Radiotherapy Plus Cisplatin With or Without Lapatinib for Non-Human Papillomavirus Head and Neck Carcinoma: A Phase 2 Randomized Clinical Trial.

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Factors associated with loss to follow-up after radiation therapy for head and neck cancer.

OBJECTIVES: Head and neck cancer (HNC) patients are at high risk for late occurring radiation-related morbidity and recurrence, necessitating close long-term medical surveillance. This study identified factors associated with becoming lost to follow-up (LTFU) at a comprehensive cancer center. MATERIALS AND METHODS: Patients were drawn from survivors who received radiation for HNC at a single institution between 2001 and 2018. LTFU was defined as living patients without a clinical encounter within 2 years of the data query. RESULTS: In total, 537 patients met the inclusion criteria and 57 (10.6%) were identified as LTFU. Individual comparisons identified time since completing radiation, non-White race and being unmarried as associated with LTFU. Multiple regression identified time since treatment and being unmarried as factors associated with LTFU. A decision tree correctly sorted 89.4% using time, distance, and marital status. CONCLUSION: Time since radiation, distance to clinic, and being unmarried were factors associated with becoming LTFU.

Predictors of In-Hospital Death in Patients with Lung Cancer Admitted for Acute Radiation Pneumonitis: A Healthcare Cost and Utilization Project (HCUP) Analysis.

BACKGROUND: Radiation pneumonitis (RP) is a dose-limiting and potentially fatal toxicity of thoracic radiotherapy most often seen in patients treated for primary lung cancer. The purpose of this study was to identify predictors of in-hospital death among lung cancer patients admitted for acute RP in the Healthcare Cost and Utilization Project (HCUP) database. MATERIALS AND METHODS: The HCUP National Inpatient Sample database was queried from 2012 through 2016 to capture adult lung cancer patients admitted to the hospital with a principal diagnosis of acute RP. Multivariate logistic regression modeling and χ2 tests were used to determine predictors of in-hospital death. RESULTS: Of the 882 patients with lung cancer admitted for RP, 67 patients (7.6%) died during the hospitalization and 90 patients (10.2%) required mechanical ventilation. Of those requiring mechanical ventilation, 38 patients (42.2%) died. The average age at hospitalization was 70.4 years (range, 35-90). Of those factors associated with death on univariate analysis, interstitial lung disease (odds ratio [OR] = 6.14; 95% confidence interval [CI], 1.9-19.4; P = .002), pulmonary hypertension (OR = 3.1; 95% CI, 1.6-6.2; P = .001), diabetes mellitus (OR = 2.0; 95% CI, 1.1-3.3; P = .013), and more affluent Zip Code (OR = 1.9; 95% CI, 1.1-3.2; P = .021) remained statistically significant on multivariate logistic regression. CONCLUSION: In the largest reported cohort of patients with lung cancer hospitalized with a principal diagnosis of acute RP, the presence of interstitial lung disease, pulmonary hypertension, diabetes mellitus, and more affluent Zip Code were associated with in-hospital death. Comorbid diagnoses may be useful for risk-stratified management of inpatients with RP.

A Phase 1b trial of prexasertib in combination with chemoradiation in patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: This study explored the feasibility of safely combining prexasertib, with cisplatin-radiotherapy (Part A) or cetuximab-radiotherapy (Part B) in patients with previously untreated, locoregionally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Escalating doses of prexasertib were administered in each combination using a modified Time-to-Event Continual Reassessment Method. Pharmacokinetic (PK) analysis was performed using standard non-compartmental methods of analysis. Antitumor activity was evaluated using RECIST version 1.1. RESULTS: In Part A, 7 patients received 20 mg/m2 prexasertib and cisplatin-radiotherapy. This dose exceeded the maximum tolerated dose (MTD); no other prexasertib dose was assessed. In Part B, 18 patients received prexasertib (20-40 mg/m2) and cetuximab-radiotherapy. The 30 mg/m2 dose of prexasertib was determined as the MTD. Febrile neutropenia was the dose-limiting toxicity in each arm. Most common treatment-emergent adverse events with both combinations were neutropenia, thrombocytopenia, dysphagia, stomatitis, dry mouth, anemia, radiation skin injury [reported term radiation dermatitis], and nausea. PK of prexasertib was consistent with previously published data following prexasertib monotherapy. Overall response rate in Parts A and B was 71.4% and 83.3%, respectively. The small number of patients and follow-up limits the interpretation of efficacy data. CONCLUSION: This study did not establish a safe dose of cisplatin-radiotherapy. However, it demonstrates the proof-of-principle that prexasertib could be safely combined with cetuximab-radiotherapy. These data will provide the basis to leverage the potential radio-sensitization properties of a CHK1 inhibitor in combination with radiation or other targeted agents in a variety of therapeutic settings.

