Short-course radiotherapy combined with CAPOX and PD-1 inhibitor for the total neoadjuvant therapy of locally advanced rectal cancer: the preliminary single-center findings of a prospective, multicentre, randomized phase II trial (TORCH)
Wang Yaqi, Shen Lijun, Wan Juefeng, Zhang Hui, Wang Yan, Wu Xian, Wang Jingwen, Wang Renjie, Sun Yiqun, Tong Tong, Huang Dan, Wang Lei, Sheng Weiqi, Zhang Xun, Cai Guoxiang, Xu Ye, Cai Sanjun, Zhang Zhen, Xia Fan
Abstract
ObjectiveTotal neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC.
MethodsTORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3–4 acute adverse effects (AEs) etc.
ResultsUp to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27–69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2–3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0–1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III–IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted.
ConclusionsSCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III–IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.
Key words:
Rectal neoplasms, locally advanced; Short-course radiotherapy; Immunotherapy; Total neoadjuvant therapy; Complete response; Watch and wait; Adverse effects
Contributor Information
Wang Yaqi
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
Shen Lijun
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
Wan Juefeng
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
Zhang Hui
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
Wang Yan
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
Wu Xian
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
Wang Jingwen
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
Wang Renjie
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Sun Yiqun
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Tong Tong
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Huang Dan
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Wang Lei
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Sheng Weiqi
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Zhang Xun
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Ultrasound, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Cai Guoxiang
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Xu Ye
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Cai Sanjun
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Zhang Zhen
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
Xia Fan
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
