Swanson, David Michael

6006 Background: IMPT has unique biologic and physical properties compared with IMRT, limits radiation dose beyond the targeted tumor volumes, and is a novel de-intensification strategy for the management of head and neck tumors. This study was designed to compare the outcomes for patients with OPC after chemoradiation therapy (CRT) with IMRT vs IMPT. Methods: This is a multi-center, randomized, phase III non-inferiority OPC trial Stage III/IV (AJCC 7th) squamous cell carcinoma stratified patients by human papillomavirus status, smoking status, and receipt of induction chemotherapy (IC). The primary endpoint was the rate of progression-free survival (PFS) rate at 3 years, where progression was defined as disease recurrence or death. Under the null hypothesis, H0: r ≥ 1.535 established the margin for non-inferiority of IMPT. Secondary endpoints include overall survival (OS), treatment-related malnutrition, and gastrostomy-tube dependence. Analyses were conducted on intent-to-treat (ITT; n=440), per-protocol (PP; n=296), and as-treated (AT; n=397) populations. Results: Patients (n=440) were randomized to undergo IMRT(n=219) or IMPT (n=221) at 21 institutions. The median age was 61 years and HPV/p16 was positive in 95%. IC was the initial treatment in 13% of patients. All patients were treated with CRT to 70 Gy in 33 fx with bilateral neck treatment, and post-CRT surgical lymph node dissection occurred in 8%. The median follow-up was 3.14 years. In the ITT analysis, the hazard ratio (HR) for disease progression or death at 3 y was 0.87 (95%CI 0.56,1.35); p=0.006 and the corresponding HR for death (OS) was 0.63 (95%CI 0.36-1.10) suggesting a protective affect with IMPT. In PP analysis, the PFS HR was 0.85 (95%CI 0.52,1.38); p=0.009 and HR for death (OS) was 0.60 (95%CI 0.32-1.12). In the AT analysis, PFS HR was 0.88 (95%CI 0.56,1.37); p=0.007 and the corresponding HR for death (OS) was 0.70 (95%CI 0.40-1.22). For each analysis above, the null hypothesis was rejected and IMPT was non-inferior to IMRT. PP gastrostomy-tube dependence decreased with IMPT vs. IMRT from 42% to 28% (p=0.019), and more IMPT patients sustained their nutrition with end of treatment weight loss < 5% from baseline: 24% vs 14% (p=0.037). Conclusions: IMPT is non-inferior to IMRT and has emerged as a standard of care CRT approach for OPC that reduces malnutrition and gastrostomy-tube dependence. Clinical trial information: NCT01893307 .

3528 Background: CALGB 80405 is a phase III clinical trial of FOLFOX and FOLFIRI w/ randomly assigned cetuximab or bevacizumab. Novel machine learning approaches to the study dataset provide valuable insights into CRC prognosis and management of CRC progression. Methods: Using a Monte Carlo Bayesian Generalized Linear Model analytical platform, we built an ensemble of models for overall survival (OS). We used 99 baseline and demographic variables, including 1904 patients w/ 1o side and 949 w/ KRAS wild-type status. Building an ensemble of predictive models reduces risk of overfitting, estimates model uncertainty and identifies key variables by model consensus as measured by ensemble frequency (freq). We fit gender and 1o side (L vs R) stratum-specific models to examine differences in drivers of disease in those strata. Results: 1o side (avg Cox hazard ratio = 0.89, R side reference), ECOG performance status (1.30, reference level 0), AST concentration (1.01), peripheral neutrophil percentage (1.01) and local primary and abdominal site of disease indicators (1.22; 1.26) were key variables predictive of OS ( > 75% freq). In 1o side stratum-specific models, urine protein level (1.61), treatment intent (0.75, nonpalliative as reference) and hemoglobin concentration (0.85) were more associated w/ L side progression (freq > 85% in L stratum model, < 20% in R), while liver and lung sites of disease (2.3; 1.09) were more associated w/ R side progression (freq > 65% in R stratum model, < 20% in L). Predictors of 1o left-sidedness included age (avg log odds ratio = 0.02), hemoglobin (0.41), and abdominal (3.79) and liver (0.68) sites of disease. Modest differences in disease prognostic factors existed between genders: women more influenced by metastatic status, age, liver site of disease and creatinine level; men more influenced by urine protein level and prior diabetes. Conclusions: 1o side plays a central role in potentially explaining both variation in OS and differences in drivers of OS. Availability of these measures at baseline enables better sense of disease course at initiation of treatment. Support: U10CA180821, U10CA180882, Eli Lilly & Co., Genentech, Pfizer Clinical trial information: NCT00265850.