Colorectal Cancer
Conditions
Keywords
stage III rectal cancer, adenocarcinoma of the rectum, stage II rectal cancer
Brief summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Chemoradiotherapy (combining chemotherapy with radiation therapy) before surgery may shrink the tumor so that it can be removed. Giving chemotherapy after surgery may kill any remaining tumor cells. PURPOSE: This randomized phase II trial is studying two different regimens of neoadjuvant chemoradiotherapy and adjuvant chemotherapy and comparing how well they work in treating patients who are undergoing surgical resection for locally advanced rectal cancer.
Detailed description
OBJECTIVES: * Evaluate the pathologic complete response rate in patients with locally advanced rectal cancer undergoing surgical resection treated with 2 different regimens of neoadjuvant chemoradiotherapy and adjuvant chemotherapy. * Evaluate the time to treatment failure and patterns of failure in patients treated with these regimens. * Evaluate the incidence of hematologic and non-hematologic grade 3-4 toxicity (preoperatively, postoperatively, and overall) in patients treated with these regimens. * Evaluate the quality of life of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to clinical stage of tumor (T3 vs T4). Patients are randomized to 1 of 2 treatment arms. Quality of life is assessed at baseline, within 1 week after completion of radiotherapy, within 1 week after completion of adjuvant chemotherapy (12 months), and then at 24 months. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
RADIATIONRadiation Therapy
Pelvic radiation therapy given once daily 5 days a week for 6 weeks, 45 Gy in 25 fractions + boost of 5.4 Gy in 3 fractions for a total dose of 50.4 Gy.
DRUGCapecitabine 1650 mg/m^2/day
825 mg/m\^2 q12 hours (1650 mg/m\^2/day) orally 5 days per week during radiotherapy.
DRUGCapecitabine 1200 mg/m^2/day
600 mg/m\^2 q12 hours(1200 mg/m\^2/day) orally 5 days per week during radiotherapy.
DRUGIrinotecan
50mg/m\^2 IV over 1 hour on days 1, 8, 22, and 29
DRUGOxaliplatin
50mg/m\^2 IV over 2 hours on days 1, 8, 15, 22, and 29
PROCEDURESurgery
All patients will undergo surgery four to eight weeks following the completion of radiation therapy. The choice of procedure abdominoperineal resection (APR), low anterior resection (LAR), or LAR/coloanal anastomosis is at the discretion of the surgeon.
DRUGFolinic Acid
400 mg/m\^2 IV over 2 hours Day 1 (postoperatively) ,every 14 days, for nine 14-day cycles.
DRUGFluorouracil
5-fluorouracil bolus 400 mg/m\^2 IV push Day 1 (postoperatively), every 14 days, for nine 14-day cycles. 5-fluorouracil infusion 2400 mg/m\^2 IV continuous infusion over 46 hours, beginning day 1, every 14 days, for nine 14-day cycles.
Sponsors
National Cancer Institute (NCI)
Radiation Therapy Oncology Group
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. Adenocarcinoma of the rectum originating at or below 12 cm from the anal verge without evidence of distant metastases 2. Patient must be 18 years of age or greater. 3. Potentially resectable en bloc based upon surgeon evaluation 4. Clinical stages T3 or T4, based upon endorectal ultrasound, or physical examination (only acceptable for T4 lesions). 5. Absolute neutrophil count of \> 1500 per microliter and platelet count \> 100,000 per microliter; aspartate aminotransferase (AST) and alkaline phosphatase \< 2.5 X upper limit of normal (ULN), bilirubin \< = 1.5 ULN, calculated creatinine clearance \> 50 ml/min using Cockcroft-Gault formula: * CrCl male = (140 - age) x (wt. in kg) / (Serum Cr) x 72 * CrCl female = 0.85 x (CrCl male) 6. Zubrod performance status 0-2 7. No history of other malignancies within 5 years, except non-melanoma skin cancer, in situ carcinoma of the cervix, or ductal carcinoma in situ of the breast. Previous invasive cancer permitted if disease free at least 5 years. 8. Signed study-specific informed consent prior to randomization
Exclusion criteria
1. Any evidence of distant metastasis 2. Synchronous primary colon carcinomas, except T1 lesions (full colonoscopy not required for enrollment) 3. Extension of malignant disease to the anal canal 4. Prior radiation therapy to the pelvis 5. Prior chemotherapy for malignancies 6. Pregnancy or lactation, (exclusion due to potential adverse effects of therapy). Women of childbearing potential with either a positive or no pregnancy test (serum or urine) at baseline. Women/men of childbearing potential not using a reliable and appropriate contraceptive method. (Postmenopausal women must have been amenorrheic for at least 12 months to be considered to be of non-childbearing potential.) Patients will agree to continue contraception for 30 days from the date of the last study drug administration. 7. Serious, uncontrolled, concurrent infection(s). 8. Participation in any investigational drug study within 4 weeks preceding the start of study treatment. 9. Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months. 10. Evidence of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake. 11. Other serious uncontrolled medical conditions that the investigator feels might compromise study participation. 12. Major surgery within 4 weeks of the study treatment. 13. Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome. 14. Known, existing uncontrolled coagulopathy. 