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

Sponsor

Walter Reed Army Medical Center (U.S. Fed)

Overall Status

Unknown status

CT.gov ID

NCT01167725

Collaborator

National Cancer Institute (NCI) (NIH)

340

Enrollment

Locations

Arms

170

Patients Per Site

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Biological: bevacizumab Biological: cetuximab Drug: FOLFIRI regimen Drug: FOLFOX regimen Drug: capecitabine Drug: fluorouracil Drug: irinotecan hydrochloride Drug: leucovorin calcium Drug: mitomycin C Drug: oxaliplatin Procedure: therapeutic conventional surgery	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

340 participants

Allocation:

Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2010

Anticipated Primary Completion Date :

May 1, 2014

Arms and Interventions

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 Biological: cetuximab Given IV Drug: FOLFIRI regimen Given IV Drug: FOLFOX regimen Given IV Drug: capecitabine Given IV Drug: fluorouracil Given IV Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin 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 Biological: cetuximab Given IV Drug: FOLFIRI regimen Given IV Drug: FOLFOX regimen Given IV Drug: capecitabine Given IV Drug: fluorouracil Given IV Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV Drug: mitomycin C Given intraperitoneally Drug: oxaliplatin Given IV Procedure: therapeutic conventional surgery Patients undergo cytoreductive surgery

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

Biological: cetuximab

Given IV

Drug: FOLFIRI regimen

Given IV

Drug: FOLFOX regimen

Given IV

Drug: capecitabine

Given IV

Drug: fluorouracil

Given IV

Drug: irinotecan hydrochloride

Given IV

Drug: leucovorin calcium

Given IV

Drug: oxaliplatin

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

Biological: cetuximab

Given IV

Drug: FOLFIRI regimen

Given IV

Drug: FOLFOX regimen

Given IV

Drug: capecitabine

Given IV

Drug: fluorouracil

Given IV

Drug: irinotecan hydrochloride

Given IV

Drug: leucovorin calcium

Given IV

Drug: mitomycin C

Given intraperitoneally

Drug: oxaliplatin

Given IV

Procedure: therapeutic conventional surgery

Patients undergo cytoreductive surgery

Outcome Measures

Primary Outcome Measures

Overall survival (OS) []

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Agnes Hospital Cancer Center	Baltimore	Maryland	United States	21229
2	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096