YGYNO-975804; No. of pages: 6; 4C: 4 Gynecologic Oncology xxx (2015) xxx–xxx

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Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study Clemens B. Tempfer a,⁎, Guido Winnekendonk b, Wiebke Solass c, Reinhard Horvat d, Urs Giger-Pabst c, Juergen Zieren c, Guenther A. Rezniczek a, Marc-André Reymond c a

Department of Obstetrics and Gynecology, Ruhr University Bochum, Bochum, Germany Department of Radiology, Ruhr University Bochum, Bochum, Germany Department of Surgery, Ruhr University Bochum, Bochum, Germany d Department of Pathology, Medical University of Vienna, Vienna, Austria b c

H I G H L I G H T S • 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.

a r t i c l e

i n f o

Article history: Received 19 January 2015 Accepted 11 February 2015 Available online xxxx Keywords: Recurrent ovarian cancer Platinum-resistant Chemotherapy Intraabdominal High pressure

a b s t r a c t 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. © 2015 Elsevier Inc. All rights reserved.

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, ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Ruhr University Bochum-Marienhospital Herne, Hoelkeskampring 40, 44625 Herne, Germany. Fax: +49 2323 499 393. E-mail address: [email protected] (C.B. Tempfer).

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 [3–6]. One potential way to overcome the

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Please cite this article as: Tempfer CB, et al, Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.009

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C.B. Tempfer et al. / Gynecologic Oncology xxx (2015) xxx–xxx

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 [7–9]. 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. Materials and methods Women with ROCPC after at least two lines of standard systemic chemotherapy were eligible for enrolment in this open-label, singlearm, phase 2 study. Specifically, women with ‘platinum-sensitive’ recurrence, i.e. recurrence N 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 chemotherapy, were required to have undergone at least one chemotherapy line in addition to the adjuvant regimen. Lastly, women with ‘platinum-refractory’ recurrence, i.e. recurrence during the adjuvant chemotherapy, were required to have undergone at least one chemotherapy line in addition to the adjuvant regimen. Using these criteria, all women entering the study had a platinum-resistant tumor at the time of study entry. Institutional review board approval for this study was obtained (Ethics Committee of the Ruhr University Bochum, Bochum, Germany; registry number 4515-12 FF; issue date Jan 28, 2013). This study was approved by the German national drug safety agency (BfArM; registry number 61-39104039261). This study was registered with ClinicalTrials.gov, number NCT01809379, and EudraCT, number 2012-004397-26. All women signed an informed consent form. Women were eligible, if they had clinical and/or radiological evidence of PC; an age between 18 and 85 years; a good performance status (Karnofsky Index N 70%), a diagnosis of recurrent disease with disease progression; blood, electrolyte counts, liver, and renal function parameters within 10% of the normal range established in the laboratory of the study institution; had provided written informed consent, and were postmenopausal or ovariectomized. Women were ineligible, if they had extraabdominal metastatic disease including retroperitoneal disease such as aortic/paraaortic lymph node recurrence with the exception of isolated pleural carcinomatosis/ effusion; had underwent chemotherapy or surgery within the last four weeks prior to study enrolment or a previous treatment with the maximum cumulative dose of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones; had a history of allergic reactions to cisplatin or other platinum containing compounds or doxorubicin; had severe renal impairment or severe hepatic impairment with organ-specific functional parameters Ntwice the upper norm; had a history of myocardial insufficiency not controlled by concurrent medication, severe cardiac arrhythmia not controlled

