Neo-adjuvant Chemoradiation With Oxaliplatin/5-FU in Rectal Cancer

• ClinicalTrials.gov Identifier: NCT00831181
• Recruitment Status: Completed
• First Posted: January 28, 2009
• Results First Posted: March 20, 2018
• Last Update Posted: March 20, 2018
• Sponsor: Beth Israel Medical Center
• Information provided by (Responsible Party): Beth Israel Medical Center

Study Description

Brief Summary:

RATIONALE: 5FU based neoadjuvant chemoradiation (nCRT) is the standard of care for Stage II/III rectal cancer. Pathologic complete response (pCR) and downstaging have been associated with improved outcomes. The addition of oxaliplatin (OXA) to neoadjuvant therapy may reduce distant disease recurrence. Adjuvant treatment with OXA for rectal cancer has been motivated by benefits demonstrated in stage III colon cancer.

Objective: To determine the feasibility, toxicity, and efficacy of preoperative OXA/5FU and RT followed by total mesorectal excision (TME) and adjuvant

PURPOSE: This phase II trial is studying the side effects and how well giving neo-adjuvant combination chemotherapy with radiation works in treating patients undergoing surgery for rectal cancer.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer	Drug: 5-FU; Drug: Oxaliplatin; Drug: leucovorin; Procedure: mesorectal excision	Phase 2

Detailed Description:

OBJECTIVES:

Primary

• To assess the complete pathologic response rate in patients with rectal cancer treated with radiation, modified neoadjuvant FOLFOX 6 chemotherapy followed by total mesorectal excision and adjuvant modified FOLFOX 6 chemotherapy.

Secondary

• To observe the overall pathologic response rate in these patients.
• To correlate pathologic staging with preoperative ultrasound and pelvic MRI staging.
• To assess toxic side effects of these regimens in these patients.
• To assess patterns of disease relapse, disease-free survival outcomes, and overall survival outcomes of these patients.

OUTLINE:

Patients with stage II/III rectal cancer were treated with OXA 60mg/m2 weekly continuous infusion 5FU of 225 mg/m2/d d1-5 with pelvic RT of 1.8Gy/d for 28 doses. Adjuvant therapy consisted of 6 cycles of biweekly FOLFOX6.

Surgery: Patients undergo total mesorectal excision by anterior resection or an abdominal perineal resection within 4 weeks after completion of neoadjuvant therapy.

Adjuvant therapy: Within 4 weeks after surgery, patients receive modified FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium IV over 2 hours on day 1 and continuous fluorouracil IV over 46 hours on days 1-2. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients complete quality of life assessment questionnaires at baseline and at each follow-up visit.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and annually thereafter.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Open-labeled, Prospective Study to Determine the Efficacy of Preoperative Chemoradiation With Oxaliplatin/5-FU in Locally Advanced Rectal Cancer Followed by Total Mesorectal Excision and FOLFOX6
• Study Start Date: July 2004
• Actual Primary Completion Date: November 2009
• Actual Study Completion Date: November 2009

Arms and Interventions

Arm

Intervention/treatment

Experimental: Preoperative Chemoradiation; Preoperative Chemoradiation with oxaliplatin/5-FU followed by mesorectal excision and 5-FU / leucovorin (FOLFOX 6)

Drug: 5-FU; 5-FU: continuous infusion via portable pump during all RT (approximately 33 days); Other Name: fluorouracil; Drug: Oxaliplatin; Oxaliplatin: 50mg/m2 weekly dosing during RT (Day 1); Other Name: Eloxatin; Drug: leucovorin; Folinic Acid (Leucovorin): 400 mg/m2; 2-hour IV infusion simultaneously with oxaliplatin; Other Name: Folinic Acid; Procedure: mesorectal excision; mesorectal excision

Outcome Measures

Primary Outcome Measures :

1. Pathologic Response and Complete Response [ Time Frame: Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, an average of 3.5 months ]

   Pathologic Response and Complete Response to preoperative therapy will be determined at the time of surgical resection. All grossly visible areas of ulceration and/or induration with be measured and submitted for histological evaluation.

   The unit of measure is the tumor response rate to preoperative chemoradiation.

