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Critical appraisal of sorafenib in the treatment of Chinese patients with renal cell carcinoma.

ABSTRACT: Renal cell carcinoma (RCC) accounts for 3% of all malignancies, and is the most aggressive cancer of the genitourinary system. Metastatic RCC is naturally resistant to chemotherapy and radiotherapy, and immunotherapy is of little benefit. In recent years, the emergence of molecular-targeted therapies has largely changed the therapeutic approach to metastatic RCC. These novel multikinase inhibitors have now become first-choice therapy because of their activity in inhibiting both cell proliferation and tumor angiogenesis. Sorafenib is the first tyrosine kinase inhibitor found to be effective in treating patients with metastatic RCC. Due to its good efficacy and safety, this agent is recommended as both first-line and second-line therapy for metastatic RCC in the People's Republic of China. Sorafenib seems to be more effective in patients of Chinese ethnicity than in western patients, and is well tolerated with a manageable toxicity profile, even at higher dosages and when used in combination with other anticancer agents. Novel biomarkers for predicting the efficacy of sorafenib have potential clinical value for guiding individualized targeted therapy.

SUBMITTER: Ye DW

PROVIDER: S-EPMC4057324 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Critical appraisal of sorafenib in the treatment of Chinese patients with renal cell carcinoma.

Ye Ding-Wei DW Zhang Hai-Liang HL

OncoTargets and therapy 20140606

Renal cell carcinoma (RCC) accounts for 3% of all malignancies, and is the most aggressive cancer of the genitourinary system. Metastatic RCC is naturally resistant to chemotherapy and radiotherapy, and immunotherapy is of little benefit. In recent years, the emergence of molecular-targeted therapies has largely changed the therapeutic approach to metastatic RCC. These novel multikinase inhibitors have now become first-choice therapy because of their activity in inhibiting both cell proliferatio ...[more]

PMID: 24944516

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Project description:BackgroundAngiogenesis plays a role in tumor growth and is partly mediated by factors in both the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) pathways. Durable clinical responses with VEGF tyrosine kinase inhibitors (TKIs) may be limited by intrinsic tumor resistance. We hypothesized that FGF signaling may impact clinical responses to sorafenib.MethodsNephrectomy material was available from 40 patients with metastatic renal cell carcinoma (RCC) enrolled in a phase II clinical trial of sorafenib ± interferon (ClinicalTrials.gov Identifier NCT00126594). Fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor substrate 2 alpha (FRS2α) expression was assessed by in situ hybridization and immunofluorescence, respectively. The relationship between fibroblast growth factor pathway marker levels and progression-free survival (PFS) was analyzed using Kaplan-Meier and Cox proportional hazards regression methods.ResultsUnivariate analysis indicated that more intense FGFR1 staining was associated with shorter PFS (log-rank P = 0.0452), but FRS2α staining was not significantly associated with PFS (log-rank P = 0.2610). Multivariate Cox proportional hazards regression models were constructed for FGFR1 and FRS2α individually, adjusting for baseline Eastern Cooperative Oncology Group performance status, treatment arm and anemia status. When adjusted for each of these variables, the highest intensity level of FGFR1 (level 3 or 4) had increased progression risk relative to the lowest intensity level of FGFR1 (level 1) (P = 0.0115). The highest intensity level of FRS2α (level 3 or 4) had increased progression risk relative to the lowest intensity level of FRS2α (level 1) (P = 0.0126).ConclusionsIncreased expression of FGFR1 and FRS2α was associated with decreased PFS among patients with metastatic RCC treated with sorafenib. The results suggest that FGF pathway activation may impact intrinsic resistance to VEGF receptor inhibition.

Project description:BackgroundThe perception that older cancer patients may be at higher risk than younger patients of toxic effects from cancer therapy but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials and the known toxic effects of cytotoxic chemotherapy. It is not known how older patients respond to targeted therapy.MethodsThis retrospective subgroup analysis of data from the phase 3, randomized Treatment Approach in Renal Cancer Global Evaluation Trial examined the safety and efficacy of sorafenib in older (age >or=70 years, n = 115) and younger patients (age <70 years, n = 787) who received treatment for advanced renal cell carcinoma. Patient demographics and progression-free survival were recorded. Best tumor response, clinical benefit rate (defined as complete response plus partial response plus stable disease), time to self-reported health status deterioration, and toxic effects were assessed by descriptive statistics. Health-related quality of life was assessed with a Cox proportional hazards model. Kaplan-Meier analyses were used to summarize time-to-event data.ResultsMedian progression-free survival was similar in sorafenib-treated younger patients (23.9 weeks; hazard ratio [HR] for progression compared with placebo = 0.55, 95% confidence interval [CI] = 0.47 to 0.66) and older patients (26.3 weeks; HR = 0.43, 95% CI = 0.26 to 0.69). Clinical benefit rates among younger and older sorafenib-treated patients were also similar (83.5% and 84.3%, respectively) and were superior to those of younger and older placebo-treated patients (53.8% and 62.2%, respectively). Adverse events were predictable and manageable regardless of age. Sorafenib treatment delayed the time to self-reported health status deterioration among both older patients (121 days with sorafenib vs 85 days with placebo; HR = 0.66, 95% CI = 0.43 to 1.03) and younger patients (90 days with sorafenib vs 52 days with placebo; HR = 0.69, 95% CI = 0.59 to 0.81) and improved quality of life over that time.ConclusionsAmong patients with advanced renal cell carcinoma receiving sorafenib treatment, outcomes of older (>or=70 years) and younger (<70 years) patients were similar.

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Critical appraisal of sorafenib in the treatment of Chinese patients with renal cell carcinoma.

Publications

Critical appraisal of sorafenib in the treatment of Chinese patients with renal cell carcinoma.

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