Where are we in the salvage treatment of metastatic bladder cancer?: Beyond the Abstract

More than two decades have passed since the heady days of the eighties when cisplatin-based regimen showed unprecedented hope in the first line treatment of patients with metastatic bladder cancer. These initial reports were followed by subsequent regimens including methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or gemcitabine and cisplatin (GC).

The results were impressive with improvement in objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Unfortunately, the following years were less contributory without efficient salvage treatment options for progressing bladder cancer (1). To date, the only consensual agreement is to rechallenge platinum-sensitive patients who progress no less than six months after the last treatment (2).

Treatment options to salvage recurrent bladder cancer after first-line therapy are limited to small phase II trials. In examining the older agents, monotherapy with ifosfamide was the only viable options achieving an ORR of 20% (3). Newer generations of vinka alkaloids (Vinflunine), anti-folate (Pemetrexed), and anti-microtubules (Paclitaxel) also failed short with an ORR between 5 and 18%. In line with these results, the different treatment combinations evaluated have yielded better ORR without affecting OS (2). The option of administering alternative first-line regimens to salvage recurrent bladder cancer showed interesting results with an ORR of 30% when using MVAC in eligible patients treated previously with GC (4). However, the combination of Gemcitabine and Paclitaxel (GP) was more extensively studied to overcome the toxicities associated with the aforementioned regimens. The initial phase II trial of the GP regimen allowed 30% ORR  but included 21- and 14-day cycles with a 4 months gain in survival with the longer cycle (5). The phase III trial of this regimen compared 6-cycle course of 21-day GP with maintenance treatment until progression and yielded 50% ORR without affecting OS (6). 

The rationale of targeted therapies has been developed in the 1990s. Today, 26 years later, the role of targeted therapies in bladder cancer has not been established. In vivo studies demonstrated potential effect in targeting EGFR, FGFR-3, VEGF, mTOR, STAT3, AR and CD24 (7). Unfortunately, these targets reflect tumor diversity rather than targetable options. Effectively, the results of their inhibition were not replicated in clinical trials even when combined with cytotoxic chemotherapy (8). One promising combination include Pazopanib and weekly Docetaxel yielded 60% ORR and 10.4 months OS (9). The high mutational burden and the molecular heterogeneity of urothelial cancer have paved the way for the immune checkpoint inhibitors (ICI) to continue their success story that started with melanoma, lung cancer and renal cell carcinoma (10). Urothelial cancers have been lately in the spotlight with several phase 1b/2 trials evaluating the efficacy of different anti-PD-1 (Nivolumab and Pembrolizumab) and anti-PD-L1 (Avelumab, Durvalumab and Atezolizumab) in the second line metastatic urothelial cancers. The use of ICI in heavily pretreated patients with high burden of visceral metastasis was characterized by an ORR ranging between 18-31% and an acceptable safety profile with 5-21% grade 3-4 adverse events (11).

The quality of life of patients with metastatic bladder cancer has only recently been evaluated. The trial consisted in comparing Vinflunine to best supportive care in a randomized control phase III design. Vinflunine resulted in improved clinical benefit and did not decrease health-related quality of life (13). This paper by Bellmunt et al. is the first phase III trial in the salvage setting which renders hypothetically Vinflunine as the standard of care in second-line treatment of bladder cancer. However, this study did not compare Vinflunine to the newer agents such as Paclitaxel that did have interestingly similar results in our experience (14). The only conclusion to be retained from these data is that treatments may be beneficial clinically without altering the quality of life. Thus arises the concept of personalizing the treatment to the patient’s characteristics.  

Written by: Elie El Rassy1, Tarek Assi1, Fouad Aoun2

Department of Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Lebanon

Department of Urology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Lebanon

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