Adjuvant chemotherapy in bladder cancer patients with histological variants: time to change the approach?

Bladder cancer (BCa) is a common malignancy, with about 81,190 estimated new cases and 17,240 estimated deaths in the United States in 2018 (1). Neoadjuvant cisplatin-based combination chemotherapy (NAC) followed by radical cystectomy (RC) with bilateral pelvic lymph node dissection is currently considered the standard of care in muscle-invasive bladder cancer (MIBC) patients (2). However, 5 years survival after surgery is approximately 50% (3). In this regard, adjuvant cisplatin based-chemotherapy (AC) improves survival outcomes and should be administered in medically fit, NAC naïve patients with pT3/4 and/or positive nodes diseases at RC (2).

A recent meta-analysis of eleven randomized clinical trials has shown significantly improved progression free survival [hazard ratio (HR) 0.64; 95% CI, 0.49–0.85] and overall survival (OS) (HR 0.79; 95% CI, 0.68–0.92) in patients treated with AC compared to those treated with RC alone (4). These trials, however, focused on pure urothelial carcinoma (UC) only. On the other hand, BCa encompasses a wide spectrum of malignancies, including thirteen UC varieties and several non-urothelial types (5,6). Each of these histopathological entities has shown to be associated with different survival outcomes, probably due to the underlying presence of specific mutational landscapes (5,7-9). Given the heterogeneous behavior of these conditions, a “one size fits all” approach in the therapeutic setting might not be ideal (9). Moreover, considering that from one tenth to one third of BCa patients are diagnosed with a non-pure UC, a tailored treatment might have a big impact in the overall management of these conditions (7,8,10,11).

Different studies have shown that there is an unmet need in the definition of the optimal approach after RC in the subset of patients with MIBC and a non-pure urothelial type disease (9-11). Berg et al. assessed the impact of AC vs initial observation after RC in AC candidates affected by pure UC and histological variants (12). The aim of the study was to assess OS based on the time of RC to the date of death in the two treatment groups. UC variants analyzed in the study included micropapillary and sarcomatoid differentiation, squamous cell carcinoma (SCC), adenocarcinoma, and neuroendocrine tumors, which are some of the most common subtypes of BCa (9,10,13). Using the National Cancer Data Base, 15,397 patients with nonmetastatic localized BCa and positive lymph nodes (T2N+) or locally advanced stage (≥ T3N0/N+) were included in the analysis, since it is believed that these patients benefit the most from AC. Patients who underwent NAC were excluded. Of note, patients who received AC after 90 days from surgery were included into the initial observation cohort, considering them under a salvage chemotherapy regimen. Overall, 3,053 patients of 13,210 (23%) with a pure UC and 430 of 2,187 (24%) with a non-pure UC subtype underwent RC and subsequent AC. Patients treated with AC were younger (64 vs. 70 years, P<0.001) and with fewer comorbidities (Charlson Comorbidity Index 0=74% vs. 67%, P<0.001) compared to those who underwent observation. At the multivariable analysis, the use of AC was associated to a benefit in OS in patients with pure UC (HR 0.87; 95% CI, 0.82–0.91; P<0.001) or micropapillary differentiation (HR 0.87; 95% CI, 0.52–1.14; P=0.04) (4). On the other hand, all the others achieved similar OS outcomes in both studied cohorts. In a sensitivity analysis, patients with positive lymph nodes only (T2N+, T3N+, and T4N+) affected by adenocarcinoma, sarcomatoid differentiation, neuroendocrine tumors of the bladder, and UC obtained a significantly better OS benefit in the AC treatment group rather than in the initial observation group.

Taken together, these results underline that non-pure urothelial MIBC is predominantly not sensible to the current therapeutic regimens used in AC and that patient’s performance status does not significantly influence OS. Moreover, although in previous studies lymph-node positivity has not clearly shown to drive a specific aggressive potential per se (14), BCa variants with prevalent node spread might bear diverse biological features and increased susceptibility to chemotherapeutic regimens. This hypothesis is supported by the results of a recent analysis by Kaushik et al. (11) regarding the role of AC in a group of 18 patients with small cell carcinoma of the bladder. The authors of this study found a statistically significant difference in terms of lymph node positivity in patients treated with AC (61% vs. 28%; P=0.01), who furthermore presented a superior 5 year-OS and cancer specific survival (CSS) compared to the AC naïve group.

This investigation from Berg et al. confirms several previous findings. Mitra et al. (15), in a recent multi-institutional study, analyzed 41 patients with micropapillary urothelial carcinoma (MUC) treated with AC, who obtained improved recurrence free survival and OS (P<0.01) from different AC regimens. The lack of a benefit in survival outcomes from AC in the SCC, the sarcomatoid differentiation and the adenocarcinoma is aligned with previous discoveries and underlines the limited effectiveness of chemotherapy regimens in these aggressive entities (16-18). Conversely, the absence of a significant improvement from AC in OS in the neuroendocrine variant is in contrast with previous results, which have highlighted the chemosensitive nature of this histology, both in the neoadjuvant and the adjuvant setting (17).

The study from Berg et al. is not devoid of limitations. First, the examined cohort includes patients treated between 2004 and 2015. Over this time frame, criteria, terminology and clinical understanding of UC variant diagnosis have been evolving (19). These aspects might have influenced the ability and the sensibility of pathologists in the histology description, resulting in either an over- or an underreporting. Second, the lack of a centralized pathologic review has been associated with a reduced identification of variant histologies. This aspect is probably related to the under-reporting of variant histology in community practice, due to frequent interobserver variability and to the rarity of these entities, whose identification results consequently challenging for not adequately trained pathologists (19-24). Third, the retrospective nature of this study addresses once again the chance of a misclassification bias and of other inherent drawbacks associated with this study approach. Fourth, the incomplete reporting and the heterogeneity of the AC regimens might mislead the interpretation of results. A sub stratification per type of chemotherapy regimen might help to identify better performing drug combinations. Fifth, this study lacks insight about molecular features, which are increasingly demonstrating a potential role in the diagnostic workup, prognosis definition and treatment selection (18,25). Due to these limitations, it is not possible to infer generalizable conclusions from this investigation.

Nonetheless, we acknowledge that this paper gives an overview on the effects of systemic therapy after RC on a group of poorly considered entities, using a relatively consistent number of patients. Moreover, it raises awareness on the need to further clarify the effects of AC in BCa variants and to better investigate other combinations of treatment after RC in order to reduce morbidity and optimize oncologic outcomes.

Acknowledgments

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30. [Crossref] [PubMed]
2. Leow JJ, Bedke J, Chamie K, et al. SIU-ICUD consultation on bladder cancer: treatment of muscle-invasive bladder cancer. World J Urol 2019;37:61-83. [Crossref] [PubMed]
3. Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006;24:296-304. [Crossref] [PubMed]
4. Kim HS, Jeong CW, Kwak C, et al. Adjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and network meta-analysis of randomized clinical trials. Oncotarget 2017;8:81204-14. [PubMed]
5. Moschini M, D'Andrea D, Korn S, et al. Characteristics and clinical significance of histological variants of bladder cancer. Nat Rev Urol 2017;14:651-68. [Crossref] [PubMed]
6. Humphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol 2016;70:106-19. [Crossref] [PubMed]
7. Xylinas E, Rink M, Robinson BD, et al. Impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy. Eur J Cancer 2013;49:1889-97. [Crossref] [PubMed]
8. Moschini M, Shariat SF, Lucianò R, et al. Pure but Not Mixed Histologic Variants Are Associated With Poor Survival at Radical Cystectomy in Bladder Cancer Patients. Clin Genitourin Cancer 2017;15:e603-7. [Crossref] [PubMed]
9. Moschini M, Dell'Oglio P, Luciano' R, et al. Incidence and effect of variant histology on oncological outcomes in patients with bladder cancer treated with radical cystectomy. Urol Oncol 2017;35:335-41. [Crossref] [PubMed]
10. Klaile Y, Schlack K, Boegemann M, et al. Variant histology in bladder cancer: how it should change the management in non-muscle invasive and muscle invasive disease? Transl Androl Urol 2016;5:692-701. [Crossref] [PubMed]
11. Kaushik D, Frank I, Boorjian SA, et al. Long-term results of radical cystectomy and role of adjuvant chemotherapy for small cell carcinoma of the bladder. Int J Urol 2015;22:549-54. [Crossref] [PubMed]
12. Berg S, D'Andrea D, Vetterlein MW, et al. Impact of adjuvant chemotherapy in patients with adverse features and variant histology at radical cystectomy for muscle-invasive carcinoma of the bladder: does histologic subtype matter? Cancer 2019;125:1449-58. [Crossref] [PubMed]
13. Stroman L, Nair R, Russell B, et al. The impact of non-urothelial variant histology on oncological outcomes following radical cystectomy. BJU Int 2019. [Epub ahead of print]. [Crossref] [PubMed]
14. Marks P, Gild P, Soave A, et al. The impact of variant histological differentiation on extranodal extension and survival in node positive bladder cancer treated with radical cystectomy. Surg Oncol 2019;28:208-13. [Crossref] [PubMed]
15. Mitra AP, Fairey AS, Skinner EC, et al. Implications of micropapillary urothelial carcinoma variant on prognosis following radical cystectomy: a multi-institutional investigation. Urol Oncol 2019;37:48-56. [Crossref] [PubMed]
16. Martin JW, Carballido EM, Ahmed A, et al. Squamous cell carcinoma of the urinary bladder: systematic review of clinical characteristics and therapeutic approaches. Arab J Urol 2016;14:183-91. [Crossref] [PubMed]
17. Alanee S, Alvarado-Cabrero I, Murugan P, et al. Update of the International Consultation on Urological Diseases on bladder cancer 2018: non-urothelial cancers of the urinary bladder. World J Urol 2019;37:107-14. [Crossref] [PubMed]
18. Matulay JT, Narayan VM, Kamat AM. Clinical and Genomic Considerations for Variant Histology in Bladder Cancer. Curr Oncol Rep 2019;21:23. [Crossref] [PubMed]
19. Lopez-Beltran A, Henriques V, Montironi R, et al. Variants and new entities of bladder cancer. Histopathology 2019;74:77-96. [Crossref] [PubMed]
20. Warrick JI. Clinical Significance of Histologic Variants of Bladder Cancer. J Natl Compr Canc Netw 2017;15:1268-74. [Crossref] [PubMed]
21. Linder BJ, Boorjian SA, Cheville JC, et al. The impact of histological reclassification during pathology re-review--evidence of a Will Rogers effect in bladder cancer? J Urol 2013;190:1692-6. [Crossref] [PubMed]
22. Lopez-Beltran A, Cheng L, Raspollini MR, et al. Variants of Bladder Cancer: The Pathologist's Point of View. Eur Urol 2017;16:210-22. [Crossref]
23. Shah RB, Montgomery JS, Montie JE, et al. Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital. Urol Oncol 2013;31:1650-5. [Crossref] [PubMed]
24. Gordetsky J, Collingwood R, Lai WS, et al. Second Opinion Expert Pathology Review in Bladder Cancer: Implications for Patient Care. Int J Surg Pathol 2018;26:12-7. [Crossref] [PubMed]
25. Al-Ahmadie H, Iyer G. Updates on the Genetics and Molecular Subtypes of Urothelial Carcinoma and Select Variants. Surg Pathol Clin 2018;11:713-23. [Crossref] [PubMed]