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 »  Abstract
 » Introduction
 » Conclusions
 » Acknowledgment
 »  Sunitinib Malate...
 »  References
 »  Article Tables

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  Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 1  |  Page : 102-108
 

Current evidence and the evolving role of sunitinib in the management of renal cell carcinoma


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Urologic Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Urologic Oncology, Hinduja Hospital, Mumbai, Maharashtra, India

Date of Web Publication28-Apr-2016

Correspondence Address:
K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.180824

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 » Abstract 

The development of targeted agents has expanded the anticancer arsenal available to oncologists and revolutionized the field of cancer treatment. In patients with advanced renal cell carcinoma (RCC), small molecule targeted therapies have improved clinical outcomes compared with cytokine-based treatments. Sunitinib malate is one such drug that has demonstrated clinical efficacy in patients with metastatic renal cell carcinoma (mRCC). This oral, multi-targeted tyrosine kinase inhibitor is approved for use in multiple countries for the treatment of advanced RCC and gastrointestinal stromal tumor patients who have progressed on imatinib therapy. In patients with advanced RCC, sunitinib significantly improves clinical outcomes with a favorable safety profile compared with conventional treatment with interferon-a. The clinically proven treatment and safety outcomes have led investigators to evaluate the merits of sunitinib therapy in the adjuvant and neoadjuvant setting in patients with mRCC. In the neoadjuvant setting, preliminary data suggest that sunitinib can effectively reduce the primary tumor and facilitate surgical resection in patients with locally advanced and mRCC. Post-operative complications were observed in some patients, but the overall safety profile and efficacy suggests that mRCC patients with surgically inoperable tumors may benefit from neoadjuvant sunitinib therapy. Ongoing clinical trials should provide insight into the value of sunitinib as adjuvant therapy.


Keywords: Adjuvant, carcinoma renal cell, molecular targeted therapy, neoadjuvant, sunitinib


How to cite this article:
Noronha V, Joshi A, Bakshi G, Tongaonkar H, Prabhash K. Current evidence and the evolving role of sunitinib in the management of renal cell carcinoma. Indian J Cancer 2016;53:102-8

How to cite this URL:
Noronha V, Joshi A, Bakshi G, Tongaonkar H, Prabhash K. Current evidence and the evolving role of sunitinib in the management of renal cell carcinoma. Indian J Cancer [serial online] 2016 [cited 2019 Dec 15];53:102-8. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/102/180824



 » Introduction Top


Renal cancer has been estimated to account for approximately 2% of all cancer cases globally, with more than 200,000 new cases being diagnosed each year world-wide.[1] The most common manifestation of renal cancer is renal cell carcinoma (RCC), which originates in the lining of the proximal tubule and accounts for about 85% of all renal cancer cases. The remaining cases consist of cancer of the renal pelvis and other rare malignancies.[2] One major obstacle in the effective diagnosis and treatment of RCC is early detection, which has yet to be fully realized. As a consequence, it has been estimated that over 50% of RCC cases are detected incidentally during imaging tests ordered for other reasons. In addition, between 25% and 30% of patients with RCC are initially diagnosed due to symptoms of metastases.[3]

