First Indian Study on Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Procedure for Advanced Peritoneal Carcinomatosis Secondary to Epithelial Ovarian Cancer

  • S. P. Somashekhar
  • Ashwin Kyatsandra Rajagopal
  • Shabber S. Zaveri
  • Rohit Kumar Chandrashekhar
  • Amit Rauthan
  • Sushmita H. Rakshit
Original Article
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Abstract

Background

Peritoneal carcinomatosis is a common evolution in ovarian cancers. Although majority of patients have option of cytoreductive surgery and HIPEC, a few with recurrent cancers who are not eligible for curative approach can undergo pressurized intraperitoneal aerosol chemotherapy (PIPAC) which is an emerging field of research with major therapeutic potential. It is a safe and innovative approach, which enhances the effect of chemotherapy without major toxicity.

Methods

Between June 2017 and December 2017, 9 PIPAC applications in 3 patients with pressurized aerosol solution of cisplatin and doxorubicin every 6 weeks at 37 °C and 12 mmHg for 30 min were performed. The patient demographics, perioperative findings, adverse events, and outcomes were prospectively recorded.

Results

Nine PIPAC administrations were performed in 3 patients with peritoneal carcinomatosis secondary to ovarian cancer. The median hospital stay was 1 day. There were no major perioperative complications. CTCAE grade 2 was observed in 1 patient, for abdominal pain and nausea. Renal and hepatic functions were not impaired. Of the 3 patients, two patients had partial response, and one had stable disease.

Conclusion

Our results show the feasibility and safety of PIPAC in Indian patients with advanced ovarian cancer. The procedure has low morbidity with no mortality with short learning curve. It can be easily adopted as a palliative option apart from systemic chemotherapy.

Keywords

PIPAC Peritoneal carcinomatosis Indian patients CRS HIPEC Intraperitoneal Chemotherapy Ovarian cancer 

Introduction

Peritoneal carcinomatosis (PC) is very common in ovarian cancer, and its 5-year survival depends on its stage which is 15–20% in stage III and only 5% in stage IV patients. Usual treatment approaches such as systemic drugs are not very effective. Most patients die with progression of peritoneal disease. Resistance of PC to systemic chemotherapy is explained by molecular mechanisms and by limited drug distribution [1]. A multimodal treatment based on an aggressive local approach of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with systemic therapy was tried with promising results. There is a considerable body of published evidence supporting the use of this multimodal approach, but unfortunately, only selected patients may undergo this combined procedure and complication rate remains significant so that this therapy is not accepted by all oncologists [2]. Standard treatment is radical surgery with adjuvant chemotherapy. CRS and HIPEC can only be offered to highly defined set of patients, taking into consideration the tumor type, the extent of disease, invasion of the small bowel and the general condition of the patient [3]. But in many cases recurrence is very common with poor outcome. Thus, there is a need to develop new therapies for these majority of peritoneal metastasis patients not eligible for CRS and HIPEC.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering normothermic chemotherapy into the abdominal cavity as an aerosol under pressure. This concept seems to enhance the effectiveness of intraperitoneal chemotherapy by taking advantage of the physical properties of gas and pressure by generating an artificial pressure gradient and enhancing tissue uptake and distributing drugs homogeneously within the closed and expanded peritoneal cavity. Thus, due to the high local bioavailability during PIPAC, the chemotherapy dosage can be reduced which in turn largely prevents systemic side effects and organ toxicity.

Preliminary experiences reported in the literature has documented the positive outcome of applying pressure into the peritoneal cavity [4, 5, 6], by counterbalancing the elevated tumoural interstitial fluid pressure [7] and enhancing drug depth penetration with superior distribution. Early studies in patients with peritoneal metastases secondary to ovarian [8] or other abdominal cancers [9, 10] have shown some efficacy and good tolerability; in particular, PIPAC does not induce either significant liver or renal toxicity [11] or significant gastrointestinal symptoms [12]. There is an obvious medical need for better therapeutic options in peritoneal metastasis prolonging survival and preserving QoL by reducing both disease-related symptoms and therapy side effects.

In experimental animal model studies PIPAC resulted in a higher local concentration with deeper tissue penetration of drugs [13, 14]. The first application of PIPAC in 2011 was well tolerated, with regression of size of peritoneal nodules observed and its superior pharmacological properties confirmed. Systemic drug concentration in PIPAC remained low with no local complications and almost no hepatic and renal toxicity [15, 16].

PIPAC is currently used for palliative setting in selected patients with trials ongoing. We report the technical aspects, our observations and outcomes with PIPAC procedure in Indian patients with advanced ovarian cancer.

Methods

PIPAC programme for patients with advanced peritoneal carcinomatosis was introduced at Manipal Comprehensive Cancer Centre from June 2017. Training was provided to educate the healthcare providers about the technical and safety aspects of the procedure.

