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SIU 2019 39th Annual Society of International Urology Congress

SIU 2019: Debate - Adjuvant Therapy for Muscle Invasive Bladder Cancer

Athens, Greece (Urotoday.com) Dr. Soloway ended this session of bladder cancer controversies and gave a discussion supporting the role of adjuvant chemotherapy in muscle-invasive bladder cancer (MIBC).

According to all urology guidelines, neoadjuvant chemotherapy (NAC) should be given to MIBC patients with clinical T2-T4 disease followed by radical cystectomy. 
Cisplatin is the most active agent for urothelial cancer. However, in order to give it, the patient needs to have adequate renal and cardiac function, which unfortunately results in 40% of patients not being ineligible.

The use of non-cisplatin-based NAC is controversial and not supported by prospective randomized controlled trials. One of the suggested medications to replace cisplatin was carboplatin but it confers significantly inferior results.1 

The problem with adjuvant chemotherapy is that due to the high rate of complications following radical cystectomy, approximately 50-60% of patients would not be able to receive it.2 Furthermore, there is an approximately 25-30% readmission rate after radical cystectomy, also precluding the receipt of adjuvant chemotherapy.2

The use of NAC by physicians in the hospitals and patients had not been accepted immediately after its endorsement and inclusion by all guidelines. In 1998-2003 the use of NAC was reported to be only 1.2%, in 2007- 13%, and in 2010 – 21%.3 

The dilemmas that are associated with the use of NAC include:

  1. The majority of patients do not receive it ultimately due to complications, impaired renal function, etc.
  2. The benefit of NAC is not that high
  3. It can delay surgery significantly
  4. Many patients perceive it to be toxic
  5. A substantial percentage of patients refuse chemotherapy
  6. At radical cystectomy the rate of pT0 is reported to be 10-15% even without NAC

Therefore, the therapeutic option of adjuvant chemotherapy becomes more tempting. Reports have shown that with adjuvant chemotherapy the overall survival for pT3-4 pN0-N+ is 50% and for pT2 it is 70%. The 5-year overall survival is 20% if residual MIBC is present or if there were positive lymph nodes after NAC.

In a large retrospective analysis including 3,947 patients who underwent radical cystectomy without NAC, 24% received adjuvant chemotherapy between 1979 and 2008. Adjuvant chemotherapy was shown to confer an overall survival benefit, due to its significant effect in the highest risk group, with a HR of 0.75 for high-risk patients harboring pT3-4 disease and/or positive nodes.4 

Additionally, a meta-analysis including data from 6 prospective randomized controlled trials with 491 patients treated with cisplatin-based adjuvant chemotherapy was discussed by Dr. Soloway. The results of this meta-analysis showed a 25% reduction in all cause death, with a hazard ratio of 0.75, and a 3-years overall survival benefit of 9%.5 Another meta-analysis including 945 patients from 9 trials showed a trend for overall survival benefit with a HR of 0.77, p=0.044, and disease-free survival HR of 0.66. Adjuvant chemotherapy conferred a 23% risk reduction.6 

In summary, despite this data, there is a limited number of patients in all meta-analyses which makes it difficult to recommend adjuvant chemotherapy for all MIBC patients following radical cystectomy.7 

Concluding his talk, Dr. Soloway stated that NAC is still the optimal therapeutic choice for patients with clinical disease stage T3-T4 or positive nodes, assuming that the patient can receive it. It is possible to consider adjuvant chemotherapy for patients with pT2-T4. Immunotherapy should be considered if Pt3-T4 or positive nodes exist, after the patient had received cisplatin-based NAC and radical cystectomy. 

Presented by: Mark Soloway, MD, Chief of Urologic Oncology at Memorial Healthcare System, Aventura, Florida

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  

References:
1. Funt SA, Rosenberg JE. Systemic, perioperative management of muscle-invasive bladder cancer and future horizons. Nature reviews Clinical oncology 2017; 14(4): 221-34.
2. Donat SM, Shabsigh A, Savage C, et al. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol 2009; 55(1): 177-85.
3. Reardon ZD, Patel SG, Zaid HB, et al. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol 2015; 67(1): 165-70.
4. Svatek RS, Shariat SF, Lasky RE, et al. The Effectiveness of Off-Protocol Adjuvant Chemotherapy for Patients with Urothelial Carcinoma of the Urinary Bladder. Clinical Cancer Research 2010; 16(17): 4461-7.
5. Feifer AH, Taylor JM, Tarin TV, Herr HW. Maximizing cure for muscle-invasive bladder cancer: integration of surgery and chemotherapy. European urology 2011; 59(6): 978-84.
6. Leow JJ, Martin-Doyle W, Fay AP, Choueiri TK, Chang SL, Bellmunt J. A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol 2014; 66(3): 529-41.
7. Vashistha V, Quinn DI, Dorff TB, Daneshmand S. Current and recent clinical trials for perioperative systemic therapy for muscle invasive bladder cancer: a systematic review. BMC Cancer 2014; 14(1): 966.