A Review of Renal Cell Carcinoma

US Pharm. 2007;32(1)(Oncology suppl):7-21.

In the United States, kidney cancer (renal cell carcinoma) is estimated to be the seventh most common cancerous condition diagnosed in men and the 13th most common in women, accounting for 2.7% of all malignant conditions.¹ Throughout 2006, an estimated 38,890 new cases of kidney and renal pelvis cancer will be diagnosed, and approximately 13,000 patients with the disease will die.¹ Renal cell carcinoma occurs in a male-female ratio of 1.7:1, with peak incidence in the sixth to eighth decades of life.^1-4 It is more prevalent in persons of northern European ancestry than in those of Asian or African descent.² There has been a steady increase in the incidence of renal cell carcinoma over the past several decades, which may be partly explained by greater use of diagnostic imaging. In addition, mortality rates among patients with renal cell carcinoma have increased over the past two decades.^2,3

Etiology and Risk Factors
Renal cell carcinoma commonly occurs in sporadic form, and only 1% to 4% of renal cell carcinoma cases are associated with an inherited syndrome.⁴ While the specific etiology of sporadic renal cell carcinoma is unknown, several possible causal factors have been examined.^2,5

Cigarette smoking contributes to 24% to 30% of renal cell carcinoma cases. Additionally, persons with cystic kidney disease undergoing chronic dialysis are estimated to have a 30- to 100-fold increased risk of renal cell carcinoma.^2,5 Other risk factors include hypertension, diuretic use, phenacetin use, and obesity. Environmental and occupational exposure to toxins may also predispose persons to an increased risk of renal cell carcinoma, although this has not been proved with absolute certainty.⁵ 

Renal cell carcinoma is also associated with von Hippel-Lindau (VHL) disease, an autosomal-dominant disease. Evidence has shown that the VHL gene is mutated in a high percentage of tumors among patients with sporadic clear cell renal carcinoma.^2,5,6 Other chromosomal abnormalities, such as deletions and translocation of chromosome 3p, are also associated with VHL disease and sporadic renal cell carcinoma.²

Symptoms and Clinical Presentation
A variety of symptoms of renal cell carcinoma may occur, although most patients remain asymptomatic until the disease becomes advanced. Hematuria (i.e., blood in the urine) is the most common symptom upon clinical presentation. Pain, hematuria, and an abdominal or flank mass occur in approximately 10% of patients. This classic triad of symptoms is indicative of metastatic disease and is associated with a poor prognosis. Other common symptoms include normocytic/normochromic anemia, fever, and weight loss. Less common but often described symptoms include hypercalcemia, polycythemia, and hepatic dysfunction not associated with liver metastases.^2,5

Forty-five percent of patients present with localized disease, while 25% present with locally advanced disease, and 30% present with metastatic disease. The most common sites for metastases are lung, soft tissues, bone, and liver.⁵

Diagnosis
Currently, there are no recommended screening modalities for the early diagnosis of renal cell carcinoma. Diagnosing suspected renal cell carcinoma begins with a careful medical history evaluation and a physical examination. The medical history assessment should include the identification of potential risk factors as well as an evaluation of the patient's symptoms. 

If renal cell carcinoma is suspected, additional studies should be performed. Radiographic evaluation can determine the presence of a renal mass and aid in diagnosis. There is no single imaging method that is best for diagnosing renal cell carcinoma. Abdominal and pelvic CT, renal ultrasound, renal arteriography, renal venography, and abdominal and pelvic MRI can each provide unique information regarding tumor size and extent of extrarenal disease. Multiple imaging techniques are often utilized to provide the greatest amount of information possible.^2,5

Contrast-enhanced CT is the technique of choice for imaging a renal mass because it is able to provide information about renal artery and vein involvement as well as local lymph node involvement, and because it can usually differentiate cystic masses from solid masses.^2,5 CT can provide the following information about a tumor: size, location, relationship to local vessels, presence of extracapsular spread, and whether there is invasion to adjacent organs.

Ultrasound provides information about extrarenal extension of tumor, lymph node involvement, adrenal involvement, and infiltration of adjacent viscera. Ultrasound is also useful for differentiating between solid and cystic masses.

