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Keywords:

  • renal cell carcinoma;
  • body mass index;
  • survival;
  • meta-analysis

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Statistical Analysis
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

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.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Statistical Analysis
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study cohort

We identified 1,543 patients who underwent initial radical (n = 1,259) or partial (n = 284) nephrectomy for RCC at the Samsung Medical Center, Seoul, Republic of Korea, between October 1994 and December 2008. Data were abstracted from retrospective medical record review using a standardized data collection form. This study was approved by an institutional review board at Samsung Medical Center.

Data collection

The following baseline clinical and pathologic data, assessed by physicians, nurses, and surgical pathologists at first diagnosis or at the time of nephrectomy, were abstracted; age at the time of nephrectomy, gender, past and current alcohol and smoking habits, history of diabetes and hypertension, presence of weight loss, RCC symptoms and distant metastases at diagnosis, histological subtype,16 stage,17 size and location of tumor, laterality, Fuhrman nuclear grade [I–IV],18 and regional lymph node involvement. Patients were asked whether they had weight loss when compared with their usual weight when their weight was measured at the first visit. All patients had a preoperative clinical abdominal computed tomography scan before nephrectomy for tumor staging, including the status of regional lymph nodes near the kidney (N stage) and the presence of distant metastases (M stage). Pathologic (pTNM) evaluation was performed according to microscopic examination of surgically resected specimens of RCC and then classified based on the 6th TNM Classification of Malignant Tumours. Histologic subtype was classified as clear cell, papillary, chromophobe, collecting duct RCC and unclassified cell carcinoma, and coded according to criteria specified in the International Classification of Disease for Oncology.19 Tumor size was measured at the time of macroscopic examination. The American Society of Anesthesiologists (ASA) score was assessed by anesthesiologists. BMI (kg/m2) was calculated based on a direct measurement of height and weight at diagnosis. The erythrocyte sedimentation rate (ESR) was determined according to the quantitative capillary photometry method.

Mortality information

The patient's medical records were electronically linked to death certificates via unique 13-digit personal identification number in the Korean National Statistical Office,20 the system of which complete ascertainment of deaths reached to 96.2%.21 Causes of death were determined by a medical record review by physicians, the patient's death certificate or autopsy report, and coded according to the Korean Standard Classification of Causes of Death,22 which was based on the International Classification of Disease for Oncology 10th edition.23

Statistical Analysis

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Statistical Analysis
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Cohort analysis

Patients were classified using the Asian-specific BMI cutoff values24 as follows: underweight <18.5; normal weight 18.5 to <23 [reference group]; overweight 23 to <25 and obesity ≥25. These values were chosen because there is evidence that excess risks of developing chronic diseases (i.e., diabetes and cardiovascular disease) or of mortality from all-cause occur at lower BMI levels in Asians than in Caucasians.25, 26 Asians have a higher percentage of visceral fat and lower percentage of lean body mass when compared with Caucasians with the same BMI.27

We tested whether baseline characteristics among RCC patients were different across BMI categories using the chi-square test. The primary outcomes were OS and cancer-specific survival (CSS), defined as the time from nephrectomy to death from any and cancer-specific cause, respectively. Person-months of follow-up were calculated starting from the date of surgery to the date of death or to the end of the follow-up time (December 31, 2008). OS and CSS curves for patients in four BMI categories were plotted using the Kaplan–Meier method, and the log-rank test was used for the group comparisons. We obtained the hazard ratios (HRs) and 95% confidence intervals (CIs) using the Cox proportional hazards models with time elapsed (months). All Cox models were stratified on age at diagnosis (years) and sex. Multivariate models included weight loss, stage, smoking, nephrectomy type, histological subtype, Fuhrman grade, symptom presence, tumor size and ESR. Because additional adjustment for alcohol intake, ASA score and tumor location had no appreciable influence on the results, these variables were not included in the analyses. We tested for linear trends across categories of BMI by assigning each patient the median value for the category and modeling this value as a continuous variable.

We performed subgroup analyses to examine whether the association of BMI (<25 or ≥25) with OS or CSS varied across strata of weight loss, stage, tumor size, histological subtype and symptom presence. We evaluated effect modification by the likelihood ratio test, comparing models with and without a cross-product term of BMI and potential effect modifiers. In the sensitivity analyses, patients who had metastasis (n = 90) or patients who died during the first 2 years of follow-up (n = 98) were excluded to investigate whether weight loss due to RCC influenced our results.

