POUT Trial May Lead to New Standard of Care for UTUC

Adjuvant platinum-based chemotherapy within 90 days of nephroureterectomy reduces disease recurrence among patients with locally advanced upper tract urothelial carcinoma (UTUC), according to long-awaited results from the POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial (NCT01993979).

In the phase 3 trial, 132 patients (pT2–T4, pN0–N3, M0 or pTany, N1–3, M0) were assigned to chemotherapy and 129 patients to surveillance (standard care) after surgery. Adjuvant chemotherapy significantly improved disease-free survival by 55% at a median follow-up of 30.3 months, with a 3-year disease-free estimate of 71% compared with 46% for surveillance.

In addition, adjuvant chemotherapy improved metastasis-free survival by 52% compared with surveillance, with a 3-year metastasis-free rate of 71% vs 53%, respectively, Alison Birtle, MD, of the Royal Preston Hospital in the United Kingdom, and colleagues reported in The Lancet.

With respect to safety, 44% of the chemotherapy group vs 4% of the surveillance group experienced acute grade 3 or worse treatment-emergent adverse events.

“Our data, therefore, suggest that adjuvant platinum-based chemotherapy should be recommended as a new standard of care after nephroureterectomy for all patients with locally advanced UTUC in whom there are no definitive contraindications to chemotherapy,” Dr Birtle’s team wrote. “This regimen should be routinely considered for all patients in this population, and future studies should focus on combinations with novel agents in the adjuvant setting, which might further improve the prognosis for locally advanced UTUC.”

The adjuvant chemotherapy regimen involved four 21-day cycles of intravenous cisplatin (70 mg/m²) or carboplatin (when glomerular filtration rate [GFR] was 30 to 50 mL/min/1.73 m²) on day 1 and intravenous gemcitabine (1000 mg/m²) on days 1 and 8.

“Although the POUT trial has shown superiority of adjuvant chemotherapy over surgery alone, it is not clear that patients previously planned for neoadjuvant chemotherapy should now defer treatment until surgery is complete,” Dr Birtle’s team wrote. “However, until further robust evidence becomes available, we propose that adjuvant treatment should be considered the preferred setting for future trials of perioperative chemotherapy in UTUC.”

“Uro-oncologists now need to decide whether disease-free survival benefit represents an appropriate bar for practice change,” Simon J Crabb, MBBS, PhD, of the University Hospital Southampton commented in an accompanying editorial. “Validation of disease-free survival as a surrogate for overall survival benefit is not yet formally established. Overall survival was a secondary endpoint but is not yet mature and will be the key question for planned future updates from POUT.”

Tolerability and toxicity of the platinum-based chemotherapy regimens were acceptable and as expected, Dr Crabb noted. No treatment-related deaths were reported. Quality-of-life data suggest that negative effects from chemotherapy resolved by 6 months. POUT investigators safely administered cisplatin at GFRs down to 50 mL/min/1.73 m², which possibly supports re-evaluation of the cutoff of 60 mL/min/1.73 m² used in most urothelial carcinoma trials, Dr Crabb wrote.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

References

Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomized controlled trial [published online March 5, 2020]. Lancet. doi: 10.1016/S0140-6736(20)30415-3

Crabb SJ. Treatment of upper urinary tract urothelial carcinoma [published online March 5, 2020]. Lancet. doi: 10.1016/S0140-6736(20)30519-5

This article originally appeared on Renal and Urology News