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Obesity and the Risk of Bladder and Kidney Cancer

Obesity and the Risk of Bladder and Kidney Cancer
—Obesity is well-recognized as a risk factor for kidney cancer and seems to increase the risk of bladder cancer, but its impact on survival outcome in patients with either cancer remains inconclusive.

By Gloria Arminio Berlinski, MS
Reviewed by Michael S. Leapman, MD
An estimated 35% of the U.S. adult population were considered obese in 2014, and researchers predict that by 2030 the prevalence of obesity in the U.S. will increase to about 50% for men and to 45%-52% for women.1,2 Excess body weight is recognized as a significant risk factor for cancer development and mortality. According to a 2016 report by the International Agency for Research on Cancer (IARC) Working Group, there is sufficient evidence from epidemiological studies to support the association of obesity with 13 different types of cancer, including kidney cancer.1,3 The IARC Working Group, however, considered the evidence to be presently inadequate for bladder cancer, although other experts more recently suggested an increased risk of bladder cancer in obese individuals.1,3,4

Take Note
Obesity is an established risk factor for renal cell carcinoma, although its effect on survival is less clear, with some studies showing reduced survival in obese patients and other studies suggesting an “obesity paradox.”
This obesity paradox may be explained away by methodological limitations, but according to emerging evidence, it is plausible that obese patients express less aggressive RCC tumors.
Obesity appears to increase bladder cancer risk, although further corroborating evidence is required, and findings are contradictory regarding its effect on survival outcome.
A strong connection with kidney cancer

Obesity is a well-established risk factor for renal cell carcinoma (RCC).1 In a meta-analysis including 221 prospective observational studies on body mass index (BMI) and cancer incidence, kidney cancer had the third highest obesity-related risk.5 Moreover, it appears that the clear cell histologic subtype is most closely associated with obesity.1

The association of obesity and kidney cancer outcomes, including cancer-specific mortality, are not as well understood. Gild and colleagues recently reviewed the evidence regarding obesity and bladder and kidney cancer incidence and mortality.They indicate in their 2017 review that in contrast to previous evidence from two large prospective studies which found an association among higher BMI with poorer cancer-specific survival in kidney cancer patients, growing data suggest an association between obesity and reduced mortality. This seeming “obesity paradox” in RCC was first demonstrated prospectively by Donin and fellow researchers, who found significantly improved overall survival among obese patients compared to patients with normal body weight.1

As Lennon and colleagues note, the obesity paradox may be explained by a number of methodological limitations in studying this relationship, including “the crudeness of BMI as an obesity measure, confounding, detection bias, reverse causality, and a specific form of the selection bias, known as collider bias.”6 Gild and colleagues point out, however, that the reason for this paradox may not stem at all or solely from methodological obstacles, but from the expression of less-aggressive kidney tumors in obese patients.1

An emerging link with bladder cancer

Gild and colleagues report that studies supporting a link between obesity and bladder cancer are accumulating, although findings in the literature are inconsistent, overall, and guidelines (including those from the American Urological Association and Society of Urologic Oncology) to date do not consider obesity to be a risk factor for bladder cancer.1

Data from a meta-analysis including 14 prospective cohort studies recently published by Zhao and colleagues (from?) suggest that bladder cancer was associated with obesity, but not with being overweight. In an analysis consisting of over 5 million patientsl, including 12,642 diagnosed with bladder cancer during follow-up, the authors observed an “almost linear” trend of increasing bladder cancer risk with BMIs exceeding 30 kg/m2 that was not seen among patients with lower BMIs in the over-weight range (25-29.9).4 It is important to note that all of the analyzed studies controlled for cigarette smoking, but few took physical activity or family history of cancer into account.4

Using data from the Cancer Genome Atlas, Sun and colleagues investigated the link between risk factors and molecular subtypes of muscle-invasive bladder cancer among 372 patients. Their newly published findings demonstrated that in general, patients with basal-like tumor subtypes were older and obese and started smoking at an early age compared to patients with luminal-like subtypes.7

