Bethesda Handbook of Clinical Oncology, 2nd Edition

Genitourinary

13

Renal Cell Cancer

Hung T. Khong*

Christopher Klebanoff^†

Susan Bates^‡

*USA Cancer Research Institute, University of South Alabama, Mobile, Alabama

^†Emory School of Medicine, Atlanta, Georgia

^‡Cancer Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

EPIDEMIOLOGY

• In the year 2003, there was an estimated 3% of adult malignancies, with 31,900 new cases and 11,900 deaths from renal cancer.
• The male-to-female ratio for renal cancer is 2:1.
• In the United States, the incidence rates for renal cell carcinoma (RCC) are higher among blacks than among whites (Table 13.1).
• Age at diagnosis is usually greater than 40 years, with the median age in the mid-60s.
• Cancer of the renal tubular epithelium accounts for 90% of all malignancies arising in the kidney. Most of the remaining cases are transitional cell carcinoma of the renal pelvis.
• Surveillance, Epidemiology, and End Results (SEER) data indicate that the incidence and mortality rates for RCC have increased steadily in all race and sex groups from 1975 through 1995 (Figs. 13.1 and 13.2; Table 13.1).

ETIOLOGY AND RISK FACTORS

• Tobacco use contributes to one third of all cases of RCC in the United States—current smokers exhibit 40% higher risk than nonsmokers; the risk increases per pack-year history.
• High consumption of fried or sautéed meat is another risk factor.
• Obesity, particularly in women, contributes to the risk for developing RCC.
• Exposure to asbestos and petroleum products increases the chances of developing RCC.
• End-stage renal disease with development of acquired cystic disease of the kidney is a major risk factor; patients with cystic changes in the kidney who undergo dialysis exhibit a 30-times higher risk than the general population.

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• Hereditary disease:

1. von Hippel-Lindau (VHL) disease is a familial syndrome with an autosomal dominant inheritance pattern, associated with retinal hemangiomas, central nervous system (CNS) hemangioblastomas, renal cysts and RCC, pheochromocytoma, and epididymal cysts. RCC is found to develop in 25% of VHL patients (data have been collected from literature reviews: total number of VHL patients is 706 and total number of RCC cases reported is 176). The mean age at onset is 44 years.
2. Hereditary nonpapillary RCC develops because of translocation between the short arm of chromosome 3 (3p) and chromosome 6, 8, or 11, as is seen in some familial RCC kindreds.
3. Hereditary papillary RCC (HPRCC) type I is associated with a mutation of the aMET protooncogene at 7q31.3. aMET encodes a transmembrane receptor tyrosine kinase.
4. Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer that was recently linked to mutations in the fumarate hydratase (FH) gene. The renal cancers may have either type II papillary or collecting duct morphology
5. Renal chromophobe and oncocytoma is linked to the Birt–Hogg–Dubé syndrome, a dermatologic disorder characterized by cutaneous hair follicle tumors (fibrofolliculomas), pulmonary cysts, and renal tumors. The Birt–Hogg–Dubé syndrome gene has been found at 17p11.2 and is associated with chromophobe (34%), oncocytoma (5%), hybrid chromophobe–oncocytomas (50%), clear cell carcinoma (9%), and papillary renal cancer (2%).

PATHOLOGIC CLASSIFICATION

For pathologic classification, see Table 13.2.

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CLINICAL PRESENTATION

The classic triad of hematuria, abdominal pain, and abdominal mass occurs in only 10% of patients (Tables 13.3, 13.4, 13.5, 13.6 and 13.7).

DIAGNOSIS

For diagnosis of RCC in patients, see Table 13.8.

STAGING AND PROGNOSIS

Two commonly used staging systems for RCC are the modified Robson system and the tumor–node–metastases (TNM) system proposed by the American Joint Committee for Cancer

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(AJCC) (Table 13.9). The TNM system is preferred because it more accurately describes the extent of tumor involvement.

Prognosis: 5-year survival rates in patients with RCC based on gender and race is given in Table 13.10 (see Fig. 13.3).

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TREATMENT

Surgery

• Nephrectomy is the only curative treatment for localized RCC.
• Radical nephrectomy is defined as resection of the kidney, ipsilateral adrenal gland, regional lymph nodes, and perirenal fat.
• Lymph node dissection is not therapeutic but allows more accurate staging.
• Ipsilateral adrenalectomy may be reserved for patients with large upper-pole disease and/or with tumor involvement of the adrenal gland, as suggested by computerized tomography (CT).
• Partial nephrectomy may be performed in patients for whom standard nephrectomy would significantly impair renal function. Recent studies have shown that in patients with localized tumors 4 cm or less in greatest dimension (including those patients with unilateral disease and a normal contralateral kidney), nephron-sparing surgery offers long-term disease survival comparable to that obtained after radical nephrectomy.
• In selected stage IV patients who present (or relapse) with a solitary metastasis, nephrectomy and resection of the metastasis may be the primary treatment of choice.
• Adjuvant therapies (radiation or systemic therapy) have not been shown to prevent or decrease relapse rates.
• Nephrectomy should be considered before systemic therapy in select patients with metastatic RCC. Studies have shown improved survival in patients who have undergone nephrectomy followed by immunotherapy for metastatic disease.

