Surgical excision of the renal tumor remains the primary method of local disease control and is performed in patients with stage I, II, or III disease.44 In patients with advanced disease, treatment options for patients following nephrectomy have been limited to immunotherapy approaches with interferon alfa (IFN-α) and/or interleukin-2 (IL-2) until recently. Most patients are currently treated with one of the targeted therapies.
In patients with localized disease confined to the kidney (stages I, II, and III), the initial treatment recommendation is surgical removal with curative intent. In patients with initially localized disease who undergo nephrectomy, 20% to 30% will relapse, with most relapses occurring in the first 2 years after surgery. Once patients have developed metastatic disease, the goal of therapy is to control disease burden and prolong survival while maximizing quality of life.44
Sidebar: Clinical Controversy
Traditionally, the Response Evaluation Criteria in Solid Tumors (RECIST) model has been used to evaluate treatment response rates in solid tumors. Whether this remains the optimal method of assessing response rates in patients receiving targeted therapies is unknown, as the drugs may result in tumor death and internal tumor necrosis without much change in the tumor size itself.
Surgery represents the initial therapy for most patients with RCC, regardless of stage. Surgical options include total nephrectomy and nephron-sparing surgery and depend on numerous patient-specific factors, including the size and location of the renal tumor, whether multiple tumors are present, and whether the patient has a single kidney or has a concurrent disease with a risk of multiple kidney tumors, such as a known genetic predisposition. Radical nephrectomy involves excision of the total kidney, Gerota fascia, and ipsilateral adrenal gland following ligation of the renal vein and artery. Nephrectomy is preferred for patients with large tumors (4 to 7 cm), depending on the location of the tumor. Centrally located tumors are more amenable to total resection than partial nephrectomy.44,45 Regardless of the functional capacity of the remaining kidney, total nephrectomy has been associated with a higher risk of developing chronic kidney disease, which explains why nephron-sparing techniques have become more common.46
Nephron-sparing surgery usually refers to partial nephrectomy, but it can also be used to describe probe-based thermal ablation procedures such as radiofrequency ablation (RFA) and cryoablation. The long-term efficacy of these two techniques has not yet been established, with some reports suggesting higher local recurrence rates compared with actual surgical excision.47 Because RFA and cryoablation can result in localized fibrotic reactions, surgical salvage following relapse can be compromised, and these procedures are typically reserved for patients who are not surgical candidates but still desire aggressive localized therapy. The most common nephron-sparing procedure is partial nephrectomy, which has been shown, in appropriately selected patients, to have equivalent outcomes as those seen in patients receiving total nephrectomy.48 Partial nephrectomy candidates are those with smaller lesions (usually less than 4 cm) that are located in the cortical region of the kidney. Patients with bilateral tumors and those with already compromised renal function are also partial nephrectomy candidates.
In addition to surgical removal of the tumor, some surgeons recommend extended lymphadenectomy. The procedure is controversial if there is no known lymph node involvement, but supporters suggest the procedure can be prognostic because positive nodal findings on lymphadenectomy can indicate systemic involvement, which often results in distant metastatic disease, even following lymph nodes removal.44,49 Although nearly one-third of patients will relapse following surgery, adjuvant therapy does improve relapse-free survival in patients who initially present with localized disease. Radiation therapy is also not recommended. As a result, observation is the recommended strategy, with imaging of the chest and abdomen every 4 to 6 months after surgery and then as clinically indicated.44,50
Surgery is still used for patients with distant (stage IV) disease and may consist of surgical resection of the renal tumor and/or metastectomy, or removal of metastatic sites. Ideal candidates are those who have minimal regional lymphadenopathy and a solitary site of metastatic disease. Metastatic sites amenable to resection include the lung, bone, brain, and soft tissue.44,49 The benefits of surgical resection in patients with metastatic disease treated with IFN have been demonstrated in two randomized trials. Patients with metastatic RCC in both studies were randomized to nephrectomy followed by IFN or IFN alone. In a combined analysis, the median OS was 13.6 months for the nephrectomy followed by IFN group as compared with 7.8 months for the IFN alone group (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.55–0.87, P = 0.002).51–53 Patients with metastatic disease only involving the lung, good prognostic features, and a performance status of 0 or 1 appear to benefit the most from nephrectomy followed by IFN. The mechanism for the apparent improved OS is unknown, but nephrectomy may reduce total tumor burden and increase the time for tumor burden to develop or may eliminate the primary source of immunosuppressive cytokines and tumor-producing growth factors. The benefit of newer targeted therapies is also being evaluated in this setting.50 Finally, palliative nephrectomy may be an option for patients with symptoms related to their primary tumor where removal can provide symptom relief.
