The Effect of Radiation Modality on Outcomes of Patients Receiving Adjuvant Chemoradiotherapy for Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma: A Secondary Analysis of SWOG S0809

Abstract

<h3>Purpose/Objective(s)</h3> The phase II intergroup S0809 trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in patients with resected EHCC or GBCA demonstrated promising efficacy and tolerability, with a median overall survival of 35 months. Both 3-dimensional radiotherapy (3D) and intensity-modulated radiotherapy (IMRT) were permitted on the trial. Patients received 45 Gy to regional lymph nodes, with a tumor bed boost to a total of 52.5-59.4 Gy in 25-33 fractions, with radiation technique and dose given at the investigator's discretion. Given the range of permitted radiation modalities and doses administered, we performed a post hoc analysis of the effect of radiation modality on outcomes of patients treated on SWOG S0809. <h3>Materials/Methods</h3> Eligibility criteria included diagnosis of EHCC or GBCA after radical surgery, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine and capecitabine followed by concurrent capecitabine and radiotherapy, 45 Gy to regional nodes, with a tumor bed boost to 52.5-59.4 Gy [3D: 54 or 59.4 Gy (optional for R1) in 1.8 Gy fractions; IMRT 52.5 Gy or 55 Gy (optional for R1) in 2.1-2.2 Gy fractions]. Baseline characteristics were evaluated using the Mann-Whitney U-test for age and chi-squared test for categorical variables. Disease-free survival (DFS), local recurrence-free survival and distant metastasis-free survival were evaluated using the Kaplan-Meier method. Rates of adverse events were evaluated using Fisher's two-sided exact test. <h3>Results</h3> Of the 79 patients enrolled on the trial from 2008 to 2012, 69 patients (87%) received radiotherapy. The minority (20.2%) of patients were treated with 3D, while 79.8% were treated with IMRT. There were no differences in utilization of 3D vs. IMRT based on site of disease, margin status or lymph node status. The 2-year DFS was 60% for 3D and 52% for IMRT (<i>P</i> = 0.73). Only 7.1% of patients treated with 3D experienced local recurrence, while 18.2% of patients treated with IMRT experienced local recurrence (<i>P</i> = 0.41). Distant metastases developed in 21.4% of patients treated with 3D and 47.3% of patients treated with IMRT (<i>P</i> = 0.15). While no patients treated with 3D experienced grade 3+ gastrointestinal (GI) toxicity, 18.2% of patients treated with IMRT experienced grade 3+ GI toxicity (<i>P</i> = 0.19). Grade 3+ hematologic toxicity was seen in 60% of patients treated with IMRT and 71.4% of patients treated with 3D (<i>P</i> = 0.54). One grade 5 GI toxicity was seen in the IMRT cohort. <h3>Conclusion</h3> Both 3D and IMRT are effective modalities for chemoradiotherapy in the adjuvant treatment of EHCC and GBCA, with similar rates of DFS, local control, and toxicity. Given potential for GI toxicity, future trials should include prospective contour and plan review.