNP examination, and questionnaires pre-IMRT, 6 months post-IMRT, 12 months post-IMRT, and 24 months post-IMRT. Time-to-event and incidence of LCNP was estimated with competing risk methods. Literature review (1977-2015) summarized published LCNP outcomes. RESULTS: Three of 59 oropharyngeal cancer survivors with a minimum 2-year follow-up developed hypoglossal palsy ipsilateral to the index tumor (median latency 6.7 years; range 4.6-7.6 years). At a median of 5.7 years, cumulative incidence of LCNP was 5%. LCNP preceded progressive dysphagia in all cases. Published studies found median incidence of radiation-associated LCNP was 10.5% after NPC, but no OPC cancer-specific estimate. CONCLUSION: Although uncommon, the potential for late LCNP preceding swallowing deterioration highlights the importance of long-term functional surveillance in OPC survivorship.

Predicting two-year longitudinal MD Anderson Dysphagia Inventory outcomes after intensity modulated radiotherapy for locoregionally advanced oropharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: To determine the factors associated with longitudinal patient-reported dysphagia as measured by the MD Anderson Dysphagia Inventory (MDADI) in locoregionally advanced oropharyngeal carcinoma (OPC) survivors treated with split-field intensity modulated radiotherapy (IMRT). STUDY DESIGN: Retrospective patient analysis. METHODS: A retrospective analysis combined data from three single-institution clinical trials for stage III/IV head and neck carcinoma. According to trial protocols, patients had prospectively collected MDADI at baseline, 6, 12, and 24 months after treatment. OPC patients with baseline and at least one post-treatment MDADI were included. Longitudinal analysis was completed with multivariate linear mixed effects modeling. RESULTS: There were 116 patients who met inclusion criteria. Mean baseline MDADI composite was 88.3, dropping to 73.8 at 6 months, and rising to 78.6 and 83.3 by 12 and 24 months, respectively (compared to baseline, all P < .0001). Tumor stage and smoking status were significant predictors of longitudinal MDADI composite scores. Patients with T1, T2, and T3 tumors had 15.9 (P = .0001), 10.9 (P = .0049), and 7.5 (P = .0615), respectively, higher mean MDADI composite than those with T4 tumors, and current smokers had a 9.4 (P = .0007) lower mean MDADI composite than never smokers. CONCLUSIONS: Patients report clinically meaningful dysphagia early after split-field IMRT for locoregionally advanced OPC that remains apparent 6 months after treatment. MDADI scores recover slowly thereafter, but remain depressed at 24 months compared to baseline. Higher tumor stage and smoking status are important markers of patient-reported function through the course of treatment, suggesting these are important groups for heightened surveillance and more intensive interventions to optimize swallowing outcomes. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:842-848, 2017.

Long-Term, Prospective Performance of the MD Anderson Dysphagia Inventory in "Low-Intermediate Risk" Oropharyngeal Carcinoma After Intensity Modulated Radiation Therapy.

PURPOSE: To characterize long-term MD Anderson Dysphagia Inventory (MDADI) results after primary intensity modulated radiation therapy (IMRT) for oropharyngeal carcinoma (OPC) among patients with "low-intermediate risk" OPC who would be eligible for current trials (eg, ECOG 3311, NRG HN002, CRUK PATHOS). METHODS AND MATERIALS: A retrospective pooled analysis combined data from 3 single-institution clinical trials for advanced-stage head and neck carcinoma. Inclusion criteria were clinical stage III/IV OPC (T1-2/N1-2b, T3/N0-2b) treated with definitive split-field IMRT and prospectively collected MDADI at baseline and at least 1 posttreatment interval available in trial databases. Patients were sampled to represent likely human papillomavirus (HPV)-associated disease (HPV+/p16+ or <10 pack-years if HPV/p16 unknown). The MDADI composite scores were collected at baseline and 6, 12, and 24 months after treatment. Pairwise tests were Bonferroni corrected for multiple comparisons. RESULTS: Forty-six patients were included. All received bilateral neck irradiation with a median dose of 70 Gy and systemic therapy (57% concurrent, 43% induction only). Overall the mean baseline MDADI composite score was 90.1, dropping to 74.6 at 6 months (P<.0001) and rising to 78.5 (P<.0001) and 83.1 (P=.002) by 12 and 24 months relative to baseline, respectively, representing a clinically meaningful drop in MDADI scores at 6 months that partially recovers by 24 months (6 vs 24 months, P=.05). Poor MDADI scores (composite <60) were reported in 4%, 11%, 15%, and 9% of patients at baseline and 6, 12, and 24 months, respectively. Fifteen percent of patients had a persistently depressed composite score by at least 20 points at the 24-month interval. CONCLUSION: "Low-intermediate risk" patients with OPC treated with laryngeal/esophageal inlet dose-optimized split-field IMRT are highly likely to report recovery of acceptable swallowing function in long-term follow-up. Only 15% report poor swallowing function and/or persistently depressed MDADI at 12 months or more after IMRT. These data serve as a benchmark future trial design and endpoint interpretation.

Reduced acute toxicity and improved efficacy from intensity-modulated proton therapy (IMPT) for the management of head and neck cancer.

Cancers in the head and neck area are usually close to several critical organ structures. Traditional external-beam photon radiation therapy unavoidably exposes these structures to significant doses of radiation, which can lead to serious acute and chronic toxicity. Intensity-modulated proton therapy (IMPT), however, has dosimetric advantages that allow it to deposit high doses within the target while largely sparing surrounding structures. Because of this advantage, IMPT has the potential to improve both tumor control and toxicity. To determine the degree to which IMPT can reduce toxicity and improve tumor control, more randomized trials are needed that directly compare IMPT with intensity-modulated photon therapy. Here we examine the existing evidence on the efficacy and toxicity of IMPT for treating cancers at several anatomic subsites of the head and neck. We also report on the ability of IMPT to reduce malnutrition, and gastrostomy tube dependence and improve patient-reported outcomes (PROs).

Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer - A case matched analysis.

BACKGROUND: Owing to its physical properties, intensity-modulated proton therapy (IMPT) used for patients with oropharyngeal carcinoma has the ability to reduce the dose to organs at risk compared to intensity-modulated radiotherapy (IMRT) while maintaining adequate tumor coverage. Our aim was to compare the clinical outcomes of these two treatment modalities. METHODS: We performed a 1:2 matching of IMPT to IMRT patients. Our study cohort consisted of IMPT patients from a prospective quality of life study and consecutive IMRT patients treated at a single institution during the period 2010-2014. Patients were matched on unilateral/bilateral treatment, disease site, human papillomavirus status, T and N status, smoking status, and receipt of concomitant chemotherapy. Survival analyzes were performed using a Cox model and binary toxicity endpoints using a logistic regression analysis. RESULTS: Fifty IMPT and 100 IMRT patients were included. The median follow-up time was 32months. There were no imbalances in patient/tumor characteristics except for age (mean age 56.8years for IMRT patients and 61.1years for IMPT patients, p-value=0.010). Statistically significant differences were not observed in overall survival (hazard ratio (HR)=0.55; 95% confidence interval (CI): 0.12-2.50, p-value=0.44) or in progression-free survival (HR=1.02; 95% CI: 0.41-2.54; p-value=0.96). The age-adjusted odds ratio (OR) for the presence of a gastrostomy (G)-tube during treatment for IMPT vs IMRT were OR=0.53; 95% CI: 0.24-1.15; p-value=0.11 and OR=0.43; 95% CI: 0.16-1.17; p-value=0.10 at 3months after treatment. When considering the pre-planned composite endpoint of grade 3 weight loss or G-tube presence, the ORs were OR=0.44; 95% CI: 0.19-1.0; p-value=0.05 at 3months after treatment and OR=0.23; 95% CI: 0.07-0.73; p-value=0.01 at 1year after treatment. CONCLUSION: Our results suggest that IMPT is associated with reduced rates of feeding tube dependency and severe weight loss without jeopardizing outcome. Prospective multicenter randomized trials are needed to validate such findings.

Clinical Outcomes and Patterns of Disease Recurrence After Intensity Modulated Proton Therapy for Oropharyngeal Squamous Carcinoma.

PURPOSE: A single-institution prospective study was conducted to assess disease control and toxicity of proton therapy for patients with head and neck cancer. METHODS AND MATERIALS: Disease control, toxicity, functional outcomes, and patterns of failure for the initial cohort of patients with oropharyngeal squamous carcinoma (OPC) treated with intensity modulated proton therapy (IMPT) were prospectively collected in 2 registry studies at a single institution. Locoregional failures were analyzed by using deformable image registration. RESULTS: Fifty patients with OPC treated from March 3, 2011, to July 2014 formed the cohort. Eighty-four percent were male, 50% had never smoked, 98% had stage III/IV disease, 64% received concurrent therapy, and 35% received induction chemotherapy. Forty-four of 45 tumors (98%) tested for p16 were positive. All patients received IMPT (multifield optimization to n=46; single-field optimization to n=4). No Common Terminology Criteria for Adverse Events grade 4 or 5 toxicities were observed. The most common grade 3 toxicities were acute mucositis in 58% of patients and late dysphagia in 12%. Eleven patients had a gastrostomy (feeding) tube placed during therapy, but none had a feeding tube at last follow-up. At a median follow-up time of 29 months, 5 patients had disease recurrence: local in 1, local and regional in 1, regional in 2, and distant in 1. The 2-year actuarial overall and progression-free survival rates were 94.5% and 88.6%. CONCLUSIONS: The oncologic, toxicity, and functional outcomes after IMPT for OPC are encouraging and provide the basis for ongoing and future clinical studies.

Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus.

BACKGROUND: Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab. PATIENTS AND METHODS: We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus. RESULTS: The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)). CONCLUSION: The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.

Radiation therapy (with or without neck surgery) for phenotypic human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: Favorable outcomes for human papillomavirus-associated oropharyngeal cancer have led to interest in identifying a subgroup of patients with the lowest risk of disease recurrence after therapy. De-intensification of therapy for this group may result in survival outcomes that are similar to those associated with current therapy but with less toxicity. To advance this effort, this study analyzed the outcomes of oropharyngeal cancer patients treated with or without systemic therapy. METHODS: This was a retrospective study of patients with oropharyngeal cancer treated between 1985 and 2012. The criteria for inclusion were ≤10 pack-years of cigarette smoking and stage III/IVA cancer limited to T1-3, N1-N2b, and T3N0 disease. A survival analysis was performed with the primary endpoint of progression-free survival (PFS). RESULTS: The cohort included 857 patients. Systemic therapy was given to 439 patients (51%). The median survival was 80 months. The 2-year PFS rate was 91%. When the analysis was limited to 324 patients irradiated without systemic therapy, the 2- and 5-year PFS rates were 90% and 85%, respectively. Furthermore, for these 324 patients, the 5-year PFS rates for T1, T2, and T3 disease were 90%, 83%, and 70%, respectively. The 5-year PFS rate for patients treated with systemic therapy for T3 disease was 77% (P = .07). CONCLUSIONS: According to the low-risk definition currently established in cooperative trials, the patients had a 2-year PFS rate approximating 90%. When patients who were treated with radiation alone were evaluated, no compromise was observed in this high rate of PFS, which is higher than the 2-year PFS thresholds used in current cooperative trials. Cancer 2016;122:1702-7. © 2016 American Cancer Society.