Renal Cell Carcinoma

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancy and 90% to 95% of neoplasms arising from the kidney.¹ It is the sixth leading cause of cancer death in the United States.² Approximately 31 200 new cases of RCC were diagnosed in the United States in 2000 and more than 11 900 affected individuals died. This disease often presents with few symptoms but it can have diverse paraneoplastic manifestations. It displays relative resistance to radiation and chemotherapy, although there have been occasional durable responses to interleukin 2 (IL-2)–based immunotherapy. Recent insights into the genetic changes associated with RCC have provided new targets for therapy.

Renal cell carcinoma is a challenging diagnosis. It often remains clinically occult for most of its course.The simultaneous presence of the classic clinical triad of flank pain, hematuria, and flank mass is uncommon (10%) and is indicative of advanced disease.³ Twenty-five percent to 39% of patients with RCC are asymptomatic with the diagnosis made incidentally from a radiologic study obtained for other reasons.³ Frequently, the first symptoms are from metastatic lesions or paraneoplastic syndromes, including hypercalcemia, erythrocytosis, and nonmetastatic hepatocellular enzyme elevation (Stauffer syndrome). Polyneuromyopathy, amyloidosis, anemia, fever, cachexia, weight loss, dermatomyositis, and hypertension also are associated with RCC.

Hereditary and nonhereditary (sporadic) renal carcinomas are associated with structural alterations of the short arm of chromosome 3p. At least 4 hereditary syndromes associated with RCC are recognized: von Hippel-Lindau (VHL) syndrome, hereditary papillary renal carcinoma, familial renal oncocytoma associated with Birt-Hogg-Dube syndrome, and hereditary renal carcinoma.⁴

Renal cell carcinoma develops in approximately 40% of patients with VHL disease and is a major cause of death among these patients. Deletions of chromosome 3p occur commonly in RCC associated with VHL disease. The VHL gene is also mutated or displays a loss of heterozygosity in a high percentage of nonhereditary renal carcinomas, resulting in the overproduction of hypoxia-inducible factors with consequent increase in vascular endothelial growth factor (VEGF).^{5 - 6} Vascular endothelial growth factor is one of the most important proangiogenic factors in normal and neoplastic angiogenesis and is a therapeutic target in RCC clinical trials.

Hereditary papillary renal carcinoma is an autosomal dominant inherited disorder. Affected individuals develop bilateral, multifocal papillary renal carcinoma with associated secondary germline mutations in the tyrosine kinase domain of the Met gene. Individuals with familial renal oncocytoma can develop bilateral, multifocal oncocytoma (benign proliferation of renal epithelia) with rare transformation into oncocytic neoplasms of the kidney. The associated Birt-Hogg-Dube syndrome is an autosomal dominant syndrome characterized by predisposition to benign tumors of the hair follicle, colonic polyps or malignancy, and pulmonary cysts.

In the late 1800s, pathologists observed that the lipid content of renal cancer cells was similar to that observed in adrenal tissue. The term hypernephroma was coined by Birch-Hirschfeld in 1894 based on the belief that adrenal rests within the kidney gave rise to kidney cancer.⁷ Although hypernephroma is a misnomer, the term persists in medical usage.

There are 4 major histologic subtypes of renal cancer: clear cell (conventional RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Sarcomatoid changes (morphology showing spindle cells) can be observed within any RCC subtype. Several benign conditions, such as oncocytoma and metanephric adenoma, arise from the proliferation of renal epithelia, but these rarely undergo malignant change. The cell of origin and genetic abnormalities associated with the 4 major histologic subtypes of renal cell carcinoma are shown in Figure 1 and Table 1.⁸

Surgery is the treatment of choice for the initial presentation of RCC. There is no proven role for radiation or chemotherapy as adjuvant treatments. Radiation and chemotherapy can be used for palliation, but they do not confer improvement in disease-free or overall survival. Immunotherapy is appropriate for selected patients with metastatic disease and research protocols are appropriate for many patients.

