The Outcome of Patients with Advanced Pure Squamous or Mixed Squamous and Transitional Urothelial Carcinomas Following Platinum-based Chemotherapy

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1 The Outcome of Patients with Advanced Pure Squamous or Mixed Squamous and Transitional Urothelial Carcinomas Following Platinum-based Chemotherapy EFSTATHIOS KASTRITIS 1, MELETIOS-ATHANASIOS DIMOPOULOS 1, NIKOLAOS ANTONIOU 2, CHARALAMBOS DELIVELIOTIS 2, MICHAEL CHRISOFOS 2, ANDREAS SKOLARIKOS 2, DIMITRA GIKA 1 and ARISTOTLE BAMIAS 1 1 Department of Clinical Therapeutics, Alexandra Hospital, Athens; 2 Second Department of Urology, University of Athens, School of Medicine, Athens, Greece Abstract. Background: There is limited information about the benefit from systemic chemotherapy in non-pure Transitional Cell Carcinomas (TCCs) of the urothelial tract. In this study the efficacy of platinum-based chemotherapy in patients with pure squamous or mixed carcinomas was retrospectively analysed and compared with that in pure TCCs. Patients and Methods: Analysis included 446 consecutive patients treated with platinum-based chemotherapy for advanced or metastatic urothelial cancer. There were 389 (87%) patients with pure TCC, 15 (3.5%) with pure Squamous Cell Carcinomas (SCC) and 42 (9.5%) patients had mixed histology (TCC+SCC) tumors. Results: There were no statistically significant differences in baseline characteristics (gender, PS, haemoglobin, sites of metastases) although disease in the pelvis was more frequent in mixed tumors than in pure TCCs (46% vs. 30%, p=0.034). Median survival for patients with TCC histology was 11.3 months, for SCC patients 13.6 months and 10.4 months for patients with mixed histology(p=0.720). Response rates were 44% for patients with TCC, 27% for patients with SCC and 34% for mixed histology patients (p=0.210). Multivariate analysis showed that presence of visceral metastases and poor performance, were associated with worse prognosis in mixed histology tumors. Conclusion: Non-transitional histology does not predict for an inferior survival after platinum-based chemotherapy for advanced urothelial carcinoma. Well-known prognostic factors in transitional cell carcinomas were also associated with prognosis in mixed carcinomas. Correspondence to: Aristotle Bamias, MD, Ph.D., 31 Komninon St., Haidari, , Athens, Greece. Tel: , Fax , abamias@med.uoa.gr Key Words: Non-urothelial, platinum, metastatic, urothelial, squamous, mixed tumors, carboplatin, bladder cancer. Bladder cancer is the fourth most common tumor in the United States with 57,400 new cases and 12,500 deaths because of this disease in 2003 (1). Transitional cell carcinomas (TCCs) comprise the majority of urothelial tract cancers, while squamous cell carcinomas (SCCs), adenocarcinoma, small cell carcinoma and non epithelial tumors account only for 5-10% of urothelial tract tumors in Europe and USA (2, 3). SCCs are uncommon in the Western world and they have been linked with chronic bladder irritation due to indwelling catheters, chronic cyclophosphamide use or chronic bladder infections. These tumors have different pathogenesis from the SCCs, linked with Schistosoma haematobium infection in the Middle East and Egypt. More common than pure SCCs or adenocarcinomas are TCCs with focal or extensive squamous or glandular differentiation. These tumors are considered of mixed histology and classified according to WHO (4, 5) as variants of transitional cell carcinoma, accounting for as much as 20% of all TCCs (3, 6-10). There are reports which indicate that non-pure TCCs may differ from pure TCCs. It has been reported from a small series of patients with non-schistosoma related SCCs that these tumors tend to recur locally rather than with distant metastases (11, 12), while others indicate that patients with mixed TCC tumors may have increased risk of relapse after cystectomy for invasive disease (6, 8, 13) or may be more resistant to local radiotherapy (14). These data suggest that TCCs with squamous differentiation may have different, more aggressive, biological behavior than pure TCCs in patients with resectable tumors, but there are no studies about their specific prognostic significance in patients with metastatic disease. The activity of platinum-based combination chemotherapy in transitional cell carcinoma of the urothelial tract is well documented, with a response rate ranging from 28% to 70%, in various phase II and III studies (10, 15-24). Nevertheless, the efficacy of systemic chemotherapy in non-transitional cell /2006 $

