BACKGROUND:The National Cancer Institute Moonshot℠ research initiative calls for improvements in the analysis and reporting of treatment toxicity to advise key stakeholders on treatment tolerability and inform regulatory and clinical decision-making. This study illustrates alternative approaches to toxicity evaluation using the National Surgical Adjuvant Breast and Bowel Project (NSABP-R04) clinical trial as an example. METHODS:NSABP-R04 was a neoadjuvant chemo-radiation trial in stage II-III rectal cancer patients. A 2x2 factorial design was used to evaluate whether the addition of oxaliplatin (Oxa) to 5-fluorouracil (5FU) or capecitabine (Cape) with radiation therapy improved local-regional tumor control. The toxicity index (TI), which accounts for the frequency and severity of toxicities, was compared across treatments using multivariable probabilistic index models (PIMs), where Pr A < B indicates the probability that higher values of TI were observed for A when compared to B. Baseline age, gender, performance status (PS), body mass index (BMI), surgery type and stage were evaluated as independent risk factors. RESULTS:A total of 4,560 toxicities from 1,558 patients were analyzed. Results from adjusted PIMs indicate that oxaliplatin-containing regimens had statistically significant (p < 0.001) probability for higher TI compared to regimens without oxaliplatin: Pr 5FU < 5FU + Oxa = 0.619 (95% CI 0.560-0.674); Pr 5FU< Cape + Oxa = 0.627 (95% CI 0.568-0.682); Pr Cape < 5FU + Oxa =0.587 (95% 0.527-0.644); and Pr Cape < Cape+ Oxa = 0.596 (95% 0.536-0.653).When compared to other existing toxicity analysis methods, TI provided greater power to detect differences between treatments. CONCLUSIONS:This paper uses standard data collected in a cancer clinical trial to introduce descriptive and analytic methods that account for the additional burden of multiple toxicities. These methods may provide a more accurate description of a patient's treatment experience that could lead to individualized dosing for better toxicity control. Future research will evaluate the generalizability of these findings in trials with similar drugs.