Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study
Introduction
Ovarian cancer is a rare disease with a life-time risk of 1 · 7% [1]. It is, however, the most lethal of all pelvic malignancies with recurrence rates of 60–85% within five years after primary treatment [1], [2]. Recurrent ovarian cancer is difficult to treat and intravenous chemotherapy with platinum compounds, taxanes, anthracyclines, gemcitabine, topotecan, and trabectedin in various combinations and sequences are typically used. These regimens achieve median overall survival rates after the first, second, third, fourth, and fifth relapses of 17.6 (95% CI 16.4–18.6), 11.3 (10.4–12.9), 8.9 (7.8–9.9), 6.2 (5.1–7.7) and 5.0 (3.8–10.4) months, respectively [2].
Intraperitoneal chemotherapy (IPC) in patients with recurrent ovarian cancer is an experimental approach limited by poor drug distribution and tumor penetrance [3], [4], [5], [6]. One potential way to overcome the pharmacokinetic limitations of IPC is to apply chemotherapy as a pressurized aerosol in order to take advantage of the physical properties of gas and pressure [1]. This approach is based on the assumption that intraabdominal application of chemotherapy under pressure will enhance tumor drug distribution and uptake [7], [8], [9]. In an animal model using five pigs PIPAC had a better distribution of a pressurized test dye within the abdominal cavity and a better penetration into the peritoneum compared to peritoneal lavage [10]. In addition, improved drug penetration was suggested in an ex vivo study using a fluorescence-marked non-toxic therapeutic agent (Dbait) [11].
Based on these experimental data, pressurized intraperitoneal aerosol chemotherapy (PIPAC) with doxorubicin and cisplatin was applied to three end-stage patients with recurrent peritoneal carcinomatosis (PC) [12]. In these preliminary applications, PIPAC resulted in high local tumor concentrations of doxorubicin (4.1 μmol/g) and induced regression of peritoneal nodules with limited hepatic and renal toxicity. In a case series of 18 patients with recurrent ovarian cancer and PC, PIPAC led to an objective tumor response in six patients with an acceptable toxicity [13]. In addition, PIPAC has been shown to be safe regarding occupational health aspects such as operation theater air contamination with aerosol chemotherapy particles [14].
Based on this preliminary information, we tested PIPAC with cisplatin and doxorubicin in patients with recurrent, platinum-resistant ovarian, fallopian, or peritoneal cancer and PC (ROCPC) in a phase 2 trial.
Section snippets
Materials and methods
Women with ROCPC after at least two lines of standard systemic chemotherapy were eligible for enrolment in this open-label, single-arm, phase 2 study. Specifically, women with ‘platinum-sensitive’ recurrence, i.e. recurrence > 6 months after completion of the adjuvant chemotherapy, were required to have undergone at least two chemotherapy lines in addition to the adjuvant regimen. Women with ‘platinum-resistant’ recurrence, i.e. recurrence within 6 months after completion of the adjuvant
Results
64 patients with ROCPC were accrued and enrolled between Feb 11, 2013, and Feb 17, 2014, and the data were locked on Sep 13, 2014. Laparoscopic non-access rate was 11/64 (17%). 53 patients received at least one cycle of the study medication (intention-to-treat [ITT] population) and are thus included in the safety and efficacy analyses. 34 patients underwent 3 cycles of PIPAC (per-protocol [PP] population). Nine and 10 patients underwent 2 cycles and 1 cycle of PIPAC, respectively. In these 19
Comment
Our study shows that PIPAC with intraperitoneal cisplatin and doxorubicin is active and well tolerated in women with ROCPC with 62% of patients in this trial achieving a clinical benefit. Histological tumor response and PCI improvement were seen in 62% and 76% of patients, respectively. Of note, QoL scores for global physical health, nausea/vomiting, appetite loss, diarrhea, constipation, physical health, cognitive health, fatigue, and emotional scores improved during therapy. The mean time to
Conflict of interest statement
One of the authors (MAR) discloses that he is holding a patent of the high-pressure device used to deliver the intraperitoneal chemotherapy described in this paper and that he has received royalties from Reger Medizintechnik GmbH, Rottweil, Germany. The other authors have no conflicts of interest.
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