Lipid microsphere bound oxycodone for pain management in patients receiving radiotherapy for head and neck cancer.

BACKGROUND: Wax microsphere bound oxycodone was developed as an abuse-deterrent opioid and maintains a similar pharmacokinetic profile whether administered with or without an intact capsule. We hypothesized that microsphere oxycodone could be utilized for extended release analgesia in patients undergoing radiation (RT) for head-and-neck cancer (HNC) and would not need to be discontinued due to dysphagia or gastrostomy tube dependence. METHODS AND MATERIALS: We performed a prospective trial that enrolled participants > 18 years with histologically confirmed HNC who were scheduled to receive RT. Analgesia was prescribed in accordance with the WHO pain ladder. Microsphere oxycodone was initiated when total daily opioid dose exceeded 30 mg of morphine sulfate equivalent and was titrated weekly during RT. Pain level and effect on quality of life were assessed using the Brief Pain Inventory. The primary feasibility endpoint was frequency of microsphere oxycodone discontinuation within 3 months of RT for reasons other than pain resolution. RESULTS: Twenty-six eligible patients were enrolled. Microsphere oxycodone was initiated in 16 (61.5%) patients. Six (23.1%) patients utilized a gastrostomy tube to administer microsphere oxycodone during all or part of RT. Microsphere oxycodone was discontinued in 1 (7.6%) patient due to perceived inefficacy. No patients were discontinued due to toxicity or difficulty with administration. Ratings for average pain was 3.1 (± 3.4) at enrollment, 4.0 (± 2.4) at week 6 of RT, and 1.8 (± 2.2) at 3-month follow-up. CONCLUSIONS: These results support the feasibility and safety of microsphere oxycodone for extended release analgesia among patients with HNC undergoing RT.

Epigenetic stratification of head and neck cancer survivors reveals differences in lycopene levels, alcohol consumption, and methylation of immune regulatory genes.

BACKGROUND: Inflammation has been associated with higher rates of recurrence and mortality in head and neck cancer (HNC). While the biological mechanisms predisposing patients to heightened inflammatory states remain largely unknown, DNA methylation has been proposed to reflect systemic inflammation. In this analysis, we attempt to identify meaningful epigenetic patterns in HNC survivors by stratifying individuals based on DNA methylation profiles in leukocytes. RESULTS: We used hierarchical clustering to uncover three distinct methylation patterns among HNC survivors. Each group displayed a unique methylation signature in inflammatory pathways including cytokine and B-cell receptor signaling. Additionally, we examined physiological, clinical, and lifestyle parameters related to inflammation, such as circulating carotenoid and cytokine levels, cancer treatment type, and alcohol consumption. Specifically, we identified one group of survivors who had significant differential methylation of transcriptional and translational regulators as well as genes in the T-cell receptor signaling pathway, including hypermethylation of CD40 ligand (CD40LG) and Tec protein tyrosine kinase (TEC) and hypomethylation of CD8A. This group also displayed high circulating lycopene levels. We identified another group that had distinctive methylation in the toll-like receptor (TLR) signaling pathway, including hypomethylation of TLR5, a component of the inhibitor of nuclear factor-kappa B kinase complex (CHUK), and two mitogen-activated protein kinases (MAP3K8 and MAP2K3). This group also had hypermethylation of mitochondrial ribosomal genes along with higher rates of alcohol consumption. CONCLUSION: The correlation between lycopene, alcohol consumption, DNA methylation, and inflammation warrants further investigation and may have implications in future recommendations and interventions to impact health outcomes in HNC survivors.

