Upper Tract Urothelial Carcinoma - Adjuvant Chemotherapy for all Patients?
UTUC is a rare disease, with approximately 1400 new cases and 240 deaths per year in the United Kingdom.1 The local and metastatic recurrence rate is approximately 50%.2 Approximately 60% of UTUC cases are invasive at diagnosis. The standard treatment is radical nephroureterectomy followed by surveillance. There was insufficient evidence to recommend adjuvant systemic chemotherapy for invasive UTUC. Previous studies of systemic chemotherapy in locally advanced UTUC are limited, with mostly retrospective reviews with small sample sizes.
A meta-analysis examining the role of adjuvant chemotherapy in UTUC,3 has included one prospective study, albeit very small, and nine retrospective studies comparing 482 patients who received cisplatin chemotherapy to 1300 patients who underwent nephroureterectomy alone. The pooled hazard ratio for overall survival across three cisplatin-based studies was 0.43, p=0.023 compared with surgery alone. The disease-specific survival also had a hazard ratio of 0.49. Another older study published in 2006 assessed the role of adjuvant chemotherapy in 43 patients who underwent radical nephroureterectomy, with a median follow-up of 30 months. 4 This study compared adjuvant chemotherapy to observation. This study showed a clear benefit for the adjuvant chemotherapy (63.6% vs. 37.5%). There was also a clear advantage in the overall survival, in favor of the adjuvant chemotherapy arm (28% vs. 81%). A similar study, published in the BJU Int in 2015 did not show any difference between adjuvant chemotherapy and adjuvant chemotherapy. 5 In a large population-based study, based on the national cancer database (NCDB) 6, a clear advantage was seen in favor of the patients treated with chemotherapy.
A meta-analysis has proven that neoadjuvant chemotherapy in the setting of muscle-invasive bladder cancer, improves overall survival. However, data regarding the role of neoadjuvant chemotherapy in UTUC is controversial.
In the last section of her discussion, Dr. Birtle discussed the POUT trial. This was the first randomized clinical trial for patients with UTUC. The POUT trial assessed the added benefit of using platinum-based chemotherapy in the adjuvant setting in patients undergoing a radical nephroureterectomy. This was a multicenter phase III randomized trial of preoperative chemotherapy vs. surveillance in UTUC patients. In this trial, 260 patients with locally advanced or node-positive UTUC (pT2-T4 N0-3 M0) were recruited from 2012 to 2017. The patients were then randomized (1:1) to 4 cycles of gemcitabine-cisplatin (GC)/gem-carboplatin (GFR 30-49 ml/min), or surveillance 90 days following a nephroureterectomy. Patients with a GFR < 30, and those with an incompletely resected macroscopic disease where excluded from the trial. Patients were followed closely with cross-sectional imaging and cystoscopy every six months for the first two years and transitioned to an annual follow-up for a total of 5 years. The primary end-point for the trial was disease-free survival (DFS), with metastasis-free survival (MFS), overall survival (OS), toxicity and quality of life (QoL) as secondary end-points.
It was expected to recruit 338 patients to detect a 15% improvement in 3-year DFS; however, the trial was stopped early by the safety monitoring committee due to significant improvement in observed DFS. The intention to treat analysis was conducted on 260 patients with 131 patients undergoing chemotherapy treatment and 131 followed by a surveillance protocol. Baseline characteristics were balanced between the groups, with most patients being male (67.7%) and older (median age of 69). Many of the enrolled patients had the pT3 disease (30% pT2, 65% pT3) and were node negative following node dissection (91%). Of patients undergoing chemotherapy, 66% were treated with Gem-Cis, and 68% completed the four planned chemotherapy cycles. Toxicities observed were consistent with those that usually appear after the usage of this high-dose chemotherapy regimen. Approximately 50% of patients undergoing chemotherapy developed a grade 3 or greater adverse event with only one patient suffering a death related to an upper GI bleed.
A significant difference in DFS (HR 0.49 [CI 0.31-0.76], p=0.001) was observed at a median follow-up of 17.3 months. Following adjustment for nodal involvement the difference was more pronounced with an HR 0.47 [CI 0.30-0.74), p=0.001). On univariate analysis, positive margins and receipt of gem-carboplatin had a non-significant improvement on DFS following chemotherapy, which may be related to the early follow-up and low numbers in these groups. On secondary end-points, adjuvant chemotherapy was also associated with an improvement in metastasis-free survival (HR 0.49 (0.30-0.78), p=0.002). Finally, a separation in the OS curves was seen, but the difference remained non-significant likely related to the immature timing of the analysis.
Concluding this talk, Dr. Birtle mentioned again that the POUT trial provides novel and convincing high-level evidence on the added benefit of adjuvant chemotherapy in patients with locally advanced or node-positive UTUC. The benefit of adjuvant chemotherapy appears to be inferior in those treated with carboplatin and those with positive resection margins. While data on overall survival difference is still immature, Dr. Birtle believes that adjuvant platinum-based chemotherapy should be considered a new standard of care in these patients.
Presented by: Alison Birtle, MD, Royal Preston, United Kingdom
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the Global Conference on Bladder Cancer 2018 - September 20-21, 2018 Madrid, Spain
References:
1. UK Cancer Stats 2017
2. Zinke H, Neves RJ. Feasibility of conservative surgery for transitional cell cancer of the upper urinary tract. Urol Clin North Am 1984; Nov 11: 717–24
3. Leow JJ et al. Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol. 2014 Jul;66(1):42-54.
4. Kwak C et al. Prevention of nephrolithiasis by Lactobacillus in stone-forming rats: a preliminary study. Urol Res. 2006 Aug;34(4):265-70.
5. Hellenthal NJ, et al. Adjuvant chemotherapy for high-risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration. J. Urol 2009 Sep;182(3):900-6
6. Seisen T et al. Effectiveness of Adjuvant Chemotherapy After Radical Nephroureterectomy for Locally Advanced and/or Positive Regional Lymph Node Upper Tract Urothelial Carcinoma. J Clin Oncol. 2017 Mar 10;35(8):852-860.