Renal cell carcinoma: diagnosis and treatment, 1994-2003.

Renal cell carcinoma (RCC) is the most common malignancy of the kidney and accounts for approximately 3% of adult cancers (1). RCC is more common in men than in women (ratio 2:1), and the median age at diagnosis is approximately 60 years. Although primarily a cancer of the proximal tubular epithelium (85%), RCC also includes nonepithelial kidney tumors, Wilms' tumor, and tumors of the renal pelvis (1, 2). During 2005, it is estimated that approximately 36,000 new cases of kidney cancer will be diagnosed and 16,000 people will die of the disease in the USA (3). There are wide regional differences in the incidence of RCC in the USA (4). Annual estimates of the incidence for RCC indicate steady increases, with over a third of newly diagnosed patients presenting with advanced or metastatic disease (5–8). Surgical resection (including cytoreduction nephrectomy and/or metastasectomy) remains the most viable treatment option in patients regardless of the stage of disease at presentation (9–11). Despite recent advances in cancer therapy, the prognosis for patients with metastatic RCC remains dismal, with <5% overall 5-year survival. The role of systemic therapy in this setting has been studied; however, it has a limited effect on outcome and overall survival. Based on morphologic, cytogenetic, and molecular criteria, there are five distinguishable types of RCC: clear cell (60%– 80%), papillary (7%–14%), chromophobe (4%–10%), oncocytic (2%–5%), and collecting duct carcinomas (1%–2%) (12, 13). A small percentage of patients have tumors of undefined cellular morphology. Several genetic mutations are associated with hereditary RCC (e.g., von Hippel-Lindau gene and c-met protooncogene). The sporadic forms of clear cell carcinoma likewise have a high frequency of VHL mutations or hypermethylation (6). The various tumor types have widely different disease courses; for example, genetic variants of papillary and collecting duct tumors are particularly aggressive cancers associated with short survival times (14), and eosinophilic variants of chromophobe tumors often have an indolent clinical course (15). Recent evidence suggests increased mortality (median survival of 9.4 months) in patients with non–clear-cell tumors, which tend to be resistant to chemotherapy and immunotherapy (2). Sarcomatoid tumors are high-grade transformants within each tumor type that carry a particularly poor prognosis for survival (16). RCC is classified first according to disease stage and then according to disease grade. Stage of disease, defined using the TNM classification, differentiates size of primary tumor (T0–T4), lymph node involvement (N0–N2), and extent of metastasis into the vena cava and other tissues (M0–M1) (17). Tumor (nuclear) grade (G1–G4) reflects the differentiation of tumor cells as defined microscopically by increased nuclear size, irregularity, and nucleolar prominence (18). Nuclear grade is highly predictive of the development of metastatic disease. Surgical resection (nephrectomy and partial nephrectomy) is the preferred treatment for localized primary tumors in patients with stage I through stage IV disease, but surgical cure of disease is strongly dependent on stage and grade of disease. For example, following radical nephrectomy, the overall 5-year survival of patients with stage IV disease is only 29.1%, with a corresponding 10-year survival of 0%. In contrast, patients with stage I disease have estimated 5-and 10-year survival rates of nearly 100% (19). Patients with metastatic RCC have a poor prognosis, and relapse from therapy is common: those with larger renal or lymph node–positive tumors have postoperative metastatic recurrence rates of 59% by 12 months, 83% by 24 months, and 93% by 36 months (20). Radical nephrectomy combined with immunotherapy has been shown to significantly increase survival in patients with metastatic RCC beyond time periods achieved with immunotherapy alone (21, 22). However, nephrectomy may have limited clinical benefit in patients with unresectable or metastatic RCC. These patients, and those with recurrent disease following therapy, are candidates for additional chemotherapy or immunotherapy. A variety of cytokines have been studied in patients with metastatic RCC. Two of these agents, interleukin 2 (rIL-2) and interferon-alpha (IFNα), have reproducible antitumor effects: objective response rates of 15% to 31%, which may be durable in some patients (23–33). Unfortunately, the majority of patients with metastatic RCC do not benefit from these therapies. At present, four novel agents with significantly greater antitumor activity are under evaluation in large, multinational phase III trials. It is expected that several will be approved by the Food and Drug Administration within the next 1 to 2 years.