Colorectal Cancer
Conditions
Keywords
stage IIA rectal cancer, stage IIIA rectal cancer, stage IIIB rectal cancer
Brief summary
The standard treatment for locally advanced rectal cancer involves chemotherapy and radiation, known as 5FUCMT, (the chemotherapy drugs 5-fluorouracil/capecitabine and radiation therapy) prior to surgery. Although radiation therapy to the pelvis has been a standard and important part of treatment for rectal cancer and has been shown to decrease the risk of the cancer coming back in the same area in the pelvis, some patients experience undesirable side effects from the radiation and there have been important advances in chemotherapy, surgery, and radiation which may be of benefit. The purpose of this study is to compare the effects, both good and bad, of the standard treatment of chemotherapy and radiation to chemotherapy using a combination regimen known as FOLFOX, (the drugs 5-fluorouracil (5-FU), oxaliplatin and leucovorin) and selective use of the standard treatment, depending on response to the FOLFOX. The drugs in the FOLFOX regimen are all FDA (Food and Drug Administration) approved and have been used routinely to treat patients with advanced colorectal cancer.
Detailed description
OUTLINE: This is a multicenter, phase II/III study. Patients are stratified according to ECOG performance status (0 or 1 vs 2) and randomized to 1 of 2 treatment regimens. Patients will receive full supportive care while on this study. OBJECTIVES: Primary 1. Phase II component: To assure that neoadjuvant FOLFOX followed by selective use of 5FUCMT group (Group 1) maintains the current high rate of pelvic R0 resection and is consistent with non-inferiority for time to local recurrence (TLR). 2. Phase III component: To compare neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) to standard 5FUCMT (Group 2) with respect to the primary endpoint of the Disease-Free Survival (DFS). Secondary 1. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard group 5FUCMT (Group 2) with respect to the proportion of patients who achieve a pathologic complete response (pCR) at the time of surgical resection. 2. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard 5FUCMT (Group 2) with respect to overall survival. 3. To evaluate and compare the adverse event profile and surgery complications between two groups. 4. To estimate the proportion of patients in the selective group (Group 1) who receive: 1) pre-operative 5FUCMT; 2) post-operative 5FUCMT; 3) either pre- or post-operative 5FUCMT. 5. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard 5FUCMT (Group 2) with respect to Local Recurrence (TLR) 6. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard 5FUCMT (Group 2) with respect to Neoadjuvant Response Score (NAR) Event monitoring of patients will continue up to 8 years post randomization.
Interventions
DRUGFOLFOX (chemotherapy)
Oxaliplatin 85 mg/m\^2 IV over 2 hours on day 1, leucovorin 400 mg/m\^2 bolus IV over 2 hours on day 1 and 5-fluorouracil 400 mg/m\^2 bolus over 5-15 minutes then 2400 mg/m\^2 continual over 46-48 hours total dose IV on days 1-2. The treatment schedule repeats based on the group. Dose modifications are allowed based on adverse events.
OTHER5 FUCMT (chemoradiation)
5-fluorouracil 225 mg/m\^2 per day continuous IV infusion administered concurrently with radiation therapy for 5 or 7 days per week OR capecitabine 825 mg/m\^2 twice daily administered orally and concurrently with radiation therapy for 5 days per week. Dose modifications are allowed based on adverse events.
PROCEDUREsurgery
low anterior resection with total mesorectal excision
PROCEDUREmagnetic resonance imaging or endorectal ultrasound
Sponsors
National Cancer Institute (NCI)
Canadian Cancer Trials Group
Alliance for Clinical Trials in Oncology
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
Registration Inclusion Criteria: 1. Age ≥ 18 years at diagnosis 2. Diagnosis of rectal adenocarcinoma 3. Radiologically measurable or clinically evaluable disease as defined in the protocol 4. ECOG Performance Status (PS): 0, 1 or 2 5. For this patient, the standard treatment recommendation in the absence of a clinical trial would be combined modality neoadjuvant chemoradiation followed by curative intent surgical resection 6. Candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy according to the primary surgeon 7. Primary surgeon is credentialed or is willing to be credentialed in Total Mesorectal Excision (TME), which entails submission of photos of a single TME specimen either before enrolling the first patient or by using the surgeon's 1st accrued case. 8. Clinical Stage: T2N1, T3N0, T3N1. * N2 disease is to be estimated as four or more lymph nodes that are ≥ 10 mm. * Clinical staging should be estimated based on the combination of the following assessments: physical exam by the primary surgeon, CT or PET/CT scan of the chest/abdomen/pelvis and either a pelvic MRI or an ultrasound (ERUS). If a pelvic MRI is peformed, it is acceptable to perform CT of the chest/abdomen, ommitting CT imaging of the pelvis. 9. The following laboratory values obtained ≤ 28 days prior to registration: * Absolute neutrophil count (ANC) ≥ 1500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin \> 8.0 g/dL * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) * SGOT (AST) ≤ 3 x ULN * SGPT (ALT) ≤ 3 x ULN * Creatinine ≤1.5 x ULN 10. Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only 11. Patient of child-bearing potential is willing to employ adequate contraception 12. Provide informed written consent 13. Willing to return to enrolling medical site for all study assessments Registration
Exclusion criteria
1. Clinical T4 tumors 2. Primary surgeon indicates need for abdominoperineal (APR) at baseline 3. Evidence that the tumor is adherent to or invading the mesorectal fascia on imaging studies such that the surgeon would not be able to perform an R0 resection (one with negative margins) 4. Tumor is causing symptomatic bowel obstruction (patients who have had a temporary diverting ostomy are eligible). 5. Chemotherapy within 5 years prior to registration. Hormonal therapy is allowable if the disease free interval is ≥ 5 years. 6. Any prior pelvic radiation 7. Other invasive malignancy ≤ 5 years prior to registration. Exceptions are colonic polyps, non-melanoma skin cancer, ductal carcinoma in situ, bladder carcinoma in situ, or carcinoma-in-situ of the cervix. 8. Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. * Pregnant women * Nursing women * Men or women of childbearing potential who are unwilling to employ adequate contraception 9. Co-morbid illnesses or other concurrent disease which, in the judgment of the clinician obtaining informed consent, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pelvic R0 Resection Rate | Up to 5 years | Number of Participants with Pelvic R0 Resection |
| DFS | Up to 5 years | Disease-free Survival (DFS): The distribution of DFS by group will be estimated using the method of Kaplan-Meier. 5 year disease free rates by treatment group with confidence intervals based on Kaplan-Meier curves will be reported. Log-rank test will be used to compare DFS between two treatment groups. Hazard ratio with confidence interval will be estimated based on Cox proportional hazard model. The Cox proportional hazard model will be used for multivariate analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rates of Receiving Pre- or Post-operative 5FUCMT | Up to 5 years | Rates of Receiving 5FUCMT: For selective group patients, the proportion of patients who received 1) pre-operative 5FUCMT, 2) post-operative 5FUCMT, 3) either pre or post-operative 5FUCMT, and confidence intervals (according to approach of Duffy and Santner) will be reported. |
| Pathologic Complete Response | Up to 8 years | Pathologic Complete Response (pCR): The pCR rate is defined as number of patients who achieve pCR divided by total number of patients included in the analysis population (see definition in Section 16.3.3.1) in each group. Patients who didn't undergo surgery will be classified as non-pCR. Point estimate and confidence interval (according to approach of Duffy and Santner) will be calculated by treatment groups. Chi-square test will be used to compare the pCR rates between groups. |
| Neoadjuvant Rectal Score | Up to 5 years | neoadjuvant rectal (NAR) score =\[5 \* pN - 3(cT - pT) + 12\]\^2/9.61. cT is an element of the set {1, 2, 3, 4}, pT is in {0, 1, 2, 3, 4}, and pN is in {0, 1, 2}. cT clinical tumor stage, pT pathologic tumor stage, pN pathologic nodal stage. Low (NAR \<8), intermediate (NAR = 8-16), and high (NAR \>16). Low is better and high is worse. |
| Local Recurrence (TLR): | Up to 5 years | Time to Local Recurrence (TLR): The distribution of TLR by group will be estimated using the method of Kaplan-Meier. 5 year local recurrence free rates by treatment group with confidence intervals based on Kaplan-Meier curves will be reported. The comparison of the cumulative incidence of local recurrence between groups, treating distant recurrence and death as competing risks using the test of Gray (Annals of Statistics, 1988) will be conducted. |
| Overall Survival | Up to 5 years | Overall Survival (OS): OS is defined as time from randomization to the date of death due to all causes. The distribution of OS by group will be estimated using the method of Kaplan-Meier. Five year survival rates by treatment group with confidence intervals based on Kaplan-Meier curves will be reported. Logrank test will be used to compare OS between two treatment groups. Hazard ratio with confidence interval will be estimated based on Cox proportional hazard model. The Cox proportional hazard model will be used for multivariate analysis. |
Countries
Canada, Israel, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Patients will receive FOLFOX chemotherapy once every two weeks for 6 cycles total over a period of 12 weeks. After completing FOLFOX chemotherapy, the patient will have an MRI scan or endorectal ultrasound (ERUS) to examine the tumor. If the tumor has not decreased in size by at least 20%, the patient will receive 5FUCMT (radiation with chemotherapy). If the tumor has decreased in size by 20%, then the patient will proceed directly to surgery. \>
\> If all borders of the tumor are normal post surgery, then the patient receives six additional cycles of FOLFOX chemotherapy. If all borders of the tumor are not normal then the patient receives chemoradiation therapy for 5.5 weeks after surgery. After chemoradiation, additional cycles of FOLFOX or similar chemotherapy will be recommended for 4 cycles or 8 weeks. \>
\> FOLFOX (chemotherapy): Oxaliplatin 85 mg/m\^2 IV over 2 hours on day 1, leucovorin 400 mg/m\^2 bolus IV over 2 hours on day 1 and 5-fluorouracil 400 mg/m\^2 bolus over 5-15 minutes then 2400 mg/m\^2 continual over 46-48 hours total dose IV on days 1-2. The treatment schedule repeats based on the group. \>
\> 5 FUCMT (chemoradiation): 5-fluorouracil 225 mg/m\^2 per day continuous IV infusion administered concurrently with radiation therapy for 5 or 7 days per week OR capecitabine 825 mg/m\^2 twice daily administered orally and concurrently with radiation therapy for 5 days per week. | 585 |
| Group 2 Patients receive 5FUCMT including chemotherapy and radiation therapy for 5.5 weeks. Patients will be given either 5-fluorouracil or capecitabine and radiation therapy. After the chemoradiation therapy is completed, patients will proceed directly to surgery. Post-surgery, patients will receive FOLFOX chemotherapy once every two weeks for 8 cycles total over a period of 16 weeks. \>
\> FOLFOX (chemotherapy): Oxaliplatin 85 mg/m\^2 IV over 2 hours on day 1, leucovorin 400 mg/m\^2 bolus IV over 2 hours on day 1 and 5-fluorouracil 400 mg/m\^2 bolus over 5-15 minutes then 2400 mg/m\^2 continual over 46-48 hours total dose IV on days 1-2. The treatment schedule repeats based on the group. Dose modifications are allowed based on adverse events.\>
\> 5 FUCMT (chemoradiation): 5-fluorouracil 225 mg/m\^2 per day continuous IV infusion administered concurrently with radiation therapy for 5 or 7 days per week OR capecitabine 825 mg/m\^2 twice daily administered orally and concurrently with radiation therapy for 5 days per week. Dose modifications are allowed based on adverse events.\>
\> surgery: low anterior resection with total mesorectal excision | 543 |
| Total | 1,128 |
Baseline characteristics
| Characteristic | Group 2 | Total | Group 1 |
|---|---|---|---|
| Age, Continuous | 57 years | 57 years | 57 years |
| Body-mass index | 28.1 kg/m^2 | 28.3 kg/m^2 | 28.4 kg/m^2 |
| Clinical stage T2 node positive | 38 Participants | 101 Participants | 63 Participants |
| Clinical stage T3 node negative | 198 Participants | 430 Participants | 232 Participants |
| Clinical stage T3 node positive | 307 Participants | 596 Participants | 289 Participants |
| Country of residence Canada | 45 Participants | 96 Participants | 51 Participants |
| Country of residence Switzerland | 9 Participants | 19 Participants | 10 Participants |
| Country of residence United States | 489 Participants | 1013 Participants | 524 Participants |
| ECOG performance-status score 0 or 1 | 540 Participants | 1122 Participants | 582 Participants |
| ECOG performance-status score 2 | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 48 Participants | 96 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 475 Participants | 991 Participants | 516 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 20 Participants | 41 Participants | 21 Participants |
| Highest education level College degree or higher | 199 Participants | 405 Participants | 206 Participants |
| Highest education level High school diploma or GED certificate | 201 Participants | 415 Participants | 214 Participants |
| Highest education level Less than high school | 29 Participants | 58 Participants | 29 Participants |
| Highest education level Some college | 102 Participants | 221 Participants | 119 Participants |
| History of cardiovascular disease No | 445 Participants | 924 Participants | 479 Participants |
| History of cardiovascular disease Yes | 98 Participants | 204 Participants | 106 Participants |
| History of diabetes No | 460 Participants | 964 Participants | 504 Participants |
| History of diabetes Yes | 83 Participants | 164 Participants | 81 Participants |
| Primary rectal tumor on digital examination Rectal tumor not palpable | 259 Participants | 549 Participants | 290 Participants |
| Primary rectal tumor on digital examination Rectal tumor palpable | 277 Participants | 567 Participants | 290 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 50 Participants | 31 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 49 Participants | 32 Participants |
| Race (NIH/OMB) More than one race | 40 Participants | 70 Participants | 30 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 467 Participants | 959 Participants | 492 Participants |
| Rectal tumor location >10 cm from anal verge | 109 Participants | 236 Participants | 127 Participants |
| Rectal tumor location ≤5 cm from anal verge | 89 Participants | 172 Participants | 83 Participants |
| Rectal tumor location >5 to ≤10 cm from anal verge | 344 Participants | 719 Participants | 375 Participants |
| Rectal tumor location | 8 cm | 8 cm | 8 cm |
| Sex: Female, Male Female | 173 Participants | 389 Participants | 216 Participants |
| Sex: Female, Male Male | 370 Participants | 739 Participants | 369 Participants |
| Staging performed with MRI No | 85 Participants | 176 Participants | 91 Participants |
| Staging performed with MRI Yes | 458 Participants | 952 Participants | 494 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 74 / 585 | 67 / 543 |
| other Total, other adverse events | 582 / 585 | 534 / 543 |
| serious Total, serious adverse events | 10 / 585 | 7 / 543 |
Outcome results
Primary
DFS
Disease-free Survival (DFS): The distribution of DFS by group will be estimated using the method of Kaplan-Meier. 5 year disease free rates by treatment group with confidence intervals based on Kaplan-Meier curves will be reported. Log-rank test will be used to compare DFS between two treatment groups. Hazard ratio with confidence interval will be estimated based on Cox proportional hazard model. The Cox proportional hazard model will be used for multivariate analysis.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | DFS | 114 Participants |
| Group 2 | DFS | 113 Participants |
p-value: 0.00590.2% CI: [0.74, 1.14]kaplan meier
Primary
Pelvic R0 Resection Rate
Number of Participants with Pelvic R0 Resection
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | Pelvic R0 Resection Rate | 529 Participants |
| Group 2 | Pelvic R0 Resection Rate | 495 Participants |
Secondary
Local Recurrence (TLR):
Time to Local Recurrence (TLR): The distribution of TLR by group will be estimated using the method of Kaplan-Meier. 5 year local recurrence free rates by treatment group with confidence intervals based on Kaplan-Meier curves will be reported. The comparison of the cumulative incidence of local recurrence between groups, treating distant recurrence and death as competing risks using the test of Gray (Annals of Statistics, 1988) will be conducted.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | Local Recurrence (TLR): | 9 Participants |
| Group 2 | Local Recurrence (TLR): | 7 Participants |
95% CI: [0.44, 3.16]
Secondary
Neoadjuvant Rectal Score
neoadjuvant rectal (NAR) score =\[5 \* pN - 3(cT - pT) + 12\]\^2/9.61. cT is an element of the set {1, 2, 3, 4}, pT is in {0, 1, 2, 3, 4}, and pN is in {0, 1, 2}. cT clinical tumor stage, pT pathologic tumor stage, pN pathologic nodal stage. Low (NAR \<8), intermediate (NAR = 8-16), and high (NAR \>16). Low is better and high is worse.
Time frame: Up to 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 | Neoadjuvant Rectal Score | Low (< 8) | 157 Participants |
| Group 1 | Neoadjuvant Rectal Score | Intermediate (8-16) | 247 Participants |
| Group 1 | Neoadjuvant Rectal Score | High (> 16) | 130 Participants |
| Group 2 | Neoadjuvant Rectal Score | Low (< 8) | 161 Participants |
| Group 2 | Neoadjuvant Rectal Score | Intermediate (8-16) | 230 Participants |
| Group 2 | Neoadjuvant Rectal Score | High (> 16) | 114 Participants |
Secondary
Overall Survival
Overall Survival (OS): OS is defined as time from randomization to the date of death due to all causes. The distribution of OS by group will be estimated using the method of Kaplan-Meier. Five year survival rates by treatment group with confidence intervals based on Kaplan-Meier curves will be reported. Logrank test will be used to compare OS between two treatment groups. Hazard ratio with confidence interval will be estimated based on Cox proportional hazard model. The Cox proportional hazard model will be used for multivariate analysis.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | Overall Survival | 74 Participants |
| Group 2 | Overall Survival | 67 Participants |
95% CI: [0.74, 1.44]
Secondary
Pathologic Complete Response
Pathologic Complete Response (pCR): The pCR rate is defined as number of patients who achieve pCR divided by total number of patients included in the analysis population (see definition in Section 16.3.3.1) in each group. Patients who didn't undergo surgery will be classified as non-pCR. Point estimate and confidence interval (according to approach of Duffy and Santner) will be calculated by treatment groups. Chi-square test will be used to compare the pCR rates between groups.
Time frame: Up to 8 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | Pathologic Complete Response | 117 Participants |
| Group 2 | Pathologic Complete Response | 124 Participants |
Secondary
Rates of Receiving Pre- or Post-operative 5FUCMT
Rates of Receiving 5FUCMT: For selective group patients, the proportion of patients who received 1) pre-operative 5FUCMT, 2) post-operative 5FUCMT, 3) either pre or post-operative 5FUCMT, and confidence intervals (according to approach of Duffy and Santner) will be reported.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | Rates of Receiving Pre- or Post-operative 5FUCMT | 61 Participants |
| Group 2 | Rates of Receiving Pre- or Post-operative 5FUCMT | 543 Participants |