MRI may be helpful when ultrasound and CT are nondiagnostic and/or when radiographic contrast cannot be administered due to poor renal function or allergy. MRI may also be helpful in identifying the extent of involvement with the nephron collecting system or inferior vena cava, showing local anatomy, and identifying whether direct capsular spread is present.²

Renal arteriography is not commonly used to diagnose renal cell carcinoma but may be useful in patients with a small, indeterminate renal mass or for defining large tumor vasculature in patients undergoing surgery.

An evaluation of extra-abdominal disease sites must also be done to look for potential metastatic tumor sites. Lung or bone involvement can be identified with the use of chest x-ray. Chest CT is usually unnecessary if chest x-ray results are normal. If a patient has an elevated alkaline phosphate level or symptoms suggestive of bone metastases, a bone scan should be performed.² Head CT might also be performed to evaluate whether brain metastases are present.

Histology
Pathologic classification of kidney cancers is based upon cell of origin and tumor location.⁶ Eighty-five percent to 90% of kidney cancers are renal cell carcinomas that begin within renal cortex epithelium.^3,6 There are a number of different histology types that occur in renal epithelium malignancies; 75% of cases are of clear cell histology, 15% are of either type 1 or type 2 papillary histology, and 5% are of chromophobe and oncocytic histology.⁵ Each histology has a different clinical course and is caused by different genes. In general, clear cell carcinomas tend to behave aggressively, while chromophobic carcinomas are more indolent.⁷

Staging and Prognosis
Historically, the most common staging system used was the Robson modification of the Flocks and Kadesky system.⁵ In the mid-1980s, the tumor, nodes, and metastases (TNM) classification system was introduced and validated by the American Joint Committee on Cancer.⁷ By the mid to late 1990s, the TNM system, a more accurate method for classifying the extent of tumor involvement, took precedence for kidney cancer staging.

The TNM system classifies cancer stages based on the size of the tumor, the extent of local invasion, the number of regional positive lymph nodes, and the presence of distant metastasis (Tables 1 and 2). TNM stage is the most consistent variable determining patient prognosis. Survival decreases as stage of disease increases (Figure 1).^5,7 The majority of patients are diagnosed with localized disease, as seen in Figure 2.

Another important variable in prognosis is the performance status of the patient, which is commonly assessed using the Eastern Cooperative Oncology Group (ECOG) performance status scale ( Table 3).⁷ Patients with an ECOG performance status score from 0 to 2 may be more likely to tolerate aggressive therapy, whereas patients with a performance status score of 3 or 4 may not be able to tolerate surgery or other therapies.^5,7

Other factors that influence survival include clinical signs and symptoms (fever and weight loss), laboratory values (e.g., serum lactate dehydrogenase, serum calcium concentration, and hemoglobin level), and tumor grade and histology.^5,7,8 Progression-free interval is also an indicator of survival. The longer the interval between definitive treatment and disease recurrence, the longer the projected survival.³ Factors influencing prognosis are listed in Table 4.

The University of California, Los Angeles, Integrated Staging System (UISS) incorporates histological grade and performance status into the TNM classification system.^5,7 Although not widely used currently, integrated staging systems may be used with more frequency in the future.

Treatment
Management options for renal cell carcinoma are determined by stage of disease.³

Localized (Stage I-III) Renal Cell Carcinoma

Surgery: Surgery is the only known curative therapy for early-stage renal cell carcinoma. Radical nephrectomy, which includes complete removal of the Gerota's fascia, kidney, and ipsilateral adrenal gland, is considered the gold standard.^5,7,9

Most patients who undergo surgery as treatment for localized disease are able to achieve disease control. About 20% to 30% of patients experience relapse.³ Most relapses occur systemically, with metastases in the lungs being the most common distant site and occurring in more than half of patients.³ Less than 2% of radical nephrectomy patients and approximately 3% of partial nephrectomy patients experience local recurrence (i.e., recurrence at the operative site or regional lymph nodes).⁷ Most relapses occur within three years of nephrectomy, with a median time to relapse of one to two years. Local recurrences can be successfully treated with surgery. In patients who may be left with little or no renal function following radical nephrectomy, partial nephrectomy may help to preserve the kidney to ensure adequate kidney function.¹⁰

