The approvals of sunitinib, sorafenib and temsirolimus have dramatically altered the management of renal cell carcinoma (RCC). The combination of bevacizumab and interferon (IFN)-α was recently approved in Europe and may soon receive regulatory approval in the United States. Several other novel agents are being evaluated in clinical trials and are likely to emerge as useful additions to the therapeutic armamentarium. Given the rapid emergence of novel agents, their respective roles in specific settings require further elucidation. Specifically, the choice of agents for first-line therapy of metastatic RCC requires an understanding of risk stratification as well as histologic subtype (clear cell or non-clear cell). Since patients will eventually progress even with the appropriate treatment, salvage therapy needs to be defined. The role of cytoreductive nephrectomy in the era of these novel agents must also be defined.
RISK STRATIFICATION OF ADVANCED RCC
Knowledge of risk stratification is important because recent trials have appropriately included specific prognostic groups based on clinical features noted at diagnosis. The widely used Memorial Sloan-Kettering Cancer Center (MSKCC) risk group categorization was formulated based on the analysis of 670 patients, most of whom had previously received cytokines. Five “poor risk” features were defined: Karnofsky performance status (KPS) < 80; serum calcium > 10 (corrected for albumin); hemoglobin below normal; absence of prior nephrectomy; and lactate dehydrogenase (LDH) > 1.5 x upper limit of normal . The median survivals were 20, 10 and 4 months for patients in the good category (no risk factors), intermediate (1-2 risk factors) and poor risk (≥ 3 risk factors), respectively. Approximately half of all patients had intermediate-risk disease, while the other half was almost evenly divided between good and poor risk disease. In another analysis of 463 patients at MSKCC treated only with first line IFN-α, similar adverse prognostic factors emerged, except for the substitution of “absence of nephrectomy” with “time from initial diagnosis to start of therapy < 1 year” . The median survivals were 30, 14 and 5 months for good (no risk factors), intermediate (1-2 risk factors) and poor risk patients (≥3 risk factors), respectively.
These MSKCC criteria were validated in a separate dataset at the Cleveland Clinic in an analysis of 353 patients . In addition to 4 of the 5 MSKCC criteria (excluding KPS), prior radiotherapy and the presence of hepatic, lung, and retroperitoneal nodal metastases were found to be prognostic factors. Using the number of metastatic sites as a surrogate for individual sites (0-1 versus 2-3), MSKCC risk groups were expanded to accommodate these 2 additional prognostic factors. Similar prognostic factors were also subsequently demonstrated to be important for cytokine-pretreated patients in an analysis of 251 patients from MSKCC . Pretreatment features associated with a shorter survival were low KPS, low hemoglobin and high serum calcium. The median time to death in patients with zero risk factors was 22 months; with 1 of the risk factors survival was 11.9 months and with 2 or more risk factors it was 5.4 months.
FIRST-LINE THERAPY IN CLEAR CELL RCC
Sunitinib was compared with IFN-α in a trial of 750 patients in the first-line setting in patients with clear cell RCC (CC-RCC) (Table 1) . Eligible patients had a clear cell component, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate hematologic, coagulation, hepatic, renal, and cardiac function. Exclusion criteria were brain metastases, uncontrolled hypertension and significant cardiovascular events during the preceding 12 months. The proportion of patients in the good, intermediate and poor risk groups was 34%, 59% and 7%, respectively. Approximately 90% of patients had undergone cytoreductive nephrectomy. Sunitinib yielded a significantly longer median progression-free survival (PFS) (11 versus 5 months) and response rate (RR) of 37% and 31% (Investigator and Independent review) versus 9% and 6% (Investigator and Independent review). Almost all responses were partial responses. On subset analysis, all risk groups appeared to benefit, with the caveat that the poor risk subset was comprised of a very small cohort of patients. Health-related quality of life was also significantly better in the sunitinib group. Survival data are expected, but will be confounded by the availability of other active agents in the salvage setting. Patients in the sunitinib group had higher rates of grade 3 diarrhea (5% versus none), vomiting (4% versus 1%), hypertension (8% versus 1%), and hand - foot syndrome (5% versus no cases). Grade 3 decline in the left ventricular ejection fraction seldom occurred (2% versus 1%) and was reversible. Modest myelosuppression was observed with grade 3-4 neutropenia, thrombocytopenia and anemia in 12%, 8% and 4%, respectively. A total of 38% and 32% of patients on sunitinib had dose interruption and dose reduction, respectively. Recent data also reveal that thyroid function abnormalities appear to be common in patients with metastatic renal cell carcinoma treated with sunitinib, therefore routine monitoring is warranted . These data have established sunitinib as the reference standard for advanced CC-RCC (Table 2).
