Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

12. Kidney Cancer

Mark T. Andolina, Colleen Darnell, and Olivier Rixe

I. RENAL CELL CARCINOMA (RCC)

An enhanced understanding of RCC has led to advances in both medical management and innovations in surgical management. Small tumors less than 4 cm and selected tumors 4 to 7 cm, formerly treated with open radical nephrectomy, are now treated with laparoscopic partial nephrectomy with similar oncologic outcomes. In addition to surgical advances, the past 5 years have seen a wealth of new biologic and targeted drugs that have activity in RCC.

A. Histopathology

Clear cell carcinoma of the kidney, an adenocarcinoma arising from the proximal convoluted tubules (PCTs), accounts for 85% of primary renal neoplasms. The inactivation or deletion of the Von Hippel-Lindau (VHL) gene on chromosome 3p is associated with an enhanced production of vascular endothelial growth factor (VEGF), and is found in 50% to 60% of sporadic clear cell renal carcinomas. VEGF is believed to augment the growth of new blood vessels typically seen with clear cell kidney cancer and its metastases.

Papillary carcinomas account for 10% and also arise from the PCTs but are distinct from clear cell carcinomas, are often multifocal, and are often with multiple genetic abnormalities. Papillary carcinomas are further divided into two subtypes depending on pathology, gene expression, and prognosis. Type I tend to be a lower grade at diagnosis and carry a better prognosis, while Type II tend to be a higher grade with a poorer prognosis. The remaining 5% of renal carcinomas include oncocytomas (well-differentiated adenocarcinomas) and chromophobic and transitional carcinomas. Wilms tumor (nephroblastoma) is seen predominantly in childhood.

The most widely used and most predictive grading system for renal cell cancer is the Fuhrman Nuclear Grade.

B. Epidemiology

Kidney cancer is listed among the world's 10 most common cancers. More than 57,000 Americans were diagnosed with kidney cancer in 2009, an increase from approximately 36,000 in 2006. Males account for 60% of diagnoses and African-Americans have the highest rate of any racial or ethnic group. Nearly 13,000 patients will die in 2010 from kidney cancer.

C. Risk factors

In general, cigarette smoking roughly doubles the risk of kidney cancer with an increased dose-dependent risk in heavy smokers. Approximately 30% of males and 25% of females with renal cancer have a history of tobacco use. Industrial exposure to cadmium, asbestos, petroleum byproducts, and ingestion of the drug phenacetin (analgesic nephropathy) has been associated with a higher risk. Lesser risk factors include acquired multicystic kidney disease, patients with end-stage renal disease who are on hemodialysis, obesity, and hypertension. Several hereditary conditions predispose patients to renal cell cancers. Notably, VHL disease, an autosomal dominant hereditary condition involving the inac-tivation of the tumor-suppressor VHL gene, predisposes patients to a variety of neoplasms including clear cell histology renal carcinoma. Inactivation of the VHL gene stimulates angiogenesis through VEGF and its receptor targets in new therapeutic agents. The VHL gene is also mutated in a high number of sporadic or non-hereditary RCCs.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder associated with fibrofolliculomas (benign hair follicle tumors), pulmonary cysts, and renal cancers most commonly of the chromophobe, oncocytoma histology, or a hybrid of the two subtypes. BHD syndrome is caused by a germline mutation in the tumor-suppressor BHD gene, which encodes a novel protein folliculin that has an unknown function.

D. Clinical characteristics

The most common clinical signs and symptoms of renal cancer include hematuria (56% of patients), flank pain (38%), abdominal mass (36%), weight loss (27%), and fever (11%). However, the classic triad of hematuria, flank pain, and abdominal mass occurs in less than 20% of patients and many are asymptomatic until the disease is advanced. Twenty-five percent of renal cancers are found incidentally in radiographic imaging, and 30% of patients will have metastatic disease at diagnosis. Common metastatic sites are lung (75%), soft tissues (36%), bone (20%), and liver (18%); brain metastases are often a late manifestation. Hypercalcemia is present in up to 20% of patients despite the absence of bony metastases and is related to ectopic production of parathyroid hormone–related protein, osteoclast activating factor, or tumor necrosis factor. Erythrocytosis due to excess erythropoietin production has been described in 3% of patients. Ectopic production of other hormones including renin and glucagon produce clinical manifestations of hypertension and hyperglycemia, respectively. Stauffer syndrome, identified in up to 20% of patients, is a hepatic dysfunction associated with elevated alkaline phosphatase, transaminases, activated partial thromboplastin time, and hepatomegaly in the absence of liver metastases.

