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Modifiable risk factors to reduce renal cell carcinoma incidence: Insight from the PLCO trial
Urologic Oncology: Seminars and Original Investigations ] (2018) ∎∎∎–∎∎∎
Original article
Modifiable risk factors to reduce renal cell carcinoma incidence: Insight from the PLCO trial Jonathan Gelfond, M.D., Ph.D.a, Osamah Al-Bayati, M.B.Ch.B.b, Aashish Kabra, M.D.b, Kevan Iffrig, M.D.b, Dharam Kaushik, M.D.b, Michael A. Liss, M.D., M.A.S., F.A.C.S.b,c,* a
Department of Biostatistics, University of Texas Health Science Center San Antonio, San Antonio, TX b Department of Urology, University of Texas Health Science Center San Antonio, San Antonio, TX c Department of Surgery, South Texas Veterans Healthcare System, San Antonio, TX Received 22 November 2017; received in revised form 7 March 2018; accepted 17 April 2018
Abstract Introduction: Identify modifiable factors contributing to renal cell carcinoma in the PCLO to target disease prevention and reduce health care costs. Methods: The prostate, lung, colorectal, and ovarian database were queried for the primary outcome of kidney cancer. Demographics were investigated, specifically focusing on modifiable risk factors. Statistical analysis includes the Student t-test for continuous variables, chi-squared or Fisher’s exact tests for dichotomous and categorical variables for bivariate analysis. The Cox proportional hazards model was used in a multivariate time-to-event analysis. Results: We investigate existing data relating specifically to renal cancer. After missing data were excluded, we analyzed 149,683 subjects enrolled in the prostate, lung, colorectal, and ovarian trial and noted 0.5% (n ¼ 748) subjects developed renal cancer. Age, male gender, body mass index, diabetes, and hypertension were all significant associated with renal cancer in bivariate analysis (P o 0.05). Men have a significant increased risk of kidney cancer over women (hazard ratio [HR] ¼ 1.85; 95% CI: 1.58–2.16; P o 0.0001). Nonmodifiable risk factors that are associated with kidney cancer include age (HR ¼ 1.05; 95% CI: 1.01; 1.05, P ¼ 0.001). Modifiable risk factors include obesity measured by body mass index (HR ¼ 1.05; 95% CI: 1.02–1.07; P o 0.0001), hypertension (HR ¼ 1.32; 95% CI: 1.13–1.54; P ¼ 0.0004), and smoking in pack-years (HR ¼ 1.04; 95% CI: 1.02–1.07; P ¼ 0.0002). Conclusions: Obesity, hypertension, and smoking are the 3 modifiable risk factors that could aggressively be targeted to reduce renal cell carcinoma. Published by Elsevier Inc.
Keywords: Kidney cancer; Renal cancer; Modifiable risk factors; Smoking; Body mass index; Obesity; Hypertension; Blood pressure; Renal cell cancer; Lifestyle; Prevention
1. Introduction Kidney cancer is estimated to have as worldwide incidence of 270,000 cases yearly and nearly 116,000 deaths [1]. In the Unites states, estimates indicate 65,000 new cases and over 13,000 deaths from kidney and renal pelvis cancers in 2013 with approximately 35% presenting as metastatic disease [2].
⁎
Corresponding author. E-mail address: [email protected] (M.A. Liss). https://doi.org/10.1016/j.urolonc.2018.04.011 1078-1439/Published by Elsevier Inc.
Although there is no recommendation for screening for renal cell carcinoma (RCC), the frequency of RCC continues to rise [3]. The rising number of RCC cases is believed to be a result of improved imaging techniques and increased incidental tumor discovery [4]. However, it has been found that there is marked regional variability, likely related to demographic, environmental, and genetic factors [5]. Moreover, RCC can be attributed to the increased prevalence of associated risk factors such as obesity and hypertension [3]. Risk factors that can be changed to potentially effect health outcomes have been termed modifiable risk factors. The modification of risk factors may
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J. Gelfond et al. / Urologic Oncology: Seminars and Original Investigations ] (2018) ∎∎∎–∎∎∎
have the potential to reduce incidence of RCC and potentially improve survival. Lifestyle modifications have been shown to reduce the incidence of a variety of cancers as well as improve cancer specific survival [6]. Therefore, lifestyle interventions can be an inexpensive preventative and adjunctive program tailored to the individual patient and may affect outcomes. To investigate specific modifiable lifestyle risk factors, we examine the prostate, lung, colorectal, and ovarian (PLCO) screening trial for potential impact of altering these factors.
Did the participant ever have high blood pressure? and was a dichotomous answer (Yes vs. No). 2.3. Statistical analysis
2.2. Outcomes and risk factors
PLCO database were queried for the primary outcome of kidney cancer. Demographics were investigated, specifically focusing on modifiable risk factors, such as smoking, obesity, and hypertension. Statistical analysis included testing for bivariate associations between renal cancer status and risk factors using the Student t-test for continuous variables, chi-squared or Fisher’s exact tests for dichotomous or categorical variables. The incidence of RCC was modeled using Cox proportional hazards models excluding data from subjects with missing data for any model covariates, and all risk factors were considered within the same model adjusting for demographics and comorbidities. Deaths due to other causes were treated as censored. Factors that increase medical surveillance in general may be associated with an increase in risk of RCC due to increase likelihood of diagnosis, while not being causally related to RCC. These factors include comorbidities such as diabetes and hypertension and also include being randomized to the trials intensive screening arm. We examined the effect of these factors using Cox proportional hazard models.