   Pathologic complete response (pCR) is defined as no evidence of invasive tumor cells on pathologic examination of the primary rectal cancer.

   Tumor regression grade (TRG) will be quantitated into five grades:

   TRG 1 (complete regression) -absence of residual cancer and fibrosis extending from the site of original tumor through the layers of the rectal wall.

   TRG 2 characterized by the presence of rare residual cancer cells scattered through the fibrosis.

   TRG 3 characterized by an increase in the number of residual cancer cells, but fibrosis still predominant.

   TRG 4 -residual cancer outgrowing fibrosis. TRG 5 characterized by absence of regressive changes.

Secondary Outcome Measures :

1. Treatment Toxicity [ Time Frame: Weekly during chemoradiation treatment (3 months). Bi-weekly during adjuvant FOLFOX therapy (3.5 months). ]
   Toxicity was assessed weekly during neoadjuvant chemotherapy and radiation therapy, bi-weekly during adjuvant FOLFOX therapy.
2. Complete Resectability Rates [ Time Frame: Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, 3 months after beginning of chemoradiation treatment. ]
   Complete resectability rates assessed by circumferential margin.
3. Local Regional Control [ Time Frame: median follow-up 22 months post-TME ]
   subjects were followed for median of 22 months post-surgery
4. Disease-free Survival [ Time Frame: median 22 months follow-up ]
5. Overall Survival [ Time Frame: median follow-up 22 months ]
6. Patterns of Disease Failure, Including Local Recurrence and Distant Metastasis Assessed by CT Scan [ Time Frame: median follow-up 22 months ]
7. Number of Participants With Comparison of Preoperative Stage With Post-treatment Pathologic Stage [ Time Frame: Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, 3 months after beginning of chemoradiation treatment. ]
   Thin-section high resolution pelvic MRI was used to image the tumor prior to chemoradiation and repeated prior to surgery, and then compared to post-treatment pathological stage.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

• Histologically proven adenocarcinoma of the rectum with no distant metastases.
• T3-4N0M0, TanyN1-3M0 assessed by clinical exam, TRUS, MRI and CT
• The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 centimeters of the anal verge by protoscopic examination.
• No prior chemotherapy or pelvic irradiation.
• ECOG performance status 0-1
• Age 18 to 70 years
• ANC >= 1500/mm3 and platelets >= 100,000/mm3
• Serum creatinine <= 1.5 x ULN; bilirubin <= 1.5 x ULN; ALT<= 2.5 x ULN

Exclusion Criteria

• Pregnant or lactating females; patients not practicing active contraception while sexually active.
• No other serious medical condition
• A psychiatric disorder that would prohibit the subject from participating fully.
• Peripheral neuropathy > grade 1
• History within the past 5 years of a cancer diagnosis except for non-melanomatous skin cancers or in situ cervix carcinoma.
• HIV positive patients

Contacts and Locations

Locations

United States, New York

Beth Israel Medical Center - Philipps Ambulatory Care Center

New York, New York, United States, 10003

St. Luke's-Roosevelt Hospital Center - Roosevelt Division

New York, New York, United States, 10019

Sponsors and Collaborators

Beth Israel Medical Center

Investigators

• Principal Investigator: Peter Kozuch, MD; Beth Israel Medical Center

More Information

• Responsible Party: Beth Israel Medical Center
• ClinicalTrials.gov Identifier: NCT00831181
• Other Study ID Numbers: CDR0000633360; BIMCP-OX-08-006 ( Registry Identifier: BIMCP-OX-08-006 ); AVENTIS-BIMCP-OX-08-006 ( Other Grant/Funding Number: AVENTIS-BIMCP-OX-08-006 )
• First Posted: January 28, 2009
• Results First Posted: March 20, 2018
• Last Update Posted: March 20, 2018
• Last Verified: February 2018

Keywords provided by Beth Israel Medical Center:

stage II rectal cancer; stage III rectal cancer; adenocarcinoma of the rectum

Additional relevant MeSH terms:

Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Leucovorin; Fluorouracil; Oxaliplatin; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antidotes; Protective Agents; Vitamin B Complex; Vitamins; Micronutrients