The prognosis and treatment outcome of patients with advanced renal cell carcinoma have substantially improved with the multitude of currently available molecularly targeted therapies. The rapid addition of novel therapeutic options has made the treatment algorithm complex and has created a significant challenge for the community oncologist, who is faced with selecting a drug for a given patient from a growing list of agents. The optimal treatment sequence remains to be determined, and effective management of side effects and toxicities is currently the key. These targeted therapies are associated with toxicity profiles that are classically distinct from those associated with conventional chemotherapy agents. In order to help community oncologists optimize patient outcomes, this review summarizes clinical issues associated with specific therapies and the background pivotal data.
Approximately 58,240 patients were diagnosed with and 13,040 died of cancer of the kidney and renal pelvis in 2010,1 and the incidence of this cancer is reported to be increasing.2 Renal cell carcinoma (RCC), originating within the renal cortex, constitutes about 85% to 90% of primary renal tumors. The most common subtype of RCC is clear cell carcinoma, arising from the proximal tubule, and constitutes approximately 75% to 85% of new diagnoses.
The past several decades have witnessed a significant increase in the understanding of the biology of RCC, leading to development of many new therapeutic targets and a greater availability of newer drugs for RCC management. A majority of kidney cancers are believed to be related to changes in a gene called von Hippel–Lindau (VHL). A loss of functional VHL gene results in an increased amount of a protein known as hypoxia-inducible factor, which thereafter leads to highly vascular tumors. Overexpression of hypoxia-inducible factor in kidney cancer is also related to stimulation of a receptor called the mammalian target of rapamycin (mTOR). Both the vascular endothelial growth factor (VEGF) and the mTOR pathways clearly provide opportunities for the development of molecularly targeted drugs in RCC (Figure).
Reprinted with permission from Courtney et al. Curr Oncol Rep. 2009;11(3):218-226.
GF indicates growth factor; GFR, growth factor receptor; HIF, hypoxia-inducible factor; mTORC1, mTORC2, mammalian target of rapamycin complexes 1 and 2; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol 3-kinase; SDF, stromal cell-derived factor; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau.
Dramatic and sustained remissions had been seen occasionally in RCC patients with medications known to invoke immune responses. Until only about five years ago, immunotherapeutic agents such as interleukin-2 or interferon alfa were the mainstay of initial treatment of RCC. It is thought that immunotherapeutic agents cause killing of tumor cells by activated T cells and natural killer cells. Among the various immunotherapeutic strategies used to treat advanced RCC, high-dose bolus interleukin-2 induced durable remissions in about 15% to 20% of patients, but its use had been limited by severe toxicity and the need for specialized care (eg, admission to an intensive-care unit) during treatment. Therefore, this treatment approach was largely restricted to carefully selected patients with optimal organ function, who could withstand the possibility of severe hypotension.3 Subsequently, lower-dose interleukin-2 regimens were used to decrease toxicity, but they appeared to be less effective. Response rates (about 10%-15%) have also been seen with low-dose interleukin-2 and interferon alfa.
Better understanding of the molecular biology of RCC led to identification of new therapeutic targets, which in turn led to development of molecular therapies that have now been integrated into the routine treatment algorithm of patients with advanced RCC. These novel therapies targeting the VEGF or the mTOR pathway are both more active as well as less toxic than immunotherapies that were used before.
The importance of angiogenic pathways in the biology of RCC is now well established. As with many other tumors, RCC must induce new blood vessels in order to receive nutrients and oxygen required for progressive cancer growth. VEGF is the strongest proangiogenic protein, and inhibiting VEGF has been proven to be of clinical value in many malignancies, including metastatic RCC.
