Impact of Multimodal Treatment on Survival in Patients with Metastatic Urothelial Cancer

european urology 52 (2007) 1106–1114

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Bladder Cancer

Impact of Multimodal Treatment on Survival in Patients with Metastatic Urothelial Cancer Takashige Abe a,*, Nobuo Shinohara a, Toru Harabayashi a, Ataru Sazawa a, Satoru Maruyama a, Shin Suzuki b, Katsuya Nonomura a a b

Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Urology, Kohnan Hospital, Sapporo, Japan

Article info

Abstract

Article history: Accepted February 23, 2007 Published online ahead of print on March 6, 2007

Objectives: Systemic combination chemotherapy remains the mainstay of treatment for metastatic urothelial cancer. Although initial response rates are 50–70%, these responses are usually transient. The present study investigated the impact of multimodal treatment including metastasectomy on survival in patients with metastatic urothelial cancer. Methods: Between 1989 and 2005, 48 patients with metastatic urothelial cancer underwent systemic chemotherapy at our institution. The majority received conventional cisplatin-based chemotherapy, whereas some patients underwent novel chemotherapeutic regimens mainly as salvage therapy with or without resection of metastases, aiming to improve the outcome. The relationship between clinical characteristics and survival was analyzed using the Cox proportional hazards model. The characteristics analyzed were sex, age, primary site, prior systemic chemotherapy, histology of primary lesion, white blood cell counts, hemoglobin levels, metastatic sites, total number of chemotherapy courses, and resection of the primary lesion and metastasis. Results: Median survival-time was 17 mo (95% confidence interval, 9–27 mo) for all 48 patients. Using a multivariate model, five or more chemotherapy cycles ( p = 0.0022), absence of liver, bone, and local recurrence ( p = 0.0146), and resection of metastasis ( p = 0.0006) were independent significant predictors of prolonged survival. Median survival time in the 12 patients with metastasectomy was 42 mo, which was significantly longer than that of patients who did not undergo metastasectomy (10 mo). Conclusions: The number of chemotherapy cycles, sites of metastasis, and metastasectomy had an impact on survival. In selected patients, a multimodal approach including metastasectomy may contribute to long-term disease control.

Keywords: Chemotherapy Metastasectomy Prognostic factor Urothelial cancer

# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, Hokkaido University Graduate School of Medicine, North-15, West-7, North Ward Sapporo, 060-8638, Japan. Tel. +81 11 7161161 x 5949; Fax: +81 11 7067853. E-mail address: [email protected] (T. Abe). 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2007.02.052

european urology 52 (2007) 1106–1114

1.

Introduction

Systemic chemotherapy is the mainstay of treatment for metastatic urothelial cancer. Modern cisplatinbased combination chemotherapy regimens have shown overall response rates of approximately 50–70% [1,2]. Of these, methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) is the standard chemotherapy regimen for initially unresectable or metastatic urothelial cancer [3–6]. In Japan, the combination of methotrexate, epirubicin, and cisplatin (MEC) is a relatively frequent choice, based on a prospective randomized trial showing that the response rate and incidence of adverse effects after MEC were almost equal to those after MVAC [7]. Although MVAC and MEC are highly effective initially, long-term survival is achieved in only a small proportion of patients. To improve the outcome, several approaches have been investigated. One approach is to use novel chemotherapeutic agents. Paclitaxel, docetaxel, ifosfamide, and gemcitabine are among the most active newly identified agents for urothelial cancer. A large number of phase 1 and 2 trials using these agents in two- and threedrug combination regimens have been evaluated [8–17] and the combination of gemcitabine/cisplatin (GC) has become a new standard treatment in metastatic urothelial cancer in Europe and North America based on the randomized trial showing similar survival but a more favorable toxicity profile for GC compared to MVAC [8]. Another approach is to perform resection of metastasis to achieve surgical complete response. The group from the M. D. Anderson Cancer Center (Houston, TX, USA) reported a 31-mo median overall survival in patients who were free of disease after metastasectomy [18]. Although several reports have supported the positive role of metastasectomy [19,20], the impact on survival remains controversial. Between 1989 and 2005, 48 patients with metastatic urothelial cancer were treated by systemic chemotherapy at our hospital. Some patients underwent novel chemotherapeutic regimens mainly as salvage therapy with or without metastasectomy, aiming to improve the outcome. In this study, we retrospectively reviewed our experience to clarify the impact of multimodal treatment including metastasectomy on survival in patients with metastatic urothelial cancer. 2.

