Andrew Renehan's research study is looking at the impact of BMI on cancer-related survival in chemotherapy-naïve patients with non-metastatic colorectal and endometrial cancer: a federation meta-analysis of trial data
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Since outline, the main changes in our application have been to address panel's queries, strengthen rationale for our design, and more realistically estimate the project outputs. The World Cancer Research Fund (WCRF), and work from the present researchers, have shown excess weight (commonly expressed as elevated body mass index, BMI) is a risk factor for several cancers. By extension, elevated BMI at or after cancer diagnosis might be associated with a poor prognosis, and indeed, many studies show such associations. This is a key rationale for weight management strategies in cancer survivorship programmes. However, interpretation of analyses in the cancer post-diagnosis setting is susceptible to several major sources of confounding and biases. Such was the extent of these concerns that the WCRF 2014 report on Breast Cancer Survivorship concluded that evidence was suggestive but limited. We argue that the optimum setting to test such associations is as secondary analyses of trial data, where confounding and biases can be minimised. Even better is to preform individual patient data (IPD) meta-analyse across these trials to increasing estimate precision. The cancers of interest here are colorectal (CRC) and endometrial (EC). We found two reported IPD meta-analyses of BMI and prognosis in colon cancer in adjuvant chemotherapy trials (see confounding issues under objectives), and found no IPD meta-analysis of the associations of BMI and outcome in rectal cancer or EC.
We will test the hypothesis that elevated BMI, measured at or after diagnosis in patients with CRC and EC, are associated with reduced overall survival (OS) or disease-free survival (DFS) compared with normal weight. To reduce the confounding of chemotherapy dose capping/reduce chemotherapy intensity/pharmacokinetic variability in obese patients, the 'clean' primary cohorts within the trials will consist of surgery only chemotherapy-naïve non-metastatic patients.
Primary outcome measures are five-year OS; secondary endpoints are five-year DFS. We established a 'federation' of principal investigators from published trials. The confirmed collaborative of chemotherapy-naïve participants with measured BMI numbers 7,675 patients with CRC and 1,847 women with EC – these datasets represent twice as large as anything hereto gathered. Based on these samples, for CRC, we have 92% power for OS and 98% power for DFS; and for EC, 93% power for OS and 97% power for DFS. The power calculation showed that these numbers are underpowered for interactions by gender, sub-site or histological sub-type, but concurrently demonstrated that to achieve sufficient power would require unattainable and unavailable sample sizes (x4 fold). Trial leads will attend a set-up workshop to establish mechanisms to share data. The federation approach means that for some trial data can stay at source and the analyses comes to the data. We will test relationships between peri- and post-diagnosis BMI and OS, and DFS, using BMI as categorical and continuous variable, exploring linear and non-linear relationships. We will explore for the obesity paradox. A priori stratified analyses and sensitivity analyses will be performed.
Given the novel approach of a large-scale within-trials IPD meta-analysis, embedded in a low risk of confounding analytical platform, this project will deliver a significant new contribution to the two WCRF themes on relationships between food, nutrition and physical activity (here, obesity) with cancer prognosis and outcome in cancer survivors. Specifically, through two high-quality publications, the findings will offer unbiased information to weight management strategies in survivors of colorectal and endometrial cancers.
Excess body weight is commonly quantified by body mass index (BMI), with values greater than 25 kg/m2 referred to as overweight and obese. From the World Cancer Research Fund (WCRF) Continuous Update Project (CUP), we know that elevated BMI values are associated with increased risk of several cancers. High on this list of 'obesity-related cancers' are colorectal (bowel) and endometrial (womb) cancers. These cancers are the focus of this study. Elevated BMI values may be linked with poorer survival in cancer patients. But this link remains a hypothesis and has yet to be proven. Nonetheless many clinicians and cancer societies support the guidance that weight reduction among overweight and obese cancer survivors might reduce the risk of cancer recurrences. Evidence is needed to support this hypothesis; however it is challenging to obtain unbiased evidence. This is due to something called confounding. Examples of confounding in patients with cancer and who are also overweight or obese include the following: heavier people might not be diagnosed with cancer until it is in a more advanced stage; cancer patients who are obese might receive less aggressive cancer treatment; among patients with cancer who do receive standard care and where subsequent chemotherapy is administered, obese patients may not tolerate this treatment due to different metabolisms. Thus, overweight and obese patients with cancer might appear to have a worse survival which is not necessarily be directly due to their body weight.
We aim to undertake analyses, known as secondary analyses, in data from already published trials and address the question that elevated BMI values in patients with cancer link with poorer survival. We will analyse two types of survival outcomes: overall survival (all deaths) and disease-free survival (disease recurrence plus deaths).
In preparation for this grant, we have established a network or 'federation' of principal investigators from published trials. From these, there are over 7,600 patients with colorectal cancer and over 1,800 women with endometrial cancer. These datasets represent twice as large as anything hereto gathered. There are three parts to our analyses. First, we will use data from trials after surgery. This will mean that cancer stage and treatments will be very similar for all patients. Second, our main analysis will focus on patients treated by surgery only (without chemotherapy). This will reduce the confounding mentioned above. Finally, we will perform these analyses across several trials to increase the power of the analysis.
The methods proposed in this project are novel, analytically robust, and large-scale. Accordingly, this project will deliver a significant new contribution to the two WCRF themes on relationships between food, nutrition and physical activity (here, obesity) with cancer prognosis and outcome in cancer survivors. Specifically, the findings will offer unbiased information to weight management strategies in survivors of colorectal and endometrial cancers.