Systemic Chemotherapy With or Without Intraperitoneal Chemohyperthermia in Treating Patients Undergoing Surgery for Peritoneal Carcinomatosis From Colorectal Cancer

Phase III Study Evaluating the Use of Systemic Chemotherapy and Chemohyperthemia Intraperitoneal Preoperatively (CHIP) and After Maximum Resection of Peritoneal Carcinomatosis Originating With Colorectal Cancer

RATIONALE: Drugs used in chemotherapy, such as leucovorin, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether systemic chemotherapy is more effective with or without intraperitoneal chemohyperthermia in treating patients with peritoneal carcinomatosis from colorectal cancer.

PURPOSE: This randomized phase III trial is studying systemic chemotherapy to see how well it works compared with or without intraperitoneal chemohyperthermia in treating patients undergoing surgery for peritoneal carcinomatosis from colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Primary Peritoneal Cavity Cancer
• Intervention / Treatment: Drug: leucovorin calcium; Drug: fluorouracil; Drug: oxaliplatin; Procedure: hyperthermia treatment

Detailed Description

OBJECTIVES:

Primary

• Compare overall survival of patients with peritoneal carcinoma of colorectal origin undergoing complete surgical resection and receiving systemic chemotherapy with versus without intraperitoneal chemohyperthermia.

Secondary

• Evaluate recurrence-free survival of these patients.
• Evaluate treatment toxicities.
• Determine morbidity from surgical complications.
• Determine prognostic factors of survival.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center, residual tumor status (R0/R1 vs R2 ≤ 1 mm), prior regimens of systemic chemotherapy (first vs ≥ second), and preoperative systemic chemotherapy for metastatic disease (yes vs no). Patients are randomized to 1 of 2 treatment arms.

All patients undergo maximal surgical resection of the tumor.

• Arm I: Patients receive standard systemic chemotherapy comprising leucovorin calcium IV followed by fluorouracil IV over 30 minutes. Systemic chemotherapy will continue for at least 6 months (before and/or after surgery). Patients must stop systemic chemotherapy at least 1 month before receiving intraperitoneal chemohyperthermia (CHIP). If bevacizumab is given as neoadjuvant therapy, then systemic chemotherapy must be discontinued 6 weeks before beginning CHIP. Patients undergo CHIP comprising oxaliplatin intraperitoneally during surgery and hyperthermia for 30 minutes.
• Arm II: Patients undergo surgery and receive standard systemic chemotherapy comprising leucovorin calcium IV followed by fluorouracil IV over 30 minutes. Systemic chemotherapy will continue for at least 6 months (before and after surgery).

Tumor markers (ACE and CA 19-9) are assessed at baseline, at 1 month after surgery, and then at follow-up visits.

After completion of study therapy, patients are followed at 1 and 3 months, every 3 months for 3 years, and then every 6 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 264
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France, 49036
    • Centre Paul Papin
  • Clamart, France, 92141
    • Hopital Antoine Beclere
  • Clermont Ferrand, France, 63003
    • CHU Estaing
  • Colombes Cedex, France, 92701
    • Louis Mourier Hospital
  • Dijon, France, 21034
    • Hopital Du Bocage
  • Grenoble, France, 38043
    • CHU de Grenoble - Hopital de la Tronche
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Montpellier, France, 34298
    • Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
  • Nantes-Saint Herblain, France, 44805
    • Centre Regional Rene Gauducheau
  • Nice, France, F-06202
    • Hopital de l'Archet CHU de Nice
  • Paris, France, 75970
    • Hopital Tenon
  • Paris, France, 75010
    • Hôpital Lariboisière
  • Paris, France, 75005
    • Institut Curie
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud
  • Reims, France, 51056
    • Institut Jean Godinot
  • Strasbourg, France, 67098
    • Hopital Universitaire Hautepierre
  • Toulouse, France, 31059
    • Centre Hospitalier Regional de Purpan
  • Vandoeuvre-les-Nancy, France, 54511
    • Centre Alexis Vautrin
  • Villejuif, France, F-94805
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer

  • Peritoneal carcinoma extension ≤ 25 (Sugarbaker Index) (determined intraoperatively)

    • Planning to receive standard systemic chemotherapy

      • Chemotherapy for metastatic cancer should be initiated 3 months after surgery
    • No extraperitoneal metastases, including liver and lung metastasis
    • No carcinomatosis of other origin besides colorectal, in particular appendical carcinomatosis
• Macroscopically complete resection (R1) or surgical reduction of tumor to a residual thickness ≤ 1 mm (R2) is possible

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Life expectancy > 12 weeks
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 3 times ULN
• Alkaline phosphatase ≤ 3 times ULN
• Creatinine ≤ 1.25 times ULN
• Eligible for surgery
• No peripheral neuropathy > grade 3
• Not pregnant or nursing
• No other cancer in the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix
• No inability to submit to follow-up medical testing for geographical, social, or psychological reasons
• Affiliated with a social security program
• Not deprived of liberty or under supervision

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemohyperthermia
• No concurrent participation in another study of first-line therapy for this cancer

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients undergo surgery and receive standard systemic chemotherapy comprising leucovorin calcium IV followed by fluorouracil IV over 30 minutes. Systemic chemotherapy will continue for at least 6 months (before and after surgery). Patients also undergo CHIP comprising oxaliplatin intraperitoneally during surgery and hyperthermia for 30 minutes.	Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV; Drug: oxaliplatin; Given during surgery; Procedure: hyperthermia treatment; Given intraperitoneally during surgery
Experimental: Arm II; Patients undergo surgery and receive standard systemic chemotherapy comprising leucovorin calcium IV followed by fluorouracil IV over 30 minutes. Systemic chemotherapy will continue for at least 6 months (before and after surgery).	Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	until 3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Recurrence-free survival	until 3 years
Toxicity by NCI CTCAE v.3.0	until 5 years after surgery
Morbidity from surgical complications (abdominal, extra-abdominal, aplasia)	until 2 months after surgery

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Francois Quenet, MD, Institut du Cancer de Montpellier - Val d'Aurelle

Publications and helpful links

General Publications

• Quenet F, Elias D, Roca L, Goere D, Ghouti L, Pocard M, Facy O, Arvieux C, Lorimier G, Pezet D, Marchal F, Loi V, Meeus P, Juzyna B, de Forges H, Paineau J, Glehen O; UNICANCER-GI Group and BIG Renape Group. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):256-266. doi: 10.1016/S1470-2045(20)30599-4. Epub 2021 Jan 18.

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: October 8, 2008
• First Submitted That Met QC Criteria: October 8, 2008
• First Posted (Estimate): October 9, 2008

Study Record Updates

• Last Update Posted (Estimate): August 30, 2016
• Last Update Submitted That Met QC Criteria: August 29, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: stage IV rectal cancer; stage IV colon cancer; recurrent colon cancer; recurrent rectal cancer; peritoneal carcinomatosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Peritoneal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Abdominal Neoplasms; Carcinoma; Colorectal Neoplasms; Peritoneal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: CDR0000595024; FRE-FNCLCC-ACCORD-15/0608; EUDRACT-2006-006175-20; EU-20847