Systemic Treatment

Hormone Therapy and Chemotherapy

• Hormone therapy and chemotherapy appear to have little effect on the treatment of metastatic RCC.
• A review of 155 trials that studied 80 single chemotherapeutic agents showed a median overall response rate of 4%. The overall response rates for vinblastine and 5-fluorouracil (5-FU) and for vinblastine and 5-fluorodeoxyuridine (FUDR) were 6% to 9% and 5% to 8%, respectively. A recent trial combining gemcitabine with infusional 5-FU reported a 17% response rate. However, follow-up trials adding to that regimen yielded lower response rates.

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• Patients should be encouraged to enroll in clinical trials.
• A randomized placebo-controlled clinical trial testing the vascular endothelial growth factor (VEGF) antibody, bevacizumab (Avastin), demonstrated an improved time to progression in patients receiving the highest dose, that is, 10 mg per kg (P<0.001).
• New therapeutic agents reported at the 2004 American Society of Clinical Oncology (ASCO) meeting indicated significant response rates in patients with metastatic disease. These agents include SU11248 and BAY 43-9006; both agents are tyrosine kinase inhibitors thought to inhibit the VEGF receptor. It has been reported in abstracts that 24% of patients treated with SU11428 have shown partial response.

Interleukin-2

• High-dose interleukin-2 (IL-2) is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic RCC (Table 13.11).
• Long-acting therapeutic response was seen in a small number of patients treated with high-dose IL-2. (8% of patients showed partial responses, with a median response duration of 54 months for all responses, and 7% of patients exhibited complete responses; median duration for all complete responses has not been reached.) These results have been confirmed in other clinical studies.
• High dose of IL-2: 600,000 to 720,000 U per kg i.v. infused over 15 minutes once every 8 hours until toxicity or up to 14 doses for 5 days. The cycle is repeated once after a 7- to 10-day rest, with one or two additional courses repeated every 6 to 12 weeks if there is evidence of tumor stabilization or regression.
• Low dose (i.v.): 72,000 U per kg i.v. bolus every 8 hours to a maximum of 15 doses every 7 to 10 days for two cycles (one course), with an additional course if there is evidence of tumor stabilization or regression. One or two additional courses may be given if further regression is observed.
• Low dose (s.c.): First 5-day cycle—18 million units per day s.c., for 5 days (week 1). Subsequent 5-day cycles—9 million units per day s.c., for 2 days, and then 18 million units per day s.c., 3 days per week (weeks 2 to 6).

Interferon-α

• Interferon-α (IFN-α) produces response rates of approximately 12% to 15%; 2% to 5% complete responses are generally seen in patients with pulmonary metastases.
• Usual regimens: 5 to 10 MU per m²s.c., three to five times a week or daily.
• A recent randomized study demonstrated a modest survival benefit for nephrectomy in patients with metastatic kidney cancer who were being treated with interferon; the survival in patients treated with interferon and nephrectomy was 11.1 months compared to 8.1 months for patients treated with interferon alone (p= 0.05). A survival advantage was also observed in a similar randomized trial from the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group.

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Combination of Interleukin-2 and Interferon-α

• Recombinant interleukin-2 (rIL-2): 20 million units per m²s.c., days 3 to 5, weeks 1 and 4; 5 million units per m² s.c., days 1, 3, and 5, weeks 2, 3, 5, and 6.
• Recombinant interferon-α 2 (rIFN-α 2): 6 million units per m²s.c., day 1, weeks 1 and 4; 6 million units per m² s.c., days 1, 3, and 5, weeks 2, 3, 5, and 6. Cycle is repeated every 8 weeks.

Notably, several trials reported response rates and overall survival of combination regimens (IL-2 and IFN-α, with or without 5-FU) similar to that of high-dose IL-2 alone.

Other Biologic Therapy

In a recent randomized, phase II trial, the anti-VEGF antibody, bevacizumab, was shown to significantly prolong the time to progression of disease in metastatic–renal cancer patients. There was no statistical difference in overall survival between the treatment and placebo groups in the last analysis.

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