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IMPORTANCE: Novel toxicity metrics that account for all AE grades and frequency of events within a grade may enhance toxicity reporting in clinical trials. OBJECTIVES: To evaluate the feasibility of using the Toxicity Index (TI) methodology in two prospective anal cancer trials, and to evaluate whether more conformal radiation (using IMRT) results in improved toxicity as measured by the TI. DESIGN: Ancillary analysis of two prospective trials SETTING: Data from 2 NRG multicenter trials PARTICIPANTS: Patients with stage II-III anal cancer treated with definitive 5-FU/MMC and concurrent IMRT as part of the NRG/RTOG 0529 trial (12/2006–3/2008) or nonconformal RT enrolled on NRG/RTOG 9811 (10/1998–6/2005). EXPOSURES: All patients received chemoradiation with 5-FU/Mitomycin using IMRT or nonconformal RT. MAIN OUTCOMES AND MEASURES: The TI for all adverse events and for combined Gastrointestinal (GI)/Genitourinary (GU)/Hematologic (Heme)/Dermatologic (Derm) events in patients treated with nonconformal RT on the 5-FU/MMC arm of NRG/RTOG 9811 were compared to patients treated with IMRT on NRG/RTOG 0529. Multi-variable probabilistic models controlling for demographic predictors of TI were evaluated. RESULTS: Fifty one patients were treated with IMRT on NRG/RTOG 0529 and 324 on the standard 5-FU/MMC arm of NRG/RTOG 9811. Patients treated on NRG/RTOG 0529 had lower median TI compared to patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events [3.935 vs 3.996, P=0.014]. Median TI in patients requiring a treatment break was higher than those patients not requiring a break [4.00 vs 3.937, P

ImportanceFor many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes.ObjectiveTo analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT).Design, Setting, and ParticipantsThis study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute–sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023.ExposuresTreatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy.Main Outcomes and MeasuresThe outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable.ResultsThe analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07).Conclusions and RelevanceResults of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.