The primary outcome of this study was kidney cancer incidence defined by questionnaire and medical record confirmation. Predictor variables were obtained from the baseline questionnaire. The World Health Organization standard categorization of body mass index (BMI) was used. Weights less than 27 kg were truncated and considered out of range. Heights less than 48 in were truncated and out of range. For female participants, heights greater than 78 in are out of range and for male participants, heights greater than 84 in are out of range. After BMI is calculated, BMI values less than 15 kg/m2 are out of range. Hypertension was obtained via questionnaire answering:
2.3.1. Results After missing data were excluded, we analyzed 149,683 subjects enrolled in the PLCO trial and noted 0.5% (n ¼ 748) subjects developed renal cancer. Age, male gender, BMI, diabetes, and hypertension were all significant associations with renal cancer in univariate analysis (all o 0.05) (Table 1). Men have a significantly increased risk of kidney cancer over women (hazard ratio [HR] ¼ 1.85; 95% CI: 1.58; 2.16, P o 0.0001) (Table 2). Nonmodifiable risk factors that are associated with kidney cancer include age (HR ¼ 1.05; 95% CI: 1.01–1.05, P ¼ 0.001). Modifiable risk factors include obesity
2. Methods 2.1. Study population After IRB approval and data transfer agreement, we obtained de-identified data from subjects enrolled in the PLCO Cancer Screening Trial. The PLCO is a National Cancer Institute sponsored randomized trial investigating the effects of screening on cancer outcomes in subjects aged 55 to 74 years from 1993 to 2001 and have followed them for 13 years.
Table 1 Demographics and comorbidities by renal cancer status Variable Age, mean (median; IQR) Gender, no. (%) Female Male Body mass index, mean (median; IQR) Race/ethnicity no. (%) White, non-Hispanic Black, non-Hispanic Hispanic Family history of renal cancer, no. (%) Diabetes, no. (%) Myocardial Infarction, no. (%) Hypertension, no. (%) Stroke, no. (%)
No renal cancer 62.6 (62; 58–67) 75,728 (50.8) 73,201 (49.2) 27.3 (26.6; 24–29.8) 131,640 7,659 2,795 2,183 11,424 13,411 50,526 3,605
(88.4) (5.1) (1.9) (1.5) (7.7) (9.1) (34.1) (2.4)
Renal cancer
P value
63.3 (63; 59.2–67)
o0.001 o0.001
261 (34.6) 493 (65.4) 28.6 (27.9; 25.1–31.2) 681 35 17 12 73 95 326 22
(90.3) (4.6) (2.3) (1.6) (9.7) (12.7) (43.5) (2.9)
o0.001 0.09
0.89 0.05 0.001 o0.001 0.44
J. Gelfond et al. / Urologic Oncology: Seminars and Original Investigations ] (2018) ∎∎∎–∎∎∎
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Table 2 Cox proportional hazards model for renal cancer in the PLCO Variable
HR
95% CI
P value
Age Screening arm Body mass index Diabetes Education (college) Hypertension (yes vs. no) Smoker (pack decades) Black, non-Hispanic vs. white Hispanic vs. white Other vs. white Family history of renal cancer Gender (male vs. female)
1.03 1.13 1.05 1.07 0.96 1.32 1.04 0.92 1.12 0.65 1.13 1.85
[1.01, [0.98, [1.03, [0.83, [0.92, [1.13, [1.02, [0.65, [0.67, [0.42, [0.64, [1.58,
0.0001 0.09 o0.0001 0.59 0.08 0.0004 0.0002 0.64 0.66 0.05 0.68 o0.0001
1.04] 1.31] 1.06] 1.38] 1.01] 1.54] 1.07] 1.31] 1.88] 1.01] 2] 2.16]
measured by BMI (HR ¼ 1.05; 95% CI: 1.02–1.07, P o 0.0001), hypertension (HR ¼ 1.32; 95% CI: 1.13– 1.54; P ¼ 0.0004), and smoking in pack decades (HR ¼ 1.04; 95% CI: 1.02–1.07; P ¼ 0.0002). This implies that a person with 5 kg/m2 lower BMI has 22% less risk for cancer relative to another person with all other factors equal. A person who smokes an additional 20 packyears has 8% greater risk relative to a person with all other factors equal. When smoking is considered as dichotomous variable (pack-years 4 0) the increase in risk due to any smoking history is about 20% (HR ¼ 1.21, 95% P ¼ 0.01). However, the effect size of the dichotomous smoking risk factor depends on the average number of pack-years of smokers in the sample. Among participants who ever smoked, we found that those who identified as current regular smokers had a 33% higher risk relative to those who did not (i.e., quit or no longer smoking) (HR ¼ 1.33; 95% CI: 1.05–1.68; P ¼ 0.017). Fig. 1 indicates that the increase in risk due to smoking is approximately the same in males and females. Fig. 2 demonstrates the risk increase to due hypertension (P o 0.001), and while the effect appears to be greater in females than males, the hypertension by gender interaction is not statistically significant (P ¼ 0.11). Fig. 3 shows the change in risk due to BMI category (P o 0.0001). There is no statistically significant difference in the effects of BMI on cancer risk in men and women (P ¼ 0.5). Missing data and the effect of general medical surveillance to increase diagnosis were considered as potential sources of bias. The rate of missing data for variables ranged from 0% to 1.5%. BMI (1.5%) and pack-years smoking (1.2%) had the highest rates of missing data, but overall the data were mostly complete, and 96% of observations had no missing data. Although some factors that increase medical surveillance such as diabetes were not associated with RCC risk (P ¼ 0.59) other such factors like randomization to intensive screening arm was significant in men (HR ¼ 1.2; 95% CI: 1.0–1.45; P ¼ 0.04), but not in women (P ¼ 0.9) or the combined data (P ¼ 0.09).
