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Treatment of Peritoneal Cancer With Surgery, Perfused Heated Cisplatin and Chemotherapy

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ClinicalTrials.gov Identifier: NCT00004547
Recruitment Status : Completed
First Posted : February 4, 2000
Results First Posted : November 22, 2011
Last Update Posted : November 18, 2015
Sponsor:
Information provided by (Responsible Party):
Marybeth Hughes, M.D., National Institutes of Health Clinical Center (CC)

Tracking Information
First Submitted Date  ICMJE February 3, 2000
First Posted Date  ICMJE February 4, 2000
Results First Submitted Date  ICMJE August 30, 2011
Results First Posted Date  ICMJE November 22, 2011
Last Update Posted Date November 18, 2015
Study Start Date  ICMJE January 2000
Actual Primary Completion Date August 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 13, 2011)
  • Number of Participants With Disease-free Survival [ Time Frame: On study date until the first scan with imageable disease, assessed up to 100 months or more. ]
    Participants who achieve either a six or twelve month disease free interval based on radiographic imaging and symptoms.
  • Number of Participants With a Response [ Time Frame: Patients were assessed every three months for one year and then every 6 months ]
    Response is assessed by measuring the time to clinical or radiographic recurrence of disease. Patients will be followed with computed tomography (CT) scans. At any time point where there is evidence of progressive disease in the peritoneal cavity (imageable tumor nodules or new onset of ascites) the patients will be scored as failing within the abdominal cavity.
  • Number of Participants With Adverse Events [ Time Frame: only assessed during the perioperative period (i.e. up to 90 days following surgery) ]
    Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 13, 2011)
  • Percentage of Participants Who Had Paclitaxel and 5-fluorouracil (5-FU) Analysis Performed [ Time Frame: Perioperative day 7-12 after surgery ]
    Paclitaxel and 5-FU levels in plasma and perfusate will be determined by standard high-performance liquid chromatography (HPLC). Samples will be collected just prior to (Time 0) the infusion of the intraperitoneal dwell of 5-FU and paclitaxel, at the following time intervals after the conclusion of the intraperitoneal dwell infusion (15 minutes, 1 hour, 6 hour, 12 hour, 24 hour, 48 hour).
  • Quality of Life Questionnaire Score [ Time Frame: preop, 6 weeks postop and then 3, 6, 9, and 12 months the first year and then every 6 months until the patient is off study ]
    The Short-Form-36 Health Survey (SF-36) and the Functional Assessment of Cancer Therapy Disease Specific for Colorectal Cancer (FACT-C) will be given to the patients upon admission preoperatively, then 6 weeks postoperatively, and then 3, 6, 9, and 12 months for the first year and then every 6 months until the patient goes off study. These forms summarize a participants positive and negative aspects that characterize one's psychological (emotional(, physical, and social well-being at a point in time. For detailed information about the questionnaires, please see the Protocol Link module.
  • Signal Transduction Pathways in Tumor Tissue Versus Normal Tissue [ Time Frame: once during surgery ]
    Signal transduction pathways were measured using reverse phase protein lysate microarray to determine if the pathways are distinct in tumor versus normal tissue.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Peritoneal Cancer With Surgery, Perfused Heated Cisplatin and Chemotherapy
Official Title  ICMJE Phase II Trial of Continuous Hyperthermic Peritoneal Perfusion (CHPP) With Cisplatin Plus Early Postoperative Intraperitoneal Paclitaxel and 5-Fluorouracil for Peritoneal Carcinomatosis
Brief Summary

This study will test the effectiveness of an experimental treatment for peritoneal cancer involving surgical removal of the tumor, perfusion of the abdomen during surgery with a heated solution of the drug cisplatin, and post-surgery combination chemotherapy in the abdomen with fluorouracil (5-FU) and paclitaxel.

Patients with certain peritoneal cancer whose tumors are confined to the abdomen may be eligible for this study. Candidates are screened with a medical history and physical examination, including blood tests, electrocardiogram and possibly bone scan, brain magnetic resonance imaging (MRI), and chest, abdomen and pelvic CT scans.

Participants undergo surgery to remove as much tumor as possible. Part of the intestines, pancreas, stomach or the entire spleen may also be removed if they are affected. During surgery, after the tumor has been removed, two catheters (thin plastic tubes) are placed in the abdomen. A chemotherapy solution containing the anti-cancer drug cisplatin heated to a temperature of about 108.6 degrees (10 degrees above normal body temperature) is then delivered into the abdomen through one catheter and drained through another. During treatment, a drug called sodium thiosulfate is given through a vein to reduce the risk of side effects of cisplatin, particularly kidney damage. After 90 minutes of bathing the abdomen with this solution, the drug is rinsed from the abdomen and the catheters removed. Another small catheter is then placed and left inside the abdomen with one end coming out through the skin. Seven to 12 days after the operation, the anti-cancer drugs 5-FU and paclitaxel are given through this catheter.

