Word of Wisdom

Re: Risk Factors for Renal Cell Carcinoma in the VITALStudy

Macleod LC, Hotaling JM, Wright JL et al.

J Urol 2013;190:1657–61

Experts’ summary:

Besides the established risk factors of increasing age, smoking,

male sex, and genetic predisposition for diagnosis of renal cell

carcinoma (RCC), little consensus exists regarding other risk

factors for RCC. Macleod et al. utilized the VITAL study cohort

to confirm commonly accepted risk factors and evaluate more

controversial risk factors for incidental RCC. Between the

years 2000 and 2002, the study enrolled 77 260 Washington

state residents between 50–76 yr of age. These patients com-

pleted a questionnaire providing demographic and lifestyle/

health information.

Among this cohort, 249 participants were diagnosed

with incidental RCC through December 31, 2009. Using a

fully adjusted multivariate model to predict incidental RCC

diagnosis, the authors found statistical significance for

obesity (body mass index >35 vs <25 kg/m2; hazard ratio

[HR]: 1.71; 95% confidence interval [CI]: 1.06–2.79),

smoking (>37.5 vs 0 pack-years; HR: 1.58; 95% CI: 1.09–

2.29), hypertension (HR: 1.70; 95% CI: 1.30–2.22), kidney

disease (HR: 2.58; 95% CI: 1.21–5.50), and viral hepatitis

(HR: 1.80; 95% CI: 1.03–3.14). There was a decreased risk of

diagnosis for female sex (HR: 0.55; 95% CI: 0.41–0.72).

Diabetes mellitus was only significant using a base model

for age/sex, and other hypothesized risk factors (race;

alcohol, fruit, or vegetable consumption) had no statistical

significance.

Experts’ comments:

Macleod et al. used the VITAL study to confirm known risk

factors for RCC (smoking, hypertension, kidney disease, male

sex) and to identify additional, more controversial risk factors

(obesity, viral hepatitis) using a population-based question-

naire. This study emphasizes the ongoing trend in the medical

and urologic communities that patient comorbidity may play

a role in incidence, disease-specific survival, and overall sur-

vival for a number of malignancies, including RCC. To illustrate

this point, Sand et al. [1] reported a significant relationship

between degree of comorbidity and incidental RCC diagnosis.

Furthermore, Deckers et al. [2] assessed whether sodium

intake, a modifiable risk factor of hypertension, was an inde-

pendent risk factor for RCC in the Netherlands Cohort Study.

This study included 120 852 patients whose lifestyles and

diets were assessed at baseline through questionnaires and

who were then followed for 17.3 yr. During this time, there

were 485 cases of RCC; sodium intake was associated with an

increased risk of RCC ( p trend = 0.03), and there was an

additional increased risk of high-sodium and low-fluid intake

( p interaction = 0.02).

Macleod et al. found a threshold effect curve (>22.5

pack-years) for the risk of RCC associated with cigarette

smoking. This comorbid effect was also confirmed by Ehdaie

et al. [3], who analyzed 1625 patients at Memorial Sloan-

Kettering Cancer Center who were surgically treated for

clear cell RCC between 1995 through 2012. They found that

a smoking history of >20 pack-years was associated with

increased risk of advanced disease (odds ratio: 1.43; 95% CI:

1.02–2.00) and that smoking exposure was associated with

significantly increased risk of death from non–cancer-

specific causes.

The findings from the VITAL study, in conjunction with

previous studies, stress the importance of overall patient

health and modifiable risk factors when analyzing risk

factors for RCC. This highlights the opportunity for public

health intervention for both the prevention of RCC and

possibly for survival in patients previously diagnosed with

RCC.

Conflicts of interest: The authors have nothing to disclose.

References

[1] Sand KE, Hjelle KM, Rogde AJ, Gudbrandsdottir G, Bostad L, Beisland

C. Incidentally detected renal cell carcinomas are highly associated

with comorbidity and mortality unrelated to renal cell carcinoma.

Scand J Urol 2013;47:462–71.

[2] Deckers IA, van den Brandt PA, van Engeland M, et al. Long-term

dietary sodium, potassium and fluid intake; exploring potential

novel risk factors for renal cell cancer in the Netherlands Cohort

Study on diet and cancer. Br J Cancer 2014;110:797–801.

[3] Ehdaie B, Furberg H, Zabor EC, Hakimi AA, Russo P. Comprehensive

assessment of the impact of cigarette smoking on survival of clear

cell kidney cancer. J Urol 2014;191:597–602.

E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 7 8 4 – 7 8 9

avai lable at www.sciencedirect .com

journal homepage: www.europeanurology.com

Zachary Klaassena, John M. DiBiancob, Qiang Lia,

Martha K. Terrisa,*aSection of Urology, Medical College of Georgia – Georgia Regents

University, Augusta, GA, USAbRoss University School of Medicine, Roseau, Commonwealth of

Dominica, West Indies

*Corresponding author. Section of Urology, Medical College of

Georgia – Georgia Regents University, 1120 Fifteenth Street,

Room BA 8414, Augusta, GA 30912-4050, USA.

