Adjuvant Chemo Halves Recurrence Risk in Rare Urothelial Cancer

Liam Davenport

March 11, 2020

Patients with upper tract urothelial carcinoma (UTUC) who were treated with platinum-based chemotherapy following surgery had half the risk of their cancer recurring compared with those who were followed with observation.

These results, from the POUT trial, show that platinum-based chemotherapy reduced the risk of progression by 55%, with 71% of patients disease-free at 3 years vs 46% of those on surveillance.

The study was published online March 5 in The Lancet.

It 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," commented lead investigator Alison Birtle, MD, Rosemere Cancer Centre, Royal Preston Hospital, United Kingdom.

"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, she added in a statement.  

In their study, the researchers concluded that, in patients who are able to receive it, platinum-based chemotherapy "should be adopted as a new standard of care for patients with locally advanced UTUC...[and] should be routinely considered for all patients in this population."

Approached for comment, Guru Sonpavde, MD, bladder cancer director at the Dana-Farber Cancer Institute, Boston, Massachusetts, agreed that this is the first 'positive' trial of adjuvant chemotherapy in this setting.

It "constitutes a welcome advance for the therapy of these patients," he told Medscape Medical News.

However, Sonpavde noted that the trial "also raises some major questions that will need to be answered."

The surgery involved was a radical nephroureterectomy, and this loss of  kidney will render "a significant proportion of patients...ineligible for the more optimal cisplatin-based chemotherapy," he noted.

"Therefore, should we prefer the neoadjuvant approach for patients likely to have invasive disease...and incur the risk of overtreating some patients without invasive disease?" Sonpavde asked.

Difficulties in Running Trials in Rare Cancers

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare tumor, accounting for approximately 10% of all renal tumors and only 5% of all urothelial carcinomas, with an estimated annual incidence of almost two cases per 100,000 inhabitants in Western countries, according to a 2019 review in BMC Urology.

"Running clinical trials in patients with rare cancers comes with its challenges, including finding enough people to take part, so it's fantastic to see such clear evidence of patient benefit from this study," commented study coordinator Emma Hall, PhD, The Institute of Cancer Research, London, UK.

"It shows how important it is to run studies like this to improve treatment options for patients with rarer forms of cancer," she added in a statement.

Study Details

The phase 3, open label POUT trial recruited patients with UTUC who had undergone radical nephroureterectomy in National Health Service hospitals and were fit enough to receive adjuvant chemotherapy within 90 days.

The team enrolled 261 patients at 57 hospitals between June 2012 and November 2017, at which point recruitment was closed as a result of having met the early stopping criteria for efficacy.

All patients were metastasis-free. The median age was 68.5 years. The vast majority (94%) of patients had stage pT2–T3 disease, with 91% also staged N0. A glomerular filtration rate ≥50 mL/min was seen in 64%.

Patients were randomly assigned to surveillance (n = 129) or four 21-day cycles of chemotherapy, comprising intravenous cisplatin or carboplatin on day 1 and intravenous gemcitabine on days 1 and 8.

A total of 132 patients were assigned to chemotherapy. One withdrew, and seven did not start treatment. Of the remaining 126 patients, 75% received all four cycles of treatment.

Over a median follow-up of 33 months, adjuvant chemotherapy was associated with a significant improvement in disease-free survival vs surveillance, at a hazard ratio of 0.45 (P =.0001).

Three-year event-free survival estimates were 71% for chemotherapy vs 46% for surveillance, at an absolute difference of 25%.

Median disease-free survival was 29.8 months (2.5 years) for patients assigned to surveillance and was not reached for chemotherapy.

The results were "largely unchanged"after taking into account known prognostic factors, the team reports.

Treatment-emergent adverse events of grade 3 or more were seen in 44% of chemotherapy patients and 4% of those managed with surveillance (P < .0001).

Chemotherapy patients were more likely than those assigned to surveillance to experience at least grade 3 reductions in neutrophils (36%) and platelet counts (10%), febrile neutropenia (6%), and vomiting (6%).

Questions Remain to Be Answered

Commenting further on the new results, Dana-Farber's Sonpavde wondered whether these new results in UTUC could be extrapolated to muscle invasive bladder cancer.

He noted that it is "generally considered reasonable" to offer adjuvant cisplatin-based but not carboplatin-based chemotherapy to those who did not receive neoadjuvant chemotherapy, "so the POUT trial partly validates this current practice."

Finally, Sonpavde wondered whether carboplatin plus gemcitabine should be offered to cisplatin-ineligible bladder and UTUC patients as adjuvant therapy.

Such patients, he noted, are also candidates for one of the ongoing trials of an immunotherapy, in this case pembrolizumab (Keytruda, Merck), as adjuvant therapy.

"Notably, one of the phase 3 trials, IMvigor010, evaluating adjuvant atezolizumab [Tecentriq, Genentech] compared to observation as adjuvant therapy for muscle-invasive bladder or UTUC failed to demonstrate improved disease-free survival," he added.

Sonpavde added that the PROOF-302 trial will evaluate adjuvant infigratinib (BridgeBio Pharma) vs placebo for muscle-invasive, high-risk urothelial carcinoma with fibroblast growth-factor receptor genomic alterations.

POUT was supported by Cancer Research UK with program grants to support the work of Institute of Cancer Research (ICR) Clinical Trials and Statistics Unit. This study represents independent research supported by the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the ICR.

Birtle reports personal fees from Bayer, Janssen, Astellas, Roche, and Sanofi Genzyme, and research support from Sanofi Genzyme, all outside of the submitted work. Hall reports grants from Cancer Research UK, during the conduct of the study; grants from MSD, Janssen-Cilag, Aventis Pharma (Sanofi), Accuray, Varian, and Roche, outside of the submitted work; and grants and nonfinancial support from AstraZeneca and Bayer, outside of the submitted work. Sonpavde has disclosed no relevant financial relationships.

The Lancet. Published online March 5, 2020. Full text

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