Study design and participants
An Adjuvant chemotherapy in patients with clinical T3b/T4,N+ Rectal cancer undergoing Neoadjuvant Chemoradiotherapy (ACRNaCT) trial was conducted as a prospective, multicenter, randomized phase III study, consisting of two parts based on postoperative pathological stage. Overviews of enrollment and interventions are depicted in Fig. 1. Patients will be recruited from 29 Chinese institutions. Eligible patients will be diagnosed through magnetic resonance imaging (MRI) with T3b/T4,N+ rectal cancer and are histologically confirmed adenocarcinoma of the rectum (size of tumor < 10 cm from anal verge) without distant metastases. There will be no contraindications of anesthesia, operation, and CRT as well. Inclusion criteria include: (1) Age 18 to 75 years. (2) The lesion must be within 12 cm of the anus as measured by endoscopy. (3) Histologically confirmed diagnosis of rectal carcinoma. (4) Computed tomography (CT), MRI, and endoscopic ultrasound (EUS) verified as clinical stage III rectal cancer without involvement of other organs. (5) No evidence of multiple primary cancers. (6) Sufficient organ function. (7) Signed written informed consent form. Exclusion criteria include: (1) Younger than 18 or older than 75 years. (2) Synchronous or metachronous malignancy within 5 years. (3) Patients with intestinal obstruction, perforation or bleeding who require emergency surgery. (4) Patients with a history of pelvic irradiation. The American Society of Anesthesiologists (ASA) grade IV or V. (5) Women who are pregnant (confirmed by serum b-HCG in women of reproductive age) or breast feeding. (6) Severe mental disorders. (7) Patients with severe emphysema, interstitial pneumonia, or ischemic heart disease who cannot tolerate surgery. (8) Patients who received steroid therapy within one month. (9) Patients or family members misunderstand the conditions and goals of this study. The withdrawal criteria include: (1) Distant metastasis is confirmed by abdominal exploration or postoperative pathology. (2) Patients receive other treatment, which is not related to the present study. The situation that patients receive subsequent therapy after relapse or metastasis is permitted. (3) Patients with intestinal obstruction or perforation or bleeding who require emergency surgery after inclusion in the study. (4) Patients decide to withdraw from the study with any reasons. (5) Patients who cannot receive therapy any more due to non-neoplastic diseases. (6) Patients who cannot finish planed procedure due to any reasons.
For patients with pCR or yp stage I, the study was designed as a non-inferiority trial to compare the long-term outcomes of patients in observational group and those in treatment group with 5-fluorouracil. For patients with yp stage II or III, the study was designed as a superiority trial of 5-fluorouracil in combination with oxaliplatin compared with 5-fluorouracil alone in adjuvant setting. Participants will be allocated 1:1 to an intervention group or a control group after obtaining pathological data. Recruitment initiated in November 2018 and is expected to be completed in December 2020. The trial has been registered in ClinicalTrials.gov on January 30, 2018 (Registration No. NCT03415763), and also, that was registered in Chinese Clinical Trial Registry on November 12, 2018 (Registration No. ChiCTR1800019445).
Sample size
The sample size is based on the log-rank test. For patients with pCR or yp stage I, the estimated 3-year DFS was 85% for the 5-fluorouracil and 75% for the observation arm. With 80% power and probability errors of 5%, the upper limit of the two-sided 95% confidence interval (95% CI) of the hazard ratio (HR) will not exceed 1.6. Almost 192 patients will be required in each study group. For patients with yp stage II or III, the estimated 3-year DFS was 55% for the 5-fluorouracil alone and 67% for 5-fluorouracil in combination with oxaliplatin arm. With 80% power and probability errors of 5%, approximately 190 patients will be required in each study group.
Randomization process
The minimization technique will be used in the current trial. Stratification factors are age, yield pathological stage and distance from tumor to the anal verge. Patients will be randomly assigned using a central randomization system without masking.
Neoadjuvant radiotherapy
Preoperative radiotherapy will be consisted of 50–50.4 Gy in 25–28 fractions (1.8–2 Gy), 5 fractions/week. Intensity-modulated radiation therapy will be conducted for the whole pelvis.
