Adjuvant Chemotherapy for High Risk Upper Tract Urothelial Carcinoma: Results From the Upper Tract Urothelial Carcinoma Collaboration

Adjuvant Chemotherapy for High Risk Upper Tract Urothelial Carcinoma: Results From the Upper Tract Urothelial Carcinoma Collaboration Nicholas J. Hellenthal,* Shahrokh F. Shariat, Vitaly Margulis, Pierre I. Karakiewicz, Marco Roscigno, Christian Bolenz, Mesut Remzi, Alon Weizer, Richard Zigeuner, Karim Bensalah, Casey K. Ng, Jay D. Raman, Eiji Kikuchi, Francesco Montorsi, Mototsugu Oya, Christopher G. Wood, Mario Fernandez, Christopher P. Evans and Theresa M. Koppie From the University of Vienna (MR), Vienna and Medical University Graz (RZ), Graz, Austria, University of Texas M. D. Anderson Cancer Center (VM, CGW), Houston and University of Texas Southwestern (SFS, CB), Dallas, Texas, Vita-Salute University (MR, FM), Milan, Italy, Keio University School of Medicine (EK, MO), Tokyo, Japan, University of Michigan (AW), Ann Arbor, Michigan, Universitatsklinikum Mannheim (CB), Mannheim, Germany, University of California-Davis (NJH, CPE, TMK), Sacramento, California, Cornell University (CKN, JDR), New York, New York, Clinica Alemana de Santiago (MF), Santiago de Chile, Chile, University of Montreal (PIK), Montreal, Quebec, Canada, and University of Rennes (KB), Rennes, France Abbreviations and Acronyms ECOG Eastern Cooperative Oncology Group MVAC methotrexate, vinblastine, doxorubicin and cisplatin UC urothelial carcinoma UTUC upper tract UC Submitted for publication December 16, 2008. Study received institutional review board approval. * Correspondence: Department of Urology, 4860 Y St., Suite 3500, University of California- Davis Medical Center, Sacramento, California 95817 (telephone: 916-734-2893; FAX: 916-734- 8094; e-mail: nicholas.hellenthal@ucdmc.ucdavis. edu). Financial interest and/or other relationship with Antigenics, Pfizer, Bayer/Onyx, Kidney Cancer Association and Ethicon. Purpose: There is relatively little literature on adjuvant chemotherapy after radical nephroureterectomy in patients with upper tract urothelial carcinoma. We determined the incidence of adjuvant chemotherapy in high risk patients and the ensuing effect on overall and cancer specific survival. Materials and Methods: Using an international collaborative database we identified 1,390 patients who underwent nephroureterectomy for nonmetastatic upper tract urothelial carcinoma between 1992 and 2006. Of these cases 542 (39%) were classified as high risk (pt3n0, pt4n0 and/or lymph node positive). These patients were divided into 2 groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohorts. Results: Of high risk patients 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p 0.001). Median survival in the entire cohort was 24 months (range 0 to 231). There was no significant difference in overall or cancer specific survival between patients who did and did not receive adjuvant chemotherapy. However, age, performance status, and tumor grade and stage were significant predictors of overall and cancer specific survival. Conclusions: Adjuvant chemotherapy is infrequently used to treat high risk upper tract urothelial carcinoma after nephroureterectomy. Despite this finding it appears that adjuvant chemotherapy confers minimal impact on overall or cancer specific survival in this group. Key Words: kidney; ureter; carcinoma, transitional cell; chemotherapy, adjuvant; mortality UPPER tract urothelial carcinoma is relatively rare, accounting for approximately 5% of genitourinary malignancies, although evidence suggests that the incidence is increasing. 1 Radical nephroureterec- 900 www.jurology.com 0022-5347/09/1823-0900/0 Vol. 182, 900-906, September 2009 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2009 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2009.05.011

