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
Chapter 13
Kidney Cancer
Walter D.Y. Quan Jr.
Mikhail Vinogradov
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
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Table 13.1. Staging and prognosis of kidney cancer | ||||||||||||||||||||
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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.
D. Staging
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,
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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
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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.
Suggested Readings
Atkins MB, Hidalgo M, StadlerWM, et al. Randomised Phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909 918.
Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheralblood stem-cell transplantation. N Engl J Med 2000;343:750 758.
Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the raf kinase and VEGF inhibitor sorafenib (BAy 43 9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 2005;23:380.
Figlin RA, Pierce WC, Kaboo R, et al. Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2, and cytokineprimed or CD8(+) selected tumor infiltrating lymphocytes from primary tumor. J Urol 1997;158(3):740 745.
Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for highdose recombinant interleukin-2 therapy in patients with renal cell carcinoma. Cancer J Sci Am 2000;6(Suppl 1):S55 S57.
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Gollob J, Richmond T, Jones J, et al. Phase II trial of sorafenib plus interferon alpha 2b as first or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol 2006;24(Suppl 18S):226s.
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(31):7889 7896.
Hudes G, Carducci P, Tomczak J, et al. A phase 3, randomized, 3-arm study of Temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of firstline, poor-risk patients with advanced renal cell carcinoma (adv RCC). J Clin Oncol 2006;24(18S):LBA4. ASCO Annual Meeting Proceedings Part I.
Mandell JS, McLaughlin JK, Schlehofer B, et al. International renalcell study. IV. Occupation. Int J Cancer 1995;61:601 605.
McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;23(1):133 141.
Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17(8):2530 2540.
Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16 24.
Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 2005;23:1028 1043.
Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokineactivated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987;316:889 897.
Rosenberg SA, LotzeMT, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokineactivated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 1993;85:622 632.
Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin-2. JAMA 1994;271:907 913.
Ryan CW, Goldman BH, Lara PN Jr, et al. Sorafenib plus interferona2b as first-line therapy for advanced renal cell carcinoma: SWOG 0412. J Clin Oncol 2006;24 (Suppl 18S):223s.
Schwartzentruber D. Guidelines for the safe administration of highdose interleukin-2. J Immunother 2001;24:287 292.
Thompson JA, Shulman KL, Benyunes MC, et al. Prolonged continuous intravenous infusion interleukin-2 and lymphokine-activated killer-cell therapy for metastatic renal cell carcinoma. J Clin Oncol 1992;10:960 968.
Yang JC. Bevacizumab for patients with metastatic renal cancer: an update. Clin Cancer Res 2004;10(18 Pt 2):6367S 6370S.