Novel Therapies in Urothelial Carcinoma

A Biomarker-Driven Approach

G. Iyer; J. E. Rosenberg

Disclosures

Ann Oncol. 2018;29(12):2302-2312. 

In This Article

Abstract and Introduction

Abstract

Urothelial malignancies, including carcinomas of the bladder, ureters, and renal pelvis comprised ~8% of new cancer cases in the USA in 2016. In the metastatic setting, 15% of patients exhibit long-term survival following cisplatin-based chemotherapy and in patients with recurrent disease, response rates to second-line chemotherapy are generally 15%–20% with a 3-month progression-free survival. However, recent advances in immunotherapy represent an opportunity to significantly improve patient outcomes. Moreover, the advent of next-generation sequencing has resulted in both an improved understanding of the fundamental genetic changes that characterize urothelial carcinoma (UC) and identification of several candidate biomarkers of response to various therapies. Incorporation of prospective genotyping into clinical trials will allow for the identification and enrichment of patients most likely to respond to specific targeted therapies and chemotherapy. Combining different therapeutic classes to enhance outcomes is also an area of active research in UC.

Introduction

In 2017, ~150 000 people will be diagnosed with UC in the USA and around 32 000 are likely to die of their disease.[1] Urothelial malignancies include carcinomas of the bladder, ureters, and renal pelvis and are more common in men than women (3 : 1) and in Caucasians than African Americans (2 : 1).[2] The most common of the urothelial malignancies, accounting for an estimated 54% of cases and 52% of deaths, is urinary bladder cancer.[1] Tobacco smoking and occupational exposures (e.g. arylamines) are the leading risk factors for developing urothelial bladder carcinoma in the USA and contribute to an increased risk of recurrence.[2,3] Disease stage is closely related to prognosis. Patients with well-differentiated, noninvasive primary papillary lesions (Ta) without carcinoma in situ have a 95% survival rate, whereas those with higher-grade lesions that have invaded the sub-epithelial lamina propria (T1) have a 10-year survival rate of 50%; muscle-invasive urothelial carcinoma (UC) (T2) has a 5-year disease-specific survival rate of 40%–65%.[2] However, a 5-year survival rate of only 0%–30% can be expected if lymph nodes are involved (stage IV).[2]

Patients with organ-confined disease are managed with surgical intervention, chemotherapy, radiotherapy, or a combination of these treatment modalities. Transurethral resection of the bladder tumor (TURBT) with or without intravesical therapy is generally recommended in patients with superficial bladder cancer.[4] Patients with high-grade, recurrent nonmuscle invasive bladder cancer can be managed with radical cystectomy (RC) before the development of muscle invasion.[2,4] Patients with muscle-invasive disease are optimally managed with neoadjuvant cisplatin-based chemotherapy in eligible patients followed by RC and a bilateral pelvic lymph node dissection, or trimodality therapy consisting of a maximal TURBT followed by chemo-radiotherapy.

The chemotherapeutic management of patients with muscle-invasive and metastatic UC has changed little in over 20 years. Platinum-based combinations remain the standard-of-care in perioperative (as neoadjuvant and adjuvant therapy) and first-line metastatic settings.[4] Cisplatin-containing combination chemotherapy with either gemcitabine or methotrexate/vinblastine/doxorubicin is recommended for those patients with advanced surgically unresectable or metastatic disease who are able to tolerate cisplatin.[4] Despite refinements in treatment schedules and toxicity management, median survival achieved with these treatments is 12 − 15 months, either in clinical trials[5–7] or in real-world settings.[8] To address these limitations, intensification strategies including new triplet or quadruplet strategies, or dose-dense therapies, were developed with subsequent improvements in objective response rates but not median overall survival.[9–12]

Advances in the understanding and identification of genetic alterations underlying the spectrum of urothelial malignancies hold out hope for improved outcomes through the development of targeted therapies. Additionally, the recent approval of five immunotherapy agents in the USA has led to a transformation in the management of patients with advanced UC, although only a minority of patients displays responses to this class of agents and predictive biomarkers of sensitivity to immunotherapy have yet to be validated.[13,14] Despite recent treatment advances, there remains an unmet need for the improved management of patients with UC. This paper provides an overview of the current state-of-the art of therapy for urothelial malignancies, provides insight into the paucity of successful treatments, and offers some perspectives on future directions for additional research, with a focus on the benefits of using prospective biomarker-driven approaches to patient management.

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