Alison J. Birtle, MD, MBBS, MRCP, FRCR
Data from the phase III POUT clinical trial demonstrated that adjuvant platinum-based chemotherapy improves disease-free survival (DFS) and metastasis-free survival (MFS) in patients with upper tract urothelial carcinoma (UTUC). Alison J. Birtle, MD, MBBS, MRCP, FRCR, a consultant clinical oncologist for Lancashire Teaching Hospitals, NHS Foundation Trust in the United Kingdom, presented the results at the 2018 Genitourinary Cancers Symposium.
The results of the trial indicated to Birtle and her colleagues that adjuvant platinum-based chemotherapy should be considered a new standard of care in UTUC. “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,” she said. The current standard of care for this patient population is a radical nephroureterectomy.
There is a strong rationale for using chemotherapy in this patient population, as UTUC shares a similar etiology with MIBC. There is evidence that MIBC is chemosensitive, Birtle said, and the strongest evidence is in the neoadjuvant setting. Moreover, neoadjuvant chemotherapy could be important for patients with UTUC because prior to surgery, patients have both kidneys and can handle the treatment better.
“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 commented.
To address these concerns, in the phase III, randomized, multicenter POUT trial (NCT01993979), 261 patients were randomized to receive either chemotherapy (n = 131) or surveillance (n = 129). The median follow-up was 19.3 months, the primary endpoint was DFS, and the secondary endpoint was MFS. Patient characteristics were mostly balanced between the 2 arms in terms of age group, sex, pathological stage, and nodal involvement.
Eligible patients had UTUC stage pT2 to pT4 disease, with pN0, M0, or pTany N1 to N3 nodal status, provided that abnormal nodes were resected at surgery. They also had to have a World Health Organization performance status of 0 or 1, without distant metastases, and a glomerular filtration rate (GFR) of greater than 30 mL/min. Patients who had concurrent MIBC were excluded from the trial, but patients with nonmuscle invasive bladder cancer were accepted.
Patients in the chemotherapy group were administered 4 cycles of adjuvant chemotherapy delivered within 90 days of their nephroureterectomy and were further stratified to receive gemcitabine with either cisplatin or carboplatin based on their renal function. Patients who had suboptimal renal function (GFR 30-49 mL/min) received carboplatin instead of cisplatin. In terms of DFS, patients on the chemotherapy arm did significantly better after 3 years than those receiving surveillance (HR, 0.49; 95% CI, 0.31-0.76; P
= .001). Chemotherapy also demonstrated benefit in MFS after 3 years versus surveillance (HR, 0.49; 95% CI, 0.30-0.78; P
= .002). There was also a benefit seen in overall survival (OS), although Birtle said the data are immature and the 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 that prior to the POUT trial, there was insufficient evidence to recommend adjuvant systemic chemotherapy for invasive UTUC, and there is no current international consensus on systemic treatment in this setting. One previous study indicated that adjuvant systemic chemotherapy may 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.
Additionally, recent data from the EORTC 30994 study also demonstrated an improvement in progression-free survival with adjuvant chemotherapy, although no significant benefit was seen in OS. This trial served as part of the rationale for the phase III POUT trial.
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.