Fig. 1. The incidence of renal cell cancer (RCC) by smoking status. The curves represent the risk of RCC (0–1) in each group adjusting for the average effects of hypertension, education, treatment arm, body mass index, race, family history, and diabetic status. (Color version of the figure available online.)
3. Discussion In our investigation of the PLCO screening trial, we identified 3 modifiable lifestyle interventions that could be implemented to reduce the incidence of renal cancer: hypertension, obesity, and smoking. The strongest factor for developing RCC was a positive answer on the baseline
Fig. 2. The incidence of renal cell cancer (RCC) by hypertension status. The curves represent the risk of RCC (0–1) in each group adjusting for the average effects of smoking, education, treatment arm, body mass index, race, family history, and diabetic status.(Color version of the figure available online.)
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J. Gelfond et al. / Urologic Oncology: Seminars and Original Investigations ] (2018) ∎∎∎–∎∎∎
Fig. 3. The incidence of renal cell cancer (RCC) by body mass index. The curves represent the risk of RCC (0–1) in each group adjusting for the average effects of hypertension, smoking, education, treatment arm, race, family history, and diabetic status. (Color version of the figure available online.)
questionnaire of whether or not the subject had hypertension. If “yes” the patient had a 32% increased risk of RCC then nonhypertensive patients over the next 13 years. Hypertension has previously been associated with the risk of developing RCC. A number of articles have focused on longitudinal outcomes of various aspects of hypertension and incident RCC [7–12]. All studies have shown higher rates of incident RCC in patients with hypertension. The largest studies were from Sweden (n = 855) and the United States (n = 759) both showing increasing risk of RCC with severity of hypertension [7,12]. Both studies stress the importance of diastolic as well as systolic blood pressure. Case-control studies investigated hypertension as an all-ornone event; however, one study noted that patients with more poorly controlled are 2 times more likely to also have renal cell cancer [13]. In our study, while the effect appears to be greater in females than males as demonstrated in Fig. 2, the hypertension by gender interaction is not statistically significant (P ¼ 0.11). inconsistent with our study, a large study shows the same finding with slight increase the risk in women with hypertension than men even the statistical significant was not reached [14], this may be in part, due to the existence of hidden confounders in normotensive men with relatively higher incidence of cancer than normotensive women, such as alcohol consumption and occupational toxin exposure in men, and high parity in women [15,16]. Further studies will have required to investigate these differences. Clinical trials are needed to determine if aggressive control of hypertension, as well as, which antihypertensive medication could provide benefits of preventing RCC. We
could not include the antihypertensive medications as possible risk factor, however, most of the epidemiological studies conclusions were more consistent with identification of high blood pressure as an independent factor to the RCC incidence, rather than the antihypertension medications [11,17–19]. Shapiro et al. [19] noted that diuretic antihypertensive medications did not have an influence of incident RCC. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers have seem to peak some interest in reducing cancer specific death in other cancers including kidney cancer [20–22]. However, other studies have refuted that any one antihypertensive medication increases or decreased the risk of RCC, but it is whatever provides the best patient-specific hypertension control [23]. The second strongest predictor of incident RCC was an elevated BMI (i.e., obesity). A positive correlation between obesity and kidney cancer incidence has been well documented in the literature [7,8]. The HRs range from 1.5 to 2 for the highest BMI associated with kidney cancer. Most case-control studies observed positive associations of obesity with prevalence renal cell carcinoma with increasing BMI [24–27]. BMI was almost uniformly used in casecontrol studies to examine the association of obesity and tended to be dose dependent [25,28]. Other measures of obesity include overall weight, waist circumference, and waist-to-hip ratio [29,30]. There is no statistically significant difference in the effects of BMI on cancer risk in men and women (P = 0.5). Also, we noticed a pronounced effect of obesity with BMI 430 kg/m2 on RCC incidence when compare it to the overweight (BMI: 25–29 kg/m2). This consistent with one study that found that obese with BMI 430 kg/m2 patients were more than 50% more likely to have RCC than those with BMI o30 kg/m2 [31]. A high level of obesity-related hormone such as IGFBP-3 was found significantly associated with the incidence RCC in patient with BMI 430 kg/m2 rather than overweight 25 to 29 kg/m2 in a study that suggest theses hormones as independent factors for RCC [32]. Again, these findings need to be carefully considered in future studies. The reason obesity influences renal carcinogenesis has not been fully elucidated. Previous studies suggest a link between insulin resistance and insulin-like growth factor (IGF-1), sex steroid hormones, and adiponectin. Additionally, a recent publication by Shu et al. [33] from MD Anderson Cancer Center noted within a 17 miRNA gene profile, miR-204-5p in particular was associated with kidney cancer recurrences and may be partially mediated by regulating the expression of targeted obesity-related genes. However, recent controversy was introduced by revealing a paradox of increasing BMI and improved RCC survival [34]. They noted a biological association of fatty acid synthase expression from tumors in the Cancer Genome Atlas. Fatty acid synthase immunohistochemical staining was inversely proportional to BMI and correlated with overall survival. Other groups have confirmed the paradox [35].
