Inclusion criteria
- Age between 20 and 70 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower, or age between 71 to 75 years with an ECOG performance status of 0
- Pathologically confirmed high-risk stage III CC (pT4N1-2 or pTanyN2)
- Successful R0 resection for CC above the upper rectum within 60 d prior to screening
- Adequate organ functions, as determined by laboratory tests after operation and before screening
- absolute neutrophil count ≥ 2×106 cells/mL
- hemoglobin ≥ 9.0 g/dL, platelet count ≥ 100×106 cells/mL
- alanine aminotransferase/aspartate aminotransferase ≤ 2.5 times the upper limit of normal (ULN)
- serum total bilirubin levels ≤ 1.5 times the ULN
- alkaline phosphatase levels ≤ 2.5 times the ULN
- serum creatinine levels ≤ 1.5 times the ULN or creatinine clearance > 50 mL/min based on the Cockcroft-Gault formula
- Ability to understand and willingness to provide written informed consent
- A life expectancy of at least 5 years
Exclusion criteria
- Presence of distant metastases
- Lower and middle rectal cancer requiring radiotherapy
- Postoperative complications of grade 4 or higher according to the Clavien-Dindo classification
- Underlying medical or systemic conditions that impede chemotherapy administration
- Known hypersensitivity to all relevant tests or treatment components
- Familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer
- Inflammatory bowel disease
- Presence of other incurable prior malignancies
- Pregnancy (confirmed by serum beta-human chorionic gonadotropin test) or lactation
- Any other circumstances that, at the discretion of the investigator, might result in exclusion from the study
Interventions
Treatment and toxicity assessment
Patients will be randomized into two treatment arms - Arm A, the experimental arm, and arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX or mFOLFOX 6 every 2 weeks, respectively. The mFOLFIRINOX regimen consists of intravenous irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, and leucovorin 400 (or levoleucovorin 200) mg/m2 on day 1 and continuous infusion of 5-FU 1200 mg/m2/d intravenously for the next 2 d (total 2400 mg/m2 over 48 h). The mFOLFOX 6 regimen consists of intravenous oxaliplatin 85 mg/m2, leucovorin 400 (or levoleucovorin 200) mg/m2, and bolus 5-FU 400 mg/m2 on day 1 and continuous infusion of 5-FU 1200 mg/m2/d intravenously for the next 2 d (total 2400 mg/m2 over 48 h).
Although there is no absolute contraindication with other treatments, caution will be exercised when co-administering these with drugs that might cause toxicities such as cardiotoxicity, hepatotoxicity, nephrotoxicity, myelodysfunction, and neurotoxicity. Toxicity will be monitored by taking the patient history and conducting laboratory tests before the initiation of the next cycle of treatment.
The drug dose could be adjusted at the discretion of the investigator, if necessary, because of toxicity, and the reduced dose could be sustained for subsequent cycles. Discontinuation will be considered after sustained toxicity despite dose reduction and management, recurrence during treatment, or on patient request.
Recurrence assessment
Recurrent assessment, including carcinoembryonic antigen measurement, abdominopelvic computer tomography (CT), and chest radiography or CT, will be performed after every 4 cycles of treatment and postoperatively every 4 months for 2 years and every 6 months for the next 3 years. The modality and interval of evaluation could be added and adjusted at the discretion of the investigator, if necessary. If recurrence is detected during treatment, study treatment will be discontinued and a standard personalized treatment will be conducted. If recurrence is detected during the follow-up period, a standard personalized treatment will be conducted. The participant timeline is presented in Table 1.
[Position of Table 1]
Table 1. Timeline of enrollment, intervention, assessment, and surveillance in FROST trial
Visit1
|
Screening
|
Chemotherapy period
|
Follow-up period
|
|
C1D1
|
C2–3D1
C5–7D1
C9–11D1
|
C4D1
C8D1
C12D1
|
F1–5
|
F6, F7
|
Interval
|
|
|
2 weeks
(-4 d/+7 d)
|
4 months
(-14/+30 d)
|
6 months
(-14/+30 d)
|
Informed consent
|
X
|
|
|
|
|
|
Screening number
|
X
|
|
|
|
|
|
Complication check2
|
X
|
|
|
|
|
|
Criteria check
|
X
|
X
|
|
|
|
|
Randomization
|
|
X
|
|
|
|
|
Performance status check
|
X
|
X
|
X
|
X
|
|
|
Medical history and physical examination
|
X
|
X
|
X
|
X
|
X
|
X
|
Height, weight, BSA3
|
|
X
|
X
|
X
|
|
|
Vital sign4
|
X
|
X
|
X
|
X
|
|
|
Laboratory test5
|
X
|
X
|
X
|
X
|
X
|
X
|
Pregnancy test 6
|
X
|
|
X (even-numbered cycles)
|
|
|
Treatment
|
|
X
|
X
|
X
|
|
CEA7
|
X
|
|
|
X
|
X
|
X
|
Imaging study8
|
|
|
|
X
|
X
|
X
|
Colonoscopy9
|
|
|
|
|
X
|
X
|
Safety assessment
|
|
X
|
X
|
X
|
|
|
Efficacy assessment
|
|
|
|
X
|
X
|
X
|
1. The next visit is based on the previous visit date. In the treatment phase, the first day of each treatment cycle (e.g., C1D1, C2D1...) is the reference date.
