Sunitinib, Pazopanib or Sorafenib for the Treatment of Patients with Late Relapsing Metastatic Renal Cell Carcinoma Matteo Santoni,* Alessandro Conti, Camillo Porta, Giuseppe Procopio, Cora N. Sternberg, Umberto Basso, Ugo De Giorgi, Sergio Bracarda, Mimma Rizzo, Cinzia Ortega, Francesco Massari, Roberto Iacovelli, Lisa Derosa, Cristina Masini, Michele Milella, Giuseppe Di Lorenzo, Francesco Atzori, Maria Pagano, Sebastiano Buti, Rocco De Vivo, Alessandra Mosca, Marta Rossi, Chiara Paglino, Elena Verzoni, Linda Cerbone, Giovanni Muzzonigro, Massimo Falconi, Rodolfo Montironi, Luciano Burattini, Daniele Santini and Stefano Cascinu From the Clinica di Oncologia Medica (MS, LB, SC) and Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche, Clinica di Urologia (AC, GM), AOU Ospedali Riuniti, Universita Politecnica delle Marche, and Division of Pancreatic and Digestive Surgery (MF) and Section of Pathological Anatomy (RM), Universita Politecnica delle Marche, School of Medicine, AOU Ospedali Riuniti, Ancona, Medical Oncology, IRCCS San Matteo University Hospital Foundation,Pavia (CP, CP), Department of Medical Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan (GP, RI, EV), Department of Medical Oncology, San Camillo and Forlanini Hospitals (CNS, LC), Medical Oncology A, Regina Elena National Cancer Institute (MM) and Oncologia Medica, University Campus Bio-Medico Roma (DS), Rome, Medical Oncology 1, Istituto Oncologico Veneto, IRCCS, Padova (UB), IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-I.R.S.T., Meldola (FC) (UDG), Department of Oncology, Istituto Toscano Tumori, Ospedale San Donato USL-8, Arezzo (SB), Department of Medical Oncology, Cardarelli Hospital (MR), and Genitourinary Cancer Section, Medical Oncology Division, Department of Endocrinology and Oncology, University Federico II (GDL), Napoli, Oncology Foundation of Piedmont, Institute for Cancer Research and Treatment, Laboratory Medicine, Candiolo (CO), Medical Oncology, ‘G.B. Rossi’ Academic Hospital, University of Verona, Verona (FM), UO Oncologia Medica 2 Universitaria Azienda Ospedaliero-Universitaria Pisana Istituto Toscano Tumori, Pisa (LD), Oncology Division, Department of Oncology and Hematology, University of Modena e Reggio Emilia, Modena (CM), Medical Oncology Unit, Azienda Ospedaliero Universitaria of Cagliari, Cagliari (FA), Department of Oncology, Oncology Unit, Azienda Ospedaliera AsMN, Istituto di Ricovero e cura a carattere scientifico, Reggio Emilia (MP), Department of Oncology, University Hospital of Parma, Parma (SB), Medical Oncology, S. Bortolo Hospital, Vicenza (RDV), Medical Oncology, Maggiore della Carita Hospital, University of Eastern Piedmont “A. Avogadro”, Novara (AM), and S.C. Oncologia Medica, Azienda Ospedaliera di Perugia, Ospedale S. Maria della Misericordia, Perugia (MR), Italy

Purpose: Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma. Materials and Methods: Data were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy. Results: A total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0e25.1), and 14.1 months for sorafenib (95% CI 11.0e29.0) and pazopanib (95% CI 11.2enot reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were

Abbreviations and Acronyms DCR ¼ disease control rate DFS ¼ disease-free survival LR ¼ late relapsing mRCC ¼ metastatic renal cell carcinoma MSKCC ¼ Memorial Sloan Kettering Cancer Center mTOR ¼ mammalian target of rapamycin NA ¼ not applicable OS ¼ overall survival

Accepted for publication July 10, 2014. Nothing to disclose. Study received ethical committee approval. * Correspondence: Clinica di Oncologia Medica, AOU Ospedali Riuniti, Universita Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy (telephone: þ39 0715964263; FAX: þ39 0715964269; e-mail: [email protected]).

Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 378 and 379. 0022-5347/15/1931-0041/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.

http://dx.doi.org/10.1016/j.juro.2014.07.011 Vol. 193, 41-47, January 2015 Printed in U.S.A.

PFS ¼ progression-free survival RCC ¼ renal cell carcinoma TKI ¼ tyrosine kinase inhibitor VEGFR ¼ vascular endothelial growth factor receptor

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TYROSINE KINASE INHIBITORS FOR LATE RELAPSING RENAL CELL CARCINOMA

associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival. Conclusions: Patients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib. Key Words: recurrence; survival; carcinoma, renal cell; protein-tyrosine kinases

RENAL cell carcinoma is a therapeutic challenge for clinicians. Clear cell RCC is the most common histological subtype and is relatively resistant to chemotherapy or radiotherapy.1,2 Five-year survival is up to 95% when the disease is confined to the kidney (stage T1-2) but just 10% to 15% in patients with metastatic RCC. About 30% of RCC cases have already metastasized at first diagnosis and widespread metastatic disease develops in another 30% to 40% after initial resection.3,4 Few guidelines on followup (mainly based on expert opinions) are currently available and some have been highly criticized.5 In 2001 the University of California-Los Angeles Integrated Staging System was designed to include TNM stage, Eastern Cooperative Oncology Group performance status and Fuhrman grade in a unique prognostic nomogram to stratify patients into 3 risk groups of low, intermediate and high risk for localized and metastatic disease.6 In clinical practice postoperative surveillance for patients with localized and locally advanced RCC is performed on a regular basis for at least 5 years. Late recurrence of RCC is not a rare event. Several studies have reported that 4.7% to 11% of patients experienced recurrence more than 10 years after initial nephrectomy.7e9 The development of targeted agents directed toward vascular endothelial growth factor10,11 or its receptor (VEGFR)12e15 and mTOR inhibitors16,17 has led to major advances in the management of patients with mRCC. However, despite recent success, complete responses to antiangiogenic therapies are rare and after initial disease control, relapse eventually occurs during targeted therapy.18 Thus, a better characterization of the mRCC population is strongly needed to optimize patient selection for specific treatment strategies. In this study we analyze the clinicopathological features and outcome of patients with LR-RCC who were diagnosed more than 5 years after initial nephrectomy and were treated with a first line VEGFR-TKI at recurrence. We also investigated the prognostic impact of the sites of metastatic disease on the outcome of these patients.

MATERIALS AND METHODS Study Population We retrospectively collected clinical data of patients treated with the VEGFR-TKI sorafenib, sunitinib or pazopanib for mRCC diagnosed more than 5 years after initial radical nephrectomy. Patients were treated at 21 Italian institutions between January 2005 and July 2013. Patient data were collected consecutively to avoid selection bias. Inclusion criteria were tumor surgically treated with radical nephrectomy not metastatic at diagnosis, long disease-free survival defined as more than 5 years and clear cell histology. All patients included in the analyses were without radiological evidence of distant metastatic disease (M0) at nephrectomy. Patients were excluded from analysis if they had missing information about DFS, sites of metastasis or choice of therapy. The disease control rate was defined as the sum of the percentage of complete remission, partial remission and stable disease achieved during TKI treatment. Patients were treated with sunitinib (orally at a dose of 50 mg daily 4 weeks on, 2 weeks off), sorafenib (400 mg orally twice daily) or pazopanib (at a dose of 800 mg orally daily) as first line therapy. This study was performed in accordance with approval by the ethical committee of the institutions included in this analysis.

Statistical Analysis The primary outcomes of this study were overall survival and progression-free survival from the beginning of first line therapy to event (death or progression) or censoring. The secondary aim was to investigate the prognostic significance of various metastatic sites. PFS was defined as the time from the start of first line TKI therapy to clinical or radiographic progressive disease (according to the Response Evaluation Criteria in Solid Tumors, RECIST v.1.1),19 drug discontinuation, death or censoring. Data were retrospectively collected from medical chart review and electronic records. Survival analysis was conducted via the Kaplan-Meier product limit method and the Mantel-Haenszel log rank test was used to compare survival among groups. A Cox regression model was applied to the data with a univariate and multivariate approach. Variables included in the univariate analysis were gender, age, T stage at initial diagnosis, Fuhrman grade, sarcomatoid differentiation, perirenal fat infiltration, lymphovascular invasion, time from surgery to metastatic disease, number of metastatic sites, MSKCC risk group, targeted therapy used as first line and sites of metastasis.

