Phase III Randomised Clinical Trial for Stage III Ovarian Carcinoma Randomising Between Secondary Debulking Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy
Rationale: Ovarian cancer is the second most common gynaecologic cancer in the Netherlands
preceded by endometrial cancer. It is however the leading cause of death among women with
gynaecologic malignancies with an annual mortality rate of 9 per 100.000. The majority of
the patients are diagnosed with a high stage ovarian carcinoma due to the fact that symptoms
occur at a late stage of the disease and screening methods for ovarian cancer are
suboptimal. Optimal treatment consists of a combination of chemotherapy and debulking
surgery. Despite the appearance of localized disease and the absence of obvious residual
tumour following primary treatment, the majority of patients (80%) will have persistent
disease or will develop recurrent disease. Additional strategies are warranted to reduce the
recurrence rate and increase disease free survival and overall survival in this group of
The concept of administering intraperitoneal chemotherapy is based on the ideas on
peritoneal dialysis. Intraperitoneal drug therapy is designed to maximize drug delivery to
the tumour with generally acceptable systemic side effects associated with IV administration
of the drug. This strategy is especially attractive for treatment of ovarian carcinoma,
which remains largely restricted to the abdominal cavity for most of its natural history. So
far 3 randomised controlled trials have shown an overall and progression-free survival
benefit when cisplatin is administered postoperatively by the IP route in patients with
stage III, optimally resected disease. These studies however found that the majority of
patients did not complete all planned 6 cycles due to catheter related problems. An
alternative way of administering chemotherapy intra abdominally whilst bypassing the use of
a catheter intra- abdominally is provided by perfusion of the abdomen during surgery under
hyperthermic conditions. This study compares the interval debulking plus or minus the
perfusion of the abdomen with chemotherapy under hyperthermic conditions during surgery
Objective: The primary objectives of this study are comparing the duration of recurrence
free survival following completion of treatment between the 2 study arms.
Secondary objectives of this study involve toxicity and morbidity, quality of life, tumour
response following treatment and overall survival of the study arm compared to the standard
Study design: Phase III randomised trial Study population: Patients diagnosed with stage III
ovarian carcinoma, peritoneal cell carcinoma or tuba carcinoma who are eligible for interval
debulking surgery either following primary chemotherapy or following incomplete primary
debulking and chemotherapy. Age between 18 - 76 yr old.
Intervention: One group undergoes interval debulking with hyperthermic perfusion of the
abdominal cavity with cisplatin 100 mg/m2 at the end of surgery. The other group is treated
by interval debulking only.
Main study parameters/endpoints: Recurrence free survival Nature and extent of the burden
and risks associated with participation, benefit and group relatedness: Participants of the
study will be asked to fill in quality of life questionnaires (12 times in 2 year). Blood
samples will be taken following written informed consent before treatment, during surgery
and during follow-up visits for marker studies and proteomics studies (10 times during 2
year). For patients participating in the pharmacokinetic studies (20) 2 tissue samples will
be taken from the abdominal cavity during surgery and blood samples will be taken 6 times
during and after surgery.
During follow-up 3 monthly visits will be scheduled in the first 2 years and 6-monthly
visits during year 3-5. During these follow-up visits routine physical exam including pelvic
exam and vaginal ultrasound (optional) is performed. CT-scans will be performed in the first
2 years before randomisation and 4 times at follow-up.
Risks of participating in this trial are related to the abdominal perfusion of cisplatin.
This can cause systemic effects such as: nephrotoxicity, bone marrow toxicity,
neurotoxicity, and longer hospital stay. It can also increase the chance on bowel
perforation of a bowel anastomoses resulting in a longer hospital stay and possibly surgical
intervention. To prevent systemic side effects of intra-abdominally administered cisplatin,
sodium thiosulphate is administered intravenously during surgery.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Duration of recurrence free survival.
Willemien J van Driel, MD
The Netherlands Cancer Institute
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)