Metastatic urothelial carcinoma is primarily a disease of the elderly, with a median overall survival of approximately 15 months. Cisplatin-based combination chemotherapy is standard first-line treatment for eligible patients, with carboplatin-based regimens used as an alternative for patients considered unfit to receive cisplatin. Prognostic models incorporating clinical risk factors have been validated, and molecular characteristics that predict for treatment response are under investigation. This review summarizes the current status of first-line treatment of metastatic urothelial carcinoma in platinum-eligible patients as well as prognostic and predictive models in this disease.
Key points
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Metastatic urothelial carcinoma occurs primarily in an elderly population.
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The median overall survival of patients with metastatic urothelial carcinoma is approximately 15 months.
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Cisplatin-containing regimens are standard first-line therapy in eligible patients.
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In patients unfit to receive cisplatin, carboplatin-containing regimens are appropriate alternatives.
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Prognostic models incorporating clinical risk factors have been validated; molecular prognostic models are under investigation.
Introduction
Carcinoma of the bladder is a common malignancy in the United States, with an estimated incidence of 74,690 cases in 2014, and a median age at diagnosis of 73 years. Approximately 20% to 25% of all patients develop metastatic disease, resulting in an estimated 15,580 deaths in 2014.
Greater than 90% of urothelial carcinomas (UCs) occur in the bladder, with a smaller number occurring in the ureter, renal pelvis, and urethra. Given the preponderance of disease originating in the bladder, treatments derived from studies of metastatic bladder cancer are extended to patients with UC originating in other sites.
Metastatic UC is generally incurable, with a median survival of approximately 14 to 15 months with modern chemotherapy regimens. The most effective first-line regimens for this disease are cisplatin-based, with carboplatin-based regimens used as an alternative for unfit patients. This article focuses on prognostic and predictive factors for metastatic UC, and reviews the current status of first-line treatment of patients who are eligible for platinum-based therapy.
Introduction
Carcinoma of the bladder is a common malignancy in the United States, with an estimated incidence of 74,690 cases in 2014, and a median age at diagnosis of 73 years. Approximately 20% to 25% of all patients develop metastatic disease, resulting in an estimated 15,580 deaths in 2014.
Greater than 90% of urothelial carcinomas (UCs) occur in the bladder, with a smaller number occurring in the ureter, renal pelvis, and urethra. Given the preponderance of disease originating in the bladder, treatments derived from studies of metastatic bladder cancer are extended to patients with UC originating in other sites.
Metastatic UC is generally incurable, with a median survival of approximately 14 to 15 months with modern chemotherapy regimens. The most effective first-line regimens for this disease are cisplatin-based, with carboplatin-based regimens used as an alternative for unfit patients. This article focuses on prognostic and predictive factors for metastatic UC, and reviews the current status of first-line treatment of patients who are eligible for platinum-based therapy.
First-line treatment of metastatic disease
Combination Cisplatin-Containing Chemotherapy is Standard First-Line Treatment
Cisplatin has been used for the treatment of epithelial malignancies since the 1970s, with initial reports describing response rates ranging from 30% to 70% for advanced UC treated with cisplatin-containing regimens. These response rates were higher than observed with other chemotherapeutic agents at the time, establishing cisplatin as a preferred first-line agent in this disease. One study comparing cisplatin, methotrexate, and vinblastine (CMV) versus methotrexate and vinblastine revealed increased overall survival (OS) in the CMV arm, confirming the advantage of platinum-containing regimens in the first-line setting.
Methotrexate, vinblastine, adriamycin, and cisplatin: standard first-line therapy
A landmark randomized study compared single-agent cisplatin with combination methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) in 269 patients with advanced UC. MVAC was superior with respect to overall response rate (RR) (39% vs 12%), progression-free survival (PFS) (10.0 vs 4.3 months), and median OS (12.5 vs 8.2 months). MVAC was also compared with cisplatin, cyclophosphamide, and doxorubicin (CISCA), and was shown to be superior. These studies established the superiority of MVAC over other cisplatin-containing regimens. However, the toxicity of MVAC was significant, with increased rates of myelosuppression, neutropenic fever, and mucositis limiting the use of this regimen in a primarily elderly population with frequent comorbidities.
