HIPEC ROC I: A phase i study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum‐based chemotherapy in patients with platinum‐sensitive recurrent epithelial ovarian cancer

Abstract

This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence !6 months after first-line therapy) were included according to the classical 313 dose-escalation design at three dose levels-60, 80 and 100 mg=m 2 . After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43 C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg=m 2 . The remaining five patients treated with 100 mg=m 2 tolerated their treatment well. The recommended phase II dose was established at 100 mg=m 2 . The mean peritoneal-to-plasma AUC ratio was 19Á5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg=m 2 has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinumsensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg=m 2 . The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

Total or Subtotal Colectomy in Patients Undergoing Surgery for Primary or Recurrent Epithelial Ovarian Cancer

“…Hyperthermic intraoperative chemotherapy is also a feasible option in platin-sensitive recurrence [19], survival benefit is being evaluated in ongoing prospective trials [20]. …”

Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancers: Is there a role?

“…Zivanovic et al, in a phase I trial, demonstrated both feasibility and an acceptable toxicity profile of HIPEC utilizing cisplatin 100 mg/m 2 following optimal tumor cytoreduction in the primary setting. The authors propose this dose as the recommend phase II dose in future studies (27). In our study, when comparing toxicity profiles between mitomycin C and platinum-containing agents, the rates of toxicities are similar except for the rate of transient renal dysfunction; this may be due to the difference in patient populations as the majority of our patients had at least one prior platinum based chemotherapy regimen.…”

Introducing Hyperthermic Intraperitoneal Chemotherapy into Gynecological Oncology Practice - Feasibility and Safety Considerations: Single-Center Experience

“…The purpose of this study was to determine the safety, feasibility, MTD, pharmacokinetics and pharmacodynamics of cisplatin administered as HIPEC in patients undergoing secondary CS. The data from this study have been published [23] and prove the feasibility of this approach. In the process of introducing HIPEC into practice, several considerations and precautions regarding the perioperative management in the setting of a multidisciplinary approach had to be taken into account.…”

“…12 patients in all were treated according to protocol and only 1 dose-limiting toxicity, a temporary renal insufficiency, occurred at the level of 100 mg/m² BSA, so that this level was repeated successfully with another 3 patients. The results of this study including pharmacological and pharmacokinetic data demonstrated that a dose of 100 mg cisplatin/m² was safe and feasible [23]. There was no increase in perioperative morbidity, and, in addition to HIPEC, all patients received standard therapy.…”