Gild and colleagues indicate from their review that the influence of obesity on bladder cancer survival remains inconclusive. For instance, they note that a landmark prospective study by Calle and fellow researchers found no significant relationship between BMI and death from bladder cancer among more than 900,000 U.S. adults,1 On the other hand, they observe that more recent studies appear to show a connection between obesity and worse outcomes in urothelial carcinoma of the bladder.1 In a recent retrospective study by Dabi and colleagues, obesity also was shown to be correlated with an elevated risk of cancer recurrence and cancer-specific mortality among a cohort of 701 patients with muscle-invasive urothelial carcinoma of the bladder who had undergone radical cystectomy.8 Leiter and fellow researchers, on the other hand, found from their study of 537 patients from eight previous Phase II and Phase III clinical trials that overall and progression-free survival outcomes were similar for obese and non-obese patients with metastatic urothelial carcinoma receiving palliative chemotherapy.2

Gild and colleagues conclude in their review, “Taken together, growing evidence suggests an association between obesity and bladder cancer incidence; however, conclusions with regard to survival require further investigation at this time.”

Possible pathways

“The exact mechanisms by which obesity influences carcinogenesis and cancer progression are poorly elucidated and may differ by cancer type,” explain Gild and colleagues. The interplay of extreme hormonal changes in obesity appears to underlie the connection between excess body weight and cancers of the kidney and bladder.1

In particular, insulin resistance and, in turn, hyperinsulinemia and elevated levels of insulin-like growth factor 1 may stimulate tumor cell growth and thwart apoptosis.4,5 The inflammatory effects of adipokines and the proliferative effects of steroid hormones in adipose tissue are also considered as possible biologic mechanisms linking obesity to cancers of the kidney and bladder.1

Breaking the link?

To date, it’s not known whether weight loss or pharmacological targeting of the possible obesity-related pathological mechanisms can attenuate cancer risk or improve cancer outcomes in obese patients.9

Because research findings on how obesity may affect survival outcomes in patients with kidney or bladder cancer remain contradictory, “no clear-cut recommendation regarding weight management can be given at this time,” write Gild and colleagues. “However, in the general population, given the rising prevalence of overweight in children and adults, obesity might constitute a major future cancer burden and physicians should raise awareness, encourage weight loss and prevent weight gain in their patients.”1

Published: October 25, 2017

1. Gild P, Ehdaie B, Kluth LA. Effect of obesity on bladder cancer and renal cell carcinoma incidence and survival. Curr Opin Urol. 2017, 27:409–414.
2. Leiter A, Doucette J, Krege S, et al. Obesity and outcomes in patients with metastatic urothelial carcinoma. Bladder cancer. 2016;2:341-349.
3. Lauby-Secretan B, Scoccianti C, Loomis D, et al. Body fatness and cancer: viewpoint of the IARC Working Group. N Engl J Med. 2016;375:794–798.
4. Zhao L, Tian X, Duan X, et al. Association of body mass index with bladder cancer risk: a dose response meta-analysis of prospective cohort studies. Oncotarget. 2017;8:33990-34000.
5. Kovesdy CP, Furth SL, Zoccali C, et al. Obesity and kidney disease: hidden consequences of the epidemic. Clinical Kidney Journal. 2017;10:1–8.
6. Lennon H, Sperrin M, Badrick E, et al. The obesity paradox in cancer: a review. Curr Oncol Rep. 2016;18: 56.
7. Sun X, Hoadley KA, Kim WY, et al. Age at diagnosis, obesity, smoking, and molecular subtypes in muscle-invasive bladder cancer. Cancer Causes Control. 2017 Jun;28:539-544.
8. Dabi Y, Rouscoff Y, Anract J, et al. Impact of body mass index on the oncological outcomes of patients treated with radical cystectomy for muscle-invasive bladder cancer. World J Urol. 2017 Feb;35:229-235.
9. Goodwin PJ, Chlebowski RT. Obesity and cancer: Insights for clinicians. J Clin Oncol. 2016. 34:4197-4202.

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