by concurrent medication, or recent myocardial infarction or myelosuppression; had an immunocompromised status such as immunosuppressive therapy or a known disease of the immune system; were previously enrolled in the present study; and had underwent any form of previous intraabdominal chemotherapy or intraabdominal antibody therapy. Also, women were not allowed to undergo any cancer-specific treatment during the trial. Secondary debulking surgery was not allowed during PIPAC treatment. The PIPAC procedure was performed as follows: after insufflation of a 12 mm Hg CO2 pneumoperitoneum, two balloon safety trocars (5 and 12 mm, Applied Medical, Duesseldorf, Germany) were inserted into the abdominal wall in an operating room equipped with laminar airflow. Video documentation was started and the PC Index (PCI) was determined according to Sugarbaker, based on lesion size and distribution [15]. Using a pictorial of the abdomen, each location of a 13 point list (central abdominal wall, epigastrium, right lower abdominal wall, right upper abdominal wall, right flank, left lower abdominal wall, left upper abdominal wall, left flank, pelvis, upper jejunum, lower jejunum, upper ileum, lower ileum) received a peritoneal carcinomatosis grade ranging from 0 to 3, i.e. no visible carcinomatosis, isolated tumor nodules, multiple tumor nodules, and confluent lesions. The sum of all 13 grades was noted as PCI. A biopsy was taken for histologic confirmation of PC during the first procedure and all following procedures in order to ascertain tumor regression. Ascites volume was documented and ascites was removed. Then, a nebulizer (Reger Medizintechnik, Rottweil, Germany) was connected to an intravenous high-pressure injector (Mark 7 Arterion®, Medrad, Germany) and inserted into the abdomen. The tightness of the abdomen was documented via a zeroflow of CO2. A pressurized aerosol containing cisplatin at a dose of 7 · 5 mg/m2 body surface in a 150 ml NaCl 0.9% solution followed by doxorubicin at a dose of 1 · 5 mg/m2 body surface in a 50 ml NaCl 0.9% solution were applied via a nebulizer and an injector. The dosage used in this cohort study was based on previous clinical experience in patients with peritoneal carcinomatosis treated with PIPAC in this dosage and formulation [12,13]. Injection parameters were set at a flow rate of 30 ml/min and a maximum upstream pressure of 200 psi in the high-pressure injector. The injection was remote-controlled to minimize personnel exposure. After application of both drugs, the therapeutic capnoperitoneum was maintained for 30 min at a temperature of 37 °C. Then, the chemotherapy aerosol was exsufflated via a closed line over two sequential microparticle filters into the airwaste system of the hospital. Finally, trocars were retracted and laparoscopy ended. No drainage of the abdomen was applied. The PIPAC procedure was repeated three times every 4–6 weeks. Concomitant cytoreductive surgery was not allowed per protocol. The primary endpoint of the study, objective tumor response (OTR), was measured according to RECIST criteria, version 1.1 at the end of treatment cycle 3 [16]. Peritoneal, sub-peritoneal, visceral, and pleural manifestations were assessed separately. CT scans were assessed by the Radiology Department, Ruhr University Bochum, Marienhospital Herne. In addition, patients of the per-protocol (PP) population were asked to present for a follow-up CT scan 3 months after completion of 3 PIPAC cycles. CT scans of these patients were then collected, anonymized, and scored by a board-certified radiologist (GW), blinded to previous CT results and all clinical data. Histologic regression was assessed by the Department of Pathology, Ruhr University Bochum, Klinikum Bergmannsheil. In addition, all slides were collected, anonymized, and scored by a board-certified gyneco-pathologist (RH), blinded to the previous histological diagnoses and all clinical data. Histopathological tumor regression was graded as follows: vital tumor cells, mild regression, strong regression, and no tumor cells as previously described [17]. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [18]. In addition, we measured C-reactive protein (CRP) and creatinine in the serum on the day before, the first day after, and the third day after each cycle of

Please cite this article as: Tempfer CB, et al, Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.009

C.B. Tempfer et al. / Gynecologic Oncology xxx (2015) xxx–xxx

PIPAC. A doubling of the initial CRP value was defined as grade 1 adverse event and a tripling of the initial CRP value as grade 2 adverse event. Quality of life was measured by the EORTC QLQ-C30 questionnaire, a validated tool for assessing quality of life in cancer patients [19]. Quality of life was recorded one the day before each PIPAC. All p-values are two-tailed and a p-value b 0.05 was considered statistically significant. The sample size was calculated on the basis of a Simon two-stage design for a phase 2 study. Based on clinical trials of women with recurrent ovarian cancer undergoing experimental chemotherapy regimens after ≥2 lines of standard chemotherapy reporting a clinical benefit rate (CBR) of 25–60%, we regarded a proportion of patients with a CBR of 40% or more as proof of efficacy of PIPAC in this patient population and of less than 20% as insufficient to continue the assessment. Assuming a risk of α = 0.05 (type I error) and β = 0.10 (type II error), we needed to include 45 patients. Analysis was by intention to treat. Assuming a drop-out rate of 10%, we intend to recruit at least 50 women for this trial. Analysis was performed using nonparametric tests since data were not normally distributed. Values are given as medians. Survival was modeled in a Kaplan–Meier survival curve. We used the statistical software SPSS 11.0 for Windows (SPSS 11.0, SPSS Inc., Chicago, IL) for statistical analysis.