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The third strongest modifiable risk factor was identified as smoking. Several longitudinal studies investigating smoking and the incidence of kidney cancer noted an increased risk of kidney cancer (relative risk of 1.3–2.3) [8–11,36]. However, unlike blood pressure control and weight loss, smoking cessation has been significantly associated with a reduced incidence of RCC [37–39]. Few studies have addressed all of these modifiable risk factors. Park et al. [40] performed a retrospective review of over 1,000 Korean patients who underwent surgical intervention for low stage kidney cancer addressing hypertension, BMI, and smoking. They noted that control of blood pressure and maintaining a healthy weight (not underweight) improved overall and cancer specific survival, but do not offer extrapolation regarding kidney cancer prevention strategies. The authors specifically mention perioperative blood pressure ≥ 160/100 mmHg to be harmful, but did not identify an association with smoking. Lotan et al. [41] used the PLCO study to propose the identification of a screening population at high-risk for developing kidney cancer, which included age over 60 years, male sex, smoking intensity, and obesity. A study showed a higher 5-year cancer-specific survival rate was significantly seen in patients with incidental RCC than for symptomatic tumors [42]. In another study, low metastasis was found at follow up of patients who diagnosed with incidental RCC [43]. Therefore, time is ripe for a prospective assessment regarding identification of a high-risk population to develop kidney cancer to not only test targeted screening, but provide behavioral modification as a prevention strategy. Limitations of the study include the retrospective analysis of prospectively collected data interjecting bias into subanalysis of a trial not powered to investigate incident renal cancers specifically. Some of our analysis relied on questionnaire data, which can suffer from inaccuracies and recall bias. 4. Conclusions Obesity, hypertension, and smoking are the three modifiable risk factors that could aggressively be targeted to reduce RCC. In particular, future investigation regarding aggressive management of hypertension with lower systolic and diastolic pressures than 140/90 set by the Joint National Committee and weight loss interventions, especially in at risk men, could prove to be the most beneficial prevention strategy. Further research is needed to elucidate mechanism of increased incidence of RCC in these patients. References [1] Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615–21. [2] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11–30.
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[3] Decastro GJ, McKiernan JM. Epidemiology, clinical staging, and presentation of renal cell carcinoma. Urol Clin North Am 2008; 35:581–92:[vi]. [4] Nguyen MM, Gill IS, Ellison LM. The evolving presentation of renal carcinoma in the United States: trends from the Surveillance, Epidemiology, and End Results program. J Urol 2006;176:2397– 400:[discussion 2400]. [5] Ridge CA, Pua BB, Madoff DC. Epidemiology and staging of renal cell carcinoma. Semin Intervent Radiol 2014;31:3–8. [6] Stein CJ, Colditz GA. Modifiable risk factors for cancer. Br J Cancer 2004;90:299–303. [7] Haggstrom C, Rapp K, Stocks T, et al. Metabolic factors associated with risk of renal cell carcinoma. PLoS ONE 2013;8:e57475. [8] Macleod LC, Hotaling JM, Wright JL, et al. Risk factors for renal cell carcinoma in the VITAL study. J Urol 2013;190:1657–61. [9] Setiawan VW, Stram DO, Nomura AM, Kolonel LN, Henderson BE. Risk factors for renal cell cancer: the multiethnic cohort. Am J Epidemiol 2007;166:932–40. [10] Washio M, Mori M, Khan M, et al. Diabetes mellitus and kidney cancer risk: the results of Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). Int J Urol 2007; 14:393–7. [11] Flaherty KT, Fuchs CS, Colditz GA, et al. A prospective study of body mass index, hypertension, and smoking and the risk of renal cell carcinoma (United States). Cancer Causes Control, 16; 1099–106. [12] Chow WH, Gridley G, Fraumeni JF Jr., Jarvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med 2000;343:1305–11. [13] Colt JS, Schwartz K, Graubard BI, et al. Hypertension and risk of renal cell carcinoma among white and black Americans. Epidemiology 2011;22:797–804. [14] Shen T, Shu X-O, Xiang Y-B, et al. Association of hypertension and obesity with renal cell carcinoma risk: a report from the Shanghai Men’s and Women’s Health Studies. Cancer Causes Control 2015;26: 1173–80. [15] Vatten LJ, Trichopoulos D, Holmen J, et al. Blood pressure and renal cancer risk: the HUNT Study in Norway. Br J Cancer 2007;97:112–4. [16] Lindgren AM, Nissinen AM, Tuomilehto JO, et al. Cancer pattern among hypertensive patients in North Karelia, Finland. J Human Hypertens 2005;19:373–9. [17] Yuan JM, Castelao JE, Gago-Dominguez M, et al. Hypertension, obesity and their medications in relation to renal cell carcinoma. Br J Cancer 1998;77:1508–13. [18] McLaughlin JK, Chow WH, Mandel JS, et al. International renal-cell cancer study. VIII. Role of diuretics, other anti-hypertensive medications and hypertension. Int J Cancer 1995;63:216–21. [19] Shapiro JA, Williams MA, Weiss NS, Stergachis A, LaCroix AZ, Barlow WE. Hypertension, antihypertensive medication use, and risk of renal cell carcinoma. Am J Epidemiol 1999;149: 521–30. [20] Araujo WF, Naves MA, Ravanini JN, Schor N, Teixeira VP. Reninangiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice. Urol Oncol 2015;33:389: [e381–387]. [21] Izzedine H, Derosa L, Le Teuff G, Albiges L, Escudier B. Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma. Ann Oncol 2015;26:1128–33. [22] Keizman D, Huang P, Eisenberger MA, et al. Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. Eur J Cancer 2011;47:1955–61. [23] Weikert S, Boeing H, Pischon T, et al. Blood pressure and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition. Am J Epidemiol 2008;167:438–46.