ADJUVANT CHEMOTHERAPY FOR HIGH RISK UPPER TRACT UROTHELIAL CANCER 901 tomy with excision of an ipsilateral bladder cuff via a laparoscopic or open approach remains the gold standard treatment in patients with UTUC and a functional contralateral kidney. Pathological status at nephroureterectomy, in particular tumor grade, stage and lymph node status, was documented to impact cancer specific survival. 2 The 5-year survival rate in patients with pt1 or lesser lesions is reported to be greater than 90%, although this rate decreases to less than 50% for pt3 and higher lesions. 2 Clinical trials demonstrate that UC is a chemosensitive tumor. 3 There is good evidence to suggest that when chemotherapy is administered in a neoadjuvant setting, it improves survival in patients with invasive bladder UC. 4 However, in the adjuvant setting the role of chemotherapy is more controversial. 5 Small series show measurable survival benefits specifically in patients treated with chemotherapy for metastatic or unresectable UTUC. 6 However, the survival effects of chemotherapy are difficult to ascertain in patients with high risk (pt3 or greater, or node positive), nonmetastatic UTUC. These patients are much fewer in number and it is often difficult to predict tumor stage before nephroureterectomy. This has resulted in a paucity of literature on adjuvant chemotherapy and its role in the treatment of high risk UTUC after nephroureterectomy. Using a database from an international collaborative group we identified the incidence and trends of administration of adjuvant chemotherapy in patients with high risk UTUC. We also determined predictors of overall and cancer specific survival, in particular differences in outcomes attributable to the receipt of adjuvant chemotherapy. MATERIALS AND METHODS Patients and Databases We used a database comprising patients from the UTUC Collaboration, representing those from academic centers in Houston and Dallas, Texas; Rennes, France; Tokyo, Japan; Sacramento, California; Graz and Vienna, Austria; Milan, Italy; Mannheim, Germany; Ann Arbor, Michigan; New York, New York; Santiago, Chile; and Montreal, Quebec, Canada who were treated with nephroureterectomy for clinically nonmetastatic UTUC during 1992 to 2006. Patients were divided into a high risk group (pt3n0, pt4n0 and/or lymph node positive) and then categorized as to whether they received adjuvant chemotherapy. All pathological specimens were reviewed by a trained institutional genitourinary pathologist using the American Joint Committee on Cancer TNM staging system and the WHO grading system relevant to time of diagnosis. Population During the mentioned time frame we collected clinical and pathological data on 1,390 patients who underwent nephroureterectomy for UTUC at the 12 participating institutions. Of these patients 542 (39%) were candidates for adjuvant chemotherapy based on pathological stage pt3 or greater and/or node positivity. Patients in this group were 27 to 97 years old at diagnosis (mean age 69) and 180 (33%) were women. Clinical features evaluated were age, gender, tumor grade and stage, ECOG performance status, adjuvant chemotherapy status, cause of death if applicable and time from cancer diagnosis to death. In all patients chemotherapy and performance status were known at the time of review. To meet criteria for adjuvant chemotherapy treatment must have been started within 3 months of undergoing nephroureterectomy. Cancer specific cause of death was defined as death from UC. Statistical Analysis Our primary outcome measures were the likelihood of receiving adjuvant chemotherapy, and overall and cancer specific survival in high risk patients who did and did not undergo chemotherapy. Cohorts were defined by gender (male or female), age group (less than 60, 60 to 69, 70 to 79 and 80 years or greater), ECOG performance status before surgery (0, 1, 2 or 3), pathological tumor grade (low or high) and pathological tumor stage (T3N0, T4N0 or N ). The chi-square test was used to examine the relationship among the various cohorts and the receipt of adjuvant chemotherapy. For multivariate regression we combined ECOG status into 2 groups (0 and 1 or greater). We then used Cox proportional hazard modeling and Kaplan-Meier analysis to evaluate overall and cancer specific survival based on chemotherapy status between the cohorts. Statistical analysis was performed with STATA, version 10.0. RESULTS We identified 542 patients who underwent