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 women the second and/or third PIPACs were not performed due to clinical disease progression. The flow of the patients through the study is shown in Fig. 1. A protocol violation occurred in one patient.

Screening (February 2013 to February 2014) n=97 Enrollment n=64 Failure to Apply 1st PIPAC (Laparoscopic Non-Access Rate) n=11/64 (17%)

Patients With At Least 1 PIPAC Intention-To-Treat (ITT) Population n=53 Patients Not Receiving the Preplanned 3 PIPACs Due to Disease Progression n=19/53 (36%)

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Table 1 Patient characteristics of 53 women with recurrent, platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer undergoing pressurized intraperitoneal aerosol chemotherapy (PIPAC). Patient characteristic

Variable

Number of patients Age (years; mean, ±SD) ECOG performance score 0 1 2 3 Previous chemotherapy regimens (median, range) Previous radiation Presence of pleural effusion Presence of ascites Ascites volume (ml; median, range) PCI (mean, ±SD) Serum CA 125 (U/ml; mean, ±SD) Site of disease Ovary Fallopian tube Peritoneum Cell type Serous papillary adenocarcinoma Mucinous adenocarcinoma Other Previous immunotherapy No Yes Previous surgery No Yes

53 62 (±10) 32 (60%) 20 (38%) 0 1 (2%) 3 (2, 8) None 5/53 (9%) 22/53 (42%) 483 (0, 4500) 16.3 (±9.9) 1558 (±3964) 47 (89%) 2 (4%) 4 (7%) 48 (91%) 1 (2%) 4 (7%) 29 (55%) 24 (45%) 0 53 (100%)

SD, standard deviation; ECOG, Eastern Cooperative Oncology Group; PCI, Peritoneal Cancer Index; ml, milliliter.

This patient had underwent only one prior chemotherapy regimen. She underwent all three PIPAC cycles and was included in the safety and efficacy analyses. In 3/53 patients, no tumor was identified in the peritoneal biopsy specimens taken during PIPAC. These patients had evidence of recurrent disease based on CT scan, serum CA-125, and/or intraoperative PCI assessment and were included in the safety and efficacy analyses. Patient characteristics are given in Table 1. Efficacy In the ITT population, 33/53 (62%) patients had an objective response to treatment. Three patients had a partial response and 30 patients had stable disease. 17 patients progressed and 3 patients were not evaluable for this endpoint. One patient was a screening failure and two patients were lost to follow-up. In a second, blinded radiological analysis of the PP population with 31 eligible patients, response rates were comparable. 16/31 (52%) patients had an objective response to treatment. One patient had a partial response and 15 patients had stable disease. Histological tumor regression was observed in 33/53 (62%) patients in the ITT population and in 26/34 (76%) patients in the PP population. In an external blinded histological Table 2 Histological assessment of tumor regression in 53 women with recurrent, platinumresistant ovarian, fallopian tube, or primary peritoneal cancer undergoing pressurized intraperitoneal aerosol chemotherapy (PIPAC). Population

Patients With All 3 PIPACs According to Protocol Per-Protocol (PP) Population n=34 Patients Lost to Follow-Up n=0

Fig. 1. Flow diagram of the patients' flow through the study.

In house pathological assessment ITT population (n = 53) PP population (n = 34) External blinded pathological assessment ITT population (n = 53) PP population (n = 34)

Moderate regression

Strong regression

Overall regression

21 16

12 10

33/53 (62%) 26/34 (76%)

20 14

18 16

38/53 (72%) 30/34 (88%)

ITT, intention to treat; PP, per protocol.

Please cite this article as: Tempfer CB, et al, Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.009

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Fig. 2. Intraoperative findings (macroscopy) during laparoscopy before the 1st, 2nd, and 3rd pressurized intraperitoneal aerosol chemotherapy (PIPAC) treatment cycles (panels a1, a2, and a3, respectively). During the course of therapy, sclerosis of peritoneal nodules was observed as well as scarring of the visceral and the parietal peritoneum. Corresponding histological specimens taken during the 1st, 2nd, and 3rd PIPACs demonstrated regressive tumor changes, fibrosis, and acute and chronic inflammation (panels b1, b2, and b3, respectively).