Patients with histologically verified peritoneal metastasis secondary to epithelial ovarian cancer were taken up to study the outcome of PIPAC. These patients were presented in the interdisciplinary tumour board, and the indication for therapy was decided on a case-by-case basis. PIPAC was offered when option of CRS and HIPEC was not possible because of poor general condition (ECOG ≥ 2), advanced PCI, and/or unresectability because of diffuse small bowel involvement. Patients were eligible if they had blood and electrolyte counts, liver, renal, and cardiopulmonary function parameters within 10% of the normal range. All patients were counselled, and their informed consent was obtained. The institutional review board and ethics committee approval was obtained.

The data were documented according to institutional rules, including electronic archiving and video recording of the procedures. Histological tumour response was assessed by an oncopathologist. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE).

Technique of PIPAC

All operations were performed under general anaesthesia; a standard operating protocol was followed with emphasis on handling and exposure to chemotherapy. An antibiotic prophylaxis with a single dose of cefuroxime 1.5 g IV was administered 30 min before surgery.

After insufflation of a 12 mmHg pneumoperitoneum (with open access or Veress needle), two 5-mm trocars were inserted into the abdominal wall. Ascites was aspirated and sent for cytology testing. Extent of peritoneal carcinomatosis was determined based on PCI score. A centimetric local peritonectomy was performed for peritoneal biopsies in all cases to improve accuracy of anatomopathology. The generation of aerosol requires a disposable 9-mm microinjector (Capnopen®, Capnomed, Villingendorf, Germany) which was connected to an intravenous high-pressure injector (AngiomatIllumena Injector®, LiebelFlarsheim, USA) and inserted into the abdomen through a 12-mm access port.

Safety measures were taken to prevent any exposure of drugs to the operating team [17]. The procedure was performed in an operating room equipped with laminar air flow. Tightness of the abdomen was documented via a zero flow of CO2 to prevent OT contamination. The chemotherapy injection was remote-controlled, and nobody remained in the operating room during the application. The laparoscopic and anaesthesia monitors are oriented towards the OT door window to facilitate monitoring by the doctors from outside (Fig. 1).
Fig. 1

OT setup during PIPAC procedure. All the OT personnel must be out during the procedure. The chemotherapy drug is sprayed intraperitoneally by the Capnopen which is connected to the high-pressure injector

The patients were treated with pressurized aerosol of cisplatin 7.5 mg/m2 in 150 ml NaCl 0.9% solution followed by doxorubicin 1.5 mg/m2 in 50 ml NaCl 0.9% solution [8]. Aerosol flow rate was 30 ml/min, and maximal upstream pressure was 200 psi as per recommendation. The therapeutic capnoperitoneum was then maintained for 30 min. Then, the chemotherapy aerosol was released safely via a closed aerosol waste system into the air waste system of the hospital or by a Buffalo Filter. Trocars were retracted, and laparoscopy was ended. No drainage of the abdomen was placed. Patients were discharged the following day if there were no adverse effects [17] (Fig. 2).
Fig. 2

Diagrammatic representation of pressurized intraperitoneal aerosol chemotherapy.

(Reproduced from Ref. [15] after permission Prof Marc Reymond)

Data of all patients who underwent PIPAC procedure were included in a prospectively maintained database. Safety, tolerability, and postoperative complications were assessed by physical examination results and laboratory assessments, and adverse events were recorded according to CTCAE criteria.

The four-tier Peritoneal Regression Grading Score (PRGS) was used for assessment of histological response. It allows to maximize staging accuracy in treatment after PIPAC and facilitates comparison by using an uniform terminology and staging system [8]. The proposed scale ranges from 1 (complete response) to 4 (no response) and is based on typical histological features of regression including fibrotic changes, necrosis, and presence of acellular mucin deposits [18].

Results

A total of 9 successful PIPAC procedures were carried out in 3 patients with PC secondary to epithelial ovarian cancer. Two patients had ECOG performance of 2, and the last had performance status of 1. All three patients were symptomatic with abdominal pain and/or sub-acute obstruction. All patients were pretreated with systemic chemotherapy.

Patient characteristics and preoperative details are summarized in Table 1. In one patient, entry to the abdominal cavity was difficult because of adhesions and minimal adhesiolysis had to be performed for port access. Mean operating time was 98.6 min (80–120). No intraoperative complications or allergic reactions were noted. The mean hospital stay was 1.6 (range 1–3), and median stay was 1 day. Mean PCI was 19.6 (range 17–23). PIPAC was well tolerated with acute and cumulative local toxicities of PIPAC under control, and no severe side effects were observed. Adverse events were noted and graded as per CTCAE. Abdominal pain CTCAE ≤ 2 was noted in one patient. None of the patients needed reoperation. There was no postoperative mortality. The operative findings and perioperative outcomes are described in Table 2.
Table 1

Patient characteristics and preoperative details

Variable

Value

No. of patients

3

Age, years (median)

43

PCI, mean

19.2

ECOG, median

2

Previous surgery

3 (100%)

Previous systemic chemotherapy

 ≥ 2 lines

2

 1 line

1

Table 2

Operative findings and perioperative outcomes

Patient

Previous chemotherapy

PCI before PIPAC

Ascites

PIPAC procedures

Chemotherapy used

Operative time (min)

Hospital stay (days)

Adverse effects (CTCAE 1–4)

Peritoneal Regression Grading Score [18]

