SUO 2020: Debate: Neoadjuvant vs. Adjuvant Chemotherapy for UTUC

(UroToday.com) Neoadjuvant chemotherapy (NAC) is the standard of care for muscle-invasive bladder cancer. However, upper tract urothelial carcinoma (UTUC) is not the same as bladder cancer, with a higher rate of invasive disease. The survival of high grade and high stage disease UTUC remains poor (Figure 1), and downstaging in urothelial cancer is highly predictive of improved survival¹.

Figure 1 – Disease-specific survival rate in UTUC in relation to (A) pT stage, (B) grade¹:

Platinum-based chemotherapy is most effective, but cisplatin requires adequate glomerular filtration rate (GFR). Nephroureterectomy reduces GFR by 24%, and depending on the GFR cutoff used to administer cisplatin-based chemotherapy², the following can be seen:

For GFR of 60 ml/min – 49% are eligible preoperatively while only 19% are eligible postoperatively
For GFR of 45 ml/min – 80% are eligible preoperatively while only 55% are eligible postoperatively

NAC has also been shown to result in pathologic downstaging³ (Figure 2). And improve overall and disease-specific survival⁴ (Figure 3). A recent meta-analysis has also shown a clear benefit of NAC in both overall survival and cancer-specific survival⁵ (Figure 4).

Figure 2 – Pathologic tumor classification³:

Figure 3 - Disease-specific survival in relation to neoadjuvant chemotherapy in UTUC:

Figure 4 – Forest Plot of Studies Evaluating The Efficacy of Neoadjuvant Chemotherapy For UTUC on (a) Overall Survival (OS), (b) Cancer-Specific Survival (CSS)⁵

Lastly, the landmark POUT trial⁶, a phase 3, an open-label prospective randomized-controlled trial conducted at 71 hospitals in the UK, was discussed. This trial showed that Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. However, 40% of the enrolled patients were cisplatin-ineligible, and 21% of the patients had to cross over to being treated with carboplatin. These subsets of patients did not demonstrate a statistically significant benefit when treated with adjuvant chemotherapy (Figure 5).

Figure 5: Subgroup analysis of disease-free survival in the POUT trial:

In conclusion, outcomes for invasive UTUC are poor. There is enough evidence to suggest that perioperative cisplatin-based chemotherapy for UTUC works to improve survival. It is important to remember that there is a high rate of chronic kidney disease following radical nephroureterectomy. Therefore, NAC should be the logical choice to improve survival in UTUC patients. There is a need to conduct randomized trials to assess NAC for UTUC. The POUT-2 trial will target FGFR-3, assessing the role of immune-oncology (the PROOF trial⁷).

Presented by: Jen-Jane Liu, MD, Assistant Professor of Urology, School of Medicine, Oregon Health & Science University, Portland, Oregon

Written by: Hanan Goldberg, MD, MSc, Assistant Professor, Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, @GoldbergHanan during the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC

References:

1. Lehmann J, Suttmann H, Kovac I, et al. Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival. European urology 2007; 51(5): 1281-8.
2. Kaag MG, O'Malley RL, O'Malley P, et al. Changes in renal function following nephroureterectomy may affect the use of perioperative chemotherapy. European urology 2010; 58(4): 581-7.
3. Matin SF, Margulis V, Kamat A, et al. Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer 2010; 116(13): 3127-34.
4. Porten S, Siefker-Radtke AO, Xiao L, et al. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma. Cancer 2014; 120(12): 1794-9.
5. Leow JJ, Chong YL, Chang SL, Valderrama BP, Powles T, Bellmunt J. Neoadjuvant and Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A 2020 Systematic Review and Meta-analysis, and Future Perspectives on Systemic Therapy. European urology.
6. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. The Lancet 2020; 395(10232): 1268-77.
7. Pal SK, Daneshmand S, Matin SF, et al. PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring FGFR3 alterations. Journal of Clinical Oncology 2020; 38(6_suppl): TPS600-TPS.

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