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- Material and Methods
- Statistical Analysis
Growing evidence suggests that obesity, an established cause of renal cell cancer (RCC), may also be associated with a better prognosis. To evaluate the association between RCC survival and obesity, we analyzed a large cohort of patients with RCC and undertook a meta-analysis of the published evidence. We collected clinical and pathologic data from 1,543 patients who underwent nephrectomy for RCC between 1994 and 2008 with complete follow-up through 2008. Patients were grouped according to BMI (kg/m2): underweight <18.5, normal weight 18.5 to <23, overweight 23 to <25 and obese ≥25. We estimated survival using the Kaplan–Meier method and Cox proportional hazard models to examine the impact of BMI on overall survival (OS) and cancer-specific survival (CSS) with adjustment for covariates. We performed a meta-analysis of BMI and OS, CSS and recurrence-free survival (RFS) from all relevant studies using a random-effects model. The 5-year CSS increased from 76.1% in the lowest to 92.7% in the highest BMI category. A multivariate analysis showed higher OS [hazard ratio (HR) = 0.45; 95% CI: 0.29–0.68) and CSS (HR = 0.47; 95% CI: 0.29–0.77] in obese patients than in normal weight patients. The meta-analysis further corroborated that high BMI significantly improved OS (HR = 0.57; 95% CI: 0.43–0.76), CSS (HR = 0.59; 95% CI: 0.48–0.74) and RFS (HR = 0.49; 95% CI: 0.30–0.81). Our study shows that preoperative BMI is an independent prognostic indicator for survival among patients with RCC.
Kidney cancer incidence has been rising steadily world-wide with a 2.6% annual increase in the US between the years 1997 and 20071 and a 6.0% annual increase in South Korea between the years 1999–2007.2 Accounting for 85% of all kidney cancer in adults, renal cell carcinoma (RCC) has a relatively poor prognostic outlook with no major breakthrough in primary treatment. However, overall survival (OS) rate has been increasing, with 5-year relative survival rate reaching 74.7% among men and 75.3% among women in South Korea during 2003–2007,2 probably due to earlier diagnosis through improved diagnostic tools and detection of slow growing or even nonlethal RCC. Novel therapeutic approaches are needed, and there is indeed evidence that, for some cancers, lifestyle factors such as physical activity, diet and obesity, may also influence recurrence and survival after cancer diagnosis.3
Overweight and obesity is one of few established causes for RCC,4, 5 accounting for an estimated 40% of all cases in the US and 30% in Europe.6, 7 Paradoxically, patients with higher body mass index (BMI) also had a significantly better RCC prognosis than those with lower BMI in several studies.8–15 However, a possible association between obesity and RCC survival has not been yet generally accepted as causal and there has been no comprehensive systematic review of this association. We therefore analyzed a large cohort of Korean patients with RCC and then undertook a comprehensive meta-analysis of all informative studies published until recently.
- Top of page
- Material and Methods
- Statistical Analysis
In this large Korean cohort study of patients, we found that obese patients with RCC had a 53% lower risk of dying from RCC compared with normal weight patients with RCC. Significant inverse associations for OS and CSS were still observed when we limited the analysis to patients who had low stage or did not experience weight loss. Our meta-analysis further confirmed significant associations between high preoperative BMI and improved OS, CSS and RFS.
Obese patients were more likely to have favorable clinical and pathologic conditions at diagnosis, including lower stage, lower ESR and lower Fuhrman grade, smaller tumor size and absence of symptoms and distant metastasis when compared with under-to-normal weight patients. We therefore carefully adjusted for stage, tumor size, grade, symptom presence, and baseline weight loss, which may be related to patient survival. Although adjustment for other important risk factors associated with survival weakened the association for both OS and CSS, the association between obesity and RCC prognosis remained strong and highly significant. When the analysis was restricted to patients without any weight loss or those with early stage, we still observed improved OS and CSS with high BMI. When we excluded patients who died during the first 2 years of follow-up to reduce possible effects of reverse causality, OS and CSS remained higher for obese patients when compared with those with normal weight. Of the three studies excluded in our meta-analysis due to the absence of information on HRs, two studies showed that high BMI was significantly associated with better survival rate,40, 41 but one found no association.42
In the subgroup analyses, the pooled HR of OS with stratification for histological subtypes and that of CSS with stratification for symptom presence-adjustment and geographical location may partially explain the heterogeneity between studies in our meta-analysis. Publication bias was present for OS and CSS, perhaps because nonsignificant findings were less likely to be published. However, the strong inverse associations between BMI and OS and CSS in our current data and the lack of evidence of publication bias for RFS in a meta-analysis support improved RCC survival with high BMI.
The mechanism by which preoperative obesity may improve RCC survival is not well understood, although mechanisms linking obesity with RCC incidence have long been studied.43 A recent study showed an association between preoperative nutritional deficiency and poor OS and disease-free survival in RCC patients who underwent renal surgery.32 Patients with higher BMI, who generally have large appetites and high lipid concentrations,44, 45 may adequately preserve their fat and muscle mass, thus allowing better nutritional status and potential survival advantage. It may be plausible that obesity indicates favorable general health condition rather than it being responsible for improved outcomes. We also cannot rule out the possibility that obese patients may be diagnosed and treated in the early stages of RCC and therefore have subsequent improved survival when compared with normal weight patients probably because obese patients are at higher likelihood of being screened for any other disease. However, when we controlled for tumor stages and conducted stratified analysis by tumor stage (pT1/2 vs. pT3/4), we still found that patients in the low stages had improved OS and CSS with high BMI.
The current Korean cohort study included large sample sizes and a large number of RCC mortality cases with a retrospective long-term follow-up. We were able to adjust for clinically and pathologically important confounding factors, although unmeasured or remaining confounding factors may exist. However, we lack information about modifiable lifestyle factors and change in BMI throughout the follow-up period after surgery. The patients of the current study may not be representative for the population of patients with RCC in South Korea; however, inclusion of study patients from one large general hospital, well-equipped with an electronic medical record system could be one of our study strengths because of its high quality of information. In addition, underlying biological mechanism behind obesity and RCC survival in this patient group may not differ from general RCC patient population.
To our knowledge, this meta-analysis is the first systematic review of preoperative BMI and RCC survival. Because studies included in this meta-analysis obtained detailed medical records containing clinical and pathologic information at hospitals, the accuracy of the information is relatively high. Ascertainment of outcome was linked to internal medical review or National Death Index in most studies; thus, selection bias resulting from differential ascertainment of outcomes may not explain the results of our meta-analysis.
In conclusion, these findings suggest that high BMI prior to renal surgery is associated with improved OS, CSS and RFS when compared with low BMI. This evidence may provide new insight into the effects of preoperative high BMI on improvements in RCC survival, and this could help physicians in predicting overall prognosis. Further research is needed to explain the biological mechanisms responsible for the benefit of high BMI on improved RCC survival, and to determine whether other modifiable lifestyle factors contribute to RCC survival.