assessment of the peritoneal biopsy specimens, results were comparable with regression rates of 38/53 (72%) patients in the ITT population and in 30/34 (88%) patients in the PP population. Table 2 demonstrates moderate, strong, and overall histological regression rates in the ITT and PP populations based on in house and external, blinded assessment. PCI improvement on repeated video-laparoscopy was observed in 26/34 (76%) patients who underwent all 3 PIPACs. Intraoperative findings during laparoscopy before the 1st, 2nd, and 3rd PIPACs are demonstrated in Fig. 2. During the course of therapy, sclerosis of peritoneal nodules was observed as well as scarring of the visceral and the parietal peritoneum. Corresponding histological specimens taken during the 1st, 2nd, and 3rd PIPACs demonstrated regressive tumor changes, fibrosis, and acute and chronic inflammation. Overall survival and progression-free survival curves of the ITT and PP populations are given in Fig. 3. The cumulative overall survival rate of the ITT population after one year was 50% with a mean survival time of 331 days (95% confidence interval [CI] 291–371 days). The mean time to progression was 144 days (95% CI 122–168 days). In the PP population, cumulative overall survival was 63% after one year

with a mean survival time of 407 days (95% CI 347–468). Mean time to progression of the PP population was 174 days (95% CI 150–199). Safety and quality of life There were no treatment-related deaths. No CTCAE grade 4 toxicity was observed. CTCAE grade 3 toxicities were as follows: 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). Acute and chronic toxicities during treatment are reported in Table 3. Quality of life was measured using the EORTC QLQ-30 questionnaire at 3 time points (one day before PIPACs 1, 2, and 3, respectively). Seven, 4, and 6 patients did not fill in the questionnaires and thus had missing values at time points 1, 2, and 3, respectively. Fig. 4 shows EORTC QLQ30 results. Specifically, global physical health scores demonstrated a continuous improvement during therapy. EORTC QLQ-30 global physical health scores were 52 · 0 (95% CI 45 · 8–58 · 3), 58 · 1 (95% CI 50 · 7–65 · 6), and 59 · 5 (95% CI 51 · 3–67 · 6) at time points PIPAC

Fig. 3. Overall survival (panel a) and progression-free survival (panel b) of 53 women who had undergone at least one pressurized intraperitoneal aerosol chemotherapy (intention-totreat population; ITT) and of 34 women who had undergone all three PIPAC cycles (per-protocol population; PP).

Please cite this article as: Tempfer CB, et al, Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.009

C.B. Tempfer et al. / Gynecologic Oncology xxx (2015) xxx–xxx Table 3 Acute and chronic adverse events in 53 patients undergoing pressurized intraperitoneal aerosol chemotherapy (PIPAC). Adverse event

Grade 1

Grade 2

Grade 3

Trocar hernia Abdominal pain Bowel obstruction Hemorrhage Intraoperative bleeding Cystitis Urosepsis Cardiac Neurological Renal Pulmonary Inflammatorya

0 53/53 (100%) 0 0 0 0 0 6 (11%) 1 (2%) 1 (2%) 0 10 (19%)

0 0 0 0 0 1 (2%) 0 0 0 1 (2%) 5 (9%) 25 (47%)

2 (4%) 2 (4%) 1 (2%) 1 (2%) 1 (2%) 0 1 (2%) 0 0 0 0 0

a

Increase of C-reactive protein.

1, PIPAC 2, and PIPAC 3, respectively. EORTC QLQ-30 symptom scores for nausea/vomiting, appetite loss, diarrhea, and constipation decreased during therapy. In addition, physical, cognitive, and emotional scores increased and fatigue scores decreased during therapy. On the other hand, pain and dyspnea scores increased during therapy. 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

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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 progression was 144 days. Together, these data suggest that PIPAC may be a palliative treatment option for selected women with ROCPC. PIPAC should be further investigated in comparative clinical trials. Our data are consistent with previous experience with PIPAC in patients with ROCPC. Anecdotal evidence [12] and retrospective case series [15] demonstrated objective tumor response and histological tumor regression with acceptable local and systemic toxicity. Since CTCAE grade ≥ 3 adverse events were observed previously in women undergoing PIPAC and concomitant cytoreductive surgery [13], we have not allowed debulking procedures in this phase II trial. Our data confirm that PIPAC is safe and efficacious in patients with ROCPC when applied without concomitant cytoreductive surgery. The above cited clinical reports together with the results of our phase II trial indicate that clinical benefit can be achieved in patients with ROCPC. Of note, most women in our trial were heavily pretreated with a median number of 3 and up to 8 prior chemotherapy regimens, indicating that PIPAC may be able to overcome platinum resistance at least in a fraction of women. This may be related to the high local chemotherapy concentrations achieved by the intraabdominal application [10,11]. Another factor may be the chemical peritonitis induced by intraabdominal application of cytotoxic drugs. Consistent with this assumption, we observed that 35/53 (66%) patients had marked transient elevations of C-reactive protein indicating some form of local inflammatory response to PIPAC.