Gemcitabine and cisplatin: an appropriate alternative to methotrexate, vinblastine, adriamycin, and cisplatin
In an effort to improve on the response and toxicity of MVAC, cisplatin-containing doublets incorporating other chemotherapeutic agents have been tested. One regimen, gemcitabine and cisplatin (GC), showed promising results in single-arm phase II studies. Based on these findings, this regimen was advanced to a phase III trial comparing it with MVAC in 405 patients with stage IV UC. Both arms had similar RRs (46%–49%) and OS (13.8–14.8 months), with improved toxicity profile in the GC arm. Although this study was designed to show superiority of GC and was underpowered to prove equivalency, the similar disease outcomes and favorable toxicity profile of GC have established this regimen as an appropriate first-line treatment for patients with metastatic UC.
Building on the GC backbone, a phase III randomized study compared paclitaxel, cisplatin, and gemcitabine (PCG) with GC in patients with advanced and metastatic UC. Although RRs were higher in the PCG arm, the study failed to show a statistically significant OS benefit.
Alternative dosing regimens
The advent of growth factor support (granulocyte colony-stimulating factor [G-CSF]) has allowed for the investigation of dose-dense chemotherapy regimens, with the goal of reducing myelosuppression and improving response. A key randomized study compared standard MVAC administered in 4-week cycles and high-dose intensity MVAC (HD-MVAC) administered in 2-week cycles with G-CSF. Although no statistically significant difference in OS was seen, RRs and PFS were higher and toxicity rates were lower in the HD-MVAC arm. As a result, HD-MVAC, also called dose-dense MVAC (ddMVAC), is now considered an option in the first-line setting. ddMVAC was also compared with a dose-dense GC regimen, wherein treatment was administered in 2-week cycles with G-CSF support. This study was limited by premature closure, precluding firm conclusions.
GC was traditionally given in 4-week cycles, with gemcitabine administered on days 1, 8, and 15, resulting in significant rates of hematologic toxicity and treatment delay. Two studies, one in non–small cell lung cancer and the other in metastatic UC, compared 4-week dosing versus a 3-week schedule in which gemcitabine was administered on days 1 and 8. Both found similar RRs, with a better toxicity profile in the 3-week dosing arm, concluding that 3-week dosing of GC is an appropriate alternative. Additionally, in an effort to reduce cisplatin toxicity, several phase II trials investigated GC with split-dose cisplatin, wherein the drug is administered at 35 to 45 mg/m 2 on days 1 and 8 instead of the full dose of 70 mg/m 2 on day 1. All concluded that the split-dose regimen is active and well tolerated. Although no clear evidence shows that split-dose cisplatin is equivalent to full-dose, the studies described earlier suggest that split-dose cisplatin may be a reasonable alternative with less toxicity for selected patients.
Other Platinum Agents in Patients Unfit to Receive Cisplatin
The evidence described previously strongly supports the use of cisplatin in the first-line treatment of patients with metastatic UC. However, cisplatin toxicity limits its use, particularly in patients with a glomerular filtration rate of less than 60 mL/min and those with baseline neuropathy. To this end, regimens incorporating other platinum drugs have been investigated. Several early-phase studies examined gemcitabine and oxaliplatin in patients unfit to receive cisplatin, suggesting that it is an active and tolerable combination in this population, but the regimen has not been tested in larger studies.
Carboplatin combination regimens have been investigated more extensively. However, multiple studies, although underpowered, established the superiority of cisplatin over carboplatin-containing regimens. One such study compared MVAC with methotrexate, carboplatin, and vinblastine (M-CAVI), revealing higher RRs and survival in the MVAC arm. Another randomized study comparing MVAC with carboplatin and paclitaxel closed early because of poor accrual, but seemed to favor the MVAC arm. A third underpowered study comparing GC with gemcitabine and carboplatin also seemed to favor the cisplatin arm.
Despite the apparent superiority of cisplatin to carboplatin, many patients are considered unfit to receive cisplatin because of poor performance status or comorbidities. An expert consensus statement was released in 2011 with the goal of defining unfit patients ( Table 1 ). For those patients, carboplatin-containing regimens may be appropriate because of the toxicity profile. A randomized study compared two carboplatin-containing regimens, M-CAVI and gemcitabine/carboplatin, in unfit patients. Although median survival was comparable, toxicity was significantly lower with gemcitabine/carboplatin, establishing it as an appropriate first-line regimen in this patient population. A triplet regimen consisting of gemcitabine, carboplatin, and paclitaxel was also tested in a phase II trial, revealing a favorable response rate of 68% and median survival of 14.7 months.
