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Intra-operative hyperthermic intraperitoneal chemotherapy for prevention and treatment of peritoneal metastases from gastric cancer: a narrative review.

ABSTRACT: Peritoneal metastasis (PM) from gastric cancer (GC) has long been regarded as the terminal disease, lacking of effective treatments. In recent 40 years, cytoreductive surgery (CRS) plus perioperative intraperitoneal chemotherapy, including hyperthermic intraperitoneal chemotherapy (HIPEC), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), and early post-operative intraperitoneal chemotherapy (EPIC), has been recommended as a preferred treatment option for some selected patients with GCPM. Intraperitoneal free cancer cells were recognized as the pathological cause of PM and the primary target for intraperitoneal chemotherapy. There were a lot of evidence demonstrating that HIPEC could effectively eradiate intraperitoneal free cancer cells and prolong overall survival in GCPM. However, there are still no standard HIPEC protocols. This review summarized the current HIPEC regimens used in GCPM from a literature search, trying to conclude the optimal HIPEC in GCPM, and indicate the future direction of HIPEC study. Moreover, the new data on the exploration of HIPEC in GCPM at Shijitan Hospital, Capital Medical University was shared. In conclusion, there was not enough evidence from publications and our own experience to conclude a recommended HIPEC regimen for GCPM. There is urgent need for standardizing HIPEC protocols worldwide. Accordingly, more international collaborations focusing on pharmacology and HIPEC-related parameters to generate high level evidence are essential.

SUBMITTER: Ji ZH

PROVIDER: S-EPMC8100728 | 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.

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Intra-operative hyperthermic intraperitoneal chemotherapy for prevention and treatment of peritoneal metastases from gastric cancer: a narrative review.

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