Chemotherapeutic Agents for Urologic Oncology

Introduction

The main goal of chemotherapy is to cure cancer by killing the neoplastic cells. To keep the cancer from metastasizing, chemotherapy may be used in combination with other cancer treatments, such as surgery and radiotherapy. In widespread, fast-growing cancers, chemotherapy reduces cellular proliferation, eases symptoms, and improves the quality of life. When it is employed after the primary tumor has been treated by some other modality,it is called adjuvant chemotherapy. Sometimes neoadjuvant chemotherapy is employed, which refers to the initial use of chemotherapy in patients with localized cancer in order to reduce tumor burden, there by rendering local therapy (surgery or radiotherapy) more effective. A common procedure in human cancer therapy is combination chemotherapy that refers to the parallel or sequential use of several different antineoplastic agents in order to enhance their effectiveness. Combining chemotherapy with targeted therapies is an investigational approach under development. This chapter presents a comprehensive overview of the use of chemotherapeutics and targeted agents in the treatment of urologic malignancies.

Bladder Cancer

Bladder cancer is the most common malignancy of the urinary tract and as the incidence of the

disease rises, more effective treatment options are urgently needed.

Non-muscle Invasive (TaT1)

Bladder Cancer

At initial diagnosis, most bladder tumors are stage Ta or T1 papillary tumors. Non-muscle invasive papillary bladder cancer is managed with transurethral resection (TUR) of the tumor and for most patients with one immediate postoperative intravesical instillation of chemotherapy within 6 h after tumor resection. The choice of drug (mitomycin C, epirubicin or doxorubicin) is optional, and no single drug can be considered superior with regards to efficacy.1,2 Further treatment depends on the patient’s risk of recurrence and progression to muscleinvasive disease. In order to predict this risk, a scoring system and risk tables have been developed based on the European Organisation for Research and Treatment of Cancer (EORTC) database, which provided individual data of 2,596 patients diagnosed with TaT1 tumors and randomized in seven studies.2,3 Table 13.1 provides a scoring system based on the most significant clinical and pathological characteristics. The European Association of Urology (EAU) working group suggests to use a three-tier system reflecting the EORTC risk tables, which defines low-,intermediate-,and high-risk groups for recurrence and progression (Table 13.2). In patients at low risk of tumor recurrence and

CIS carcinoma in situ.

progression, no further treatment is recommended before recurrence.1,2 Immediate instillation of chemotherapy is contraindicated in patients with known or suspected bladder perforation following TUR as severe complications related to extravasation of the drug have been reported. In patients at an intermediate or high risk of recurrence and an intermediate risk of progression, one immediate instillation of chemotherapy should be followed by additional adjuvant intravesical chemotherapy or a minimum of 1 year Bacillus Calmette-Guérin (BCG) immunotherapy. A meta-analysis comparing intravesical chemotherapy to TUR alone,showed

Muscle Invasive Bladder Cancer

For patients with stage T2 or higher muscle invasive cancers, treatment is usually radical cystectomy. However, this standard treatment only provides 5-year survival in about 50% of patients.8,9 Several randomized phase III studies have demonstrated a 5–7% improvement in survival at 5 years after neoadjuvant cisplatin-con- taining combination chemotherapy in muscle invasive bladder cancer, irrespective of the type of definite treatment (about 82% chemo combination regimens).10-12 This strategy is not recommended in patients with performance status³2 and impaired renal function. It is important to note that chemotherapy alone is not recommended as primary therapy for localized bladder cancer.9 Chemotherapy can be used as a component of a bladder-preserving strategy that combines TUR and chemotherapy with or without radiation.9,13 This multimodality bladder-preserving strategy is a reasonable option for carefully selected patients seeking an alternative to radical cystectomy with a comparable long-term survival rate of 50–60% at 5 years’ follow-up. Although bladder-preserving

strategies may be appealing in a small proportion of patients, these protocols should be considered investigational because cystectomy and bladder-sparing strategy have never been directly compared in a randomized trial.9,13 Even if a patient has shown a complete response, close surveillance for the potential development of recurrences remains necessary. To date, the use of adjuvant chemotherapy after radical cystectomy for patients with pT3/4 and/or lymph node positive disease (N+) without clinically detectable metastases is still debated. So far, it should only be used in the context of clinical trials.9

Metastatic Bladder Cancer

Responses with single-agent chemotherapy in patients with metastatic bladder cancer are usually of short duration and complete responses are rare. The median survival in these patients is only about 6–9 months.9 Cisplatincontaining combination chemotherapy with gemcitabine-cisplatin (GC), methotrexate-vin- blastine-adriamycin-cisplatin (M-VAC), preferably with granulocyte-colony stimulating factor (G-CSF), or high-dose intensity M-VAC

(HD-MVAC) with G-CSF is the standard firstline chemotherapy for “fit” patients with metastatic bladder cancer. Cisplatin-containing combination chemotherapy (M-VAC and GC) is able to achieve a median survival of up to 14 months, while before the development of effective chemotherapy patients with metastatic urothelial cancer rarely exceeded the median survival of 3–6 months. HD-MVAC with GCSF is less toxic and more efficacious than classic M-VAC in terms of dose density, complete response, and 2-year survival rate. However, there is no significant difference in median survival between the two regimens (15.1 months for HD-MVAC and 14.9 months for M-VAC).9,18 Several newer regimens have failed to demonstrate superiority in terms of overall survival (OS) when compared to classic M-VAC. The addition of a third agent to doublet combinations is still being studied.Performance status and the presence or absence of visceral metastases are independent prognostic factors for survival and are at least as important as the type of chemotherapy administered. Besides these prognostic factors, treatment decisions should be based on a patient’s renal function to decide whether the patient is “fit” enough to