Patients and methods

Forty-eight patients with metastatic urothelial cancer were treated by systemic chemotherapy at our institution between 1989 and 2005. Fifteen patients already demonstrated metas-

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tases at diagnosis of invasive cancer, whereas metastases developed after resection of the primary site in 33 patients. Thirty-seven patients had distant metastases (visceral metastases or distant lymph node [LN] metastasis) and 11 had locally advanced disease (initially unresectable disease, recurrence of the surgical bed, regional LN recurrence). Cisplatin-based combination chemotherapy was performed as the initial therapy in most of the patients. Furthermore, some patients underwent novel chemotherapeutic agents such as paclitaxel or gemcitabine mainly as salvage therapy, aiming to improve the outcome. Finally, 20 patients underwent at least two different regimens. In 12 patients, resection of metastasis, so-called ‘‘metastasectomy,’’ was performed to render the patient disease-free during the treatment course. We generally considered the metastasectomy in the situation that the patients had metastasis in a sole organ with a small number of metastases, good performance status (PS), and good response to chemotherapy although we did not have strict prospective criteria. In the situations contrast to the abovementioned ones (eg, more than four lung metastases, several organ metastases), we rather considered second-line chemotherapy. Patients received a median of four cycles (range, 1–17) of systemic chemotherapy. Survival was measured from the time of initiation of chemotherapy until death or last followup. Thirteen clinical features were examined by univariate analysis for their association with survival. The variables considered were sex (male vs. female), age (66 yr vs. >66 yr), primary site (bladder alone vs. others), prior systemic chemotherapy (yes vs. no), histology of primary lesion (pure urothelial cancer vs. others), white blood cell (WBC) count (10,000 cells/ml vs. <10,000 cells/ml), hemoglobin (10 g/dl vs. 10 g/dl), LN metastasis (yes vs. no), lung metastasis (yes vs. no), presence of liver, bone, or local metastasis (yes vs. no), total number of chemotherapy (5 courses vs. <5 courses), resection of primary lesion (yes vs. no), and metastasectomy (yes vs. no). Survival curves were estimated by Kaplan-Meier methods and survival distributions were compared by the log-rank test. The Cox proportional hazards model was applied for multivariate analysis using commercially available software. A p < 0.05 was considered significant.

3.

Results

3.1.

Patient characteristics

Table 1 shows characteristics of the patients. Median patient age at start of chemotherapy was 66 yr (range: 48–74 yr). The primary tumor site was the bladder in 23 patients, upper urinary tract in 16 patients, both in 8 patients, and urethra in one patient. Chemotherapy regimens used in the current series are shown in Table 2. Forty patients received cisplatin-based combination chemotherapy (MEC in 30 and MVAC in 10); novel chemotherapy regimens were applied in about half the patients mainly as salvage therapy. Finally, 20 patients

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european urology 52 (2007) 1106–1114

Table 1 – Patient – characteristics No. Total no. of patients

48

Sex Male Female

40 8

Age, yr

Median 66

Primary site Bladder Upper urinary tract Both Urethra

23 16 8 1

Pathology of primary site Pure urothelial carcinoma Others (mixed or undifferentiated) Baseline laboratory data White blood cell count, cells/ml Hemoglobin, g/dl Platelets, 104cells/ml Lactic dehydrogenase, IU/l Calcium, mg/dl

Range

48–74

43 5

Fig. 1 – Kaplan-Meier overall survival curve for all patients.