Adjuvant Therapy: There is no role for adjuvant therapy in patients with localized renal carcinoma except under investigational protocol. Radiation, chemotherapy, and biologic or immunomodulating therapies have not been shown to reduce relapse rates following definitive surgical treatment. Observation after nephrectomy is currently the standard of care for disease stages I, II, and III.³  

Advanced (Stage IV) Renal Cell Carcinoma
Surgery: Surgery as palliative therapy may be considered for a select group of patients. Patients with a solitary site of metastasis or patients with a solitary recurrence following nephrectomy are considered surgical candidates. Additionally, patients with symptoms related to the primary tumor and bulkiness of disease--such as fever, nausea, pain, or gastrointestinal obstruction--may have a nephrectomy to improve their quality of life. ³

Neoadjuvant Therapy: Improvement in survival has been seen with the administration of immunomodulating therapy before surgery.^3,5 A pooled analysis from two trials showed a 5.8-month increase in median survival with the addition of interferon-alpha before cytoreductive nephrectomy.¹¹

Adjuvant Therapy: The National Comprehensive Cancer Network (NCCN) Kidney Cancer Clinical Practice Guidelines advise that patients with good prognostic features, good performance status, and metastases only to the lung are most likely to benefit from systemic therapy after nephrectomy.³

Chemotherapy: Renal cell carcinoma is minimally responsive to chemotherapy. A comprehensive review of 83 trials involving more than 4,000 patients reported a chemotherapy response rate of 6%.¹² 

Historically, patients have shown some response to therapy with the single agents floxuridine, 5-fluorouracil, and vinblastine. Floxuridine and 5-fluorouracil are antimetabolites that work by inhibiting thymidylate synthase, a pivotal enzyme that catalyzes the de novo production of thymidylate and thymidine nucleotides that are necessary for DNA synthesis.⁵ Vinblastine binds to tubulin, causing inhibition of the mitosis phase of the cell cycle.⁵ A comprehensive review reported overall response rates of 43% or lower in patients receiving floxuridine, an overall response rate of 10% in patients taking 5-fluorouracil, and overall response rates of 7% or lower in patients receiving vinblastine.⁵ 

More recently, single-agent therapy with capecitabine or gemcitabine has shown some benefit when used in patients with metastatic disease. A phase II study evaluating the use of capecitabine in 26 patients in whom first- or second-line therapy with immunotherapy had failed found that 8.7% of patients exhibited a partial response.¹³ Another phase II trial evaluating the use of gemcitabine in 37 patients with metastatic or inoperable renal cell carcinoma yielded a response rate of 8.1%.¹⁴

Multiple studies have been done evaluating combination chemotherapy regimens for advanced-stage renal cell carcinoma. Clinical trials evaluating the safety and efficacy of combinations using 5-fluoropyrimidines and gemcitabine are currently under way. Two recent trials using different combinations of capecitabine and gemcitabine have reported a partial response rate of 15%, with 53% of patients having stable disease.^15,16 Another trial using a combination of gemcitabine and 5-fluorouracil has demonstrated a partial response rate of 17%. ¹⁷ However, until more information is available, combination chemotherapy for metastatic renal cell carcinoma remains investigational.

The chemoresistance exhibited by renal cell carcinoma is unexplained, and consequently, unlike other solid tumor treatments, chemotherapy is not commonly pursued as treatment for advanced kidney cancer. The NCCN guidelines recommend single-agent chemotherapy as an option for first-line treatment of metastatic renal cell carcinoma in patients with non–clear cell histology.³

Hormone Therapy: Since the 1960s, progestins and androgens have been evaluated for use in the treatment of renal cell carcinoma. Medroxyprogesterone acetate has been used in the past, but efficacy has been found to be poor, with an overall response rate of 2%.⁵ This agent is not recommended as systemic therapy for metastatic renal cell carcinoma.³

The antiestrogen tamoxifen has also been studied as a treatment for metastatic renal cell carcinoma. Unfortunately, response rates were low, ranging from 3% to 7%.⁵ Toremifene, another antiestrogen, showed an initial response rate of 17%; however, additional studies have been unable to duplicate this response.⁵ Anti­ estrogens are not recommended as a treatment option for stage IV renal cell carcinoma.³

Immunotherapy: Renal cell carcinoma transiently evokes an immune response that results in spontaneous and dramatic remissions. Unfortunately, review of cases of spontaneous regression shows that the majority of them are short lived, with duration of response lasting two to 13 months.⁵ Consequently, the phenomenon of spontaneous regression should not be depended upon as therapy for renal carcinoma.