Reduced Margin Stereotactic Body Radiation Therapy for Early Stage Non-Small Cell Lung Cancers.

Purpose Our study reports the clinical outcomes of patients treated with 5-mm isotropic margin, fiducial-guided stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). We also sought to assess the effect of histological subtype on local control. Methods We retrospectively reviewed the charts of all patients treated with SBRT for NSCLC between 2007 and 2017 at our institution. All patients who had implanted fiducial markers, planning target volume (PTV) margins of 5 mm or less, early stage disease (T1-T2, N0), and at least one follow-up CT were included in this analysis. Estimates of local control were generated using the Kaplan-Meier method, and differences between survival curves were assessed using the log-rank test. Results A total of 152 patients met the inclusion criteria for this analysis, with a median follow-up of 27.9 months. Patients received 54 Gy in three fractions for peripheral tumors and 48-52.5 Gy in four to five fractions for central tumors. NSCLC histology was adenocarcinoma in 69 (45.4%) cases, squamous cell carcinoma in 65 (42.8%) cases, and other or non-subtyped in 18 (11.8%) cases. Across the entire cohort, the two-year estimate of local control was 95.1%. When histology was considered, the two-year estimate of local control among patients with adenocarcinoma was 95.6% as compared with 85.0% for patients with other subtypes (p=0.044). Conclusions Fiducial-guided, isotropic 5-mm PTV margin for thoracic SBRT did not compromise local control compared with historical standards. In this series, patients with adenocarcinoma experienced improved local control compared with squamous cell carcinoma.

Head and neck cancer survivors' preferences for and evaluations of a post-treatment dietary intervention.

BACKGROUND: Dietary preferences vary depending on cancer type. The purpose of this study was to report dietary intervention preferences and a study program evaluation from post-treatment head and neck cancer survivors participating in a dietary intervention. METHODS: Between January 2015 and August 2016, 24 head and neck cancer survivors participated in a 12-week randomized clinical dietary intervention trial that promoted weekly consumption of 2.5 cups of cruciferous vegetables and 3.5 cups of green leafy vegetables. At study completion, survivors completed a preferences survey and a study program evaluation to probe interests and improvement aspects for planning future dietary intervention trials. Descriptive statistics (means and frequencies) were generated for multiple choice question responses. Responses to open-ended questions were recorded and grouped based on themes, and verified by quality assurance checks by a second study team member. RESULTS: Twenty-three survivors completed the preferences and evaluation surveys (response rate 96%). Overall, most participants reported a preference for one-on-one telephone counseling from a registered dietitian nutritionist before beginning treatment. Ninety-six percent of participants ranked the overall study program as "very good" to "excellent," and all agreed the objectives of the study were clear, the study staff was helpful and easy to contact, and the registered dietitian nutritionist was knowledgeable. CONCLUSIONS: Future research and dietary intervention planning for head and neck cancer survivors should focus on strategies to promote one-on-one telephone or other distance-based counseling combined with face-to-face visits, according to survivor preference.

Feasibility Outcomes of a Pilot Randomized Clinical Trial to Increase Cruciferous and Green Leafy Vegetable Intake in Posttreatment Head and Neck Cancer Survivors.