Median 6650

4000–17300

Median Median Median Median

8–16.5 11.8–49.2 153–601 7.9–10.2

Prior chemotherapy Yes No

13 35

Resection of primary site Yes No

36 12

Metastatic site Lymph node Lung Liver Bone Local recurrence

32 15 4 9 8

Resection of metastasis Yes No

12 36

12.4 26 309.5 8.7

underwent at least two different regimens. As for surgery, definitive resection of the primary tumor was achieved in 36 patients. Metastasectomy was performed in 12 patients. Fig. 1 represents the

Table 2 – Chemotherapy regimens used in the current series No. of patients MVAC (methotrexate, vinblastine, adriamycin, cisplatin) MEC (methotrexate, etoposide, cisplatin) PIN (paclitaxel, ifosfamide, nedaplatin) Paclitaxel + carboplatin Docetaxel + gemcitabine Gemcitabine + carboplatin Paclitaxel + gemcitabine Nedaplatin monotherapy Paclitaxel monotherapy Administration of at least 2 different regimens

10 30 20 6 4 2 1 1 1 20

Kaplan-Meier estimate of overall survival for all patients. The median survival time for all patients was 17 mo (95% confidence interval [CI], 9–27 mo]. 3.2.

Summary of metastasectomy

The details of clinical courses of patients with metastasectomy are shown in Table 3. Two of the 12 patients underwent metastasectomy initially, 7 patients did after fewer than five courses of systemic chemotherapy, and the remaining 3 after more than four courses of chemotherapy. Lobectomy was most frequently performed (7 patients). Although 10 of the 48 patients had lung metastasis without other sites of metastases, 3 patients did not undergo metastasectomy because of more than four lung metastases, lung metastasis with pleural invasion, and progressive disease in one patient each. Lymphadenectomy was performed in 3 patients and resection of local recurrence in 2. Although we had 9 patients with bone metastasis, 8 patients of them had other metastatic sites too (lymph node, lung, liver). Therefore, theses patients were not good candidates for metastasectomy. As for liver metastasis, we did not have the patients with solely liver metastasis. Pathology demonstrated that viable cancer remained in all 7 patients with lung metastasis, whereas 2 of 3 patients who underwent lymphadenectomy and one of 2 who underwent resection of local recurrence did not have residual disease. Of the 10 patients with residual disease, 6 underwent adjuvant chemotherapy and 4 did not because they rejected further chemotherapy. Five patients underwent repeat metastasectomy. 3.3.

Univariate survival analysis

Thirteen factors were subjected to univariate analysis for prognostic significance (Table 4).

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Table 3 – Clinical courses of the 12 patients with metastasectomy Patient No. 1 2 3 4 5 6 7 8 9 10 11 12

Patient No. 1 2 3 4 5 6 7 8 9 10 11 12

Age/ Gender

Origin

Site of Mets.

No. of Mets.

Induction CTx.

48/M 70/F 70/M 66/M 73/M 70/F 55/F 72/M 69/M 54/M 67/M 55/F

UUT, bladder UUT UUT UUT UUT UUT UUT UUT UUT bladder bladder bladder

lung lung lung cervical LNs lung lung extended abdominal LNs lung cervical LNs lung local recurrence lung, local recurrence

1 1 4 uncountableb 2 3 uncountable more than 5 uncoutable 3 1 3

MVAC  4 none nedaplatin  4 MEC  2 MEC  2 none MEC  2 + PIN  10 MVAC  2 + PIN  6 + GC  1 PIN  6 MEC  3 MEC  3 PIN  3

Metastasectomy/ Pathology

Adjuvant CTx.

Recurrence

Repeat metastasectomy

Further CTx.

lobectomy/viable lobectomy/viable lobectomy/viable lymphadenectomy/nonviable lobectomy/viable lobectomy/viable lymphadenectomy/nonviable lobectomy/viable lymphadenectomy/viable lobectomy/viable pelvic exenteration/viable resection of local recurrence/viable

MVAC2 MVAC2 none none none MEC3 none no DG6 MEC2 none PIN

lung, bone lung lung none lung lung LNs, bone lung, bone LNs, liver lung bone inguinal LNs

none lobectomy lobectomy none none lobectomy  2 none none none lobectomy  2 none lymphadenectomy