Concurrent chemotherapy
Capecitabine is administrated concurrently with radiotherapy from day 1 to day 5. Patients receive capecitabine (825 mg/m2) orally. Alternatively, irinotecan and capecitabine are delivered concurrently with radiotherapy. Patients receive capecitabine (625 mg/m2) orally in combination with weekly irinotecan for five consecutive weeks according to the UGT1A1/28 genotype (days 1, 8, 15, 22, and 29). The dose of weekly irinotecan is 80 mg/m2 in patients with the *1*1 genotype and 65 mg/m2 in those with the *1*28 genotype.
Consolidative chemotherapy
Consolidative chemotherapy in form of XELOX (capecitabine and oxaliplatin) or XELIRI (capecitabine and irinotecan) is performed for three cycles for 3 weeks after completion of chemoradiotherapy. XELOX (oxaliplatin (130 mg/m2) as a 2-h infusion on day 1, followed by capecitabine (1000 mg/m2) twice daily for 14 days every 3 weeks) is delivered if patients receive capecitabine. XELIRI (irinotecan (200 mg/m2) on day 1, followed by capecitabine (1000 mg/m2) twice daily for 14 days every 3 weeks) is delivered if patients receive capecitabine in combination with weekly irinotecan.
Resection
Patients will undergo restaging 2 or 3 weeks after completion of neoadjuvant CRT. Surgery will be undertaken following principles of TME for patients who are appropriate for undergoing resection. For patients who have locally unresectable disease, additional chemotherapeutic cycles are needed. Alternatively, chemotherapy regimens can be changed. Watch-and-wait nonoperative approach is not recommended for clinical complete responders in terms of high-risk of recurrence. For patients who refuse undergoing surgery, the risk of relapse will be informed. These participants will not be excluded from our study and sustained clinical complete response for 12 months or longer should be reached under intensive surveillance.
Adjuvant chemotherapy
According to postoperative pathological stage, patients with pCR or yp stage I will be randomly assigned (1:1) into two groups of observation and ACT with 5-fluorouracil. Patients with yp stage II or III will also be randomly assigned to (1:1) the treatment groups receiving either 5-fluorouracil or 5-fluorouracil plus oxaliplatin as ACT. The use of a course of three cycles of ACT is recommended. In 5-fluorouracil group, patients daily receive capecitabine (1250 mg/m2) twice for 14 days every 3 weeks orally. In 5-fluorouracil plus oxaliplatin group, adoption of XELOX (oxaliplatin (130 mg/m2) as a 2-h infusion on day 1, followed by daily capecitabine (1000 mg/m2) twice for 14 days every 3 weeks) or mFOLFOX6 (oxaliplatin (85 mg/m2), leucovorin (400 mg/m2), and fluorouracil (400 mg/m2) followed by continuous infusion of fluorouracil (2400 mg/m2) for 46–48 h, repeated every 2 weeks) is optional.
Follow-up
History, physical examination, tumor markers test, ultrasound imaging of abdomen and pelvis, and radiography of chest will be carried out every 3 months for the first 2 years and every 6 months thereafter. Abdominopelvic CT or MRI and CT scan of chest will be conducted annually. Colonoscopy will be scheduled at 1, 3, and 5 years for post-treatment surveillance.
Outcomes
The primary endpoint is 3-year DFS and the secondary endpoints are 3- and 5-year OS, 5-year DFS, and the rate of local recurrence and adverse events resulted from CRT and patients’ quality of life. DFS is calculated from the date of surgery to the date of recurrence. OS is defined as the time from surgery to death.
Data collection, management and monitoring
All data will be collected in form of an electronic case report form (eCRF) through an electronic data capture (EDC) system. The data center located at Fudan University Shanghai Cancer Center will be in charge for quality control of study data. The EDC system will check the data automatically and data managers will review the eCRFs regularly. The queries will be sent out to each investigator. The data monitoring committee (DMC) is made up of three surgeons who have no conflict of interest in this study. DMC is responsible for reviewing efficacy and toxicity of intervention independently from the investigators and reporting severe adverse events. No regular auditing is scheduled.
Statistical analysis
Continuous measures will be compared using the Wilcoxon rank-sum test. Chi-square or Fisher’s exact test will be utilized to compare categorical variables. The DFS and OS will be estimated using the Kaplan-Meier method. The Cox proportional hazards model will be employed to identify the prognostic factors. No interim analysis will be planned as well.
Protocol version
Version 1.0.