Despite this treatment, up to 30% of patients experience recurrence, underscoring the need for better management strategies and a deeper understanding of the disease.1 Histologic variants of urothelial carcinoma (UC), present in about 10% of UTUC cases, include squamous, glandular, micropapillary, and sarcomatoid features. These variants are linked to more aggressive disease and poorer outcomes, and they can respond differently to chemotherapy.
The phase 3 POUT trial established adjuvant platinum-based chemotherapy as a standard post-RNU treatment for locally advanced UTUC, demonstrating improved disease-free survival (DFS).2 However, no prospective trials have specifically addressed perioperative chemotherapy for UC with histologic variants, making the effect of adjuvant chemotherapy on UTUC with histologic variants (VUTUC) uncertain. The rarity of these variants complicates the feasibility of conducting prospective randomized controlled trials (RCTs). Therefore, using advanced statistical methods to adjust for confounding variables and mimic RCT conditions is a more feasible approach.
In our recent study, we evaluated the effectiveness of adjuvant chemotherapy in patients with nonmetastatic localized and locally advanced VUTUC following RNU.3 Among the 368 UTUC patients analyzed, 131 had VUTUC including squamous and/or glandular(n = 67), micropapillary (n = 43), and sarcomatoid (n = 22) variants. We observed that VUTUC patients who received adjuvant chemotherapy were generally younger and had a higher post-operative glomerular filtration rate (GFR).
To address the challenge of conducting RCTs due to the rarity of VUTUC, we employed stabilized inverse probability of treatment weighting (sIPTW).4 sIPTW reduces selection bias by balancing covariate distribution between treatment groups, stabilizing weights to maintain sample size and reduce variance, thus decreasing type I errors more effectively than unstabilized IPTW. Compared to propensity score matching (PSM), sIPTW retains the entire sample, allowing for less information loss. We used sIPTW to adjust for confounders such as age, pathologic T and N stages, postoperative renal function, and history of neoadjuvant chemotherapy (NAC). Additionally, multivariable Cox regression adjusted for tumor size, concomitant CIS, margin positivity, lymphovascular invasion, and perineural invasion. Subgroup analyses examined the impact of adjuvant chemotherapy on specific histologic subtypes (squamous/glandular, micropapillary, and sarcomatoid).
Our study demonstrated that adjuvant chemotherapy significantly improves time to recurrence (TTR) in VUTUC patients (HR 0.42, 95% CI 0.21-0.83, p = 0.01), but does not significantly affect overall survival (OS) (HR 0.68, 95% CI 0.35-1.30, p = 0.25). Subgroup analysis revealed that squamous/glandular (p = 0.02) and micropapillary variants (p = 0.03) benefited from TTR from adjuvant chemotherapy, whereas sarcomatoid variants did not (p = 0.91).
These findings suggest that, while adjuvant chemotherapy is effective for TTR in VUTUC, similar to it is effective in pure UTUC, its benefit for OS remains unclear and warrants further investigation. A tailored approach based on histologic subtypes could refine clinical practice. Until focused RCTs are conducted on each variant and chemotherapy response in VUTUC, adjuvant chemotherapy remains the best available option for most VUTUC cases, except for sarcomatoid variants. For sarcomatoid VUTUC, alternative therapeutic strategies, such as immune checkpoint inhibitors or combination therapy, should be investigated.
Written by, Jungyo Suh, MD, Urologist, Data Scientist, and Assistant Professor, Department of Urology, Asian Medical Center, Ulsan University College of Medicine, Seoul, South Korea
References:
- Rouprêt M, Seisen T, Birtle AJ, et al: European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. European Urology 2023; 84: 49–64.
- 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: 1268–1277.
- Park I, Suh J, Lim B, et al: Effectiveness of Adjuvant Chemotherapy in Variant Histology Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy: Stabilized Inverse Probability Treatment Weighting Analysis of Single Center Experience. Clinical Genitourinary Cancer 2024: 102069.
- Xu S, Ross C, Raebel MA, et al: Use of Stabilized Inverse Propensity Scores as Weights to Directly Estimate Relative Risk and Its Confidence Intervals. Value in Health 2010; 13: 273–277.
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