ANTICANCER RESEARCH 26: 3865-3870 (2006)
The Outcome of Patients with Advanced Pure Squamous or Mixed Squamous and Transitional Urothelial Carcinomas Following Platinum-based Chemotherapy EFSTATHIOS KASTRITIS1, MELETIOS-ATHANASIOS DIMOPOULOS1, NIKOLAOS ANTONIOU2, CHARALAMBOS DELIVELIOTIS2, MICHAEL CHRISOFOS2, ANDREAS SKOLARIKOS2, DIMITRA GIKA1 and ARISTOTLE BAMIAS1 1Department
2Second
of Clinical Therapeutics, Alexandra Hospital, Athens; 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 status, 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, 124 62, Athens, Greece. Tel: +30-210-3381546, Fax +30210-3381511, e-mail:
[email protected] Key Words: Non-urothelial, platinum, metastatic, urothelial, squamous, mixed tumors, carboplatin, bladder cancer.
0250-7005/2006 $2.00+.40
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, 610). 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
3865
ANTICANCER RESEARCH 26: 3865-3870 (2006) 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.
3866
Table I. Patient characteristics. SCC
Mixed tumors
p-value
342 (88%) 47 (12%)
12 (80%) 3 (20%)
35 (83%) 7 (17%)
0.487
286 (75%) 97 (25%)
12 (80%) 3 (20%)
30 (73%) 12 (27%)
0.872
255 (72%) 97 (28%)
6 (55%) 5 (45%)
29 (76%) 9 (24%)
0.120
329 (85%) 60 (15%)
11 (73%) 4 (27%)
33 (79%) 9 (21%)
0.333
186 (48%) 198 (52%)
7 (48%) 8 (52)
20 (49%) 21 (51%)
0.990
342 (90%) 39 (10%)
14 (93%) 1 (7%)
38 (91%) 4 (9%)
0.897
195 (50%) 193 (50%)
5 (33%) 10 (67%)
15 (36%) (27 64%)
0.100
114 (30%) 271 (70%)
6 (40%) 9 (60%)
19 (46%) 22 (54%)
0.034
84 (22%) 301 (78%)
1 (7%) 14 (93%)
6 (14%) 36 (86%)
0.207
241 (63%) 144 (37%)
9 (60%) 6 (40%)
23 (55%) 19 (45%)
0.605
81 (21%) 299 (79%)
2 (13%) 13 (87%)
7 (17%) 35 (83%)
0.606
79 (21%) 301 (79%)
2 (13%) 13 (87%)
6 (14%) 36 (86%)
0.491
TCC
Gender male female ECOG performance status 0.1 >1 Creatinine clearance ≥50 ml/min