15. No concurrent cimetidine allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response Rate | After protocol surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation | A pathologic complete response (pCR) was defined as no evidence of residual cancer histologically; disease progression or death before surgery was considered less than pCR (even without surgical specimen). All cases were reviewed by the study's surgical oncology co-chair for the determination of pCR. Each arm was first analyzed alone. If the arm had 9 or more pCRs in 48 evaluable pts, then the null hypothesis (H0) of 10% pCR rate would be rejected in favor of the alternative hypothesis of 25%, providing 90% power with a two-sided 10% type I error rate. If both arms reject H0, then statistical selection theory would be used to choose the arm for further study in a phase III trial. If only one arm has acceptable pCR rate, then that arm would be pursued in a phase III trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Local-regional Failure Rate at 4 Years | From randomization to four years | Local-regional failure is defined as any of the following: no clinical complete response (cCR) in the primary site and/or nodes at any time after treatment completion (persistence), recurrence and/or progression in the primary site and/or nodes after cCR, and nonprotocol surgery to the primary site after cCR. Time to local-regional failure is defined as time from randomization to date of failure, last known follow-up (censored), or death without local-regional failure (competing risk). Local-regional failure rates are estimated by the cumulative incidence method. |
| Distant Failure Rate at 4 Years | From randomization to four years | Time to distant failure is defined as time from randomization to date of the appearance of distant metastases, last known follow-up (censored), or death without distant failure (competing risk). Distant failure rates are estimated by the cumulative incidence method. |
| Second Primary Rate at 4 Years | From randomization to four years | Time to second primary is defined as time from randomization to date of the appearance of a second primary cancer, last known follow-up (censored), or death without second primary (competing risk). Second primary rates are estimated by the cumulative incidence method. |
| Disease-free Survival Rate at 4 Years | From randomization to four years | Disease-free survival time is defined as time from randomization to date of local-regional failure, the appearance of distant metastases, the appearance of a second primary failure, or date of death from any cause/ Disease-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact. |
| Number of Participants With Grade 3+ Treatment-related Adverse Events | From start of treatment to end of follow-up. Maximum follow-up is 5.2 years. | Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively | From start of treatment to surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation. If no surgery, then <= 90 days from start of treatment. | Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively | From post-surgery to before chemotherapy (CT), or within 60 days of surgery if no postoperative CT. Approximately 10-16 weeks to 14-22 weeks from randomization based on CT starting 4-6 weeks after surgery. | Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Tumor Marker Evaluation Using Preoperative Tissue Biopsy Specimens and Surgically Resected Tissue Specimens | End of study | — |
| Survival Rate at 4 Years | From randomization to four years | Survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method. |
| Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Post-operative Chemotherapy | Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy | Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A positive number indicates improvement in QOL. |
| Change From Baseline in QLQ-C30 Global Health Status Score at Two Years | Baseline and two years | Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A negative number indicates improvement in symptoms. |
| Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Chemoradiation | Baseline and completion of chemoradiation approximately 6-8 weeks from randomization | The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. |
| Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Post-operative Chemotherapy | Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy | The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. |
| Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Two Years | Baseline and two years | The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. |
| Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Completion of Chemoradiation | Baseline and completion of chemoradiation, approximately 6-8 weeks from randomization | The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. |
| Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Post-operative Chemotherapy | Baseline and completion of post-operative chemotherapy, approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy | The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. |
| Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Two Years | Baseline and two years | The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. |
| Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Chemoradiation | Baseline and completion of chemoradiation, approximately 6-8 weeks from randomization | Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A positive number indicates improvement in QOL. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neoadjuvant Chemoradiation With Irinotecan Patients receive neoadjuvant therapy comprising radiotherapy, 1200mg/m2/day oral capecitabine and irinotecan. Surgery 4-8 weeks after RT. Postoperative chemotherapy (folinic acid, fluorouracil, and oxaliplatin) 4-6 weeks after surgery. | 52 |
| Neoadjuvant Chemoradiation With Oxaliplatin Patients receive neoadjuvant therapy comprising radiotherapy, 1650mg/m2/day oral capecitabine and oxaliplatin. Surgery 4-8 weeks after RT. Postoperative chemotherapy (folinic acid, fluorouracil, and oxaliplatin) 4-6 weeks after surgery. | 52 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Accrued prior to chemotherapy amendment | 18 | 17 |
| Overall Study | Ineligible / no protocol treatment | 3 | 4 |
Baseline characteristics
| Characteristic | Neoadjuvant Chemoradiation With Irinotecan | Neoadjuvant Chemoradiation With Oxaliplatin | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 56 years | 57 years |
| Sex: Female, Male Female | 19 Participants | 14 Participants | 33 Participants |
| Sex: Female, Male Male | 33 Participants | 38 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 70 / 70 | 67 / 68 |
| serious Total, serious adverse events | 37 / 70 | 36 / 68 |