MEC  3 none MVAC  3 + MEC  1 none none (Taxol + carboplatin)  3 DG  2 none none none none GC  1

Response PR – NC PR PR – PR CRa PR PR PR PR

Followup (months), outcome 66, CD 83, CD 42, CD 92, Death 27, CD 149, AWC 67, AWC 40, CD 19, CD 24, CD 9, CD 46, NED

Mets. = metastasis; CTx. = chemotherapy; M = male; F = female; UUT = upper urinary tract; LNs = lymph nodes; GC = gemcitabine + carboplatin; DG = docetaxel + gemcitabine; CR = complete response; PR = partial response; NC = no change; CD = cancer death; AWC = alive with cancer; NED = no evidence of disease; other abbreviations as in Table 2. a Lung metastasis was regrowing soon after the chemotherapy and lobectomy were done. b It was difficult to count the mass of metastatic lymph nodes.

The following factors were associated with an adverse prognosis: sex, WBC count, total number of chemotherapy cycles, presence of liver, bone, or local recurrence, and resection of primary lesion or of metastases.

who did not undergo metastasectomy (10 mo, 95%CI, 6–17 mos).

3.4.

In the current study, we have characterized prognostic factors in patients with metastatic urothelial carcinoma treated with systemic chemotherapy. The majority underwent conventional cisplatin-based combination chemotherapy and certain patients received novel chemotherapeutic agents mainly as salvage therapy with or without metastasectomy. The current analysis indicated that absence of liver, bone, and local recurrence, the number of chemotherapy cycles (five or more chemotherapy cycles), and resection of metastasis were independent significant predictors of prolonged survival. The presence of visceral disease has already demonstrated prognostic significance in series of patients treated with the MVAC regimen. Bajorin et al

Multivariate survival analysis

Four factors with univariate significance were entered into the multivariate regression analysis using the Cox proportional hazard model. These factors were selected because of significance on univariate analysis and perceived clinical relevance. Of these, five or more chemotherapy cycles, resection of metastases, and absence of liver, bone, and local recurrence were independently significant predictors of prolonged survival (Table 5). Fig. 2 shows Kaplan-Meier survival curve by resection of metastases. Median survival time in 12 patients with metastasectomy was 42 mo (95%CI, 19–92 mo), which was significantly longer than that of patients

4.

Discussion

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Table 4 – Results of univariate analysis No. of patients

Median survival, mo (95%CI)

Sex Male Female

40 8

13 (9–24) 28 (5–not reached)

0.0266

Age 66 yr >66 yr

27 21

19 (9–28) 12 (5–31)

0.4572

Primary site Bladder only Others

23 25

12 (6–24) 24 (9–40)

0.1005

Prior systemic chemotherapy Yes No

13 35

13 (8–27) 17 (8–31)

0.3274

Histology of primary lesion Pure urothelial carcinoma Others

43 5

17 (9–28) 19 (6–42)

0.6670

White blood cell count 10,000 cells/ml <10,000 cells/ml

5 43

6 (4–12) 20 (10–28)

0.0062

Hemoglobin 10 g/dl <10 g/dl

43 5

19 (10–28) 8 (6–66)

0.3117

Lymph node metastasis Yes No

32 16

13 (7–28) 17 (9–40)

0.6461

Lung metastasis Yes No

15 33

27 (7–42) 13 (8–24)

0.1676

Presence of liver, bone, local metastasis Yes No

18 30

7 (5–12) 28 (19–40)

0.0003

Total number of chemotherapy cycles 5 courses <5 courses

22 26

31 (19–44) 7 (5–10)

0.0004

Resection of primary lesion Yes No

36 12

24 (9–28) 8 (5–17)

0.0199

Resection of metastasis Yes No

12 36

42 (19–92) 10 (6–17)

