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Hyperthermic intraperitoneal chemotherapy in prevention of gastric cancer metachronous peritoneal metastases: a systematic review.

ABSTRACT: Gastric cancer progression resulting in metachronous peritoneal metastasizing is almost always associated with an adverse prognosis. This review discusses various options of preventing metachronous peritoneal metastases in radically operated gastric cancer patients. Also examined are different hyperthermic intraperitoneal chemotherapy (HIPEC) regimens employed in gastric cancer treatment, postoperative morbidity and mortality rates and long-term treatment outcomes. The authors also review their own experience of using HIPEC based on the combination of cisplatin and doxorubicin in doses of 50 mg/m² at 42 °C for 1 h to prevent gastric cancer peritoneal dissemination. As a result, progression-free survival rose from 19.6%±5.6% to 47.1%±6.3% (P_log-rank <0.001) and dissemination-free survival-from 22.7%±6.0% to 51.9%±6.3% (P_log-rank <0.001). It is noted that the combination of the described HIPEC regimen with systemic chemotherapy helped raise metastases-free 3-year survival rate to up to 91.0%±9.0% (P_log-rank =0.025) compared with 48.6%±6.4% for patients who underwent only a combined surgery/HIPEC treatment. HIPEC is a promising combined treatment strategy for radically operated gastric cancer patients that can improve patient survival and decrease peritoneal dissemination rate. However, the number of randomized studies on adjuvant HIPEC are still insufficient for a subgroup assessment of efficacy of the given chemotherapy regimens and generation of evidence-based recommendations on the individual use of chemotherapy agents and their combinations, and HIPEC procedural techniques. Further prospective randomized studies are needed to assess the practicability of complementing HIPEC with adjuvant systemic chemotherapies.

SUBMITTER: Reutovich MY

PROVIDER: S-EPMC8100708 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival, but recurrence rates are high. The aim of this study was to create a preclinical platform for the development of more effective intraperitoneal chemotherapy strategies. METHODS:Using organoid technology, five tumour cultures were generated from malignant ascites and resected peritoneal metastases. These were used in an in vitro HIPEC model to assess sensitivity to mitomycin C (MMC) and oxaliplatin, the drugs used most commonly in HIPEC. The model was also used to test a rational combination treatment involving MMC and inhibitors of the checkpoint kinase ATR. RESULTS:MMC was more effective in eliminating peritoneal metastasis-derived organoids than oxaliplatin at clinically relevant concentrations. However, the drug concentrations required to eliminate 50 per cent of the tumour cells (IC50) were higher than the median clinical dose in two of five organoid lines for MMC, and all five lines for oxaliplatin, indicating a general resistance to monotherapy. ATR inhibition increased the sensitivity of all peritoneal metastasis-derived organoids to MMC, as the IC50 decreased 2·6-12·4-fold to well below concentrations commonly attained in clinical practice. Live-cell imaging and flow cytometric analysis showed that ATR inhibition did not release cells from MMC-induced cell cycle arrest, but caused increased replication stress and accelerated cell death. CONCLUSION:Peritoneal metastasis-derived organoids can be used to evaluate existing HIPEC regimens on an individual-patient level and for development of more effective treatment strategies. Surgical relevance Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has improved prognosis of patients with peritoneal metastases from colorectal cancer, but disease recurrence is common. More effective and personalized HIPEC is urgently needed. Organoid technology is frequently used for drug screens, as patient-derived organoids can accurately predict clinical therapeutic response in vitro. A panel of organoids was established from peritoneal metastases from colorectal cancer and used to develop a model for testing HIPEC regimens in vitro. Patient-derived organoids differed in sensitivity to commonly used chemotherapeutics, in line with variable clinical outcomes following cytoreductive surgery-HIPEC. Combining MMC with an ATR inhibitor improved the efficacy of MMC. Peritoneal metastasis-derived organoids can be used as a platform to test novel (combination) strategies that increase HIPEC efficacy. In the future, organoids could be used to select patent-tailored HIPEC regimens.

Project description:BackgroundCareful selection of patients with colorectal peritoneal metastases (PM) for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is crucial. It remains unknown whether the time of onset of colorectal PM (synchronous vs metachronous) influences surgical morbidity and survival outcomes after CRS with HIPEC.MethodsPatients with histologically proven colorectal PM who underwent CRS with HIPEC between February 2006 and December 2017 in two Dutch tertiary referral hospitals were retrospectively included from a prospectively maintained database. The onset of colorectal PM was classified as synchronous (PM diagnosed at the initiational presentation with colorectal cancer) or metachronous (PM diagnosed after initial curative colorectal resection). Major postoperative complications (Clavien-Dindo grade ≥ 3), overall survival (OS), and disease-free survival (DFS) were compared between patients with synchronous colorectal PM and those with metachronous colorectal PM using Kaplan-Meier analyses, proportional hazard analyses, and a multivariate Cox regression analysis.ResultsThe study enrolled 433 patients, of whom 231 (53%) had synchronous colorectal PM and 202 (47%) had metachronous colorectal PM. The major postoperative complication rate and median OS were similar between the patients with synchronous colorectal PM and those with metachronous colorectal PM (26.8% vs 29.7%; p = 0.693 and 34 vs 33 months, respectively; p = 0.819). The median DFS was significantly decreased for the patients with metachronous colorectal PM and those with synchronous colorectal PM (11 vs 15 months; adjusted hazard ratio, 1.63; 95% confidence interval, 1.18-2.26).ConclusionsMetachronous onset of colorectal PM is associated with early recurrence after CRS with HIPEC compared with synchronous colorectal PM, without a difference in OS or major postoperative complications. Time to onset of colorectal PM should be taken into consideration to optimize patient selection for this major procedure.

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Hyperthermic intraperitoneal chemotherapy in prevention of gastric cancer metachronous peritoneal metastases: a systematic review.

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