Until the last decade, pharmacological treatment options for RCC were limited. Before the advent of targeted therapies, the two most commonly used agents were the immunomodulatory cytokines interleukin (IL)-2 and interferon-a (IFNa). Despite being first-line pharmacologic agents for RCC for almost 2 decades, cytokine-based therapies failed to fulfill the treatment needs of patients with RCC due to limitations in treatment outcomes and safety. For example, in the pivotal trial evaluating high dose (HD) IL-2 in patients with stage IV RCC, the objective response rate (ORR) was a modest 14% (90% confidence interval, 10-19%), with 5% and 9% of patients achieving a complete or partial response (PR), respectively.[4] In more recent studies, the ORR with HD-IL2 in patients with metastatic RCC (mRCC) has been reported to be around 20%.[5],[6] In addition to modest response rates (RRs), IL-2 is also associated with dose-limiting toxicity that restricts its use in some patients.[7] Unlike IL-2 therapy, IFNa has a more favorable toxicity profile, which likely accounts for its more widespread use.[7] Treatment outcomes with IFNa however have also been reported as modest in patients with RCC. In a report by Motzer et al.,[8] a retrospective analysis of six clinical trials evaluating IFNa in patients with mRCC (n = 463) yielded an overall RR of 11%, with a median overall survival (OS) of 13.1 months and median progression-free survival (PFS) of 4.7 months. Because of these modest RRs and/or associated risks, cytokine-based therapies are of marginal benefit to patients with stage IV mRCC, who have an estimated 5-year survival rate of 23%. Given that almost one-third of patients with RCC are diagnosed with metastases,[3] there remained an existing unmet need for effective pharmacological intervention in mRCC in the era of cytokine-based therapy.

Within the last 10 years, the treatment repertoire for mRCC has expanded to include small molecule targeted agents. One primary target of many of these agents is the cellular cascade facilitating angiogenesis. Angiogenesis is essential for tumor growth as well as tumor invasion and metastatic dissemination. Receptor tyrosine kinases that have been shown to be critical to the angiogenesis pathway are vascular endothelial growth factor receptors (VEGFRs-1, -2 and -3) and platelet-derived growth factor receptors (PDGFRs-a and -b).[9] Sunitinib malate, bevacizumab and pazopanib are tyrosine kinase inhibitors (TKIs) that inhibit angiogenesis by preventing vascular endothelial growth factor (VEGF)-mediated cellular signaling. The targeted agent temsirolimus also inhibits angiogenesis, but through inhibition of mammalian target of rapamycin. Compared with conventional treatment with IFNa, drugs such as sunitinib,[10] bevacizumab plus IFNa,[11],[12] and temsirolimus [13] have been shown to significantly improve the ORR and PFS in patients with mRCC; pazopanib was shown to be superior to placebo.[14]

The substantial responses observed with targeted agents in the treatment of patients with mRCC have sparked interest in their use in the neoadjuvant and adjuvant setting. Potential benefits with such therapy include reduction of the patient's overall tumor burden and tumor down staging.[15] Currently, however, there is limited data available on the role of TKIs in this setting, especially with regard to prospective randomized trials. In addition, the timing and duration of such therapy remains unclear. The purpose of this review is an assessment of the available data pertaining to the use of targeted agents in the pre-surgical/neoadjuvant and adjuvant setting.


 » Sunitinib Malate (SUTENT ®) Top


Properties

Sunitinib malate (SUTENT ®) is an oral, TKIs with multiple targets that include: VEGFRs-1, -2 and -3, PDGFRs-a and -b, stem-cell factor receptor (KIT), FMS -like tyrosine kinase 3, colony-stimulating factor 1 receptor and glial cell line-derived neurotrophic factor receptor (rearranged during transfection). Sunitinib is currently approved multi-nationally for the treatment of advanced RCC and for gastrointestinal stromal tumors (GIST) after disease progression on or intolerance to imatinib mesylate.[16],[17]

Sunitinib exerts its antiangiogenic effects by disrupting the pro-angiogenic activity of growth factor signaling in both endothelial cells and pericytes. More specifically, sunitinib-mediated inhibition of VEGF prevents the endothelial cell proliferation and vascularization that are necessary for primary tumor growth and establishment of metastases.[17] In addition, inhibition of PDGFRs diminishes the proliferation and growth of pericytes and fibroblasts that support and stabilize endothelial cells.[17],[18]

Dosing recommendation rationale

The recommended starting dose of sunitinib for GIST and advanced RCC is a single, 50 mg oral tablet taken once daily either with or without food. A single treatment cycle with sunitinib lasts 6 weeks and consists of 4 weeks on treatment followed by 2 weeks off.

The pharmacokinetic properties of sunitinib were determined in a dose escalation study in 28 patients receiving sunitinib doses ranging from 15 mg/m 2 to 59 mg/m 2 (total dose ranged from 50 mg every other day up to 150 mg daily). Patients included in the study had advanced solid malignancies for which no other therapy was possible. At the maximum-tolerated doses (≥75 mg daily), the main dose-limiting toxicities included reversible grade 3 asthenia and grade 3 hypertension. At the dose of 50 mg daily, the main adverse events (AEs) reported included: Sore mouth, edema and thrombocytopenia. Doses ≥50 mg daily were also associated with hair and skin discoloration. Although clinical efficacy was not a primary objective of this study, investigators also assessed tumor progression in 22 evaluable patients. In patients treated with ≥50 mg sunitinib daily, results showed four patients with PRs and two patients with stable disease with >90% tumor necrosis. At doses ≥75 mg daily (n = 6), tumor responses were accompanied by reduced intratumoral vascularization and central tumor necrosis. The latter, however, eventually led to organ perforation or fistula in four patients. Based on these dose escalation results, 50 mg sunitinib daily was chosen as the recommended dose. At this dose, plasma concentrations of sunitinib ranged from 50 to 100 ng/mL. The maximum concentration was achieved approximately 5 h after administration and the half-life ranged from 41 to 86 h.[19]

The pharmacokinetic properties of 50 mg sunitinib daily were evaluated further in a study by Houk et al.[20] Investigators performed meta-analysis using data from 14 studies (n = 590) to assess pharmacokinetics and to identify covariates that may contribute to variability in exposure to sunitinib. The 14 studies analyzed consisted of 12 Western studies and 2 Japanese studies. Covariates of interest included: Gender, age, body weight, race (Asian vs. non-Asian), creatinine clearance, Eastern Cooperative Oncology Group performance status (ECOG PS) score and tumor type. Results obtained using nonlinear mixed-effects modeling estimated that individual covariates may account for between 2% and 17% of changes in area under the curve (AUC) and/or maximum plasma concentration (Cmax) of sunitinib among all patients. In addition, the inter-individual variability of AUC and Cmax was evaluated in male Caucasian patients and estimated to be 30%. Based on these results, the authors concluded that individual covariates minimally affected sunitinib pharmacokinetics. The recommended dose of 50 mg daily, therefore, can be administered to any of the subpopulations evaluated in the study without the necessity for dose adjustment.

In a separate study by Houk et al.,[21] the authors evaluated the relationship between exposure to sunitinib and clinical endpoints. Data from six studies (n = 639 with pharmacodynamic data, n = 443 with pharmacokinetic parameter estimates) in patients with advanced solid tumors, including GIST and mRCC, were pooled and used for the meta-analysis. The range of sunitinib doses used in the study was between 25 and 150 mg daily, with the majority of patients receiving 50 mg/day. Results showed that increased exposure to sunitinib correlated with longer time to progression (TTP), longer OS and a greater chance at achieving an antitumor response. The authors also reported some increased risk of AEs with increased exposure (e.g., fatigue and diastolic blood pressure elevation), but these events were generally mild to moderate in severity. Together, the data confirms that maintenance of sunitinib therapy with the recommended dosing regimen of 50 mg/day in a 4/2 schedule provides clinical benefits with an acceptable safety profile in patients with cancer.