2 carcinomas or mixed transitional carcinomas has not been adequately studied. It has been suggested that SCCs or nonpure TCCs may be more resistant to chemotherapy, although limited data exist about their outcome after chemotherapy for advanced or metastatic disease (7, 9, 10, 12, 25, 26). However, mixed transitional carcinomas are traditionally managed in a similar way to pure TCCs. In order to study the outcome of patients with non pure TCCs of the bladder, ureter and renal pelvis with unresectable, recurrent or metastatic disease who received platinum-based chemotherapy, we conducted a retrospective analysis of patients who were treated in our department and compared the outcome of these patients with that of patients with pure TCCs. Patients and Methods Between October 1996 and September 2005, 451 consecutive patients received frontline platinum (cisplatin or carboplatin)- based chemotherapy for advanced, unresectable or metastatic bladder, ureter or renal pelvis cancer. In order to evaluate the role of histology we divided patients into 3 groups: 1) patients with pure TCC histology, 2) patients with mixed histology which was defined as the presence of focal or extensive squamous differentiation together with a TCC component, irrespective of the extend of the squamous component (4, 5, 14); 3) Patients with pure SCCs. Five patients had pure adenocarcinoma of the bladder and were not included in the analysis. Among the 446 patients who were included in our analysis, 32 (7%) patients received CIMV (Cisplatin, Ifosphamide, Methotrexate, Vinblastine), 172 (39%) patients received DC (docetaxel, cisplatin), 100 (22%) patients received MVDC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin), 14 (3%) patients received High Dose MVDC, 8 (2%) patients received GCis (Gemcitabine, Cisplatin), 106 (24%) received CaG (Carboplatin, Gemcitabine) and 14 (3%) patients received other platinum based regimens. Most patients were treated in the context of serial phase II or phase III studies. Survival was calculated from the day of initiation of therapy for metastatic disease until date of death or last contact for patients still alive at the time of follow-up. Patients with bidimensionally measurable disease, who received treatment and had at least one follow-up tumor assessment, were eligible for response evaluation. Standard WHO criteria were used for classifying response. In an intention-to-treat analysis non-evaluable patients were considered as non-responders. Statistical analysis. All analyses were performed using the SPSS statistical software (SPSS for Windows, version 13.1, SPSS Inc., Chicago, IL, USA). Differences between pure TCCs and nonpure TCCs patients were examined with a 2 test for categorical variables, whereas the t-test was used for continuous variables. Survival curves were produced with the Kaplan-Meier method and compared between arms with the stratified log-rank test. For univariate and multivariate analyses of survival, the Cox proportional hazards model was used. Throughout the analysis a p-value of less than 0.05 was used to denote statistical significance. Table I. Patient characteristics. Results TCC SCC Mixed p-value tumors Gender male 342 (88%) 12 (80%) 35 (83%) female 47 (12%) 3 (20%) 7 (17%) ECOG performance (75%) 12 (80%) 30 (73%) >1 97 (25%) 3 (20%) 12 (27%) Creatinine clearance 50 ml/min 255 (72%) 6 (55%) 29 (76%) <50 ml/min 97 (28%) 5 (45%) 9 (24%) Primary site bladder 329 (85%) 11 (73%) 33 (79%) renal pelvis/ureter 60 (15%) 4 (27%) 9 (21%) Prior cystectomy yes 186 (48%) 7 (48%) 20 (49%) no 198 (52%) 8 (52) 21 (51%) Hemoglobin (gr/dl) (90%) 14 (93%) 38 (91%) <10 39 (10%) 1 (7%) 4 (9%) Visceral metastases yes 195 (50%) 5 (33%) 15 (36%) no 193 (50%) 10 (67%) (27 64%) Pelvic relapse yes 114 (30%) 6 (40%) 19 (46%) no 271 (70%) 9 (60%) 22 (54%) Bone metastases yes 84 (22%) 1 (7%) 6 (14%) no 301 (78%) 14 (93%) 36 (86%) Lymph nodes yes 241 (63%) 9 (60%) 23 (55%) no 144 (37%) 6 (40%) 19 (45%) Lung metastases yes 81 (21%) 2 (13%) 7 (17%) no 299 (79%) 13 (87%) 35 (83%) Liver metastases yes 79 (21%) 2 (13%) 6 (14%) no 301 (79%) 13 (87%) 36 (86%) TCC: Transitional Cell Carcinoma; SCC: Squamous Cell Carcinoma. Patients and disease characteristics are shown in Table I. Among 451 consecutive patients treated, 446 were included in the analysis, 389 (86%) had pure TCC, 15 (3.5%) had pure SCC and 42 (9.5%) patients had mixed histology. Five patients (1%) had pure adenocarcinoma and were not included in the analysis due to their small number. Baseline characteristics were generally similar among the three groups. The bladder was the primary site of disease for 329 (85%) of patients with pure TCCs, 11 (73%) of patients with pure SCCs and 33 (79%) of patients with mixed histology tumors (p=0.333). Disease in the pelvis (including bladder relapse or relapse in the tumor bed after cystectomy) was 3866

