Hypoxic Isolated Abdominal Perfusion (HAP) chemotherapy for non-operable advanced staged ovarian cancer with peritoneal carcinosis: an experience in 45 platinum-refractory ovarian cancer patients

Abstract

In order to break through drug resistance in platinum-refractory ovarian cancer, augmented drug exposure was administered to the abdomen by means of an isolated perfusion system. Four cycles of isolated hypoxic abdominal perfusion with cisplatin, adriamycin, and mitomycin were conducted in 4-week intervals. Cisplatin and adriamycin were chosen because of their increased cytotoxicity under hypoxic conditions. Chemofiltration was performed for prophylaxis of cumulative toxicity of adriamycin and mitomycin. The study included 45 patients with recurrent epithelial ovarian cancer who had prior platinum containing therapies (3, stage Federation of Gynecology and Obstetrics (FIGO) IIIB; 20, stage FIGO IIIC; 22; stage FIGO IV). The median survival rate in stage FIGO IIIBC was 12 months, and in stage IV was 10 months. The tumor marker decreased to complete response or partial response at 17.8% and 55.6% of the patients. CT or MRI visualization showed complete response in 4.1%, and partial response was in 54.1%. Complete resolution of ascites was noted in 30% of cases and substantial reduction in another 43%. Toxicity was generally low. Quality of life was improved in the majority of cases. Bone-marrow suppression ranged between WHO grade 1 and 2, and in patients with previous third- or fourth-line chemotherapy, it was WHO grade 3. Isolated hypoxic abdominal perfusion with chemofiltration for patients with progressive and platinum-refractory stage III and IV ovarian cancer is an effective therapy, breaking through chemoresistance and offering comparably long survival at good quality of life.

Keywords: Chemoresistance; Intra-arterial chemotherapy; Isolated abdominal perfusion; Ovarian cancer; Quality of life.

Fig. 1

Isolated hypoxic abdominal perfusion via a femoral access. The balloon catheters are positioned beneath the diaphragm and connected with an extracorporeal roller pump

Fig. 2

Observational survival rates of 45 advanced staged, heavily pretreated, recurrent ovarian cancer patients on hypoxic abdominal perfusion chemotherapy. Three patients were staged FIGO IIIB, 20 patients were stage IIIC, and 22 patients were staged IV. Survival times were estimated using the Kaplan–Meier product limit estimator, and follow-up for surviving patients was minimum 18 months; median follow-up was 26 months

Fig. 3

Response rates of 45 advanced staged, heavily pretreated, recurrent metastatic ovarian cancer patients on hypoxic abdominal perfusion chemotherapy. Response classification was complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Responses of a clinical benefit (CR, PR, SD) endured at least 8 weeks

Fig. 4

Drug concentration levels of cisplatin (a) and MMC (b) in the tumor supplying arteria (violet), the tumor draining vein (blue), and the peripheral vein (green) during and after a hypoxic abdominal perfusion. Measurements inside the perfusion circuit (arterial and venous) have been made at minute 1, 2, and 3, and then every 2 min until 35 min after drug injection. Drug levels in the peripheral vein have been measured at minute 1, 5, and after releasing of perfusion balloons at minute 15. Given drug regimen was 50 mg cisplatin and 20 mg mitomycin as a bolus injection. Both charts derive from the same perfusion event

Fig. 5

Adverse effects after systemic chemotherapy (green) and hypoxic abdominal perfusion (HAP blue). Ovarian cancer patients filled in a questionnaire about adverse effects after chemotherapy. Each possible adverse effect is scaled on a spectrum from 1 to 6 for increasing severeness of side effects. Mean reduction of adverse events was 1.86 points for hypoxic abdominal perfusion compared to systemic chemotherapy, that patients perceived at an earlier treatment period (confidence interval for 1.86 (with 91% CI 0.5)