E-mail address: mterris@gru.edu (M.K. Terris).

http://dx.doi.org/10.1016/j.eururo.2014.07.047

Re: Clinical Outcomes for Patients with Metastatic RenalCell Carcinoma Treated with Alternative SunitinibSchedules

Atkinson BJ, Kalra S, Wang X, et al.

J Urol 2014;191:611–8

Expert’s summary:

The authors retrospectively evaluated patients treated with

sunitinib for metastastic renal cell carcinoma (mRCC). A tradi-

tional schedule (TS; 4 wk on and 2 wk off treatment) was

compared with alternative schedules (ASs; 2 wk on and 1 wk

off or 1 wk on and 3–4 d off). An AS was indicated either up front

or after toxicity while on TS. Progression-free survival (PFS)

and overall survival (OS) probabilities were defined as end

points, supplemented by multivariable Cox regression models.

Approximately half of the 187 patients continually received TS,

whereas the other half received some form of AS. Median PFS

was 9 mo and median OS was 25.6 mo for the whole population.

Comparing TS and AS showed a median PFS of 4.3 mo versus

14.5 mo and OS of 17.7 mo versus 33 mo in favor of AS.

On multivariable analysis, TS independently predicted

decreased OS.

Expert’s comments:

While other smaller series focused mainly on decreased tox-

icity with regimens of 2 wk on and 1 wk off [1,2], this present

larger series, consisting of a routine clinical population, also

showed improved outcomes from AS. PFS and OS were slightly

inferior to the sunitinib phase III trial [3] (PFS: 9 mo vs 11 mo;

OS: 25.6 mo vs 28 mo); however, differences between TS and

AS regarding both PFS and OS were tremendous. Hazard ratios

for AS regarding OS were 0.49 on univariable analysis and

0.55 on multivariable analysis.

Now, if survival can be doubled by administering AS, does

that mean we had chosen a suboptimal schedule for years? In

this regard, the results should be interpreted with caution. It

has been shown that side effects like hypertension [4] and

hypothyroidism [5] may serve as surrogates for favorable

treatment outcome. In this study, the main indication for

switching from TS to AS was toxicity. Consequently, it

appears plausible that the observed survival difference may

represent a selection of patients showing better treatment

response, which was reflected by increased toxicity. This

variable, however, was not adjusted for in the multivariable

analysis. If included, toxicity would probably remain an

independent predictor, whereas AS would vanish.

This study shows that either side effects or change of

treatment schedule by itself may predict improved survival;

however, the observed survival differences were highly

relevant. This study is hypothesis generating in two

respects: Would either treating to toxicity or changing

treatment schedule be the way to go to improve the

outcome of mRCC patients under sunitinib? The observed

results certainly deserve evaluation in prospective trials.

Conflicts of interest: Richard Zigeuner is a paid speaker for Amgen,

Bayer, GSK, Novartis, Pfizer, and Roche and an advisory board member

for Pfizer and receives travel support from Amgen, Astellas, Bayer, GSK,

Novartis, Pfizer, Roche, and Takeda.

References

[1] Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off

schedule of sunitinib is associated with decreased toxicity in met-

astatic renal cell carcinoma. Eur J Cancer 2014;50:1084–9.

[2] Kondo T, Takagi T, Kobayashi H, et al. Superior tolerability of altered

dosing schedule of sunitinib with 2-weeks-on and 1-week-off in

patients with metastatic renal cell carcinoma–comparison to stan-

dard dosing schedule of 4-weeks-on and 2-weeks-off. Jpn J Clin

Oncol 2014;44:270–7.

[3] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa

in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24.

[4] Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of

efficacy in patients with metastatic renal cell carcinoma treated

with sunitinib. J Natl Cancer Inst 2011;103:763–73.

[5] Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients

with renal cell carcinoma: blessing or curse? Cancer 2011;117:

534–44.

Richard Zigeuner*

Department of Urology, Medical University of Graz, Graz, Austria

*Department of Urology, Medical University of Graz,

Auenbruggerplatz 5/6, A-8036 Graz, Austria.

E-mail address: Richard.zigeuner@medunigraz.at.

http://dx.doi.org/10.1016/j.eururo.2014.07.048

Re: Enzalutamide in Metastatic Prostate Cancer BeforeChemotherapy

Beer TM, Armstrong AJ, Rathkopf DE, et al.; PREVAIL

Investigators

N Engl J Med 2014;371:424-33

Experts’ summary:

PREVAIL is a multinational, double-blind, randomised

trial comparing enzalutamide, which is an oral androgen

receptor inhibitor, and placebo. Beer et al. demonstrated

that enzalutamide in chemotherapy-naı̈ve patients with

metastatic castration-resistant prostate cancer (mCRPC)

had significant clinical benefits including better rates of

E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 7 8 4 – 7 8 9 785