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[24] Beebe-Dimmer JL, Colt JS, Ruterbusch JJ, et al. Body mass index and renal cell cancer: the influence of race and sex. Epidemiology 2012;23:821–8. [25] Brennan P, van der Hel O, Moore LE, et al. Tobacco smoking, body mass index, hypertension, and kidney cancer risk in central and eastern Europe. Br J Cancer 2008;99:1912–5. [26] Liao LM, Weinstein SJ, Pollak M, et al. Prediagnostic circulating adipokine concentrations and risk of renal cell carcinoma in male smokers. Carcinogenesis 2013;34:109–12. [27] Shu X, Lin J, Wood CG, Tannir NM, Wu X. Energy balance, polymorphisms in the mTOR pathway, and renal cell carcinoma risk. J Natl Cancer Inst 2013;105:424–32. [28] Hu J, Mao Y, White K, Canadian Cancer Registries Epidemiology Research G: Overweight and obesity in adults and risk of renal cell carcinoma in Canada. Soz Praventivmed 2003;48: 178–85. [29] Wilson KM, Cho E. Obesity and kidney cancer. Recent Results Cancer Res 2016;208:81–93. [30] Pischon T, Lahmann PH, Boeing H, et al. Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 2006;118:728–38. [31] Lowrance WT, Thompson RH, Yee DS, Kaag M, Donat SM, Russo P. Obesity is associated with a higher risk of clear-cell renal cell carcinoma than with other histologies. BJU Int 2010; 105:16. [32] Liao LL, Hofmann JN, Cho E, Pollak MN, Chow W-H, Purdue MP. Circulating levels of obesity-related markers and risk of renal cell carcinoma in the PLCO cancer screening trial. Cancer Causes Control 2017;28:801–7. [33] Shu X, Hildebrandt MA, Gu J, et al. MicroRNA profiling in clear cell renal cell carcinoma tissues potentially links tumorigenesis and recurrence with obesity. Br J Cancer 2016.
[34] Albiges L, Hakimi AA, Xie W, et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations. J Clin Oncol 2016;34:3655–63. [35] Choi Y, Park B, Jeong BC, et al. Body mass index and survival in patients with renal cell carcinoma: a clinical-based cohort and metaanalysis. Int J Cancer 2013;132:625–34. [36] Blakely T, Barendregt JJ, Foster RH, et al. The association of active smoking with multiple cancers: national census-cancer registry cohorts with quantitative bias analysis. Cancer Causes Control 2013;24:1243–55. [37] Theis RP, Dolwick Grieb SM, Burr D, Siddiqui T, Asal NR. Smoking, environmental tobacco smoke, and risk of renal cell cancer: a population-based case-control study. BMC Cancer 2008;8:387. [38] Hu J, Ugnat AM, Canadian Cancer Registries Epidemiology Research G: Active and passive smoking and risk of renal cell carcinoma in Canada. Eur J Cancer 2005;41:770–8. [39] Parker AS, Cerhan JR, Janney CA, Lynch CF, Cantor KP. Smoking cessation and renal cell carcinoma. Ann Epidemiol 2003;13:245–51. [40] Park B, Jeong BC, Seo SI, Jeon SS, Choi HY, Lee HM. Influence of body mass index, smoking, and blood pressure on survival of patients with surgically-treated, low stage renal cell carcinoma: a 14-year retrospective cohort study. J Korean Med Sci 2013;28:227–36. [41] Lotan Y, Karam JA, Shariat SF, et al. Renal-cell carcinoma risk estimates based on participants in the prostate, lung, colorectal, and ovarian cancer screening trial and national lung screening trial. Urol Oncol 2016;34:167:[e169–116]. [42] Tsui KH, Shvarts O, Smith RB, Figlin R, de Kernion JB, Belldegrun A. Renal cell carcinoma: prognostic significance of incidentally detected tumors. J Urol 2000;163:426–30. [43] Rabjerg M, Mikkelsen MN, Walter S, Marcussen N. Incidental renal neoplasms: is there a need for routine screening? A Danish singlecenter epidemiological study. APMIS 2014;122:708–14.
Original article
Modifiable risk factors to reduce renal cell carcinoma incidence: Insight from the PLCO trial Jonathan Gelfond, M.D., Ph.D.a, Osamah Al-Bayati, M.B.Ch.B.b, Aashish Kabra, M.D.b, Kevan Iffrig, M.D.b, Dharam Kaushik, M.D.b, Michael A. Liss, M.D., M.A.S., F.A.C.S.b,c,* a
Department of Biostatistics, University of Texas Health Science Center San Antonio, San Antonio, TX b Department of Urology, University of Texas Health Science Center San Antonio, San Antonio, TX c Department of Surgery, South Texas Veterans Healthcare System, San Antonio, TX Received 22 November 2017; received in revised form 7 March 2018; accepted 17 April 2018
Abstract Introduction: Identify modifiable factors contributing to renal cell carcinoma in the PCLO to target disease prevention and reduce health care costs. Methods: The prostate, lung, colorectal, and ovarian database were queried for the primary outcome of kidney cancer. Demographics were investigated, specifically focusing on modifiable risk factors. Statistical analysis includes the Student t-test for continuous variables, chi-squared or Fisher’s exact tests for dichotomous and categorical variables for bivariate analysis. The Cox proportional hazards model was used in a multivariate time-to-event analysis. Results: We investigate existing data relating specifically to renal cancer. After missing data were excluded, we analyzed 149,683 subjects enrolled in the prostate, lung, colorectal, and ovarian trial and noted 0.5% (n ¼ 748) subjects developed renal cancer. Age, male gender, body mass index, diabetes, and hypertension were all significant associated with renal cancer in bivariate analysis (P o 0.05). Men have a significant increased risk of kidney cancer over women (hazard ratio [HR] ¼ 1.85; 95% CI: 1.58–2.16; P o 0.0001). Nonmodifiable risk factors that are associated with kidney cancer include age (HR ¼ 1.05; 95% CI: 1.01; 1.05, P ¼ 0.001). Modifiable risk factors include obesity measured by body mass index (HR ¼ 1.05; 95% CI: 1.02–1.07; P o 0.0001), hypertension (HR ¼ 1.32; 95% CI: 1.13–1.54; P ¼ 0.0004), and smoking in pack-years (HR ¼ 1.04; 95% CI: 1.02–1.07; P ¼ 0.0002). Conclusions: Obesity, hypertension, and smoking are the 3 modifiable risk factors that could aggressively be targeted to reduce renal cell carcinoma. Published by Elsevier Inc.
