Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study

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Highlights

  • Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was studied in women with recurrent ovarian cancer.

  • Tumour regression on histology was observed in 26/34 (76%).

  • Quality of life including physical health, nausea/vomiting, appetite loss, diarrhea, and constipation improved during therapy.

Abstract

Objective

Recurrent ovarian, fallopian or peritoneal cancer with peritoneal carcinomatosis (ROCPC) is resistant to systemic chemotherapy. We assessed the safety and activity of laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with this cancer.

Methods

In this open-label, single-arm phase 2 study, patients underwent 3 courses q 28–42 days of PIPAC with doxorubicin 1 · 5 mg/m2 followed by cisplatin 7 · 5 mg/m2. A pressure of 12 mm Hg and a temperature of 37 °C were applied for 30 min/course. The primary endpoint was the proportion of patients who had an objective tumor response (OTR) according to RECIST version 1.1 criteria. Analysis was by intention to treat. Secondary endpoints were tumor regression on histology, PC Index improvement on repeated video-laparoscopy, and quality of life measured with the EORTC QLQ-30 questionnaire.

Results

Sixty-four patients were enrolled. Laparoscopic non-access rate was 11/64 (17%). 53 patients were eligible for analyses. 33/53 (62%) patients had an OTR — three had a partial response and 30 patients had stable disease. Tumor regression on histology and PC Index improvement were observed in 26/34 (76%) and in 26/34 (76%) patients who underwent all 3 PIPACs. There were no treatment-related deaths. No grade 4 toxicity was observed. Grade 3 toxicities were trocar hernia (n = 2), bowel obstruction (n = 2), abdominal pain (n = 2), hematoma (n = 1), intraoperative bleeding (n = 1), and cystitis with urosepsis (n = 1). EORTC QLQ-30 global physical health scores, nausea/vomiting, appetite loss, diarrhea, and constipation improved during therapy.

Conclusion

PIPAC is well tolerated and active in women with ROCPC and warrants further investigation in these patients.

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.

References (19)

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    The drug dose administered by PIPAC is seven to ten times less than that used intravenously, which limits adverse effects of the chemotherapy. PIPAC has been applied to PC of all origins [3–10], and performed in more than 39 countries worldwide [11]. Several recent studies have provided evidence that a therapeutic regimen combining PIPAC and systemic chemotherapy provides improved survival in the treatment of PC, without altering quality of life (QOL), even improving it [3,4,12–17].

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