Resection of the primary site is the only known effective treatment for localized RCC. In selected circumstances, resection is also used for metastatic disease. Radical nephrectomy is the standard surgical procedure for localized renal carcinoma and involves complete removal of Gerota fascia and its contents, including the kidney, perirenal fat, and ipsilateral adrenal gland, with or without an ipsilateral lymph node dissection. Laparoscopic nephrectomy is an attractive alternative for the removal of kidneys with small-volume RCC.⁹ This procedure incurs less morbidity and is associated with shorter recovery time and less blood loss than open nephrectomy. The need for pain medications is also reduced. Twenty percent to 30% of patients with clinically localized disease develop metastatic disease after nephrectomy.³

Approximately 25% to 30% of patients have metastatic disease at diagnosis and more than 95% of these have multiple metastases.¹⁰ Palliative nephrectomy can be considered for alleviation of pain, hemorrhage, malaise, hypercalcemia, erythrocytosis, or hypertension in patients with metastatic disease. Disease-free survival increases after resection of primary tumor and isolated metastasis excision, and a small proportion of patients remain free of recurrence. Studies have also documented regression of metastatic RCC after removal of the primary tumor, although this happens infrequently.¹¹ Recent randomized studies show a survival advantage for patients with metastatic RCC who undergo up-front nephrectomy followed by immunotherapy.^{12 - 13}

Renal cell carcinoma is refractory to most chemotherapeutic agents. Although some chemotherapy agents such as gemcitabine and fluorouracil have activity in RCC, they rarely offer durable remissions. On occasion biological therapies induce durable remission of RCC. One of the first biologics found to have activity in RCC was interferon alfa. Interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. The interferons stimulate host mononuclear cells, enhance expression of major histocompatibility complex molecules, and have a direct antiproliferative effect on renal tumor cells in vitro. Leukocyte-derived interferon alfa has an objective response rate (complete or partial regression of tumor deposits) of approximately 15% (range, 0%-29%).¹⁴ Durable responses are rare.

Another biologic with activity in RCC is IL-2, a T-cell growth factor and activator of T cells and natural killer cells, which affects tumor growth in vivo by activating lymphoid cells without direct effects on tumor proliferation. More than 300 different dose regimens for IL-2 have been described in the literature; however, the highest response rate and the greatest proportion of durable complete responses in patients with metastatic RCC occur with the original high-dose regimen (600 000 to 720 000 IU/kg every 8 hours for 5 days),¹⁵ which results in a 19% response rate with 5% complete responses. Toxicities are a consequence of immune activation and include fever, malaise, capillary leak with resultant hypotension, azotomia, metabolic and electrolyte abnormalites, and neurocortical toxicity. The majority of complete responses to IL-2 were durable. Eighty percent of patients who achieved a complete response were alive 15 years after treatment.¹⁵ The median duration of partial responses to IL-2 is 20 months.

A promising experimental approach to RCC is vaccination to stimulate an immune response. A variety of vaccine strategies have been attempted, including using autologous tumor,¹⁶ autologous tumor with IL-2 or granulocyte-macrophage colony-stimulating factor adjuvant therapy,^{17 - 18} dendritic cell vaccines,¹⁹ or heat shock protein peptide complex 96.²⁰ Vaccine therapy is generally well-tolerated and occasionally can induce antitumor responses. There is a suggestion of a modest prolongation of disease-free interval in a recently published clinical trial in patients with high-risk local disease receiving autologous vaccine.¹⁶ Phase III studies are under way to validate vaccine therapy in RCC.

Nonmyeloablative allogeneic stem-cell transplantation can induce sustained regression of metastatic RCC in patients who have had no response to conventional immunotherapy. In 1 recent trial,²¹ 19 patients with refractory metastatic RCC who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed up with an infusion of peripheral blood stem cells from a human leukocyte antigen–identical sibling or a sibling with a mismatch of a single human leukocyte antigen. Patients with no response received as many as 3 infusions of donor lymphocytes. Two patients died of transplantation-related causes and 8 died from progressive disease. In 10 patients (53%), metastatic disease regressed: 3 patients had a complete response and 7 had a partial response. One of the deaths was in a responding patient. The durations of these responses continue to be assessed. Further clinical trials are needed to confirm these findings and to evaluate long-term benefits.

