Original Paper

Urologia

Received: May 6, 2014 Accepted after revision: August 11, 2014 Published online: January 30, 2015

Urol Int DOI: 10.1159/000366522

Internationalis

Long-Term Outcomes of Organ Preservation in Patients with Small Cell Carcinoma of the Bladder Jairam R. Eswara a Niall M. Heney a Chin-Lee Wu b W. Scott McDougal a  

 

 

 

Departments of a Urology and b Pathology, Massachusetts General Hospital, Boston, Mass., USA  

Key Words Small cell carcinoma · Bladder · Cystectomy · Chemotherapy · Radiation

Abstract Background: Small cell carcinoma of the bladder is an uncommon but clinically aggressive disease. There is no standard surgical or medical management for the disease. Methods: Between 1995 and 2009, 28 patients underwent transurethral resection (TUR) and/or cystectomy, chemotherapy, and/or radiation for small cell carcinoma of the bladder at our institution. Results: The median follow-up for survivors was 34 months. Patients presented most often with muscleinvasive disease (T2–4 – 89%), and 21% had lymph node/ distant metastases. Tobacco use and chemical exposure were noted in 64 and 4% of patients, respectively. Patients with T1–2N0M0 had a median survival of 22 months compared to 8 months for those with more advanced disease (p  = 0.03). Patients with T3–4 or nodal/metastatic disease who were given chemotherapy had an improved survival compared to those with T3–4 or nodal/metastatic disease who did not undergo chemotherapy (13 vs. 4 months, p = 0.005). The median time to recurrence of the entire cohort was 8 months, overall and cancer-specific survival was 14 months, and 5-year survival was 11%. Conclusions: Small cell carcinoma of the bladder is an aggressive disease with poor outcomes. Patients with T1–2N0M0 disease survived

© 2015 S. Karger AG, Basel 0042–1138/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/uin

longer than those with advanced disease. Patients with T3–4 or nodal/metastatic disease had improved survival with chemotherapy. © 2015 S. Karger AG, Basel

Background

Small cell carcinoma of the bladder is an uncommon but clinically aggressive entity. It comprises less than 1%  of all bladder cancers, making prospective studies challenging [1, 2]. Similar to small cell carcinoma of other organs such as the lung and GI tract, it has a poor prognosis. There is no standard surgical or medical management for the disease, although many centers perform radical cystectomy in patients who have no evidence of metastasis [3, 4]. The chemotherapy regimen used is similar to small cell carcinoma of the lung, consisting primarily of platinum-based chemotherapy and etoposide [5]. As a result, most centers advocate some combination of partial or radical cystectomy with neoadjuvant or adjuvant chemotherapy with or without radiation [6–8]. Previous studies have reported a median survival of 2 years or less [7, 9, 10]. Given the poor prognosis of this disease, a multimodal treatment is advisable, and an organ-preserving approach may be indicated in select patients. The purpose of this study was to report the clinical Jairam R. Eswara, MD Department of Urology, Massachusetts General Hospital 55 Fruit Street Boston, MA 02114 (USA) E-Mail jeswara @ partners.org

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Methods This was an institutional review board-approved study of patients who underwent transurethral resection (TUR) and/or cystectomy, chemotherapy, and/or radiation for small cell carcinoma of the bladder between 1995 and 2009 by 6 urologists at a single institution. Data were retrospectively gathered from the electronic medical records. All slides were re-reviewed by a urologic pathologist (CLW). Clinical assessment of nodal status and metastases was performed by abdominal pelvic computed tomography (CT) in all patients, lymph node biopsy in 1 patient, and oophorectomy in 1 patient. The diagnosis of small cell carcinoma in the pathological specimen was based on immunohistochemical staining. Cytokeratin staining was considered positive if it was observed for any of the following antigens: AE1, CAM 5.2, CK7, or CK20 [11–13]. A standard open partial or radical cystectomy with or without a regional lymph node dissection with ileal conduit was performed in 13 patients for both non-muscle-invasive and muscle-invasive disease based on surgeon preference. For those whose only surgery was transurethral resection, it was done to completely remove all visible tumor. Chemotherapy was administered to 13 patients, and the regimen varied but most commonly involved 4 cycles of cisplatin 50–70 mg/m2 or carboplatin 400 mg/m2 and etoposide 75 mg/m2. Other agents included gemcitabine, ara-C, adriamycin, cyclophosphamide, taxol, methotrexate, vinblastine, melphalan, and estramustine. A dose of 42–64.8 Gy was given to those who underwent radiation therapy. The Student’s t-test and Wilcoxon rank-sum test were used to compare continuous normally and non-normally distributed variables, respectively. The log-rank test was used to compare KaplanMeier curves. All statistical analyses calculated were two sided with a significance of 0.05. JMPs version 8.0 (SAS Institute, Cary, N.C., USA) was used for all calculations.