The safety and efficacy of sunitinib administered in a continuous, once daily dosing regimen has also been evaluated in two separate phase II studies. In the first study Escudier et al.[22] used an open-label trial to evaluate sunitinib on a continuous dosing schedule in 107 patients with cytokine-refractory mRCC. Patients were given 37.5 mg of sunitinib daily as a starting dose; dose titration (up to 50 mg/day or down to 25 mg/day) was permitted based on investigators' assessment of the type and grade of AE. Overall, 24 patients (22%) successfully completed the study (i.e., 1 year on study). The remaining 83 patients discontinued due to disease progression (65 patients [61%], includes 1 death), AEs (16 patients) or consent withdrawal (two patients). The efficacy of this dosing regimen was determined in 102 evaluable patients who received at least one dose of sunitinib. ORR was 20%, with a median PFS and OS of 8.2 and 19.8 months, respectively, at a median follow-up of 26.4 months. Asthenia (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%) and anorexia (8%) were the most commonly reported grade 3 AEs among all patients. Dose reduction due to grade 3/4 AEs occurred in 46 patients (43%). The pharmacokinetics of sunitinib and its metabolite were similar in patients receiving the continuous dosing regimen versus those receiving the intermittent 4/2 dosing regimen, based on comparison of dose-corrected Cmin values.

In the second study by Motzer et al.,[23] investigators compared the recommended 50 mg 4/2 dosing regimen of sunitinib against 37.5 mg continuous dosing regimen as first-line therapy in 289 patients with either clear cell locally recurrent or mRCC (effect trial). Preliminary analysis showed a trend toward later TTP in patients receiving the 4/2 regimen of sunitinib compared with the continuously dosed regimen (9.9 months vs. 7.1 months respectively; hazard ratio [HR] =0.773; P = 0.090). ORR was 32.2% versus 28.1% (P = 0.444); median OS was 23.1 months versus 23.5 months (P = 0.615). AE profiles were also similar between treatment regimens, with the most common AEs being asthenia (both 62%), nausea (56% vs. 49%) and diarrhea (56% vs. 64%). Final analysis from this study should provide insight into the utility of sunitinib administered as a first-line, continuous dose regimen in patients with mRCC.

Sunitinib in patients with mRCC

In the pivotal trial demonstrating the efficacy of sunitinib in patients with mRCC, sunitinib was compared with IFNa, the standard of care as first-line treatment.[10],[24],[25] Patients with mRCC (n = 750) were randomized to receive repeated 6 week cycles of either sunitinib or IFNa. The primary efficacy endpoint was PFS, with secondary efficacy endpoints including ORR and OS. The ORR was significantly higher in patients treated with sunitinib compared with patients receiving IFNa (47% vs. 12%, respectively; P < 0.001).[10] Median PFS was significantly longer in sunitinib-treated patients (11 months vs. 5 months in IFNa-treated patients; P < 0.001).[25] Median OS was numerically longer in sunitinib-treated patients, albeit not significantly (26.4 months vs. 21.8 months in IFNa-treated patients; HR = 0.821; P = 0.051).[10] It is worth noting, however that patient crossover to active therapy confounded interpretation of OS results in the phase III trials of sunitinib, pazopanib and bevacizumab plus IFNa.[10],[11],[14]

Treatment benefits with sunitinib were also shown to extend into health-related quality-of-life (HRQoL) in patients from the pivotal trial. Using results from the Functional Assessment of Cancer Therapy-Kidney Symptom Index and its disease-related symptoms subscale (FKSI-DRS) as the primary HRQoL endpoint, investigators found that sunitinib-treated patients reported significantly better scores in FKSI-DRS (P < 0.05).[24]

Following the pivotal trial, the efficacy of sunitinib was evaluated in a broader range of mRCC patients through the expanded access program (EAP).[26] The EAP was a large-scale, open access trial that included previously treated and treatment-naïve patients at least 18 years of age with mRCC. Exclusion criteria included patients who previously received sunitinib and patients with any acute or psychiatric medical condition considered inappropriate for inclusion by study investigators. Overall, 4,564 patients were enrolled with the inclusion of 4,371 patients in the modified intent-to-treat population. This population included 7% with brain metastases, 13% with ECOG PS score ≥2, 13% non-clear cell RCC and 32% of patients' ≥65 years of age. All patients received open-label sunitinib at the recommended dose using the standard 6 week treatment cycle. Treatments outcomes were analyzed from 3,464 evaluable patients. The ORR was 17% in the overall population and in the subgroup of patients who were ≥65 years of age; 9% in patients with ECOG PS ≥2; and 11% in patients with non-clear cell RCC. The median PFS in the total population was 10.9 months and the OS was 18.4 months. Safety outcomes were also reported, with diarrhea and fatigue being the most common treatment-related AEs (44% and 33%, respectively). Fatigue and thrombocytopenia were the most common grade 3-4 AEs (8% each).[26]

The efficacy and safety of sunitinib in the Asian population has also been evaluated using a sub-analysis of EAP data.[27] Overall, 325 patients were included in the sub-analysis with 212 patients identified at Asian study sites (i.e., Hong Kong, Korea, Malaysia, Philippines, Singapore, Taiwan and Thailand) and the remaining 113 patients identified at non-Asian sites. Overall, the efficacy and safety of sunitinib was similar between Asian and non-Asian patients. Among Asians, however, there were differences in safety outcomes between study sites. For example, Asian patients from Asian study sites showed a higher incidence of hematologic AEs and dermatologic/mucosal AEs compared with Asians at non-Asian study sites and non-Asian patients. In Asian patients who received prior radiation or cytokine therapy, the incidence of grade 3/4 hematological AEs was also higher compared with their non-Asian counterparts, regardless of the study site. The basis for this variability in safety is not completely understood. Interestingly, recent evidence suggests that genomic variability in the VEGF and VEGFR genes may contribute, in part, to the differences in safety and efficacy among patients receiving anti-VEGF therapy.[28],[29]

Prognostic factors for treatment in patients with mRCC

Identification of prognostic factors in mRCC was first reported by Motzer et al.[30] in untreated patients, then cytokine-treated patients.[8] These results were later validated in patients receiving TKI therapy in separate studies by Heng et al.[31] and Patil et al.[32] The common prognostic factors among these three studies are: Patient performance status, time from diagnosis to treatment, high corrected serum calcium level and low hemoglobin.

In addition, data from the EAP has expanded the demographic and clinical characteristics of patients receiving sunitinib. The availability of data from a broader base of patients provides an opportunity for researchers to identify additional patient populations with poor prognostic factors and their response to sunitinib treatment. Analysis of data from EAP patients showed that increased age (≥65 years of age), low performance status and brain metastases could be safely treated with sunitinib. In comparison to historical controls, improvements in PFS and OS were observed for patients with low performance status and brain metastases.[26]

Predictive factors for the use of sunitinib in mRCC

Predictive factors have yet to be identified in prospective, randomized clinical trials. In a retrospective analysis; however, results from 139 sunitinib-treated patients with mRCC showed that the presence of bone metastases was associated with poor RR, PFS and OS. Conversely, higher RR and longer PFS and OS were observed in patients with exclusive lung and/or lymph node metastases.[33] A separate study by Rini et al.[34] also showed that the development of sunitinib-induced hypertension was also associated with improved RR, PFS and OS in patients with mRCC compared with patients who did not develop hypertension during treatment. Finally, in a smaller study, investigators reported an association between cytokine levels and outcomes in patients with mRCC; patients with elevations in tumor necrosis factor-a and metalloproteinase-9 levels showed no response to sunitinib.[35]

Predictive factors have also been evaluated using pharmacogenetic analysis. In a study by van Erp et al.,[36] data from 136 sunitinib-treated patients with mRCC were evaluated. Results showed an association between specific polymorphisms in genes encoding the drug transporters ABCB1 and ABCG2 and longer PFS and OS. A smaller study in 28 sunitinib-treated patients with mRCC suggested that OS was longer in patients showing a decrease in the number of Foxp3+ cells after two or three cycles of therapy.[37] Lastly, retrospective analysis of 23 sunitinib-treated patients indicated that tumor transcript levels of VEGF121 and VEGF165 were significantly higher in patients who responded to treatment versus those who did not.[38] Together, these data provide the rationale for further studies of potential predictive factors in prospective, randomized clinical trials.

Sunitinib as neo-adjuvant and adjuvant therapy

Debulking nephrectomy followed by systemic therapy is the current standard of care in patients with RCC who are optimal candidates for the procedure.[39] The benefits of this treatment regimen were demonstrated in two clinical trials evaluating the procedure in combination with IFNa.[40],[41],[42] In the new era of targeted therapies; however, the benefits and risks of surgical intervention combined with targeted treatment are not completely understood. In the following sections, we review data examining the efficacy of targeted agents as neoadjuvant therapy and also discuss ongoing or proposed trials aimed at evaluating the efficacy and safety of targeted agents as adjuvant therapy.

Neo-adjuvant therapy

[Table 1] summarizes the characteristics and outcomes of several studies that evaluated the merits of sunitinib as neo-adjuvant therapy in patients with RCC. Many of the studies listed are retrospective reviews. In the first retrospective study by Bex et al.,[43] the response to neo-adjuvant sunitinib therapy was assessed in 10 RCC patients with surgically complex primary tumors or bulky loco-regional metastases from an EAP. The authors reported a 14% median reduction in tumor size in six of the ten surgery-limiting tumor sites (SLTSs) according to response evaluation criteria in solid tumors (RECIST) criteria. This effect appeared to be most prominent in the first 2-4 months. While none of the patients showed a PR at SLTSs, there was one complete remission and two PRs due to shrinkage at distant metastatic sites. Despite failure to achieve a PR in SLTSs, cytoreductive surgery was reconsidered in three patients. The authors cautioned however that the successful resection in these three patients could not be conclusively attributed to neoadjuvant therapy with sunitinib.
Table 1: Studies evaluating the efficacy and safety of sunitinib in the neoadjuvant setting in patients with advanced RCC

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In another retrospective study by Thomas et al.,[44] the effect of neoadjuvant sunitinib on primary tumors was evaluated in 19 patients with advanced RCC. The tumors in these patients were regarded as unsuitable for surgery due to locally advanced disease or extensive metastatic burden. Following neoadjuvant sunitinib treatment, there was a 16% rate of PRs, 37% rate of stable disease and 47% showed disease progression according to RECIST criteria. Primary tumor reduction was observed in 8 (42%) of patients, with a mean reduction of 24% (ranging 2-46%). At a median follow-up of 6 months, nephrectomy was reconsidered in 4 (21%) of patients while 5 died from disease progression. At the last follow-up, patients who underwent resection were alive with no significant surgical morbidity.

In the neoadjuvant setting, the anti-angiogenic effects of TKIs may present potential issues with wound healing after surgical resection. To address this issue, Thomas et al.[45] further evaluated the safety of targeted agents in the neoadjuvant setting in a separate retrospective review. The study included 19 patients with advanced RCC and an unresectable primary tumor or bilateral RCC that could not undergo partial nephrectomy. Neoadjuvant therapy included treatment with sunitinib, sorafenib or bevacizumab plus IL-2. After systemic treatment, all patients underwent surgery to remove the primary tumor, with a total of 21 surgeries overall. Major perioperative complications were reported in 3 (16%) patients. Finally, 2 (11%) patients experienced minor wound complications that included a wound seroma and a ventral hernia.

In the last retrospective review, Silberstein et al.[46] evaluated the feasibility and efficacy of neo-adjuvant sunitinib before nephron-sparing surgery (NSS). The study included 12 RCC patients (14 kidneys total) with renal insufficiency or a solitary kidney/bilateral renal tumors, or with bilateral renal tumors in the setting of locally advanced disease or in locally advanced disease in a solitary kidney. PRs were achieved in the primary tumor of four kidneys while stable disease was achieved in the primary tumors of the remaining 10. In 5 of the 12 patients who presented with metastases, two achieved PRs while the remaining three achieved stable disease. Following neoadjuvant sunitinib, all patients underwent NSS, with two patients requiring bilateral concurrent NSS. Final pathology showed negative tumor margins in all 14 kidneys and post-operative dialysis was not required in any patients.

Case study reports have also chronicled the effectiveness of neoadjuvant sunitinib in the treatment of RCC. Ansari et al.[47] reported successful use of sunitinib to downstage recurrent renal tumors in a solitary kidney to permit NSS. Patient was dialysis-free at the 6 month follow-up and showed no evidence of disease recurrence. In another case report by Kroeger et al.,[48] neoadjuvant sunitinib was administered to a patient with advanced RCC and extended tumor thrombus. Histological evaluation of tissue from this patient indicated that an active reaction of immunological cells against tumor structures was associated with sunitinib treatment.

The favorable outcomes reported in these retrospective reviews and case studies have provided sufficient rational for a number of ongoing prospective phase II clinical trials evaluating the efficacy of sunitinib in the neoadjuvant setting. Preliminary results from one such study were reported by Powles et al.[49] The trial included 56 patients with mRCC and a Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score indicating intermediate or poor risk disease. Investigators reported a 5% response in the primary tumor according to RECIST standards, with no local progression. Nearly, 20% of patients, however, showed progression of systemic disease prior to surgery. Overall, 71% of patients underwent nephrectomy with 20% experiencing surgical complications including 1 death.

Together, the current data suggest that sunitinib therapy in the neoadjuvant setting can effectively reduce the primary tumor with an acceptable safety profile. However, randomized, controlled, long-term studies are needed to provide substantial evidence of the neoadjuvant effectiveness of sunitinib.[50] It should also be noted that none of the patients evaluated in these studies were diagnosed with non-clear cell RCC (confirmed either histologically or by virtue of excluding non-clear cell patients from the study). The benefits of neoadjuvant sunitinib; therefore, do not extend to non-clear cell RCC.

Adjuvant therapy

The potential benefits and risks of targeted agents as adjuvant therapy have yet to be determined. Because targeted agents have improved outcomes in patients with mRCC, clinical trials are currently underway to determine their utility in the adjuvant setting.[51] The adjuvant sorafenib or sunitinib in unfavorable RCC) trial was initiated in 2006 to compare sunitinib and sorafenib after radical or partial nephrectomy in patients with locally advanced RCC. Clinical endpoints in this randomized, phase III trial include disease-free survival, OS and safety, with study sites in the United States and Canada. Trial completion is expected in 2016.[52]

In Europe, the CARMINA trial addresses the safety and efficacy of sunitinib in the adjuvant setting in patients with RCC. The phase III study will recruit 700 patients presenting with the primary tumor in situ and adjuvant sunitinib will be compared with treatment with sunitinib alone.[53]


 » Conclusions Top


Sunitinib has revolutionized the treatment of RCC and its use has resulted in longer PFS and OS than either IFNa or other targeted therapies that have been evaluated in large-scale studies.[10],[11],[12],[54],[55],[56] Administration of sunitinib to a wide range of patients with advanced RCC has greatly increased our understanding of best practice. Sunitinib can be safely administered for >2 years, although most patients will require dose adjustment. Discontinuation of sunitinib treatment is not recommended as it may lead to disease progression. In the neoadjuvant setting, sunitinib has been shown to reduce the primary tumor burden and facilitate surgical intervention with a favorable safety profile. The benefits of neoadjuvant sunitinib therapy, however, are limited to patients with advanced clear cell RCC. Evaluation of both tumor and patient characteristics, including ongoing pharmacogenetic assessments, are providing information that may permit selection of patients with advanced RCC who are optimal candidates for treatment with sunitinib.

Sunitinib is already established as a standard first-line therapy for advanced RCC. More information on certain aspects such as dose-related evaluations, sequencing, patient selection and nephrectomy decision will become available as data from several ongoing trials is obtained and analyzed. These data may support the evolving role of sunitinib in the neoadjuvant and adjuvant setting in patients with advanced RCC.


 » Acknowledgment Top


We would like to thank Pfizer, Inc. for providing assistance for medical writing.

 
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