Several angiogenic inhibitors have been approved, and many others are in clinical development for RCC. Two different approaches proven to have clinical activity in blocking the VEGF pathway in RCC are inhibition by small-molecule tyrosine kinase (TK) inhibitors (eg, sunitinib, sorafenib, pazopanib) and binding with an antibody (bevacizumab). Small-molecule TK inhibitors block the intracellular domain of the VEGF receptor, while bevacizumab binds with circulating VEGF and prevents activation of the VEGF receptor.4 In contrast to older immunotherapies, these newer agents demonstrated both significantly superior efficacy and better safety profiles, and thus changed the management landscape of metastatic RCC. Although all phase III pivotal studies showed prolongation in progression-free survival (PFS) and a strong trend toward improved overall survival (OS), only one of these studies increased OS to the level of statistical significance.5
The mTOR pathway, which has a central role in the regulation of cell growth, is dysregulated in multiple cancer types. This pathway stimulates protein synthesis after receiving input from multiple signals including growth factors, hormones, nutrients, and other stimulants. The mTOR pathway is involved in additional critical cellular functions (eg, protein degradation), as well as in angiogenesis, and is most dysregulated in patients with poor prognostic factors such as high nuclear grades.6 Use of mTOR pathway inhibitors represents a relatively novel therapeutic approach in the targeted treatment of malignancies. So far, two mTOR inhibitors, temsirolimus and everolimus, have been approved and widely characterized for treatment of advanced RCC. These agents lead to G1 growth arrest after binding to a protein complex and inhibiting mTOR, and have been shown to be effective in both first-line and second-line advanced RCC.7,8 The first-line trial showed improved overall survival; the second-line trial was halted by the Data & Safety Monitoring Board after 191 progression events were observed, with progression occurring in 65% (90/138) of placebo patients compared with 37% (102/272) of everolimus-treated patients. Patients on placebo crossed over to the active drug after the trial was halted. The significantly improved PFS in the everolimus arm remained consistent throughout trials in all three Memorial Sloan-Kettering Cancer Center risk groups.8 Clearly mTOR inhibitors are proven and highly active agents in advanced RCC and also have proven effects on OS, the hardest endpoint to achieve.
With the availability of 4 VEGF inhibitors and two mTOR inhibitors for advanced RCC, it becomes challenging to choose therapeutic options for a patient. Complicating this choice is the fact that none of these agents has been compared head-to-head in a clinical trial, and a cross-study comparison of efficacy endpoints may lead to erroneous conclusions. The only thing that can be stated definitely about efficacy is that out of four phase III trials of VEGF inhibitors in advanced RCC, one has shown a survival improvement while the other three trials have not shown survival improvements. In contrast, among the two phase III trials of mTOR inhibitors, one has shown survival improvement and one was stopped after an interim analysis showed a high-magnitude difference in PFS.
Because the efficacy of these different agents is likely to be similar, the choice of therapy in advanced RCC is more likely to be individualized by physicians on the basis of the patients’ comorbidities and the side effects they can tolerate. There are clearly differences in side effects between the VEGF inhibitors and the mTOR inhibitors, and understanding these differences may help when making personalized decisions. Although all VEGF inhibitors could lead to serious cardiovascular and thromboembolic events, the most serious event related to mTOR inhibitor class is drug-induced pneumonitis. The baseline comorbidities (eg, hypertension, heart disease, or cerebrovascular disease vs preexisting pulmonary dysfunction) are likely the most important factors in choosing between the two classes of agents. Even among VEGF inhibitors, there are some differences between oral VEGF TK inhibitors and bevacizumab. In the following three sections, I discuss the side effects associated with these three broad categories of medications used in advanced RCC: oral small-molecule VEGF TK inhibitors, bevacizumab, and mTOR inhibitors.
The most extensive data regarding the side effects from oral VEGF TK inhibitors come from patients treated with sunitinib and sorafenib.
Small-molecule VEGF TK inhibitors are associated with hypertension and, less commonly, renal disease. A systematic review analyzed the incidence of hypertension in more than 4500 patients treated with sorafenib in nine prospective studies.9 New-onset hypertension was reported in 23% of patients and was considered severe or life-threatening in 6%. In a separate analysis of approximately 5000 patients from 13 clinical trials treated with sunitinib, the incidence of all-grade and high-grade hypertension was 22% and 7%, respectively.10 This meta-analysis also found a significant risk of renal dysfunction. Both of these studies concluded that there is significant risk of developing hypertension with these drugs.
The Investigational Drug Steering Committee of the National Cancer Institute convened an interdisciplinary cardiovascular toxicities expert panel to evaluate the risk of hypertension and renal dysfunction with VEGF inhibitors and to make recommendations. The panel recommended conducting a formal risk assessment for potential cardiovascular complications in patients receiving VEGF inhibitors,11 and also suggested proper agent selection, dosing, and scheduling of follow-up so that the complications associated with excessive or prolonged elevation in blood pressure could be avoided.
VEGF TK inhibitors are also associated with a slight but definite increased risk of arterial thromboembolic events. In a systematic review that included more than 10,000 patients treated with sunitinib or sorafenib in 10 trials, the incidence of arterial thromboembolic events was 1.4%, which was threefold the risk found in the control population.12 The phase III pazopanib trial also reported similarly elevated risk of arterial thromboembolic events compared with placebo.13
VEGF TK inhibitors have also been reported to increase the risk of cardiotoxicity. In retrospective series and clinical trials, sunitinib has been associated with a decline in left ventricular ejection fraction in up to 28% of treated patients and clinical heart failure in up to 15% of treated patients. Among the patients treated in the pivotal randomized trial leading to sunitinib approval for treatment of advanced RCC, 21% of patients experienced a decline in left ventricular ejection fraction, and this decline was symptomatic in 10% of the patients.14 Presence of hypertension and a history of coronary artery disease are believed to increase this risk of cardiac toxicity.
