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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Adjuvant FL | Active Comparator | FL (5-FU 380 mg/m2, leucovorin 20 mg/m2 on D1-5 q 4 weeks X 4 cycles) |
|
| Adjuvant FOLFOX | Experimental | 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Adjuvant FL | Drug | 5-Fluorouracil 380 mg/m2, leucovorin 20 mg/m2 on D1-5 q 4 weeks X 4 cycles |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | up to 3 years after completion of treatment |
| 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. | up to 3 years after completion of treatment |
| 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. | up to 3 years after completion of treatment |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tae Won Kim, Professor | Asan Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Cancer Center | Goyang | South Korea | ||||
| Seoul National Unversity Bundang Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31593484 | Derived | Hong YS, Kim SY, Lee JS, Nam BH, Kim KP, Kim JE, Park YS, Park JO, Baek JY, Kim TY, Lee KW, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial. J Clin Oncol. 2019 Nov 20;37(33):3111-3123. doi: 10.1200/JCO.19.00016. Epub 2019 Oct 8. | |
| 25201358 |
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1 screening failure due to raised carcinoembryonic antigen concentration
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Adjuvant FOLFOX |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | intention-to-treat population (all randomised patients) | Posted | Count of Participants | Participants | up to 3 years after completion of treatment |
|
3 years
12 patients in the fluorouracil plus leucovorin group and 10 in the FOLFOX group were not received the planned treatment because of withdrawal. 4 patient in the FOLFOX group were not received the planned treatment because of ineligible.
Death was assessed for all randomized participants. Adverse Events were assessed for all treated participants.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Fluorouracil+Leucovorin Group | 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 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Leucopenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
not specific
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Tae Won Kim | Asan Medical Center | +82-2-3010-3910 | twkimmd@amc.seoul.kr |
Not provided
| ID | Term |
|---|---|
| D012004 | Rectal Neoplasms |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
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| ID | Term |
|---|---|
| D005472 | Fluorouracil |
| D002955 | Leucovorin |
| D000077150 | Oxaliplatin |
| ID | Term |
|---|---|
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
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| Adjuvant FOLFOX | Drug | 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 |
|
|
| Up to 3 years after completion of treatment. |
| 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. | the time from the date of randomization to the date of disease relapse, , assessed up to 5 years |
| Seongnam |
| South Korea |
| Asan Medical Center | Seoul | South Korea |
| Samsung Medical Center | Seoul | South Korea |
| Seoul National University Hospital | Seoul | South Korea |
| Yeonsei University Hosptial | Seoul | South Korea |
| Derived |
| Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, Park JO, Kim SY, Kim TY, Kim JH, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014 Oct;15(11):1245-53. doi: 10.1016/S1470-2045(14)70377-8. Epub 2014 Sep 4. |
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
| BG002 | Total | Total of all reporting groups |
| years |
|
| Age, Customized | Count of Participants | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| ECOG PS | Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 0=Fully active, able to carry on all pre-disease performance without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; | Count of Participants | Participants |
|
| Distance of the primary tumour from the anal verge | Count of Participants | Participants |
|
| Tumor differentiation | Count of Participants | Participants |
|
| Preoperative radiotherapy Dose | Median | Full Range | cGY |
|
| Preoperative radiotherapy duration | Median | Full Range | weeks |
|
| Concurrent chemotherapy during preoperative radiotherapy | Count of Participants | Participants |
|
| Concurrent chemotherapy during preoperative radiotherapy | Interval between end of preoperative chemoradiotherapy and surgery (weeks) | Median | Full Range | weeks |
|
| Type of surgery | Count of Participants | Participants |
|
| Pathological T stage | The post-neoadjuvant treatment tumor size which is determined by examining tissue removed during an operation. ypT0=No evidence of primary tumor; ypT1=Tumor invades the submucosa; ypT2=Tumor invades muscularis propria; ypT3=Tumor invades through the muscularis propria into pericolorectal tissues; ypT4=Tumor penetrates to the surface of the visceral peritoneum or directly invades or adheres to other organs or structures | Count of Participants | Participants |
|
| Pathological N stage | The post-neoadjuvant treatment the extent of regional lymph node involvement which is determined by examining tissue removed during an operation. ypN0=No regional lymph node metastasis; ypN1a=Metastasis in one regional lymph node; ypN1b=Metastasis in 2-3 regional lymph nodes; ypN2a=Metastasis in 4-6 regional lymph nodes; ypN2b=Metastasis in seven or more regional lymph nodes | Count of Participants | Participants |
|
| yp stage | stage grouping to assign an overall stage using ypT and N categories. Stage II(ypT3N0, ypT4N0), Stage III(ypTanyN1a, ypTany N1b, ypTanyN2a, ypTany N2b) | Count of Participants | Participants |
|
| Grade of tumour regression | Count of Participants | Participants |
|
| Lymphovascular invasion | Count of Participants | Participants |
|
| Time from surgery to randomisation (weeks) | Median | Full Range | weeks |
|
| OG001 | 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 |
|
|
|
| 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. | Among intention-to-treat population (all randomised patients), Patients with pathological stage III disease | Posted | Count of Participants | Participants | up to 3 years after completion of treatment |
|
|
|
|
| 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. | Among intention-to-treat population (all randomised patients), Patients with pathological stage II disease | Posted | Count of Participants | Participants | up to 3 years after completion of treatment |
|
|
|
|
| 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. | intention-to-treat population (all randomised patients) | Posted | Count of Participants | Participants | Up to 3 years after completion of treatment. |
|
|
|
|
| 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. | intention-to-treat population (all randomised patients) | Posted | Count of Participants | Participants | the time from the date of randomization to the date of disease relapse, , assessed up to 5 years |
|
|
|
| 21 |
| 161 |
| 0 |
| 149 |
| 149 |
| 149 |
| EG001 | FOLFOX Group | 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 | 10 | 160 | 0 | 146 | 146 | 146 |
| neutropenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (3.0) | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | CTCAE (3.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Allergic reaction | Immune system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Sensory neuropathy | Nervous system disorders | CTCAE (3.0) | Systematic Assessment |
|
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| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D006571 |
| Heterocyclic Compounds |
| D005575 | Formyltetrahydrofolates |
| D013763 | Tetrahydrofolates |
| D005492 | Folic Acid |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D003067 | Coenzymes |
| D045762 | Enzymes and Coenzymes |
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
| Distant metastasis |
|
| Lung |
|
| Liver |
|
| Lymph node |
|
| Bone |
|
| Peritoneum |
|
| Other* |
|