Marc-André Reymond

Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin in colorectal peritoneal metastasis

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an experimental drug delivery method that applies chemotherapy into the abdominal cavity as an aerosol under pressure. We present the first results obtained with PIPAC in colorectal peritoneal metastasis (CPM).

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

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/m(2) followed by cisplatin 7·5 mg/m(2). 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.

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

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/m(2) and doxorubicin 1.5 mg/m(2) at 12 mmHg 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.

Quality of life of patients with end-stage peritoneal metastasis treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC)

BACKGROUND Quality of Life (QoL) plays an important role in patients with peritoneal metastasis and is deteriorating continuously until death. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an innovative palliative treatment of peritoneal metastasis. We present the first QoL results under PIPAC therapy. METHODS Retrospective analysis of QLQ30 questionnaire results during repeated courses of PIPAC applications in palliative patients with pretreated peritoneal metastasis. RESULTS 91 patients (M:F = 40:51, median age 64 (34-77) years) with 158 PIPAC applications were analyzed. 86% patients had previously received systemic chemotherapy. Peritoneal metastasis was advanced (Peritoneal Carcinomatosis Index I = 16 ± 10). At admission, only moderate impairment of functioning (62-83%) and symptom scores (17-47%) was observed. 48 patients received at least 2 PIPAC every 6 weeks. After PIPAC # 1, the global physical score deteriorated slightly (from 82% to 75%), but improved after PIPAC # 2 (up to 89%). Gastrointestinal symptoms (nausea/vomiting, constipation, diarrhoea, anorexia) remained stable under PIPAC therapy. CONCLUSIONS Quality of life was relatively high in this group of patients with advanced, pretreated peritoneal metastasis, explaining their wish for further therapy. Functioning scores and disease-related symptoms were not altered for at least 3 months in the patients able to receive repeated PIPAC. Except for a transient moderate increase of pain scores, PIPAC did not cause therapy-related QoL deterioration, especially no gastrointestinal symptoms.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in a woman with pseudomyxoma peritonei: A case report

Highlights • This is the first report of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a woman with pseudomyxoma peritonei.• PIPAC achieved clinical and histological disease remission.• PIPAC with cisplatin and doxorubicin may be effective in pseudomyxoma peritonei.

Pressurized intraperitoneal chemotherapy (PIPAC) in women with gynecologic malignancies: a review

SummaryObjectiveThe objective of this study was to provide an overview of published and ongoing trials of pressurized intraperitoneal chemotherapy (PIPAC) in ovarian cancer.DesignThe study comprised a systematic literature review.ResultsWe identified 10 studies, including 2 ex vivo and in vitro studies, 6 clinical studies, and 2 ongoing clinical trials using PIPAC in women with recurrent ovarian cancer and pseudomyxoma peritonei. Experimental evidence and clinical study data demonstrate that PIPAC increases peritoneal cavity coverage and depth of peritoneal infiltration, and is technically feasible. Occupational safety has been established. PIPAC has demonstrated antitumor activity based on histological, radiological, and clinical evidence. The toxicity of PIPAC is manageable and restricted to Common Terminology Criteria for Adverse Events grade 2–3 events when used without concomitant cytoreductive surgery. Further clinical trials assessing efficacy and dose escalation are ongoing.ConclusionsPIPAC is technically feasible, has a safe local and systemic safety profile, and has antitumor activity in women with peritoneal carcinomatosis from recurrent ovarian cancer.ZusammenfassungZielsetzungZiel dieser systematischen Literaturübersicht war die Erfassung der publizierten experimentellen und klinischen Daten zur pressurized intraperitoneal chemotherapy (PIPAC) bei Frauen mit gynäkologischen Malignomen und Peritonealkarzinose (PC).MethodikSystematische Literaturübersicht über experimentelle und klinische Studien zum Thema PIPAC anhand der öffentlich zugänglichen Datenbanken PUBMED, EMBASE, Cochrane Controlled Trials Register, EudraCT und des US NIH ClinicalTrials.gov Registers.ErgebnisseWir identifizierten 10 Studien, davon 2 ex-vivo und in-vitro Studien, 6 klinische Studien an Frauen mit rezidiviertem Ovarialkarzinom und Pseudomyxoma peritonei, sowie 2 laufende klinische Studien über PIPAC bei Frauen mit PC und Ovarialkarzinom-Rezidiv. Die experimentelle Evidenz und die Ergebnisse der klinischen Studien zeigen, dass mittels PIPAC die peritoneale Benetzungsfläche erhöht und die peritoneale Infiltrationstiefe erhöht werden kann und dass PIPAC technisch durchführbar ist. Die Arbeitssicherheit von PIPAC wurde unter kontrollierten Bedingungen bestätigt. Die verfügbaren klinischen Daten belegen eine Antitumoraktivität von PIPAC, basierend auf histologischen, radiologischen und klinischen Beobachtungsdaten. Die lokale und systemische Toxizität der Methode ist mit CTCAE Grad 2–3 Ereignissen gering, falls PIPAC ohne konkomitante zytoreduktive Chirurgie angewandt wird. Weitere klinische Studien zur Effektivität und Dosiseskalation werden derzeit durchgeführt.SchlussfolgerungenPIPAC ist technisch durchführbar, sicher in Anwendung und Patientinnentoxizität und hat nachweisliche Antitumoraktivität bei Frauen mit PC und Ovarialkarzinom oder PMP.

