Title: Cytoreductive surgery with hyperthermic intraoperative peritoneal chemotherapy versus standard of care in people with peritoneal metastases from colorectal, ovarian or gastric origin: Systematic review and individual participant data meta-analyses of effectiveness and cost-effectiveness
Funder: Department of Health and Social Care

Abstract: Background to the research _x000D_ Each year, approximately 7 million people worldwide (including 160,000 people in UK) develop cancers of the bowel, ovary, or stomach. Around 10% of these patients develop ‘peritoneal metastases’ where the cancer has spread to the lining of the abdomen. The usual treatment (or ‘standard of care’) for these patients is chemotherapy – the use of drugs that aim to kill cancer cells. Some patients also receive an operation to remove the cancer, known as cytoreductive surgery. _x000D_ _x000D_ Despite these treatments, people with peritoneal metastases from bowel, ovary, or stomach cancer have a short life expectancy, ranging from 6 months to 2 years. There is a clear need to improve the outcomes for these patients. One treatment that may help is known ‘hyperthermic intraoperative peritoneal chemotherapy’ (HIPEC). This is where, straight after receiving cytoreductive surgery, patients are given chemotherapy that has been heated to 42°C, delivered into the lining of the abdomen. _x000D_ _x000D_ Several studies have shown that cytoreductive surgery (CRS) plus HIPEC improves survival compared to standard of care. However, there have been some questions about the results of these studies. Importantly, some people develop complications following their treatment. Therefore, it is uncertain whether to recommend CRS+HIPEC for use in these patients._x000D_ _x000D_ Aims of the research _x000D_ Our research has three main aims: _x000D_ 1. To determine whether CRS + HIPEC improves survival and other outcomes for people with peritoneal metastases from the bowel, ovary, and stomach cancer compared with standard of care._x000D_ 2. To establish the extent of complications following treatment with CRS + HIPEC compared with standard of care. _x000D_ 3. To determine whether CRS + HIPEC should be used routinely in the NHS for people with peritoneal metastases from these cancers and whether it provides good value for money. _x000D_ _x000D_ Design and methods used _x000D_ We plan to bring together the results of all of the trials that have compared CRS + HIPEC with standard of care. We will look at the results for patients with cancer of the bowel, ovary or stomach. This type of research is called a systematic review and meta-analysis. The type of systematic review and meta-analysis we are planning uses ‘individual participant data’ or ‘IPD’ from all of the trials we find. This involves collecting and performing analysis using data on individual participants in the studies. IPD meta-analysis is often called the ‘gold standard’ because it produces better estimates of the effects of treatments and allows us to find out more about how well they work in different types of patients. _x000D_ _x000D_ Patient and public involvement _x000D_ A patient representative was involved in the preparation of this grant proposal; they will be involved in the research steering group and will help with writing the plain language report of the findings, disseminating the findings to patient groups and social media and in determining the design of future studies. Training and support (including payment and covering incidental expenses) will be provided._x000D_ _x000D_ Dissemination_x000D_ We plan to publish our results in relevant, high quality medical journals and present the findings at international conferences.We also plan to speak to some organisations and associations directly to make our results easy for clinicians to access.We will also work with representatives from patient support groups, to communicate our findings to communities of patients and the public.

Lay abstract: Research question_x000D_ Does cytoreduction surgery (CRS) plus hyperthermic intraoperative peritoneal chemotherapy (HIPEC) improve survival and/or quality of life compared to systemic chemotherapy alone or CRS alone or both in combination (standard of care: SoC) in people with peritoneal metastases (from colorectal, ovarian, or gastric cancers) who can withstand major surgery and is it cost-effective in the NHS setting?_x000D_ _x000D_ Background_x000D_ There is uncertainty about whether CRS+HIPEC improves survival and/or quality of life compared to SoC in people with peritoneal metastases who can withstand major surgery._x000D_ _x000D_ Aims and objectives_x000D_ Primary objectives_x000D_ To compare the relative benefits and harms of CRS+HIPEC versus SoC in people with peritoneal metastases from colorectal, ovarian, or gastric cancers eligible to undergo CRS+HIPEC by a systematic review and individual participant data (IPD) meta-analysis._x000D_ _x000D_ Secondary objectives_x000D_ To compare the cost-effectiveness of CRS+HIPEC versus SoC from an NHS and PSS (personal social services) perspective using a model-based cost-utility analysis._x000D_ _x000D_ Methods_x000D_ We will perform a systematic review of literature by updating the searches from MEDLINE, EMBASE, Cochrane library, Science Citation Index as well as trial registers. Two members of our team will independently screen the search results and identify RCTs comparing CRS+HIPEC versus SoC for inclusion based on full texts for articles shortlisted during screening. We will assess the risk of bias in the trials and obtain data related to baseline prognostic characteristics, details of how CRS+HIPEC and SoC were performed, how long people were followed-up, and outcome data related to overall survival, disease progression, health-related quality of life, treatment related complications, and resource utilisation data by contacting the study authors and obtaining data at the individual participant level. _x000D_ _x000D_ Using individual participant data (IPD), we will perform a two-step IPD, i.e. calculate the adjusted effect estimate from each included study and then perform a random-effects model meta-analysis. We will perform various subgroup analyses and metaregression to investigate potential sources of heterogeneity and identify whether a subset of participants benefits from CRS+HIPEC and perform sensitivity analyses to test the robustness of results to assumptions. _x000D_ _x000D_ We will also perform a model-based cost-utility analysis to assess whether CRS+HIPEC is cost-effective in the NHS setting._x000D_ _x000D_ Timelines for delivery_x000D_ Pre-award: Set up IPD collaborative after finalising the study selection._x000D_ Post-award: Protocol finalisation and secure NHS electronic database set-up completed by 6 months, data collection for at least one topic completed by 18 months, data collection for all three topics by 24 months, data cleaning for all three topics by 30 months, and final report by 3 years._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ We will provide information on the effectiveness and cost-effectiveness of CRS+HIPEC versus SoC, the requirement for further RCTs, the design of such studies using an IDEAL framework, and the establishment of prospective registers to collect long-term data._x000D_ _x000D_ We will contact the relevant Royal Colleges and NHS departments to disseminate the information. We will also present our findings in conferences, publish the findings in peer reviewed journals, disseminate the findings through relevant patient support group websites and social media.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS