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Pharmacokinetics of cisplatin during open and minimally-invasive secondary cytoreductive surgery plus HIPEC in women with platinum-sensitive recurrent ovarian cancer: a prospective study.

ABSTRACT: OBJECTIVE:Evidences from animal models seem to suggest that minimally invasive surgery may enhance cisplatin diffusion when the drug is administered in the context of post-operative hyperthermic intraperitoneal chemotherapy (HIPEC). The present study evaluates the cisplatin pharmacokinetic profile in a prospective series of women with platinum sensitive recurrent epithelial ovarian cancer treated with open secondary cytoreductive surgery (O-SCS) or minimally-invasive secondary cytoreductive surgery (MI-SCS). METHODS:Cisplatin levels were assessed at 0, 20, 40, 60, and 120 minutes in: 1) blood samples, 2) peritoneal perfusate, and 3) peritoneal biopsies at the end of HIPEC. Median Cmax has been used to identify women with high and low drug levels. Progression-free survival (PFS) was calculated as the time elapsed between SCS+HIPEC and secondary recurrence or last follow-up visit. RESULTS:Nine (45.0%) women received MI-SCS, and 11 (55.0%) O-SCS. At 60 minutes, median cisplatin Cmax in peritoneal tissue was higher in patients treated with MI-SCS compared to O-SCS (Cmax=8.262 ?g/mL vs. Cmax=4.057 ?g/mL). Furthermore, median cisplatin plasma Cmax was higher in patients treated with MI-SCS compared to O-SCS (Cmax=0.511 vs. Cmax=0.254 ?g/mL; p-value=0.012) at 120 minutes. With a median follow-up time of 24 months, women with higher cisplatin peritoneal Cmax showed a longer PFS compared to women with low cisplatin peritoneal levels (2-years PFS=70% vs. 35%; p-value=0.054). CONCLUSIONS:We demonstrate for the first time that minimally invasive route enhances cisplatin peritoneal tissue uptake during HIPEC, further evaluations are needed to confirm the correlation between peritoneal cisplatin levels after HIPEC and survival. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01539785.

SUBMITTER: Petrillo M

PROVIDER: S-EPMC6543101 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Pharmacokinetics of cisplatin during open and minimally-invasive secondary cytoreductive surgery plus HIPEC in women with platinum-sensitive recurrent ovarian cancer: a prospective study.

Petrillo Marco M Zucchetti Massimo M Cianci Stefano S Morosi Lavinia L Ronsini Carlo C Colombo Andrea A D'Incalci Maurizio M Scambia Giovanni G Fagotti Anna A

Journal of gynecologic oncology 20190301 4

<h4>Objective</h4>Evidences from animal models seem to suggest that minimally invasive surgery may enhance cisplatin diffusion when the drug is administered in the context of post-operative hyperthermic intraperitoneal chemotherapy (HIPEC). The present study evaluates the cisplatin pharmacokinetic profile in a prospective series of women with platinum sensitive recurrent epithelial ovarian cancer treated with open secondary cytoreductive surgery (O-SCS) or minimally-invasive secondary cytoreduct ...[more]

PMID: 31074245

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Project description:BACKGROUND:Improvement in treatment for patients with recurrent ovarian cancer is needed. Standard therapy in patients with platinum-sensitive recurrent ovarian cancer consists of platinum-based chemotherapy. Median overall survival is reported between 18 and 35 months. Currently, the role of surgery in recurrent ovarian cancer is not clear. In selective patients a survival benefit up to 62 months is reported for patients undergoing complete secondary cytoreductive surgery. Whether cytoreductive surgery in recurrent platinum-sensitive ovarian cancer is beneficial remains questionable due to the lack of level I-II evidence. METHODS/DESIGN:Multicentre randomized controlled trial, including all nine gynecologic oncologic centres in the Netherlands and their affiliated hospitals. Eligible patients are women, with first recurrence of FIGO stage Ic-IV platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, who meet the inclusion criteria. Participants are randomized between the standard treatment consisting of at least six cycles of intravenous platinum based chemotherapy and the experimental treatment which consists of secondary cytoreductive surgery followed by at least six cycles of intravenous platinum based chemotherapy. Primary outcome measure is progression free survival. In total 230 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION:Where the role of cytoreductive surgery is widely accepted in the initial treatment of ovarian cancer, its value in recurrent platinum-sensitive epithelial ovarian cancer has not been established so far. A better understanding of the benefits and patients selection criteria for secondary cytoreductive surgery has to be obtained. Therefore the 4th ovarian cancer consensus conference in 2010 stated that randomized controlled phase 3 trials evaluating the role of surgery in platinum-sensitive recurrent epithelial ovarian cancer are urgently needed. We present a recently started multicentre randomized controlled trial that will investigate the role of secondary cytoreductive surgery followed by chemotherapy will improve progression free survival in selected patients with first recurrence of platinum-sensitive epithelial ovarian cancer.

Project description:BACKGROUND:In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. METHODS:SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03983226.

Project description:BackgroundUpfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes.MethodsThis open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates.DiscussionThis is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM.Trial registrationClinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016-001865-99 .

Dataset Information

Pharmacokinetics of cisplatin during open and minimally-invasive secondary cytoreductive surgery plus HIPEC in women with platinum-sensitive recurrent ovarian cancer: a prospective study.

Publications

Pharmacokinetics of cisplatin during open and minimally-invasive secondary cytoreductive surgery plus HIPEC in women with platinum-sensitive recurrent ovarian cancer: a prospective study.

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