Standard Therapy With or Without Surgery and Mitomycin C in Treating Patients With Advanced Limited Peritoneal Dissemination of Colon Cancer

Pilot / Phase III Randomized Trial Comparing Standard Systemic Therapy to Cytoreduction + Hyperthermic Intraperitoneal Mitomycin C + Standard Systemic Therapy in Patients With Limited Peritoneal Dissemination of Colon Adenocarcinoma

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Heating mitomycin C to several degrees above normal body temperature and infusing it into the area around the tumor may kill more tumor cells. Giving mitomycin C after surgery may kill any remaining tumor cells. It is not yet known whether standard therapy is more effective with or without surgery followed by mitomycin C.

PURPOSE: This randomized phase III trial is studying standard therapy with or without surgery and mitomycin C in treating patients with advanced limited peritoneal dissemination of colon cancer

Study Overview

• Status: Unknown
• Conditions: Colorectal Cancer
• Intervention / Treatment: Biological: bevacizumab; Drug: oxaliplatin; Drug: leucovorin calcium; Drug: fluorouracil; Biological: cetuximab; Drug: irinotecan hydrochloride; Drug: FOLFOX regimen; Drug: FOLFIRI regimen; Drug: capecitabine; Drug: mitomycin C; Procedure: therapeutic conventional surgery

Detailed Description

OBJECTIVES:

Primary

• To compare the overall survival (OS) of patients with advanced limited peritoneal dissemination of colon adenocarcinoma treated with systemic therapy with vs without cytoreduction surgery and hyperthermic intraperitoneal mitomycin C.
• To compare the relative OS at 1 year of patients treated with these regimens.

Secondary

• To compare the progression-free survival (PFS) of patients treated with these regimens.
• To compare the relative PFS at 1 year of patients treated with these regimens.
• To compare the quality of life of patients treated with these regimens.
• To compare the toxicity burden of these regimens in these patients.
• To compare the OS and PFS according to patients' peritoneal surface tumor genotype for the NAD(P)H (quinone oxidoreductase 1 [NQO1] 609C >T polymorphism [wild type vs heterozygous/homozygous mutant]) in patients treated with these regimens.
• To compare circulating tumor cells in patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to presentation (synchronous vs metachronous carcinomatosis), ECOG performance status (0 vs 1), disease volume (measurable vs non-measurable), prior first-line therapy for advanced disease (chemo-naïve vs prior first-line therapy), planned chemotherapy (oxaliplatin vs irinotecan vs fluorouracil/leucovorin calcium vs capecitabine), and planned biologic therapy (bevacizumab vs cetuximab vs none). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive standard systemic therapy, at the discretion of patients' oncologist, comprising combinations of fluorouracil, leucovorin calcium, irinotecan hydrochloride, oxaliplatin, and/or capecitabine (including FOLFOX4, mFOLFOX6, CapeOx, or FOLFIRI) with or without bevacizumab (beginning 4-6 weeks after major surgery) or cetuximab*. Treatment repeats in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may crossover to arm II.

NOTE: *For patients with KRAS wild-type tumors.

• Arm II: Patients undergo cytoreduction surgery and hyperthermic intraperitoneal mitomycin C over 45-90 minutes. Beginning 8 weeks after surgery, patients receive standard systemic therapy as in arm I. Treatment with systemic therapy repeats for 6 courses in the absence of disease progression or unacceptable toxicity.

Blood and tissue samples may be collected from patients for correlative studies.

Patients complete SF-36 Health Survey; Functional Assessment of Cancer Therapy-Colorectal (FACT-C); Feeling Sad, Down, or Depressed (CES-D); and a Brief Pain Inventory quality-of-life questionnaires at baseline and then periodically during study.

After completion of study therapy, patients are followed up periodically for 5 years.

• Study Type: Interventional
• Enrollment (Anticipated): 340
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • St. Agnes Hospital Cancer Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed colon adenocarcinoma meeting the following criteria:

  • Newly diagnosed disease
  • Advanced disease
  • Confirmed synchronous or metachronous limited peritoneal disease dissemination
  • No appendiceal or rectal cancer
  • No signet ring cell type

• Disease amenable to complete cytoreduction surgery as indicated by:

