Hyperthermic Intraoperative Intraperitoneal Chemotherapy of Recurrent Ovarian Cancer - A Feasibility Study
Between 1997 and 2001 the incidence of ovarian cancer in Switzerland was 15.8 per 100'000
women and ranks fifth among the cancer incidence in women. Nearly half of the patients die
of the disease leading to a mortality rate of 7.7 per 100'000. Together with pancreatic
cancer, ovarian cancer ranks fifth among cancer related deaths in women. The most common
form of ovarian cancer is the epithelial ovarian cancer with an incidence of 91.1%. Thus, in
the following the term ovarian cancer will refer solely to malignant epithelial ovarian
cancer (78.6% of all ovarian cancers) excluding borderline or low malignancy epithelial
ovarian tumors (12.5%).
Early stages of the disease (FIGO I - IIA) show practically no symptoms, thus 80% of ovarian
cancers are diagnosed at later stages (FIGO IIB - IV), a main reason for the high mortality.
Treatment for all stages are surgical removal of visible and resectable tumor nodules,
ovaries, uterus, omentum, pelvic and paraaortic lymph nodes, in advanced stages tumor
infested organs or organ parts have to be removed (=cytoreduction or debulking). Survival
time strongly depends on the completeness of the cytoreduction. Surgery is followed by a
chemotherapy of carboplatin and paclitaxel or carboplatin alone (except for the low risk
FIGO stage IA, G1).
Published survival rates after therapy vary considerably and are mainly dependent on the
stage of the tumor and the remaining tumor size (some tumor masses cannot be resected due to
the proximity to vital organs like major blood vessels).
_____Stage______survival after 5 years
- FIGO I........76% - 93%
- FIGO II.......60% - 74%
- FIGO III......23% - 41%
- FIGO IV..........11%
(from J. S. Berek & N. F. Hacker, Practical Gynecologic Oncology 3ed. Philadelphia:
Lippincott Williams & Wilkins, 2000, 504.)
Even with optimal debulking and adjuvant chemotherapy about 55% of all patients suffer from
recurrent ovarian cancer which is considered essentially an incurable disease, since the
response rate of a secondary treatment is 30% and the median survival is about 60 weeks.
Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC)
Unless the tumor has already metastasized (FIGO IV) ovarian cancer tumor nodules are
restricted to the peritoneal cavity. Since standard chemotherapy is applied intravenously
the cytotoxic drugs can reach the cancer cells only by diffusion into the peritoneum or via
the blood stream by the sometimes poor vascularisation of the tumor nodules. To improve the
exposure of the tumor to the cytotoxic drugs clinical trials were performed to deliver the
chemotherapy directly into the peritoneum (intraperitoneal chemotherapy). While this type of
therapy shows very promising results, it also has some serious drawbacks: permanent
catheters have to be implanted, even distribution of the instillate is difficult and
sometimes linked with considerable discomfort for the patient.
Alternatively the intraperitoneal chemotherapy can be applied directly after the
cytoreductive surgery (intraoperative intraperitoneal chemotherapy). Since the peritoneum is
completely opened, the perfusate can easily reach all surfaces and the surgeon can
facilitate the distribution by gentle agitation with his hands. Since the whole procedure is
performed during the surgery under full anesthesia the patient does not have to suffer
additional discomfort. While intraperitoneal chemotherapy can be applied repeatedly like
conventional chemotherapy, the intraoperative chemotherapy can only be performed once. Thus,
the effectiveness of the treatment should be as high as possible. This can be achieved by
using the highest possible drug concentration and by increasing the temperature of the
perfusate to approximately 42°C (hyperthermic intraoperative intraperitoneal chemotherapy).
The rational for the hyperthermic treatment is several fold. First, it has been shown that
some tumors can be killed by elevated temperatures alone. Second, the elevated temperatures
increase the diffusion rate of the drugs into the tumor and thus the drug can penetrate
deeper into the tumor nodules. Furthermore, elevated temperatures increase the cell membrane
permeability and thus the uptake of the cytotoxic drugs by the tumor cells. Finally, with
some cytotoxic drugs, like cisplatin, the cytotoxicity can be increased about 50 fold by a
temperature increase from 37°C to 42°C in tissue culture models.
Rationale for performing the trial:
Most studies performing hyperthermic intraoperative intraperitoneal chemotherapy dose the
cytotoxic drugs according to the body surface (like 50 mg/m² cisplatin) in analogy to
systemic, intravenous chemotherapy (usually using the same dose). Although there seems to be
a correlation between body surface and blood volume, the pharmacodynamics of drugs dosed by
the body surface is still highly variable and thus dosing on the body surface is
increasingly considered controversial for systemic administration. However, only very few
drugs are dosed differently, e.g. carboplatin.
For hyperthermic intraoperative intraperitoneal chemotherapy dosing by the body surface
makes even less sense, since the aim is the highest possible drug concentration in the
peritoneum without undue local and systemic toxicity. Furthermore, most studies using
intraoperative chemotherapy vary the volume of the perfusate according to the size of the
patient. Since the amount of cytotoxic drug is already fixed by the dosing on the body
surface (amount [mg] = dose [mg/m²] x body surface [m²]) the effective concentration (mg/l)
in the perfusate can vary considerably between patients. On the other hand pharmacokinetic
analyses have shown that reducing the concentration of the cytotoxic drug in the perfusate
reduces the efficacy even if the amount of the drug remains the same.
In this study the safety of a new dosing regime will be evaluated. The concentration of
cisplatin in the perfusate will be held constant independent of body weight or size to
achieve the highest effectiveness of the chemotherapy. However, if the amount of cisplatin
would exceed the equivalent of 62.5 mg/m² body surface, dosing would be again based on the
body surface (62.5 mg/m²) for safety reasons.
The primary endpoint is the safety of the treatment. All patients should be able to receive
full dose systemic carboplatin chemotherapy after completion the trial treatment.
Patients undergo cytoreductive surgery to remove all visible tumor nodules.
After the cytoreduction the hyperthermic intraoperative intraperitoneal chemotherapy is
performed. For 90 min 42°C warm cisplatin solution (25 mg/l) is perfused through the
peritoneum. Afterwards cisplatin will be removed by repeatedly rinsing the peritoneum with
Ringer lactate solution. During the whole procedure the patient will receive a strong
hydration according to a predefined protocol.
The concentration of platinum will be determined in perfusate, plasma and urine at various
Various published pharmacokinetic models of cisplatin clearance will be tested with the data
obtained. Furthermore, we want to test whether pharmacokinetic parameters might correlate
with nephrotoxicity to allow a prediction of nephrotoxic events.
Tumor tissue removed during the cytoreduction will be used for various in vitro experiments:
- Histological examination for infiltrating lymphocytes and determination of the
- Determine the depth of platinum infiltration after treatment of the tumor nodules under
various conditions with cisplatin (in vitro)
- Analysis of tumor cell biology after chemotherapy and heat treatment in vitro (protein
phosphorylation, release of second messengers)
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Fitness for Systemic Chemotherapy
Are patients fit to receive six courses of systemic carboplatin chemotherapy after completion of trial. If chemotherapy starts within 3 months after surgery and at least 4 courses could be administered, patient is considered fit. If chemotherapy is stopped early for reasons clearly unrelated to study treatment (e.g. platinum resistance), patient is also considered fit.
3 months post operation
Markus Lüdin, MD
Cantonal Hospital St. Gallen, Department of Surgery