What is the role of systemic chemotherapy in renal transitional cell carcinoma treatment?

Updated: Nov 05, 2019
  • Author: Bagi RP Jana, MD, MBA, MHA, FACP; Chief Editor: E Jason Abel, MD  more...
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Answer

The combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is the best-studied chemotherapy regimen for upper urinary tract TCC. Durable, complete responses were obtained in only 5-10% of patients. Serious complications were encountered in 41% of patients; treatment-related mortality was 2-4%.

Gemcitabine-based combinations (gemcitabine + cisplatin or carboplatin) have activity similar to MVAC in bladder cancer but are associated with less toxicity. [16] Some studies found the combination of gemcitabine and paclitaxel to be as effective as cisplatin-based therapies, with less nephrotoxicity. However, in a study compared the incidence of vascular thromboembolic events (VTEs) in patients with metastatic or unresectable UC who were treated with gemcitabine and carboplatin (GCb); gemcitabine, carboplatin, and bevacizumab (GCbBev), or gemcitabine and cisplatin (GCis), researchers found high incidence (>20%) of VTEs in patients treated with GCb and GCbBev. [17]

A meta-analysis by Giannatempo et al concluded that adding a taxane (paclitaxel or docetaxel) to gemcitabine and platinum as first-line therapy for advanced or metastatic UC showed a trend for improved overall survival. Median overall survival with taxanes was 15.5 mo, versus 12.5 mo without taxanes (P=0.056). However, the addition of a taxane led to an increase in grade 3 or higher neurotoxicity P=0.051), regardless of the specific platinum agent used. [18]

In a retrospective study, DiLorenzo and colleagues found that approximately half of the patients treated with second-line chemotherapy went on to receive third-line treatment. The study also found the median overall survival associated with the use of third-line chemotherapy was 31 (28–36) weeks. Significantly longer overall survival was seen in patients receiving single-agent cyclophosphamide than in patients treated with platinum-based combinations. [19]

Immunotherapy with checkpoint inhibitors is a promising development in the treatment of urothelial carcinoma. Atezolizumab, a monoclonal antibody to programmed death ligand 1 (PD-L1), was approved in May 2016 for treatment of locally advanced or metastatic urothelial carcinoma of the bladder in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. [20]

A phase II trial of atezolizumab as first-line treatment in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin therapy demonstrated encouraging durable response rates, survival, and tolerability. [21]

Nivolumab, a monoclonal antibody to programmed death–1 receptor (PD-1) was approved in February 2017 for treatment of locally advanced or metastatic urothelial carcinoma of the bladder in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. [22]

Clinical trials of other immune checkpoint inhibitors, including pembrolizumab, durvalumab, avelumab, and a combination of nivolumab and ipilimumab are in advanced stages, and are expected to lead to approval of many of these agents or combinations in the near future. [23]

Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immunotherapy. In an open-label phase II study of erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, Loriot et al reported an objective tumor response in 40% of previously treated patients with locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. [24]


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