Phase III POUT Data Supports Adjuvant Chemotherapy as Standard for Patients With UTUC

According to results from the phase III POUT trial, adjuvant platinum-based chemotherapy improved disease-free survival and metastasis-free survival in patients with upper tract urothelial carcinoma. These results indicated that adjuvant platinum-based chemotherapy could be a new standard of care for UTUC, investigators said.

Alison J. Birtle, MD, MBBS, MRCP, FRCR

According to results from the phase III POUT trial, adjuvant platinum-based chemotherapy improved disease-free survival (DFS) and metastasis-free survival (MFS) in patients with upper tract urothelial carcinoma (UTUC). These results indicated that adjuvant platinum-based chemotherapy could be a new standard of care for UTUC, investigators said.

These findings were presented at the 2018 Genitourinary Cancers Symposium by Alison J. Birtle, MD, MBBS, MRCP, FRCR, a consultant clinical oncologist for Lancashire Teaching Hospitals, NHS Foundation Trust in the United Kingdom.

“Although the incidence of upper tract urothelial carcinoma is rare and there are about 1400 new cases diagnosed in the [United Kingdom] every year, stage for stage, it is a more lethal diagnosis than muscle-invasive bladder cancer [MIBC[, with about 60% of patients [with UTUC] muscle invasive at diagnosis,” Birtle said. The current standard of care is radical nephroureterectomy.

Strong rationale supports the use of chemotherapy in this patient population. UTUC shares a similar etiology with MIBC, and there is evidence that MIBC is chemosensitive, Birtle said. The strongest evidence is in the neoadjuvant setting, where chemotherapy could be essential to patients with UTUC prior to surgery when patients have both kidneys and can tolerate the treatment.

“However, there are some concerns about giving neoadjuvant chemotherapy at this stage—not least because of the lack of histological diagnosis for some patients—and this might lead to overtreatment in patients with noninvasive papillary carcinoma or for some patients who ultimately turn out not to have cancer,” Birtle added.

The the phase III, randomized, multicenter POUT trial (NCT01993979) addressed this issue by enrolling 261 patients, randomizing them to receive either chemotherapy (n = 131) or surveillance (n = 129). There was a median follow-up of 19.3 months, with a primary endpoint of DFS and secondary endpoint of MFS. Patient characteristics across the 2 arms were similar in terms of age, sex, pathological stage, and nodal involvement.

Overall, eligible patients had UTUC stage pT2 to pT4 disease, with pN0, M0, or pTany N1 to N3 nodal status, as long as abnormal nodes were resected at surgery. It was also required that the patients have a World Health Organization performance status of 0 or 1, without distant metastases, and a glomerular filtration rate (GFR) higher than 30 mL/min. Patients with concurrent MIBC were excluded, but patients with nonmuscle invasive bladder cancer were accepted in this trial.

In the chemotherapy arm, patients recieved 4 cycles of adjuvant chemotherapy within 90 days of their nephroureterectomy and were further stratified, based on their renal function, to receive gemcitabine with either cisplatin or carboplatin. Patients with suboptimal renal function (GFR 30-49 mL/min) were given carboplatin instead of the cisplatin.

In terms of DFS, the chemotherapy arm demonstrated significantly better results after 3 years (HR, 0.49; 95% CI, 0.31-0.76;P= .001). Benefit was also found with chemotherapy in regard to MFS after 3 years versus surveillance (HR, 0.49; 95% CI, 0.30-0.78;P= .002). A benefit was also seen in overall survival (OS), but Birtle said the data are immature and follow-up is still ongoing.

The adverse events (AEs) seen in the POUT trial were consistent with known chemotherapy toxicity profiles. “This is a chemotherapy study, so of course we get chemotherapy-related adverse effects,” Birtle commented. Most AEs were grade 1 to 3, with 24.8% of patients in the surveillance arm and 62.1% of patients in the chemotherapy arm experiencing toxicities of any grade. The most common chemotherapy-related AEs included decreased neutrophil count, hypertension, decreased platelet counts, febrile neutropenia, nausea, vomiting, and hearing impairment.

Birtle noted there was insufficient evidence before this trial to recommend adjuvant systemic chemotherapy for invasive UTUC. Also, there is no current international consensus on systemic treatment in this setting. In 1 previous study, investigators suggested that adjuvant systemic chemotherapy could provide therapeutic benefit in patients with UTUC, but it was a retrospective study with a small sample size (n = 43).

“Of the 32 patients who did receive chemotherapy, there did seem to be a tantalizing hint of an improvement in DFS and OS, but this would need to be explored further in subsequent studies,” Birtle said in consideratino of the small small study.

Recent data from the EORTC 30994 study found an improvement in progression-free survival with adjuvant chemotherapy. However, no significant benefit was found in OS. This trial served as part of the rationale for the phase III POUT trial.

Reference:

Birtle AJ, Chester JD, Jones RJ, et al. Results of POUT: a phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). Presented at: 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, CA. Abstract 407. meetinglibrary.asco.org/record/157669/abstract.