COUNTERPOINT: Is Cystectomy Needed for Small-Cell Bladder Cancer?

Marisa A. Kollmeier, MD

Radiation therapy with concurrent chemotherapy is an effective treatment strategy for small-cell bladder cancer.

Small-cell bladder cancer (SCBC) is a rare malignancy that accounts for fewer than 1% of all bladder cancer subtypes.[1] The clinical presentation and risk factors for SCBC are identical to the more common bladder histologies, although prognostically these tumors behave more aggressively. Histologically, these tumors are composed of sheets of small, round, blue hyperchromatic cells with little cytoplasm, and they stain positively for neuroendocrine markers (ie, chromogranin, synaptophysin, and neuron-specific enolase).[2] Importantly, 38% to 70% of cases will also exhibit a coexisting non–small-cell carcinoma component, including urothelial carcinoma, adenocarcinoma, or squamous cell carcinoma, supporting the hypothesis that these tumors may arise from a single cancer stem cell that then differentiates into diverse cell types.[3] The rarity of this entity precludes a standard management approach, and it is unclear whether these tumors should be managed in a similar fashion as other bladder histologies or whether treatment should be analogous to smallcell carcinomas of other primary sites. In either case, definitive radiation therapy with concurrent chemotherapy is an appropriate treatment option for localized SCBC.

The standard management of urothelial carcinoma of the bladder is either radical cystectomy or multimodality bladder preservation therapy. Bladder preservation therapy using a multimodality approach, inclusive of maximally complete transurethral resection (TUR), radiation therapy, and concurrent chemotherapy, has demonstrated outcomes comparable with surgical series in many retrospective and prospective studies.[4-9] With appropriate patient selection and an integrated multimodality approach to treatment, bladder preservation rates of 75% to 80% and overall survival rates of 50% to 60% have been reported. Furthermore, the functionality of retained bladders is well-preserved, since long-term urinary morbidity following chemoradiation is low.[5,6] In a series of 112 patients treated with TUR followed by concurrent chemoradiation using cisplatin/5-fluorouracil, 79% of surviving patients with an intact bladder were delighted or pleased with their urinary function.[10] Close surveillance and prompt cystectomy for muscle-invasive recurrence is an essential component that requires patient motivation and multidisciplinary participation for success of this therapy.

Whether similar success with multimodality bladder preservation is achievable with variant histology bladder tumors such as small-cell carcinoma is difficult to know, since published series are small and retrospective. What is known is that small-cell carcinomas appear to behave more aggressively than typical bladder histologies, with higher rates of distant metastases and lower survival rates.[11,12] According to a recent Surveillance, Epidemiology, and End Results analysis, 50% of SCBC cases are diagnosed with locally advanced/metastatic disease.[1] Even with localized disease, the median overall survival rates are poor (< 20 months),[1] suggesting that integration of systemic therapy is crucial to optimal outcomes for SCBC. Additionally, the potential quality-of-life benefit of a bladder-sparing approach is particularly appealing in this setting, since many patients will have distant recurrence and do not necessarily benefit from a more aggressive surgical approach. Alarmingly, curative multimodality treatment for these cancers is currently underutilized and should be considered whenever feasible.[1]

Since the histology and aggressive clinical behavior of SCBC is similar to small-cell carcinoma of the lung, it is reasonable to make management decisions by extrapolating from the lung cancer experience. Small-cell carcinoma of the lung accounts for nearly 15% (~240,000 new cases per year) of all primary pulmonary malignancies and therefore has a larger published experience.[13] Standard management of limited-stage small-cell lung cancer consists of early onset of systemic platinum-based chemotherapy and early integration of local radiation, with surgery having little role. In fact, the superiority of radiotherapy over surgery was established over 40 years ago in a randomized trial comparing surgery (median survival, 6.5 months) and radiation therapy (median survival, 9.9 months).[14] Most chemotherapy strategies integrate etoposide and cisplatin for a minimum of 4 cycles, with improved survival outcomes if thoracic radiation therapy is given early or concurrently with chemotherapy.[15] Additionally, due to the propensity for tumor repopulation, treatment intensification using hyperfractionated accelerated chemoradiation has demonstrated improved survival compared with conventionally fractionated radiation therapy.[16] Continuing advances in both radiation techniques and tailoring chemotherapy remain the focus of thoracic oncologists treating this disease.

Published data reporting the outcomes of SCBC with chemoradiation are predominantly small, single-institution retrospective series. Chemotherapy regimens in these series are not often standardized. Few studies have been published that use concurrent chemoradiation approaches; these limitations make review of the literature challenging. In a cohort of 19 patients (T1-T4, N0-2) treated with neoadjuvant and/or concurrent chemotherapy with radiation therapy reported by Mattes et al, 2-year overall survival was 78% and local control was achieved in 75% of patients.[17] The majority of published chemoradiation series use sequential chemotherapy followed by radiation therapy. In a series of 27 patients with limited-stage disease (TX-T4, N0-1) reported by Meijer et al using a variety of sequential chemotherapy regimens followed by radiation therapy (median dose, 60 Gy), the complete response rate was 70%, with a 5-year overall survival rate of 26% (compared with 0% for nonresponders). Importantly, the majority of recurrences in this series (12 of 20) were distant.[18] Bryant et al recently reported a case series of 11 patients with T3-4N0-2 SCBC treated with TUR and either sequential or concurrent chemoradiation using various chemotherapy regimens.[19] Although only 55% received concurrent chemoradiation, 8 of 11 patients had a complete response and the local control rate was 78%. Unfortunately, distant metastases were problematic, with a distant metastases–free survival of only 27%.

Although comparison of multimodality bladder preservation strategies with surgical series for SCBC is difficult, it appears that neoadjuvant chemotherapy and response to chemotherapy are important prognostic factors for both approaches. In a prospective study of neoadjuvant platinum-based chemotherapy (doxorubicin/ifosfamide alternating with cisplatin/etoposide), 78% of patients (14 of 18) were pathologically downstaged, with a median survival of 58 months.[11] Lynch et al reported a significant improvement in disease-specific survival with the addition of neoadjuvant chemotherapy (median, 4 cycles) prior to cystectomy compared with cystectomy alone (70% vs 20%; P < .001).[20] It is difficult to compare these results with the published chemoradiation series, since the majority of these patients were ≤ T2 and node-negative, but it is clear that multimodality treatment is crucial.

The optimal choice of local therapy for SCBC is currently unknown. Based on the limited, retrospective experience in both surgical series and chemoradiation series, both neoadjuvant chemotherapy followed by radical cystectomy and neoadjuvant and/or concurrent chemotherapy with radiation therapy are reasonable treatment options. Because of the aggressive metastatic potential of these tumors, optimization of systemic therapy is essential. Future trials using novel systemic agents in addition to local therapy (either surgery or radiation) are crucial for this rare entity.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Koay EJ, Teh BS, Paulino AC, Butler EB. A Surveillance, Epidemiology, and End Results analysis of small cell carcinoma of the bladder: epidemiology, prognostic variables, and treatment trends. Cancer. 2011;117:5325-33.

2. Pant-Purohit M, Lopez-Beltran A, Montironi R, et al. Small cell carcinoma of the urinary bladder. Histol Histopathol. 2010;25:217-21.

3. Abrahams NA, Moran C, Reyes AO, et al. Small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases. Histopathology. 2005;46:57-63.

4. Rödel C, Grabenbauer GG, Kühn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol. 2002;20:3061-71.

5. Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology. 2002;60:62-7; discussion 67-8.

6. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014;32:3801-9.

7. Hafeez S, Horwich A, Omar O, et al. Selective organ preservation with neoadjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder. Br J Cancer. 2015;112:1626-35.

8. James ND, Hussain SA, Hall E, et al. Radiation with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366:1477-88.

9. Oh KS, Soto DE, Smith DC, et al. Combined-modality therapy with gemcitabine and radiation therapy as a bladder preservation strategy: long-term results of a phase I trial. Int J Radiat Oncol Biol Phys. 2009;74:511-7.

10. Weiss C, Engehausen DG, Krause FS, et al. Radiochemotherapy with cisplatin and 5-fluorouracil after transurethral surgery in patients with bladder cancer. Int J Radiat Oncol Biol Phys. 2007;68:1072-80.

11. Siefker-Radtke AO, Kamat AM, Grossman HB, et al. Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin in small-cell urothelial cancer. J Clin Oncol. 2009;27:2592-7.

12. Sved P, Gomez P, Manoharan M, et al. Small cell carcinoma of the bladder. BJU Int. 2004;94:12-7.

13. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220-41.

14. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of the bronchus. Ten-year follow-up. Lancet. 1973;2:
63-5.

15. Pijls-Johannesma M, De Ruysscher D, Vanstreenkiste J, et al. Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials. Cancer Treat Rev. 2007;33:461-73.

16. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340:265-71.

17. Mattes MD, Kan CC, Dalbagni G, et al. External beam radiation therapy for small cell carcinoma of the urinary bladder. Pract Radiat Oncol. 2015;5:e17-e22.

18. Meijer RP, Meinhardt W, van der Poel HG, et al. Local control rate and prognosis after sequential chemoradiation for small cell carcinoma of the bladder. Int J Urol. 2013;20:778-84.

19. Bryant CM, Dang LH, Stechmiller BK, et al. Treatment of small cell carcinoma of the bladder with chemotherapy and radiation after transurethral resection of a bladder tumor. Am J Clin Oncol. 2014 Feb 10. [Epub ahead of print]

20. Lynch SP, Shen Y, Kamat A, et al. Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center. Eur Urol. 2013;64:307-13.