TYROSINE KINASE INHIBITORS FOR LATE RELAPSING RENAL CELL CARCINOMA

In patients with a first relapse consisting of a single metastasis, OS and PFS were calculated from initiation of systemic treatment with TKIs for metastatic spread. Continuous covariates (age, time from surgery) were grouped into discrete ordinal categories. Patients were stratified into 4 groups based on age (younger than 60 years, between 60 and 75 years and older than 75 years) and into 3 groups based on DFS (more than 5 to 10 years, more than 10 to 15 years and more than 15 years). The proportionality of hazards was checked with graphic analysis of scaled Schoenfeld residuals. Variables not fitting at univariate analysis were excluded from the multivariate model. No multicollinearity of the grouped covariates was checked. The significance level in the univariate model for inclusion in the multivariate final model was more liberally set at a 0.2 level according to previously published studies.20,21 All other significance levels were set at a 0.05 value and all p values were 2-sided. Statistical analysis was conducted with “R” statistical software version 2.15.2.

RESULTS Analysis of Clinical and Pathological Characteristics Data from 2,490 patients with mRCC were analyzed and 307 patients were identified who had experienced metastatic disease after a DFS of more than 5 years after initial radical nephrectomy. Of these patients 269 (11%) were treated with TKIs for LR-RCC and were included in this analysis, while 38 patients were treated with chemotherapy (11), immunotherapy (18) or bevacizumab (9). Median age was 66 years (range 29 to 87) and most patients were men (71%). Karnofsky Performance Status was 80 or less in 27 patients (10%). Pathological subtype was clear cell RCC in all patients as requested per protocol. At first diagnosis Fuhrman nuclear grade was grade (G) 1 in 17 patients (6%), G2 in 141 (52%), G3 in 69 (26%), G4 in 13 (5%) and unknown in 29 (11%). Lymphovascular and perirenal fat infiltration were present in 33 (12%) and 31 (12%) patients, respectively, while sarcomatoid differentiation was identified in 11 (4%). Patient characteristics are summarized in supplementary table 1 (http://jurology.com/). LR was asymptomatic in 158 patients (59%), and was found during radiological and clinical followup. In the other 111 patients the main symptoms at presentation were pain (39, 14%), asthenia (22, 8%), laboratory abnormalities (17, 6%) and dyspnea (12, 4%). The number of metastatic sites at recurrence was 1 in 76 patients (28%) and 2 or more in 193 patients (72%). In 22 patients (8%) the first relapse consisted of a single metastasis that was treated with metastasectomy. The most frequent sites for LR were lung (56%), followed by lymph nodes (31%, with 20%

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retroperitoneal, 8% mediastinal and 3% to other sites), bone (21%), pancreas (16%), liver (16%), adrenal gland (15%), contralateral kidney (14%), soft tissue (8%), brain (7%), nephrectomy bed (5%), thyroid (3%), pleura (3%), spleen (1%) and stomach (1%) (table 1). Prognostic categories using MSKCC criteria and Heng/International Metastatic Renal Cell Carcinoma Database Consortium criteria are reported in supplementary table 1 (http://jurology. com/). Analysis of First Line PFS and OS Median time to recurrence was 7.9 years (range 5.1 to 35.0). Median followup from relapse was 4.9 years (range 0.4 to 7.3). Median OS from first line VEGFR-TKI was 45.5 months (95% CI 40.8e58.6). For the good, intermediate and poor prognostic groups median OS was 58.6, 35.1 and 7.5 months, respectively (p

Sunitinib, pazopanib or sorafenib for the treatment of patients with late relapsing metastatic renal cell carcinoma.

Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outco...
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