Endometrial cancer is the sixth most common malignancy in women with over 380,000 new cases globally in 2018 (1). The majority of women are diagnosed with localized disease, and in the United States alone there are approximately 727,700 endometrial cancer survivors (2).

Endometrial cancer is an obesity-driven malignancy, with the alarming rates of obesity contributing to increases in incidence and mortality.

Obesity negatively impacts prognosis for endometrial cancer patients with a meta-analysis of women with endometrial cancer showing that a 10% increase in BMI increased odds of all-cause mortality by 9.2% (3). Calle et al. reported that morbidly obese (BMI > 40) endometrial cancer survivors had a 6.25 times increased risk of death compared to normal weight endometrial cancer survivors, with cardiovascular disease (CVD) being the leading cause of death (4). Felix and colleagues reported that women with endometrial cancer were 8.8 times more likely to die of CVD compared to women in the general population (5).

Therefore, we conducted a pilot study evaluating a 12-week home-based physical activity and nutrition counseling intervention to assess feasibility, safety, and effect on the cardiorespiratory fitness, CVD risk profile, and immune response endometrial cancer survivors.

Our findings demonstrated that a home-based exercise and nutrition counseling program is feasible based on 80% adherence to walking sessions and favored altered body composition in those initiating the study exercise and nutrition intervention. The walking sessions were safe and there were no serious or life-threatening events. There was a high rate of drop-out during the study pre-intervention phase of the study which included the baseline cardiorespiratory testing and BODPOD measurements. Given this high rate of discontinuation prior to the exercise and nutrition intervention, and lack of information regarding reason for withdrawal, further research is needed to overcome barriers to implementation.

No serious or life-threatening adverse events occurred during this study. The musculoskeletal injuries reported were likely secondary to increased activity and were similar to adverse events reported in previous weight-loss interventions (7–9). In addition, our findings revealed a significant decrease in total body mass, fat mass, and BMI.

There were no significant improvements in markers of cardiorespiratory fitness or other CVD risk factors observed. The presence of baseline EKG abnormalities in seven of nine patients was alarming and further highlights the need for intervention to improve the cardiovascular health of these women.

Our novel exploratory analyses of T-cell function show a significant improvement in IFNγ production from CD⁴⁺ and CD8⁺ T-cells towards the tumor associated antigen MAGE-A4, and a non-significant trend for MAGE-A3 suggesting that T-cells post-intervention are more capable of recognizing tumor antigens. In these women there was a significant increase in relative VO_2peak (p=0.043) suggesting a relationship with cardiorespiratory fitness and immune function. In healthy individuals, a single bout of exercise generated an enhanced T-cell response to tumor antigens, suggesting a beneficial role for exercise and tumor control by T-cells (6). Whether improved T-cell response will result in reduced risk for endometrial cancer recurrence remains unclear. Though the mechanisms remain unknown, our findings suggest physical activity and diet may enhance cytotoxic T-cell responses to cancer antigens. A previous investigation of endometrial morphology and molecular pathways following bariatric surgery-induced weight loss demonstrated reduction in biomarkers of insulin resistance (hemoglobin A1C, HOMA-IR) and inflammation (hsCRP, IL-6) demonstrating potential mechanisms by which weight loss may impact endometrial cancer risk (10). Another investigation of biomarkers in obese women following bariatric surgery similarly demonstrated reduction in inflammatory markers, including CRP, IL-1Ra and IL-6, following weight loss (11). The reduction in inflammatory markers following bariatric surgery suggest that weight loss contributes to a favorable immune environment that may restore the endometrium to a lower risk state. Our findings of an enhanced cytotoxic T-cell response following an exercise and nutrition counseling intervention further suggest a possible role of exercise and/or nutrition on immunologic response. Further investigation is needed to provide insight in potential regulatory mechanisms of exercise, nutrition, and/or weight loss on immune function.

Previous weight-loss interventions in other patient populations at increased risk of CVD have shown improvements in markers of cardiovascular fitness and CVD risk factors (12, 13). While improvement in body mass was seen in our pilot cohort, we believe that the lack of favorable changes on markers of cardiorespiratory fitness and lipid profile was secondary to the small sample size and short-term intervention.

