Neoplasms

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Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

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Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Oxaliplatin

Leucovorin

Fluorouracil

Capecitabine

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. Patient observation with follow up evaluations and event monitoring will occur up to 8 years post randomization.

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. Patient observation with follow up evaluations and event monitoring will occur up to 8 years post randomization.

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.

FOLFOX (chemotherapy)

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.

5 FUCMT (chemoradiation)

low anterior resection with total mesorectal excision

surgery

magnetic resonance imaging or endorectal ultrasound

Deborah Schrag, MD

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.

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.

PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery

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)

Number of Participants with Pelvic R0 Resection

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.

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.

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.

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 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.

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.

National Cancer Institute (NCI)

Canadian Cancer Trials Group

Alliance for Clinical Trials in Oncology

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.

Group 1

surgery: low anterior resection with total mesorectal excision

Group 2

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.

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

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

Switzerland

United States

Country of residence

Body-mass index

History of diabetes

History of cardiovascular disease

Less than high school

High school diploma or GED certificate

Some college

College degree or higher

Highest education level

0 or 1

ECOG = 0: Fully active, able to carry on all pre-disease performance without restriction. \> ECOG = 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. \> ECOG = 2: Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours. \> ECOG = 0 is better. ECOG = 2 is worse.

ECOG performance-status score

Rectal tumor not palpable

Rectal tumor palpable

Primary rectal tumor on digital examination

Rectal tumor location

≤5 cm from anal verge

>5 to ≤10 cm from anal verge

>10 cm from anal verge

T2 node positive

T3 node negative

T3 node positive

T1 is if the maximum pre-biopsy diameter was ≤ 2 cm and had at most one of the following high-risk features: poorly differentiated histology, location on the mucosal (non-hair bearing) lip or ear, presence of perineural invasion, or depth of invasion to Clark's level ≥ IV or \> 2 mm.T2 is if \> 2 cm in maximum pre-biopsy diameter or had ≥ 2 of the 7th edition AJCC high-risk features. T3 is if invaded the one or more of the facial bones (including the maxilla, mandible, orbit, or temporal bones.

Clinical stage

Staging performed with MRI

Dr.Deborah Schrag

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.

* 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.

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. Patient observation with follow up evaluations and event monitoring will occur up to 8 years post randomization.

\>

\> 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

Pelvic R0 Resection Rate

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

Pathologic Complete Response

Overall Survival

Rates of Receiving Pre- or Post-operative 5FUCMT

Local Recurrence (TLR):

Low (< 8)

Intermediate (8-16)

High (> 16)

Neoadjuvant Rectal Score

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.

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. Patient observation with follow up evaluations and event monitoring will occur up to 8 years post randomization.\>

\> 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

Spots Global Cancer Trial Database for magnetic resonance imaging or endorectal ultrasound