|TABLE 1. Reported randomized trials for advanced RCC
|TABLE 2. Choice of agents in the treatment of RCC
Bevacizumab plus interferon
The AVOREN trial (Avastin for renal cell cancer) randomized 649 previously untreated patients with a significant clear cell component (>50%) to first-line IFN- α 2a plus placebo or IFN-α 2a plus bevacizumab (Table 1) . Eligibility criteria included prior nephrectomy or partial nephrectomy (with negative resection margins), a KPS ≥ 70% and normal hepatic, hematologic and renal function. Only minimal proteinuria at baseline was allowed (≥ 0.5 g in 24 hours). Exclusion criteria included brain metastases, ongoing full-dose anticoagulation or anti-platelet aggregation treatment, uncontrolled hypertension, clinically significant cardiovascular disease, or chronic glucocorticoid treatment. Only 8-9% of patients had poor risk disease by MSKCC criteria. The addition of bevacizumab to IFN-α 2a significantly increased PFS (median 10.2 versus 5.4 months, HR = 0.63, p <.0001) and investigator assessed objective response rate (30.6% versus 12.4%; p <.0001). The median PFS for combination bevacizumab and IFN-α versus the IFN-α group was 12.9 months versus 7.6 months in the favorable prognosis group, 10.2 months versus 4.5 months in the intermediate prognosis group, and 2.2 months versus 2.1 months in the poor prognosis group. A trend toward improved OS was observed with the addition of bevacizumab to IFN-α 2a (p =.0670), although this analysis was confounded because physicians were encouraged to offer bevacizumab to patients on the placebo arm after the interim PFS analysis and due to the increasing availability of TKIs (tyrosine kinase inhibitors). Analysis of survival in these subgroups revealed a hazard ratio (HR) of 0.69 in the favorable prognosis group, 0.74 in the intermediate prognosis group, and 0.87 in the poor prognosis group. Therefore, MSKCC good and intermediate risk patients appear to garner most of the benefit; however, benefit in the poor risk group would have been difficult to detect because there were so few patients in this group. Given the PFS reported in a previous trial of bevacizumab alone of 8.5 months in the first-line setting, the value of adding IFN-α 2a is unclear . Randomized trials with single agent bevacizumab alone would be needed to fully define the activity of this agent in the front line setting. In the second-line setting following cytokines, the RR with a similar dose of single agent bevacizumab (10 mg/kg) was 10% with a median time to progression of 4.8 months . Toxicity in the combination arm of this study was considerable and occurred in 60% of patients. Much of the toxicity could be related to the IFN-α 2a, as toxicity in this arm was 45%. The incidence of interferon-related toxicities was 10% higher per patient-year in the bevacizumab plus IFN-α group than in the control group. Grade 3- 4 adverse events with bevacizumab included 4 gastrointestinal perforations (1%) and 10 thromboembolic events (3%). Seven (2%) patients with hypertension discontinued treatment due to this event and 16 (5%) patients discontinued bevacizumab due to proteinuria. Toxic deaths were reported in 8 (2%) patients who received bevacizumab and in 7 (2%) patients who did not receive the drug. Only 3 (<1%) deaths among those who received bevacizumab were deemed to be possibly related to bevacizumab. The combination of bevacizumab and IFN-α 2a can be considered a legitimate option for the first line therapy of advanced good and intermediate risk CC-RCC (Table 2).