Another adverse event frequently observed in patients treated with VEGF TK inhibitors is thyroid dysfunction, most commonly hypothyroidism. In a single institution series of 73 patients treated with sunitinib, 56 patients (77%) had abnormal thyroid function tests consistent with hypothyroidism, and 47 had clinical signs or symptoms possibly related to hypothyroidism.15 Thyroid hormone replacement was given to 17 patients, 9 of whom had an improvement in symptoms. In addition to hypothyroidism, some reports have also described transient thyrotoxicosis with sunitinib. Although thyroid dysfunction also occurs in patients treated with sorafenib, it appears to be less frequent. Because of the high prevalence of hypothyroidism, regular surveillance of thyroid-stimulating hormone levels is warranted during sunitinib therapy.
A variety of cutaneous effects are also seen with oral VEGF TK inhibitors. The most common skin manifestation is a hand-foot skin reaction, which differs in its clinical presentation from the classical acral erythema caused by conventional chemotherapeutics. Patients treated with VEGF TK inhibitors who develop cutaneous effects have localized tender lesions, appearing as blisters or hyperkeratosis in areas of trauma or friction. Hyperkeratosis is frequent, developing in more than one-half of affected patients, and typically presents as yellowish, painful, hyperkeratotic plaques localized to the pressure sole areas such as heels or metatarsals. The frequency of cutaneous effects appears to be higher with sorafenib (30%-60%) than with sunitinib (10%-20%). Cutaneous side effects are recognized to increase with cumulative exposure to the drugs. An international consensus panel recommends that preexisting hyperkeratotic areas and calluses should be removed with a manicure and/or pedicure, using appropriately sterilized instruments, and exposure of hands and feet to hot water should be avoided, as this is believed to exacerbate symptoms.16
Elevations of the pancreatic enzymes lipase and amylase have been reported with VEGF TK inhibitors, although overt pancreatitis is rare. Blood glucose levels may be reduced in diabetic patients, and thus should be monitored in patients who are treated with VEGF TK inhibitors and have the comorbidity of diabetes. Antidiabetic medications may need to be adjusted.
Severe and occasionally fatal hepatotoxicity has also been observed. Therefore, patients treated with these agents should be monitored for evidence of liver toxicity, and treatment should be interrupted or discontinued if evidence of toxicity is observed.
Skeletal muscle wasting is a common phenomenon in patients with advanced cancer. However, it is also known to be an adverse effect associated with the use of VEGF TK inhibitors. The loss of muscle mass contributes to asthenia and fatigue, and is mostly progressive with cumulative exposure.
Among the three broad groups of medications classified in this discussion, the agent with the most data on adverse events is bevacizumab. Hypertension is a frequent side effect of bevacizumab, and guidelines for pretreatment assessment, monitoring, and management of elevated blood pressure in patients receiving bevacizumab are available.11 Although the effects of bevacizumab on hypertension, cardiac toxicity, arterial and venous thromboembolic events, and albuminuria appear similar to those of oral VEGF TK inhibitors, a few of the side effects more commonly seen with oral VEGF TK inhibitors are not seen with bevacizumab. These include thyroid dysfunction, cutaneous effects, pancreatic and liver enzyme elevations, and skeletal wasting. On the other hand, hemorrhage and gastrointestinal perforations are known to occur with bevacizumab; these complications are not commonly seen with oral VEGF TK inhibitors.
mTOR inhibitors have specific class-associated adverse events, making it critical to recognize and manage them appropriately. In a recent review article, Rodriguez-Pascual et al17 describe the most relevant emergent toxicities and their management and conclude that most of the toxicities, if recognized and managed appropriately, should resolve with minimal impact on patients’ quality of life or on the antitumor efficacy of the anticancer therapy.
