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Year : 2009  |  Volume : 1  |  Issue : 1  |  Page : 9-14 Table of Contents     

Metastatic renal cell carcinoma: A guide to therapy based on current evidence

Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

Date of Submission01-Feb-2009
Date of Acceptance25-Feb-2009

Correspondence Address:
Toni K Choueiri
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, 44 Binney Street, Dana 1230, Boston, MA 02115
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DOI: 10.4103/0974-7796.48781

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Metastatic renal cell carcinoma (RCC) was, until recently, considered a challenging disease to treat with few therapeutic options of limited benefit. The past few years have seen spectacular advances in the treatment of this disease based on understanding the molecular pathways behind tumor growth and angiogenesis. This progress has led to the development of targeted therapies such as the receptor tyrosine kinase inhibitors sunitinib and sorafenib, the anti-vascular endothelial growth factor antibody bevacizumab, and a class of rapamycin analogues that includes temsirolimus and everolimus that have each demonstrated clinical efficacy in patients with metastatic RCC. The goal of this manuscript is to review the current evidence based on large randomized trials and propose a rationale paradigm for the treatment of this disease.

Keywords: Bevacizumab, everolimus, mammalian target of rapamycin, renal cell carcinoma, sunitinib, sorafenib, temsirolimus, vascular endothelial growth factor, von Hippel-Lindau

How to cite this article:
Choueiri TK. Metastatic renal cell carcinoma: A guide to therapy based on current evidence. Urol Ann 2009;1:9-14

How to cite this URL:
Choueiri TK. Metastatic renal cell carcinoma: A guide to therapy based on current evidence. Urol Ann [serial online] 2009 [cited 2021 Nov 27];1:9-14. Available from: https://www.urologyannals.com/text.asp?2009/1/1/9/48781

   Introduction Top

Critical tumoral pathways in renal cell cancer and justified targets

The high resistance of renal cell carcinoma (RCC) to conventional chemotherapy agents that target DNA as well as the very modest activity of cytokines (interferon-alpha (IFN-α) and interleukin-based therapies) coupled with significant treatment toxicity has led to active research efforts in this area. [1] A comprehensive understanding of the underlying molecular biology of RCC has established tumor angiogenesis as a relevant therapeutic target in clear cell RCC, the most common RCC histological subtype (90% of all metastatic RCC). [2] The pathogenesis of clear cell RCC was elucidated by the discovery of the von Hippel-Lindau (VHL) gene in the familial cancer syndrome which overall represents less than 5% of all kidney cancer cases. [3] VHL is a tumor suppressor gene in which biallelic gene inactivation promotes tumorigenesis. One allele is inactivated through a deletion (also known as loss of heterozygosity) observed in over 90% of sporadic clear cell RCC. [4],[5] The remaining VHL allele can be inactivated either through a gene mutation or promoter methylation. [6],[7] This process leads then to an abnormal VHL protein (pVHL). This particular protein normally targets hypoxia-inducible factor (HIF) for proteolysis. [8] However, in the setting of an aberrant pVHL, HIF is able to upregulate the transcription of multiple hypoxia inducible genes involved in proliferation, angiogenesis, and metabolism, including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), epidermal growth factor receptor (EGFR), transforming growth factor-α (TGF-α), and many others. This cascade of events induces endothelial cell division and migration, protects endothelial cells from apoptosis, and leads to cancer growth and progression. [9] Among these growth factors, VEGF is probably the most important direct mediator of tumor angiogenesis. [10] Inhibitors targeting the VEGF signaling pathway have undergone extensive clinical testing in clear cell RCC. [11]

The mammalian target of rapamycin (mTOR) pathway (phosphoinositide 3-kinase/Akt pathway) has a central role in the regulation of cell growth and increasing evidence suggests its deregulation in kidney cancer. Receiving input from multiple signals, including growth factors, hormones, nutrients, and other factors, this pathway stimulates protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase. In addition, signaling through the mTOR complex results in HIF upregulation and transactivation of HIF target genes mentioned previously, and subsequent activation of receptor tyrosine kinases in endothelial and tumor cells. [12],[13] Hence, use of inhibitors of the pathway represents another targeted strategy for the targeted treatment of RCC.

Targeted therapy as initial systemic treatment of patients with metastatic renal cell carcinoma: Data from phase III trials


Sunitinib is a potent and selective inhibitor of VEGFR and PDGFR. [14] In vitro assays with sunitinib have demonstrated inhibition of ligand-dependent VEGFR-2 and PDGFR-B phosphorylation as well as inhibition of VEGF-induced proliferation of endothelial cells. [15] A phase I trial with sunitinib showed responses in patients with RCC and identified 50-mg daily dose given on a 4-weeks on/2-weeks off schedule as the recommended phase II dose and noticed significant activity in patients. [16]

Two multicenter uncontrolled phase II trials of sunitinib in metastatic RCC have been conducted. Both trials enrolled cytokine-refractory patients. The first trial included 63 patients with all histologic subtypes and demonstrated an objective response rate (ORR) of 40% and stable disease for greater than three months in an additional 27% of patients. [17] The second trial included 106 patients and restricted eligibility to clear cell RCC and required both prior nephrectomy and defined progression after prior cytokine therapy. This trial reported an ORR of 39%. Toxicity in these trials, most commonly grade 1 or 2, included asthenia, nausea, diarrhea, stomatitis, and cytopenias. [18]

Based on the aforementioned two uncontrolled clinical trials, a landmark multicenter phase III trial of sunitinib versus interferon-alpha (IFN-α) was recently reported. In a large multicenter study, 750 patients with previously untreated, metastatic RCC were randomized to receive either repeated 6-week cycles of sunitinib or IFN-α (at a dose of 9 MU given subcutaneously three times weekly). The vast majority of patients were low or intermediate risk per Memorial Sloan Kettering Cancer Center (MSKCC) risk criteria. [19] The primary endpoint was progression-free survival (PFS). Secondary endpoints included the ORR, overall survival (OS), patient-reported outcomes, and safety. Median PFS was significantly longer in the sunitinib group (11 months) than in the IFN-α group (five months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32-0.54; P < 0.001). Sunitinib was also associated with a higher ORR (31 vs. 6%) and better quality of life than did patients in the IFN-α group (P < 0.001 for both comparisons). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with IFN-α, whereas diarrhea was more frequent in the sunitinib group. [20] Fatigue could be attributed in part to the possible hypothyroidism associated with sunitinib, as shown in later reports. [21] This study introduced sunitinib as a standard of care in untreated advanced RCC patients. An update of this study at the 2008 American Society of Clinical Oncology (ASCO) meeting showed an OS benefit from sunitinib that was more pronounced in patients who did not receive any poststudy treatment. [22]

Bevacizumab (in combination with Interferon-alpha)

Bevacizumab is a recombinant monoclonal antibody (93% of human origin) which binds and neutralizes all biological isoforms of VEGF. [23] Initial phase I trials with bevacizumab involved patients with advanced cancer and concluded that bevacizumab can be safely administered intravenously at doses up to 10mg/kg and some patients with RCC showed significant tumor shrinkage. [24]

A randomized phase II trial in metastatic clear cell RCC patients who failed interleukin-2, was among the first studies to show clinical benefit in targeting the angiogenic pathway in RCC. Yang et al. randomized 116 patients to receive placebo, low dose (3mg/kg), or high dose (10mg/kg) bevacizumab given intravenously every two weeks. [25] At a median follow up of 27months, there were four partial responses (10%), all in the high-dose bevacizumab arm. An intent-to-treat analysis demonstrated a significant prolongation of time to progression (TTP) in the high dose bevacizumab arm compared to placebo (4.8 vs. 2.5 months; P < 0.001 by log rank test). Toxic effects were minimal and reversible, with 21% grade 3 hypertension and 64% proteinuria (without renal insufficiency) the primary treatment-associated toxic effects. [26] Follow-up has demonstrated no further toxic side effects, including four patients who have continued on therapy without progression for as long as five years. [26]

Data from the Yang et al. trial have suggested that although bevacizumab delayed progression, it might best be combined with other therapies in RCC (such as IFN-α) to optimize results, and several trials were conducted to test this hypothesis. Two large phase III trials - an intergroup US trial and a European trial - comparing this agent in combination with IFN-α with subcutaneous IFN-α only, a generally accepted valid comparison arm at that time for patients with metastatic RCC, have recently been reported. The European trial (known as the AVOREN trial) randomized 649 patients to receive IFN-α alone with placebo or bevacizumab. Patients treated on the bevacizumab arm had higher response rate (30 vs. 13%, P < 0.0001) and TTP (10.2vs. 5.4months, P < 00.0001). Estimated overall survival (OS) was also higher in the bevacizumab-containing treatment arm but did not reach the predefined level of statistical significance. The incidence of grade 3 and 4 adverse events for the bevacizumab/IFN-a arm was significantly higher than the placebo-containing arm (60 vs. 45%, respectively) and included mainly fatigue (23%), proteinuria (6.5%), and hypertension (4%). Since IFN regimens are generally associated with significant toxicity and IFN dose reduction results in an improvement in overall tolerability and/or quality of life in patients [27] subgroup analysis from the AVOREN trial was carried out to determine the effect of IFN dose reduction, from 6 or 3MIU, after the development of IFN-attributed toxicity. [28] This retrospective analysis indicated that the dose of IFN used in combination with bevacizumab can be reduced to manage IFN-related toxicity, enabling patients to remain on therapy, while maintaining efficacy.

