Cancer Therapy: Clinical The Effectiveness of Off-Protocol Adjuvant Chemotherapy for Patients with Urothelial Carcinoma of the Urinary Bladder Robert S. Svatek 1,2 , Shahrokh F. Shariat 4 , Robert E. Lasky 2 , Eila C. Skinner 5 , Giacomo Novara 6 , Seth P. Lerner 3 , Yves Fradet 7 , Patrick J. Bastian 8 , Wassim Kassouf 9 , Pierre I. Karakiewicz 10 , Hans-Martin Fritsche 11 , Stefan C. Müller 12 , Jonathan I. Izawa 13 , Vincenzo Ficarra 6 , Arthur I. Sagalowsky 4 , Mark P. Schoenberg 14 , Arlene O. Siefker-Radtke 1 , Randall E. Millikan 1 , and Colin P.N. Dinney 1 Abstract Purpose: The role of adjuvant chemotherapy for patients with high-risk urothelial carcinoma of the bladder (UCB) is not well defined. Here we address the value of adjuvant chemotherapy in patients un- dergoing radical cystectomy for UCB in an off-protocol routine clinical setting. Experimental Design: We collected and analyzed data from 11 centers contributing retrospective co- horts of patients with UCB treated with radical cystectomy without neoadjuvant chemotherapy. Patients were grouped into quintiles based on their risk of disease progression using estimates from a fitted mul- tivariable Cox proportional hazards model. The association of adjuvant chemotherapy with survival was explored across separate quintiles. Results: The cohort consisted of 3,947 patients, 932 (23.6%) of whom received adjuvant chemother- apy. Adjuvant chemotherapy was independently associated with improved survival (hazard ratio, 0.83; 95% confidence interval, 0.72-0.97%, P = 0.017). However, the effect of adjuvant chemotherapy was sig- nificantly modified by the individual's risk of disease progression such that an increasing benefit from adjuvant chemotherapy was seen across higher-risk subgroups (P < 0.001). There was a significant im- provement in survival between the treated and nontreated patients in the highest-risk quintile (hazard ratio, 0.75; 95% confidence interval, 0.62-0.90; P = 0.002). This group was characterized by an estimated 32.8% 5-year probability of cancer-specific survival, with 86.6% of patients having both advanced path- ologic stage (≥T 3 ) and nodal involvement. Conclusion: Adjuvant chemotherapy is associated with a significant improvement in survival for pa- tients treated in an off-protocol clinical setting. Selective administration in patients at the highest risk for disease progression, such as those with advanced pathologic stage and nodal involvement, may optimize the therapeutic benefit of adjuvant chemotherapy. Clin Cancer Res; 16(17); 4461–7. ©2010 AACR. Urothelial carcinoma of the bladder (UCB) is the 4th most common cancer in men in the United States (1). Radical cystectomy and pelvic lymphadenectomy is the gold standard treatment for those patients with muscle- invasive or high-risk nonmuscle invasive disease (2). This operation provides local cancer control and improves long-term survival (3, 4). Unfortunately, however, disease recurrence is observed in 30% to 56% of patients under- going surgery, most often the result of occult metastatic disease (4, 5). The prognosis for patients with disease re- currence following cystectomy is poor. As a result, systemic perioperative chemotherapy has been explored as an ad- junct to surgery in both neoadjuvant (preoperative) and adjuvant (postoperative) settings. Cisplatin-based combination neoadjuvant chemothera- py renders a 5% to 7% absolute survival benefit for patients Authors' Affiliations: 1 University of Texas MD Anderson Cancer Center, 2 University of Texas Health Science Center in Houston, Center for Clinical Research and Evidence-Based Medicine, and 3 Baylor College of Medicine, Houston, Texas; 4 University of Texas Southwestern Medical Center, Dallas, Texas; 5 University of Southern California, Los Angeles, California; 6 University of Padua, Padua, Italy; 7 Laval University, Québec City, Québec, Canada; 8 Ludwig-Maximilians-Universität München, Klinikum Grosshadern, Munich, Germany; 9 McGill University Health Centre and 10 University of Montréal, Montréal, Quebec, Canada; 11 University of Regensburg, Regensburg, Germany; 12 Universität Bonn, Bonn, Germany; 13 University of Western Ontario, London, Ontario, Canada; and 14 Johns Hopkins University, Baltimore, Maryland Note: List of contributing institutions: Baylor College of Medicine, Houston, Texas; John Hopkins University, Baltimore, Maryland; Laval University, Québec City, Québec, Canada; Ludwig-Maximilians-Universität München, Klinikum Grosshadern, Munich, Germany; McGill University Health Centre, Montréal, Quebec, Canada; University of Padua, Padua, Italy; University of Regensburg, Regensburg, Germany; University of Southern California, Los Angeles, California; University of Texas M.D. Anderson Cancer Center, Houston, Texas; University of Texas South- western Medical Center, Dallas, Texas; and University of Western Ontario, London, Ontario, Canada. Corresponding Author: Colin P.N. Dinney, Division of Urology M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3250; Fax: 713-794-4824; E-mail: cdinney@mdanderson.org. doi: 10.1158/1078-0432.CCR-10-0457 ©2010 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 4461 Research. on May 29, 2020. © 2010 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst July 22, 2010; DOI: 10.1158/1078-0432.CCR-10-0457