Athens, Greece (UroToday.com) Dr. Roland Seiler presented after Dr. Andrea Necchi, supporting the role of chemotherapy in the neoadjuvant setting of treating muscle invasive bladder cancer (MIBC), as opposed to immunotherapy.
Radical cystectomy is the gold standard for the treatment of MIBC. Ways of improving the prognosis of patients undergoing radical cystectomy include perfecting the technique of radical cystectomy,1 improving pelvic lymph node dissection (PLND),2 and using novel surgical tools.3
Dr. Seiler suggested another approach, whereby improving the prognosis should be done by administrating additional systemic treatments, rather than modifying the surgical technique. This has been done with the introduction of cisplatin-based chemotherapy.
Cisplatin was first approved by the FDA in 1978. 13 years later the first randomized controlled trial (RCT) on cisplatin was performed,4 and since then 12 RCTs were performed. 25 years later the first meta-analysis was done,5 and since then 3 meta-analyses have been performed including 3500 patients. 41 years later, neoadjuvant chemotherapy (NAC) had been defined as first line treatment.
When comparing all these data to that of neoadjuvant immunotherapy, there have been 0 RCTs, 0 meta-analyses, and so far only 150 patients have received it in the neoadjuvant bladder cancer setting. According to Dr. Seiler, this is reason enough why NAC should be considered standard of care.
NAC has repeatedly shown a 5-10% survival benefit at 5 years,6 and approximately 35-40% of patients treated with NAC appear to benefit with complete downstaging7 (Figure 1). In the future, we might be able increase these percentages by optimizing patient selection using biomarkers and discovery of novel agents. This has been previously shown with the ERCC2 mutation. If this mutation is present, it confers an enhanced response to cisplatin chemotherapy.8
Another example is the finding that defects in DNA repair genes predict response to NAC9 (Figure 2). From these findings bladder sparing approaches can be formed based on DDR panel mutations. If these mutations are present, one could consider sparing the bladder due to the excellent response resulting from NAC. There is currently a randomized trial analyzing this exact question (Figure 3).
Additionally, the bladder cancer molecular subtypes have also shown variance in their response to chemotherapy, with the basal subtype responding very well to chemotherapy, showing improved survival, compared to other molecular subtypes10 (Figure 4).
Lastly, the COXEN trial will attempt to assess a correlation between molecular analysis of patients (including gene expression, sequencing, microRNA, and SNP) and two different NAC regimens – dose dense MVAC or gemcitabine and cisplatin (Figure 5). The initial results were presented at the ASCO meeting in Chicago, in 2019 (Table 1).
Figure 1 – Survival benefit and downstaging of neoadjuvant chemotherapy
Figure 2 – Mutation of genes involved in DNA damage repair confer enhanced response to neoadjuvant chemotherapy:
Figure 3 – Randomized trial assessing bladder sparing approach based on DDR panel:
Figure 4 – Impact on survival and cisplatin-based treatment in the various molecular subtypes:
Figure 5 – COXEN trial design:
Table 1 – COXEN trial initial results:
Concluding his talk, Dr. Seiler emphasized that systemic therapy is the way to go to improve outcomes in bladder cancer. We need to remember that one strategy will not fit all patients and surgical downstaging limits non-comparative trials. The currently formulating treatment paradigm is based on tumor biology and is summarized elegantly in Figure 6.
Figure 6 - Treatment strategy according to tumor biology:
Presented by: Roland Seiler, PhD, Professor, University of Bern, Bern Switzerland
Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA, Twitter: @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece
- Kessler TM, Burkhard FC, Perimenis P, et al. Attempted nerve sparing surgery and age have a significant effect on urinary continence and erectile function after radical cystoprostatectomy and ileal orthotopic bladder substitution. The Journal of urology2004; 172(4 Pt 1): 1323-7.
- Gschwend JE, Heck MM, Lehmann J, et al. Extended Versus Limited Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Survival Results from a Prospective, Randomized Trial. European Urology2019; 75(4): 604-11.
- Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. Lancet (London, England)2018; 391(10139): 2525-36.
- Wallace DM, Raghavan D, Kelly KA, et al. Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. British journal of urology1991; 67(6): 608-15.
- Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet (London, England)2003; 361(9373): 1927-34.
- Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant Chemotherapy plus Cystectomy Compared with Cystectomy Alone for Locally Advanced Bladder Cancer. New England Journal of Medicine2003; 349(9): 859-66.
- Rosenblatt R, Sherif A, Rintala E, et al. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur Urol2012; 61(6): 1229-38.
- Van Allen EM, Mouw KW, Kim P, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer discovery2014; 4(10): 1140-53.
- 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 Urol2015; 68(6): 959-67.
- 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 Urol2017; 72(4): 544-54.