Individualized prediction of risk of metachronous peritoneal carcinomatosis from colorectal cancer

Segelman, Josefin; Akre, Olof; Gustafsson, Ulf; Bottai, Matteo; Martling, Anna

doi:10.1111/codi.12552

Cited by 62 publications

(69 citation statements)

References 22 publications

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“…Peritoneal metastases (PMs) develop in approximately 10 per cent of patients with colorectal cancer 1 . These patients generally have a very poor prognosis, with a median survival of only 6-9 months without treatment 2 .…”

Section: Introductionmentioning

confidence: 99%

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

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Bolhaqueiro

Elias

et al. 2019

British Journal of Surgery

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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. 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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Section: Introductionmentioning

confidence: 99%

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

Ubink

Bolhaqueiro

Elias

et al. 2019

British Journal of Surgery

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“…In 2014, Segelman et al . developed and investigated risk score models that combined important clinicopathological factors to predict the risk of peritoneal recurrence on an individual basis . The study included 8044 patients with Stage I–III CRC.…”

Section: Patient Selection: Does T4 Warrant Proactive Management?mentioning

confidence: 99%

Prevention of peritoneal recurrence in high‐risk colorectal cancer and evidence of T4 status as a potential risk factor

Kyang

Valle

Alzahrani

et al. 2018

ANZ Journal of Surgery

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Peritoneal metastasis (PM) following primary resection of colorectal cancer is common. The combined use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has significantly improved the survival outcome of patients with colorectal PM (CRPM). Diagnosing and treating early PM is essential as its extent is correlated with poorer outcomes. There are two novel therapies - second-look surgery and synchronous hyperthermic intraperitoneal chemotherapy - that are proposed to prophylactically treat or intervene early in the disease process to reduce the incidence and adverse outcomes associated with PM. These strategies are limited to patients at high risk of developing CRPM, including those that had synchronous PM or ovarian metastases resected at primary tumour removal, or a perforated primary tumour. The data on advanced primary tumour (T4) as a prognostic factor for PM after primary resection suggest that T4a tumours are prognostically worse than T4b. This literature review outlines the evidence, feasibility and safety regarding the pre-emptive treatments, as well as the relevance of T4a tumours as a risk factor for metachronous CRPM.

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“…PM developing in the follow-up period after curative treatment of the primary colorectal tumor is called metachronous PM. Eventually, ~5% of the patients develop clinically relevant metachronous PM during the disease course 14–16. Given the PM rate of up to 40% in autopsy studies, the previously mentioned percentages are thought to be an underestimation of reality 17.…”

Section: Epidemiology Of Colorectal Pmmentioning

confidence: 99%

“…Since the possibilities for preventing metachronous PM are more promising than for synchronous PM, the evidence regarding risk factors for metachronous metastases is more extensive. According to several studies, independent risk factors for metachronous PM are advanced T and N stage, emergency surgery, a colon versus rectal primary, and free intraperitoneal cancer cells before and/or after primary tumor resection 14–16,19. Besides these factors, mucinous adenocarcinomas and signet ring cell carcinomas tend to metastasize more frequently to the peritoneum than other histological subtypes 7…”

Section: Risk Factors For Colorectal Pmmentioning

confidence: 99%

Patient selection for cytoreductive surgery and HIPEC for the treatment of peritoneal metastases from colorectal cancer

Simkens

Rovers

Nienhuijs

et al. 2017

CMAR

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Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a viable option for selected patients with peritoneal metastases (PM) from colorectal origin, resulting in long-term survival and even cure in some cases. However, adequate patient selection for this treatment is currently one of the major challenges. The aim of this review is to provide a comprehensive overview of clinically relevant factors associated with overall survival. This may help to guide clinicians through the complex interplay of patient, tumor, and treatment characteristics to adequately select patients who benefit the most from this extensive surgical treatment. First, basic principles of colorectal PM and the CRS and HIPEC treatment will be discussed. According to available literature, especially extent of peritoneal disease, completeness of cytoreduction, and signet ring cell histology have great influence on the outcome after CRS and HIPEC. Other factors that seem to have a negative prognostic value are the presence of liver metastases and the absence of treatment with neo-adjuvant systemic therapy. Prognostic models combining the above-mentioned factors, such as the Colorectal Peritoneal Metastases Prognostic Surgical Score nomogram, may provide clinically relevant tools to use in everyday practice.

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Individualized prediction of risk of metachronous peritoneal carcinomatosis from colorectal cancer

Cited by 62 publications

References 22 publications

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

Prevention of peritoneal recurrence in high‐risk colorectal cancer and evidence of T4 status as a potential risk factor

Patient selection for cytoreductive surgery and HIPEC for the treatment of peritoneal metastases from colorectal cancer

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