Fig. 4. Quality of life scores according to the EORTC QLQ-C30 questionnaire during pressurized intraperitoneal aerosol chemotherapy (PIPAC) treatment cycles 1–3. GHS = global health score; QoL = quality of life.

Please cite this article as: Tempfer CB, et al, Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.009

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A potential beneficial aspect of PIPAC compared with systemic cytotoxic chemotherapy may be its side effect profile. In order to objectify the impact of PIPAC on the quality of life of study participants, we have systematically measured quality of life scores using the EORTC QLQ-30 questionnaire. Global physical health scores continuously improved from PIPAC 1 to PIPAC 2 and to PIPAC 3. It is of note that gastrointestinal scores such as those for nausea/vomiting, appetite loss, diarrhea, and constipation decreased during therapy. This indicates that PIPAC stabilizes PC and leads to an improvement of bowel function. In addition, physical, cognitive, and emotional scores improved and fatigue scores decreased during therapy supporting the notion that the study patients experienced a clinical benefit from PIPAC. Notorious systemic side effects of chemotherapy such as alopecia, peripheral neurotoxicity, nausea, and myelosuppression did not occur with PIPAC. PIPAC is a local therapy and local abdominal pain after PIPAC was expected based on previous experience with intraperitoneal chemotherapy [3,4,6]. In the present study, EORTC QLQ-30 pain scores increased during treatment and all patients reported at least some form of abdominal pain. Of note, 4% of patients experienced CTCAE grade 3 abdominal pain. These results underscore the need for an adequate pharmacological pain control when using PIPAC. Pleural carcinomatosis and pleural effusion with dyspnea and discomfort are common symptoms in patients with ROCPC [1,2]. PIPAC is a strictly local abdominal treatment and therefore it cannot address this therapeutic need. Consequently, EORTC QLQ-30 dyspnea scores continuously increased during PIPAC treatment. This is a limitation of this therapy and underscores the need for close monitoring of these patients. However, an alternative explanation for the increased rate of dyspnea during PIPAC is tumor-associated fatigue. Therefore, pleural effusions should be ruled out with radiologic imaging in symptomatic patients undergoing PIPAC. This phase II study has limitations. First, patients in this trial were highly selected. For example, women with liver and lung metastases were excluded. Thus, the external validity of this study is limited. Second, the number of patients in this phase II trial may obscure rare adverse events and toxicities. Also, we have no long-term follow-up data and cannot rule out late adverse events such as bowel sclerosis. Scarring of the tumor nodules attached to the bowel has been observed on videolaparoscopy and 11% of the patients had CTCAE grade 1 cardiac events. Future studies and further follow-up of the patients investigated in this study should assess whether these specific side effects will become clinically relevant in the long term. Another issue is patient heterogeneity regarding the number of previous chemotherapy lines and the initial status regarding platinum-sensitivity. We cannot rule out that this might have affected the response rates to PIPAC as well as survival and quality of life data. Finally, the PCI used in this study has been developed as a staging tool for PC, whereas we used it as a measure of therapy response. Specifically, response assessment may be inaccurate because it is difficult to differentiate between scars and vital tumor tissue. In summary, PIPAC is active in ROCPC, easy to perform, and well tolerated. It is associated with an increase in quality of life. Whether or not PIPAC is a clinically meaningful therapeutic option in the setting of palliative ovarian cancer treatment remains to be seen. Further comparative clinical trials testing the efficacy of PIPAC versus or in addition to systemic chemotherapy are warranted. Also, other chemotherapy

compounds such as taxanes, topotecan, and gemcitabine should be investigated in PIPAC protocols in this patient population. These agents may be more effective than cisplatin given the platinum-resistant nature of ROCPC. Lastly, combining cytotoxic agents with bevacizumab may be an attractive option for future PIPAC trial designs. 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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Please cite this article as: Tempfer CB, et al, Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.009