Background
Obesity is increasingly recognized as a risk factor for cancer [
1]. Currently, there is consensus that obesity serves as a risk factor for eight different malignancies, i.e., endometrial, colorectal, renal, esophageal, breast (post-menopausal), thyroid, gall bladder, and pancreas [
2‐
4]. Moreover, obesity also serves as a poor prognostic indicator for several other cancers – at least 15 in total [
5]. In prostate cancer, obesity is not associated with the overall risk for disease, but it does place men at increased risk for more aggressive cancer and disease-specific mortality [
6]. A recent multinational study involving 10,106 prostate cancer cases from eight cohorts with an average follow-up of 8.2 years found that each 5 unit increase in prediagnostic body mass index (BMI: kg/m
2) was associated with an 8 % increase in mortality (p-trend = 0.01) [
7]. Weight gain after diagnosis and primary treatment was examined in an earlier study among 26,479 prostate cancer patients; here, each 5 unit increase in BMI was associated with 21 % increased risk of biochemical recurrence (Relative Risk: 1.21, 95 % Confidence Interval: 1.11-1.31 P < 0.01) [
8].
Despite strong observational evidence that a higher BMI is associated with more aggressive and progressive cancer, major gaps exist in our understanding of that relationship with key research questions being: Are weight loss interventions feasible in populations with cancer? Does intentional weight loss result in improved cancer control? What are the mechanisms by which negative energy balance affects tumor biology and the host environment? Are the effects of caloric restriction and increased energy expenditure through physical activity similar or do they differ?
To date, there have been roughly 20 weight loss trials among various oncology patient populations that have been completed or are currently in the field that address some of these questions. Most of these trials have been conducted in breast cancer survivors and are modest in size; results show feasibility, safety, and a significant impact on reducing adiposity and improving health-related quality of life - largely focusing on physical functioning and fitness [
9]. In addition, many have assessed the impact of weight loss on circulating biomarkers, such as insulin and related entities (insulin-like growth factors and binding proteins), adipokines, inflammatory markers, sex steroid hormones, and related binding proteins. Findings have been compiled in a review by Reeves et al. [
9] and show significant reductions in insulin in 2-of-6 studies [
10‐
15], and leptin in 3-of-3 studies [
10,
14,
15]; however, other results are inconclusive largely due to inadequate statistical power. As of yet, no studies have been completed that assess the impact of intentional weight loss on recurrence or cancer-specific mortality, though there are currently two European trials in the field with this goal, i.e., the Simultaneous Study of Docetaxel-Gemcitabine Combination adjuvant treatment, and Extended Bisphosphonate and Surveillance (SUCCESS-C) and the Diet and Androgens (DIANA-5) trials [
16,
17]. In prostate cancer, there have been only three reported weight loss studies. The largest of these, the RENEW trial (Reach Out to ENhancE Wellness in Older Cancer Survivors) enrolled 261 prostate cancer survivors within a study cohort that also included 380 other survivors of breast and colorectal cancer [
18]. In this study, significant reductions in body weight occurred and were associated with improvements in physical functioning (the primary endpoint of the trial). The two other randomized trials have been modest in size with sample sizes of 8 and 19 [
19,
20], and also showed successful weight loss. In the trial by Wright et al. [
20] pre-post changes in serum insulin-like growth factor binding protein (IGFBP)-3 were observed between the control (−6.9 %) and intervention groups (+2.8 %); though no differences were observed in insulin, c-peptide, IGF-1 and adiponectin – again, likely due to inadequate power. Despite the fact that both of these last two trials were conducted in the presurgical setting, neither investigated the impact of caloric restriction on tumor tissue.
The ability to ascertain the impact of interventions directly on tumor tissue is considered a particular strength of presurgical trials, and it is reasoned that by monitoring intervention effects on Ki-67 proliferation rates (a well-accepted tumor marker used for pharmacologic studies and also one that has shown to be sensitive to changes in diet and nutritional status) [
21‐
23], the efficacy of an intervention could be assessed in a much shorter period of time and with much smaller numbers of participants; moreover, the biological mechanisms through which the intervention exerts its therapeutic potential could be ascertained directly. Originally proposed as a resourceful way of testing chemopreventive agents, Kelloff and colleagues proposed the use of presurgical models over a wide range of cancers in a hallmark paper published over two decades ago [
24]. Since this time, they have been used for the evaluation of therapeutic agents [
22,
25‐
28], but have been used far less frequently to assess the impact of complementary therapies that encompass diet and exercise with the expressed intent of assessing the impact of the intervention on the tumor. While the biological effects of lifestyle interventions are believed to be far less potent than pharmacological agents, a phase II RCT conducted among 161 patients scheduled for prostatectomy found significantly lower Ki-67 proliferation indexes in men randomized to receive a 3-week regimen of 30 g/day of ground flaxseed vs. those who did not receive it [
21,
29]. Thus, this trial serves as proof of concept that presurgical trials are indeed viable and valuable for testing lifestyle interventions. However, their use has not been evaluated in studies of energy balance that are aimed at assessing the impact of caloric restriction or increased physical activity on tumor tissue.