The results of the Cancer and Leukemia Group-B trial (CALGB), similar to AVOREN but without a placebo control, were recently reported, confirming improved outcomes with bevacizumab plus IFN-α compared to IFN-α alone . Of the 732 patients enrolled, 85% had undergone prior nephrectomy, while 26% had good risk, 64% intermediate risk and 10% had poor risk disease. The median time to progression was 8.5 months in patients receiving bevacizumab plus IFN compared to 5.2 months with IFN monotherapy (HR 0.71, p <.0001). Bevacizumab plus IFN had a higher objective RR (25.5% versus 13.1%, p <.0001). Mature data including survival are still pending, but physicians in the CALGB were not encouraged to cross patients over from the IFN arm to add bevacizumab in responding patients when the interim PFS analysis data were revealed. Toxicities were more common in the bevacizumab plus IFN group. Some 80% had ≥ Grade 3 side effects as compared to 61% in the IFN group; including grade 3 hypertension (9% versus 0%), anorexia (17% versus 8%), fatigue (35% versus 28%) and proteinuria (13% versus 0%).
A randomized phase II trial of 3 different doses of temsirolimus, the mTOR (mammalian target of rapamycin) inhibitor, demonstrated an objective response rate of 7% and a minor response rate of 26%. Most patients in the study had been treated previously with cytokine therapy. Median time to tumor progression was 5.8 months and median survival was 15 months. Intermediate and poor risk patients appeared to selectively benefit compared to historical controls . Temsirolimus, IFN-α 2a and combination temsirolimus plus IFN-α 2a were compared in a subsequent 626- patient phase III trial that selected patients with poor risk RCC based on early signals of activity in this population (Table 1) [11,12]. The eligibility criteria did not mandate a clear cell component or previous cytoreductive nephrectomy. Approximately 80% of patients accrued actually had CC-RCC and 67% of patients had undergone previous nephrectomy. At least 3 of the following 6 poor prognostic factors were required: a serum LDH > 1.5 times the upper limit of the normal; a hemoglobin level below the lower limit of normal; a corrected serum calcium level > 10 mg per deciliter; a time from initial diagnosis to randomization < 1 year; a KPS of 60 or 70, or multiple organ metastases. These poor risk criteria are slightly modified from the original MSKCC criteria, and essentially allowed the accrual of mostly poor, and some intermediate risk patients according to the original MSKCC criteria. Other salient eligibility criteria included fasting cholesterol ≥ 350 mg/dL and triglyceride ≥ 400 mg/dL, and those with brain metastases were eligible if they were neurologically stable and did not require glucocorticoids after surgical resection or radiotherapy. The temsirolimus group received 25 mg of temsirolimus in a weekly 30-minute intravenous infusion. Premedication with 25 to 50 mg of intravenous diphenhydramine or a similar H1 blocker was given approximately 30 minutes before each infusion as prophylaxis against an allergic reaction. The combination-therapy group received 15 mg of temsirolimus in a 30-minute infusion weekly along with IFN.
Median survival was 7.3 months in the IFN group, 10.9 months in the temsirolimus group, and 8.4 months in the combination group. When compared with interferon alone this translated into a 49% improvement in median survival in patients treated on the single agent temsirolimus arm. Treatment with temsirolimus alone was associated with a HR for death of 0.73, while the combination of IFN plus temsirolimus resulted in an HR of 0.96. Therefore, unlike temsirolimus alone, the combination of temsirolimus plus IFN did not improve OS. This could be due to lower doses of both agents in the combination group as well as more dose delays and reductions secondary to toxicities. According to independent radiologic assessments, the median PFS for the IFN, temsirolimus, and combination-therapy groups were 3.1, 5.5, and 4.7 months, respectively. The objective RRs of 4.8%, 8.6%, and 8.1% among patients receiving IFN, temsirolimus, and combination therapy, respectively, did not differ significantly. The proportion of patients with stable disease for at least 6 months or an objective response was greater with temsirolimus (32.1%) and combination-therapy (28.1%) than with IFN (15.5%) (p < .001 and p = .002, respectively). On exploratory subset analysis, the effect of temsirolimus on OS was greater among patients under 65 years of age than among older patients and among patients with a serum LDH > 1.5 times the upper limit of the normal. Additionally, patients with non CC-RCC appeared to benefit relatively more than those with CC-RCC. The most common grade 3-4 adverse effects of temsirolimus were asthenia (11%), rash (4%), anemia (20%), nausea (2%), dyspnea (9%), diarrhea (1%), peripheral edema (2%), hyperlipidemia (3%), and hyperglycemia (11%). These symptoms were usually manageable with supportive care or a reduction in the drug dose. Temsirolimus alone was associated with fewer grade 3-4 adverse events compared to IFN alone. Based on these data derived from a large phase III trial, temsirolimus should be considered the preferred agent for poor risk RCC, and perhaps the preferred agent for non CC-RCC (Table 2), although this will be evaluated in future trials.
The United States Food and Drug Administration (FDA) approved intravenous high-dose (HD) interleukin (IL)-2 in 1992 for metastatic RCC based on a small fraction (~7%) of patients that had durable complete remissions (CRs) and apparent cures . Since then, numerous clinical trials have been conducted demonstrating improved objective response rates and response duration when HD IL-2 was compared to other administration schedules of IL-2 and IFN [14,15]. Unfortunately, no randomized trial has demonstrated an overall survival advantage and therefore its use remains controversial and limited. Additionally, the commonly observed life-threatening toxicities of HD IL-2 and costs severely limit its application on a broader scale [13-15].The best outcomes have been associated with good and intermediate risk CC-RCC, histologic features (clear cell and alveolar features; absence of papillary and granular features), carbonic anhydrase IX (G250 antigen) expression and certain gene expression profiles [16-19]. The Cytokine Working Group recently launched the HD IL-2 “Select” trial to prospectively determine if predictive factors (baseline immune function, immunohistochemical markers and gene expression patterns) can identify patients with advanced RCC more likely to respond to HD IL-2 than a historical, unselected patient population (Table 2).
Role of cytoreductive nephrectomy
Two randomized trials demonstrated a significant survival advantage in metastatic RCC with cytoreductive nephrectomy followed by IFN-α [20,21]. Retrospective reviews also suggest that this approach may improve outcomes in patients receiving HD IL-2 . Most patients accrued on trials with novel TKIs had undergone prior nephrectomy. However, the role of prior nephrectomy in improving outcomes in the era of these novel highly active agents remains to be defined. The paradigm of presurgical systemic therapy followed by cytoreductive nephrectomy can be employed to develop individualized therapy, elucidate mechanisms of resistance and develop reliable prognostic and predictive biomarkers. Early data suggest that administration of the novel anti-angiogenic agents before surgery is not associated with increased perioperative mortality or morbidity . The M.D. Anderson Cancer Center reported that discontinuing bevacizumab at least 4 weeks before surgery and sorafenib/sunitinib at least 24 hours before surgery is feasible. In an ongoing prospective clinical trial at M.D. Anderson, patients are randomized to upfront surgery followed by sunitinib 2 weeks after the operation, or sunitinib for 1-4 weeks before nephrectomy performed 24 hours after discontinuation of sunitinib, and then followed by resumption of sunitinib.
SECOND-LINE THERAPY IN CLEAR CELL RCC
The TARGET Trial (Treatment Approaches in Renal Cancer Global Evaluation) enrolled 903 patients with good and intermediate risk CC-RCC and compared sorafenib to placebo following prior cytokine therapy (Table 1) . Other salient eligibility criteria included therapy within the previous 8 months; Eastern Cooperative Oncology Group performance status 0-1; a life expectancy of at least 12 weeks; adequate bone marrow, liver, pancreatic, and renal function; and a prothrombin time or partial-thromboplastin time of less than 1.5 times the upper limit of normal. Patients with brain metastases or previous exposure to VEGF (vascular endothelial growth factor) pathway inhibitors were excluded. The median PFS was 5.5 months with sorafenib and 2.8 months with placebo (HR = 0.44, p <.01). Responses were seen in 10% of patients receiving sorafenib and in 2% of those receiving placebo (p <.001). The survival improvement of 13.5% for sorafenib was not significant (median 17.8 versus 15.2 months; HR = 0.88; p = .146). However, secondary analysis censoring crossover data showed a significant OS benefit for sorafenib (HR = 0.78; p = .0287), since patients received benefit from sorafenib upon crossover . Severe grade 3-4 diarrhea, rash, fatigue, hypertension and hand-foot skin reactions occurred in a small proportion (1-6%) of patients with sorafenib. A smaller randomized phase II trial in the first line setting did not demonstrate improved outcomes with sorafenib compared to IFN-α . Sorafenib is an active agent, but is increasingly reserved for salvage therapy following other agents given the lack of robust first line data (Table 2). Sunitinib has also been demonstrated in two separate phase II trials to have significant activity following prior cytokines [27,28]. The level of activity and tolerability appeared similar to the observations in the first line setting. Similarly, bevacizumab alone and temsirolimus alone are modestly active following prior cytokines (Table 2) [9,11].
Prior TKI, bevacizumab or temsirolimus
Generally, patients progressing after prior TKIs, bevacizumab or temsirolimus are candidates for clinical trials. However, small reports support the presence of only partial cross-resistance between available novel anti-angiogenic agents. In a retrospective report from the Cleveland Clinic, 30 patients received sunitinib or sorafenib following prior antiangiogenic therapies (thalidomide, lenalidomide, bevacizumab, volociximab, axitinib, sorafenib, sunitinib) . Thirteen of 16 patients who received sunitinib had some tumor shrinkage, including 9 with a partial response. Ten of 14 patients treated with sorafenib had some tumor shrinkage, including 1 with a partial response. The median time to progression for the entire cohort was 10.4 months. In a report from France of 90 patients who received sunitinib and sorafenib in sequence (68 patients received sorafenib first, 22 received sunitinib first), partial response or stable disease was observed as best response in the second treatment in both sequences . Only 6 patients had progressive disease with both drugs. Another report also supports the presence of partial cross-resistance between sunitinib and sorafenib . In a phase II trial, 61 patients received sunitinib following bevacizumab . Sixteen percent exhibited partial responses and another 61% had stable disease, with a median PFS of approximately 24 weeks.
In a recently reported phase II trial, 27 assessable patients with CC-RCC refractory to either bevacizumab (n=11) or sunitinib (n=16) were treated with sorafenib . No objective responses were observed, although 9 patients (33%) had ≥ 5% decrease in tumor burden, with a median PFS of 3.7 months. Interestingly, there was no association of tumor shrinkage with response to prior therapy. Toxicities were significant with grade 3 toxicities experienced by 67% of patients. Hence, a rationale can generally be made for continued targeting of angiogenesis with a sequence of different agents (Table 2).
THERAPY IN NON-CLEAR CELL RCC
Based on the large randomized trial comparing temsirolimus with IFN demonstrating improved overall survival and a more profound benefit for the subset with non-CC RCC, temsirolimus may be considered an option in the first-line therapy for non-CC RCC with poor-risk features (Table 2) . In another report, 41 patients with papillary and 12 with chromophobe histologies who received sorafenib or sunitinib were analyzed . Response rate, PFS and overall survival for the entire cohort were 10%, 8.6 months, and 19.6 months, respectively. Three (25%) of 12 patients with chromophobe RCC achieved a response, while 2 (4.8%) of 41 papillary RCC patients responded. However, these outcomes are clearly suboptimal and a clinical trial is an excellent alternative.
ONGOING CLINICAL TRIALS FOR ADVANCED RCC
Notwithstanding the improved outcomes seen with the above agents, all patients with RCC, including previously untreated patients, are legitimate candidates for clinical trials since current therapy is palliative and not curative. The thrust of ongoing clinical research is to continue to explore novel agents, devise optimal combination and sequencing strategies, revisit the role of cytoreductive nephrectomy, evaluate these agents in the adjuvant setting, and discern factors predictive of response. The BEST trial is planned to compare the following 4 arms: bevacizumab alone; bevacizumab plus temsirolimus; bevacizumab plus sorafenib; and sorafenib plus temsirolimus. An industry-sponsored trial is comparing sunitinib with sunitinib plus bevacizumab, and another trial will compare sunitinib with sunitinib plus enzastaurin, a novel orally administered inhibitor of protein kinase C (PKC)-β and Akt. Overlapping toxicities have rendered some combinations unfeasible (e.g. sunitinib and temsirolimus). The ongoing renal EFFECT trial compares 2 schedules of sunitinib (50 mg daily for 4 of every 6 weeks and 37.5 mg daily continuous). A phase II clinical trial of pazopanib (another new broad-spectrum tyrosine kinase inhibitor) in untreated or cytokine/bevacizumab pretreated RCC has demonstrated promising activity accompanied by a favorable toxicity profile . A placebo-controlled phase III trial of pazopanib in a similar population has completed accrual and results are pending. Upon this landscape, a plethora of other novel targeted agents are undergoing clinical testing, e.g. axitinib [36,37]. In the salvage setting following prior TKIs, a randomized trial, RECORD-1 (Renal cell cancer treatment with oral RAD001 given daily), comparing everolimus (oral mTOR inhibitor) with placebo has also completed accrual; the trial has shown an improvement in PFS favoring everolimus . Other salvage trials following prior sunitinib are planned or ongoing: temsirolimus versus sorafenib, and axitinib versus sorafenib. Another randomized phase II trial led by M.D. Anderson is planned to determine the appropriate sequencing of sunitinib, temsirolimus and bevacizumab. Biomarkers predictive of outcomes and response are being developed and may make it possible to individualize therapy and confer a higher therapeutic index .
The burgeoning list of active agents for RCC therapy presents a unique set of challenges. However, the rational selection of currently approved agents for the therapy of patients with RCC in different settings is feasible by implementing evidence-based medicine. It is also critical to remember that the vast majority of patients are not cured with currently approved agents, and continued support of clinical trial programs is essential. Incorporation of risk factor models (as outlined above) will enable the clinician to apply the data from published randomized trials and select patients for a particular agent that mirror the eligibility criteria utilized in the trial (Table 1). For instance, sunitinib improved outcomes in the phase III trial in which the vast majority of patients had good or intermediate risk disease (Level I evidence) (Table 2). Patients with clear cell histology and poor risk MSKCC prognostic features should receive temsirolimus as initial therapy (Level I evidence). Likewise, patients who have received cytokines as initial therapy should receive sorafenib as second-line therapy (Level I evidence). Based upon results of phase II trials, patients who are initially treated with bevacizumab or cytokines benefit from sunitinib as second-line therapy (Level II evidence). Patients with non-clear cell RCC should receive temsirolimus, as this is the only agent formally studied in a randomized trial (Level I evidence), or be considered for enrollment in a clinical trial. The algorithm has several limitations due to the lack of published data. In particular, the selection of therapy after failure of sunitinib, sorafenib, and temsirolimus is not clear and will depend upon the results of ongoing and planned clinical trials. However, it is clear that that cytokines are no longer the standard first-line therapy for metastatic renal carcinoma; their precise role, if any, will need to be defined by ongoing and future clinical studies.
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