Keywords: Kidney cancer; Renal cancer; Modifiable risk factors; Smoking; Body mass index; Obesity; Hypertension; Blood pressure; Renal cell cancer; Lifestyle; Prevention
1. Introduction Kidney cancer is estimated to have as worldwide incidence of 270,000 cases yearly and nearly 116,000 deaths [1]. In the Unites states, estimates indicate 65,000 new cases and over 13,000 deaths from kidney and renal pelvis cancers in 2013 with approximately 35% presenting as metastatic disease [2].
⁎
Corresponding author. E-mail address: [email protected] (M.A. Liss). https://doi.org/10.1016/j.urolonc.2018.04.011 1078-1439/Published by Elsevier Inc.
Although there is no recommendation for screening for renal cell carcinoma (RCC), the frequency of RCC continues to rise [3]. The rising number of RCC cases is believed to be a result of improved imaging techniques and increased incidental tumor discovery [4]. However, it has been found that there is marked regional variability, likely related to demographic, environmental, and genetic factors [5]. Moreover, RCC can be attributed to the increased prevalence of associated risk factors such as obesity and hypertension [3]. Risk factors that can be changed to potentially effect health outcomes have been termed modifiable risk factors. The modification of risk factors may
2
J. Gelfond et al. / Urologic Oncology: Seminars and Original Investigations ] (2018) ∎∎∎–∎∎∎
have the potential to reduce incidence of RCC and potentially improve survival. Lifestyle modifications have been shown to reduce the incidence of a variety of cancers as well as improve cancer specific survival [6]. Therefore, lifestyle interventions can be an inexpensive preventative and adjunctive program tailored to the individual patient and may affect outcomes. To investigate specific modifiable lifestyle risk factors, we examine the prostate, lung, colorectal, and ovarian (PLCO) screening trial for potential impact of altering these factors.
Did the participant ever have high blood pressure? and was a dichotomous answer (Yes vs. No). 2.3. Statistical analysis
2.2. Outcomes and risk factors
PLCO database were queried for the primary outcome of kidney cancer. Demographics were investigated, specifically focusing on modifiable risk factors, such as smoking, obesity, and hypertension. Statistical analysis included testing for bivariate associations between renal cancer status and risk factors using the Student t-test for continuous variables, chi-squared or Fisher’s exact tests for dichotomous or categorical variables. The incidence of RCC was modeled using Cox proportional hazards models excluding data from subjects with missing data for any model covariates, and all risk factors were considered within the same model adjusting for demographics and comorbidities. Deaths due to other causes were treated as censored. Factors that increase medical surveillance in general may be associated with an increase in risk of RCC due to increase likelihood of diagnosis, while not being causally related to RCC. These factors include comorbidities such as diabetes and hypertension and also include being randomized to the trials intensive screening arm. We examined the effect of these factors using Cox proportional hazard models.
The primary outcome of this study was kidney cancer incidence defined by questionnaire and medical record confirmation. Predictor variables were obtained from the baseline questionnaire. The World Health Organization standard categorization of body mass index (BMI) was used. Weights less than 27 kg were truncated and considered out of range. Heights less than 48 in were truncated and out of range. For female participants, heights greater than 78 in are out of range and for male participants, heights greater than 84 in are out of range. After BMI is calculated, BMI values less than 15 kg/m2 are out of range. Hypertension was obtained via questionnaire answering:
2.3.1. Results After missing data were excluded, we analyzed 149,683 subjects enrolled in the PLCO trial and noted 0.5% (n ¼ 748) subjects developed renal cancer. Age, male gender, BMI, diabetes, and hypertension were all significant associations with renal cancer in univariate analysis (all o 0.05) (Table 1). Men have a significantly increased risk of kidney cancer over women (hazard ratio [HR] ¼ 1.85; 95% CI: 1.58; 2.16, P o 0.0001) (Table 2). Nonmodifiable risk factors that are associated with kidney cancer include age (HR ¼ 1.05; 95% CI: 1.01–1.05, P ¼ 0.001). Modifiable risk factors include obesity
2. Methods 2.1. Study population After IRB approval and data transfer agreement, we obtained de-identified data from subjects enrolled in the PLCO Cancer Screening Trial. The PLCO is a National Cancer Institute sponsored randomized trial investigating the effects of screening on cancer outcomes in subjects aged 55 to 74 years from 1993 to 2001 and have followed them for 13 years.