  • Peritoneal Cancer Index (PCI) ≤ 20 by helical CT scan and/or staging laparoscopy
  • No parenchymal hepatic metastases
  • No clinical (jaundice), biochemical (abnormally elevated serum bilirubin and/or alkaline phosphatase), or radiological (by ultrasound, CT scan, or MRI) biliary obstruction
  • No symptomatic malignant ascites requiring palliative paracentesis
  • Small volume of disease in the gastro-hepatic ligament defined by a < 5 cm mass in the epigastric region on cross-sectional imaging
  • No cross-sectional imaging findings indicative of multi-segmental (> 1 site) small bowel obstruction, small bowel loops matted together, or gross disease of the small bowel mesentery characterized by distortion, thickening, or loss of mesenteric vascular clarity
  • No clinical or radiological evidence of hematogenous or distant nodal (retroperitoneal, pelvic, mediastinal, peri-portal, or peri-aortic) metastasis

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• ANC > 1,200/mm³
• WBC > 4,000/mm³
• Platelet count 150,000/mm³

• INR ≤ 1.5

  • Patients on therapeutic anticoagulant for unrelated medical condition such as atrial fibrillation or anti-thrombocyte treatment allowed provided treatment can be withheld for operation
• Total serum bilirubin ≤ 1.5 mg/dL (> 1.5 mg/dL for patients with Gilbert syndrome)
• Alkaline phosphatase < 2.5 times upper limit of normal (ULN)
• AST < 1.5 times ULN
• Serum creatinine normal
• BUN normal
• Not pregnant or nursing
• Fertile patients must use effective contraception

• No history of severe congestive heart failure or severe pulmonary disease

  • Patients who are status post-revascularization procedures with satisfactory cardiac function are eligible
• No acute myocardial infarction within the past 6 months
• No significant history of a medical problem or co-morbidity (e.g., severe congestive heart failure or active ischemic heart disease) that would preclude a major abdominal operation
• No concurrent second malignancy requiring systemic therapy
• No psychiatric or addictive disorders, or other conditions that would preclude the patient from meeting the study requirements

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior second-line systemic treatment for metastatic colon adenocarcinoma

  • Patients who received prior adjuvant therapy for colon adenocarcinoma and/or prior first-line systemic therapy for metastatic colon adenocarcinoma are eligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I; Patients receive standard systemic therapy, at the discretion of patients' oncologist, comprising combinations of fluorouracil, leucovorin calcium, irinotecan hydrochloride, oxaliplatin, and/or capecitabine (including FOLFOX4, mFOLFOX6, CapeOx, or FOLFIRI), bevacizumab, or cetuximab. Treatment repeats in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may crossover to arm II.	Biological: bevacizumab; Given IV; Drug: oxaliplatin; Given IV; Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV; Biological: cetuximab; Given IV; Drug: irinotecan hydrochloride; Given IV; Drug: FOLFOX regimen; Given IV; Drug: FOLFIRI regimen; Given IV; Drug: capecitabine; Given IV
Experimental: Arm II; Patients undergo cytoreduction surgery and hyperthermic intraperitoneal mitomycin C over 45-90 minutes. Beginning 8 weeks after surgery, patients receive standard systemic therapy as in arm I. Treatment with systemic therapy repeats for 6 courses in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given IV; Drug: oxaliplatin; Given IV; Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV; Biological: cetuximab; Given IV; Drug: irinotecan hydrochloride; Given IV; Drug: FOLFOX regimen; Given IV; Drug: FOLFIRI regimen; Given IV; Drug: capecitabine; Given IV; Drug: mitomycin C; Given intraperitoneally; Procedure: therapeutic conventional surgery; Patients undergo cytoreductive surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall survival (OS)

Secondary Outcome Measures

Outcome Measure
Quality of life
Progression-free survival (PFS)
Toxicity burden
Circulating tumor cells
Comparison of OS and PFS according to patients' peritoneal surface tumor genotype for the NAD(P)H

Collaborators and Investigators

• Sponsor: Walter Reed Army Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Alexander Stojadinovic, MD, Walter Reed Army Medical Center

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Anticipated): May 1, 2014

Study Registration Dates

• First Submitted: July 21, 2010
• First Submitted That Met QC Criteria: July 21, 2010
• First Posted (Estimate): July 22, 2010

Study Record Updates

• Last Update Posted (Estimate): January 24, 2012
• Last Update Submitted That Met QC Criteria: January 21, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: stage IV colon cancer; stage III colon cancer; mucinous adenocarcinoma of the colon
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Colonic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Alkylating Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Antibiotics, Antineoplastic; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Capecitabine; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Levoleucovorin; Mitomycins; Mitomycin; Cetuximab
• Other Study ID Numbers: CDR0000681540; WRAMC-8214