Traditional cytotoxic therapy has demonstrated minimal efficacy in the treatment of RCC. Numerous agents have been investigated, the most active being gemcitabine, vinblastine, and 5-fluorouracil. However, response rates of more than 4% to 6% were rarely observed with single agents.22 Intrinsic resistance to chemotherapy may be partially explained by increased expression of the multidrug resistance gene (mdr1), which encodes for a P-glycoprotein (Pgp) transmembrane pump involved in drug efflux. Variable expression of the mdr1 gene has been found throughout many normal human tissues and in a number of different tumor types. Normal kidney tissue and various carcinomas of the kidney express high levels the md1 gene.54,55 A number of different chemotherapeutic agents have shown high levels of resistance in RCC tumors expressing the Pgp drug transporter. Overexpression of other drug transporter proteins, including the multidrug-resistance-associated proteins (MRPs), may also play a role in the development of resistance, along with other mechanisms, such as alterations in glutathione metabolism and proteins involved with regulation of apoptosis, ultimately leading to failure of cells to undergo programmed cell death.56
Patients with RCC occasionally experience spontaneous regression of their disease, which has led researchers to hypothesize that RCC evokes a host immune response and study immunotherapy for RCC.57 IFN and IL-2 have been investigated in numerous trials and combinations and were the standard of care for patients with metastatic RCC until the recent emergence of targeted therapy. Their low response rates and high toxicity have resulted in their current roles being limited, with ongoing trials to determine their potential in combination regimens.
IL-2 (aldesleukin) is a glycoprotein primarily produced by helper T lymphocytes that stimulates the growth and cytotoxicity of T lymphocytes. IL-2 has been associated with response rates of 6% to 30%. Although the complete response rate is only about 4% to 6%, some of these complete responses are durable.50,58 The FDA-approved dose of IL-2 is 600,000 international units/kg IV over 15 minutes given every 8 hours for a maximum of 14 doses. Following this initial treatment, the schedule is repeated 9 days later for an additional 14 doses, as tolerated. Because of the significant toxicity of IL-2, treatment delays and discontinuations are frequent. The most common reported toxicities are hypotension (71%), diarrhea (67%), chills (52%), vomiting (50%), dyspnea (43%), and peripheral edema (28%), in addition to increases in bilirubin (40%), serum creatinine (33%), and electrolyte abnormalities.59 Many of these effects are related to capillary leak syndrome. Inpatient administration and intensive monitoring and supportive care are required, and many institutions will administer IL-2 in an intensive care setting. Many patients are not candidates for IL-2 therapy because of their age (>60 years), comorbidities, organ function, and poor performance status.
IFNs are naturally occurring glycoproteins produced by macrophages and lymphocytes in response to foreign antigens as part of the host immunity. They exert their antitumor effects by activating cytotoxic T and NK cells, enhancing expression of cell surface antigens (i.e., major histocompatibility class I), and modulating gene expression.60,61 A number of different IFNs have been studied for the treatment of metastatic RCC, including IFN-α, -β, and -γ. The response rates are similar among the different IFNs, but IFN-α is most commonly used to treat RCC.
