Targeted Therapy for Metastatic Renal Cell Carcinoma

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 01/2007; 24(35):5601-8. DOI: 10.1200/JCO.2006.08.5415
Source: PubMed


The discovery of a relationship for the VHL tumor suppressor gene, hypoxia inducible factor-1 alpha, and vascular endothelial growth factor in the growth of clear-cell renal cell carcinoma (RCC) has identified a pathway for novel targeted therapy. This study evaluated the impact of these agents on metastatic RCC (mRCC), and highlights recent phase II and III trials. A systematic review examined the clinical data for novel targeted agents in mRCC, with a focus on randomized phase II and III trials of the novel targeted agents sunitinib, temsirolimus, sorafenib, and bevacizumab. Several agents, including the small-molecule targeted inhibitors sunitinib, temsirolimus, sorafenib, and the monoclonal antibody bevacizumab, have demonstrated antitumor activity in randomized trials. Superior activity was found with sunitinib and temsirolimus versus cytokines in first-line therapy. Improved progression-free survival was reported with sorafenib and bevacizumab given second-line compared with placebo. Targeted therapies show promising activity in this disease, and they have been changing patient management. Sunitinib and sorafenib were recently approved by the US Food and Drug Administration for treatment of mRCC, These drugs are currently included in clinical practice.

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    • "Activation of the c-MET oncogene is characteristic of papillary RCC type I, particularly in the hereditary PRCC syndrome and a subset of sporadic PRCC [8]. This finding offers a clear opportunity to test newly developed inhibitors of this tyrosine kinase in this subset of RCC [44,47]. Although these effective biologic agents may be used in a more individualized approach to metastatic RCC therapy, their novelty infers a paucity of clinical data about their toxic effects or management of their therapy-limiting complications in the setting of metastatic RCC [30]. "
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    ABSTRACT: Renal cell carcinoma (RCC) is known for its ability to metastasize synchronously or metachronously to various anatomic sites. Distinguishing histologic subtypes of metastatic RCC has become increasingly important, as prognosis and therapy can differ dramatically between subtypes. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping metastatic RCC in light of these potential therapeutic implications. Specimens from 103 cases of metastatic RCC were retrieved, including 32 cases originally diagnosed as metastatic clear cell renal cell carcinoma (CCRCC), 8 as metastatic papillary renal cell carcinoma (PRCC), and 63 metastatic RCC without a specific subtype. Immunohistochemistry was performed with antibodies against cytokeratin 7 (CK7) and alpha-methylacyl-CoA racemase (AMACR). Dual color interphase fluorescence in situ hybridization was utilized to assess for deletion of chromosome 3p and trisomy of chromosomes 7 and 17 in all tumors. Chromosome 3p deletion was detected in 41% of all metastatic RCC specimens, and trisomy of chromosomes 7 and/or 17 was detected in 16%. Of metastatic CCRCC, chromosome 3p deletion was detected in 63%. Of metastatic PRCC, 75% showed trisomy of chromosomes 7 and/or 17. Of the tumors not previously classified, 6% were positive for CK7, and 64% were positive for AMACR; 35% showed chromosome 3p deletion, and 16% showed trisomy of chromosomes 7 and/or 17. Combined analysis of immunohistochemistry and cytogenetics enabled reclassification of 52% of these metastatic tumors not previously classified. Our findings support the utility of immunohistochemistry and cytogenetics for subtyping metastatic RCC.
    Molecular Cancer 02/2014; 13(1):39. DOI:10.1186/1476-4598-13-39 · 4.26 Impact Factor
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    • "other solid and hematologic malignancies [19] [20] [21] [22]. CR in mRCC treated with AAs is a rare event [23]. The percentage of patients reaching CR in the registration studies for sunitinib, sorafenib, pazopanib , and bevacizumab was less than 3% [6] [8] [9] [24]. "
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    ABSTRACT: Antiangiogenic agents (AAs) have reported grater efficacy compared to interferon. Despite these advances, radiological complete response to therapy is rare. We meta-analyzed the incidence of complete response in patients treated with AAs and in controls in main randomized clinical trials for first-line therapy in metastatic renal cell carcinoma. PubMed was reviewed for phase II-III randomized clinical trials with AAs vs. non-AAs in patients with good or intermediate prognosis. We calculated the relative risk of events in patients assigned to AAs compared to control. Five RCTs were found; four were phase III and one was phase II. A total of 2747 patients was valuable for final analysis and randomized to receive AAs or control. Patients in the control-group had interferon (85%) or placebo (15%); patients in the AAs-group received bevacizumab (48%), sunitinib (26%), pazopanib (20%) or sorafenib (6%). The incidence of complete response in patients treated with AAs was 2.0% (95% CI, 1.2-2.8) compared to 1.4% (95% CI, 0.7-2.1) in the control arm. Comparing the different type of AAs, the incidence of complete response was 2.5% (95% CI, 1.2-3.8) in the bevacizumab group and 1.6% (95% CI, 0.1-2.5) in the TKIs group. The relative risk to have a complete response was 1.52 (95% CI, 0.85-2.73; p=0.16) in patients treated with AAs compared to controls; this was found higher in patients treated with TKIs compared to bevacizumab. The complete response is a rare event in metastatic kidney tumor, even if AAs reported greater efficacy in terms of progression-free survival and of overall response rate, they did not increase the curative rate of metastatic disease. Probably, some biologic factors other than angiogenesis may influence the complete response in this disease.
    Cancer Treatment Reviews 09/2013; 40(2). DOI:10.1016/j.ctrv.2013.09.003 · 7.59 Impact Factor
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    • "RCC is considered to be an immunogenic tumour (Tsavaris et al, 1996). This evidence is based on several reports, such as the incidence of spontaneous regressions observed in a small number of these patients (De Riese et al, 1991) and its response rate to immunotherapy (Alexandrescu and Dasanu, 2006; Motzer and Bukowski, 2006; Yang and Childs, 2006), such as high-dose IL-2, suggesting that host immune response to RCC has a role in the disease control. However, based on the complexity of the interaction between tumour and host immune responses, there is still a great deal of information to be discovered both on the effects of targeted agents on immune system and, otherwise, on the role of immune cells in tumour response to targeted therapies (Santoni et al, 2012). "
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    ABSTRACT: Background: Everolimus is a mammalian target of rapamycin inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between pre-treatment neutrophil-to-lymphocyte ratio (NLR) and the outcome of patients treated with everolimus for mRCC. Methods: Ninety-seven patients with mRCC were treated with everolimus till April 2013 in our institutions. Patients were stratified in two groups with NLR >3 (Group A) vs <3 (Group B). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier method. Gender, age, Motzer prognostic group, PFS on first-line therapy, neutrophilia and NLR were included in the Cox analysis to investigate their prognostic relevance. Results: Median OS and PFS were 10.6 and 5.3 months, respectively. Median OS was 12.2 months in Group A and 24.4 months in Group B (P=0.001). Median PFS was 3.4 months in Group A and 9.9 months in Group B (P<0.001). At multivariate analysis, only Motzer prognostic group and NLR were independent prognostic factors for OS and PFS. Conclusion: Pre-treatment NLR is an independent prognostic factor for patients with mRCC treated with second- or third-line everolimus. This should be investigated and validated in prospective studies.
    British Journal of Cancer 09/2013; 109(7). DOI:10.1038/bjc.2013.522 · 4.84 Impact Factor
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