BACKGROUND: Higher intakes of cruciferous vegetables (CVs) and green leafy vegetables (GLVs) in observational studies are associated with improvements in survival and cancer-related biomarkers in patients diagnosed with head and neck cancer (HNC). These results have yet to be corroborated in a randomized clinical trial (RCT). OBJECTIVE: Determine the feasibility of implementing a 12-week RCT to increase CV and GLV intake in posttreatment HNC survivors. DESIGN AND PARTICIPANTS: This was a two-arm RCT conducted among 24 posttreatment HNC survivors. Survivors were recruited from a southeastern, National Cancer Institute-designated Comprehensive Cancer Center between January 2015 and September 2016. INTERVENTION: There were two groups: (1) an experimental group (n=12) receiving weekly 15- to 30-minute telephone dietary counseling from a registered dietitian nutritionist stressing 2.5 cups per week CVs and 3.5 cups per week GLVs, and (2) an attention control group (n=12) receiving weekly 15- to 30-minute telephone dietary counseling from a registered dietitian nutritionist focusing on general healthy eating for cancer survivors. Participants completed a baseline survey, three 24-hour dietary recalls, phlebotomy, and anthropometric measures prior to randomization and at the end of the 12-week study period. The experimental group also completed weekly vegetable record recalls. MAIN OUTCOME MEASURES: Primary outcomes included feasibility, recruitment, retention, adherence, and safety. Secondary outcomes included inflammatory markers and carotenoids. STATISTICAL ANALYSES PERFORMED: Descriptive statistics were generated for demographic, epidemiological, and clinical variables as well as the primary feasibility outcomes. Between- and within-group comparisons of mean serum cytokine and carotenoid levels were performed using appropriate statistical tests depending on their respective distributions for the purpose of generating preliminary effect sizes. RESULTS: Overall, 350 incident HNC cases were screened for eligibility, and 98 were eligible for study participation. Reasons for ineligibility and exclusion included deceased (n=93); wrong or inactive telephone numbers, or unable to be reached, or lost to follow-up (n=93); not meeting inclusion criteria (n=39); and too ill to participate (n=27). Of the 98 eligible HNC cases, 24 agreed to participate, for an enrollment rate of 25%. The most common reason for nonparticipation was distance (n=48), as participants were asked to report for two on-site assignments. The retention rate was 96%. Mean intervention adherence rates for weekly goals were 67% CV, 74% GLV, and 71% overall. Completion rate of weekly counseling calls was 90%. The experimental group reported an overall mean increase of 5.5 cups GLV and 3.5 cups CV per week from baseline intake, respectively. No significant between- or within-arm differences were observed for inflammatory markers or carotenoids. CONCLUSION: A posttreatment intervention aimed at increasing CV and GLV intake in HNC survivors is feasible. A larger RCT is needed to assess the efficacy of this intervention on disease outcomes.

Longitudinal assessment of anchored transponder migration following lung stereotactic body radiation therapy.

PURPOSE: To assess the long-term stability of the anchored radiofrequency transponders and compare displacement rates with other commercially available lung fiducial markers. We also sought to describe late toxicity attributable to fiducial implantation or migration. MATERIALS AND METHODS: The transponder cohort was comprised of 17 patients at our institution who enrolled in a multisite prospective clinical trial and underwent bronchoscopic implantation of three anchored transponders into small (2-2.5 mm) airways. We generated a comparison cohort of 34 patients by selecting patients from our institutional lung SBRT database and matching 2:1 based on the lobe containing tumor and proximity to the bronchial tree. Assessment of migration was performed by rigidly registering the most recent follow-up CT scan to the simulation scan, and assessing whether the relative geometry of the fiducial markers had changed by more than 5 mm. Toxicity outcomes of interest were hemoptysis and pneumothorax. RESULTS: The median follow-up of patients in the transponder cohort was 25.3 months and the median follow-up in the comparison cohort was 21.7 months. When assessing the most recent CT, all fiducial markers were within 5 mm of their position at CT simulation in 11 (65%) patients in the transponder group as compared to 23 (68%) in the comparison group (P = 0.28). One case of hemoptysis was identified in the transponder cohort, and bronchoscopy confirmed bleeding from recurrent tumor; no cases of hemoptysis were noted in the comparison cohort. No case of pneumothorax was noted in either group. CONCLUSION: No significant difference in the rates of fiducial marker retention and migration were noted when comparing patients who had anchored transponders placed into small airways and a 2:1 matched cohort of patients who had other commercially available lung fiducial markers placed. In both groups, no late or chronic toxicity appeared to be related to the implanted fiducial markers.

First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma With Combined BRAF and MEK Inhibition.