Although IFN has been used to treat RCC for 2 decades, it is not approved by the FDA for the treatment of advanced or metastatic RCC. Overall response rates to IFN generally range from 5% to 20%.58,60,62 Two randomized trials demonstrated a survival benefit with IFN. IFN-α plus vinblastine was compared with vinblastine alone in 160 patients with advanced RCC. Both groups received vinblastine at 0.1 mg/kg IV every 3 weeks, and the combination group also received IFN at a dose of 3 million units subcutaneously or intramuscularly three times a week for the first week, then 18 million units subcutaneously three times a week thereafter. Median OS was significantly improved in the combination group compared with the vinblastine alone group at 67.6 weeks and 37.8 weeks (P = 0.005), respectively.63 In another study, IFN-α was compared with medroxyprogesterone acetate 300 mg daily in 350 patients with metastatic RCC. IFN-α was dosed at 5 million units × two doses, then increased to 10 million units three times a week for a total of 12 weeks. The median OS was 8.5 months as compared with 6 months for IFN-α and medroxyprogesterone, which translated into a 28% reduction in the risk of death in the IFN-α group (P = 0.017).64 Based on these studies, IFN remains the comparator for novel treatments in metastatic RCC. It is better tolerated than IL-2 and can be self-administered at home. However, >90% of patients experience chills, fever, asthenia, fatigue, headache, diarrhea, and liver function abnormalities, and some patients develop depression and other neuropsychiatric symptoms.
Since 2005, six new drugs have been approved either as first- or second-line therapy: sunitinib, sorafenib, pazopanib, bevacizumab (in combination with interferon), temsirolimus, and everolimus (Table 146–4).
Table 146-4 Comparison of Targeted Agents in Patients with Metastatic Renal Cell Carcinoma |Favorite Table|Download (.pdf)
Table 146-4 Comparison of Targeted Agents in Patients with Metastatic Renal Cell Carcinoma
|Targeted Agent||Indication (NCCN Guidelines Category of Recommendation)44||Dosing||Adverse Effects||Precautions||Drug Interactions|
|Sunitinib5,66a||First-line therapy for metastatic RCC (category 1) and second-line after progression on cytokine therapy (category 1) or tyrosine kinase inhibitor (category 2A)||50 mg orally daily × 4 weeks, then off 2 weeks||Leukopenia, thrombocytopenia, diarrhea, nausea, vomiting, anorexia, constipation, mucositis, hypertension, hand–foot syndrome, hair discoloration, hypothyroidism, decreased LVEF|
Discontinue sunitinib if clinical manifestations of CHF occur.
Delay or reduce dose if no clinical manifestations of CHF but EF <50% and >20% below baseline
CYP 3A4 inducers may decrease sunitinib exposure
CYP 3A4 inhibitors may increase sunitinib exposure
|Sorafenib69b||Second-line therapy for metastatic RCC after progression on cytokine therapy (category 1) or tyrosine kinase therapy (category 2A) and first-line therapy only in select patients (category 2A)||400 mg orally twice daily||Diarrhea, nausea, vomiting, anorexia, fatigue, hand–foot syndrome, desquamating rash, hypertension, fatigue, cardiac ischemia, hemorrhagic events||Consider discontinuing therapy if clinical manifestations of cardiac ischemia or hemorrhagic event occurs|
UGT1A1 and UGT1A9 substrates may have increased exposure when coadministered with sorafenib due to inhibition of glucuronidation
Docetaxel and doxorubicin exposure may increase when coadministered with sorafenib
CYP 3A4 inducers may decrease sorafenib exposure
|Pazopanib9c||First-line therapy for metastatic RCC (category 1) and second-line after progression on cytokine therapy (category 1) or tyrosine kinase inhibitor (category 3)||Initiate at 400 mg orally daily and increase to 800 mg orally daily||ALT elevation, leukopenia, thrombocytopenia, diarrhea, nausea, vomiting, hypertension, hair discoloration, QT prolongation, hemorrhage, thromboembolism, hypothyroidism||Temporarily discontinue therapy in patients undergoing surgery|
CYP 3A4 inducers may decrease pazopanib exposure
CYP 3A4 inhibitors may increase pazopanib exposure
|Bevacizumab7,71d||First-line therapy for metastatic RCC in combination with interferon (category 1) and second-line monotherapy after progression on cytokine therapy (category 2B)||10 mg/kg IV every 2 weeks||Epistaxis, hemorrhage, delayed wound healing, hypertension, thromboembolic events, proteinuria, GI perforation, dry skin, rhinitis, taste alteration||Do not administer within 4 weeks of surgery; monitor blood pressure and urine protein||None known|
|Temsirolimus6e||First-line therapy for metastatic RCC in patients with poor prognosis (category 1) and an option for patients of other risk groups (category 2B). Second-line therapy after progression on cytokine therapy (category 2B) or tyrosine kinase therapy (category 2B)||25 mg IV once weekly|
Anorexia, asthenia, edema, hypersensitivity reactions, infections, interstitial lung disease, mucositis, nausea, rash, wound healing complications
Laboratory abnormalities: anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypophosphatemia, leukopenia, lymphopenia, thrombocytopenia, and elevated alkaline phosphatase, aspartate transaminase, and serum creatinine
|Avoid live vaccinations and close contact with those who received live vaccines; monitor blood glucose, serum cholesterol, creatinine, triglycerides, liver function tests, chemistry, and hematologicparameters|
CYP3A4 inhibitors may increase exposure
CYP3A4 inducers may decrease exposure
|Everolimus8f||Second-line therapy following progression on tyrosine kinase therapy (category 1)||10 mg orally daily|
Abdominal pain, asthenia, cough, dehydration, diarrhea, dyspnea, fatigue, infections, pneumonitis, and stomatitis
Laboratory abnormalities: anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased serum creatinine
|Hepatic impairment (Child-Pugh class B), reduce dose to 5 mg orally daily; avoid live vaccinations and close contact with those who received live vaccines; monitor blood glucose, serum cholesterol, creatinine, triglycerides, liver function tests, chemistry, and hematologic parameters|
CYP3A4 and PgP inhibitors may increase exposure
CYP3A4 inducers may decrease exposure
Sunitinib is an orally administered antiangiogenic agent that inhibits multiple tyrosine kinases, including VEGFR and PDGFR.65 Sunitinib is approved for the first-line treatment of metastatic RCC (NCCN guidelines, category I).44 That approval was based on a randomized, phase III clinical trial, which compared sunitinib with IFN-α2a as first-line therapy in 750 patients with clear cell metastatic RCC.66 Sunitinib was administered in a 6-week cycle at 50 mg orally given daily for 4 weeks, followed by 2 weeks without treatment. IFN was administered subcutaneously three times weekly on nonconsecutive days, with a gradual dose increase from 3 million units to 9 million units over a 3-week period. Sunitinib was found to be superior to IFN, with median progression-free survival (PFS) of 11 months and 5 months (P < 0.001), respectively. The improved PFS with sunitinib was observed regardless of baseline characteristics and prognostic factors. Both treatments were generally well tolerated with a low incidence of grade 3 or 4 adverse events. The sunitinib group had higher rates of diarrhea, vomiting, hypertension, hand–foot syndrome, hair discoloration, and myelosuppression as compared with IFN-treated patients. Health-related quality of life was significantly better in the sunitinib group (P < 0.001) as compared with the IFN group. Sunitinib-treated patients also had prolonged OS as compared with interferon-treated patients (26 vs 22 months, P = 0.05), despite the fact that 25 patients in the IFN group crossed over to the sunitinib group.5 Sunitinib has been evaluated in three clinical trials as either first- or second-line therapy after progression on cytokine therapy, with response rates of 30% to 45%, which was considerably higher than the response rates observed for cytokines.50,66–68 In addition to the high response rate, sunitinib was relatively well tolerated, with most adverse events managed by supportive care or dose modification and less than 10% requiring treatment discontinuation. As a result, the NCCN guidelines recommend sunitinib for first-line therapy in patients with metastatic RCC who have never received systemic therapy (category 1) and for second-line therapy in patients who have progressed on cytokine (category 1) or tyrosine kinase inhibitor (category 2A) therapy.44
Sidebar: Clinical Controversy
There are a number of targeted agents approved by the FDA for the first-line treatment of metastatic RCC based on underlying tumor histology and MSKCC risk criteria. There are also many options for the second-line treatment of metastatic RCC, but the choice of agents becomes somewhat convoluted. This is primarily the result of fewer patients receiving the more toxic immunotherapy as first-line treatment, which, in most cases, was the active comparator for the agents approved in the second-line setting. As more options become available for the treatment of metastatic RCC, questions arise regarding the optimal sequencing of targeted agents. Clinical trials aimed at answering these questions are currently ongoing.