After complete recovery from the surgery, the catheter is removed and the patient is discharged from the hospital. Clinic visits are scheduled for periodic follow-up examination, imaging, and tests 3 and 6 months after surgery and every 6 months for up to 5 years as long as the disease does not worsen. Patients whose disease progresses are taken off the study and referred back to their local physician or referred for alternative care or other research studies.

Patients are also asked to assess how this therapy affects their general health and well being. This will require filling out two quality-of-life (QOL) questionnaires before surgery and again at each follow-up visit after surgery. Each questionnaire takes about 15 minutes to complete.

Detailed Description

Background:

Cytoreductive surgery plus aggressive combination intraperitoneal chemotherapy may significantly alter the natural history of peritoneal carcinomatosis. The purpose of this study is to examine the treatment results of continuous hyperthermic peritoneal perfusion (CHPP) with cisplatin plus early postoperative intraperitoneal dwell therapy with 5-FU and paclitaxel after cytoreductive surgery for peritoneal carcinomatosis.

Objectives:

The primary objective of this study is to determine response and survival after continuous hyperthermic peritoneal perfusion with cisplatin and early postoperative intraperitoneal dwell therapy with 5-FU and paclitaxel. Response can only be assessed by measuring the time to clinical or radiographic recurrence of disease.

The secondary objectives include the determination of pharmacokinetics of paclitaxel and 5-FU delivered into the peritoneal cavity and the impact that continuous hyperthermic peritoneal perfusion with cisplatin and early postoperative intraperitoneal dwell therapy with 5-FU and paclitaxel has on patients' health related quality of life.

The evaluation of pure populations of tumor and normal mesothelial cells to

  • determine if signal transduction pathways are distinct in tumor versus normal tissue
  • to see if specific cell pathways are activated or inhibited as a consequence of therapy.
  • to validate that this technology can provide informative data about these events as a potential surrogate for clinical benefit from therapy or biological behavior of the tumor.

Eligibility:

The patient greater than or equal to 30 kg must have histologically proven peritoneal carcinomatosis from one of the following histologies: 1) primary peritoneal mesothelioma; 2) low grade mucinous adenocarcinoma (including low grade mucinous neoplasms of borderline malignant potential); 3) adenocarcinoma of gastrointestinal tract origin (other than low grade mucinous, excluding pancreatic cancer), with disease confined to the peritoneal cavity. Patients may not have had treatment for their disease within the previous 30 days and have recovered from all toxicity. Patients must meet certain safety laboratory criteria and may not have major medical disorders that would place them at unacceptable risk for a major surgical procedure. Patients may not have received prior intraperitoneal platinum therapy.

Design:

Patients will undergo cytoreductive surgery followed by CHPP with cisplatin. A peritoneal dialysis catheter will be inserted into the peritoneal cavity at the time of laparotomy. In the early postoperative period (day 2 - 10) intraperitoneal dwell chemotherapy with paclitaxel (125 mg/M^2) and 5-FU (800 mg/M^2) will be administered. Patients will be seen 4 - 6 weeks after discharge for a physical examination and laboratory screen and QOL evaluation. Tumor marker will be included at this stage. Patients will then be seen every 3 months for the first year after surgery and every 6 months thereafter. At each visit they will undergo physical examination, laboratory screening (including tumor marker) and a CT scan of the chest, abdomen and pelvis and QOL evaluation.

The objective of this pilot study is to estimate the ability of peritoneal perfusion to achieve potentially tolerable disease free survival in patients with a variety of tumors. For each class of tumors, an appropriate, distinct median disease free survival will be targeted as the principal endpoint. The trial will be conducted as a set of three single-stage phase II studies, with an early stopping rule for clearly unacceptable outcomes. It is expected that accrual for 59 patients with adenocarcinoma of gastrointestinal origin (other than low grade mucinous), 48 patients with low grade mucinous adenocarcinoma, and 96 patients with primary peritoneal mesothelioma (total accrual of 203) will require approximately 5 -6 years.

