The use of chemotherapy in the treatment of malignant tumors of the genitourinary system serves as a paradigm for a multidisciplinary approach to cancer. The careful integration of surgical and chemotherapeutic treatments has resulted in impressive advances in the management of urologic cancer. By definition, surgical interventions are directed at local management of urologic tumors, whereas chemotherapy and biologic therapy are systemic in nature. Although there is no question that there are times in the natural history of a genitourinary tumor when only one therapeutic method is required, a multidisciplinary approach is always called for. This chapter details the importance of a joint surgical–medical approach to patients with urologic cancer. A practicing urologist should collaborate closely with a medical oncologist and should feel comfortable speaking with patients about the uses, risks, and benefits of chemotherapy.

Clinical Uses of Chemotherapy

Systemic therapy is indicated in the treatment of disseminated cancer when either cure or palliation is the goal. In addition, chemotherapy may be used as part of a multimodality treatment plan in an effort to improve both local and distant control of the tumor. An understanding of the goals and limitations of systemic therapy in each of these settings is essential for its effective use.

Curative Intent of Metastatic Disease

In considering the role of potentially curative chemotherapy in patients with metastatic disease, several factors must be taken into account. The first is the responsiveness of the tumor. Responsiveness is generally defined by the observed partial or complete responses that together constitute the overall objective response rate. The assessment of neoplasms with frequent bony metastases such as prostate cancer, renal cell carcinoma, and transitional cell carcinoma (TCC) is difficult, as a persistently abnormal bone scan does not necessarily imply residual cancer. Patients in whom the only site of disease is bone generally must be considered nonassessable by conventional measures, and if available, intermediate markers of response (such as prostate-specific antigen [PSA]) are required. The transient worsening appearance of a bone scan with therapy but which represents healing bone is termed “bone scan flare,” and can be indistinguishable from true disease progression. For this reason, assessment of all parameters including symptomatology, PSA in prostate cancer patients, CT and MRI is essential. For patients with metastatic prostate cancer in whom bone scan flare is suspected or possible, repeating scans several months later is essential.

If cure is the intent with systemic therapy, the relevant response criterion to consider is the percentage of patients achieving a complete response. This number is less than 10% in patients with metastatic renal cell carcinoma and hormone-refractory prostate cancer, 25% or less in patients with metastatic transitional cell carcinoma, and up to 80% in patients with metastatic germ cell malignancies. Under some circumstances, however (for example, in postchemotherapy residual masses in patients with germ cell carcinoma), an apparent partial response can be converted into a complete response with judicious resection (see Section Systemic Therapy Used in Conjunction with Surgery: Adjuvant and Neoadjuvant Therapy).

The second feature to consider in treating patients with potentially curative systemic therapy is the anticipated toxicity of such therapy. In general, higher levels of toxicity are acceptable if a cure can be achieved, although care must be exercised to avoid a “cure worse than the disease.” This is particularly true in the case of fairly toxic therapies such as interleukin-2 or bone marrow transplantation. These treatments can result in apparent cures of approximately 10% and 30%, respectively, of patients with metastatic renal cell carcinoma or refractory germ cell tumors (GCTs). Patients undergoing these rigorous therapies must be carefully selected and must be as fully informed as possible about potential toxicities.

Treatment of Patients with Incurable Metastatic Cancer

When the goal of systemic therapy is palliation of symptoms rather than cure, the toxicity of the treatment to be offered must be balanced against the cancer-related symptoms the patient is experiencing, and in general, more toxic therapies are not indicated. Nonetheless, an understanding of the potential capabilities of systemic therapy must be understood because even in otherwise incurable disease there may be a role for systemic therapy if there is a likelihood that the patient’s life can be prolonged with its use. This is the case for docetaxel or cabazitaxel therapy in prostate cancer and combination cisplatinum based chemotherapy in bladder cancer. In addition, systemic chemotherapy can be associated with a control of pain, and an improvement in quality of life. This appears to be the case for both mitoxantrone and docetaxel in patients with metastatic hormone refractory prostate cancer.

Systemic Therapy Used in Conjunction with Surgery: Adjuvant and Neoadjuvant Therapy

Systemic therapy administered after a patient has been rendered free of disease surgically is termed adjuvant therapy. Several important criteria must be met if adjuvant therapy is to be used outside of a research setting. First, an assessment must be undertaken of known risk factors predictive of relapse or development of distant metastases. Patients at low risk of relapse generally should not receive adjuvant therapy because they are unlikely to derive a benefit and will be unnecessarily exposed to the toxicity of therapy. Second, the proposed therapy must have been shown to decrease the rate of relapse and increase the disease-free interval (and, it is hoped, survival) in a randomized, phase III trial. Finally, because patients who are being treated with adjuvant therapy are free of disease and presumably asymptomatic, toxicity must be kept at a minimum. This opens the way to a tailored approach in which patients with high-risk disease, as determined by pathologic review of the surgical specimen, are treated in order to decrease the risk of micrometastatic disease.

By contrast, neoadjuvant therapy is administered before definitive surgical resection. Here, the potential advantages include early therapy of micrometastatic disease and tumor debulking to allow a more complete resection. Patients with known metastatic disease generally do not exhibit high enough response rates to systemic therapy to warrant local surgery following chemotherapy, with the clear exception of patients with GCT. Whether or not patients with metastatic renal cell carcinoma who exhibit a partial response to systemic therapy may benefit from resection of residual masses is not known. As with adjuvant therapy, the proposed therapy must have been demonstrated to impact favorably on rate of relapse, disease-free interval, and survival in a randomized phase III trial.

Chemotherapeutic Agents and Their Toxicity

The usefulness of antineoplastic agents lies in their therapeutic index or preferential toxicity to malignant cells over normal, nonmalignant cells. The mechanism of action of most chemotherapeutic drugs is based on their toxicity to rapidly dividing cells. Thus, in general, malignancies that have relatively rapid growth, such as GCT, are relatively chemosensitive, whereas slower growing neoplasms such as renal cell carcinoma are less sensitive. Toxicity from chemotherapeutic agents is seen primarily in normal, nonmalignant cells that are also rapidly dividing, such as hematopoietic cells in the bone marrow, gastrointestinal mucosa, and hair follicles, and is manifested in cytopenias, mucositis, and alopecia. Other common toxicities observed with agents frequently used in the treatment of genitourinary malignancies include nephrotoxicity, neurotoxicity, hemorrhagic cystitis, pulmonary fibrosis, and cardiotoxicity. Table 20–1 summarizes the spectrum of activity and primary toxicities of commonly used chemotherapeutic agents.