Table 1 Demographics and comorbidities by renal cancer status Variable Age, mean (median; IQR) Gender, no. (%) Female Male Body mass index, mean (median; IQR) Race/ethnicity no. (%) White, non-Hispanic Black, non-Hispanic Hispanic Family history of renal cancer, no. (%) Diabetes, no. (%) Myocardial Infarction, no. (%) Hypertension, no. (%) Stroke, no. (%)
No renal cancer 62.6 (62; 58–67) 75,728 (50.8) 73,201 (49.2) 27.3 (26.6; 24–29.8) 131,640 7,659 2,795 2,183 11,424 13,411 50,526 3,605
(88.4) (5.1) (1.9) (1.5) (7.7) (9.1) (34.1) (2.4)
Renal cancer
P value
63.3 (63; 59.2–67)
o0.001 o0.001
261 (34.6) 493 (65.4) 28.6 (27.9; 25.1–31.2) 681 35 17 12 73 95 326 22
(90.3) (4.6) (2.3) (1.6) (9.7) (12.7) (43.5) (2.9)
o0.001 0.09
0.89 0.05 0.001 o0.001 0.44
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Table 2 Cox proportional hazards model for renal cancer in the PLCO Variable
HR
95% CI
P value
Age Screening arm Body mass index Diabetes Education (college) Hypertension (yes vs. no) Smoker (pack decades) Black, non-Hispanic vs. white Hispanic vs. white Other vs. white Family history of renal cancer Gender (male vs. female)
1.03 1.13 1.05 1.07 0.96 1.32 1.04 0.92 1.12 0.65 1.13 1.85
[1.01, [0.98, [1.03, [0.83, [0.92, [1.13, [1.02, [0.65, [0.67, [0.42, [0.64, [1.58,
0.0001 0.09 o0.0001 0.59 0.08 0.0004 0.0002 0.64 0.66 0.05 0.68 o0.0001
1.04] 1.31] 1.06] 1.38] 1.01] 1.54] 1.07] 1.31] 1.88] 1.01] 2] 2.16]
measured by BMI (HR ¼ 1.05; 95% CI: 1.02–1.07, P o 0.0001), hypertension (HR ¼ 1.32; 95% CI: 1.13– 1.54; P ¼ 0.0004), and smoking in pack decades (HR ¼ 1.04; 95% CI: 1.02–1.07; P ¼ 0.0002). This implies that a person with 5 kg/m2 lower BMI has 22% less risk for cancer relative to another person with all other factors equal. A person who smokes an additional 20 packyears has 8% greater risk relative to a person with all other factors equal. When smoking is considered as dichotomous variable (pack-years 4 0) the increase in risk due to any smoking history is about 20% (HR ¼ 1.21, 95% P ¼ 0.01). However, the effect size of the dichotomous smoking risk factor depends on the average number of pack-years of smokers in the sample. Among participants who ever smoked, we found that those who identified as current regular smokers had a 33% higher risk relative to those who did not (i.e., quit or no longer smoking) (HR ¼ 1.33; 95% CI: 1.05–1.68; P ¼ 0.017). Fig. 1 indicates that the increase in risk due to smoking is approximately the same in males and females. Fig. 2 demonstrates the risk increase to due hypertension (P o 0.001), and while the effect appears to be greater in females than males, the hypertension by gender interaction is not statistically significant (P ¼ 0.11). Fig. 3 shows the change in risk due to BMI category (P o 0.0001). There is no statistically significant difference in the effects of BMI on cancer risk in men and women (P ¼ 0.5). Missing data and the effect of general medical surveillance to increase diagnosis were considered as potential sources of bias. The rate of missing data for variables ranged from 0% to 1.5%. BMI (1.5%) and pack-years smoking (1.2%) had the highest rates of missing data, but overall the data were mostly complete, and 96% of observations had no missing data. Although some factors that increase medical surveillance such as diabetes were not associated with RCC risk (P ¼ 0.59) other such factors like randomization to intensive screening arm was significant in men (HR ¼ 1.2; 95% CI: 1.0–1.45; P ¼ 0.04), but not in women (P ¼ 0.9) or the combined data (P ¼ 0.09).
Fig. 1. The incidence of renal cell cancer (RCC) by smoking status. The curves represent the risk of RCC (0–1) in each group adjusting for the average effects of hypertension, education, treatment arm, body mass index, race, family history, and diabetic status. (Color version of the figure available online.)
3. Discussion In our investigation of the PLCO screening trial, we identified 3 modifiable lifestyle interventions that could be implemented to reduce the incidence of renal cancer: hypertension, obesity, and smoking. The strongest factor for developing RCC was a positive answer on the baseline
Fig. 2. The incidence of renal cell cancer (RCC) by hypertension status. The curves represent the risk of RCC (0–1) in each group adjusting for the average effects of smoking, education, treatment arm, body mass index, race, family history, and diabetic status.(Color version of the figure available online.)
