Triplet Combination or Doublet Regimen Versus Chemoradiation as Neoadjuvant Therapy for Locally Advanced Rectal Cancer

A Prospectively Randomized Phase III Trial Comparing Short-term mFOLFOXIRI, Long-term mFOLFOX6 and Traditional Chemoradiation as Preoperative Neoadjuvant Therapy for Locally Advanced Rectal Cancer

Preoperative radiation with single agent chemotherapy as sensitizer is the standard care of locally advanced rectal cancer.

Local irradiation significantly increases surgical complications and impairs quality of life.

Combination chemotherapy alone seems promising and provides similar benefit to chemoradiation as neoadjuvant therapy.

Early administration of systemic therapy is also proved beneficial for long-term survival.

The purpose of this study is to compare the efficacy of chemotherapy alone with short-term modified FOLFOXIRI or long-term mFOLFOX with standard chemoradiation as neoadjuvant therapy for locally advanced rectal cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Rectal Cancer; Chemotherapy Effect
• Intervention / Treatment: Radiation: Chemoradiation; Drug: FOLFOXIRI Protocol; Drug: Folfox Protocol

Detailed Description

Patients with cT3-4 or cN+ and cM0 by pelvic MR and chest + abdominal CT scan will be randomized to the following three groups:

Group A: Traditional chemoradiation.

Fluorouracil 225 mg/m2/day continuous intravenous infusion on weekdays for five weeks; local irradiation 2GY/day on weekdays, totally 50GY.

At the end of chemoradiation, patients will receive an evaluation with MR and CT scan.

If the efficacy is defined as CR, PR or SD, the TME will be performed in 6-8 weeks since the last irradiation.

If the disease progress with the possibility of R0 resection, the operation will be given soon.

If the tumor progress to impossible for R0 resection, the salvage chemotherapy will be given accordingly.

Adjuvant chemotherapy of 6-8 cycles of mFOLFOX will be administered 3-4 weeks after R0 resection.

Group B: Short-term mFOLFOXIRI.

Oxaliplatin 85 mg/m2 on day 1; irinotecan 150 mg/m2 on day 1; leucovorin 400 mg/m2 on day 1; fluorouracil 2400 mg/m2 civ over 46h; treatment will be repeated every 14 days; prophylactic G-CSF support is recommended.

Patients are planned to receive 4 cycles of mFOLFOXIRI regimen preoperatively and postoperatively, respectively.

Before operation, efficacy evaluations will be performed every two cycles by CT and MR scan.

If the evaluation is defined as no progression without severe toxicity, the next 2 cycles will be given.

If the primary lesion progress without distant metastasis, patients will be assigned to group A.

If distant metastasis occurr during chemotherapy, patients will withdraw from the trial and be treated further at the discretion of attending physicians.

Postoperative chemotherapy will initiate 3-4 weeks after R0 resection.

Group C: Long-term mFOLFOX.

Oxaliplatin 85 mg/m2 on day 1; leucovorin 400 mg/m2 on day 1; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 civ over 46h; treatment will be repeated every 14 days.

Patients are planned to receive 8-9 cycles of mFOLFOX regimen preoperatively and 3-4 cycles postoperatively.

Efficacy evaluations will be performed every three cycles by CT and MR scan before TME.

If the evaluation is defined as no progression without severe toxicity, the next 3 cycles of mFOLFOX will be given with the maximum of 9 cyces.

If the primary lesion progress without distant metastasis, patients will be assigned to group A.

If distant metastasis occurr during chemotherapy, patients will withdraw from the trial and be treated further at the discretion of attending physicians.

Postoperative chemotherapy will initiate 3-4 weeks after R0 resection.

