Rectal Cancer
Conditions
Keywords
rectal cancer, adjuvant chemotherapy, FOLFOX
Brief summary
The purpose of this study is to evaluate the disease-free survival in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy with fluoropyrimidines and surgery followed by adjuvant combination chemotherapy with oxaliplatin/5-FU/Leucovorin vs 5-FU/Leucovorin.
Detailed description
Preoperative chemoradiotherapy with fluoropyrimidines followed by surgery is one of the standard treatments for patients with locally advanced rectal cancer; however, the role of adjuvant chemotherapy is still controversial. The aim of this study is to investigate the efficacy of adjuvant FOLFOX for rectal cancer who underwent fluoropyrimidine based chemoradiotherapy and complete total mesorectal excision.
Interventions
DRUGAdjuvant FL
5-Fluorouracil 380 mg/m2, leucovorin 20 mg/m2 on D1-5 q 4 weeks X 4 cycles
DRUGAdjuvant FOLFOX
oxaliplatin 85 mg/m2, leucovorin 200 mg/m2 on D1, 5-Fluorouracil bolus 400 mg/m2 on D1, 5-Fluorouracil continuous infusion 2400 mg/m2 for 46 hours q 2 weeks X 8 cycles
Sponsors
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed adenocarcinoma of the rectum 2. Patients who treated with preoperative chemoradiation with fluoropyrimidines followed by curative surgery without microscopic residual tumor. 3. AJCC/UICC pathologic stages of ypT3-4 or ypN+ 4. Curative surgery not less than 3 and not more than 8 weeks prior to randomization 5. No prior chemotherapy, radiotherapy and immunotherapy except preoperative chemoradiation for rectal cancer 6. ECOG PS 0-1 7. Adequate organ function 8. Informed Consent
Exclusion criteria
1. Macroscopic or microscopic evidence of remaining tumor 2. Any histologic feature other than adenocarcinoma or arisen from chronic inflammatory bowel disease 3. More than 8 weeks after curative surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Disease Recurrence | up to 3 years after completion of treatment | Disease-free survival will be measured as the time from the date of randomization to the date of disease relapse or death due to any cause. Using Cox-proportional hazard regression, the hazard ratio together with the 95% confidence interval will be reported, in addition to Kaplan-Meier estimates of the survival curves, including medians and rates with 95% confidence intervals. Intent-to-treat population included all randomised patients, and per-protocol population included patients who received at least 1 dose of chemotherapy without any violation of inclusion criteria |
| Number of Participants With Disease Recurrence With Pathological Stage III | up to 3 years after completion of treatment | Disease-free survival will be measured as the time from the date of randomization to the date of disease relapse or death due to any cause. Using Cox-proportional hazard regression, the hazard ratio together with the 95% confidence interval will be reported, in addition to Kaplan-Meier estimates of the survival curves, including medians and rates with 95% confidence intervals. Intent-to-treat population included all randomised patients, and per-protocol population included patients who received at least 1 dose of chemotherapy without any violation of inclusion criteria. |
| Number of Participants With Disease Recurrence With Pathological Stage II | up to 3 years after completion of treatment | Disease-free survival will be measured as the time from the date of randomization to the date of disease relapse or death due to any cause. Using Cox-proportional hazard regression, the hazard ratio together with the 95% confidence interval will be reported, in addition to Kaplan-Meier estimates of the survival curves, including medians and rates with 95% confidence intervals. Intent-to-treat population included all randomised patients, and per-protocol population included patients who received at least 1 dose of chemotherapy without any violation of inclusion criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Death Rate | Up to 3 years after completion of treatment. | overall survival was defined as the time from randomisation to death. We used the Kaplan-Meier method to estimate disease-free and overall survival. Patients were censored at the last follow-up if they were alive and free from disease recurrence. We used the log-rank test to compare the two survival distributions. We estimated crude and stratified hazard ratios (HRs) and their corresponding 95% CIs using the Cox proportionalhazards regression model. |
| Pattern of Recurrence | the time from the date of randomization to the date of disease relapse, , assessed up to 5 years | After the completion of study treatment, chest radiography and measurement of carcinoembryonic antigen were done every 3 months for the fi rst 2 years and every 6 months thereafter. Abdominopelvic CT scans were done every 6 months and chest CT scans annually. Colonoscopy was scheduled at 1 year, 3 years, and 5 years from the date of surgery. Local recurrence was defined as any clinically proven tumour relapse within the pelvis or perineum. Distant metastasis was defined as relapse at any other site rather than local recurrence. We regarded any local or distant recurrence as a disease recurrence event. Disease recurrence was judged by the investigators with no central review. |
Countries
South Korea
Participant flow
Recruitment details
1 screening failure due to raised carcinoembryonic antigen concentration
Participants by arm
| Arm | Count |
|---|---|
| Adjuvant Fluorouracil +Leucovorin FL (5-FU 380 mg/m2, leucovorin 20 mg/m2 on D1-5 q 4 weeks X 4 cycles)
Adjuvant FL: 5-Fluorouracil 380 mg/m2, leucovorin 20 mg/m2 on D1-5 q 4 weeks X 4 cycles | 161 |
| Adjuvant FOLFOX FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2 on D1, 5-FU bolus 400 mg/m2 on D1, 5-FU infusion 2400 mg/m2 for 46 hours q 2 weeks X 8 cycles)
Adjuvant FOLFOX: oxaliplatin 85 mg/m2, leucovorin 200 mg/m2 on D1, 5-Fluorouracil bolus 400 mg/m2 on D1, 5-Fluorouracil continuous infusion 2400 mg/m2 for 46 hours q 2 weeks X 8 cycles | 160 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible | 0 | 4 |
| Overall Study | Withdrawal by Subject | 12 | 10 |
Baseline characteristics
| Characteristic | Adjuvant FOLFOX | Total | Adjuvant Fluorouracil +Leucovorin |
|---|---|---|---|
| Age, Continuous | 55 years | 54.5 years | 54 years |
| Age, Customized Aged 65 years or older | 31 Participants | 55 Participants | 24 Participants |
| Concurrent chemotherapy during preoperative radiotherapy Capecitabine | 46 Participants | 89 Participants | 43 Participants |
| Concurrent chemotherapy during preoperative radiotherapy Fluorouracil with or without leucovorin | 107 Participants | 215 Participants | 108 Participants |
| Concurrent chemotherapy during preoperative radiotherapy Tegafur-uracil | 7 Participants | 17 Participants | 10 Participants |
| Concurrent chemotherapy during preoperative radiotherapy | 7.0 weeks | 7.0 weeks | 7.0 weeks |
| Distance of the primary tumour from the anal verge >4 and ≤8 cm | 81 Participants | 170 Participants | 89 Participants |
| Distance of the primary tumour from the anal verge ≤4 cm | 48 Participants | 93 Participants | 45 Participants |
| Distance of the primary tumour from the anal verge >8 cm | 31 Participants | 58 Participants | 27 Participants |
| ECOG PS 0 | 26 Participants | 56 Participants | 30 Participants |
| ECOG PS 1 | 134 Participants | 265 Participants | 131 Participants |
| Grade of tumour regression Minimal or no regression | 38 Participants | 90 Participants | 52 Participants |
| Grade of tumour regression Moderate regression | 85 Participants | 169 Participants | 84 Participants |
| Grade of tumour regression Near total regression | 31 Participants | 53 Participants | 22 Participants |
| Grade of tumour regression Total regression | 5 Participants | 7 Participants | 2 Participants |
| Grade of tumour regression Unknown | 1 Participants | 2 Participants | 1 Participants |
| Lymphovascular invasion Absent | 120 Participants | 240 Participants | 120 Participants |
| Lymphovascular invasion Present | 37 Participants | 78 Participants | 41 Participants |
| Lymphovascular invasion Unknown | 3 Participants | 3 Participants | 0 Participants |
| Pathological N stage ypN0 | 58 Participants | 123 Participants | 65 Participants |
| Pathological N stage ypN1a | 42 Participants | 72 Participants | 30 Participants |
| Pathological N stage ypN1b | 25 Participants | 63 Participants | 38 Participants |
| Pathological N stage ypN2a | 29 Participants | 48 Participants | 19 Participants |
| Pathological N stage ypN2b | 6 Participants | 15 Participants | 9 Participants |
| Pathological T stage ypT0 | 5 Participants | 7 Participants | 2 Participants |
| Pathological T stage ypT1 | 1 Participants | 5 Participants | 4 Participants |
| Pathological T stage ypT2 | 18 Participants | 36 Participants | 18 Participants |
| Pathological T stage ypT3 | 133 Participants | 264 Participants | 131 Participants |
| Pathological T stage ypT4 | 3 Participants | 9 Participants | 6 Participants |
| Preoperative radiotherapy Dose | 5000 cGY | 5000 cGY | 5000 cGY |
| Preoperative radiotherapy duration | 5.1 weeks | 5.05 weeks | 5.0 weeks |
| Sex: Female, Male Female | 42 Participants | 87 Participants | 45 Participants |
| Sex: Female, Male Male | 118 Participants | 234 Participants | 116 Participants |
| Time from surgery to randomisation (weeks) | 3.4 weeks | 3.5 weeks | 3.6 weeks |
| Tumor differentiation Moderately differentiated | 133 Participants | 263 Participants | 130 Participants |
| Tumor differentiation Poorly differentiated/signet ring cell/mucinous | 11 Participants | 20 Participants | 9 Participants |
| Tumor differentiation Undetermined | 3 Participants | 5 Participants | 2 Participants |
| Tumor differentiation Well differentiated | 13 Participants | 33 Participants | 20 Participants |
| Type of surgery Abdominoperineal resection | 24 Participants | 48 Participants | 24 Participants |
| Type of surgery Hartmann's procedure | 1 Participants | 3 Participants | 2 Participants |
| Type of surgery Low anterior resection | 135 Participants | 270 Participants | 135 Participants |
| yp stage II | 58 Participants | 123 Participants | 65 Participants |
| yp stage III | 102 Participants | 198 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 21 / 161 | 10 / 160 |
| other Total, other adverse events | 149 / 149 | 146 / 146 |
| serious Total, serious adverse events | 0 / 149 | 0 / 146 |
Outcome results
Primary
Number of Participants With Disease Recurrence
Disease-free survival will be measured as the time from the date of randomization to the date of disease relapse or death due to any cause. Using Cox-proportional hazard regression, the hazard ratio together with the 95% confidence interval will be reported, in addition to Kaplan-Meier estimates of the survival curves, including medians and rates with 95% confidence intervals. Intent-to-treat population included all randomised patients, and per-protocol population included patients who received at least 1 dose of chemotherapy without any violation of inclusion criteria
Time frame: up to 3 years after completion of treatment
Population: intention-to-treat population (all randomised patients)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adjuvant Fluorouracil +Leucovorin | Number of Participants With Disease Recurrence | 53 Participants |
| Adjuvant FOLFOX | Number of Participants With Disease Recurrence | 39 Participants |
p-value: 0.04795% CI: [0.434, 0.994]t-test, 1 sided
Primary
Number of Participants With Disease Recurrence With Pathological Stage II
Disease-free survival will be measured as the time from the date of randomization to the date of disease relapse or death due to any cause. Using Cox-proportional hazard regression, the hazard ratio together with the 95% confidence interval will be reported, in addition to Kaplan-Meier estimates of the survival curves, including medians and rates with 95% confidence intervals. Intent-to-treat population included all randomised patients, and per-protocol population included patients who received at least 1 dose of chemotherapy without any violation of inclusion criteria.
Time frame: up to 3 years after completion of treatment
Population: Among intention-to-treat population (all randomised patients), Patients with pathological stage II disease
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adjuvant Fluorouracil +Leucovorin | Number of Participants With Disease Recurrence With Pathological Stage II | 15 Participants |
| Adjuvant FOLFOX | Number of Participants With Disease Recurrence With Pathological Stage II | 10 Participants |
p-value: 0.4795% CI: [0.334, 1.657]t-test, 1 sided
Primary
Number of Participants With Disease Recurrence With Pathological Stage III
Disease-free survival will be measured as the time from the date of randomization to the date of disease relapse or death due to any cause. Using Cox-proportional hazard regression, the hazard ratio together with the 95% confidence interval will be reported, in addition to Kaplan-Meier estimates of the survival curves, including medians and rates with 95% confidence intervals. Intent-to-treat population included all randomised patients, and per-protocol population included patients who received at least 1 dose of chemotherapy without any violation of inclusion criteria.
Time frame: up to 3 years after completion of treatment
Population: Among intention-to-treat population (all randomised patients), Patients with pathological stage III disease
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adjuvant Fluorouracil +Leucovorin | Number of Participants With Disease Recurrence With Pathological Stage III | 38 Participants |
| Adjuvant FOLFOX | Number of Participants With Disease Recurrence With Pathological Stage III | 29 Participants |
p-value: 0.0495% CI: [0.371, 0.977]t-test, 1 sided
Secondary
Death Rate
overall survival was defined as the time from randomisation to death. We used the Kaplan-Meier method to estimate disease-free and overall survival. Patients were censored at the last follow-up if they were alive and free from disease recurrence. We used the log-rank test to compare the two survival distributions. We estimated crude and stratified hazard ratios (HRs) and their corresponding 95% CIs using the Cox proportionalhazards regression model.
Time frame: Up to 3 years after completion of treatment.
Population: intention-to-treat population (all randomised patients)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adjuvant Fluorouracil +Leucovorin | Death Rate | 21 Participants |
| Adjuvant FOLFOX | Death Rate | 10 Participants |
p-value: 0.03695% CI: [0.215, 0.97]t-test, 1 sided
Secondary
Pattern of Recurrence
After the completion of study treatment, chest radiography and measurement of carcinoembryonic antigen were done every 3 months for the fi rst 2 years and every 6 months thereafter. Abdominopelvic CT scans were done every 6 months and chest CT scans annually. Colonoscopy was scheduled at 1 year, 3 years, and 5 years from the date of surgery. Local recurrence was defined as any clinically proven tumour relapse within the pelvis or perineum. Distant metastasis was defined as relapse at any other site rather than local recurrence. We regarded any local or distant recurrence as a disease recurrence event. Disease recurrence was judged by the investigators with no central review.
Time frame: the time from the date of randomization to the date of disease relapse, , assessed up to 5 years
Population: intention-to-treat population (all randomised patients)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Lung | 29 Participants |
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Lymph node | 10 Participants |
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Local recurrence | 12 Participants |
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Bone | 4 Participants |
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Distant metastasis | 44 Participants |
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Peritoneum | 1 Participants |
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Liver | 15 Participants |
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Other* | 2 Participants |
| Adjuvant Fluorouracil +Leucovorin | Pattern of Recurrence | Any event | 53 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Other* | 2 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Any event | 39 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Local recurrence | 5 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Distant metastasis | 35 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Lung | 24 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Liver | 8 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Lymph node | 6 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Bone | 2 Participants |
| Adjuvant FOLFOX | Pattern of Recurrence | Peritoneum | 1 Participants |