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Phase III Randomised Clinical Trial for Stage III Ovarian Carcinoma Randomising Between Secondary Debulking Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy


Phase 3
18 Years
76 Years
Open (Enrolling)
Female
Ovarian Cancer

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Trial Information

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
patients.

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
(OVHIPEC).

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
arm.

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.


Inclusion Criteria:



- Age between 18 and 76 years

- Histological or cytological proven primary epithelial ovarian carcinoma or peritoneal
cancer (PPSC) or fallopian tube carcinoma FIGO stage III, including serous papillary
adenocarcinoma, mucinous adenocarcinoma and endometrioid adenocarcinoma.

- In case of pleural effusion cytology should be negative for tumour cells

- In case diagnosis is made based on cytology only (i.e. patients treated by primary
chemotherapy) additional criteria apply:

- Normal mammogram (< 6 weeks before first registration) and

- Presence of pelvic mass and

- CA 125 > 200 kU/l and

- Serum CA125/CEA ratio > 25. If the serum CA125/CEA ratio is < 25, a barium enema
or colonoscopy and gastroscopy or radiological examination of the stomach should
be negative for the presence of a primary tumour of the digeste tract (< 6 weeks
before registration) and

- Omental cake or other metastases larger than 2 cm in the upper abdomen and/or
regional lymph node metastasis irrespective of size (CT/MRI or ultrasound or
laparoscopy)

- Patients eligible for interval debulking for the following 2 reasons:

- Primary debulking surgery not feasible due to tumour extension or general
condition (patients treated by primary chemotherapy) or

- Incomplete primary debulking with residual disease > 1 cm

- In case of primary chemotherapy:

- Chemotherapy consists of 3 courses of carboplatin or cisplatin combined with
taxol

- Following 2 cycles of chemotherapy at least a 30% decrease in the sum of largest
diameter (LD) of target lesions taking as reference the baseline sum LD (RECIST
criteria, see appendix 1)

- In case of an incomplete primary debulking as indicated under 5 followed by
chemotherapy:

- Chemotherapy consists of 3 courses of carboplatin or cisplatin combined with
taxol

- General criteria:

- Fit for major surgery, ASA 1 or ASA 2

- WHO performance status 0-2

- Written informed consent

- Laboratory values: serum creatinine < 140 ┬Ámol/L; creatinine clearance > 60
ml/min (Cockroft formula); white blood cell count > 3.5 x 109/l; platelets >
100 x 109 /l

- For quality of life studies:

- Baseline questionnaires should be filled in before randomization

Exclusion Criteria:

- History of breast cancer or previous malignancies within 5 years prior to inclusion,
with the exception of radically excised basal cell or squamous cell skin cancer or
carcinoma in situ of the cervix

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Duration of recurrence free survival.

Principal Investigator

Willemien J van Driel, MD

Investigator Role:

Study Chair

Investigator Affiliation:

The Netherlands Cancer Institute

Authority:

Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:

M06OVH-OVHIPEC

NCT ID:

NCT00426257

Start Date:

February 2007

Completion Date:

December 2013

Related Keywords:

  • Ovarian Cancer
  • Ovarian Cancer
  • stage III
  • hyperthermic intraperitoneal chemotherapy
  • debulking surgery
  • HIPEC
  • Fever
  • Ovarian Neoplasms

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