Knowledge of the VHL gene and its influence on angiogenic pathways has led to a clinical trial of bevacizumab in metastatic RCC.²² Bevacizumab is a humanized antibody against VEGF, which is overexpressed in conventional RCC.A significant prolongation of disease-free survival was achieved with bevacizumab (4.8 months vs 2.5 months with placebo) in patients with clear cell histology whose disease had failed IL-2 therapy. Although there was no significant difference in overall survival, the favorable response to bevacizumab strengthens the evidence that angiogenic pathways influenced by VHL mutations are important in RCC.

Radiation may be used to treat painful osseous lesions or metastatic brain disease. It is sometimes helpful for palliation in patients whose clinical condition precludes surgery. Preoperative radiation therapy yields no survival advantage. Controversies exist concerning postoperative radiation therapy, but it may be considered in patients with perinephric fat extension, adrenal invasion, or involved margins.

A study published in 1999 addressed survival according to TNM stage of disease for patients who had undergone radical nephrectomy.²³ The 5-year disease-specific survival rate was 95% for stage T1 renal carcinoma (tumor <7 cm confined to the kidney) and 88% for stage T2 disease (tumor ≥7 cm confined to the kidney).²³ Patients with T3 renal carcinoma (tumor invading major veins or adrenal) had a 5-year disease-free survival rate of 59%; for those with T4 disease (primary tumor penetrating Gerota capsule), the rate decreased to 20%.²³

Another study of patients with radical nephrectomy, using different staging criteria, showed a survival rate of 12% to 25% for patients with regional lymph node involvement or extracapsular extension.²⁴ Although renal vein involvement did not have a markedly negative effect on prognosis, the 5-year survival rate for patients with stage IIIB RCC (involvement of lymph nodes on the renal hilum) was 18%.²⁴ In patients with effective surgical removal of the renal vein or inferior vena caval thrombus, the 5-year survival rate was 25% to 50%. Five-year survival rates for patients with stage IV disease (metastatic disease) was low (0%-20%).²⁴

Prognostic factors for predicting survival in patients with metastatic RCC have been identified.²⁵ In 1 model, the risk factors were hemoglobin less than the lower limit of normal, corrected calcium of more than 10 mg/dL (>2.5 mmol/L), lactate dehydrogenase of more than 1.5 times the upper limit of normal, less than 1 year from diagnosis to the presence of metastatic disease, and impairment of the patient's functional status (able to perform self-care but unable to do active work or normal activity [Karnofsky performance status of ≤70]). A variety of other prognostic models for RCC have been proposed.^{13 ,26 - 27}

Given the toxicity of currently available immunotherapy for RCC, it would be desirable to identify patients with a greater likelihood of response to high-dose IL-2. Preliminary studies of carbonic anhydrase IX, which regulates the proliferation and angiogenic signals from renal tubular epithelium, have shown that lower expression correlates with poor prognosis and limited response to immunotherapy.²⁸ The Cytokine Working Group²⁹ has analyzed factors influencing response in patients receiving high-dose IL-2. Individuals with clear cell carcinoma who have no granular or sarcomatoid component have a 40% response rate to IL-2. The response rate with non–clear cell histologies, on the other hand, is less than 5%.

Increased understanding of genetic factors that influence the development and growth of RCC are resulting in new therapies. Nephrectomy remains the standard management for localized disease and now has a role in selected patients with metastatic disease. The most successful existing medical therapies for metastatic disease are based on nonspecific stimulation of the immune system but these therapies induce durable remissions in only a minority of patients. A growing knowledge of angiogenesis, renal antigens, and vaccine technology may result in more effective adjuvant therapies and better options for metastatic disease, and newer prognostic factors may help select patients with greater likelihood of response.