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Society of Urologic Oncology (SUO) 21st Annual Meeting

SUO 2020: Debate: Neoadjuvant vs. Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma - Adjuvant

(UroToday.com) In this debate, Dr. Tracy Rose presented why adjuvant chemotherapy should be used in upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy. She began with a description of the POUT trial.1 This is a landmark trial, which was a phase 3, open-label prospective randomized-controlled trial conducted at 71 hospitals in the UK. 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. The primary endpoint was disease-free survival. The arms of this trial were mostly well balanced. 64% of the patients were still able to receive cisplatin following surgery.


The results showed a 55% reduction in relative risk of disease recurrence or death. The 3-year disease-free survival was 71% vs. 46% for adjuvant chemotherapy compared to no adjuvant chemotherapy (Figure 2). Moreover, the hazard ratio favored chemotherapy in all subgroups (Figure 3).

Figure 2 – Disease and metastasis-free survival in the POUT trial:

SUO_adjuvant_chemotherapy.png

Figure 3 – Subgroup analysis of disease-free survival:

SUO_disease-free_survival.png

There are also retrospective data supporting the beneficial role of adjuvant chemotherapy (when compared to observation). In an NCDB analysis, including more than 3000 patients who underwent radical nephroureterectomy with pT3-4 or N+, 762 patients received adjuvant chemotherapy. The median overall survival was 47 vs. 36 months (favoring adjuvant chemotherapy), with a five-year survival rate of 44% vs. 36% (HR 0.77, 95% CI 0.68-0.88), as shown in figure 4.

Figure 4 – Retrospective data showing overall survival advantage to patients treated with adjuvant chemotherapy:

SUO_NCDB_analysis.png

According to Dr. Rose, a minority of patients with high-grade UTUC who should get cisplatin could lose the opportunity after radical nephroureterectomy. This assumption is based on data showing that in a large retrospective study, out of 533 patients with high-grade UTUC who underwent radical nephroureterectomy, only 66 patients (12.4%) had missed the opportunity to receive cisplatinum.2 In another similarly designed study, only 9% of all patients lost the opportunity to receive cisplatin chemotherapy following surgery.3

Another important point is that the positive predictive value of high-grade pathology for >=pT2 on ureteroscopic biopsy was only 60%. Therefore, with a standard approach of neoadjuvant chemotherapy to all patients, we will be potentially overtreating 40% of patients with nephrotoxic chemotherapy prior to surgery.4

Lastly, Dr. Rose reiterated the important distinction that UTUC is not bladder cancer, as UTUC is enriched with the luminal-papillary subtype and has a T-cell depleted immune microenvirtonment.5 Luminal-Papillary tumors derive less benefit from neoadjuvant (NAC) than the basal tumors. Importantly, pathological complete response rates are lower in UTUC than in bladder cancer (Table 1).

Table 1 – pathological complete response rates:

SUO_UTUC_patients.png

There are additional relevant trials that are underway. One of them is the URANUS trial, which will assess NAC vs. adjuvant chemotherapy in UTUC patients. This will be a feasibility phase 2, randomized study (NCT02969083) (Figure 5).

Figure 5 – URANUS trial design:

SUO_URANUS_trial.png

Summarizing the data, adjuvant chemotherapy has better evidence and is more feasible. It avoids chemotherapy use in patients that don’t need treatment. It also enables treatment to patients who need treatment. Lastly, it results in a shorter time to definitive therapy, and it is the better option for chemotherapy unresponsive disease, which may be more likely in UTUC.

Presented by: Tracy L Rose, MD, MPH, Assistant Professor of Medicine, Division of Oncology, University of North Carolina, Chapel Hill, NC

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

References:

  1. 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.
  2. Xylinas E, Rink M, Margulis V, et al. Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy. BJU Int 2013; 112(4): 453-61.
  3. 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.
  4. Subiela JD, Territo A, Mercadé A, et al. Diagnostic accuracy of ureteroscopic biopsy in predicting stage and grade at final pathology in upper tract urothelial carcinoma: Systematic review and meta-analysis. European Journal of Surgical Oncology 2020; 46(11): 1989-97.
  5. Robinson BD, Vlachostergios PJ, Bhinder B, et al. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nature communications 2019; 10(1): 2977.
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SUO 2020: Debate: Neoadjuvant vs. Adjuvant Chemotherapy for UTUC - Neoadjuvant