| Category | Proposed Severity for ‘Unfit’ Classification (1 Category Must Be Met) |
|---|---|
| Performance status | WHO or ECOG grade 2 or KPS of 60%–70% |
| Renal function | <60 mL/min (calculated or measured) |
| Hearing | CTCAE v4 grade ≥2 audiometric hearing loss |
| Neuropathy | CTCAE v4 grade ≥2 peripheral neuropathy |
| Cardiac function | New York Heart Association class III heart failure |
Targeted Therapies in the First-Line Treatment of Metastatic Disease
The effectiveness of platinum-containing chemotherapy regimens in the first-line treatment of metastatic UC has been established. Current efforts are directed at investigating the added benefit of targeted therapies in this setting. Targeting angiogenesis with bevacizumab has shown promise in early-phase studies. One phase II study treated 43 patients with GC and bevacizumab, showing an overall RR of 72% and median survival of 19.1 months, leading to an ongoing phase III trial. Another study treated 51 patients unfit to receive cisplatin with combination gemcitabine, carboplatin, and bevacizumab. This study reported an RR of 49% and median OS of 13.9 months, but did not strictly meet its PFS end point.
Given the success of immune checkpoint blockade in other epithelial malignancies, significant interest has been shown in investigating the role of immunomodulatory agents in metastatic UC. An ongoing phase II trial is testing the safety and efficacy of the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blocking agent ipilimumab in combination with GC in the first-line setting.
Treatment of Variant Urothelial and Nonurothelial Histologies
More than 90% of cancers of the urinary tract are of urothelial histology, although urothelial histologic variants, including squamous and glandular differentiated tumors, are increasingly being recognized. No prospective studies have specifically addressed the treatment of urothelial variants, and these tumors are treated similarly to those of pure urothelial histology.
Pure nonurothelial urinary tract cancers are rare and poorly studied. Retrospective studies have reported variable responses with platinum-containing regimens. One prospective trial enrolled 20 patients with advanced and metastatic adenocarcinoma, squamous cell, small cell, sarcomatoid, or poorly differentiated carcinoma of the urinary tract, and treated them with combination ifosfamide, paclitaxel, and cisplatin. This regimen was noted to be active in the overall population, with a 35% response rate, albeit with inconclusive outcomes in the small histologic subsets. Pure small cell carcinoma of the bladder has been treated with a variety of platinum-containing regimens extrapolated from small cell lung cancer.
Prognostic and predictive factors
Clinical Prognostic Factors
Drawing on a database of 203 patients treated with MVAC, Bajorin and colleagues developed a prognostic model whereby Karnofsky performance status (KPS) of less than 80% and the presence of bone or visceral metastases present independent risk factors for poor prognosis in unresectable and metastatic disease. This model was subsequently validated in independent series. Recently a prognostic nomogram was developed by Galsky and colleagues, incorporating baseline performance status, number of visceral metastatic sites, white blood cell count, and response to first-line treatment as independent variables predicting survival after completion of first-line therapy.
Molecular Predictive Factors
Significant interest has been shown in identifying molecular factors that accurately predict survival and response to therapy in metastatic UC. However, currently no molecular markers are in standard clinical use in this disease.
Alterations in several genes involved in DNA damage response and repair have been correlated with response to platinum-based therapy. Multiple studies reported an association between high expression of ERCC1 and poor response to platinum-based therapy in metastatic UC and other malignancies. However, other studies found no significant correlation, and a recent report described inconsistent results with antibodies commonly used to score ERCC1 expression. Mutation in another repair gene, ERCC2 , was recently reported to correlate with platinum response in a retrospective study of patients undergoing neoadjuvant therapy for muscle-invasive bladder cancer, although further validation is needed in metastatic disease. The prognostic role of BRCA1 expression has also been investigated, but no clear association between mRNA expression and survival was observed in a retrospective study.
Microarray technology has allowed for the identification of gene signatures associated with UC molecular subtypes and platinum response. Using this technology, Takata and colleagues identified a 14-gene signature that correlates with tumor response to neoadjuvant MVAC. Another group developed an algorithm called COXEN (CO-eXpression gENe analysis) that correlates gene expression with drug response of bladder cancer cell lines, and validated this model in a group of patients treated with neoadjuvant chemotherapy. These algorithms have yet to be validated in metastatic disease. Of significant promise is the large amount of genomic data being generated through international and institutional efforts, including the Cancer Genome Atlas project. Tumor molecular characteristics, correlated retrospectively with clinical outcomes, can guide the way for the identification of prognostic and predictive markers and for the selection of targeted therapies.
Histology and Disease Prognosis
The small numbers of variant and pure nonurothelial histologies have limited investigation of their prognostic role. Although the data are not conclusive, retrospective analyses suggest that nonurothelial histologies result in worse response to chemotherapy and survival compared with UC in metastatic disease.
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