The immune system is utilized to treat renal cell carcinoma through multiple complex mechanisms. Immunomodulating pharmacologic agents are used to stimulate the activity of the immune system. 

Interferon alpha was the first cytokine to be investigated as a treatment for renal cell carcinoma. Interferon alpha is a protein with the ability to enhance phagocytic activity of macrophages, increase the cytotoxicity of natural killer cells, enhance the major histocompatibility antigen presentation pathway, and inhibit cell proliferation. Side effects of interferon alpha include fever, constitutional symptoms, fatigue, injection-site reactions, myelosuppression, skin rash, and neurologic effects. Constitutional symptoms and fatigue are considered to be dose-limiting toxicities, and there is a black box warning associated with a low incidence of life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.⁵

A multivariate analysis in which patients with advanced renal cell carcinoma were treated with interferon alpha concluded that the overall response rate was approximately 10%, with a median survival duration of 11.4 months and a five-year survival rate of 3%. ¹⁸ Additional studies have reported response rates of 29% or lower.⁵

Interferon alpha is not FDA approved for renal cell carcinoma, but it is listed as a treatment option for metastatic renal cell carcinoma in the NCCN guidelines.³ The optimal dose, schedule, and route of administration for interferon alpha is not known. Several regimens and their respective response rates are listed in Table 5. Although a small but significant benefit has been seen with use of interferon alpha, risks such as toxicity from chronic therapy and lack of long-term benefit should be considered.

Another immunomodulating therapy used for the treatment of renal cell carcinoma is interleukin-2 (IL-2). IL-2 is an autocrine factor with several immunoregulatory properties that influences the activity of T cells and natural killer cells. Recombinant human IL-2, known as Aldesleukin, is produced by genetically engineering bacteria. Aldesleukin is one of the few agents approved by the FDA for the treatment of metastatic renal cell carcinoma.

IL-2 may be administered in varying doses and schedules.^3,5 Several regimens and their respective response rates are listed in Table 6. High-dose regimens of IL-2 have demonstrated remission rates of 10% to 20%, with a median duration of response of 19 to 91 months.¹¹ Unfortunately, the high-dose regimen is associated with several severe side effects, including severe hypotension and tachycardia, capillary leak syndrome, infection, myocardial infarction, pulmonary edema, renal insufficiency, hepatic insufficiency, and central nervous system disturbances.⁵ Constitutional symptoms are also common. Due to the severity of side effects, patients receiving high-dose IL-2 are treated in an ICU setting, where frequent monitoring is available and supportive care measures can be rapidly initiated.⁵

Because of the toxicity associated with high-dose IL-2 regimens, low-dose regimens have been investigated. Several studies have shown widely varied response rates, with few durable or complete responses. Comparative studies between high- and low-dose IL-2 regimens have shown that high-dose IL-2 is superior in terms of response rate and durability of response. Low-dose IL-2 as single-agent therapy is not recommended as first-line therapy.^3,5 

IL-2 has also been studied in combination with interferon alpha with hopes of achieving a synergistic effect, since both have demonstrated benefit when used alone. Higher response rates are achieved with combination therapy (18.6%) when compared to either agent alone (6.5% to 7.5%).³ However, combination therapy is associated with greater toxicity and has failed to demonstrate an improvement in survival. IL-2 and interferon-alpha combination therapy may be a reasonable option as first-line therapy in metastatic renal cell carcinoma as recommended by the NCCN guidelines.³ 

Targeted Therapy: Recent advances in the understanding of the biology of renal cell carcinoma have led to the development of new treatments for metastatic disease. Renal cell carcinoma is a highly vascularized tumor with high vascular endothelial growth factor (VEGF) and endothelial growth factor receptor (EGFR) expression. ^5,10,13 Tumor growth is also mediated through multiple signaling pathways. Intravenous and oral agents have been developed that specifically act upon these molecular targets.

