After POUT: Implications of Perioperative Chemotherapy for Upper Tract Urothelial Carcinoma

Before the POUT Trial

Before the POUT trial, the largest randomized Phase III trial assessing perioperative chemotherapy for locally advanced UTUC, decisions in management relied primarily on retrospective studies and expert opinion. Furthermore, the data from these studies are conflicting regarding the efficacy of perioperative chemotherapy. In 2009, Hellenthal and colleagues5 used an international collaborative database to assess the utilization and outcomes of adjuvant chemotherapy after radical nephroureterectomy in patients with UTUC. They identified 1,390 patients who underwent nephroureterectomy for nonmetastatic UTUC between 1992 and 2006. Of these cases, 39% were classified as high-risk (pT3N0, pT4N0 and/or lymph node-positive). For the analysis, these patients were divided into two groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Among the 542 high-risk patients, 22% received adjuvant chemotherapy, which was more commonly administered in the context of increased tumor grade and stage (p <0.001). The median survival for the entire cohort was 24 months (range 0 to 231 months), and there was no significant difference in all-cause death (chemotherapy vs none: hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.80-1.40) or cancer-specific death (chemotherapy vs none: HR 1.26, 95% CI 0.93-1.71) between patients who did and did not receive adjuvant chemotherapy.

A subsequent study from the European Association of Urology – Young Academic Urologists and the Upper Tract Urothelial Collaboration also assessed adjuvant chemotherapy after radical nephroureterectomy.6 This study collated data from 15 centers (1,544 patients) between 2000 and 2015; patients were required to have pT2-4N0/Nx or N+ disease and had undergone a radical nephroureterectomy. The primary analysis used 1:1 propensity score matching, with inverse probability of treatment weighting with a primary endpoint of overall survival (OS). Among the 1,544 patients included, 312 received adjuvant chemotherapy and 1,232 underwent observation. In the matched analysis, there was no difference observed in OS between adjuvant chemotherapy and observation (HR 1.14, 95% CI 0.91-1.43; P = 0.268). Furthermore, a six‐month landmark analysis demonstrated little impact of early events on the treatment effect on OS, with an HR of 1.28 (95% CI 1.00–1.64; p = 0.051).

In contrast to these two studies that failed to demonstrate a benefit to adjuvant chemotherapy, a systematic review and meta-analysis published in 2014 assessed the role of adjuvant and neoadjuvant chemotherapy for patients with UTUC.7 Not surprisingly, this systematic review found no randomized trials investigated the role of adjuvant chemotherapy for UTUC. There was one prospective study comprising 36 patients that investigated adjuvant carboplatin-paclitaxel. Furthermore, there were nine retrospective studies (totaling 482 patients) among patients receiving cisplatin-based or non-cisplatin-based adjuvant chemotherapy after nephroureterectomy compared to 1,300 patients receiving nephroureterectomy alone. Across the three cisplatin-based studies, the pooled hazard ratio for OS was 0.43 (95% CI, 0.21-0.89; p=0.023) favoring adjuvant cisplatin compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24-0.99; p=0.048) favoring adjuvant cisplatin. Among the non-cisplatin-based chemotherapy studies, there was no benefit for neoadjuvant chemotherapy. For the neoadjuvant chemotherapy section of the systematic review, the authors identified two Phase II trials that demonstrated favorable pathologic downstaging rates (60%-75% downstaging to ≤pT1N0). Across two retrospective studies investigating neoadjuvant chemotherapy, there was a disease-specific survival (DSS) benefit for neoadjuvant chemotherapy, with a pooled HR of 0.41 (95% CI, 0.22-0.76; p=0.005).

The POUT Trial

The POUT trial was a Phase III, parallel group, open-label, randomized controlled trial done at 71 National Health Service (NHS) hospitals in the United Kingdom.8 Eligible patients were ≥16 years, had received a radical nephroureterectomy for UTUC, were postoperatively staged with either muscle-invasive (pT2–pT4, pNany) or lymph node-positive (pTany, pN1–3) M0 disease with predominantly transitional cell carcinoma histology, and were fit to receive adjuvant chemotherapy within 90 days of surgery. Patients also had to have a glomerular filtration rate (GFR) of ≥30 mL/min. Prespecified stratification factors included platinum chemotherapy agent (cisplatin vs carboplatin), preoperative radiologically or pathologically assessed nodal involvement (N0 vs N1 vs N2 vs N3), the status of surgical margins (positive vs negative), and treatment center. Patients were randomized 1:1 to receive either surveillance or adjuvant chemotherapy: four 21-day cycles of platinum-based chemotherapy (cisplatin 70 mg/m2) within 14 days of randomization; gemcitabine (1000 mg/m2) given on days one and eight of each cycle. Patients with impaired renal function (GFR ≥30 mL/min and <50 mL/min) received carboplatin rather than cisplatin.