2. Postoperative complications: Evaluate complications within 30 d after surgery according to the Clavien-Dindo Classification
3. BSA (body surface area)
4. Vital signs include blood pressure, heart rate, respiratory rate, and body temperature.
5. Laboratory tests include complete blood count, liver and kidney function tests, and electrolytes.
6. Pregnancy test (serum beta-human chorionic gonadotropin test): Performed on even-numbered cycles (C2, 4, 6, 8, 10, 12) only for fertile women.
7. CEA (carcinoembryonic antigen): The first test performed before surgery and during the postoperative screening period.
8. Imaging studies include abdominopelvic computed tomography (CT) and chest radiography (C4, C8, F2, F4, F6) or CT (C12, F1, F3, F5, F7).
9. Colonoscopy is recommended in F1 and F7.
|
Endpoints
Primary endpoint
The primary endpoint of the study is the 3-year DFS rate based on intention-to-treat analysis, which is defined as the proportion of patients who were alive without recurrence at 3 years from the date of surgery. It will be calculated using the time from the date of surgery to the date of recurrence detection, death, or the last follow-up. In cases where patients are lost before the 3-year mark, their data will be censored as of the last follow-up date and assessed accordingly.
Secondary endpoints
The secondary endpoints are the 3-year overall survival (OS) rate based on intent-to treat analysis, which is defined as the proportion of patients who are still alive 3 years from the date of surgery and calculated using the time from the date of surgery to the date of death or last follow-up; treatment-related toxicity according to the CTCAE (Common Terminology Criteria for Adverse Events) version 5.0; treatment discontinuation rate, defined as the proportion of participants in each arm who discontinued treatment because of toxicity or lack of compliance; and the percentage of the drug dose actually administered relative to the target drug dose. These secondary endpoints will provide valuable insights into the safety and tolerability of the adjuvant treatments compared in this study.
Randomization
Randomization will be adjusted based on the following stratification factors: pT1-3N2 versus pT4N1 versus pT4N2, and the right colon (from the cecum to the distal transverse colon above the splenic flexure colon) versus the left colon (from the splenic flexure colon to the rectosigmoid colon). This process will be conducted according to the special program on the electronic case report form (eCRF) webpage, and the result of randomization will be presented on the webpage immediately after the registration of patients. This eCRF, which includes the randomization program, was developed by the special department, the “Academic Clinical Research Operating Support System (ACROSS)” of the lead institute, which consists of data management and monitoring specialists that support investigator-oriented clinical studies. They are independent from the sponsor, and no competing interests will exist.
Data management
To conceal personal information, the allocation sequence employs the double-digit participant number and the three-digit institute number, which are automatically generated on the eCRF in order of registered participants, based on the date of acquisition of informed consent. Access to the eCRF will be exclusively granted to registered researchers involved in this study. Screening, obtaining informed consent, enrollment, registration, and data collection will be conducted by investigators or qualified clinical research coordinators. Blinding will not be implemented because of the open-label nature of the study.
Monitoring
Data safety monitoring
Completeness of data collection will be assessed when 20% of the sample completes treatment, and improvements will be made, if necessary. Treatment completion rates and rates of the incidence of serious adverse events (SAE) will be evaluated at the end of treatment for 20% and 40% of the sample, respectively.
Safety monitoring
In the event of an SAE occurring at any institution, the contents shall be promptly reported to the Institutional Review Board (IRB) of the leading and corresponding institutions using the prescribed form. If no SAEs occur, monitoring results will be included in the final report. Any protocol violations, non-compliance, or unexpected problems will also be reported to the IRB of the leading and corresponding institutes. If more than five SAE are reported at any institution, the principal investigator, along with the co-investigators, will discuss the study's sustainability and the need to potentially discontinue or modify the study. The results of this discussion will be reported to the IRB. In the event of participants experiencing physical damage as a result of participating in this study, the principal investigator shall provide compensation in accordance with the provisions of relevant laws and regulations.
Auditing
The ACROSS team will monitor data collection and protocol adherence. Auditing of investigators will be conducted at least annually and may be conducted at additional times, if necessary.
Statistical analysis
Sample size calculation
Based on previous research (11), it is anticipated that the experimental group receiving mFOLFIRINOX as adjuvant treatment will achieve a 3-year DFS rate of 77.5%, with an improvement of 12.5% compared to the control group, which is estimated to have a 65% DFS rate. To determine the sample size for the study, a power analysis was performed using the PASS (Power Analysis and Sample Size) 13.0 program (NCSS, LLC, Kaysville, Utah, USA). The calculations indicated that a minimum of 156 subjects will be required for each treatment arm, considering the desired statistical power of 80%, the significance level of 10%, and the dropout rate of 10%. Therefore, a total of 312 subjects, equally stratified and randomized, will be enrolled to ensure adequate statistical power and robust results.
Outcome assumptions
Statistical analyses for primary and secondary outcomes of the intent-to-treat group and per-protocol group will be performed using SPSS version 26 (IBM, Armonk, NY, USA).
Analysis of prognostic factors and biomarkers
Prognostic factors and biomarkers will be analyzed in this study. Information about various clinical, pathological, and molecular characteristics, including microsatellite instability, KRAS, NRAS, BRAF, and HER2 status, of the enrolled patients will be collected and assessed. The analysis of these factors will provide valuable insights into the prognosis and potential treatment response of patients with high-risk stage III CC. Through these analyses, we will identify molecular markers that might affect disease progression and treatment outcomes. This comprehensive analysis of prognostic factors and biomarkers will enhance our understanding of the underlying biology of high-risk stage III CC and could reveal important associations between these molecular characteristics and clinical outcomes, thereby guiding personalized treatment and optimized patient management.