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Options for Cisplatin-ineligible Patients with Muscle-invasive Localized Urothelial Carcinoma

Neoadjuvant chemotherapy use has been on the rise in the last 15 years for patients with high-risk localized urothelial carcinoma.  This is obviously due to randomized control data supporting an overall survival benefit.1,2  However, it has taken significant time for the field to embrace and adopt widespread use of cisplatin-based combination chemotherapy regimens in this setting.  Early reports showed neoadjuvant chemotherapy utilization rates to be 7.6% in 2006, 3 years after the original randomized control trial was published supporting the use of methotrexate, vinblastine, adriamcyin and cisplatin.3  Fortunately, utilization is increasing and by 2010 neoadjuvant chemotherapy was being administered to 20.9%.3  In certain centers of excellence, estimates of neoadjuvant chemotherapy utilization are close to 50% of cystectomized patients.4 However, the field may be peaking in uptake of neoadjuvant cisplatin-based chemotherapy utilization, and it may largely be due to the large number of men who remain “unfit” for cisplatin chemotherapy.  Standard definitions in our field for patients who are “unfit” for cisplatin include patients with at least one of the following criteria: creatinine clearance <60 ml/min, grade ≥2 hearing loss, grade ≥2 neuropathy, ECOG performance status 2, and/or New York Heart Association Class III heart failure.5

Patients who have comorbidities that render them “unfit” for cisplatin are left with no good treatment options other than cystectomy alone.  The risk of relapse for these patients remains high, but the rationale to use more tolerable agents such as carboplatin is weak and recommendations are to completely avoid chemotherapy if cisplatin cannot be safely administered.6  Additionally, with an absolute risk reduction of no more than 5-10% with cisplatin, it is not clear that a modified regimen will offer any benefit.  Hence, we must work hard to consider new systemic therapy options that offer benefit with acceptable toxicity profiles.

With the recent regulatory approvals of novel immunotherapies (e.g. PD-1 and PD-L1 antibodies) for metastatic or inoperable urothelial carcinoma, it seems logical that these and other similar agents be tested in earlier settings.  There are many ongoing adjuvant clinical trials (discussed in a previous article);7 however, the neoadjuvant setting is being less robustly explored.  Actually, the neoadjuvant setting is quite an ideal setting for biologic exploration, since there is generally readily available tissue for translational correlative studies.  Since there are no accepted standard of care neoadjuvant regimens for patients “unfit” for cisplatin with high-risk muscle-invasive urothelial carcinoma, it stands to reason that we emphasize accrual to clinical trials focused on evaluation of these patients.  Below, we highlight a few trials specifically for patients “unfit” for cisplatin; a couple trials using combination checkpoint inhibitors and also a trial combining a checkpoint inhibitor with cytotoxic chemotherapy.  Should any of these trials render promising results, our field should prioritize continued trial development for this fairly large “unfit” for cisplatin patient population.  As this patient population represents a significant unmet medical need, our field needs to continue to evaluate novel systemic therapy regimens with potential to offer improvement of long-term outcomes.

Written by: Evan Yu, MD

Highlighted Trials: 

A Pilot Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-CTLA-4 (Tremelimumab) in Patients With Muscle-Invasive, High-Risk Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Neoadjuvant Chemotherapy

Neoadjuvant Nivolumab With and Without Urelumab in Patients With Cisplatin-Ineligible Muscle-Invasive Urothelial Carcinoma of the Bladder

Neoadjuvant Pembrolizumab in Combination With Gemcitabine Therapy in Cis-eligible/Ineligible UC Subjects

References
1.  Grossman HB et al.  N Engl J Med 2003; 349:859-66.
2.  International Collaboration of Trialists et al.  J Clin Oncol 2011; 29:2171-7.
3.  Zaid HB et al.  Urology 2014; 83:75-80.
4.  Lee FC et al.  Adv Urol 2013; 2013:317190.
5.  Galsky MD et al.  J Clin Oncol 2011; 29:2432-8.
6.  Sternberg CN et al.  Eur Urol 2013; 63:58-66.
7.  Yu, EY.  (2017, May 18). No…the ball game is not over...adjuvant trials of PD-1 and PD-L1 antibodies in urothelial carcinoma must go on!