Outcome results
Primary
Pathologic Complete Response Rate
A pathologic complete response (pCR) was defined as no evidence of residual cancer histologically; disease progression or death before surgery was considered less than pCR (even without surgical specimen). All cases were reviewed by the study's surgical oncology co-chair for the determination of pCR. Each arm was first analyzed alone. If the arm had 9 or more pCRs in 48 evaluable pts, then the null hypothesis (H0) of 10% pCR rate would be rejected in favor of the alternative hypothesis of 25%, providing 90% power with a two-sided 10% type I error rate. If both arms reject H0, then statistical selection theory would be used to choose the arm for further study in a phase III trial. If only one arm has acceptable pCR rate, then that arm would be pursued in a phase III trial.
Time frame: After protocol surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation
Population: For each arm the first 48 eligible enrolled after the protocol amendment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Pathologic Complete Response Rate | 10.4 percentage of participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Pathologic Complete Response Rate | 20.8 percentage of participants |
Secondary
Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Completion of Chemoradiation
The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms.
Time frame: Baseline and completion of chemoradiation, approximately 6-8 weeks from randomization
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C38 defecation score at baseline and completion of chemoradiation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Completion of Chemoradiation | 4.8 score on a scale | Standard Deviation 21.6 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Completion of Chemoradiation | 8.8 score on a scale | Standard Deviation 21.8 |
Secondary
Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Post-operative Chemotherapy
The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms.
Time frame: Baseline and completion of post-operative chemotherapy, approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C38 defecation score at baseline and completion of chemoradiation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Post-operative Chemotherapy | -1.6 score on a scale | Standard Deviation 16.2 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Post-operative Chemotherapy | 14.6 score on a scale | Standard Deviation 16.6 |
Secondary
Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Two Years
The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms.
Time frame: Baseline and two years
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C38 defecation score at baseline and two years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Two Years | 0.4 score on a scale | Standard Deviation 20.5 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Two Years | -1.6 score on a scale | Standard Deviation 12.9 |
Secondary
Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Chemoradiation
The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms.
Time frame: Baseline and completion of chemoradiation approximately 6-8 weeks from randomization
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C38 GI score at baseline and completion of chemoradiation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Chemoradiation | 5.9 score on a scale | Standard Deviation 22.3 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Chemoradiation | 20.3 score on a scale | Standard Deviation 22.1 |
Secondary
Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Post-operative Chemotherapy
The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms.
Time frame: Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C38 GI score at baseline and completion of post-operative chemotherapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Post-operative Chemotherapy | -1.5 score on a scale | Standard Deviation 12.7 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Post-operative Chemotherapy | 3.9 score on a scale | Standard Deviation 15.4 |
Secondary
Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Two Years
The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms.
Time frame: Baseline and two years
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C38 GI score at baseline and completion of post-operative chemotherapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Two Years | 0.4 score on a scale | Standard Deviation 20.3 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Two Years | 6.7 score on a scale | Standard Deviation 12.7 |
Secondary
Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Chemoradiation
Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A positive number indicates improvement in QOL.
Time frame: Baseline and completion of chemoradiation, approximately 6-8 weeks from randomization
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C30 Global Health Status score at baseline and completion of chemoradiation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Chemoradiation | -10.3 score on a scale | Standard Deviation 23.7 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Chemoradiation | -12.2 score on a scale | Standard Deviation 23.5 |
Secondary
Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Post-operative Chemotherapy
Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A positive number indicates improvement in QOL.
Time frame: Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C30 Global Health Status score at baseline and completion of post-operative chemotherapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Post-operative Chemotherapy | -12.5 score on a scale | Standard Deviation 26.7 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Post-operative Chemotherapy | -7.1 score on a scale | Standard Deviation 15 |
Secondary
Change From Baseline in QLQ-C30 Global Health Status Score at Two Years
Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A negative number indicates improvement in symptoms.