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E. Staging

RCCs are traditionally staged using the TNM staging system (Table 12.1). Newer prognostic systems include the University of California, Los Angeles, integrated staging system (UISS) and the Memorial Sloan-Kettering Cancer Center (MSKCC) system. The UISS (Table 12.2), more predictive for localized tumors, factors in TNM staging, Fuhrman grade, and Eastern Cooperative Oncology Group performance status and stratifies patients into low-, intermediate-, or high-risk categories. The MSKCC system (Table 12.3) for advanced disease includes Karnofsky performance status, elevated lactate dehydrogenase levels, anemia, hypercalcemia, and the absence of prior nephrectomy, and predicts favorable, intermediate, or poor risk groups.

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F. Treatment considerations

1. Localized disease. The majority ofpatients present with localized disease. The preferred treatment has become laparoscopic partial nephrectomy. First performed in 1990, it is associated with less postoperative pain, a shorter recovery time, and less overall morbidity. A radical nephrectomy, which includes removal of the perinephric fat and regional lymph nodes, is indicated for tumors that are greater than 7 cm and involve the renal pelvis. Most surgical patients with limited disease are cured. There is no current recommendation for adjuvant therapy, although there are open clinical trials investigating the role for adjuvant medical therapies (see subsequent discussion). Adjuvant radiation therapy does not improve survival as RCC is relatively radioresistant.

2. Metastatic disease. For patients with a solitary metastatic lesion at presentation, or on relapse, surgical removal of the metastatic foci can occasionally be curative. Cytoreductive nephrectomy has been shown to improve survival and is indicated in patients with good performance status, no brain metastases, and without rapidly progressing extrarenal disease. Inoperable, metastatic RCC is treated with molecular targeted therapy, antiangiogenic therapy, and immunotherapy (see subsequent discussion). Neither hormonal therapy nor chemotherapy has been shown to improve survival in patients with metastatic clear cell histology renal cancer. Some patients with non-clear cell renal carcinoma respond to chemotherapy.

G. Treatment regimens

1. Immunotherapy

a. Interleukin-2 (IL-2; aldesleukin [Proleukin]) mediates its antitumor effects through activation of a patient's lymphocytes, particularly those that are CD56+, converting them into lymphokine-activated killer cells. IL-2 alone results in overall response rates of up to 20% that include long-term survivors. There is a wide range of IL-2 doses and schedules, but recent randomized data shows high-dose bolus therapy (see Chapter 33) is more likely to lead to complete responses and long-term remissions than outpatient subcutaneously administered therapy. High-dose bolus therapy is highly toxic and is associated with a capillary leak syndrome (including hypotension, fluid retention, renal and hepatic hypoperfusion, and pulmonary edema), and it requires inpatient care by experienced personnel. High-dose bolus IL-2 is still an option for selected good-risk patients.

b. Interferon yields response rates of approximately 10%. Numerous treatment doses and schedules have been utilized. A representative one is 5 million IU/m2 subcutaneously three times per week. The median response durations range between studies from 6 to 12 months. Response correlates with Karnofsky performance status greater than 80% and prior ne-phrectomy. It is rarely used now, owing to the demonstrated efficacy of several molecular targeted agents.

2. Molecular targeted agents—VEGF inhibitors

a. Sunitinib is a multikinase inhibitor that interferes with all receptors for platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR). 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 greater than 8 months have been reported. Overall survival using sunitinib as a first-line agent is 26.4 months.

b. 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 weeks versus 12 weeks) after cytokine failure.

c. 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 intravenously every 2 weeks have been utilized. Trials were performed in combination with interferon and showed improved overall survival. The activity of bevacizumab as a single agent is not well known, which led to approval by the U.S. Food and Drug Administration (FDA) of the combination in patients with metastatic RCC.

d. Pazopanib is a multi-VEGF inhibitor and PDGFRinhibitor that is the latest biologic compound to show activity in RCC. It is the latest FDA approved biologic agent for advanced RCC. The usual dosage is as follows:

1. 800 mg by mouth daily without food

2. 200 mg by mouth daily without food, if moderate hepatic impairment

3. 400 mg or less by mouth if strong inhibitors of CYP3A4 cannot be avoided, as it is metabolized primarily by enzyme.

