Feasibility of Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Patients With Diminished Renal Function

Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy with pelvic lymph node dissection remains the standard of care for patients with muscle-invasive bladder cancer (MIBC) as supported by level I evidence. Carboplatin-based chemotherapy is not an adequate substitute in this treatment setting, therefore assessing patients as being cisplatin-eligible is clinically very important. The consensus definition of cisplatin ineligibility described in a landmark article by Galsky et al almost a decade ago includes the following definitions: Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2, creatinine clearance < 60 mL/min, grade 2 or higher neuropathy, grade 2 or higher hearing loss, and New York Heart Association class III or higher heart failure. It is estimated that up to half of all patients with MIBC may be ineligible for cisplatin-based chemotherapy, most frequently due to diminished renal function. In everyday clinical practice, many patients do get treatment cisplatin-based chemotherapy for glomerular filtration rate (GFR) as low as 40 mL/min, aided by significant hydration and close monitoring of renal function. However the feasibility of cisplatin-based chemotherapy for patients with GFR < 60 mL/min has not been well described and the retrospective review described here was undertaken to address this knowledge gap.

This was a retrospective review of patients with MIBC who underwent cisplatin-based neoadjuvant therapy followed by radical cystectomy at a single institution (Cleveland Clinic) between 2005 and 2016. The GFR prior to the start of neoadjuvant chemotherapy was defined for all patients using both of the most commonly used formulas: Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD). Patients with GFR < 60 mL/min by either formula were compared to patients with GFR ≥ 60 mL/min in terms of tolerability of treatment, ability to undergo radical cystectomy, pathologic responses and long-term clinical outcomes. In total, 30 patients with low GFR and 94 patients with normal GFR were identified. Overall, the groups were pretty comparable in terms of their baseline characteristics aside from patients with low GFR being on average older (median age, 71 vs 65 years). In terms of the chemotherapy regimen used, more patients in the normal GFR group received MVAC rather than a cisplatin/gemcitabine regimen.

In terms of their ability to tolerate chemotherapy, more patients in the low GFR group required early discontinuation of chemotherapy or any chemotherapy modification (dose delays, dose reductions or discontinuation of chemotherapy) relative to patients in the normal GFR group (66% vs 40%). However, the average number of chemotherapy cycles administered was not different among the two groups (3.1 for normal vs 2.8 for low GFR) and importantly there was no difference in time to or rate of completion of curative surgery. Pathologic responses were higher in the group of patients with normal GFR, potentially reflecting more aggressive disease in patients with diminished renal function at baseline. In terms of long-term clinical outcomes, the rates of recurrence and overall survival, although numerically superior in the normal GFR group, were also not significantly different among the two groups.

Overall, this study concluded that cisplatin-based neoadjuvant chemotherapy is feasible even in patients with diminished renal function (GFR < 60 mL/min) and that for carefully selected patients in this group cisplatin-based chemotherapy remains a viable treatment option with appropriate hydration and close monitoring. Although it is important to consider the limitations of a single-institution retrospective study, this remains to date one of the larger patient cohorts to assess the feasibility and outcomes of bladder cancer patients with diminished renal function receiving cisplatin-based neoadjuvant chemotherapy.

It is also important to examine these results in the context of recently completed and currently ongoing clinical trials of neoadjuvant immunotherapy in bladder cancer patients. Two European studies examining neoadjuvant pembrolizumab (PURE-01) and atezolizumab (ABACUS) have demonstrated the clinical benefit of this approach which is also feasible for cisplatin-ineligible patients. Current ongoing studies in the United States that are actively enrolling patients include, among others, a studies of neoadjuvant atezolizumab for cisplatin-ineligible patients (NCT02451423), ipilimumab/nivolumab (NCT03387761), combination of gemcitabine/cisplatin/pembrolizumab through the Hoosier network (NCT02365766), and a cooperative group study run through PreCOG of neoadjuvant nivolumab or combination of nivolumab and lirilumab (NCT03532451). While cisplatin-based chemotherapy remains the standard of care in the neoadjuvant space for patients with muscle-invasive bladder cancer and neoadjuvant immunotherapy treatments have not yet attained regulatory approval, studies like these will be critical in expanding treatment options in this patient population while allowing more patients with diminished renal function to receive systemic treatment prior to curative surgery.

Written by: Vadim S. Koshkin, MD, Assistant Professor, Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, California; Petros Grivas, MD, PhD, Physician, Seattle Cancer Care Alliance, Associate Professor, University of Washington School of Medicine, Clinical Director, Genitourinary Cancers Program, UW Medicine, Seattle, Washington

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