• Study Type: Interventional
• Enrollment (Anticipated): 933
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ping Lan, MD; Phone Number: 86-20-38285497; Email: lanping@mail.sysu.edu.cn
• Study Contact Backup: Name: Jian Xiao, MD; Phone Number: 86-20-38285497; Email: xiaoj26@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1）Age: 18 to 75 years old;
• 2）Histological diagnosis of rectal adenocarcinoma;
• 3）Distance form anal margin ≤ 12cm: cT3-4 or cN+ and cM0 by pelvic MR and chest + abdominal CT, estimated possible for R0 resection;
• 4）There is no signs of intestinal obstruction, or obstruction of intestinal after treating with proximal colostomy has been relieved;
• 5）Patients did not previously receive rectal surgery, chemotherapy or radiation therapy , biological treatment , except for endocrine therapy;
• 6）ECOG Performance Status :0-1
• 7）Life expectancy: more than 3 years;
• 8）sufficient bone marrow, liver and kidney function.

Exclusion Criteria:

• 1）Arrhythmia requires treatment with antiarrhythmia (except for beta-blockers or digoxin), symptomatic coronary artery disease, myocardial ischemia (myocardial infarction within the last 6 months) or congestive heart failure exceeding NYHA class II;
• 2）Severe hypertension with poor control;
• 3）History of HIV infection or active phase of chronic hepatitis B or C infection with high copy viral DNA;
• 4）Other active serious infections according to NCI-CTC version 4.0;
• 5）There is preoperative evidence for distant metastasis outside pelvis;
• 6）Cachexia and organ function decompensation
• 7）History of pelvic or abdominal radiotherapy;
• 8）Multiple primary cancer;
• 9）Patients with epilepcy requiring treatment ( steroids or antiepileptic treatment);
• 10）History of other malignant tumors within 5 years, except for cured cervical carcinoma in situ or skin basal cell carcinoma;
• 11）Drug abuse and medical, psychological or social conditions interfering patient participation in research or the evaluation of research results;
• 12）Any allergy to clinical research drugs or any drugs associated with this study;
• 13）Any unstable condition or condition that may endanger safety and compliance of patients;
• 14）Pregnancy or the lactating female without adequate contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 5-Fu + RT; 5Fu + RT for five weeks --- 6-8 weeks of interval --- TME --- mFOLFOX * 6-8	Radiation: Chemoradiation; Fluorouracil 225 mg/m2/day continuous intravenous infusion on weekdays for five weeks; local irradiation 2GY/day on weekdays, totally 50GY.
Experimental: mFOLFOXIRI; mFOLFOXIRI * 4 --- TME --- mFOLFOXIRI * 4	Drug: FOLFOXIRI Protocol; Oxaliplatin 85 mg/m2 on day 1; irinotecan 150 mg/m2 on day 1; leucovorin 400 mg/m2 on day 1; fluorouracil 2400 mg/m2 civ over 46h; treatment will be repeated every 14 days; prophylactic G-CSF support is recommended.
Experimental: mFOLFOX; mFOLFOX * 9 --- TME --- mFOLFOX * 3	Drug: Folfox Protocol; Oxaliplatin 85 mg/m2 on day 1; leucovorin 400 mg/m2 on day 1; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 civ over 46h; treatment will be repeated every 14 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free survival	The interval from randomization to local recurrence, distant metastasis, death or the last follow-up.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence-free survival	The interval from randomization to local recurrence, death or the last follow-up.	3 years
Metastasis-free survival	The interval from randomization to distant metastasis, death or the last follow-up.	3 years
Surgical complication	Surgical complication including anastomotic leakage, anastomotic stricture, intestinal obstruction, postoperative pelvic bleeding and poor wound healing.	3 years
Treatment related quality of life	EORTC QOL questionaire	up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor regression grade after neoadjuvant therapy	According to pathological slides	3 months

Collaborators and Investigators

• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University
• Investigators: Principal Investigator: Ping Lan, MD, Sixth Affiliated Hospital, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2019
• Primary Completion (Anticipated): July 1, 2024
• Study Completion (Anticipated): July 1, 2029

Study Registration Dates

• First Submitted: May 22, 2019
• First Submitted That Met QC Criteria: June 2, 2019
• First Posted (Actual): June 5, 2019

Study Record Updates

• Last Update Posted (Actual): June 5, 2019
• Last Update Submitted That Met QC Criteria: June 2, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: SAHMO201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No