Editors: Skeel, Roland T.
Title: Handbook of Cancer Chemotherapy, 7th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 13 - Kidney Cancer
Walter D.Y. Quan Jr.
Approximately 38,800 Americans were diagnosed with kidney cancer in 2006. Males accounted for approximately 24,600 of these new cases and for approximately 8,000 of the 12,800 deaths that occurred. The incidence of kidney cancer is increasing.
I. Carcinoma of the kidney
A. Cell types
Clear cell cancer of the kidney, which is an adenocarcinoma that arises from renal parenchyma, accounts for 85% of primary renal neoplasms. Papillary (or chromophilic) cancer is responsible for approximately 10%. Less common are oncocytomas (well-differentiated adenocarcinomas) and chromophobic types. Wilms' tumor (nephroblastoma) is seen predominantly in childhood. The term hypernephroma is a historic term for kidney cancer and is no longer commonly used.
B. Risk factors
In general, cigarette smoking is felt to roughly double the risk of kidney cancer. Approximately 30% of men and 25% of women with this cancer have a history of tobacco use. Industrial exposure to asbestos, cadmium, and the drug phenacetin have also been associated with higher risk. Lesser risk factors include acquired multicystic disease in patients undergoing hemodialysis for chronic renal failure, obesity, and hypertension. An important link has been established with the von Hippel-Lindau gene on chromosome 3 wherein its inactivation or deletion is associated both with enhanced production of vascular endothelial growth factor (VEGF) and a higher incidence of clear cell carcinoma of the kidney. VEGF is therefore felt to augment the growth of new blood vessels typically seen with clear cell kidney cancer and its metastases ( kidney cancer is a vascular cancer ). Clear cell kidney cancer is also associated with tuberous sclerosis.
C. Clinical characteristics
Common clinical symptoms/findings of kidney cancer include hematuria (56% of patients), flank pain (38%), abdominal mass (36%), weight loss (27%), and fever (11%). The classic triad of hematuria, flank pain, and abdominal mass occurs in less than 20% of patients. Because of its propensity to display paraneoplastic syndromes, kidney cancer is sometimes described as being the internist's tumor. Up to 20% of patients without bone metastases may exhibit hypercalcemia thought to be possibly due to parathyroid hormone (PTH)-like peptide, osteoclast activating factor, or tumor necrosis factor. Excess erythropoietin production has been described in as many as 3%of patients. Other clinical manifestations may include hypertension, fever, anemia, and hyperglycemia. Up to 20% of patients may exhibit Stauffer syndrome, evidence of elevated alkaline phosphatase, activated partial thromboplastin time, liver function tests, and hepatomegaly without liver metastases. The etiology is unclear biopsies show nonspecific
Table 13.1. Staging and prognosis of kidney cancer
Metastatic disease is present at initial presentation in approximately 25% to 30% of patients. The most common sites of metastases are lung, lymph node, liver, and bone. Brain metastases are often a late manifestation. Untreated patients with metastases or patients in whom treatment fails to halt disease progression may have a particularly dire prognosis with the median survival being approximately 6 months.
The TNM staging system together with expected 5-year survival by stage is listed in Table 13.1. Factors adversely affecting prognosis include hypercalcemia, serum lactate dehydrogenase (LDH) level more than 1.5 times the upper limit of normal, Karnofsky performance status less than 80%, comorbid medical conditions, anemia, or multiple sites of metastases. Newer methods of molecular, genomic, and proteomic profilingmay further delineate prognostic factors in the future.