3 Kastritis et al: Platinum-based Chemotherapy Table II. Response rates and survival. TCCs SCCs Mixed tumors p-value Response CR, PR 171 (44%) 4 (27%) 14 (34%) No response 218 (56%) 11 (73%) 27 (66%) Time to progression (months) 7.7 (95% CI 7.2 (95% CI 7.2 (95% CI ) 2-12) 3-12) Median survival (months) 11.3 (95% CI 13.6 (95% CI 10.4 (95% CI ) ) 4-17) Table III. Univariate and multivariate analysis of factors associated with survival in patients with mixed histology tumors. Univariate p-value Multivariate p-value ECOG performance <0.001 ECOG performance Presence of visceral Presence of visceral metastases metastases Hemoglobin<10mg% <0.001 Hemoglobin<10 mg% Carboplatin vs. Cisplatinbased chemotherapy CR: complete response; PR: partial response. more frequently reported in mixed tumors than in pure TCCs (46% vs. 30%, p=0.034), although cystectomy had been performed in 48% of patients with pure TCCs and 49% of mixed tumors (p=0.990). Among patients with pure TCCs, 75 (19%) were stage IV at their initial diagnosis, 3 patients (20 %) with pure SCCs and 11 (26%) patients with mixed tumors were diagnosed initially with stage IV disease (p=0.724). About 50% of patients with pure TCC, 67% with SCCs and 64% with mixed tumors had visceral metastases at the time of diagnosis of metastatic disease, but this difference was not significant (p=0.1). Other sites of metastases (lymph nodes, lung, bone, liver) also did not differ significantly among the three histologic groups. Three hundred and forty patients (76%) received cisplatin based chemotherapy and 106 (24%) patients received carboplatin based chemotherapy. There were no significant differences in the treatment regimens between the three groups (p=0.4). There were 441 patients evaluable for response (Table II). Objective response rates [complete response (CR) and partial response (PR)] after first line chemotherapy were 44% (171 patients) for patients with TCC, 27% (4 patients) for patients with SCC and 34% (14 patients) for mixed histology patients (p=0.210). Eighty-one patients (21%) with pure TCC had stable disease after chemotherapy, 5 (33%) with pure SCC and 8 (20%) with mixed tumors (p=0.2). Median follow-up for living patients was for 14 months (range 1 to 107). Median overall survival (OS) for all patients was 11 months (95% CI 9.8 to 12.3 months). Median OS for patients with TCC histology was 11.3 months, for SCC patients 13.6 months and 10.4 months for patients with mixed histology (p=0.720) (Figure 1). Median OS for the 5 patients with adenocarcinoma was 10.1 months (95% CI 5 to 15 months). Time-to-disease progression was similar for the three histologic groups: 7.6 months for patients with pure TCC histology, 7.2 months for SCCs and 7.2 months for mixed histology patients (p=0.824). In order to define their role in the survival of patients with mixed histology the effect of established prognostic factors (16, 19), such as the presence of visceral metastases, ECOG performance, presence of anemia (Hemoglobin value <10 g/dl at presentation), cisplatin or carboplatin-based chemotherapy were analyzed. Due to the small number of SCCs patients, such analysis was not performed in this group. Univariate analysis showed that the presence of visceral metastases (p=0.002), anemia (p<0.001) and ECOG performance >1 (p<0.001) were associated with inferior outcome, while the type of chemotherapy (carboplatin- vs. cisplatin-based) was not significant (p=0.182). In multivariate analysis only visceral metastases (p=0.013) and poor performance (p=0.004) were significantly associated with poor outcome in patients with mixed tumors (Table III). Discussion About 90-95% of patients with urothelial cancer in Europe and USA have TCC histology. Nevertheless, about 10-20% (3, 6-9) of patients with TCC histology have non TCC elements and a small number have pure SCCs. In our