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.

Induction chemotherapy with or without erlotinib in patients with head and neck squamous cell carcinoma amenable for surgical resection.

PURPOSE: Neoadjuvant chemotherapy prior to definitive surgery has been utilized widely for locally advanced oral squamous cell carcinoma (OSCC). We evaluated neoadjuvant erlotinib with platinum-docetaxel vs. placebo with platinum-docetaxel in stage III-IVB OSCC patients. EXPERIMENTAL DESIGN: Patients with newly diagnosed stage III, IVA, IVB (AJCC 7th) OSCC amenable to surgical resection were included. Patients were randomized to receive up to 3 cycles of chemotherapy with concurrent erlotinib or placebo, followed by surgery. The primary endpoint was major pathologic response (MPR) rate, secondary endpoints included safety, overall (OS) and progression-free survival (PFS). RESULTS: Fifty-two patients received at least one cycle of treatment and 47 were evaluable with surgical resection. MPR rate was not different between erlotinib (30%, 7/23) and placebo arms (41.7%, 10/24) (p=0.55). At median follow up of 26.5 months, there was no difference on OS or PFS between groups. Patients who received erlotinib with chemotherapy and achieved MPR (n=7) had no recurrence. The treatment-related adverse event rates were not different between the two groups (96% vs. 96%). However, rash, mostly low grade, was more common in the erlotinib arm (79% vs. 50%). Transcriptomic analysis in the pre-treatment samples indicated that genes in protein glycosylation and Wnt signaling pathways were associated with benefit in those treated with erlotinib plus chemotherapy. CONCLUSIONS: The addition of erlotinib to platinum-taxane chemotherapy was well-tolerated but did not induce higher rates of MPR or PFS or OS survival benefit. Patients who received chemotherapy with erlotinib and achieved major pathological responses had excellent clinical outcome.

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.

Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer: A Phase 2 Clinical Trial.

Importance: In recurrent human papilloma virus (HPV)-driven cancer, immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies produces tumor regression in only a minority of patients. Therapeutic HPV vaccines have produced strong immune responses to HPV-16, but vaccination alone has been ineffective for invasive cancer. Objective: To determine whether the efficacy of nivolumab, an anti-PD-1 immune checkpoint antibody, is amplified through treatment with ISA 101, a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells, in patients with incurable HPV-16-positive cancer. Design, Setting, and Participants: In this single-arm, single-center phase 2 clinical trial, 24 patients with incurable HPV-16-positive cancer were enrolled from December 23, 2015, to December 12, 2016. Duration of follow-up for censored patients was 12.2 months through August 31, 2017. Interventions: The vaccine ISA101, 100 µg/peptide, was given subcutaneously on days 1, 22, and 50. Nivolumab, 3 mg/kg, was given intravenously every 2 weeks beginning day 8 for up to 1 year. Main Outcomes and Measures: Assessment of efficacy reflected in the overall response rate (per Response Evaluation Criteria in Solid Tumors, version 1.1). Results: Of the 24 patients (4 women and 20 men; 22 with oropharyngeal cancer; median age, 60 years [range, 36-73 years]), the overall response rate was 33% (8 patients; 90% CI, 19%-50%). Median duration of response was 10.3 months (95% CI, 10.3 months to inestimable). Five of 8 patients remain in response. Median progression-free survival was 2.7 months (95% CI, 2.5-9.4 months). Median overall survival was 17.5 months (95% CI, 17.5 months to inestimable). Grades 3 to 4 toxicity occurred in 2 patients (asymptomatic grade 3 transaminase level elevation in 1 patient and grade 4 lipase elevation in 1 patient), requiring discontinuation of nivolumab therapy. Conclusions and Relevance: The overall response rate of 33% and median overall survival of 17.5 months is promising compared with PD-1 inhibition alone in similar patients. A randomized clinical trial to confirm the contribution of HPV-16 vaccination to tumoricidal effects of PD-1 inhibition is warranted for further study. Trial Registration: ClinicalTrials.gov identifier: NCT02426892.

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.

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.

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.

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.

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.

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.

Gefitinib for patients with incurable cutaneous squamous cell carcinoma: A single-arm phase II clinical trial.

BACKGROUND: Preclinical data demonstrate a key role for the epidermal growth factor receptor (EGFR) in the carcinogenesis of cutaneous squamous cell carcinomas (CSCCs). There are, however, limited data on the efficacy of EGFR inhibitors in incurable, recurrent, and/or metastatic CSCC. OBJECTIVE: To determine the response rate to gefitinib in patients with CSCC not amenable to curative therapy including surgery or radiation. METHODS: This was a single-arm phase II study. A total of 40 patients were treated with gefitinib, 250 mg orally daily, until disease progression or intolerable toxicities. The prespecified target response rate of interest was 20%. RESULTS: The overall response rate was 16% (95% confidence interval, 0.06-0.32; 6 partial responses in 37 evaluable patients). An additional 13 patients (35%) had stable disease at 8 weeks. The median durations of response and progression-free survival were 31.4 months (95% confidence interval, 3.91-not applicable) and 3.8 months (95% confidence interval, 2.2-5.7), respectively. The side effect profile was consistent with the previous experience with gefitinib in other tumor types. LIMITATIONS: This was a single-institution, single-arm study. The prespecified target response rate was not met. CONCLUSION: Gefitinib demonstrated modest activity in incurable CSCC, with a favorable adverse event profile.

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).

Reirradiation of Head and Neck Cancers With Intensity Modulated Radiation Therapy: Outcomes and Analyses.

PURPOSE: To review our 15-year institutional experience using intensity modulated radiation therapy (IMRT) to reirradiate patients with head and neck squamous cell carcinomas (HNSCC) and identify predictors of outcomes and toxicity. METHODS AND MATERIALS: We retrospectively reviewed the records of 227 patients who received head and neck reirradiation using IMRT from 1999 to 2014. Patients treated with noncurative intent were excluded. Radiation-related acute and late toxicities were recorded. Prognostic variables included performance status, disease site, disease-free interval, chemotherapy, and RT dose and volume. Correlative analyses were performed separately for surgery and nonsurgery patients. RESULTS: Two hundred six patients (91%) were retreated with curative intent, and 173 had HNSCC histology; 104 (50%) underwent salvage resection, and 135 (66%) received chemotherapy. Median follow-up after reirradiation was 24.7 months. Clinical outcomes were worse for HNSCC patients, with 5-year locoregional control, progression-free survival, and overall survival rates of 53%, 22%, and 32%, respectively, compared with 74%, 59%, and 79%, respectively, for non-HNSCC patients. On multivariate analysis, concurrent chemotherapy and retreatment site were associated with tumor control, whereas performance status was associated with survival. Favorable prognostic factors specific to surgery patients were neck retreatment and lack of extracapsular extension, whereas for nonsurgery patients, these were a nasopharynx subsite and complete response to induction chemotherapy. Actuarial rates of grade ≥3 toxicity were 32% at 2 years and 48% at 5 years, with dysphagia or odynophagia being most common. Increased grade ≥3 toxicity was associated with retreatment volume >50 cm(3) and concurrent chemotherapy. CONCLUSIONS: Reirradiation with IMRT either definitively or after salvage surgery can produce promising local control and survival in selected patients with head and neck cancers. Treatment-related toxicity remains significant. Prognostic factors are emerging to guide multidisciplinary treatment approaches and clinical trial design.