nephroureterectomy for T3, T4 and/or node positive clinically nonmetastatic UTUC between January 1992 and December 2006. Of these high risk patients 121 (22%) received adjuvant chemotherapy. Patients received an average of 3.1 cycles of chemotherapy (range 1 to 6). Median followup was 26 months (range 0 to 231). Overall 219 patients (40%) with Table 1. Adjuvant therapy administered Chemotherapy No. Pts (%) MVAC 65 (59) Gemcitabine cisplatin 22 (20) Carboplatin paclitaxel 7 (6) Cisplatin, methotrexate vinblastine 4 (4) Cisplatin or carboplatin monotherapy 4 (4) Cisplatin, cyclophosphamide and doxorubicin 3 (3) Gemcitabine monotherapy 1 (1) Gemcitabine paclitaxel 1 (1) Gemcitabine, methotrexate cisplatin 1 (1) Paclitaxel, ifosphamide carboplatin 1 (1) Paclitaxel 1 (1) Total 110

902 ADJUVANT CHEMOTHERAPY FOR HIGH RISK UPPER TRACT UROTHELIAL CANCER Table 2. Clinical characteristics of patients with high risk UTUC No. Pts No. Adjuvant Chemotherapy (%) p Value (chi-square test) Gender: M 362 91 (25) 0.026 F 180 30 (17) Age group: Less than 60 97 33 (34) 0.001 60 69 163 45 (28) 70 79 199 36 (18) 80 or Greater 83 7 (8) Performance status: 0 377 90 (24) 0.350 1 133 27 (20) 2 26 4 (15) 3 6 0 Grade: Low 73 5 (7) 0.001 High 469 116 (25) Stage: T3N0 383 62 (16) 0.001 T4N0 32 7 (22) N 127 52 (41) Totals 542 121 (22) high risk disease died of UTUC and 58 (11%) died of other causes. Median survival in the group with chemotherapy was 24 months (range 3 to 169 months) and in the group without chemotherapy it was 26 months (range 0 to 231). Chemotherapy regimens administered varied among patients and institutions. Chemotherapy was platinum based in 97% of patients (cisplatin in 89%) and consisted of MVAC in most (table 1). After excluding 1 patient with end stage renal disease serum creatinine in those treated with MVAC increased from an average of 1.2 mg/dl preoperatively to 1.3 mg/dl after surgery and chemotherapy. Table 2 lists patients by gender, age group, performance status, tumor grade and tumor stage, showing the association in each group of receiving adjuvant chemotherapy by the chi-square test. In this analysis all variables except performance status before nephroureterectomy were independently associated with receiving chemotherapy. Chemotherapy status and gender did not confer significant cancer specific or overall survival differences. However, age group, performance status, and tumor grade and stage were significantly associated with cancer specific and overall survival (table 3). On multivariate analysis tumor grade and stage were highly predictive of overall survival (HR 2.34, p 0.001 and HR 3.40, p 0.001) and of cancer specific survival (HR 1.20, p 0.009 and HR 1.33, p 0.001, respectively, table 4). Age group and performance status were also significantly associated with overall and cancer specific survival with 1.27 times greater overall (95% CI 1.12 1.45, p 0.001) and 1.20 times greater disease specific (95% CI 1.04 1.39, p 0.013) risk of death associated with each 10-year age increase, and 1.59 times greater overall (95% CI 1.24 2.05, p 0.001) and 1.46 times greater disease specific (95% CI 1.10 Table 3. Likelihood of all cause and cancer specific death All Cause Death Ca Specific Death HR (95% CI) p Value HR (95% CI) p Value Gender: M Referent 1.0 Referent 1.0 F 1.02 (0.79 1.31) 0.869 1.02 (0.77 1.35) 0.916 Age group: Less than 60 Referent 1.0 Referent 1.0 60 69 1.71 (1.16 2.51)* 0.007 1.71 (1.13 2.59)* 0.012 70 79 1.83 (1.25 2.68)* 0.002 1.45 (0.95 2.21) 0.086 80 or Greater 2.63 (1.69 4.09)* 0.001 2.35 (1.45 3.82)* 0.001 Performance status: 0 Referent 1.0 Referent 1.0 1 1.75 (1.34 2.29)* 0.001 1.66 (1.23 2.24)* 0.001 2 1.58 (0.93 2.68) 0.090 1.15 (0.59 2.25) 0.688 3 4.35 (1.91 9.88)* 0.001 4.28 (1.74 10.51)* 0.002 Grade: Low Referent 1.0 Referent 1.0 High 2.49 (1.64 3.80)* 0.001 3.72 (2.12 6.15)* 0.001 Stage: T3N0 Referent 1.0 Referent 1.0 T4N0 2.28 (1.42 3.67)* 0.001 2.73 (1.64 4.53)* 0.001 N 1.46 (1.11 1.91)* 0.007 1.85 (1.38 2.48)* 0.001 Adjuvant chemotherapy: No Referent 1.0 Referent 1.0 Yes 1.06 (0.80 1.40) 1.26 (0.93 1.71) 0.129 * Statistically significant (95% CI does not cross 1.0).