Among the side effects observed with temsirolimus, the most frequent ones are asthenia, rash, anemia, nausea, and anorexia.7 Severe adverse events have mostly been uncommon; the incidence of the most frequent grade 3 or 4 adverse events of anemia, asthenia, and hyperglycemia was 20%, 11%, and 11%, respectively.7 A smaller proportion of patients developed hyperlipidemia. The most frequent severe adverse events in patients treated with everolimus included lympho-penia and hyperglycemia, occurring in 15% and 12% of patients, respectively.8 A smaller incidence of stomatitis (3%) has also been observed. Attention to routine hematology and blood glucose/cholesterol levels, especially in patients who have preexisting diabetes or hypercholesterolemia, will help in the overall management of these patients.
With the intravenous mTOR inhibitor temsirolimus, hypersensitivity reactions have also been reported and may be severe or life-threatening.18 Therefore, premedication with diphenhydramine is recommended with each dose of temsirolimus.
The class-specific side effect associated with mTOR inhibitors is pneumonitis. Low-grade pneumonitis is much more common than severe pneumonitis. Radiographic findings consistent with drug-induced pneumonitis have been detected in 36% of patients receiving temsirolimus in an independent review of serial radiographic studies.19 X-ray findings include ground glass opacity or consolidation, and more than 50% of these findings are asymptomatic. Common management includes antibiotics and/or glucocorticoids. Clinical suspicion of symptomatic drug-induced lung toxicity generally justifies treatment discontinuation and consideration of an alternate agent.
Like temsirolimus, everolimus has also been associated with pneumonitis. Clinical pneumonitis was suspected in 37 (14%) of the 274 patients who received everolimus in the pivotal phase III trial.20 Most of these cases were low grade (grade 1-2); 10 (3.6%) had grade 3 pneumonitis, and none had grade 4 pneumonitis. Dedicated radiologic review of available serial radiographic studies found a higher percentage of new radiographic findings, even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9% vs 15.2%). The most common radiographic findings included focally consolidative areas at the lung bases or ground glass opacity. Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in patients treated with everolimus. Monitoring and management guidelines have been suggested for patients who develop symptoms or radiographic changes while receiving everolimus, based on the grade of pneumonitis (Table).20
Baseline lung function appears to be a risk factor for development of pulmonary side effects with mTOR inhibitors. Therefore, before starting therapy with an mTOR inhibitor, an evaluation for preexisting pulmonary issues should be considered. Patients with moderate-to-severe chronic obstructive pulmonary disease or those who are unlikely to tolerate a pulmonary challenge should preferably be offered treatments other than mTOR inhibitors.
Retrospective analyses suggest lack of cross-resistance among drugs targeting the VEGF pathway and those that inhibit mTOR. The RECORD-3 trial is trying to determine the optimal sequence of a VEGF inhibitor and an mTOR inhibitor. This large phase III trial plans to randomize patients with untreated advanced RCC to sunitinib followed by everolimus versus everolimus followed by sunitinib (Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients With Metastatic Renal Cell Carcinoma [RECORD-3]; http://clinicaltrials.gov/ct2/show/NCT00903175).
There is a biologic hypothesis that synergism might be possible among VEGF and mTOR inhibitors, though combinations may also result in additive toxicity. Results of a recent phase II trial of everolimus and bevacizumab as first-line as well as second-line treatment have been published.21 The regimen was well tolerated by most patients, with the toxicity profile as expected based on the known toxicities of these two agents. Grade 3-4 proteinuria was more frequent than expected (25%) and led to treatment discontinuation in 6 patients. The study concluded that the combination of bevacizumab and everolimus is active and well tolerated in the treatment of advanced clear cell renal cancer, either as first-line treatment or after treatment with sunitinib and/or sorafenib. Cancer and Leukemia Group B is now planning to test the benefits of this combination regimen as later-line therapy after previous treatments with 1 or multiple oral VEGF TK inhibitors.22 The primary endpoint is OS, and the trial implements a futility rule based on interim evaluation of PFS.
Many adjuvant trials have been undertaken in an attempt to reduce the risk of recurrence among patients who undergo surgical resection for locally advanced renal cancer. However, no clear benefit has been identified to date. A recent meta-analysis identified 12 trials in the adjuvant setting, which used hormone therapy, biochemotherapy, chemotherapy, vaccine, or immunotherapy.23 The meta-analysis confirmed the evidence that no studied systemic therapy so far provides improvement in survival for patients who undergo surgical resection of RCC. This may change with the advent of adjuvant trials of targeted agents in resected renal cancer. Various adjuvant trials with oral VEGF inhibitors or mTOR inhibitors are currently ongoing and will determine whether an adjuvant therapeutic strategy with a molecularly targeted therapy adds value in the care of these patients.
Other experimental approaches for treatment of RCC include immunomodulatory drugs (eg, lenalidomide), vaccines, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation.