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.
Brief Title
PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery
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.
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.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Colorectal Cancer
Eligibility 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.
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.
Inclusion Criteria
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
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
Gender
All
Gender Based
false
Keywords
stage IIA rectal cancer
stage IIIA rectal cancer
stage IIIB rectal cancer
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT01515787
Org Class
Other
Org Full Name
Alliance for Clinical Trials in Oncology
Org Study Id
N1048
Overall Status
Active, not recruiting
Phases
Phase 2
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase II/III Trial of Neoadjuvant FOLFOX With Selective Use of Combined Modality Chemoradiation Versus Preoperative Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection With Total Mesorectal Excision (PROSPECT)
Primary Outcomes
Outcome Description
Number of Participants with Pelvic R0 Resection
Outcome Measure
Pelvic R0 Resection Rate
Outcome Time Frame
Up to 5 years
Outcome Description
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.
Outcome Measure
DFS
Outcome Time Frame
Up to 5 years
Secondary Ids
Secondary Id
CDR0000715321
Secondary Id
NCI-2012-00234
Secondary Id
U10CA031946
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Up to 8 years
Outcome Measure
Pathologic Complete Response
Outcome Description
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.
Outcome Time Frame
Up to 5 years
Outcome Measure
Overall Survival
Outcome Description
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.
Outcome Time Frame
Up to 5 years
Outcome Measure
Rates of Receiving Pre- or Post-operative 5FUCMT
Outcome Description
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.
Outcome Time Frame
Up to 5 years
Outcome Measure
Local Recurrence (TLR):
Outcome Description
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.
Outcome Time Frame
Up to 5 years
Outcome Measure
Neoadjuvant Rectal Score
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Rebecca Levine
Investigator Email
relevine@montefiore.org
Investigator Phone
718-405-8236