Results will be assessed by following the time to radiographic or clinical recurrence of disease and survival. Patients will be stratified for entry based on histology. This will include 3 cohorts: 1) peritoneal mesothelioma; 2) low grade mucinous adenocarcinoma (including low grade mucinous neoplasms of borderline malignant potential); and 3) adenocarcinoma of gastrointestinal origin (other than low grade mucinous).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Abdominal Neoplasm
  • Colonic Neoplasm
  • Mesothelioma
  • Peritoneal Neoplasm
Intervention  ICMJE
  • Procedure: Surgery
    Patients will undergo cytoreductive surgery to remove as much tumor as possible. Part of the intestines, pancreas, stomach or the entire spleen may also be removed if they are affected.
    Other Name: Cytoreductive surgery
  • Procedure: Continuous hyperthermic peritoneal perfusion (CHPP) with Cisplatin
    Other Names:
    • Platinol
    • Cisplatinum
  • Drug: Postoperative dwell with paclitaxel and 5-FU
    Intraperitoneal dwell chemotherapy with a combination of 5-FU and Paclitaxel will be delivered in the early postoperative period (day 7 today 12 after surgery). Patients will be premedicated with hydrocortisone (100 mg/intravenous push (i.v.p.)), diphenhydramine (50 mg i.v.p.) and ranitidine (50 mg i.v.p.) 30 minutes prior to delivering intraperitoneal chemotherapy. One liter of normal saline will be infused containing 5-FU (800 mg/M^2) and 1 L of normal saline containing paclitaxel (125 mg/M^2) will be infused over 60 minutes. The chemotherapy solution will be left in the abdominal cavity permanently for slow absorption.
    Other Name: 5-FU
Study Arms  ICMJE
  • Experimental: Peritoneal mesothelioma
    Patients with peritoneal mesothelioma suffer with intractable ascites but have a very surface oriented tumor which usually does not invade into organs and cause organ dysfunction. The main source of symptoms and cause of death is intractable ascites.
    Interventions:
    • Procedure: Surgery
    • Procedure: Continuous hyperthermic peritoneal perfusion (CHPP) with Cisplatin
    • Drug: Postoperative dwell with paclitaxel and 5-FU
  • Experimental: Low grade mucinous adenocarcinoma
    Low grade mucinous adenocarcinoma also includes low grade mucinous neoplasms of borderline malignant potential. Patients with low grade mucinous adenocarcinoma can have prolonged survival with debulking surgery alone. The majority of patients with truly malignant disease will die of complications from intraperitoneal progression of tumor within 2 to 5 years. The tumors are often surface oriented within the peritoneal cavity without metastases to other distant sites. The most common origin for this type of tumor is the appendix and ovary.
    Interventions:
    • Procedure: Surgery
    • Procedure: Continuous hyperthermic peritoneal perfusion (CHPP) with Cisplatin
    • Drug: Postoperative dwell with paclitaxel and 5-FU
  • Experimental: Adenocarcinoma of gastrointestinal origin
    Adenocarcinoma of gastrointestinal origin also includes other than low grade mucinous. Aggressive gastrointestinal adenocarcinomas such as gastric, small bowel, and colon cancer , tend to be more invasive into tissues and can more readily metastasize to distant sites. The cause of death is usually directly related to intraperitoneal progression of tumor. It is a more difficult group of patients to treat with intraperitoneal therapy because of the aggressive and invasive nature of the tumors.
    Interventions:
    • Procedure: Surgery
    • Procedure: Continuous hyperthermic peritoneal perfusion (CHPP) with Cisplatin
    • Drug: Postoperative dwell with paclitaxel and 5-FU
Publications * Dedrick RL, Myers CE, Bungay PM, DeVita VT Jr. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep. 1978 Jan;62(1):1-11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 1, 2010)
188
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
203
Actual Study Completion Date  ICMJE August 2009
Actual Primary Completion Date August 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

The patient must have histologically proven peritoneal carcinomatosis from the following histologies: primary peritoneal mesothelioma; low grade mucinous adenocarcinoma (including low grade mucinous neoplasms of borderline malignant potential); adenocarcinoma of gastrointestinal tract origin (other than low grade mucinous, excluding pancreatic cancer).

Radiologic workup must demonstrate that the disease is confined to the peritoneal cavity.

Radiologic workup or prior abdominal exploration must be consistent with disease which can be debulked to a residual size of less that 1 cm in diameter per tumor deposit.

Patients must have an Eastern Cooperative Onocology Group (ECOG) performance status of less than or equal to 2.

Patients must have a minimum expected duration of survival of greater than 8 weeks.

Patients must have recovered from any toxicity from all prior chemotherapy, immunotherapy or radiotherapy and be at least 30 days past the date of their last treatment.

EXCLUSION CRITERIA:

Patients will be excluded if they have concomitant medical problems that would place them at unacceptable risk for a major surgical procedure.

Patients at increased risk for coronary artery disease or cardiac dysfunction (e.g., age greater than 65, history of hypertension, first degree relative with atherosclerotic coronary artery disease) will undergo cardiac evaluation and will not be eligible if they demonstrate significant irreversible ischemia on a stress thallium study or an injection fraction of less than 40 percent.

Patients who have shortness of breath with minimal exertion and who are at risk for pulmonary disease (e.g., chronic smokers) will undergo pulmonary function testing and will not be eligible if their forced expiratory volume 1 (FEV1) is less than 1.2 liters or their maximum voluntary ventilation is less than 50 percent of expected.

Patients who have a baseline neurological toxicity of Grade 3 or greater will be excluded because of the potential neurotoxicity associated with platinum and paclitaxel therapy.

Patients will be ineligible if they have a creatinine of greater than 1.5 or a creatinine clearance of less 70 mL/min.

Patients will be ineligible if the white blood cell (WBC) is less than 3000/microliters or platelets are less than 75,000mL/mm(3).

Patients must have a serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within 5 times the upper limit of normal and a total serum bilirubin of less than 3 times the upper limit of normal, both of which define the upper limit of grade 2 treatment related toxicities.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00004547
Other Study ID Numbers  ICMJE 000069
00-C-0069
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Marybeth Hughes, M.D., National Institutes of Health Clinical Center (CC)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Marybeth S Hughes, M.D. National Cancer Institute, National Institutes of Health
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP