Editorial response to “Clinical complete response to neoadjuvant chemotherapy for muscle-invasive bladder cancer: contemporary outcomes of a multi-institutional cohort study”

The ultimate goal of cancer therapy is to cure the patient and restore a high quality of life. For patients with muscle invasive bladder cancer (MIBC), the ability to preserve the bladder is an important goal since it will avoid the complications of cystectomy and long-term negative implications on urinary and sexual function. It has been recognized that transurethral resection of the bladder (TUR) alone can cure a select group of patients with MIBC who have relatively small tumors (<5 cm), no palpable mass, no hydronephrosis, no enlarged lymph nodes on imaging and complete TUR (1). However, these patients are rare and TUR alone is not recommended according to guidelines unless other options are not safe or patient refuses other therapy (2). In fact, the guidelines note that patients should be informed that up to 47% of patients treated in this manner still require cystectomy and have an increased risk of bladder cancer mortality. There is level 1 evidence that neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) confers improved survival over cystectomy alone (3). In fact, patients in the methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) group had a 38% pT0 rate including 50% of patients who initially had cT2 disease. Naturally, these patients wonder if the cystectomy was necessary. The pertinent question is what would happen to the patient if the bladder was not removed and would it be worse than the 85% 5-year overall survival achieved in patients who underwent cystectomy and were found to be pT0.

The recently published retrospective study by Mazza et al. reviewed 148 patients with MIBC who underwent NAC and had a complete response (pT0) on post-NAC transurethral resection of bladder tumor (TURBT) who elected surveillance (4). At TURBT prior to NAC, most patients had a solitary cT2 tumor and only 29% had concomitant carcinoma in situ (CIS). Gemcitabine and cisplatin were used in 63% of the patients and at least 4 cycles were used in 81%. The 5-year disease-specific, overall, cystectomy-free, and recurrence-free survival rates were 90%, 86%, 76%, and 64% with 55-month median follow-up. Cancer recurred locally in 48% of the patients including 37% with non-MIBC (NMIBC) and 11% with MIBC. Salvage RC was used in 12 patients with MI recurrence and 14 patients with non-invasive recurrence of which 75% and 93% survived, respectively. In the study, there were 15 bladder cancer deaths of which 11 patients recurred in the bladder (4 MIBC and 7 NMIBC). The authors suggest that these 11 patients (7% of population) could have benefitted from an immediate RC. However, this assumes that all patients undergoing cystectomy would survive their operation.

A recent systematic review of the literature reported on outcomes of patients treated with TURBT and systemic chemotherapy as definitive treatment for locally confined MIBC (5). The review included 18 publications (518 patients) and there was also a meta-analysis performed including 10 publications (266 patients). There was a wide range of reported overall survival (20% to 87.5%) and significant variance in median follow-up (4 to 120 months). The meta-analysis found that 5-year survival rate was 72% (95% CI: 64–82%). There was limited reporting on frequency of salvage cystectomy but the mean among studies that did report cystectomy rate found it was approximately 33% (range, 0–65%). There was too much heterogeneity to compare cisplatinum based regimens to those using carboplatinum-based regimens. Also there was variability in the quality of TUR among studies.

There are potential ways to improve results of NAC. A recent multicenter, retrospective study including 319 patients with cT3–4aN0M0 disease compared ypT0N0 between the gemcitabine and cisplatin, and dose dense MVAC regimens (6). The dose dense MVAC arm was more likely to result in ypT0N0 compared to the gemcitabine and cisplatin arm (28% vs. 14.6%, P=0.005). Furthermore, there are studies that have shown that markers including mutations in DNA repair genes ATM, RB1, and FANCC (7), mutations in excision repair cross-complementation group 2 gene (8), and RNA subtyping of bladder cancer (9) may improve prediction of response to platinum-based chemotherapy. With improved selection of patients and increased use of NAC and dose dense MVAC, it is likely that the percent of patients with pT0 disease will increase. As such it is important to have prospective trials to identify which patients may safely avoid cystectomy. While retrospective studies cannot tell us who will not recur, they do shed light on patients at higher risk who should have cystectomy. Patients with residual disease on TUR after NAC, palpable disease on bimanual exam, hydronephrosis and CIS are all at increased risk for recurrence and should likely be excluded from trials. There is also a need to improve imaging since pT0 patients are not by definition also node negative.

At this time, it appears that patients who inquire about keeping their bladder after NAC still need to be encouraged to undergo cystectomy (2). The data suggests that approximately 50% of patient will recur locally and 1/3 will undergo salvage cystectomy. Furthermore, even in highly selected patients who are pT0 after NAC, 7–16% will likely die of their disease (10). Clinical trials are necessary to determine whether select patients who are pT0 after NAC and repeat TUR can safely proceed with monitoring rather than undergo cystectomy. Outcomes for such trials should involve not only overall survival but also quality of life measures.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Peng Zhang (Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2018.07.24). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19:89-93. [Crossref] [PubMed]
2. Chang SS, Bochner BH, Chou R, et al. Treatment of Nonmetastatic Muscle-Invasive Bladder Cancer: American Urological Association/American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Urologic Oncology Clinical Practice Guideline Summary. J Oncol Pract 2017;13:621-5. [Crossref] [PubMed]
3. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859-66. [Crossref] [PubMed]
4. Mazza P, Moran GW, Li G, et al. Conservative management following clinical complete response to neoadjuvant chemotherapy for muscle-invasive bladder cancer: contemporary outcomes of a multi-institutional cohort study. J Urol 2018; [Epub ahead of print]. [Crossref] [PubMed]
5. Moran GW, Li G, Robins DJ, et al. Systematic Review and Meta-Analysis on the Efficacy of Chemotherapy with Transurethral Resection of Bladder Tumors as Definitive Therapy for Muscle Invasive Bladder Cancer. Bladder Cancer 2017;3:245-58. [Crossref] [PubMed]
6. Zargar H, Shah JB, van Rhijn BW, et al. Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy. J Urol 2018;199:1452-8. [Crossref] [PubMed]
7. Plimack ER, Dunbrack RL, Brennan TA, et al. Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. Eur Urol 2015;68:959-67. [Crossref] [PubMed]
8. Liu D, Plimack ER, Hoffman-Censits J, et al. Clinical Validation of Chemotherapy Response Biomarker ERCC2 in Muscle-Invasive Urothelial Bladder Carcinoma. JAMA Oncol 2016;2:1094-6. [Crossref] [PubMed]
9. Seiler R, Ashab HAD, Erho N, et al. Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. Eur Urol 2017;72:544-54. [Crossref] [PubMed]
10. Herr HW. Editorial comment on: Bladder preservation in selected patients with muscle-invasive bladder cancer by complete transurethral resection of the bladder plus systemic chemotherapy: Long-term follow-up of a phase 2 nonrandomized comparative trial with radical cystectomy. Eur Urol 2009;55:920-1. [Crossref] [PubMed]