Sorafenib (Nexavar) is an orally bioavailable agent that inhibits multiple kinases involved in tumor proliferation and angiogenesis.^19,20 Specifically, it inhibits VEGF receptors 2 and 3, platelet-derived growth factor (PDGF) receptor beta, stem cell factor receptor (KIT), and Fms-like tyrosine kinase 3 (FLT3).^19,20 Sorafenib is FDA approved for the treatment of metastatic renal cell carcinoma.²⁰

A phase II trial and a phase III trial have evaluated the use of sorafenib in metastatic renal cell carcinoma.^21,22 Both studies showed that sorafenib significantly improved progression-free survival compared with placebo (163 to 167 days vs. 41 to 84 days).^21,22 Neither trial showed statistically significant improvement in overall survival. Common side effects included hypertension, fatigue, rash, hand-foot syndrome, alopecia, diarrhea, and nausea. The approved dose of sorafenib is 400 mg orally twice daily.²⁰

Sunitinib (Sutent) is another orally bioavailable agent that inhibits multiple kinases involved in tumor growth and angiogenesis.^19,23 It inhibits VEGF receptors 1, 2, and 3, PDGF receptors alpha and beta, KIT, and FLT3. Sunitinib is FDA approved for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors.²³

Two phase II clinical trials have evaluated response rates and durability of response to sunitinib.²⁴ Twenty-five percent to 36% of patients had an objective response lasting from 27 to 54 months. There is no information regarding overall survival benefit with use of sunitinib. Common side effects include diarrhea, nausea, fatigue, rash, skin discoloration, and hypertension.^19,24 The approved dose of sunitinib is 50 mg orally once daily for four weeks followed by two weeks off.²⁴

Bevacizumab (Avastin) is a recombinant monoclonal antibody that binds to VEGF, preventing it from binding to the VEGF receptor and inhibiting angiogenesis.¹⁶ It is under investigation for use in metastatic renal cell carcinoma. 

Two phase II trials have shown benefit of bevacizumab, either as a single agent or in combination with erlotinib.^25,26 Single-agent bevacizumab improved median time to tumor progression from 2.5 to 4.8 months when compared to placebo.²⁵ The effective dose of bevacizumab used in this trial was 10 mg/kg given intravenously every 14 days. Common side effects of bevacizumab in this setting include fatigue, hypertension, proteinuria, and epistaxis. Patients receiving bevacizumab may also have an increased risk of hemorrhage, thrombosis, gastrointestinal perforation, and myocardial infarction.

The NCCN guidelines recommend sorafenib and sunitinib as first-line agents for treatment of metastatic renal cell carcinoma. Bevacizumab is not FDA approved for renal cell carcinoma, but it is recommended by the NCCN guidelines as single-agent, second-line therapy, only after first-line therapy with another agent has failed.³

Clinical Trial Enrollment: Because of minimal responsiveness to conventional cytokine therapy and the poor survival associated with metastatic disease, it is a high priority to identify more effective agents through clinical investigation. Enrollment in clinical trials is the preferred option for patients who relapse following resection or who have metastatic disease.³ 

Conclusion
Renal cell carcinoma is a relatively rare malignancy. Surgery is the only known curative modality for patients with stage I, II, or III disease. Despite several treatment advancements in the past few years, patients with advanced stages of renal cell carcinoma will eventually die from their illness. Currently, IL-2, sorafenib, and sunitinib are the only agents that are FDA approved for the treatment of advanced renal cell carcinoma. Several other agents, including interferon alpha and several chemotherapy drugs, are recommended by the NCCN guidelines for use in stage IV disease. Additional clinical trials with investigational agents and combination regimens with chemotherapy are needed to improve treatment of renal cell carcinoma.

References

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26. Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol. 2005;23:7889-7896.

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