ADJUVANT CHEMOTHERAPY FOR HIGH RISK UPPER TRACT UROTHELIAL CANCER 903 Table 4. Multivariate Cox proportional hazard model of all cause and cancer specific death HR (95% CI)* p Value All cause death: Age group 1.27 (1.12 1.45) 0.001 Performance status 1.59 (1.24 2.05) 0.001 Tumor grade 2.34 (1.54 3.58) 0.001 Tumor stage 1.20 (1.05 1.37) 0.009 Ca specific death: Age group 1.20 (1.04 1.39) 0.013 Performance status 1.46 (1.10 1.95) 0.009 Tumor grade 3.40 (1.93 5.97) 0.001 Tumor stage 1.33 (1.15 1.54) 0.001 * Statistically significant (95% CI does not cross 1.0). 1.95, p 0.009) risk of death in patients with a performance status of 1 or greater. Upon further analysis adjuvant chemotherapy after nephroureterectomy did not significantly correlate with overall or cancer specific survival in patients with high risk disease (fig. 1). The lack of a significant difference in overall and cancer specific survival rates also held true on each subset analysis of the individual high risk groups, ie T3N0, T4N0 and N (fig. 2). Further subset analysis in the group of patients who received MVAC also failed to show a significant difference in survival favoring chemotherapy (data not shown). DISCUSSION High risk UTUC continues to be a difficult disease to treat. Outcomes after surgery for UTUC have not changed in the last 2 decades with tumor grade and stage at nephroureterectomy having key roles in determining the overall survival rate in individual series. 7,8 While low grade disease is associated with a 5-year overall survival rate approaching 94%, high grade disease confers a dismal survival rate of approximately 28%. 9 Tumor stage also accounts for a large discrepancy in overall survival with a 5-year actuarial survival rate of approximately 50% after nephroureterectomy in those with pt3 lesions, and less than 5% and 1% in patients with pt4 and node positive disease, respectively. 2 This poor survival has led investigators to readdress the treatment algorithm in patients with high risk UTUC. There are sparse data to support the use of neoadjuvant chemotherapy before nephroureterectomy for UTUC. A series of 15 patients from Japan showed a positive relationship between pathological response and the receipt of neoadjuvant chemotherapy, although this result did not achieve statistical significance. 10 While randomized, controlled studies demonstrate survival benefits of neoadjuvant chemotherapy for invasive bladder UC, the challenge of neoadjuvant chemotherapy for UTUC lies in accurate preoperative risk stratification. 4 Unlike bladder UC, it is difficult to predict which patients have high risk, organ confined UTUC before nephroureterectomy. There has been some success in stage prediction based on preoperative axial imaging, tumor grade at biopsy and selective urinary cytology but uncertainty rates are still on the order of 30% to 40%. 11 In our series only 39% of the entire cohort was at high risk and, thus, if all patients had received neoadjuvant chemotherapy, 61% would have received chemotherapy unnecessarily. Studies to date of adjuvant chemotherapy for high risk (pt3 or greater, or node positive), nonmetastatic UTUC are retrospective and significantly underpowered. A retrospective study of 27 patients from Korea with pt3n0 UTUC showed no statistically significant difference in recurrence-free or disease specific survival attributable to adjuvant MVAC, although the same group found a significant overall survival benefit favoring adjuvant chemotherapy in 43 patients with stage pt2 or worse disease regardless of tumor grade or stage. 12,13 Another retrospective study from Canada showed a 47% overall 5-year survival rate in OS HR: 1.06 (0.80-1.40), p=0.687 CSS HR: 1.26 (0.93-1.71), p=0.129 Figure 1. Overall (OS) and cancer specific (CSS) survival in patients with high risk UTUC with (red curves) vs without (blue curves) adjuvant chemotherapy.