Salivary duct carcinoma (SDC) is a rare and aggressive malignancy for which limited data exist to guide treatment decisions. With the advent of advanced molecular testing and tumor genomic profiling, clinicians now have the ability to identify potential therapeutic targets in difficult-to-treat cancers such as SDC. This report presents a male patient with widely metastatic SDC found on targeted next-generation sequencing to have a BRAF p.V600E mutation. He experienced a prolonged and robust response to first-line systemic chemotherapy with dabrafenib and trametinib. During his response interval, new data emerged to justify subsequent treatment with both an immune checkpoint inhibitor and androgen blockade after his disease progressed. To our knowledge, this is the first report of frontline BRAF-directed therapy eliciting a response in metastatic SDC.

Higher carbohydrate intake is associated with increased risk of all-cause and disease-specific mortality in head and neck cancer patients: results from a prospective cohort study.

No studies have evaluated associations between carbohydrate intake and head and neck squamous cell carcinoma (HNSCC) prognosis. We prospectively examined associations between pre- and post-treatment carbohydrate intake and recurrence, all-cause mortality, and HNSCC-specific mortality in a cohort of 414 newly diagnosed HNSCC patients. All participants completed pre- and post-treatment Food Frequency Questionnaires (FFQs) and epidemiologic surveys. Recurrence and mortality events were collected annually. Multivariable Cox Proportional Hazards models tested associations between carbohydrate intake (categorized into low, medium and high intake) and time to recurrence and mortality, adjusting for relevant covariates. During the study period, there were 70 deaths and 72 recurrences. In pretreatment analyses, high intakes of total carbohydrate (HR: 2.29; 95% CI: 1.23-4.25), total sugar (HR: 3.03; 95% CI: 1.12-3.68), glycemic load (HR: 2.10; 95% CI: 1.15-3.83) and simple carbohydrates (HR 2.26; 95% CI 1.19-4.32) were associated with significantly increased risk of all-cause mortality compared to low intake. High intakes of carbohydrate (HR 2.45; 95% CI: 1.23-4.25) and total sugar (HR 3.03; 95% CI 1.12-3.68) were associated with increased risk of HNSCC-specific mortality. In post-treatment analyses, medium fat intake was significantly associated with reduced risk of recurrence (HR 0.08; 95% CI 0.01-0.69) and all-cause mortality (HR 0.27; 95% CI 0.07-0.96). Stratification by tumor site and cancer stage in pretreatment analyses suggested effect modification by these factors. Our data suggest high pretreatment carbohydrate intake may be associated with adverse prognosis in HNSCC patients. Clinical intervention trials to further examine this hypothesis are warranted.

Establishing quality indicators for neck dissection: Correlating the number of lymph nodes with oncologic outcomes (NRG Oncology RTOG 9501 and RTOG 0234).

BACKGROUND: Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival. METHODS: The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group. RESULTS: Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P = .007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status. CONCLUSIONS: The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016;122:3464-71. © 2016 American Cancer Society.

Correlation Between the Severity of Cetuximab-Induced Skin Rash and Clinical Outcome for Head and Neck Cancer Patients: The RTOG Experience.

PURPOSE: To evaluate the severity of cetuximab-induced skin rash and its correlation with clinical outcome and late skin toxicity in patients with head and neck squamous cell carcinoma treated with chemoradiation therapy and cetuximab. METHODS AND MATERIALS: Analysis included patients who received loading dose and ≥1 cetuximab dose concurrent with definitive chemoradiation therapy (70 Gy + cisplatin) or postoperative chemoradiation therapy (60-66 Gy + docetaxel or cisplatin). RESULTS: Six hundred two patients were analyzed; 383 (63.6%) developed grade 2 to 4 cetuximab rash. Patients manifesting grade 2 to 4 rash had younger age (P<.001), fewer pack-years smoking history (P<.001), were more likely to be males (P=.04), and had p16-negative (P=.04) oropharyngeal tumors (P=.003). In univariate analysis, grade 2 to 4 rash was associated with better overall survival (hazard ratio [HR] 0.58, P<.001) and progression-free survival (HR 0.75, P=.02), and reduced distant metastasis rate (HR 0.61, P=.03), but not local-regional failure (HR 0.79, P=.16) relative to grade 0 to 1 rash. In multivariable analysis, HRs for overall survival, progression-free survival, distant metastasis, and local-regional failure were, respectively, 0.68 (P=.008), 0.85 (P=.21), 0.64 (P=.06), and 0.89 (P=.48). Grade ≥2 rash was associated with improved survival in p16-negative patients (HR 0.28 [95% confidence interval 0.11-0.74]) but not in p16-positive patients (HR 1.10 [0.42-2.89]) (P=.05 for interaction). Twenty-five percent of patients with grade 2 to 4 acute in-field radiation dermatitis experienced grade 2 to 4 late skin fibrosis, versus 14% of patients with grade 0 to 1 acute in-field radiation dermatitis (P=.002). CONCLUSION: Grade 2 to 4 cetuximab rash was associated with better survival, possibly due to reduction of distant metastasis. This observation was noted mainly in p16-negative patients. Grade 2 to 4 acute in-field radiation dermatitis was associated with higher rate of late grade 2 to 4 skin fibrosis.