0.0002

reported that the presence of lung, liver, or bone metastasis was of independent significance [21]. On long-term follow-up of intergroup study patients, Saxman et al reported that only liver and bone metastasis retained prognostic significance [22]. Recently, Bellmunt et al demonstrated that visceral disease (liver, lung, or bone) was an independent adverse prognostic factor in a series of patients treated with paclitaxel, cisplatin, and gemcitabine, indicating the clinical importance of metastatic sites across different regimens [9]. Our findings also verified the prognostic impact of metastatic sites. The current study demonstrated that the number of chemotherapy cycles and resection of metastasis had an impact on prognosis. We suppose these

p

results need to be carefully interpreted because these two characteristics could be strongly influenced by a patient’s PS. The prognostic impact of a low PS has been well documented in previous reports [9,21,22]. We could not analyze the significance of the patient’s PS before treatment in this study because the details of the PS were not always described in medical charts. It is possible that the patients with better PS received more chemotherapies and underwent metastasectomy. There is little information on whether surgical consolidation should be performed in patients with metastatic urothelial carcinoma. In 1982, Cowles et al reported a median survival of 5 yr for six patients treated with thoracotomy for metastatic

european urology 52 (2007) 1106–1114

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Table 5 – Multivariate analysis on Cox proportional hazard model Factor

No. of patients

Hazard ratio (95%CI)

White blood cell count <10,000 cells/ml 10,000 cells/ml

43 5

1 1.488 (0.516–4.289)

0.4621

Total no. of chemotherapy 5 courses <5 courses

22 26

1 2.903 (1.468–5.742)

0.0022

Any liver, bone, local recurrence No Yes

30 18

1 2.603 (1.208–5.608)

0.0146

Resection of metastasis Yes No

12 36

1 4.636 (1.933–11.121)

0.0006

bladder cancer [23]. Subsequently, several investigators have reported on the addition of surgery after chemotherapy to achieve a complete response in patients with metastatic or initially unresectable urothelial carcinoma. Dodd et al reported a 37-mo median survival and a 33% 5-yr survival rate for 30 patients after resection of viable tumor [19], whereas Miller et al reported a 46% 3-yr survival for 14 patients [20]. However, the majority of patients in these two reports were treated with resection of locally advanced, node-positive tumors, whereas distant metastatic disease sites were resected in only a few. Recently, Siefker-Radtke et al reported their experiences of metastasectomy focused on distant disease in 31 patients. The most frequently resected location was the lung in 24 cases (77%), followed by distant LNs in 4 (13%), brain in 2 (7%), and subcutaneous metastasis in one (3%); there was a 31-mo median survival time from diagnosis of metastases [18]. In the current series, 12 patients underwent metastasectomy. Ten patients received systemic chemotherapy before metastasectomy, whereas the other two underwent surgery as initial

Fig. 2 – Kaplan-Meier overall survival curve for patients with metastasectomy (&) and those without metastasectomy (*).

p

treatment of metastasis. Also in the current series, lobectomy was performed most frequently and a maximum of four lung metastases was resected in a single session. Finally, we observed a 42-mo median survival in this group, which was consistent with that of previous reports. We suppose our result further supports the concept that resection of metastasis contributes to prolonged disease control in selected patients. Based on our experience and the previous reports, a limited number of lung metastases would be one of the good indications. As described in our results, it seemed that patients with bone or liver metastasis were not good candidates for metastasectomy because the patients with these metastases usually had other sites of metastases. Appropriate selection of patients for chemotherapy after surgery is essential if this approach is to be considered for general use. Siefker-Radtke et al indicated that their strategy was to consider metastasectomy in patients who responded to chemotherapy and had recurrence at the initial or sole metastatic site, the tumor was considered surgically resectable with clear margins, and a period of disease stability with no evidence of rapid progression (3-mo interval of observation between chemotherapy and metastasectomy) although these criteria were used as a general guideline, not an absolute requirement [18]. In our series, all patients underwent metastasectomy for sole metastatic organ as shown in Table 3. As for the interval between the last systemic chemotherapy and metastasectomy, the interval was <2 mo because we tried to perform metastasectomy immediately following systemic chemotherapy. Dodd et al and Miller et al also incorporated surgery immediately following systemic chemotherapy to achieve a complete response [19,20]. Further prospective studies should be undertaken to better characterize the selection criteria, the timing of metastasectomy, and benefit from this intervention.