904 ADJUVANT CHEMOTHERAPY FOR HIGH RISK UPPER TRACT UROTHELIAL CANCER OS T3N0 HR: 1.14 (0.76-1.69), p=0.529 CS T3N0 HR: 1.35 (0.87-2.09), p=0.181 OS T4N0 HR: 0.62 (0.21-1.90), p=0.406 0 20 40 60 80 CS T4N0 HR: 0.71 (0.23-2.22), p=0.554 0 20 40 60 80 OS N+ HR: 0.80 (0.50-1.28), p=0.353 0 50 100 150 200 CS N+ HR: 0.85 (0.53-1.38), p=0.516 0 50 100 150 200 Figure 2. Overall (OS) and cancer specific (CS) survival substratified by stage in patients with high risk UTUC with (red curves) vs without (blue curves) adjuvant chemotherapy. 35 high risk patients treated with adjuvant platinum based chemotherapy, 14 which is similar to previously mentioned survival rates in patients not receiving chemotherapy. Two of the 35 patients died of chemotherapy related complications. A prospective study by Bamias et al suggests that adjuvant chemotherapy may decrease the risk of metastatic failure in high risk patients but they did not find a significant 5-year survival difference in the 36 patients studied. 15 This discordance in the literature probably accounts for the inconsistent use of chemotherapy for high risk UTUC. Indeed, we found that only 22% of patients with high risk disease received adjuvant treatment. Another plausible reason for the infrequent use of adjuvant chemotherapy may lie in the nephrotoxicity of cisplatinum based chemotherapy. The perceived risk of nephrotoxicity to an anatomical or functional solitary renal unit may deter oncologists from administering cisplatin based chemotherapy after nephroureterectomy. Moreover, changes in creatinine clearance after nephrectomy may render patients ineligible for cisplatin based chemotherapy. A recent study by Huang et al shows that 65% of patients who underwent radical nephrectomy for renal cell carcinoma had new onset chronic kidney disease, defined as a glomerular filtration rate of less than 60 ml per minute, by 3 years. 16 In our series serum creatinine in those treated with MVAC increased from an average of 1.2 mg/dl preoperatively to 1.3 mg/dl after surgery and

ADJUVANT CHEMOTHERAPY FOR HIGH RISK UPPER TRACT UROTHELIAL CANCER 905 chemotherapy, excluding 1 patient with end stage renal disease preoperatively. In our study, which is to our knowledge the largest to date, adjuvant chemotherapy was not significantly associated with overall or cancer specific survival in the entire cohort or on any subset analyses. In fact, adjuvant chemotherapy imparted a trend toward slightly worse overall and cancer specific survival, largely because it was administered more often in patients with higher stage and grade disease. Our study confirms that age, performance status, tumor grade and tumor stage are significant predictors of survival in patients with high risk UTUC. Each 10-year increase in age conferred a 1.20 times greater odds of cancer related death and patients with an ECOG status of 1 or greater had 1.46 times greater odds of dying of UTUC than those with an ECOG status of 0. These values are consistent with prior reports relating survival benefits in patients with various surgically and chemotherapeutically treated malignancies to age and performance status. 17,18 As mentioned, tumor grade and stage are also highly and perhaps most predictive of outcome in patients with UTUC. 7 It was previously suggested that the risk of cancer related death is increased at least 2-fold in patients with high grade disease compared with that in patients with low grade cancer. 19 We found a similar result since patients with high grade disease were 3.4 times more likely to die of UTUC. In regard to stage, we found that each increase in stage conferred a 1.33 times increased odds of cancer related death. This result augments a prior study demonstrating a 5-year survival rate of 56%, 0% and 12% in cases of pt3, pt4 and node positive disease, respectively. 