Sorafenib is another orally administered antiangiogenic agent that inhibits multiple tyrosine kinases, including VEGFR, PDGFR, Raf-1, fms-like tyrosine kinase receptor-3 (Flt-3), and c-kit. Sorafenib is approved for second-line treatment of metastatic RCC after progression on cytokine therapy. The approval was based on a phase III double-blind clinical trial in which 903 patients with metastatic RCC who had progressed after first-line systemic therapy were randomized to treatment with sorafenib or placebo. Study patients received sorafenib 400 mg orally twice daily continuously, or placebo twice daily, until disease progression or intolerable toxicities. Of note, 48% of patients in the placebo arm crossed over to the sorafenib arm when interim analyses demonstrated a significant PFS benefit with sorafenib as compared with placebo (5.5 months vs 2.8 months, P < 0.01). The final primary end point analysis for OS showed no difference between sorafenib and placebo therapy (17.8 months vs 15.2 months, P = 0.15), but censoring for patients who crossed over showed a significant OS benefit favoring sorafenib therapy (17.8 months vs 14.3 months, P = 0.03). Sorafenib was generally well tolerated with few grade 3 or 4 adverse events, although ∼5% of patients reported cardiac infarct or ischemic events.69 Sorafenib was also studied as first-line therapy for metastatic RCC in a phase II randomized clinical trial comparing sorafenib with IFN-α2a. Study patients received oral sorafenib 400 mg twice daily or subcutaneous IFN-α2a 9 million units three times weekly. Patients were allowed to cross over from the placebo arm to the sorafenib arm, and dose escalations up to 600 mg twice daily were permitted. The primary end point of PFS showed no difference between sorafenib and IFN therapy. However, patients reported better quality of life with sorafenib as compared with IFN therapy.4 As a result, sorafenib is recommended as second-line therapy for metastatic RCC after progression on initial systemic cytokine therapy (category 1) or tyrosine kinase inhibitor therapy (category 2A) and as first-line therapy only in select patients (category 2A).44
Pazopanib is another orally administered tyrosine kinase inhibitor that was recently approved for the treatment of metastatic RCC. Pazopanib also inhibits multiple kinase receptors, including VEGFR, PDGFR, fibroblast growth factor receptor (FGFR), c-kit, interleukin-2 receptor inducible T-cell kinase (Itk), and leukocyte-specific protein tyrosine kinase (Lck). Pazopanib was evaluated in a phase III double-blind clinical trial in which 435 patients with metastatic RCC were randomized to treatment with pazopanib 800 mg daily or placebo. The study population included 233 treatment-naive and 202 cytokine-pretreated patients. The primary end point of PFS showed a significant benefit in the pazopanib group as compared with placebo, with a median PFS of 9.2 months versus 4.2 months, respectively (P < 0.001). The PFS benefit was significant in both treatment-naive (11.1 vs 2.8 months, P < 0.001) and cytokine-pretreated (7.4 vs 4.2 months, P < 0.001) populations. Pazopanib was generally well tolerated, with few grade 3 or 4 adverse events.9 It is an option for the first-line treatment of metastatic RCC (category 1) and as second-line therapy after progression on cytokines (category 1) or tyrosine kinase inhibitor (category 3). A phase III clinical trial comparing pazopanib to sunitinib therapy as first-line treatment of metastatic RCC is anticipated to complete data collection in 2010. Pazopanib is also being studied in a single-arm phase II clinical trial as second-line therapy in patients who have progressed on sunitinib or bevacizumab therapy.