A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases.

PURPOSE: To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1 to 4 brain metastases treated with radiosurgery without whole-brain radiation therapy (WBRT). METHODS AND MATERIALS: Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase 2 trial of radiosurgery (15-24 Gy) and adjuvant temozolomide. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. RESULTS: Twenty-five patients were enrolled between 2002 and 2005; 3 were not evaluable for determining DBF. Of the remaining 22 patients, tumor types included non-small cell lung cancer (n = 8), melanoma (n = 7), and other (n = 7). Extracranial disease was present in 10 (45%) patients. The median number of tumors at the time of radiosurgery was 3 (range, 1-6). The median overall survival was 31 weeks. The median radiographic follow-up for patients who did not develop DBF was 33 weeks. Six patients developed DBF. The 1-year actuarial risk of DBF was 37%. CONCLUSIONS: In this study, there was a relatively low risk of distant brain failure observed in the nonmelanoma subgroup receiving temozolamide. However, patient selection factors rather than chemotherapy treatment efficacy are more likely the reason for the relatively low risk of distant brain failure observed in this study. Future trial design should account for these risk factors.

Pazopanib combined with radiation: in vivo model of interaction.

OBJECTIVE: Assess interaction of pazopanib, an oral antivascular endothelial growth factor inhibitor, with radiation in tumor xenograft models. METHODS: Flank xenografts in female athymic nude mice of human lung cancer cell line, A549, and head and neck cancer cell line, UM-SCC-6, were allowed to grow to ∼5×5 mm. Groups were then treated with pazopanib and/or escalating doses of radiation and tumor measurements over time compared with untreated tumor-bearing controls. Pazopanib (100 mg/kg) began 7 days before radiation and continued for 28 days. Daily radiation was 0.5, 1, 2, or 3 Gy ×5 days. RESULTS: Tumors in the A549 control group reached >4× the original size by day 36 postradiation. All treatment groups had less robust tumor growth (p<0.05) and the group receiving pazopanib+3 Gy radiation/day had tumor regression to less than baseline. In the UM-SCC-6-tumor-bearing animals, tumors in all treatment groups had less robust growth than untreated controls after day 23 post-treatment. CONCLUSION: The combination of pazopanib and radiation resulted in a trend of superior tumor growth inhibition compared with either agent alone. All treatment groups had impaired tumor progression compared with untreated controls.

Comparison of plan quality and delivery time between volumetric arc therapy (RapidArc) and Gamma Knife radiosurgery for multiple cranial metastases.