1

2 lines

17

Absent

3

Cisplatin + Doxorubicin

100

1

Nil

3

2

1 line

23

Present

3

Cisplatin + Doxorubicin

120

1

Nil

2

3

2 lines

19

Present

3

Cisplatin + Doxorubicin

110

3

Pain (2)

2

All the patients completed 3 cycles of PIPAC, and histological response assessment was performed by an oncopathologist by the Peritoneal Regression Grading Score. The four-tier PRGS is defined as grade 1: complete response; grade 2: major response; grade 3: minor response; and grade 4: no response. Two patients had partial response, and one had stable disease (Fig. 3).
Fig. 3

Intraoperative laparoscopy findings before pressurized intraperitoneal aerosol chemotherapy (PIPAC) (left upper panel) and post-PIPAC changes (right upper panel) confirming major response after 3 sittings. Before PIPAC, histology showed peritoneal infiltration by a poorly differentiated ovarian adenocarcinoma (left lower panel). Follow-up biopsies showed sustained regressive tumour changes, fibrosis, and acute and chronic inflammation (right lower panel)

Discussion

PIPAC is an innovative intraperitoneal chemotherapy concept that seems to enhance the effectiveness by taking advantage of the physical properties of gas and pressure. A “therapeutic capnoperitoneum” is created where aerosolized chemotherapy is sprayed in the carbon dioxide pneumoperitoneum. A minimum of 3 sittings is needed to observe any response. The intra-abdominal pressure increases tissue uptake and intratumoural drug concentration [4, 6], and the aerosolization of the chemotherapy agent creates micron-size drug particles reducing the average diameter of a chemotherapeutic infusion and forms a thin film of microdroplets over the entire peritoneal cavity, increasing the contact surface area between drugs and tissues. PIPAC pharmacokinetics permits homogenous drug distribution with a minimal drug dose (1/10 the dose of systemic chemotherapy). The other advantages include easy to perform with minimal learning curve, good tolerance, and being able to perform multiple applications at 6 weekly interval. It can be performed concurrently with systemic chemotherapy, especially in patients with advanced stage of peritoneal carcinomatosis having ascites and complaints of abdominal pain or sub-occlusive intestinal symptoms [15].

PIPAC induced high response rates with minimal adverse events and demonstrated its ability to induce the regression of chemoresistant peritoneal metastases [9].The pharmacological superiority of this drug delivery system over systemic delivery and conventional intraperitoneal chemotherapy for treating peritoneal metastasis is already clear [13, 14, 15], inducing high response rates with low adverse events [8, 19]. Owing to the limited penetration of chemotherapy into tumour nodules, intraperitoneal chemotherapy may be best suited for small volume disease [20].

In our series local toxicity of PIPAC was acceptable even with repeated delivery. No patient developed bowel perforation, and no severe gastrointestinal symptoms were registered. These results are in accordance with those reported in similar studies [16]. In accordance with previous observations [8, 16, 19], no significant renal toxicity was documented, probably due to 90% dose reduction as compared to systemic chemotherapy. In patients presenting with worsening quality of life because of peritoneal disease diffusion, the combination of the two treatments enables rapid symptom palliation with PIPAC. In our patients, symptomatic relief and ascites resolution were seen in all the patients. Response was very encouraging with two patients having partial response and one with stable disease.

The safety guidelines have been well established, and following this set of protocol ensures that PIPAC is safe and easily reproducible. Selection is important as patients with multiple abdominal surgeries, intestinal obstruction and poor performance status are unlikely to tolerate or derive any benefit.

PIPAC may not only be considered a palliative treatment, but in combination with systemic chemotherapy, with appropriate drug doses, it could possibly become part of the standard therapeutic course of peritoneal carcinomatosis.

Conclusion

Patients with advanced peritoneal carcinomatosis who are not candidates for curative resection have option of palliative systemic chemotherapy.

PIPAC is simple and easily reproducible with no postoperative major toxicity, and the tolerance of the procedure is usually excellent. Although there is no level 1 evidence that it can be used in palliative setting, this combined treatment as well as being ethically accepted may be a useful strategy for these patients.

Our results obtained in a small cohort of patients show safety and feasibility of PIPAC. Prospective studies are needed in order to expand the cohort of patients who can most benefit from this treatment. These studies may improve the technique and assess whether this combination therapy could become part of the standard treatment for peritoneal carcinomatosis.

Notes

Compliance with ethical standards

conflict of interest

The authors declare that, they have no conflict of interest

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Copyright information

© Association of Gynecologic Oncologists of India 2018

Authors and Affiliations

  • S. P. Somashekhar
    • 1
  • Ashwin Kyatsandra Rajagopal
    • 1
  • Shabber S. Zaveri
    • 1
  • Rohit Kumar Chandrashekhar
    • 1
  • Amit Rauthan
    • 2
  • Sushmita H. Rakshit
    • 3
  1. 1.Department of Surgical Oncology, Manipal Comprehensive Cancer CenterManipal HospitalBangaloreIndia
  2. 2.Department of Medical Oncology, Manipal Comprehensive Cancer CenterManipal HospitalBangaloreIndia
  3. 3.Pathology DepartmentManipal HospitalBangaloreIndia

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