Meta-Analysis

We conducted a systematic search of published reports in the EMBASE and MEDLINE databases through September 2011 using the following search terms: “RCC” OR “kidney cancer” AND “body mass index” OR “overweight” OR “obesity” AND “survival” OR “prognosis.” We included articles that met the following criteria: (1) OS, CSS or RFS among patients who underwent nephrectomy for RCC; (2) BMI as an exposure of interest; (3) Information provided for estimating parameters and (4) published in English. When the association between BMI and HRs of survival was not reported, we requested the data from the authors and were able to add two studies (Brookman-May October 08, 2011, Rasmuson December 09, 2011; personal communication). We pooled the HRs of each cause-specific survival (OS, CSS and RFS) using a random-effects model.28 For studies that provided HRs as continuous variable only,29–32 we recalculated them into estimates per five increment in BMI (treated as top and bottom estimates) and then pooled with categorical variables in the additional analysis.

We conducted a sensitivity analysis to examine whether the results could have been substantially influenced by any of the individual studies. Random effects meta-regression analyses were performed to explore potential sources of heterogeneity by study characteristics, including histological type (clear or non-clear cell), adjustment for symptom presence (yes or no), adjustment for tumor size (yes or no), exclusion of metastasis at baseline (yes or no) and geographic region (Western or Asian countries). The significance of heterogeneity between studies was evaluated using the I2 statistic33 and publication bias was assessed using the Egger asymmetry test.34 All analyses were conducted using the STATA statistical software package version 11 (Stata Corp., College Station, TX, USA) with a two-sided test; p < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Statistical Analysis
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

BMI and survival in the Korean Cohort Study

A total of 1,543 patients treated with nephrectomy for RCC were included in the study. During a median follow-up of 44 months, there were a total of 208 (13%) deaths, including 174 deaths due to RCC (11%). Table 1 shows the patient characteristics according to BMI categories at initial diagnosis. Overweight and obese patients were more likely to be older, male and alcohol consumers; had lower likelihood of weight loss, symptoms or metastases; had lower ESR, smaller tumor size and lower stage when compared with the underweight and normal weight patients; they were also less likely to be diagnosed with non-clear RCC and to be treated with radical nephrectomy than the underweight and normal weight patients.

Table 1. The clinical and pathologic characteristics at baseline, stratified by BMI categories1
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The 5-year survival increased monotonically with higher BMI from 76.1 to 90.8% for OS and from 76.1 to 92.7% for CSS (Table 2). The differences in OS and CSS rates between BMI categories were statistically significant (p < 0.001, log-rank test; Figs. 1a and 1b). These findings were further corroborated in both age and sex adjusted (p for trend <0.001) and multivariate-adjusted Cox proportional hazards models (p for trend <0.001; Table 2). When comparing obese patients to normal weight patients, HRs were 0.37 for OS and 0.35 for CSS in age- and sex-stratified analyses. Further adjustment for weight loss slightly attenuated the inverse association. In the final multivariate model with adjustment for weight loss, stage, smoking, tumor size, nephrectomy type, histological subtype, Furman grade and ESR, we found that obese patients had a 55% lower risk of dying from any cause and 53% lower risk of dying from RCC when compared with those with normal weight. Compared with normal weight patients, underweight patients had poorer, but not significant, OS and CSS.

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Figure 1. Kaplan–Meier curves of (a) overall survival and (b) cancer-specific survival according to BMI categories. The 5-year survival rates by preoperative BMI categories (<18.5, 18.5 to <23, 23 to <25 and ≥25kg/m2) were 76.1, 78.2, 86.0 and 90.8% for (a) overall survival, respectively; 76.1, 80.6, 89.2 and 92.7% for (b) cancer-specific survival, respectively. Abbreviation: BMI, body mass index.

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Table 2. HRs and 95% CIs of OS and CSS according to BMI categories1,2 (N (= 1,543)
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When we performed sensitivity analyses by excluding patients who died during the first 2 years of follow up (HR = 0.49; 95% CI: 0.26–0.91 for OS; and HR = 0.49; 95% CI: 0.24–1.02 for CSS) or those who had metastasis before nephrectomy (HR = 0.39; 95% CI: 0.23–0.65 for OS; and HR = 0.36; 95% CI: 0.19–0.69 for CSS) the results did not substantially differ from the main results. When we examined whether the association of OS or CSS with BMI (≥25 vs. <25) varied across potential effect modifiers, including weight loss (yes or no), stage (pT1/2 or pT3/4), grade (G1/2 or G3/4), tumor size (<5 or ≥5 cm), symptom presence (yes or no) and histological subtype (clear or nonclear cell RCC), we found that the significant inverse association was limited to the patients with clear cell RCC for both OS and CSS (p interaction = 0.01 for both OS and CSS). Although the interaction was not significant, we still found statistically significant improved OS and CSS among patients who had no weight loss or low stage (data not shown).