BACKGROUND: Volumetric modulated arc therapy (VMAT) has been shown to be feasible for radiosurgical treatment of multiple cranial lesions with a single isocenter. OBJECTIVE: To investigate whether equivalent radiosurgical plan quality and reduced delivery time could be achieved in VMAT for patients with multiple intracranial targets previously treated with Gamma Knife (GK) radiosurgery. METHODS: We identified 28 GK treatments of multiple metastases. These were replanned for multiarc and single-arc, single-isocenter VMAT (RapidArc) in Eclipse. The prescription for all targets was standardized to 18 Gy. Each plan was normalized for 100% prescription dose to 99% to 100% of target volume. Plan quality was analyzed by target conformity (Radiation Therapy Oncology Group and Paddick conformity indices [CIs]), dose falloff (area under the dose-volume histogram curve), as well as the V4.5, V9, V12, and V18 isodose volumes. Other end points included beam-on and treatment time. RESULTS: Compared with GK, multiarc VMAT improved median plan conformity (CIVMAT = 1.14, CIGK = 1.65; P < .001) with no significant difference in median dose falloff (P = .269), 12 Gy isodose volume (P = .500), or low isodose spill (P = .49). Multiarc VMAT plans were associated with markedly reduced treatment time. A predictive model of the 12 Gy isodose volume as a function of tumor number and volume was also developed. CONCLUSION: For multiple target stereotactic radiosurgery, 4-arc VMAT produced clinically equivalent conformity, dose falloff, 12 Gy isodose volume, and low isodose spill, and reduced treatment time compared with GK. Because of its similar plan quality and increased delivery efficiency, single-isocenter VMAT radiosurgery may constitute an attractive alternative to multi-isocenter radiosurgery for some patients.

Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer.

PURPOSE: To test whether altered radiation fractionation schemes (hyperfractionation [HFX], accelerated fractionation, continuous [AFX-C], and accelerated fractionation with split [AFX-S]) improved local-regional control (LRC) rates for patients with squamous cell cancers (SCC) of the head and neck when compared with standard fractionation (SFX) of 70 Gy. METHODS AND MATERIALS: Patients with stage III or IV (or stage II base of tongue) SCC (n=1076) were randomized to 4 treatment arms: (1) SFX, 70 Gy/35 daily fractions/7 weeks; (2) HFX, 81.6 Gy/68 twice-daily fractions/7 weeks; (3) AFX-S, 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy; and (4) AFX-C, 72 Gy/42 fractions/6 weeks. The 3 experimental arms were to be compared with SFX. RESULTS: With patients censored for LRC at 5 years, only the comparison of HFX with SFX was significantly different: HFX, hazard ratio (HR) 0.79 (95% confidence interval 0.62-1.00), P=.05; AFX-C, 0.82 (95% confidence interval 0.65-1.05), P=.11. With patients censored at 5 years, HFX improved overall survival (HR 0.81, P=.05). Prevalence of any grade 3, 4, or 5 toxicity at 5 years; any feeding tube use after 180 days; or feeding tube use at 1 year did not differ significantly when the experimental arms were compared with SFX. When 7-week treatments were compared with 6-week treatments, accelerated fractionation appeared to increase grade 3, 4 or 5 toxicity at 5 years (P=.06). When the worst toxicity per patient was considered by treatment only, the AFX-C arm seemed to trend worse than the SFX arm when grade 0-2 was compared with grade 3-5 toxicity (P=.09). CONCLUSIONS: At 5 years, only HFX improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity.

A technique using 99mTc-mebrofenin SPECT for radiotherapy treatment planning for liver cancers or metastases.

Radiotherapy or stereotactic body radiosurgery (SBRT) requires a sufficient functional liver volume to tolerate the treatment. The current study extended the work of de Graaf et al. (2010) [3] on the use of (99m)Tc-mebrofenin imaging for presurgery planning to radiotherapy planning for liver cancer or metastases. Patient was immobilized and imaged in an identical position on a single-photon emission computed tomography/computed tomography (SPECT-CT) system and a radiotherapy simulation CT system. (99m)Tc-mebrofenin SPECT was registered to the planning CT through image registration of noncontrast CT from SPECT-CT system to the radiotherapy planning CT. The voxels with higher uptake of (99m)Tc-mebrofenin were transferred to the planning CT as an avoidance structure in optimizing a 2-arc RapidArc plan for SBRT delivery. Excellent dose coverage to the target and sparing of the healthy remnant liver volume was achieved. This report illustrated a procedure for the use of (99m)Tc-mebrofenin SPECT for optimizing radiotherapy for liver cancers and metastases.