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Several novel chemotherapeutic regimens have been recently developed and been shown to be effective in patients with metastatic urothelial cancer. Of these, we used a new combination chemotherapy consisting of paclitaxel, ifosfamide, and nedaplatin (PIN regimen) as salvage therapy after standard cisplatin-based chemotherapy [16]. In our phase 2 trial, complete and partial responses were obtained in 5 patients and 19 patients, respectively, of the 32 patients who had previously received the MVAC or MEC regimen, with an overall response rate of 75% [16]. In the current study, the PIN regimen was administered to a total of 20 patients including 15 of 22 patients who underwent five or more cycles of chemotherapy. Although univariate analysis did not demonstrate a significant difference in overall survival between patients who received the PIN regimen and those who did not (data not shown), the small sample size and retrospective nature of this review prevents us from drawing definitive conclusions regarding the benefits of these new chemotherapeutic agents. In summary, our study showed that the number of chemotherapy cycles, metastatic sites, and metastasectomy had an impact on survival. Although our results need to be carefully interpreted because of lack of analysis of the PS of patients before treatment, heterogeneous patients group due to our limited experience, retrospective nature of our study, and lack of strict prospective criteria to select patients for novel chemotherapy agents or metastasectomy, we consider that a multimodal approach including metastasectomy would contribute to long-term disease control in selected patients.

[2] [3]

[4] [5]

[6]

[7]

[8]

[9]

[10]

5.

Conclusions

The number of chemotherapy cycles, sites of metastasis, and resection of metastases had an impact on survival. In selected patients, a multimodal approach including metastasectomy would contribute to long-term disease control.

Conflict of interest

[11] [12]

[13]

The authors have nothing to disclose. [14]

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and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985;133:403–7. Scher HI. Should single agents be standard therapy for urothelial tract tumors? J Clin Oncol 1989;7:694–7. Roth BJ, Bajorin DF. Advanced bladder cancer: the need to identify new agents in the post-M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) world. J Urol 1995;153:894–900. Sternberg CN. The treatment of advanced bladder cancer. Ann Oncol 1995;6:113–26. Loehrer Sr PJ, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992;10:1066–73. Logothetis CJ, Dexeus FH, Finn L, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 1990;8:1050–5. Kuroda M, Kotake T, Akaza H, Hinotsu S, Kakizoe T. Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group. Jpn J Clin Oncol 1998;28:497–501. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;17:3068–77. Bellmunt J, Albanell J, Paz-Ares L, et al. Pretreatment prognostic factors for survival in patients with advanced urothelial tumors treated in a phase I/II trial with paclitaxel, cisplatin, and gemcitabine. Cancer 2002;95:751–7. Bajorin DF, McCaffrey JA, Dodd PM, et al. Ifosfamide, paclitaxel, and cisplatin for patients with advanced transitional cell carcinoma of the urothelial tract: final report of a phase II trial evaluating two dosing schedules. Cancer 2000;88:1671–8. Galsky MD. The role of taxanes in the management of bladder cancer. Oncologist 2005;10:792–8. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23:4602–8. Bellmunt J, Guillem V, Paz-Ares L, et al. Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. Spanish Oncology Genitourinary Group. J Clin Oncol 2000;18: 3247–55. Sternberg CN, Calabro F, Pizzocaro G, Marini L, Schnetzer S, Sella A. Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer 2001;92:2993–8.

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[15] Hussain M, Vaishampayan U, Du W, Redman B, Smith DC. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol 2001;19:2527–33. [16] Shinohara N, Harabayashi T, Suzuki S, et al. Salvage chemotherapy with paclitaxel, ifosfamide, and nedaplatin in patients with urothelial cancer who had received prior cisplatin-based therapy. Cancer Chemother Pharmacol 2006;58:402–7. [17] Sengelov L, Kamby C, Lund B, Engelholm SA. Docetaxel and cisplatin in metastatic urothelial cancer: a phase II study. J Clin Oncol 1998;16:3392–7. [18] Siefker-Radtke AO, Walsh GL, Pisters LL, et al. Is there a role for surgery in the management of metastatic urothelial cancer? The M. D. Anderson experience. J Urol 2004;171:145–8. [19] Dodd PM, McCaffrey JA, Herr H, et al. Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients

Editorial Comment on: Impact of Multimodal Treatment on Survival in Patients with Metastatic Urothelial Cancer Aristotle Bamias Department of Clinical Therapeutics, University of Athens, Medical School, Athens, Greece [email protected] Metastatic urothelial cancer remains a highly lethal disease despite recent advances in systemic chemotherapy. Patients with lung, bone, or liver metastases have significantly worse prognosis than those with only locally advanced disease or metastases confined to lymph nodes [1]. It is, therefore, reasonable to speculate that the eradication of distant metastases may improve prognosis in these patients. In this issue of European Urology Abe et al [2] present their experience on a combined modality approach in the management of patients with advanced urothelial cancer; in 12 patients with metastatic urothelial cancer (of a total of 48) resection of metastases (lung, lymph nodes, local recurrence) was performed following systemic chemotherapy. As many retrospective analyses, this report suffers from methodologic limitations and biases, which, in conjunction with the limited number of patients precludes a definite conclusion on the role of metastasectomy in this disease. Nevertheless, some points are worth mentioning, especially in view of the limited amount of data on the subject. The median survival of 42 mo in patients who underwent metastasectomy is in concert with previous reports, showing long disease-free survival after chemotherapy and resection of metastases

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with unresectable or metastatic transitional cell carcinoma. J Clin Oncol 1999;17:2546–52. Miller RS, Freiha FS, Reese JH, Ozen H, Torti FM. Cisplatin, methotrexate and vinblastine plus surgical restaging for patients with advanced transitional cell carcinoma of the urothelium. J Urol 1993;150:65–9. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17:3173–81. Saxman SB, Propert KJ, Einhorn LH, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1997;15: 2564–9. Cowles RS, Johnson DE, McMurtrey MJ. Long-term results following thoracotomy for metastatic bladder cancer. Urology 1982;20:390–2.

[3,4]. Although a selection bias is inherent to the selection of patients for surgery (good performance status, limited metastatic disease, no significant comorbidities, good response to chemotherapy), it should be remembered that the predicted median survival of these patients according to Bajorin criteria, would be around 13 mo following methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy [1]. The role of metastasectomy can only be definitively answered by a prospective randomized study. Taking into consideration the worldwide difficulty in the accrual in studies of advanced urothelial cancer, most information will still come for analyses similar to that of Abe et al [2]. At present, metastasectomy should not be considered standard treatment. Careful selection is, therefore, imperative if it is to be offered outside the context of a clinical trial. From the available data, patients with disease restricted to the bladder or lymph nodes or to a single lung metastasis (but not liver or bone) and who experienced a major response to chemotherapy are the best candidates for this approach [4,5]. The favorable outcome of the 12 patients who underwent surgery after chemotherapy in this report of Abe et al [2] can be probably explained by the fulfillment of these criteria, although these were not set prospectively. References [1] Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17:3173–81.

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[2] Abe T, Shinohara N, Harabayashi T, et al. Impact of multimodal treatment on survival in patients with metastatic urothelial cancer. Eur Urol 2007;52:1106– 14. [3] Siefker-Radtke AO, Walsh GL, Pisters LL, et al. Is there a role for surgery in the management of metastatic urothelial cancer? The M.D. Anderson experience. J Urol 2004;171:145–8. [4] Dodd PM, McCaffrey JA, Herr H, et al. Outcome of postchemotherapy surgery after treatment with methotrex-

ate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. J Clin Oncol 1999;17:2546–52. [5] Calabro F, Sternberg CN. State-of-the-art management of metastatic disease at initial presentation or recurrence. World J Urol 2006;24:543–56. DOI: 10.1016/j.eururo.2007.02.053 DOI of original article: 10.1016/j.eururo.2007.02.052