patients, SCCs comprised 3.5% of patients with metastatic urothelial cancer, 1% had pure adenocarcinoma and 9.5% of patients had mixed tumors, characterized by the presence of squamous differentiation along with TCC. These results are in accordance with those from other Western countries (2, 3, 9, 12). In the Middle East, SCCs are one of the most common malignancies due to infection with S. haematobium, however the pathogenesis of SCCs in other parts of the world is quite different. Chronic irritation of the bladder is considered a risk factor for SCC development, but no relation to HPV infection has been found (27). SCCs originating from pure TCCs, harbour the same karyotype alterations, however when cdna microarrays were used to characterize the global gene expression patterns in bladder tumors, bladder cancer cell lines and normal bladder, it was shown that gene expression 3867

4 profiles were different between the SCCs and TCCs (28). The urothelium can undergo different pathways of differentiation under differing conditions, such as different methylation in the promoter regions of genes like caveolin-1 and p-53 (29), leading to TCCs, mixed TCCs and SCCs and pure SCCs (12, 30). In some reports SCCs arise more frequently in the upper urinary tract (12, 31), but this has not been confirmed in our study. We also concluded that the characteristics of patients with different histologies do not differ, in terms of age, gender, and ECOG performance. The presence of squamous differentiation within TCCs of the urinary bladder may be an adverse prognostic factor, associated with higher local failure rates in patients undergoing radical cystectomy for invasive disease (6, 8, 13) and these tumors seemed to respond less favorably than pure TCCs after local radiotherapy (14). This may explain the difference in regard to the presence of disease in the pelvis among patients with pure TCCs compared with those with mixed histology tumors in our study. The fact that cystectomy rates were similar among all histological groups further strengthens this speculation. Nevertheless, there are no data about the role of non-tcc elements, especially squamous cell elements, in the context of metastatic disease. Patients with mixed tumors are traditionally included in phase II or III chemotherapy trials, because it is generally accepted that this group is not different from pure TCCs. However, older studies suggested that mixed histology tumors may show poorer response to chemotherapy, while later analyses failed to show any significance of mixed histology in the prognosis of patients with metastatic disease (7, 9, 10, 26). These reports were based on substantially fewer patients than our present study. According to our analysis patients with mixed histology have the same outcome after platinum based chemotherapy as patients with pure TCCs. Our findings further support the existing practice of including mixed histologies along with pure TCCs in clinical studies. Pure SCCs responded less favorably to platinum based chemotherapy compared to pure TCCs (27% vs. 44%), but due to the small number of patients with SCCs, a statistically significant difference could not be established. Median OS did not differ significantly among groups of different histology. The small number of SCCs included in this analysis should be taken into consideration in the interpretation of these results. Nevertheless the differences in survival were minimal and, therefore, a probability that a clinically significant difference in prognosis truly exists is unlikely. The presence of visceral metastases, poor performance, and anemia are known adverse prognostic factors with respect to response to chemotherapy and survival in patients with advanced or metastatic TCCs (10, 16, 17, 32). Univariate and multivariate analysis of these factors confirmed their prognostic significance in the population of our patients with mixed carcinomas although anemia did not retain its prognostic significance in a multivariate analysis. In summary, the current study shows that patients with advanced or metastatic malignancies of the urothelial tract who have histologically mixed tumors, i.e., tumors with squamous differentiation and transitional elements, have the same prognosis with those patients who have pure TCCs. 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Eur J Cancer 42(1): 50-54, Received May 2, 2006 Revised July 10, 2006 Accepted July 13,