POUT supports adjuvant chemotherapy as ‘standard of care’ for upper tract UC
medwireNews: Individuals with upper urinary tract urothelial carcinoma (UTUC) derive a significant disease-free survival (DFS) benefit from adjuvant platinum-based doublet chemotherapy versus active surveillance, suggest phase 3 trial results.
“Chemotherapy was also associated with improved metastasis-free survival, with acceptable acute toxic effects consistent with existing data,” say the POUT researchers.
They therefore believe that “adjuvant platinum-based chemotherapy should be adopted as a new standard of care for patients with locally advanced UTUC for whom systemic chemotherapy is not contraindicated.”
The team adds: “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.”
Lead investigator Dr Alison Birtle discusses the rationale and practice-changing implications of the POUT trial.
The UK-based trial included 260 patients with UTUC that was staged as pT2–T4 pN0–N3 M0 or pTany N1–N3 M0 disease after nephroureterectomy. Participants were randomly allocated to receive either four 21-cycles of adjuvant chemotherapy – comprising cisplatin 70 mg/m2 or carboplatin AUC 4.5/5.0 given on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8 – within 90 days of surgery or to undergo active surveillance.
At a median follow-up of 30.3 months, adjuvant chemotherapy was associated with a significant 55% reduction in the risk for recurrence or death relative to surveillance, with 3-year DFS rates of 71% and 46%, respectively. The corresponding median DFS durations were unreached and 29.8 months.
The risk for metastasis or death was also a significant 52% lower with adjuvant chemotherapy than surveillance, with 3-year metastasis-free survival rates of 71% and 53%, respectively. Overall survival (OS) data were not mature at the time of analysis.
Alison Birtle, from Royal Preston Hospital in the UK, and co-investigators report in The Lancet that trial enrollment “closed early on the recommendation of the independent data monitoring committee, having met the early stopping criterion for efficacy.”
The efficacy benefit afforded by adjuvant chemotherapy came at the cost of a significantly higher rate of grade 3–5 acute treatment-emergent adverse events, at 44% versus a rate of just 4% with surveillance, with neutropenia, platelet count decrease, nausea, febrile neutropenia, and vomiting the most common events.
“For each chemotherapy regimen, adverse events accorded with those frequently reported in routine clinical practice,” note the researchers.
The author of a related commentary – Simon Crabb, from the University of Southampton in the UK – describes POUT as “an important achievement in a rare cancer.”
And although he understands that certain methodologic choices were made due to the rarity of the tumor type, such as the use of DFS instead of OS as the primary endpoint and the “pragmatic and inclusive” eligibility and surveillance criteria, Crabb stresses that “some of these choices will affect the trial’s interpretation.”
Noting that DFS has not been formally validated as a surrogate for OS in this setting and the lack of OS data in the current report, the commentator concludes: “Uro-oncologists now need to decide whether disease-free survival benefit represents an appropriate bar for practice change.”
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