Meta-analysis of BMI and survival

Figure 2 illustrates the selection process of the studies for meta-analysis. After the full-text review, 20 studies, including the current study, were included in our meta-analysis (Table 3). Of these, 10 reported OS and included a total of 6,518 patients, 15 reported CSS and included a total of 12,175 patients and 8 reported RFS and included a total of 7,165 patients. Of the 20 studies, six were conducted in Europe, six in the United States and eight in Asia. The median follow-up time ranged from 22 to 286 months for all RCC survival. Age, sex, stage and grade were considered as covariates, and patients from all stages (I through IV) were evaluated in the majority of the studies.

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Figure 2. Flowchart of study selection for inclusion in the meta-analysis.

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Table 3. Study characteristics included in the meta-analysis1
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Higher BMI was significantly associated with improved OS (HR = 0.57; 95% CI: 0.43–0.76 comparing the highest with the lowest BMI; Fig. 3a), but there was evidence of heterogeneity between the studies (p = 0.023; I2 = 56.8%). For CSS, the pooled HR (95% CI) was 0.59 (0.48–0.74; Fig. 3b) when comparing the highest BMI with the lowest BMI, with evidence of heterogeneity (p = 0.007; I2 = 55.9%). A pooled HR (95% CI) of RFS was 0.49 (0.30–0.81) when comparing the highest with the lowest BMI (Fig. 3c) with no evidence of heterogeneity (p = 0.14). A test for publication bias using Egger's test was significant for OS and CSS but not for RFS. In additional analysis, we combined continuous results (per five increments in BMI) with categorical results by treating estimates as HRs for top vs. bottom categories (five from the top). With this approach, the pooled HRs (95% CIs) were 0.65 (0.51–0.84) for OS, 0.66 (0.53–0.81) for CSS and 0.73 (0.53–1.01) for RFS.

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Figure 3. Meta-analysis of highest versus lowest BMI category and RCC survival; (a) overall survival (b) cancer-specific survival and (c) recurrence-free survival. The pooled HR estimates were obtained using a random-effects model. The relative size of the data markers indicates the weight of the sample size from each study. Abbreviations: HR, hazard ratio. CI, confidence interval. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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In a sensitivity analysis where we excluded one study at a time, none of the individual studies substantially influenced the results. When we examined differences in the associations between BMI and survival by geographic location, exclusion of patients with metastasis, adjustment for histological subtype, symptom presence or tumor size, we found a significant difference by histological subtype-adjustment for OS (p difference <0.001); pooled HRs (95% CIs) were 0.57 (0.41–0.79) in studies that adjusted for histological subtype, but 0.16 (0.05–0.54) in those that did not. For CSS, the associations varied by geographic location (p difference = 0.001) and symptom presence (p difference <0.001), which may partially contribute to between-studies heterogeneity. The association of CSS was greater in studies from Asia (HR = 0.40; 95% CI: 0.28–0.56) when compared with those from Western countries (Europe and United States) (HR = 0.70; 95% CI: 0.58–0.86). The pooled HRs were 0.42 (95% CI: 0.31–0.56) for studies adjusted for symptom presence and 0.72 (95% CI: 0.59–0.88) for studies that did not adjust for symptom presence.

Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Statistical Analysis
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Statistical Analysis
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The study was supported by the SRC Research Center for Women's Diseases of Sookmyung Women's University (2011), and Karolinska Institute, Hans-Olov Adami Distinguished Professor Award (grant number Dnr: 2368/10-221). We thank Drs. Sabine Bookman-May and Torgny Rasmuson for data provision for our meta-analysis part. We also thanks physicians and nurses who helped in abstracting medical information from the medical records in the Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine and the Korean National Statistical Office staffs for their assistance providing information on completion rate. The authors have no conflicts of interest regarding our study

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  2. Abstract
  3. Material and Methods
  4. Statistical Analysis
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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