20 This study has limitations. It is retrospective and, therefore, we could not determine the rationale behind administering or not administering chemotherapy in these patients. Postoperative patient functional status was unknown. Chemotherapeutic regimens were not standardized at participating institutions and data were incomplete in approximately 10% of the cases. CONCLUSIONS Adjuvant chemotherapy is used sparingly for high risk UTUC. In this large, multi-institutional, retrospective study there did not appear to be a significant overall or cancer specific survival benefit associated with adjuvant chemotherapy. Median survival in patients diagnosed with high risk UTUC after nephroureterectomy was on the order of 2 years regardless of the receipt of adjuvant chemotherapy. Tumor grade and stage as well as age and performance status remain important predictors of survival. As in bladder UC, there may be benefit to neoadjuvant chemotherapy. 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906 ADJUVANT CHEMOTHERAPY FOR HIGH RISK UPPER TRACT UROTHELIAL CANCER with invasive transitional cell carcinoma of the upper urinary tract. Urology 2006; 68: 53. 14. Michael M, Tannock IF, Czaykowski PM et al: Adjuvant chemotherapy for high-risk urothelial transitional cell carcinoma: the Princess Margaret Hospital experience. Br J Urol 1998; 82: 366. 15. Bamias A, Deliveliotis C, Fountzilas G et al: Adjuvant chemotherapy with paclitaxel and carboplatin in patients with advanced carcinoma of the upper urinary tract: a study by the Hellenic Cooperative Oncology Group. J Clin Oncol 2004; 22: 2150. 16. Huang WC, Sevey AS, Serio AM et al: Chronic renal disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncology 2006; 7: 735. 17. Hochster HS, Luo W, Popa EC et al: Phase II study of uracil-tegafur with leucovorin in elderly ( or 75 years old) patients with colorectal cancer: ECOG 1299. J Clin Oncol 2007; 25: 5397. 18. Langer C, Li S, Schiller J et al: Randomized phase II trial of paclitaxel plus carboplatin or gemcitabine plus cisplatin in Eastern Cooperative Oncology Group performance status 2 non-small-cell lung cancer patients: ECOG 1599. J Clin Oncol 2007; 25: 418. 19. Kang CH, Yu TJ, Hsieh HH et al: The development of bladder tumors and contralateral upper urinary tract tumors after primary transitional cell carcinoma of the upper urinary tract. Cancer 2003; 98: 1620. 20. Novara G, De Marco V, Gottardo F et al: Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multi-institutional dataset from 3 European centers. Cancer 2007; 110: 1715. EDITORIAL COMMENT These authors comprise an international collaboration that has yielded several important findings in this study and in others. They have validated the prognostic value of pathological grade and stage plus age and preoperative performance status. They rightly point out some limitations of their study, of which most stem from its retrospective nature with a short median followup but the size of their overall data set is a strength. One might point out that patients who received adjuvant chemotherapy had similar cancer specific and overall survival despite having higher risk features, potentially indicating a chemotherapy benefit. The authors conclude that adjuvant chemotherapy confers minimal impact based on their overall and subset (stage matched) analyses. Neither argument is completely valid, especially with limited data, mixed chemotherapy delivery and the small number of patients in the chemotherapy group (only 22% of the overall group) with subset analysis performed in fractions of this number (fig. 2). No firm conclusions can be drawn regarding the efficacy or lack thereof of adjuvant chemotherapy. Our cooperative groups in the United States and Europe have not been able to complete UC adjuvant trials. Although this retrospective study does not provide all of the answers, it is proof that international collaborative efforts are possible. Although all acknowledge that it will be a herculean effort, we must pull together as a urological oncology community to perform international, prospective, collaborative clinical trials for the sake of our patients. Scott T. Tagawa Departments of Medicine and Urology Weill Cornell Medical College New York, New York