Although sunitinib, sorafenib, and pazopanib are all orally administered antiangiogenic multikinase inhibitors, clinical studies have clearly demonstrated that these agents have different efficacy and toxicity profiles (Table 146–4). Sunitinib and pazopanib have been reported to improve PFS in both first- and second-line treatment settings, whereas sorafenib has demonstrated improved PFS only in the second-line treatment setting. In addition to differences in efficacy, these agents have subtle differences in their side effect profile.70 Sunitinib and pazopanib are associated with higher rates of hypertension and hair discoloration than sorafenib. Sunitinib is also associated with higher rates of hypothyroidism as compared with sorafenib. Sorafenib is associated with higher rates of gastrointestinal side effects and hand–foot syndrome as compared with sunitinib and pazopanib. It is also important to note that sunitinib is administered intermittently in a 6-week cycle (4-weeks on treatment, 2-weeks off treatment), whereas sorafenib and pazopanib are both administered continuously. Both sunitinib and sorafenib appear to have benefit in the subgroup of patients with non–clear cell histology.
Bevacizumab is a humanized monoclonal antibody that binds circulating VEGF and thus inhibits the effects of VEGF.65 Bevacizumab was studied in a phase III double-blind clinical trial in which 649 treatment-naive patients with metastatic disease were randomized to receive bevacizumab plus IFN-α2a or placebo plus IFN-α2a. Bevacizumab was administered IV at 10 mg/kg every 2 weeks until disease progression or intolerable toxicity; no dose reductions were allowed. IFN was administered subcutaneously at 9 million units three times weekly with dose reduction to 6 million or 3 million units for treatment-related toxicity.7 The primary end point of OS was not statistically different between the two treatment groups, 23.3 months versus 21.3 months for bevacizumab plus IFN and placebo plus IFN, respectively (P = 0.13).71 However, the secondary end points showed a significant benefit with the addition of bevacizumab to IFN therapy, with a PFS of 10.2 months as compared with 5.4 months with IFN plus placebo therapy (P = 0.0001). In addition, objective response rates were higher with the addition of bevacizumab to IFN, 31% as compared with 13% in the placebo plus IFN group. The most common adverse effects were related to IFN therapy, and the addition of bevacizumab did not significantly increase the toxicity of IFN. However, treatment discontinuations due to adverse events occurred more often in the bevacizumab group, with proteinuria, hypertension, and gastrointestinal perforation as the most common causes.7,71 Bevacizumab plus IFN-α2a was studied in another clinical trial (CALGB 90206), which compared it with IFN-α2a monotherapy as first-line treatment.72 The results of this study were similar, with improvements in PFS and objective response rates but no difference in OS. The combination of bevacizumab plus IFN-α2a is an option for the first-line treatment of metastatic RCC (category 1), and bevacizumab monotherapy is an option as second-line therapy (category 2B).44
Temsirolimus is an IV administered agent that inhibits mTOR. As discussed previously, mTOR is a downstream component of the PI3K/AKT pathway that ultimately results in HIF regulation.23,27 Temsirolimus was compared with IFN-α2a or the combination of the two agents in a phase III multicenter trial of 626 treatment-naive patients with higher risk metastatic RCC. About three-fourths of patients were considered high-risk (three or four of five factors), and one-fourth were considered intermediate-risk (one or two of five factors), based on the MSKCC risk classification. The IFN-α2a group received 3 million units subcutaneously three times weekly for the first week, 9 million units the second week, and 18 million units thereafter. The temsirolimus group received 25 mg IV once weekly, whereas the combination group received IFN-α2a at 3 million units subcutaneously three times weekly for the first week and 6 million units subcutaneously three times weekly and temsirolimus 15 mg IV once weekly. The study was discontinued early following the second interim