Results

In this series, 28 patients were treated for small cell carcinoma of the bladder with a median follow-up of 34 months for survivors. Patients presented most often with muscle-invasive disease: cT1 – 3/28 (11%), cT2 – 21/28 (75%), cT3 – 3/28 (11%), cT4 – 1/28 (4%) (table 1). Nodal or distant metastatic disease was present in 6 out of 28 patients (21%). The median overall and cancer-specific survival among all patients was 14 months, and 5-year overall survival was 11% (3/28). The median overall survival for patients with T1 disease was 94 months; for T2– 3N0M0, it was 13 months; for T2–3N1–2M0–1, it was 10 months; and for T4N3M1, it was 4 months. Lymphovascular invasion was noted in 10/28 patients (36%). Tobac2

Urol Int DOI: 10.1159/000366522

Table 1. Patient characteristics

Overall (n = 28) Median age, years [range] Male, % ASA score 1 2 3 Tumor stage T1N0M0 T2N0M0 T2N1M0 T2N2M0 T3N0M0 T3N1M0 T4N3M1 LVI Tobacco use Chemical exposures Concurrent TCC/CIS Previous TCC/CIS Median overall survival, months [range] Median disease-specific survival, months [range]

70 [19–89] 72 0 16 (57) 12 (43) 3 (11) 17 (61) 3 (11) 1 (4) 2 (7) 1 (4) 1 (4) 10 (36) 18 (64) 1 (4) 17 (61) 5 (18) 14 [2–144] 14 [2–144]

Figures in parentheses are percentages. * ASA = American Society of Anesthesiology.

co use and chemical exposure were noted in 64 and 4% of patients, respectively. The median time to recurrence was 8 months with 11 patients (39%) recurring. Treatment according to stage is shown in table 2. Of the 13 patients who were given chemotherapy in this series, 9 (69%) were given a cisplatin- or carboplatin-based regimen. At the time of presentation, 6 patients (21%) had disease involving the pelvic nodes. Distant metastases were present in 2 of these patients (11%) involving the colon, lung, omentum, ovary, and prostate. The median survival among those with nodal or metastatic disease was 8  months with none surviving longer than 27 months. Disease recurred in 11 patients (39%): The sites of recurrence were the pelvic nodes in 2 patients (7%), paraaortic nodes in 2 (7%), bone (left femur and scapula, right iliac crest) in 2 (7%), and bladder, pelvic sidewall, lung, brain, and adrenal in 1 patient each (4%). Concurrent urothelial carcinoma was found in 4/28 patients (14%) in other biopsies of the bladder. Of these 4 patients, all had been given intravesical BCG for TCC diagnosed before the discovery of small cell carcinoma. There was no difference in survival between those who Eswara/Heney/Wu/McDougal

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characteristics and management of this rare disease and  to identify patients who may benefit from such an approach.

Table 2. Patient treatment characteristics

Patient

T

N

M

Chemotherapy

Cystectomy

Radiation

Tumor composition

Overall survival, months

Disease status

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 4

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 2 0 0 1 3

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1

none etop, carbo none etop, carbo ara-C, dox, cyc none carbo none etop, cis taxol none none none none cis, meth, vinb etop, cis etop, estra none none none none none cis, meth, vinb etop, carbo, taxol none etop, cis cis, gem none

partial radical none none none partial none partial radical partial partial none radical none none partial none none none none none none none radical radical partial none none

none 42 Gy none none none none none none none none none 64.8 Gy none none none none 42 Gy none none none none none 42 Gy none none none none none

pure SCC pure SCC pure SCC pure SCC pure SCC pure SCC pure SCC 10% TCC pure SCC pure SCC focal CIS pure SCC pure SCC pure SCC pure SCC pure SCC pure SCC pure SCC pure SCC pure SCC pure SCC 1% TCC pure SCC pure SCC 5% TCC pure SCC pure SCC pure SCC

33 94 144 71 49 48 44 39 34 25 19 14 12 11 10 10 9 7 6 6 2 6 13 10 4 12 27 4

AWD DOD NED NED DOD DOD DOD NED NED DOC AWD DWD DOC DOC DOD DOD DOD DOC DOD DOD DOD DOD DOD DOD DOD NED DOD DOD

had concurrent urothelial carcinoma and those who did not (p = 0.39). Lymphovascular invasion of small cell carcinoma did not confer a worse prognosis (p = 0.70). There was no difference in ASA score between those who underwent partial/radical cystectomy and those who underwent TUR (p = 0.82), between those who were given chemotherapy and those who were not given chemotherapy (p = 0.73), or between those who underwent radiation and those who did not undergo radiation (p  = 0.14). There was no difference in stage between those given treatment and those who were not given treatment in any of the groups (radical/partial cystectomy p  = 0.48, chemotherapy p  = 0.63, radiation p  = 0.62). However, there was a significant difference in survival among patients who underwent chemotherapy when stratified by stage. Patients with advanced-stage disease (T3–4 or nod-

al/distant metastatic disease) who were administered chemotherapy had a significantly improved survival compared to those who were not given chemotherapy (13 vs. 4 months, p = 0.03). Three of the four patients in the advanced-stage group who were given chemotherapy were administered cisplatin-based regimens, whereas the fourth was given a carboplatin-based regimen. Of the patients who were not given chemotherapy, all were offered treatment but they refused to accept. There was no statistically significant survival advantage for patients who underwent partial/radical cystectomy (p = 0.41) or radiation (p = 0.70) when all stages were considered or when stratified by disease stage. Patients who underwent a complete TUR and were given chemotherapy had no worse survival than those patients who underwent a cystectomy and were given chemotherapy (p = 0.75). There was a dif-

Organ Preservation in Patients with Small Cell Carcinoma of the Bladder

Urol Int DOI: 10.1159/000366522

3

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etop = Etoposide; carbo = carboplatin; dox = doxorubicin; cyc = cyclophophosphamide; cis = cisplatin; meth = methotrexate; vinb = vinblastine; estra = estramustine; gem = gemcitabine; AWD = alive with disease; DOD = died of disease; NED = no evidence of disease; DOC = died of other causes.

80

Stage I–II Stage III–IV

60

p = 0.05

40 20 0

0

12

24

36

48

60

5 1

3 1

Time from diagnosis (months) Risk (n) Stage I–II 19 Stage III–IV 9

13 4

10 2

7 1

Fig. 1. Kaplan-Meier curves comparing survival of patients with stage I–II vs. stage III–IV disease.

ference in survival between patients with T1–2N0M0 and patients with T3–4 or nodal/metastatic disease with a median survival of 22 and 8 months, respectively (p = 0.03) (fig. 1). Five patients survived a minimum of 4 years. Of these patients, 2 were T1N0M0 (8- and 12-year survival), and 3 were T2N0M0 (4-, 4-, and 6-year survival). One of the patients with T1 disease underwent only TUR without chemotherapy or radiation and survived 12 years. Another patient with T1 disease underwent cystectomy with chemotherapy and radiation and survived 8 years. A partial cystectomy without chemotherapy or radiation was performed on a patient with T2 disease with a 4-year survival (the patient eventually died of urosepsis). Two patients with T2 disease underwent complete TUR, were administered chemotherapy (one with carboplatin and etoposide and the other with ara-C, adriamycin, and cyclophosphamide), and survived 6 and 4 years, respectively.