Overall response rate is 30% and progression-free survival increased from 2.8 months for placebo to 11.1 months for pazopanib. Overall survival data are not yet available.

3. Molecular targeted agents—mammalian target of rapamycin (mTOR) inhibitors

a. Temsirolimus is a novel kinase inhibitor that is a derivative of rapamycin. After temsirolimus complexes with the im-munophilin FKBP12, the complex inhibits mTOR kinase activity. mTOR, as a master regulator of cell physiology, is involved in regulation of cell growth and angiogenesis, and changes that are induced downstream from mTOR as a consequence of the temsirolimus inhibition lead to cell cycle arrest at the G1 phase. In a randomized trial comparing interferon with temsirolimus in poor-risk patients with advanced RCC, overall survival was statistically better in the temsirolimus arm (10.9 months versus 7.3 months). The usual dosage and schedule is 25 mg intravenously weekly.

b. Everolimus is a serine-threonine kinase inhibitor of mTOR. Everolimus is indicated for patients with advanced RCC who failed sorafenib or sunitinib based on a 2008 study in which progression-free survival doubled compared to placebo. The usual dosage and schedule is as follows:

1. 10 mg by mouth once daily

2. Reduce dose to 5 mg by mouth once daily for patients with Child-Pugh class B hepatic impairment or as needed to manage adverse drug reactions

3. If strong inducers of CYP3A4 are required, increase daily dose in 5 mg increments to a maximum of 20 mg once daily.

4. 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.

5. Adjuvant therapy. No adjuvant therapy has been proven to improve survival after resection. However, there are ongoing trials with both sunitinib and sorafenib in the adjuvant setting for resected RCC at high risk of relapse.

6. Combination therapy. Newer doublets including bevacizumab and erlotinib (a tyrosine kinase receptor inhibitor that targets epidermal growth factor receptor), sunitinib and interferon, and sorafenib plus interferon do not demonstrate higher activity compared to single agents.

H. Treatment strategies in the metastatic setting

IL-2 is the treatment of choice for those who can tolerate its toxicities. Sunitinib or sorafenib should be considered in patients who are not candidates for intensive IL-2 therapy. Patients who progress after one of the active agents in RCC can be tried on another. The optimal sequence of drugs is not yet known. Whenever possible, after first-line therapy, participation in a clinical trial is recommended.

Selected Readings

Overviews

Mandell JS, McLaughlin JK, Schlehofer B, et al. International renal-cell study. IV. Occupation. IntJCancer. 1995;61:601–605.

Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17(8):2530–2540.

Pancuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. JUrol. 2001;166:1611.

Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373(9669):1119–1132.

Rini BI. Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol. 2009;27(19):3225–3234.

Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol.2002;20:4559–4566.

Surgery

Chin AI, Lam JS, Figlin RA, Belldegrun AS. Surveillance strategies for renal cell carcinoma patients following nephrectomy. Rev Urol. 2006;8(1):1–7.

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Figlin RA, Pierce WC, Kaboo R, et al. Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2, and cytokine-primed or CD8( + ) selected tumor infiltrating lymphocytes from primary tumor. J Urol.1997;158(3):740–745.

Policari AJ, Gorbonos A, Milner JE, Flanigan RC. The role of cytoreductive nephrectomy in the era of molecular targeted therapies. Int J Urol. 2009;16(3): 227–233.

Immunotherapy/Targeted Agents

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.

Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombi-nant Interleukin-2 therapy in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6(Suppl 1):S55–S57.

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, Edwards DL, Baughman C, Greco A. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol. 2005;23(31):7889–7896.

Hudes G, Carducci M, Tomczak P, 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 first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC). J Clin Oncol (Meeting Abstracts). 2006;24(18S):LBA4.

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, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–456.

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, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst.1993;85: 622–632.

Ryan CW, Goldman BH, Lara PN Jr, et al. Sorafenib plus interferon-a2b 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 high-dose interleukin-2. JImmunother. 2001;24:287–292.

Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or meta-static renal cell carcinoma; results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–1068.

Yang JC. Bevacizumab for patients with metastatic renal cancer: an update. Clin Cancer Res. 2004;10(18 Pt 2):6367S–6370S.