Elsevier

Gynecologic Oncology

Volume 132, Issue 2, February 2014, Pages 307-311
Gynecologic Oncology

Activity of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with cisplatin and doxorubicin in women with recurrent, platinum-resistant ovarian cancer: Preliminary clinical experience

https://doi.org/10.1016/j.ygyno.2013.11.022Get rights and content

Highlights

  • In a prospective case series, 34 Pressurized IntraPeritoneal Aerosol Chemotherapies (PIPAC) were applied in 18 women with recurrent ovarian cancer.

  • Survival after 400 days was 62% and mean actuarial survival time was 442 days.

  • Eight women had repeated PIPAC and objective tumor response was observed in 6.

Abstract

Objective

To assess the activity of laparoscopic Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in women with recurrent, platinum-resistant ovarian cancer.

Methods

Prospective case series using repeated courses q 28–42 days of PIPAC containing cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2 at 12 mm Hg and 37 °C for 30 min. Objective tumor response was defined as tumor regression on histology and peritoneal carcinomatosis index (PCI) improvement on repeated video-laparoscopy.

Results

34 PIPAC procedures were performed in 18 women, in 8 instances combined with cytoreductive surgery (CRS). Eight women had repeated PIPAC and objective tumor response was observed in 6 (complete remission: 1; partial remission: 2; stable disease: 3). Five adverse events WHO grade  2 were noted, 3 of them after combined CRS. No perioperative mortality occurred. Median follow-up was 192 days (min. 13–max. 639). Cumulative survival after 400 days was 62% and mean actuarial survival time was 442 days. In a multivariable regression analysis with objective tumor response (yes vs. no) as the dependent variable and PIPAC (1 vs. > 1), patient age (< 75 vs.  75 years), serum CA-125 (< 1000 vs. > 1000 U/mL), and the presence of ascites (yes vs. no) as independent variables, PIPAC independently predicted objective tumor response.

Conclusion

PIPAC has activity in women with recurrent, platinum-resistant ovarian cancer and should be investigated in prospective clinical trials.

Introduction

In women with a diagnosis of ovarian cancer, disease recurrence will eventually occur in 60 to 85% of cases within five years after primary treatment [1]. Intravenous chemotherapy with platinum compounds, taxanes, anthracyclines, gemcitabine, topotecan, and trabectedin in various combinations and sequences are the mainstay of recurrence treatment with median survival rates between 4 and 10 months [2]. Intraperitoneal chemotherapy (IPC) in the clinical setting of recurrent ovarian cancer is an experimental approach. Although proven to be effective in the adjuvant setting, IPC has not been demonstrated to improve survival in clinical trials in women with recurrent disease. The potential of IPC to improve survival, however, may be high, given its potential to prolong progression-free and overall survival of patients with minimal residual disease after initial surgery [3], [4], As of yet, intraabdominal treatment strategies in recurrent ovarian cancer have been assessed in phase I and II trials predominantly in patients with malignant ascites. Agents used in these studies include chemotherapy compounds as well as antiangiogenic agents such as bevacizumab, the vascular endothelial growth factor-trap, and the trifunctional anti-EPCAM antibody catumaxomab [5]. Pharmacological limitations such as poor drug distribution within the abdominal cavity and poor penetration into peritoneal nodules have limited the success of IPC in women with recurrent disease and high disease volume [6]. Therefore, it has been claimed that innovative concepts overcoming these limitations should be explored in order to improve the efficacy of IPC [6], [7].

One potential way to overcome the pharmacokinetic limitations of IPC is to apply IPC as a pressurized aerosol in order to take advantage of the physical properties of gas and pressure [7]. This approach is based on the assumption that intraabdominal application of chemotherapy under pressure will enhance tumor drug uptake [8], [9]. As proof of concept, pressurized IPC achieved a superior distribution on the peritoneum and a better penetration into peritoneal nodules compared to conventional IPC in an ex vivo model [10]. In addition, an in vivo experimental study using five pigs yielded a better distribution of a pressurized test dye within the abdominal cavity and a better penetration into the peritoneum compared to peritoneal lavage [11]. Specifically, the stained peritoneal surface was larger after pressurized aerosol application compared with peritoneal lavage, and staining was more intense. Hidden peritoneal surfaces as well as the anterior abdominal wall were only stained in the pressurized aerosol group and the outer aspect of the peritoneal membrane was immediately stained after pressurized spraying. Experimental evidence suggests that pressurized application of a chemotherapeutic compound may result in improved tumor penetration. This hypothesis was tested in an ex vivo human peritoneal carcinomatosis tissue study [10]. In this study, a fluorescence-marked non-toxic therapeutic agent (Dbait) was detected within the tumor up to 1 mm depth in the therapeutic capnoperitoneum sample, whereas no uptake was observed in the lavage sample. In addition, biological results showed intranuclear phosphorylation of H2AX in the therapeutic capnoperitoneum sample and no activity in the lavage sample. These data suggest, but do not prove, that pressurized application of chemotherapeutic agents may also result in better penetration. Based on these data, Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) has been tested in humans with recurrent peritoneal carcinomatosis (PC) [12]. In these preliminary applications, PIPAC induced regression of peritoneal nodules with limited hepatic and renal toxicity. Specifically, gamma-glutamyltransferase was significantly elevated in the early postoperative phase, whereas aspartate aminotransferase, alanine aminotransferase, bilirubin levels, Quick-test, and serum creatinine levels were not influenced by the procedure [13]. In addition, the procedure has been shown to be safe regarding occupational health aspects such as operation theater air contamination with aerosol chemotherapy particles [14]. Here, we report on the procedures and outcomes of a preliminary series of 21 patients with recurrent, platinum-resistant ovarian cancer and PC treated with PIPAC in a compassionate use program between December 2011 and June 2013. We aimed to test the hypothesis that PIPAC is feasible, can induce histologic tumor regression and achieve a tumor response in women with recurrent, platinum-resistant ovarian cancer and PC comparable to what has been observed in patients with other malignancies [12], [13], [14].

Section snippets

Materials and methods

Between December 2011 and June 2013, 21 women with recurrent ovarian cancer were recruited. Institutional review board approval for a compassionate use program using PIPAC in women with PC was obtained. All women signed an informed consent form and underwent laparoscopy during which PIPAC was applied intraabdominally. The inclusion criteria were as follows:

  • 1.

    clinical and/or radiological evidence of PC,

  • 2.

    age between 18 and 85 years with a diagnosis of recurrent ovarian cancer with disease progression

Results

Twenty-one women were recruited. Of these, 16 women were diagnosed with ovarian cancer, 4 with primary peritoneal cancer, and one with primary fallopian tube cancer. The mean age was 63 ± 13 years. Ascites and pleural effusion were present in 16 and 9 women, respectively. Patient characteristics including the number of previous chemotherapy lines are shown in Table 1. In 3/21 women, PIPAC was attempted, but not performed due to abdominal adhesions precluding laparoscopy. Further analyses are

Comment

In this preliminary series of 18 women with recurrent, platinum-resistant ovarian cancer, PIPAC was well tolerated and achieved an objective tumor response in 6/8 cases with > 1 PIPAC. Complete remission, partial remission, and stable disease were observed in 1, 2, and 3 women, respectively and the cumulative survival after 400 days was 62%. This suggests that PIPAC may be a palliative treatment option for selected women with recurrent ovarian cancer, deserving further assessment in prospective

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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