Similarly, a large US phase III trial (CALGB 90206) randomized previously untreated clear cell RCC patients to receive bevacizumab at 10mg/kg every two weeks and subcutaneous IFN at 9MU three times weekly or IFN alone administered at the same dose and schedule. [29] With 732patients enrolled, the combination arm was associated with an increased PFS (8.5 vs. 5.2months, HR 0.71, P < 0.0001) and ORR (25.5vs. 13.1%, P < 0.0001). This study reported grade 3 or worse toxicity in ~80% of patients on the combination arm as compared with ~60% of patients receiving IFN monotherapy (P < .0001). Bevacizumab plus IFN resulted in significantly more hypertension (9 vs. 0%), anorexia (17 vs. 8%), fatigue (35 vs. 28%), and proteinuria (13 vs. 0%).

A randomized phase II trial (N = 104) studied the combination of bevacizumab and erlotinib (an EGFR inhibitor) versus bevacizumab alone as first-line therapy in metastatic RCC and did not show any clinical benefit from combining erlotinib and bevacizumab. However, it does provide the only efficacy data for front-line bevacizumab (N = 53) alone in advanced RCC. The median PFS in patients who received bevacizumab alone was 8.5 months and ORR was 13%. [30]

Targeted therapy after failure of cytokine-based agents: Phase III trials


Sorafenib is an orally active, bi-aryl urea molecule with VEGFR/PDGFR inhibition that targets tumor cell proliferation and tumor angiogenesis. [31] Sorafenib was initially developed as an inhibitor to the serine threonine kinase Raf-1 that plays an important role in tumorigenesis. [32] Ras mutations in RCC are not common, although activation of the MAPK pathway has been demonstrated in 50% of human RCC tumors. [33] Sorafenib significantly inhibited tumor growth in xenograft models in a dose-dependent fashion [34],[35] and has undergone evaluation in multiple phase I trials in refractory solid tumors. [36],[37],[38],[39] These trials identified 400 mg twice-daily of continuously dosed sorafenib as the maximal tolerated dose for phase II trials.

A phase II randomized discontinuation study with sorafenib has been reported in 202 patients with metastatic RCC. Tumor shrinkage was observed in 144 patients (71%) and a PFS advantage of 23 versus 6 weeks (P = 0.0001) was demonstrated in the randomized cohort of 65 patients. [40] Hypertension, hand-foot skin reactions (HFS), and fatigue were the major severe toxicities. These data prompted a subsequent large 903patient, placebo-controlled, randomized trial of sorafenib in cytokine refractory RCC. This trial known as treatment approach in renal cancer global evaluation trial (TARGET) reported a PFS advantage in the treatment arm of 24 versus 12 weeks (P < 0.000001), [41] despite a low (10%) response rate. The PFS benefit was demonstrated across all prognostic subgroups. All grade toxicities mainly included HFS reactions (30% with sorafenib vs. 7% with placebo), rash/desquamation (40 vs. 16%, respectively), hypertension reactions (8 vs. 1%, respectively), and fatigue (37 vs. 28%, respectively). Grade 3 and/or 4 toxicities consisted of the same reactions mentioned above but were all <6%. OS results were confounded due to cross-over. [42] A retrospective subgroup analysis of data from the TARGET trial examined the safety and efficacy of sorafenib in older patients (age >70 years) and found similar clinical and quality of life benefit compared to younger patients. [43]

Unlike sunitinib, sorafenib does not appear to have a superior activity to IFN-α in the front-line setting. A recently reported randomized phase II trial at the 2007 ASCO meeting showed a median PFS of 5.7 months versus 5.6 months for sorafenib versus IFN-α, respectively. Nevertheless, quality of life measures and overall tumor shrinkage were greater with sorafenib. [44]

Targeted therapy in patients with poor-risk disease


As mentioned previously, the mTOR is a central point of convergence for signaling pathways critical for cell proliferation, survival, energy metabolism, and apoptosis. Temsirolimus is an allosteric inhibitor of mTOR/raptor complex known as mTORC1 and an attractive therapeutic targeted in RCC. In a randomized phase II trial, 111 patients with advanced cytokine-refractory RCC were treated with three different doses (25, 75, and 250mg) of temsirolimus as weekly infusion. [45] There was no difference in outcome based on dose level. Most common adverse events like maculopapular rash, nausea, fatigue, and mucositis were rarely serious. Interestingly, patients with poor-risk features (as per the MSKCC criteria 19) experienced a median OS of 8.2months, which was superior to historical controls. Therefore, this drug has been studied in a three-arm phase III study comparing temsirolimus, IFN, and the combination of the two agents as first-line therapy for poor-risk patients with metastatic RCC. Of note, trials of VEGF-targeted agents mentioned previously included mainly patients with good and intermediate MSKCC risk groups. Inclusion criteria for the study were: Karnofsky performance status of 60 or greater and at least three of the following poor-risk features - time from diagnosis to first treatment of less than a year, corrected serum calcium >10mg/dL (>2.50mmol/L), LDH greater than 1.5times the upper limit of normal, hemoglobin less than the lower limit of normal, Karnofsky performance status of 60-70, and multiple organ sites of metastases.

Response rates were similar in all three arms and ranged between 7-11% but median OS (the primary endpoint of this study) was longer in the temsirolimus single agent arm in comparison with the other two arms (10.9 months for temsirolimus, 7.3 months for IFN, and 8.4 months for the combination, hazard ratio 0.73, P = 0.0069 for single agent temsirolimus). The authors conclude that temsirolimus as a single agent significantly improves OS of patients with metastatic RCC and poor-risk features as compared with IFN but the combination of the two drugs does not improve OS. [46]

Targeted therapy in patients who failed first-line VEGF tyrosine kinase inhibitor


Another rapalogue, everolimus (RAD001), has demonstrated activity in patients with metastatic RCC. A phase II study assessed the efficacy of daily 10mg oral dosing with everolimus in 41 metastatic clear-cell RCC patients who had failed no more than one prior therapy. Twelve patients had partial responses and median OS was 11.5 months. [47] This prompted a 2 : 1 randomized phase III study having 48 of everolimus versus placebo involving patients whose cancer had progressed through treatment with sunitinib, sorafenib, or both. [48] A total of 410 patients were enrolled and patients who had received sunitinib only, sorafenib only, or both constituted ~45, 30, and 25%. In addition, ~50% of patients had received cytokines. The primary endpoint of this trial was PFS. Treatment with everolimus resulted in a significant improvement in PFS over placebo (4 vs. 19 months, P < 0.001). Responses were low, at only 1%. All risk groups appeared to benefit. Toxicity profile was overall favorable with a low incidence of grade 3/4 toxicities including hyperglycemia (12%), hypophasphatemia (4%), hypercholesterolemia (3%), as well as fatigue, stomatitis, nausea, and pneumonitis. These findings provide level-1 evidence for the use of everolimus as second-line therapy following failure of previous tyrosine kinase inhibitors.

Development of a treatment algorithm based on current evidence

Based on the aforementioned phase III trials, we propose a novel treatment algorithm in patients with metastatic RCC. In this algorithm [Table 1], treatment options are defined according to previous treatment (first- or second-line), MSKCC risk score, type of prior therapy, and level of evidence. Level I evidence is reserved for randomized phase III trials data. Options that are considered >level II evidence come from phase II trials, subgroup analysis of phase III trials, expert opinions, as well as available de-facto options.

   Conclusion Top

In recent years, significant advances in understanding the mechanisms of growth and angiogenesis in advanced RCC have led to the development of VEGF- and mTOR-targeted therapies in this disease. Sunitinib, sorafenib, bevacizumab, temsirolimus, and everolimus demonstrated significant clinical benefit in large randomized phase III trials. These agents provide new treatments and offer hope for patients who had only few limited therapeutic options in the past. The future holds significant promise and more progress with the possibility of new agents such as axitinib and pazopanib. Furthermore, the role of clinical and molecular prognostic and predictive factors [49] continues to evolve in this disease with the possibility of individualized therapy. Several clinical trials are now focusing on optimal combination and sequence. These recent advances provide us with passion and more hope to improve our ability to treat patients with metastatic RCC.

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