Adjuvant platinum-gemcitabine chemo combo: A new SOC for UTUC?

The recently published phase III POUT* trial demonstrated that adjuvant gemcitabine-platinum chemotherapy after nephroureterectomy boosts disease free-survival (DFS) in patients with locally advanced upper urinary tract urothelial carcinoma (UTUC).

“[G]iving adjuvant platinum-based chemotherapy within 90 days after nephroureterectomy reduces subsequent rates of disease recurrence [and] should be recommended as a new standard of care (SOC) after nephroureterectomy for all patients with locally advanced UTUC in whom there are no definitive contraindications to chemotherapy,” said the authors.

Within 90 days of undergoing radical nephroureterectomy, 260 patients (median age 68.5 years, 32 percent female) with muscle-invasive (stage pT2–T4 Nany) or lymph node-positive (pTany N1–3) metastasis-free UTUC** from 57 UK sites received (randomized) either four 21-day cycles of adjuvant chemotherapy (intravenous cisplatin [70 mg/m²] or carboplatin [AUC*** 4.5 or 5] on day 1 plus gemcitabine [1,000 mg/m² on days 1 and 8]; n=131) or surveillance (n=129).

After a median follow-up of 30.3 months, patients who received adjuvant chemotherapy had significantly greater DFS than those who were on surveillance (median not reached vs 29.8 months; hazard ratio [HR], 0.45, 95 percent confidence interval [CI], 0.30–0.68; p=0.0001). An estimated 71 and 46 percent of patients assigned to chemotherapy and surveillance, respectively, were event-free at 3 years. [Lancet 2020;doi:10.1016/S0140-6736(20)30415-3]

Risk of metastasis or death was halved with chemotherapy compared with surveillance (HR, 0.48, 95 percent CI, 0.31–0.74; p=0.0007), with an estimated event-free rate of 71 and 53 percent, respectively, at 3 years.

Grade ≥3 acute treatment-emergent adverse events (AEs) occurred at a higher rate in chemotherapy compared with surveillance recipients (44 percent vs 4 percent; p<0.0001). Fifty-four serious AEs, 39 of which were treatment-related, were reported by 42 chemotherapy recipients. Chemotherapy recipients were also more likely than those on surveillance to experience grade ≥3 decrease in neutrophils or platelets, nausea, vomiting, and febrile neutropenia.

“[Nonetheless,] tolerability and toxicity of the platinum-based chemotherapy regimens tested in POUT were acceptable and consistent with previous experience,” noted Associate Professor Simon Crabb from the Cancer Sciences Unit, University of Southampton, Southampton, UK, in a commentary. [Lancet 2020;doi:10.1016/S0140-6736(20)30519-5]

A new SOC for UTUC

Overall survival (OS) data is currently immature. According to the authors, while DFS is not a substitute for OS, it may not be feasible to power a trial for OS as a primary endpoint in a cancer as rare as UTUC. Nonetheless, the marked improvements in DFS and metastasis-free survival “strongly suggest that patients have better outcomes with chemotherapy than without.”

“In view of the rarity of UTUC and the urgent need to improve outcomes, we believe that evidence is now sufficient to advocate use of gemcitabine–platinum combination chemotherapy as a SOC,” they said.

“[This] is the first [study] to show that there is a real chance for people with upper urinary tract cancer to stay free of their disease for much longer. This type of cancer has always been forgotten and to be able to deliver this, a study that everyone said was impossible, to benefit patients is a privilege,” noted study chief investigator Dr Alison Birtle from the Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK. 

“The results of our study are set to change clinical practice in the UK and internationally, and I’m hopeful that patients will start benefiting very soon,” added study co-ordinator Professor Emma Hall from The Institute of Cancer Research, London, UK.

The authors also noted that despite the preference for cisplatin, patients intolerant or contraindicated for cisplatin could potentially benefit from carboplatin instead.

“[However,] uro-oncologists now need to decide whether DFS benefit represents an appropriate bar for practice change,” Crabb pointed out. “POUT has changed practice for many clinicians, but mature OS data remain vital,” he said.

Questions remain

While neoadjuvant chemo has been utilized for muscle-invasive bladder cancer, preoperative staging of UTUC is unreliable, and as such, patients with UTUC may be over- or undertreated with a neoadjuvant chemo regimen, said the authors. As such, whether chemotherapy should be offered in the neoadjuvant or adjuvant setting remains up for debate.

“[P]otentially nephrotoxic cisplatin-based chemotherapy might be safer and more feasible for UTUC if given before nephroureterectomy, when patients retain maximum renal function. [Conversely, there is], the risk that the toxic effects of chemotherapy could prevent some individuals from proceeding with curative surgery,” they noted.