Dynamic changes of tumor gene expression during repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal cancer

BackgroundIntraperitoneal chemotherapy is used to treat peritoneal cancer. The pattern of gene expression changes of peritoneal cancer during intraperitoneal chemotherapy has not been studied before. Pressurized intraperitoneal aerosol chemotherapy is a new form of intraperitoneal chemotherapy using repeated applications and allowing repeated tumor sampling during chemotherapy. Here, we present the analysis of gene expression changes during pressurized intraperitoneal aerosol chemotherapy with doxorubicin and cisplatin using a 22-gene panel.MethodsTotal RNA was extracted from 152 PC samples obtained from 63 patients in up to six cycles of intraperitoneal chemotherapy. Quantitative real-time PCR was used to determine the gene expression levels. For select genes, immunohistochemistry was used to verify gene expression changes observed on the transcript level on the protein level. Observed (changes in) expression levels were correlated with clinical outcomes.ResultsGene expression profiles differed significantly between peritoneal cancer and non- peritoneal cancer samples and between ascites-producing and non ascites-producing peritoneal cancers. Changes of gene expression patterns during repeated intraperitoneal chemotherapy cycles were prognostic of overall survival, suggesting a molecular tumor response of peritoneal cancer. Specifically, downregulation of the whole gene panel during intraperitoneal chemotherapy was associated with better treatment response and survival.ConclusionsIn summary, molecular changes of peritoneal cancer during pressurized intraperitoneal aerosol chemotherapy can be documented and may be used to refine individual treatment and prognostic estimations.

Hyperthermic intraperitoneal chemotherapy for women with granulosa cell tumors of the ovary: a systematic review of the literature

Abstract Background: Adult and juvenile granulosa cell tumors of the ovary are rare functional sex-cord-stromal ovarian neoplasms characterized by low malignant potential and late relapse. Evidence-based management options for primary and recurrent juvenile (JGCT) and adult (AGCT) granulosa cell tumors are limited and treatment options have not been standardized. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may be an option to treat these women effectively. Methods: Systematic literature review using PubMed and the Cochrane Central Register of Controlled Trials. Results: No reports of HIPEC among women with a first diagnosis of AGCT were identified. We identified 5 reports on the safety and therapeutic efficacy of CRS and HIPEC in 19 patients with recurrent AGCT and one patient with JGCT. The pooled rate of complete cytoreduction was 95 % (18/19) with 16 % (3/19) severe morbidity and no procedure-related mortality. The median time of follow-up was 30 (range, 3 to 72) months, during which 6/19 (31 %) patients experienced a recurrence and two patients (10 %) died of the disease. Conclusion: CRS and HIPEC are a safe and potentially effective treatment option for selected women with recurrent AGCT limited to the abdomen.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in 99 women with gynecologic malignancies and peritoneal carcinomatosis: a retrospective cohort study

Objective: To assess the objective tumor response (OTR) of laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with gynecologic malignancies and peritoneal carcinomatosis (PC). Methods: Retrospective cohort study using registry data of women with repeated courses q 28 – 42 days of PIPAC with cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2. OTR was defined as histological regression. Peritoneal carcinomatosis index (PCI) improvement on video-laparoscopy and ascites volume reduction were secondary outcomes. Quality of life was assessed using the EORTC QLQ-30(+3) questionnaire. Results: 252 PIPAC procedures were performed in 99 women with PC and ovarian cancer (n = 84), fallopian tube cancer (n = 1), primary peritoneal cancer (n = 6), pseudomyxoma peritonei (n = 1), cervical cancer (n = 3), endometrial cancer (n = 3), and breast cancer (n = 1). Laparoscopic non-access rate was 17% (17/99). 50 women had > 1 PIPAC procedures. Among these women, OTR was noted in 76% (38/50) and PCI improvement on repeated video-laparoscopy in 64% (32/50). Median ascites volume decreased significantly during therapy from 762 ± 1170 ml to 167 ± 456 ml (p = 0.02). A high initial Karnofsky Index was correlated with receiving > 1 PIPACs (p < 0.0001). A high number of previous surgeries was correlated with laparoscopic non-access (p = 0.01). 20 adverse events CTCAE grade = 3 were noted. Perioperative mortality was 0%. In a multivariable regression analysis with OTR as the dependent variable, absence of ascites (odds ratio [OR] 8.45; 95% confidence interval [CI] 1.9 – 3.6; p < 0.0001), but not patient age, serum CA-125, and Karnofsky Index independently predicted OTR. EORTC QLQ-30(+3) scores for global physical health, nausea/vomiting, appetite loss, constipation, physical, role, emotional, and social functioning improved during therapy. Conclusion: PIPAC with cisplatin and doxorubicin is an active treatment in women with gynecologic malignancies and PC and preserves quality of life. Appropriate patient selection regarding performance status and the number of prior surgeries is important.