Time frame: Baseline and two years
Population: Eligible patients enrolled after the protocol amendment who have QLQ-C30 Global Health Status score at baseline and two years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Change From Baseline in QLQ-C30 Global Health Status Score at Two Years | -6.8 score on a scale | Standard Deviation 28.3 |
| Neoadjuvant Chemoradiation With Oxaliplatin | Change From Baseline in QLQ-C30 Global Health Status Score at Two Years | -1.3 score on a scale | Standard Deviation 14.4 |
Secondary
Disease-free Survival Rate at 4 Years
Disease-free survival time is defined as time from randomization to date of local-regional failure, the appearance of distant metastases, the appearance of a second primary failure, or date of death from any cause/ Disease-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact.
Time frame: From randomization to four years
Population: Eligible patients enrolled after the protocol amendment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Disease-free Survival Rate at 4 Years | 68 percentage of participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Disease-free Survival Rate at 4 Years | 62 percentage of participants |
Secondary
Distant Failure Rate at 4 Years
Time to distant failure is defined as time from randomization to date of the appearance of distant metastases, last known follow-up (censored), or death without distant failure (competing risk). Distant failure rates are estimated by the cumulative incidence method.
Time frame: From randomization to four years
Population: Eligible patients enrolled after the protocol amendment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Distant Failure Rate at 4 Years | 24 percentage of participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Distant Failure Rate at 4 Years | 30 percentage of participants |
Secondary
Local-regional Failure Rate at 4 Years
Local-regional failure is defined as any of the following: no clinical complete response (cCR) in the primary site and/or nodes at any time after treatment completion (persistence), recurrence and/or progression in the primary site and/or nodes after cCR, and nonprotocol surgery to the primary site after cCR. Time to local-regional failure is defined as time from randomization to date of failure, last known follow-up (censored), or death without local-regional failure (competing risk). Local-regional failure rates are estimated by the cumulative incidence method.
Time frame: From randomization to four years
Population: Eligible patients enrolled after the protocol amendment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Local-regional Failure Rate at 4 Years | 16 percentage of participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Local-regional Failure Rate at 4 Years | 18 percentage of participants |
Secondary
Number of Participants With Grade 3+ Treatment-related Adverse Events
Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From start of treatment to end of follow-up. Maximum follow-up is 5.2 years.
Population: Eligible patients enrolled after the protocol amendment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events | Hematologic | 20 Participants |
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events | Non-Hematologic | 32 Participants |
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events | Overall | 38 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events | Overall | 36 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events | Hematologic | 19 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events | Non-Hematologic | 29 Participants |
Secondary
Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively
Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From post-surgery to before chemotherapy (CT), or within 60 days of surgery if no postoperative CT. Approximately 10-16 weeks to 14-22 weeks from randomization based on CT starting 4-6 weeks after surgery.
Population: Eligible patients enrolled after the protocol amendment who had surgery
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively | Overall | 9 Participants |
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively | Hematologic | 1 Participants |
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively | Non-Hematologic | 9 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively | Overall | 10 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively | Hematologic | 3 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively | Non-Hematologic | 9 Participants |
Secondary
Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively
Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From start of treatment to surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation. If no surgery, then <= 90 days from start of treatment.
Population: Eligible patients enrolled after the protocol amendment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively | Overall | 14 Participants |
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively | Hematologic | 5 Participants |
| Neoadjuvant Chemoradiation With Irinotecan | Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively | Non-Hematologic | 11 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively | Hematologic | 2 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively | Non-Hematologic | 14 Participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively | Overall | 14 Participants |
Secondary
Second Primary Rate at 4 Years
Time to second primary is defined as time from randomization to date of the appearance of a second primary cancer, last known follow-up (censored), or death without second primary (competing risk). Second primary rates are estimated by the cumulative incidence method.
Time frame: From randomization to four years
Population: Eligible patients enrolled after the protocol amendment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Second Primary Rate at 4 Years | 2 percentage of participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Second Primary Rate at 4 Years | 6 percentage of participants |
Secondary
Survival Rate at 4 Years
Survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method.
Time frame: From randomization to four years
Population: Eligible patients enrolled after the protocol amendment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant Chemoradiation With Irinotecan | Survival Rate at 4 Years | 85 percentage of participants |
| Neoadjuvant Chemoradiation With Oxaliplatin | Survival Rate at 4 Years | 75 percentage of participants |
Secondary
Tumor Marker Evaluation Using Preoperative Tissue Biopsy Specimens and Surgically Resected Tissue Specimens
Time frame: End of study
Population: The data required for this analysis was not obtained and will not be obtained.