The purpose of this paper is to describe a pioneering NIH-funded (R21 CA161263) RCT that utilizes a pre-surgical model to explore the feasibility and effects of a diet and exercise weight loss intervention on tumor proliferation rates (Ki-67), as well as other outcomes in men with newly-diagnosed prostate cancer. Herein, we describe the study design, research protocol, and the necessary adjustments made in order to conduct the presurgical weight loss trial in men who elected prostatectomy as their first line of treatment for prostate cancer.
Discussion
Only two other weight loss interventions have been pursued in the presurgical cancer setting, and neither of these small studies (
n = 8 and
n = 19 [of which only half were pre-surgical cases]), [
19,
20] assessed effects on tumor tissue. Therefore, this trial will be the first to assess the impact of an acute period of negative energy balance directly on the biology of the tumor, as well as within the more global host environment. Given the growing interest in weight control as a complementary therapy to standard cancer treatment [
1], such trials can provide the mechanistic evidence needed to justify the incorporation of diet and physical activity into oncologic practice. As such, the methods listed herein can offer a helpful framework for the design of future trials, as well as data on feasibility that can be used to specifically inform recruitment, retention, and the design of presurgical interventions.
Given the need to collect surgical specimens, presurgical trials dictate collaboration with co-investigators and cancer centers that perform substantial numbers of procedures annually. Physician turnover and changes in practice can cause unforeseen delays and in fact, occurred with this trial. Therefore, partnerships with other institutions are necessary and were instrumental in achieving targeted accrual within the two-year timeframe of this study. Nevertheless, patient indecision regarding surgical treatment and its timing pose substantial barriers to both recruitment and retention. Patients are unwilling to delay their surgery and it was clear that if we were to meet our accrual target, we needed to reduce our initial 10-week intervention period to a shorter period of time. As stated, 3-weeks was selected based on the results of our previous trial [
21]. Other issues related to presurgical studies are the possibilities that surgeries can be rescheduled and patients can decide to receive their treatment elsewhere or not at all. Therefore, an adequate margin of over accrual is necessary to ultimately meet sample sizes that afford adequate power.
Our enrollment rate of almost 40 % was relatively good for a diet and exercise intervention trial among cancer survivors where reported rates of participation have ranged from 6 % to 42 % [
53]. The modifications made to shorten the study period, as well as to deliver the intervention primarily through a home-based approach that relied on telephone counseling and technologic support likely enhanced our participation. Other criteria, such as those set to assure safety are not as amenable to change and the fact that we did not observe any serious adverse events provides further support to the medical exclusions that were made. However, given that distance and travel still were listed as one of the top reasons for refusal, it might be possible to overcome these barriers through an added participant incentive or a higher reimbursement rate for travel. Fifteen dollars was all the current grant could afford and may have been too low a stipend especially if the distance between the patient’s home and the study site is substantial.
Finally, both retention and adherence exceeded the benchmarks established for this trial. Moreover, with the exception of only two men who were dissatisfied with their randomization status, there was solid rapport between the study staff and participants.
Acknowledgments
This project is funded by the National Cancer Institute (R21 CA 161263 and P30 CA13148), and the Webb Family of Birmingham, AL. The following are acknowledged for their support of the Microbiome Resource at the University of Alabama at Birmingham: School of Medicine, Comprehensive Cancer Center (P30AR050948), Center for AIDS Research (5P30AI027767) and Center for Clinical Translational Science (UL1TR000165).
We acknowledge the efforts of the following individuals who contributed their time and expertise to this investigation: Tamika Bennett; David Bryan, MA; Crystal Ellis, RN; Maryellen Williams; Armando Enriquez; Heather Hunter, MS; Brandon L Kane, MA; Margaret Nelson, RN; Denise Oelschager; Scott Tully, Jr.; and Amaad Rana. Finally, we are exceptionally grateful to all of the men who participated in this trial and without whom this research would not be possible.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
WDW (principal investigator with expertise in diet), GRH (co-investigator expertise in physical activity), and RAD (co-investigator/biostatistician) conceived of the study, participated in its design, drafted the grant application, implemented the protocol and helped to draft the manuscript. JWN, SR-B and SAT (urologic surgeons) assisted with recruitment and retention, interpretation of the data and helped to draft the manuscript. BC conducted the cellular energetic assessments and helped to draft the manuscript. CDM and TP conducted the microbiome assessments and helped to draft the manuscript. MA recruited and provided diet and exercise instruction to study participants; she oversaw data collection and cleaning and helped to draft the manuscript. YT performed gene expression studies, data management and helped to draft the manuscript. ADF assisted with data management and helped to draft the manuscript. RS provided input in the grant proposal and with regard to the implementation of the trial and helped to draft the manuscript. WEG oversaw immunohistochemistry, interpretation of the data, and helped to draft the manuscript. All authors read and approved the final manuscript.