Discussion

This study represents a single-institution study of small cell carcinoma of the bladder. Our analysis revealed that patients with advanced disease (T3–4 or nodal/metastatic disease) had a survival benefit with chemotherapy compared to those with advanced disease who did not receive chemotherapy. Also, patients with lower-stage 4

Urol Int DOI: 10.1159/000366522

disease (T1–2N0M0) had an improved overall survival compared to those with advanced disease (22 vs. 12 months). Since this disease is rare and a standard therapy has not been determined, a number of regimens have been proposed. In the largest single-institution series, SiefkerRadtke demonstrated a survival advantage for preoperative chemotherapy, including cisplatin and etoposide or ifosfamide and doxorubicin (78 vs. 36%) [7]. In one of the few prospective studies regarding small cell carcinoma of the bladder, Bex et al. showed a survival benefit in patients treated with cisplatin and etoposide regardless of stage, although it must be noted that those in the chemotherapy group had a similar survival to our entire cohort (14 vs. 14 months) [2]. Although cisplatin has been the standard at most centers, the chemotherapy regimen at our institution has increasingly substituted carboplatin for cisplatin because of its safety and ease of use. A recent SEER database analysis of small cell carcinoma of the bladder by Koay et al. found increasing incidence of the disease over time, but with a poor overall survival of 11 months [1]. They also found that the disease is increasingly being managed by transurethral resection alone, whereas the rates of partial and radical cystectomy, radiation, and chemotherapy have remained roughly the same over the past two decades. In addition, Homang identified 5 patients in his series of 25 who survived a median of 10 years [6]. All 5 had T2 or T3 disease, and 3 of the 5 were treated by TUR with adjuvant radiation. In addition, Lester identified 7 patients who underwent bladder preservation for small cell carcinoma [8]. Their regimen included platinum-based combination chemotherapy along with consolidation radiation, and they reported a complete response in 5 patients and a partial response in 1 patient. In the series from the Anglian Cancer Network, Mukesh reported on 20 patients who had small cell carcinoma of the bladder. Their analysis revealed a significant survival benefit in patients who were given chemotherapy, 33 vs. 3 months, regardless of clinical stage [10]. Similarly, Choong and others have described a survival advantage in patients who underwent cystectomy, and suggested that radical cystectomy is indicated except when metastases are present, although only one patient in their series underwent a maximal TUR [3, 4]. These studies stand in contrast, however, to both our study and one of the largest single-institution studies by Cheng, which found no survival benefit with cystectomy compared with multi-modal therapy [14]. Another study by Lynch showed an improved overall and disease-specific survival Eswara/Heney/Wu/McDougal

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Color version available online

Overall survival (%)

100

with the use of neoadjuvant chemotherapy (median OS: 159.5 vs. 18.3 months, p < 0.001; 5-year DSS: 79 vs. 20%, p < 0.001) [15]. In our analysis, patients who underwent complete TUR and were administered chemotherapy did not have a worse outcome than those who underwent a partial/ radical cystectomy with chemotherapy, although this must be tempered by the heterogeneity of the treatments used and small numbers of patients. Although cystectomy has been shown to be beneficial in other studies, these data suggest that the poor prognosis of this disease may make radical cystectomy with its inherent complications and impact on quality of life less desirable for patients with advanced disease when a similar survival can be achieved with complete TUR and chemotherapy. There was, nevertheless, a survival benefit among patients with higher-stage disease who were given chemotherapy, regardless of whether they underwent cystectomy or not. Limitations of this study, similar to most single-institution studies, include the small number of patients, the multiplicity of treatment regimens, as well as its retrospective nature. Treatment bias may be a factor in a ret-

rospective study; however, there appeared to be no statistical difference in the ASA score among any of the treatment groups. A larger, prospective randomized study would likely be able to answer these questions, although this is challenging given the rarity of the disease.

Conclusions

Small cell carcinoma of the bladder is an aggressive disease with a poor prognosis. Patients had a median time to recurrence of 8 months and a median overall survival of 14 months. Patients who had a complete TUR with chemotherapy for T1–2N0M0 had a nearly three-fold greater overall and cancer-specific survival compared to patients with T3–4 or nodal/metastatic disease. Patients who had a complete TUR with chemotherapy for T1– 2N0M0 disease did no worse than those who underwent a cystectomy with chemotherapy for T1–2N0M0 disease. Patients with T3–4 or nodal/metastatic disease had a better survival with chemotherapy, irrespective of whether a cystectomy was performed. We, therefore, advocate a multimodal approach, including chemotherapy.

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Organ Preservation in Patients with Small Cell Carcinoma of the Bladder

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