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Fig. 3. The incidence of renal cell cancer (RCC) by body mass index. The curves represent the risk of RCC (0–1) in each group adjusting for the average effects of hypertension, smoking, education, treatment arm, race, family history, and diabetic status. (Color version of the figure available online.)
questionnaire of whether or not the subject had hypertension. If “yes” the patient had a 32% increased risk of RCC then nonhypertensive patients over the next 13 years. Hypertension has previously been associated with the risk of developing RCC. A number of articles have focused on longitudinal outcomes of various aspects of hypertension and incident RCC [7–12]. All studies have shown higher rates of incident RCC in patients with hypertension. The largest studies were from Sweden (n = 855) and the United States (n = 759) both showing increasing risk of RCC with severity of hypertension [7,12]. Both studies stress the importance of diastolic as well as systolic blood pressure. Case-control studies investigated hypertension as an all-ornone event; however, one study noted that patients with more poorly controlled are 2 times more likely to also have renal cell cancer [13]. In our study, while the effect appears to be greater in females than males as demonstrated in Fig. 2, the hypertension by gender interaction is not statistically significant (P ¼ 0.11). inconsistent with our study, a large study shows the same finding with slight increase the risk in women with hypertension than men even the statistical significant was not reached [14], this may be in part, due to the existence of hidden confounders in normotensive men with relatively higher incidence of cancer than normotensive women, such as alcohol consumption and occupational toxin exposure in men, and high parity in women [15,16]. Further studies will have required to investigate these differences. Clinical trials are needed to determine if aggressive control of hypertension, as well as, which antihypertensive medication could provide benefits of preventing RCC. We
could not include the antihypertensive medications as possible risk factor, however, most of the epidemiological studies conclusions were more consistent with identification of high blood pressure as an independent factor to the RCC incidence, rather than the antihypertension medications [11,17–19]. Shapiro et al. [19] noted that diuretic antihypertensive medications did not have an influence of incident RCC. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers have seem to peak some interest in reducing cancer specific death in other cancers including kidney cancer [20–22]. However, other studies have refuted that any one antihypertensive medication increases or decreased the risk of RCC, but it is whatever provides the best patient-specific hypertension control [23]. The second strongest predictor of incident RCC was an elevated BMI (i.e., obesity). A positive correlation between obesity and kidney cancer incidence has been well documented in the literature [7,8]. The HRs range from 1.5 to 2 for the highest BMI associated with kidney cancer. Most case-control studies observed positive associations of obesity with prevalence renal cell carcinoma with increasing BMI [24–27]. BMI was almost uniformly used in casecontrol studies to examine the association of obesity and tended to be dose dependent [25,28]. Other measures of obesity include overall weight, waist circumference, and waist-to-hip ratio [29,30]. There is no statistically significant difference in the effects of BMI on cancer risk in men and women (P = 0.5). Also, we noticed a pronounced effect of obesity with BMI 430 kg/m2 on RCC incidence when compare it to the overweight (BMI: 25–29 kg/m2). This consistent with one study that found that obese with BMI 430 kg/m2 patients were more than 50% more likely to have RCC than those with BMI o30 kg/m2 [31]. A high level of obesity-related hormone such as IGFBP-3 was found significantly associated with the incidence RCC in patient with BMI 430 kg/m2 rather than overweight 25 to 29 kg/m2 in a study that suggest theses hormones as independent factors for RCC [32]. Again, these findings need to be carefully considered in future studies. The reason obesity influences renal carcinogenesis has not been fully elucidated. Previous studies suggest a link between insulin resistance and insulin-like growth factor (IGF-1), sex steroid hormones, and adiponectin. Additionally, a recent publication by Shu et al. [33] from MD Anderson Cancer Center noted within a 17 miRNA gene profile, miR-204-5p in particular was associated with kidney cancer recurrences and may be partially mediated by regulating the expression of targeted obesity-related genes. However, recent controversy was introduced by revealing a paradox of increasing BMI and improved RCC survival [34]. They noted a biological association of fatty acid synthase expression from tumors in the Cancer Genome Atlas. Fatty acid synthase immunohistochemical staining was inversely proportional to BMI and correlated with overall survival. Other groups have confirmed the paradox [35].
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The third strongest modifiable risk factor was identified as smoking. Several longitudinal studies investigating smoking and the incidence of kidney cancer noted an increased risk of kidney cancer (relative risk of 1.3–2.3) [8–11,36]. However, unlike blood pressure control and weight loss, smoking cessation has been significantly associated with a reduced incidence of RCC [37–39]. Few studies have addressed all of these modifiable risk factors. Park et al. [40] performed a retrospective review of over 1,000 Korean patients who underwent surgical intervention for low stage kidney cancer addressing hypertension, BMI, and smoking. They noted that control of blood pressure and maintaining a healthy weight (not underweight) improved overall and cancer specific survival, but do not offer extrapolation regarding kidney cancer prevention strategies. The authors specifically mention perioperative blood pressure ≥ 160/100 mmHg to be harmful, but did not identify an association with smoking. Lotan et al. [41] used the PLCO study to propose the identification of a screening population at high-risk for developing kidney cancer, which included age over 60 years, male sex, smoking intensity, and obesity. A study showed a higher 5-year cancer-specific survival rate was significantly seen in patients with incidental RCC than for symptomatic tumors [42]. In another study, low metastasis was found at follow up of patients who diagnosed with incidental RCC [43]. Therefore, time is ripe for a prospective assessment regarding identification of a high-risk population to develop kidney cancer to not only test targeted screening, but provide behavioral modification as a prevention strategy. Limitations of the study include the retrospective analysis of prospectively collected data interjecting bias into subanalysis of a trial not powered to investigate incident renal cancers specifically. Some of our analysis relied on questionnaire data, which can suffer from inaccuracies and recall bias. 4. Conclusions Obesity, hypertension, and smoking are the three modifiable risk factors that could aggressively be targeted to reduce RCC. In particular, future investigation regarding aggressive management of hypertension with lower systolic and diastolic pressures than 140/90 set by the Joint National Committee and weight loss interventions, especially in at risk men, could prove to be the most beneficial prevention strategy. Further research is needed to elucidate mechanism of increased incidence of RCC in these patients. References [1] Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615–21. [2] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11–30.
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