analysis based on temsirolimus benefit.6 Single-agent temsirolimus was found to be superior for the primary end point, with an OS of 10.9 months compared with 7.3 months for IFN alone and 8.4 months for the combination. The median PFS for the temsirolimus, IFN, and combination groups was 5.5, 3.1, and 4.7 months, respectively. Serious adverse effects were more common in the IFN groups than in the temsirolimus group, resulting in fewer dose reductions and dose delays compared with the IFN and combination groups. Patients receiving temsirolimus were more likely to experience hyperlipidemia, hyperglycemia, and hypercholesterolemia, which were expected based on the role of mTOR in the regulation of glucose and lipid metabolism. The results of this study support the use of temsirolimus for first-line treatment of patients with poor prognostic features, making it the first therapy specifically approved for this patient population. Historical data on patients with three or more poor-risk features, such as those in this study, have resulted in a median OS of 4 to 8 months compared with 7.3 months in this study.38,73–75 Based on these results, temsirolimus is recommended by NCCN for first-line treatment in patients with metastatic RCC with poor prognosis (category 1) and as an option for select patients of other risk groups (category 2B).44
Everolimus is another mTOR inhibitor, but it is available in an oral formulation. A phase II trial of everolimus in patients with predominantly clear cell histology metastatic RCC with no more than one prior therapy resulted in a modest number of partial responses or stable disease.76 Based on these data, everolimus was compared with placebo in 410 patients who experienced disease progression within 6 months of stopping sunitinib or sorafenib. This international, multicenter, double-blind, phase III trial randomized patients to everolimus or placebo. Those randomized to the everolimus group received everolimus 10 mg orally once daily continuously while in the fasting state or with a light, fat-free meal. The trial was halted after the second interim analysis based on benefit seen in the everolimus group.8 Everolimus was found to be superior to placebo for the primary end point, with a median PFS of 4 months as compared to 1.9 months (P < 0.0001). Patients in the everolimus group had a 26% probability of being progression-free at 6 months as compared with 2% in the placebo group. At the time of analysis, median OS had not been reached in the everolimus group and was 8.8 months in the placebo group. Partial responses were rare and were seen in only three patients in the everolimus group and none in the placebo group. Health-related quality of life was assessed using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-30 and Functional Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) questionnaires.77,78 Although the time to definitive deterioration of patient-reported outcomes was not different between the two groups, quality of life was sustained during treatment with everolimus relative to placebo as assessed by the EORTC QLQ-C30 and FKSI-DRS questionnaires. All adverse events occurred more frequently in the everolimus group than in the placebo group, but severe adverse effects were uncommon.8 Elevations in glucose and lipids were seen because of everolimus's ability to inhibit mTOR. Based on these results, the NCCN guidelines recommend everolimus for patients with metastatic RCC who have failed treatment with either sunitinib, sorafenib, or both (category 1).44
Temsirolimus and everolimus are both mTOR inhibitors, but they have several important differences. First, everolimus is administered orally once daily, whereas temsirolimus is administered as an intravenous infusion once weekly. Second, although most patients in the temsirolimus trial had clear cell histology (80%), the trial also included patients with other histologies (20%). Everolimus was studied only in patients with RCC exhibiting clear cell histology. Third, temsirolimus was studied in the first-line setting in patients with poor prognosis based on clinical features, whereas everolimus was studied in the second-line setting in patients who had progressed following sorafenib or sunitinib.