Among endometrial cancer survivors, there have been limited high-quality exercise and nutrition counseling interventions. The SUCCEED trial, a six-month nutrition and exercise intervention among 70 obese endometrial cancer survivors, demonstrated an increase in physical activity and weight loss (7). Basen-Engquist and colleagues reported a home-based exercise intervention in endometrial cancer survivors which showed increased physical activity, improved predicted VO_2MAX, and improved systolic blood pressure among the obese cohort (14). While these studies have shown promising results, a recent Cochrane analysis of interventions for weight loss in endometrial cancer survivors found no improvement in cancer-specific survival, overall survival, cardiovascular event frequency, or significant weight loss at six or twelve months (15).

The qualitative survey at the conclusion of the study indicated that the intervention was well received with all nine women reporting their experience to be beneficial and four specifically noting plans to continue to apply the lifestyle changes beyond the intervention period. Previous investigations of weight-loss interventions in endometrial cancer survivors have likewise shown improvements in self-efficacy and emotional well-being which correlate with weight loss (8, 12, 16, 17). The qualitative assessment was performed at the conclusion of the study and therefore qualitative data was limited to only those individuals that completed the intervention. Therefore, responses are more likely positive than from those who did not complete the intervention.

Key limitations of the study included small sample size and participant dropout. Improvements in cardiorespiratory fitness and markers of CVD will most likely require longer and more intensive intervention. Although feasibility criteria was met among individuals that initiated the exercise and nutrition intervention study phase, the generalizability of this pilot investigation is significantly limited by the small sample size. The 50% dropout rate is higher than in similar interventions aimed at weight loss in endometrial cancer survivors (19-22%) and raises concern for withdrawal bias (8, 9). This exceeded our estimated dropout rate of 25% and ultimately resulted in a lower number of pilot study participants than originally anticipated. Patients were screened only by initial interest with many women choosing not to enroll after the study requirements were described in further detail and other women enrolling in the study but later being unable or unwilling to complete the study tasks. Given that the majority of the women that withdrew from the study did so prior to initiation of the exercise and nutrition counseling intervention, more thorough counseling of the pre-intervention testing requirements may contribute to lower rates of discontinuation in future trials. The more intensive requirement for cardiopulmonary exercise testing as well as the pre and post-intervention testing requiring additional transportation may have contributed to the higher dropout rate. Despite a high drop-out rate, the results of the qualitative assessment indicate that the intervention was well-received among the women that completed the study. Unfortunately, we are unable to identify the patients that are more likely to successfully complete the intervention at this point in time. Further measures to mitigate patient discontinuation, such as more detailed discussion of study participation at time of enrollment, centralization of study visits to a single site or closer follow-up throughout the duration of the study would need to be considered prior to application of this pilot intervention on a broader scale.

In conclusion, our pilot study represents a feasible and safe method of home-base physical activity and nutrition counseling intervention for endometrial cancer survivors which led to significant improvements in weight and BMI. However, longer and more intensive studies will be needed to determine if exercise and nutrition weight loss interventions will reduce the risk of CVD and mortality in endometrial cancer survivors. Our results will inform future study designs and support funding to conduct further studies on cardiovascular biomarkers and cardiovascular fitness in endometrial cancer survivors.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Duke Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.

AAS and KH played an active role in the design of the pilot study. The IRB was drafted by AAS. AAS, KH, and ARS participated in the obtaining of funding for the study. AAS, JJ, KN and MC participated in patient recruitment. PW created a personalized nutrition plan for each patient and completed individualized nutrition counseling. JJ and MC were integral to patient recruitment, calling patients throughout the study period and recording patient data. Exploratory analysis of T-cell function was performed by DB. Statistical analysis was performed by GB and DB. The research manuscript was drafted by ARS and AAS and edited by all listed authors. All authors contributed to the article and approved the submitted version.

Charles B Hammond Research Fund (awarded 12/2017), Duke University School of Medicine, Durham, NC.

AAS reports grants from AbbVie, Amgen, Astex Pharmaceuticals Inc., Astra Zeneca, Clovis, Astellas Pharma Inc., Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Eisai, Endocyte, Exelixis, Incyte, Merck, PharmaMar, Immutep Ltd, Roche/Genentech, Seattle Genetics, Inc, TapImmune, and Tesaro outside of submitted work. She reports honoraria from advisory boards with Alexion, Aravive, Astex Pharmaceuticals Inc., Astra Zeneca, Cordgenics, Clovis, Janssen/Johnson & Johnson, Merck, Mersana, Myriad, Oncoquest, Roche/Genentech, and Tesaro outside the submitted work.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.