Safety and tolerability of different total neoadjuvant therapy strategies in patients with locally advanced rectal cancer.
Authors: Udagawa Shohei , Osumi Hiroki , Taguchi Senzo , Noguchi Tatsuki , Sakamoto Takashi , Matsui Shimpei , Mukai Toshiki , Yamaguchi Tomohiro , Yamaguchi Tomohiro , Akiyoshi Takashi , Fukuoka Shota , Yoshino Koichiro , Tamba Mikako , Shimozaki Keitaro , Wakatsuki Takeru , Ogura Mariko , Ooki Akira , Chin Keisho , Yamaguchi Kensei , Shinozaki Eiji 
Published: January 2025

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Background:
Total neoadjuvant therapy (TNT) leads to improved local control and organ preservation for locally advanced rectal cancer (LARC). The chemotherapy part of TNT may play a critical role in achieving local control and in improving OS. Few studies have focused on the toxicity associated with the chemotherapy of TNT. Furthermore, the differences in safety and tolerability between radiotherapy-first and chemotherapy-first strategies remain unclear.
Methods:
LARC patients treated with TNT between June 2020 and July 2023 at a single cancer institute were retrospectively enrolled. TNT consisted of induction chemotherapy followed by long-course chemoradiotherapy (INCT-LC-CRT) or long-course chemoradiotherapy/short-course radiotherapy followed by consolidation chemotherapy (LC-CRT-CNCT/SC-RT-CNCT). Concurrent chemotherapy in LC-CRT was capecitabine (825 mg/m
2
oral twice daily). INCT/CNCT consisted of six cycles of CAPOX (capecitabine 1000 mg/m² oral twice daily on days 1–14 and oxaliplatin 130 mg/m² intravenously on day 1 every 21 days). INCT allowed the addition of bevacizumab (7.5 mg/kg intravenously on day 1). We compared adverse events (AEs) and treatment exposure between INCT-LC-CRT, LC-CRT-CNCT and SC-RT-CNCT.
Results:
A total of 93 patients were included. Patients with INCT-LC-CRT and LC-CRT-CNCT/SC-RT-CNCT were 28 (30.1%) and 45 (48.4%)/20 (21.5%), respectively. Patients who were treated with INCT-LC-CRT (53.6%) had more N2 stage than those with LC-CRT-CNCT/SC-RT-CNCT (21.6%). Grade 3–4 AEs during chemotherapy were significantly more frequent in LC-CRT-CNCT/ SC-RT-CNCT group than in INCT-LC-CRT group (50.8% vs. 21.4%; p = 0.02). Neutropenia was the most common Grade 3–4 AEs during chemotherapy in INCT-LC-CRT group (7.4%) and LC-CRT-CNCT/SC-RT-CNCT group (27.7%). Grade 3–4 AEs during chemotherapy were not significantly different between the LC-CRT-CNCT and SC-RT-CNCT groups (36.9% vs. 40.0%; p = 0.42). All patients underwent the full radiation dose. The completion rate of six cycles of chemotherapy was no significant difference between INCT-LC-CRT group and LC-CRT-CNCT/SC-RT-CNCT group (92.9% vs. 84.6%; p = 0.37). However, LC-CRT-CNCT/SC-RT-CNCT group required significantly more dose modification during chemotherapy than INCT-LC-CRT group (75.4% vs. 46.4%; p < 0.01). Dose modification during chemotherapy between LC-CRT-CNCT and SC-RT-CNCT group was no significant difference (modification rate 77.8% vs. 70.0%; p = 0.54). Chemotherapy discontinuations due to AEs in INCT-LC-CRT group and LC-CRT-CNCT/SC-RT-CNCT group were 1(3.6%) and 6 (9.2%), respectively.
Conclusions:
Grade 3–4 AEs during chemotherapy were more frequent and required dose modification of chemotherapy in a radiotherapy-first strategy. Safety and tolerability of chemotherapy part of TNT may differ between radiotherapy-first and chemotherapy-first strategies.