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タイトルは、「Short-term outcomes of a prospective multicenter phase II trial of total neoadjuvant therapy for locally advanced rectal cancer in Japan (ENSEMBLE-1)

Annals of Gastroenterological SurgeryEarly View ORIGINAL ARTICLE Open Access Short-term outcomes of a prospective multicenter phase II trial of total neoadjuvant therapy for locally advanced rectal cancer in Japan (ENSEMBLE-1) Yoshinori Kagawa, Jun Watanabe, Mamoru Uemura, Koji Ando, Akira Inoue, Koji Oba, Ichiro Takemasa, Eiji Oki First published: 11 July 2023 Yoshinori Kagawa and Jun Watanabe contributed equally to this work as first authors. This study was registered in the Japan Registry of Clinical Trials (jRCT s051200113). Meeting presentation: The 99th Meeting of Japanese Society for Cancer of the Colon and Rectum and the 78th General Meeting of the Japanese Society of Gastroenterological Surgery. About Sections Abstract Aim To evaluate the feasibility and safety of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) in Japan. Methods This prospective, multicenter, open-label, single-arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥ 20 years, LARC within 12 cm from the anal verge, and cT3-4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short-course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (six courses) followed by total mesorectum excision (TME) was the treatment protocol. Non-operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. Results Thirty patients (male, n = 26; female, n = 4; median age, 62.5 [44–74] years; cT [T2, n = 1; T3, n = 25; T4, n = 4]; cN [N0, n = 13; N1, n = 13; N2, n = 4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%–50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients. There were no treatment-related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow-up period was 15.6 (10.5–22.8) months, with no recurrence or regrowth in NOM. Conclusions ENSEMBLE-1 demonstrated satisfactory pCR and cCR, and well-tolerated safety of TNT for patients with LARC in Japan. 1 INTRODUCTION Colorectal cancer (CRC) is the third most frequently diagnosed cancer and second leading cause of cancer-related deaths worldwide. In 2021, 732 210 newly diagnosed cases of rectal cancer and 339 022 related deaths were reported worldwide.1 The outcomes of locally advanced rectal cancer (LARC) have been improved using multimodal treatment strategies. For local control of LARC, preoperative chemoradiotherapy (CRT) for LARC has been developed in Europe and the United States,2 while lateral lymph node dissection (LLND) for LARC has been developed in Japan.3 However, over the past decade, mortality rates have not improved with preoperative CRT or LLND because LARC is associated with a high rate of distant metastasis (29%–39%).4, 5 In recent years, total neoadjuvant therapy (TNT), in which preoperative chemotherapy and (chemo)radiotherapy are administered sequentially to patients with LARC, has been developed in Europe, the United States, and Asia to improve the long-term prognosis of LARC. In contrast, the standard treatment for LARC in the Japanese guidelines is upfront surgery and adjuvant chemotherapy (ACT) with LLND as an option.6 To date, there have been no reports of prospective, multicenter clinical trials of TNT in patients with LARC in Japan. Therefore, we conducted a prospective multicenter single-arm ENSEMBLE-1 trial to evaluate the feasibility and safety of TNT in Japanese patients with LARC. 2 PATIENTS AND METHODS Trial design and participants The ENSEMBLE-1 study was a prospective, multicenter, open-label, single-arm, phase II trial conducted at five institutions (Figure 1). The study protocol was approved by the Clinical Research Review Board of Osaka General Medical Center (ID: CRB5200005) and the institutional review board of each participating hospital before the initiation of the study. All patients provided written informed consent before enrollment in the study. This study was registered in the Japan Registry of Clinical Trials (jRCT s051200113). Details are in the caption following the image FIGURE 1 Open in figure viewer PowerPoint Study design. AV, anal verge; LARC, locally advanced rectal cancer; LLND, lateral lymph node dissection; pCR, pathological complete response; SCRT, short-course radiotherapy; TME, total mesorectal excision. The eligibility criteria were as follows: (1) written informed consent obtained; (2) a histological diagnosis of primary rectal adenocarcinoma; (3) no distant metastases on computed tomography (CT) or positron emission tomography (PET), and radical resection was clinically possible; (4) age ≥ 20 years; (5) Eastern Cooperative Oncology Group Performance status (ECOG-PS) of 0 or 1 (ECOG-PS 0 for age ≥ 71 years); (6) no prior treatment for rectal cancer; (7) lower margin of the tumor was within 12 cm from the anal verge (AV); (8) clinically diagnosed as Union for International Cancer Control (UICC) TNM classification (8th edition),7 cT3-4 N0 M0 or Tany N+ M0; and (9) preserved organ function. The exclusion criteria were as follows: (1) patients undergoing major surgery, radiation therapy, or prior chemotherapy within 4 weeks of study inclusion; (2) a history of severe lung disease; (3) patients with a stent for stenosis; (4) HBs antigen or HCV antibody positivity; (5) serious comorbidities (heart failure, renal failure, liver failure, hemorrhagic peptic ulcer, intestinal paralysis, intestinal obstruction, uncontrolled diabetes, etc.); (6) active multiple cancers (simultaneous multiple cancers or metachronous multiple cancers with a disease-free period of ≤5 years); and (7) pregnancy or breastfeeding. The complete inclusion and exclusion criteria are provided in Data S1. Treatment After registration, the patient received short-course radiation therapy (SCRT) (5 Gy × 5 days; total 25 Gy), using three-dimensional conformal radiation therapy or intensity-modulated radiation therapy [IMRT], six cycles of CAPOX (capecitabine 2000 mg/m2 orally twice daily on days 1–14, oxaliplatin 130 mg/m2 intravenously on day 1, every 3 weeks), followed by total mesorectal excision (TME) or tumor-specific mesorectal excision (TSME). The protocol stipulated that CAPOX should be initiated 14 ± 3 days after completion of SCRT. If treatment could not be started due to an adverse event, it could be delayed for up to 35 days. Surgery should be performed 3–8 weeks after the last dose of CAPOX (the last day of capecitabine administration) or the date of discontinuation. The following procedures were acceptable: low anterior resection (LAR), intersphincteric resection (ISR), abdominoperineal resection (APR), and Hartmann operation. In cases where invasion of adjacent organs is suspected, combined resection of adjacent organs was also acceptable to achieve radical resection. Additional LLND was acceptable at the discretion of the surgeon. The surgical approach (laparotomy, laparoscopy, or robot-assisted surgery) was not specified. Each patient underwent tumor restaging to complete clinical response (cCR), near CR (nCR), and incomplete CR (iCR), based on colonoscopy, pelvic magnetic resonance imaging (MRI), and digital findings according to Memorial Sloan Kettering Cancer Center (MSKCC) Regression Schema8 within 1–3 weeks from the completion of CAPOX (last day of capecitabine administration), or the date of discontinuation at each of the participating institutions. The clinical response rate based on pelvic MRI was also assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Non-operative management (NOM) was allowed if a cCR was obtained in preoperative restaging, and the patient requested NOM. Pathological analysis Standard pathological analyses were performed on all resected specimens at each participating institution. The pathological primary tumor response to TNT was evaluated using the grading scale according to the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma.9 Briefly, grade 0 represents no response to treatment; grade 1a, tumor size reduction of 1/3; grade 1b, tumor size reduction of 1/3 to 2/3; grade 2, tumor size reduction of >2/3; and grade 3, complete tumor ablation. Grade 3 corresponds to a pathological complete response (pCR). Follow-up Follow-up was performed every 3 months for the first 3 years and every 6 months thereafter for up to 5 years. Tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA19-9) were assessed at each follow-up examination. Chest-abdominal-pelvic computed tomography (CT) was performed every 6 months. Total colonoscopies were performed annually. For patients with NOM, tumor markers, colonoscopy, rectal examination, pelvic MRI, and chest-abdominal-pelvic CT every 4 months were recommended in the first 2 years and every 6 months thereafter for up to 5 years. Endpoints and statistical analysis The primary endpoint was the pCR rate. The secondary endpoints were R0 resection rate and safety in terms of adverse events, relapse-free survival, overall survival, and recurrence pattern (local recurrence rate and distant recurrence rate). The pCR rate of previous phase III trials in which SCRT was followed by surgical treatment was 0.5%–1%. With reference to these results and the fact that TNT will be added in this trial, we decided to examine whether 5% can be rejected in this trial. The expected pCR rate was set to 28% for patients treated with TNT followed by surgery as the expected value of the study treatment. With a pCR rate threshold of 5%, expected value of 28%, one-sided significance level of 5%, and power of at least 80%, the sample size required by the exact binomial distribution method would be ≥19 patients. Based on the above, the expected total number of patients was set to 22. Considering the few dropouts, ineligible cases, and patients in whom resection was not performed, the target sample size was set to 27. The statistical setting was designed by a clinical statistician. The primary analysis population was a full analysis set (FAS) in which at least one dose of protocol therapy was administered, all selection criteria were met, no exclusion criteria were violated, and some data were available. The pCR rate was estimated for the FAS, and 90% exact binomial confidence bounds were calculated. The overall frequencies and percentages were summarized for the demographic and clinicopathological characteristics. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc.) and GraphPad Prism version 6.01 for Windows (GraphPad Software). 3 RESULTS Patient characteristics Thirty patients with LARC managed at five institutions between January 2021 and January 2022 were enrolled in this study. A flow diagram showing patient enrollment and progression through the study protocol is shown in Figure 2.