Metachronous Bilateral Renal Cell Carcinoma: Risk Assessment, Prognosis and Relevance of the Primary-Free Interval Tobias Klatte, Jean-Jacques Patard,* Heiko Wunderlich, Rakhee H. Goel, John S. Lam, Kerstin Junker, Jörg Schubert, Malte Böhm, Ernst P. Allhoff, Fairooz F. Kabbinavar, Maxime Crepel, Luca Cindolo, Alexandre De La Taille, Jacques Tostain,† Arnaud Mejean,‡ Michel Soulie, Laurent Bellec, Jean Christophe Bernhard, Jean-Marie Ferriere, Christian Pfister, Baptiste Albouy, Marc Colombel, Amnon Zisman, Arie S. Belldegrun and Allan J. Pantuck§ From the Departments of Urology (TK, RHG, JSL, ASB, AJP) and Medicine (FFK), University of California-Los Angeles, Los Angeles, California and Departments of Urology, University of Rennes (JJP, MC) Rennes, Centre Hospitalier Universitaire Henri Mondor (ADLT), Creteil, University of Saint-Etienne (JT), Saint-Etienne, Necker Hospital (AM), Paris, University of Toulouse (MS, LB), Toulouse, University of Bordeaux (JCB, JMF), Bordeaux, University of Rouen (CP, BA), Rouen and University of Lyon (MC), Lyon, France, University of Jena (HW, KJ, JS), Jena and University of Magdeburg (MB, EPA), Magdeburg, Germany, Università del Sannio, Benevento (LC), Italy, and Tel-Aviv University (AZ), Tel-Aviv, Israel Purpose: We evaluated the prognosis, risk factors and relevance of the primary-free interval in a large cohort with metachronous bilateral renal cell carcinoma. Materials and Methods: We studied 120 patients with metachronous, bilateral renal cell carcinoma who were treated at 12 international academic centers. Logistic regression was performed to evaluate risk factors for contralateral metachronous renal cell carcinoma during followup. Disease specific survival was evaluated with univariate and multivariate analysis. Results: Median age at diagnosis of the first and second renal cell carcinomas was 54 and 62 years, respectively. The most common histological subtype was bilateral clear cell renal cell carcinoma (89% of cases). Familial renal cell carcinoma was found in 14% of patients, von Hippel-Lindau disease was found in 4% and nonfamilial renal cell carcinoma was found in 81%. The 15-year disease specific survival rates for the first and second renal cell carcinomas were 66% and 44%, respectively. Logistic regression revealed von Hippel-Lindau disease, a family history of renal cell carcinoma, multifocal first renal cell carcinoma and young patient age as independent risk factors for contralateral renal cell carcinoma after surgery for unilateral renal cell carcinoma. A longer primary-free interval was associated with a better prognosis. When calculating disease specific survival from the diagnosis of the first renal cell carcinoma, the primary-free interval was an independent prognostic factor. Conclusions: Long-term survival rates of metachronous, bilateral renal cell carcinoma are moderate. von Hippel-Lindau disease, a family history of renal cell carcinoma, multifocal first renal cell carcinoma and young patient age are independent risk factors for contralateral renal cell carcinoma. These risk factors support close and extended abdominal surveillance following nephrectomy for unilateral renal cell carcinoma. Patients with a longer primary-free interval have a more favorable prognosis. Key Words: kidney; carcinoma, renal cell; neoplasms, second primary; risk; prognosis B ilateral RCC is a rare tumor with a reported incidence of about 3% to 5% of all patients with RCC. 1,2 Bilat- eral RCC can occur in sporadic and hereditary forms with the latter including patients with a positive family history of RCC and patients with VHL disease. 1,3,4 Synchro- nous bilateral RCC has been distinguished from metachro- nous bilateral RCC. Generally accepted, synchronous bilat- eral RCC is considered if the second primary RCC develops within 6 months from the diagnosis of the first primary RCC, whereas metachronous bilateral RCC develops later than 6 months from the diagnosis of the first primary RCC. 2,5 Surveillance of patients with RCC can be an issue. The interval between the first and second primary RCCs in pa- tients with metachronous bilateral RCC, termed the primary- free interval, may exceed 5 years. Furthermore, abdominal imaging is not universally recommended for all patients following nephrectomy due to the relative rarity of abdomi- nal recurrence. 6 Thus, identifying patients who are at higher risk for contralateral metachronous RCC is of partic- ular importance, leading to longer and more intensive fol- lowups. Otherwise patients presenting with contralateral RCC may present with symptomatic and more advanced tumors, making it more difficult to achieve the therapeutic Submitted for publication September 21, 2006. * Financial interest and/or other relationship with Bayer, Pfizer and Wilex. † Financial interest and/or other relationship with Pierre Fabre. ‡ Financial interest and/or other relationship with Bayer and Pfizer. § Correspondence and requests for reprints: Department of Urol- ogy, David Geffen School of Medicine at University of California- Los Angeles, 10833 Le Conte Ave., Room B7-298A CHS, Los An- geles, California 90025-1738 (telephone: 310-206-2436; FAX: 310- 206-4082; e-mail: apantuck@mednet.ucla.edu). 0022-5347/07/1776-2081/0 Vol. 177, 2081-2087, June 2007 THE JOURNAL OF UROLOGY ® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.01.122 2081