Clinical trial NCT01167725: Standard Therapy With or Without Surgery and Mitomycin C in Treating Patients With Advanced Limited Peritoneal Dissemination of Colon Cancer
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: mucinous adenocarcinoma of the colon
stage III colon cancer
stage IV colon cancer
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-07-22
Enrollment: 340
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall survival (OS)
Secondary outcomes:
measure: Progression-free survival (PFS)
measure: Quality of life
measure: Toxicity burden
measure: Circulating tumor cells
measure: Comparison of OS and PFS according to patients' peritoneal surface tumor genotype for the NAD(P)H
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: St. Agnes Hospital Cancer Center
state: Maryland
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
Study officials:
affiliation: Walter Reed Army Medical Center
name: Alexander Stojadinovic, MD
role: PRINCIPAL_INVESTIGATOR
References: