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Prospective data needed to address knowledge gap in adjuvant therapy for upper tract urothelial carcinoma
Evidence to support the use of adjuvant chemotherapy for patients with upper tract urothelial carcinoma undergoing radical nephroureterectomy is limited.
Retrospective studies examining this question have yielded conflicting results.
A meta-analysis of existing literature suggested a survival benefit to cisplatin-based adjuvant chemotherapy. Many of the included studies were single institutional and limited by small sample size. Further, observational studies are susceptible to biases inherent to patient selection for a given treatment, which can confound results and limit estimation of a therapy’s clinical benefit.
With these limitations in mind, Seisen and colleagues conducted an important retrospective study in which they used the National Cancer Data Base and employed statistical methods designed to mitigate such selection biases.
The researchers identified more than 3,000 patients with locally advanced — pathologic T3/T4 or node-positive disease — upper tract urothelial carcinoma who underwent radical nephroureterectomy from 2004 to 2012.
Investigators compared OS between patients who received adjuvant chemotherapy and those who underwent observation after surgery. Inverse probability of treatment weighting–adjusted analysis accounted for differences in baseline characteristics that can predict receipt of adjuvant chemotherapy.
Patients who received adjuvant chemotherapy achieved longer median OS (47.4 months vs. 35.8 months) and a higher rate of 5-year OS (43.9% vs. 35.9%) than those who were observed after surgery. Adjusted Cox proportional hazard regression analysis demonstrated a survival benefit for adjuvant chemotherapy, with an HR of 0.77 (95% CI, 0.68–0.88). Subgroup analysis showed this effect to be consistent across age, sex, comorbidity status, pathologic stage and margin status.
The researchers concluded that these findings should be considered when counseling patients with locally advanced upper tract urothelial carcinoma following nephroureterectomy.
This represents the largest study to date to examine the effect of adjuvant chemotherapy on OS among patients undergoing nephroureterectomy for upper tract urothelial carcinoma and adds significant information based on comparative effectiveness. As with all retrospective studies, significant bias is inherent in the selection of patients for observation or adjuvant chemotherapy after surgery.
The researchers consistently performed various propensity scores and sensitivity analyses and provided clear results.
Although statistical methods — including propensity score analysis — can adjust for differences between groups among measured variables, unmeasured confounders likely persist, as the researchers mention. Prior studies have demonstrated that observational studies from high-quality databases may yield improbable results that contradict prospective evidence from clinical trials; multivariate or propensity analysis may fail to prevent such erroneous results.
Although the findings of this study are robust across multiple analyses, the results must be interpreted within the context of these inherent limitations.
Despite the lack of high-level evidence, neoadjuvant cisplatin–based combination chemotherapy should be considered and discussed as an option for patients who can tolerate cisplatin and have high-grade upper tract urothelial carcinoma.
There is a huge need for level-one evidence for the use of either neoadjuvant or adjuvant chemotherapy among patients with upper tract urothelial carcinoma. Clinical trials are ongoing — including the phase 2 ECOG-ACRIN 8141 (NCT02412670) in the neoadjuvant setting — and it is incumbent upon the urology and oncology communities to appropriately refer eligible patients for these trials.
Moreover, there are three important large randomized phase 3 trials with immune checkpoint inhibitors in the adjuvant therapy of urothelial carcinoma, but they mostly include patients with bladder cancer, and they do not compare immunotherapy with chemotherapy.
Until higher-level evidence becomes available via prospective clinical trials, patients with locally advanced upper tract urothelial carcinoma — pT3/T4 or pN+ — should be evaluated and considered for adjuvant cisplatin–based combination chemotherapy, if they have not received it neoadjuvantly, and for relevant clinical trials. Moreover, there is no clear role of noncisplatin regimens in the perioperative setting. Further understanding of upper tract urothelial cancer biology can shed more light into the optimal management of this challenging disease.
References:
Giordano SH, et al. Cancer. 2008;doi:10.1002/cncr.23452.
Leow JJ, et al. Eur Urol. 2014;doi:10.1016/j.eururo.2014.03.003.
Tomaszewski JJ, et al. BJU Int. 2015;doi:10.1111/bju.12696.
For more information:
Nima Almassi, MD, is a fifth-year resident in the Glickman Urological and Kidney Institute of Cleveland Clinic. He can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: almassn@ccf.org.
Petros Grivas, MD, PhD, is assistant professor in the department of medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and associate staff genitourinary oncologist at Taussig Cancer Institute of Cleveland Clinic. He can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: grivasp@ccf.org.
Disclosure: Almassi and Grivas report no relevant financial disclosures.