Patients were followed at 3, 6, 9, and 12 months, then every 6 months to 36 months from randomization, and annually thereafter. The radiographic assessment included a CT of the thorax, abdomen, and pelvis at 3, 6, 9, 12, 18, 24, 30, and 36 months, then annually to 60 months. Cystoscopy was done every 6 months to 24 months, then annually up to 60 months after surgery. Toxicity was assessed by CTCAE v4.  Furthermore, this was the first trial in UTUC to collect patient-reported outcomes: patients filled out the EORTC quality-of-life of cancer patients questionnaire (QLQ-C30) and the EuroQol five dimensions five levels questionnaire (EQ-5D-5L) at baseline and before cycle three and at 3, 6, 12, and 24 months after randomization. The primary endpoint of this trial was DFS defined as time from randomization to either first recurrence in the tumor bed, first metastasis, or death from any cause. Secondary endpoints included metastasis-free survival (MFS), OS, treatment compliance, acute toxicity, late toxicity, and patient-reported quality of life. The trial was powered to detect a hazard ratio of 0.65 (i.e. improvement in three-year DFS from 40% to 55%; 2-sided alpha = 5%, 80% power) with Peto-Haybittle (p<0.001) early stopping rules for efficacy and inefficacy.

There were 261 patients included in the trial between June 19, 2012 and November 8, 2017 at 57 of the 71 participating centers in the UK, including 129 patients randomized to surveillance and 132 to chemotherapy; 260 patients were included in the intention to treat analysis. In October 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected to date met the early stopping rule for efficacy. Included patients were a median 68.5 years of age (IQR 62.0-74.1 years). With respect to tumor characteristics, 94% of patients had pT2-T3 disease and 91% were N0. The median follow-up was 30.3 months (IQR 18.0-47.5 months). There were 7 of 131 patients allocated to chemotherapy that did not start treatment and 75% of those that started chemotherapy received four cycles. There were 60 (47%) DFS events in the surveillance cohort and 35 (27%) in the chemotherapy cohort; as such, the unadjusted HR was 0.45 (95% CI 0.30-0.68) in favor of chemotherapy (log-rank p = 0.0001). The three-year DFS rate was 46% for surveillance (95% CI 36-56) and 71% for chemotherapy (95% CI 61-78). MFS also favored chemotherapy, with an HR of 0.48 (95% CI 0.31-0.74, log-rank p = 0.0007), and the three-year event-free rates were 53% (95% CI 42-63) for those on surveillance and 71% (95% CI 60-79) for those receiving chemotherapy. Currently, there have been 62 deaths recorded (38 for surveillance, 24 for chemotherapy) and the OS analysis is planned for when 88 deaths occur, or all patients have ≥2 years of follow-up.

Grade ≥3 toxicities were reported in 44% of chemotherapy patients and 4% surveillance patients (p < 0.0001). During the treatment period, the most common grade ≥3 toxicities in chemotherapy patients were neutropenia (36%) and thrombocytopenia (10%). Analysis of late toxicity is planned after a two-year follow-up of all patients. Quality of life questionnaires were returned by 95% of patients at baseline (95% of those allocated to surveillance and 95% of those allocated to chemotherapy), 82% at three months (81% of those allocated to surveillance and 82% of those allocated to chemotherapy), and 70% at 12 months (70% of those allocated to surveillance and 70% of those allocated to chemotherapy). The mean overall global health status score at baseline was 77% (standard deviation 19) for the chemotherapy group and 76% (standard deviation 19) for the surveillance group. Subsequently, the overall global health status was lower during chemotherapy (before cycle 3) and immediately afterward (at three months) in participants allocated chemotherapy versus surveillance, however the difference resolved by six months of follow-up.

Implications and Future Considerations Following the POUT Trial

Given the rarity of UTUC and the clinical equipoise for conducting a perioperative chemotherapy trial in this disease state, the trialist and the patients involved in this study are to be congratulated for completing this important Phase III trial. As has been discussed amongst thought leaders in the field and summarized in a discussion between Dr. Ashish Kamat and trial lead Dr. Alison Birtle, this is practice-changing data: all patients with locally advanced UTUC after radical nephrectomy should be considered for receipt of adjuvant cisplatin-based chemotherapy.

There are several important considerations as we move into the post-POUT trial era of treating locally advanced UTUC. First, patients with adequate renal function should receive the combination of cisplatin-gemcitabine adjuvant chemotherapy. Typically, a GFR of <60 mL/min is deemed “cisplatin-ineligible”, however, the POUT trial included patients with GFRs as low as 50 mL/min, which is standard practice in the UK. However, even for those with a GFR < 50 mL/min that received the combination of carboplatin-gemcitabine (n=96), there was still a non-significant DFS benefit (HR 0.66, 95% CI 0.35-1.26).8 As such, essentially all pT2–pT4, Nany or pTany, N1–3M0 patients should be considered for an adjuvant chemotherapy regimen that fits their performance status and post-radical nephroureterectomy renal function profile.

Second, the argument for adjuvant chemotherapy as standard of care should only grow stronger as the data matures. Indeed, the benefit of adjuvant chemotherapy was based on DFS and MFS benefit, however with such strong hazard ratios favoring chemotherapy vs surveillance (DFS HR 0.45; MFS HR 0.48) there likely will be a survival benefit with longer follow-up. Furthermore, early survival data reported in the POUT publication favor chemotherapy vs surveillance (38 deaths in surveillance arm; 24 deaths in chemotherapy arm). As such, there is a signal for a more than likely survival benefit based on DFS/MFS benefit and early survival data.

Third, as POUT has demonstrated a survival benefit to perioperative chemotherapy in the adjuvant setting it has re-raised questions regarding the role of neoadjuvant therapy. As nephroureterectomy removes a significant nephron mass, neoadjuvant administration would allow more patients to receive cisplatin, which is known to be more efficacious than carboplatin. However, this must be balanced against issues of poor pre-operative staging in UTUC. Unlike bladder cancer in which TURBT fairly reliably can distinguish superficial from muscle-invasive disease, this distinction is much more difficult in UTUC. Certainly, in patients with obvious invasive disease based on axial imaging and marginal renal function, extrapolation from POUT would suggest that neoadjuvant chemotherapy may be a rational approach.

Finally, the question remains as to how immunotherapy fits into the picture given the POUT data. There are currently no Phase III trials underway to address the role of immunotherapy in the adjuvant treatment of UTUC alone, however, ongoing trials assessing pembrolizumab (Neoadjuvant Pembrolizumab in Combination with Gemcitabine Therapy in Cis-eligible/Ineligible Urothelial Carcinoma Patients) in the perioperative setting for bladder urothelial carcinoma have preplanned subgroup analyses for patients with UTUC. Atezolizumab has shown real-world efficacy in metastatic UTUC, as evaluated in the SAUL study (22% included had UTUC)9, however, what role immunotherapy plays in the perioperative setting for UTUC remains to fully elucidated.

Written by: Zachary Klaassen, MD, MSc
References: 1. Rouprêt, Morgan, Marko Babjuk, Eva Compérat, Richard Zigeuner, Richard J. Sylvester, Maximilian Burger, Nigel C. Cowan et al. "European association of urology guidelines on upper urinary tract urothelial carcinoma: 2017 update." European urology 73, no. 1 (2018): 111-122.
2. Sternberg, Cora N., Iwona Skoneczna, J. Martijn Kerst, Peter Albers, Sophie D. Fossa, Mads Agerbaek, Herlinde Dumez et al. "Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial." The lancet oncology 16, no. 1 (2015): 76-86.
3. of Trialists, International Collaboration. "International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial." Journal of Clinical Oncology 29, no. 16 (2011): 2171.
4. Vale, C. A. "Advanced Bladder Cancer (ABC). Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data." Eur Urol 48, no. 2 (2005): 189-199.
5. Hellenthal, Nicholas J., Shahrokh F. Shariat, Vitaly Margulis, Pierre I. Karakiewicz, Marco Roscigno, Christian Bolenz, Mesut Remzi et al. "Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration." The Journal of urology 182, no. 3 (2009): 900-906.
6. Necchi, Andrea, Salvatore Lo Vullo, Luigi Mariani, Marco Moschini, Kees Hendricksen, Michael Rink, Roman Sosnowski et al. "Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study by the European Association of Urology–Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration." BJU international 121, no. 2 (2018): 252-259.
7. Leow, Jeffrey J., William Martin-Doyle, Andre P. Fay, Toni K. Choueiri, Steven L. Chang, and Joaquim Bellmunt. "A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma." European urology 66, no. 3 (2014): 529-541.
8. Birtle, Alison, Mark Johnson, John Chester, Robert Jones, David Dolling, Richard T. Bryan, Christopher Harris et al. "Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial." The Lancet (2020).
9. Sternberg, Cora N., Yohann Loriot, Nicholas James, Ernest Choy, Daniel Castellano, Fernando Lopez-Rios, Giuseppe L. Banna et al. "Primary results from SAUL, a multinational single-arm safety study of atezolizumab therapy for locally advanced or metastatic urothelial or nonurothelial carcinoma of the urinary tract." European urology 76, no. 1 (2019): 73-81.