E. Treatment considerations
The treatment of choice for nonmetastatic kidney cancer is radical nephrectomy, including removal of the perinephric fat and regional lymph nodes. Partial nephrectomy is an option in patients with bilateral renal tumors or a solitary kidney to avoid the necessity of dialysis. Rarely, patients with solitary metastatic lesions can be cured by surgical removal of a metastasis at the time of nephrectomy. Kidney cancer is relatively radioresistant; thus, adjuvant radiation therapy does not improve survival. Radiation therapy can be useful for palliation of painful metastasis. It is reasonable to consider patients with inoperablemetastatic disease for treatment with biologic agents, particularly IL-2,
A question of some controversy centers on whether nephrectomy should be done as an adjunct to systemic treatment in patients with metastases. Two randomized studies in metastatic disease have shown improved survival in the group treated with nephrectomy followed by interferon versus interferon alone. In contrast, a recent study with high-dose IL-2 showed no difference in response rate or survival between those undergoing nephrectomy initially and those who received IL-2 alone. Data show that approximately 35% of patients with distant metastases who undergo nephrectomy, are never able to receive any systemic treatment, usually because of disease progression.
F. Treatment regimens
Biologic response modifiers
Interleukin 2 (IL-2; Proleukin, aldesleukin) mediates its antitumor effects through activation of a patient's lymphocytes, particularly those that are CD56+, converting them into lymphokine-activated killer (LAK) cells. IL-2, alone or in combination with ex vivo-activated LAK, results in overall response rates of up to 18%. Complete responses, when obtained, tend to be long-lasting. There is a wide range of IL-2 doses and schedules, but recent randomized data suggest that high-dose therapy is more likely to lead to complete responses and a higher overall response rate than lower, subcutaneously administeredoutpatient therapy. It ismost commonlyused ina high-dose regimen of 600,000 IU/kg given in 15-minute IV infusions every 8 hours for up to 14 doses. This schedule produces responses in 15% to 22% of patients, many of long duration. Because this drug is associated with a capillary leak syndrome that can include hypotension, fluid retention, renal and hepatic hypoperfusion, and pulmonary edema, the dose and schedule mentioned in the preceding text require inpatient care. It should be used only by those experienced in its administration. Inpatient continuous infusion schedules (18 MIU/m2 given over 24 hours for up to 5 consecutive days) may also be administered.
Sunitinib is a tyrosine kinase receptor inhibitor that interferes with tumor angiogenesis. Typical dosing is 50 mg orally per day for 4 weeks followed by a 2-week rest. Partial response rates of up to 40% with median time to disease progression of more than 8 months have been reported.
Sorafenib is another tyrosine kinase inhibitor, which, at doses of 400 mg orally twice per day, has been shown to improve progression-free survival versus placebo (24 vs. 12 weeks).
Temsirolimus (TEMSR) is a novel kinase inhibitor that is a derivative of the macrolide antibiotic and immunosuppressant sirolimus (rapamycin). After temsirolimus complexes with the immunophilin FKBP12, the complex inhibits mTOR (mammalian Target Of Rapamycin) kinase activity. mTOR, as a master regulator
IFN yields response rates of approximately 10%. Numerous treatment doses and schedules have been utilized. A representative one is 5 MIU/m2 SC three times per week. The median response durations range between studies from 6 to 12 months. Response correlates with Karnofsky performance status equal to or more than 80% and prior nephrectomy.
Bevacizumab, an antibody to VEGF, has response rates of 10% with some patients having progression-free intervals as long as 5 years. Doses of up to 10 mg/kg IV every 2 weeks have been utilized.
Combination therapy. Combinations of IFN and IL-2 have been tested but have not been shown to be superior to IL-2 alone. Newer doublets including bevacizumab and erlotinib (another tyrosine kinase receptor inhibitor), sunitinib and IFN, and sorafenib plus IFN hold promise.
Cytotoxic chemotherapy/hormonal therapy. Of historic note, vinblastine, medroxyprogesterone acetate, and tamoxifen at best produce responses in fewer than 5% of patients and therefore cannot be recommended.
Adjuvant therapy. No adjuvant therapy has been proven to improve survival to date after resection of all known disease. A randomized study of high-dose bolus IL-2 versus placebo was stopped early. However, a trial comparing tyrosine kinase receptor inhibitors versus placebo has been initiated.
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