RENAL CELL CARCINOMA
Renal Cell Carcinoma: Review and Recent Advances Sarah L. Scarpace, PharmD, BCOP Assistant Professor, Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York
R
enal cell carcinoma (RCC) is a rare disease, with approximately 39,000 new cases diagnosed in 2007, accounting for about 2% of all malignancies in the United States.1 The incidence of RCC has been increasing by 2% per year for the past 65 years but the reason for this is unknown.1 In 2007, 12,000 deaths were expected from RCC, and 5-year survival was approximately 40%.1 Ninety percent of cases are of clear cell histology. RCC commonly metastasizes to liver, lung, bone, brain, and the adrenal glands. Although prognosis is influenced by tumor grade and stage, poor performance status, high lactate dehydrogenase, low hemoglobin, and high corrected serum calcium are indicators for a poor prognosis.2 The “classic� presentation of RCC is a symptom triad of flank pain, hematuria, and a palpable abdominal mass; however, about 50% of cases are found incidentally on a radiograph in patients with nonspecific symptoms, including fatigue, weight loss, and anemia.2 Risk factors include smoking, obesity, hypertension, and acquired cystic kidney disease from chronic kidney disease.1,2
Overview of drug therapy Drug therapy is primarily reserved for stage IV and relapsed/recurrent RCC. Stages I to III of RCC are surgically resected, and the use of adjuvant drug therapy is not recommended in clinical practice guidelines.1 Externalbeam radiation therapy or arterial embolization are reserved for patients who are not surgical candidates.1 The Table provides a summary of the dosing and adverse events of the drug therapies discussed. Since the US Food and Drug Administration (FDA) approval of sorafenib in 2005, sunitinib in 2006, and temsirolimus in 2007, the role of interferon alfa and high-dose interleukin-2 is more interesting as a historical treatment option for advanced/metastatic RCC. Interferon alfa is not FDA approved for RCC but yields response rates of approximately 14%, with short durability of response, ranging from 6 months to 2 years.2 The drug is also poorly tolerated, causing marked fatigue and severe depression. High-dose interleukin-2 yields better response rates (21%) with greater durability of response (median duration, 54
May 2009
Table. Dosing and Adverse Events of Targeted Therapies Used in RCC Drug
Dosing
Most common AEsa
Most common grade 3/4 AEsb
Sunitinib
50 mg PO daily for 4 weeks, then 2-week break without regard to food
LFT elevations; elevated SCr; myelosuppression; lymphopenia; elevated amylase/lipase; hypophosphatemia; diarrhea; fatigue; nausea; stomatitis; vomiting; rash; hand-foot syndrome
Lipase elevations; lymphopenia; neutropenia; elevated uric acid; hypertension; fatigue; hand-foot syndrome; diarrhea
Sorafenib
400 mg (two 200-mg tablets) PO twice daily on an empty stomach
Diarrhea; fatigue; rash; alopecia; hand-foot syndrome; nausea
Hand-foot syndrome; fatigue
Temsirolimus
25 mg IV weekly
Asthenia; rash; pain; nausea; anorexia; dyspnea; infection; hyperlipidemia; hypercholesterolemia; peripheral edema; hyperglycemia; fever; abdominal pain
Anemia; asthenia; pain; hyperglycemia; dyspnea
Bevacizumab + IFN-2a
10 mg/kg IV every 2 weeks, 9 million units subcutaneously three times a week
Fatigue; asthenia; bleeding; anorexia; hypertension; headache; diarrhea; flu-like symptoms
Fatigue; asthenia; proteinuria
Everolimus
10 mg PO daily
Stomatitis; rash; fatigue; hyperglycemia; hypercholesterolemia; hypertriglyceridemia; lymphopenia; increased SCr and LFTs; hypophosphatemia; myelosuppression
Lymphopenia; anemia; hyperglycemia
AE indicates adverse events; IFN, interferon; LFT, liver function tests; RCC, renal cell carcinoma; SCr, serum creatinine. a>20% of patients; b>5% of patients. Sources: References 3-5, 7, 10.
months) than interferon alfa but is administered on telemetry floors because of the risk of capillary leak syndrome.2 The drug is also contraindicated in patients with significant cerebrovascular disease, cardiac disease, pulmonary disease, renal disease (serum creatinine >1.5 mg/dL), hepatic disease, abnormal thallium stress test, or abnormal pulmonary function test, which limits the number of patients who are medically well enough to qualify for treatment. A small group of patients are also known to be cured by high-dose interleukin-2, but there is no known way to predict patients who may respond to therapy.2 Sunitinib, 50 mg once daily for 4 weeks with 2 weeks off, with or without food, has shown a doubling in median progression-free survival (PFS) compared with active treatment with interferon alfa (11 months vs 5 months, P <.001) in a phase 3 trial of 662 previously untreated patients with metastatic RCC.3 The most common adverse events (>20% of patients) associated
with treatment included liver function test elevations, elevated serum creatinine, myelosuppression, lymphopenia, elevated amylase and lipase, hypophosphatemia, diarrhea, fatigue, nausea, stomatitis, vomiting, hypertension, hand-foot syndrome, and rash. The most common grade 3/4 adverse events (>5% of patients) included lipase elevations, lymphopenia, neutropenia, elevated uric acid, hypertension, fatigue, hand-foot syndrome, and diarrhea.3 Sorafenib, 400 mg (two 200-mg tablets) twice daily on an empty stomach, was shown to double PFS to 167 days compared with 84 days with placebo in a phase 3 trial of 769 advanced RCC patients who were resistant to prior therapies (not including sunitinib).4 The most common side effects (>20% of patients) reported with sorafenib include diarrhea, fatigue, rash, hand-foot syndrome, alopecia, and nausea; the most common grade 3/4 toxicities (>5% of patients and statistically different compared with placebo) included hand-
foot syndrome and fatigue.4 Both sorafenib and sunitinib were studied in patients who had good performance status, were Memorial SloanKettering Cancer Center (MSKCC) low-intermediate risk, and, for more than 95%, had been treated with nephrectomy. Temsirolimus was studied in a phase 3 trial of 626 previously untreated patients with advanced RCC who were MSKCC poor-risk, only two of three of whom had been treated with nephrectomy.5 Median overall survival (OS) was significantly improved for patients who were treated with temsirolimus, 25 mg intravenous (IV) weekly (10.9 months), compared with those treated with interferon alfa, 3 million to 18 million units (depending on tolerability) subcutaneous three times a week (7.3 months) (hazard ratio [HR] for death = 0.73; P = .008).5 Patients treated with both temsirolimus and interferon alfa did not live longer than those treated with interferon alfa alone (median OS = 8.4 months;
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