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Anti-cancer Drugs Jun 2016In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was... (Review)
Review
In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was conducted to assess the clinical efficacy, safety and effect of all first-line treatments evaluated to date on health-related quality of life (HRQoL). A systematic search of Embase, Cochrane and MEDLINE databases was performed to identify randomized controlled trials (1980-2015) evaluating any targeted therapy/immunotherapy against placebo or any other targeted intervention/immunotherapy in treatment-naive patients with metastatic renal cell carcinoma. Conference proceedings from major cancer congresses (2007-2015) were handsearched. Sixteen randomized controlled trials were identified, mostly phase III. Overall, targeted therapies were associated with either improved [sunitinib, bevacizumab+interferon α (IFNα) and temsirolimus] or comparable (sorafenib) progression-free survival (PFS) versus IFNα monotherapy. Sunitinib demonstrated comparable PFS and overall survival to pazopanib, comparable PFS to sorafenib and shorter PFS compared with bevacizumab+IFNα (although no conclusions were made with regard to superiority/inferiority). Compared with sorafenib, tivozanib demonstrated a significantly longer PFS, and both tivozanib and axitinib demonstrated higher response rates. Nintedanib demonstrated comparable PFS and overall survival to sunitinib in a phase II trial. Temsirolimus, sunitinib and sorafenib treatment led to better HRQoL versus IFNα; pazopanib was associated with better HRQoL versus sunitinib. No direct meta-analyses or indirect treatment comparison analysis were undertaken because of noncomparability of the trials. In general, targeted therapies demonstrated favourable clinical efficacy and improved HRQoL compared with IFNα monotherapy. The newer therapies, tivozanib and axitinib (but not nintedanib), appeared to exhibit greater clinical benefit (response rate) than older tyrosine kinase inhibitors.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Quality of Life; Quinazolines; Quinolines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides; Sunitinib
PubMed: 26886011
DOI: 10.1097/CAD.0000000000000335 -
Critical Reviews in Oncology/hematology Mar 2016The treatment of metastatic renal cell carcinoma (mRCC) has largely improved over the last decade, due to the availability of several targeted agents (TAs). Sorafenib... (Review)
Review
Is there still a role for sorafenib in metastatic renal cell carcinoma? A systematic review and meta-analysis of the effectiveness of sorafenib over other targeted agents.
BACKGROUND
The treatment of metastatic renal cell carcinoma (mRCC) has largely improved over the last decade, due to the availability of several targeted agents (TAs). Sorafenib was the first TA to report a benefit in terms of PFS in this disease, and it has largely been used as a comparator in randomized trials. We tested its activity compared to other TAs by performing a systematic review and meta-analysis.
METHODS
MEDLINE/PubMed, the Cochrane library, and the ASCO university websites were searched for randomized phase II or III trials that compared other TAs to sorafenib in mRCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The measured outcomes were progression free survival (PFS), overall survival (OS), and the overall response rate (ORR). Sub-analyses were performed for MSKCC prognostic groups and lines of therapy.
RESULTS
A total of 3094 patients were evaluable for PFS. Other TAs significantly reduce the risk of progression compared to sorafenib (HR=0.78; 95% CI, 0.72-0.85; p<0.001). This difference remains significant in patients in a good prognostic group with respect to both first- (HR=0.61; 95%CI, 0.44-0.85; p=0.003) and second-line therapy (HR=0.58; 95% CI, 0.42-0.79; p<0.001). No significant differences were, however, found in patients with an intermediate prognosis in terms of both first- (HR=0.80; 95% CI, 0.60-1.00; p=0.05) and second-line treatment (HR=0.89; 95% CI, 0.73-1.07; p=0.21). In 2922 patients evaluable for OS, no significant difference was found between other TAs and sorafenib (HR=1.07; 95% CI, 0.97-1.18; p=0.18). A benefit was also not identified when the analysis was limited to patients treated with first or subsequent lines of therapy or in patients previously treated with sunitinib. Significant differences were found in terms of the ORR in the 2963 evaluable patients favoring other TAs (RR=1.48; 95% CI, 1.24-1.76; p<0.001). This difference remain significant when a sub-analysis was performed per line of therapy.
CONCLUSIONS
Other TAs improve PFS but not OS when compared to sorafenib. The use of sorafenib in patients with an intermediate prognosis, especially in second-line therapy, does not have a detrimental effect on PFS and might be an option for certain patients.
Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Sorafenib
PubMed: 26818051
DOI: 10.1016/j.critrevonc.2016.01.014 -
Expert Opinion on Pharmacotherapy 2015To conduct a systematic review and network meta-analysis (NMA) to assess effectiveness of first-line treatments for advanced renal cell carcinoma (RCC). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To conduct a systematic review and network meta-analysis (NMA) to assess effectiveness of first-line treatments for advanced renal cell carcinoma (RCC).
METHODS
Database searches were conducted to identify randomized controlled trials (RCTs) reporting results for eligible treatments. A fixed-effect Bayesian NMA was conducted to assess the relative effectiveness of treatments, with progression-free survival (PFS) reported as hazard ratios (HRs) and 95% credible intervals (CrIs).
RESULTS
Eleven unique RCTs were suitable for inclusion in the NMA. In the base case, in terms of PFS, sunitinib was superior compared with bevacizumab + IFN-α (HR = 0.79, 95% CrI: 0.64 - 0.96), everolimus (HR = 0.70, 95% CrI: 0.56 - 0.87), sorafenib (HR = 0.56, 95% CrI: 0.40 - 0.77) and temsirolimus + bevacizumab (HR = 0.74, 95% CrI: 0.56 - 0.96). Although, the point values for the mean and median HRs were < 1.0, there was no significant difference in PFS between sunitinib and axitinib, pazopanib or tivozanib. Although sensitivity analyses impacted the results of the NMA, no treatment was significantly more efficacious than sunitinib.
CONCLUSION
Results from this analysis suggest that there is no treatment superior to the current benchmark treatment, sunitinib, in the management of advanced RCC in the first-line setting.
Topics: Antineoplastic Agents; Bayes Theorem; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Kidney Neoplasms; Randomized Controlled Trials as Topic
PubMed: 26194211
DOI: 10.1517/14656566.2015.1058359 -
Molecular and Clinical Oncology Jul 2015Bevacizumab has demonstrated a survival benefit in patients with metastatic colorectal cancer (mCRC) when combined with chemotherapy. Several randomized clinical trials...
Bevacizumab has demonstrated a survival benefit in patients with metastatic colorectal cancer (mCRC) when combined with chemotherapy. Several randomized clinical trials comparing the efficacy and toxicity of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) against bevacizumab have been reported. The present meta-analysis was conducted to identify the potentially significant benefit of the combined treatment regimens in patients with mCRC. PubMed, Embase and Cochrane Library databases were searched for the randomized controlled trials published on or before September 2014, which compared the efficacy and toxicity of VEGFR TKIs with bevacizumab in combination with chemotherapy in patients with mCRC. The primary endpoints included progression-free survival (PFS), overall survival (OS) and overall response rate (ORR), and secondary endpoints were the toxicity profiles. Relative risks (RRs) with 95% confidence intervals (CIs) for response rate and adverse events (AEs) were calculated, as well as hazard ratios (HRs) for PFS and OS. The final analysis included 4 studies comprising a total of 1,929 intent-to-treat patients with mCRC, which compared VEGFR TKIs (cediranib and axitinib) plus chemotherapy with bevacizumab plus chemotherapy. Results demonstrated that VEGFR TKIs plus chemotherapy significantly resulted in a modest but significantly shorter PFS [hazard ratio (HR), 1.12; 95% CI, 1.00-1.25; P=0.05] compared with that of bevacizumab plus chemotherapy but not in OS (HR, 1.10; 95% CI, 0.88-1.17; P=0.87) and ORR (RR, 0.95; 95% CI, 0.85-1.05; P=0.30). VEGFR TKIs treatment showed a less favorable AE profile compared with bevacizumab, with higher rates of grade-III/IV diarrhea, fatigue, hypertension, neutropenia and thrombocytopenia, whereas a higher incidence of peripheral neuropathy associated with the bevacizumab group was observed. In conclusion, the addition of VEGFR TKIs to chemotherapy resulted in a modest but significantly shorter PFS but not in OS and ORR compared with bevacizumab. The VEGFR TKIs group showed a less favorable AE profile with higher rates of diarrhea, fatigue, hypertension, neutropenia and thrombocytopenia, whereas a higher incidence of peripheral neuropathy associated with the bevacizumab was observed.
PubMed: 26171215
DOI: 10.3892/mco.2015.572 -
Critical Reviews in Oncology/hematology May 2015A systematic review and meta-analysis was conducted to determine the relative risk (RR) of congestive heart failure (CHF) associated with approved multi-targeted... (Meta-Analysis)
Meta-Analysis Review
A systematic review and meta-analysis was conducted to determine the relative risk (RR) of congestive heart failure (CHF) associated with approved multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). Eligible studies included randomized trials comparing arms with and without an FDA-approved VEGFR TKI. Statistical analyses calculated the relative risk (RR) and 95% confidence intervals (CI). A total of 10,647 patients from 16 phase III trials and 5 phase II trials were selected. All grade CHF occurred in 138 of 5752 (2.39%) patients receiving VEGFR TKIs and 37 of 4895 (0.75%) patients in the non-TKI group. High-grade CHF occurred in 17 of 1426 (1.19%) patients receiving VEGFR TKIs and 8 of 1232 (0.65%) patients in the non-TKI group. The RR of all grade and high-grade CHF for the TKI vs. no TKI arms was 2.69 (p<0.001; 95% CI: 1.86 to 3.87) and 1.65 (p=0.227, 95% CI: 0.73 to 3.70), respectively. The RR of relatively specific TKIs (axitinib) was similar to relatively non-specific TKIs (sunitinib, sorafenib, vandetanib, pazopanib).
Topics: Antineoplastic Agents; Heart Failure; Humans; Neoplasms; Odds Ratio; Protein Kinase Inhibitors; Publication Bias; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Risk
PubMed: 25577572
DOI: 10.1016/j.critrevonc.2014.12.008 -
PloS One 2014The optimal sequencing of targeted therapies for metastatic renal cell carcinoma (mRCC) is unknown. Observational studies with a variety of designs have reported... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparative Effectiveness of Second-Line Targeted Therapies for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World Observational Studies.
OBJECTIVE
The optimal sequencing of targeted therapies for metastatic renal cell carcinoma (mRCC) is unknown. Observational studies with a variety of designs have reported differing results. The objective of this study is to systematically summarize and interpret the published real-world evidence comparing sequential treatment for mRCC.
METHODS
A search was conducted in Medline and Embase (2009-2013), and conference proceedings from American Society of Clinical Oncology (ASCO), ASCO Genitourinary Cancers Symposium (ASCO-GU), and European Society for Medical Oncology (ESMO) (2011-2013). We systematically reviewed observational studies comparing second-line mRCC treatment with mammalian target of rapamycin inhibitors (mTORi) versus vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI). Studies were evaluated for 1) use of a retrospective cohort design after initiation of second-line therapy, 2) adjustment for patient characteristics, and 3) use of data from multiple centers. Meta-analyses were conducted for comparisons of overall survival (OS) and progression-free survival (PFS).
RESULTS
Ten studies reported OS and exhibited significant heterogeneity in estimated second-line treatment effects (I2 = 68%; P = 0.001). Four of these were adjusted, multicenter, retrospective cohort studies, and these showed no evidence of heterogeneity (I2 = 0%; P = 0.61) and a significant association between second-line mTORi (>75% everolimus) and longer OS compared to VEGF TKI (>60% sorafenib) (HR = 0.82, 95% CI: 0.68 to 0.98) in a meta-analysis. Seven studies comparing PFS showed significant heterogeneity overall and among the adjusted, multicenter, retrospective cohort studies. Real-world observational data for axitinib outcomes was limited at the time of this study.
CONCLUSIONS
Real-world studies employed different designs and reported heterogeneous results comparing the effectiveness of second-line mTORi and VEGF TKI in the treatment of mRCC. Within the subset of adjusted, multicenter observational studies, second-line use of mTORi was associated with significantly prolonged survival compared with second-line use of VEGF TKI.
Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Neoplasm Metastasis; Survival Analysis
PubMed: 25493562
DOI: 10.1371/journal.pone.0114264 -
Critical Reviews in Oncology/hematology Dec 2014We performed a systematic review and comparative meta-analysis of cardiovascular toxicities associated with sunitinib, axitinib, cediranib or regorafenib; oral multi... (Meta-Analysis)
Meta-Analysis Review
Risk of cardiovascular toxicities in patients with solid tumors treated with sunitinib, axitinib, cediranib or regorafenib: an updated systematic review and comparative meta-analysis.
BACKGROUND
We performed a systematic review and comparative meta-analysis of cardiovascular toxicities associated with sunitinib, axitinib, cediranib or regorafenib; oral multi tyrosine kinase inhibitors.
PATIENTS AND METHODS
Eligible studies included randomized phase II and III trials of patients with solid tumors on sunitinib, axitinib, cediranib or regorafenib describing daily events of hypertension, left ventricular dysfunction, bleeding or thrombosis.
RESULTS
Patients treated with these four agents had a significantly increased risk of all-grade hypertension and bleeding. The RR of all-grade hypertension, bleeding, thrombosis and cardiac dysfunction were 2.78 (95% CI 2.03-3.81; p<0.00001), 1.93 (95% CI 1.41-2.64; p<0.00001), 0.85 (95% CI 0.60-1.19; p=0.50), 2.36 (95% CI 0.95-5.87; p=0.06), respectively. Exploratory subgroup analysis showed no effect of the agent used (sunitinib vs. axitinib vs. cediranib) in the risk of hypertension; while for bleeding, only the sunitinib subgroup RR was significant compared to axitinib or cediranib.
CONCLUSIONS
Our meta-analysis has demonstrated that sunitinib, axitinib, cediranib and regorafenib are associated with a higher risk of developing all grade and high grade hypertension compared with control. While for bleeding, only the sunitinib subgroup RR was significant compared to axitinib or cediranib. Clinicians should be aware of these risks and perform regular cardiovascular monitoring.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Cardiovascular Diseases; Humans; Imidazoles; Incidence; Indazoles; Indoles; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Quinazolines; Risk; Sunitinib
PubMed: 25028151
DOI: 10.1016/j.critrevonc.2014.06.003 -
Expert Review of Anticancer Therapy Sep 2014We performed a systematic review and meta-analysis of thyroid function abnormalities associated with seven vascular endothelial growth factor receptor (VEGFR) targeted... (Meta-Analysis)
Meta-Analysis Review
We performed a systematic review and meta-analysis of thyroid function abnormalities associated with seven vascular endothelial growth factor receptor (VEGFR) targeted tyrosine kinase inhibitors (sorafenib, sunitinib, axitinib, cediranib, pazopanib, regorafenib and vandetanib). Eligible studies included randomized Phase II and III trials of patients with solid tumors on sorafenib OR sunitinib OR axitinib OR cediranib OR pazopanib OR regorafenib OR vandetanib; describing events of hypothyroidism or hyperthyroidism. Our search strategy yielded 195 potentially relevant citations on the seven agents from Pubmed/Medline, CENTRAL Cochrane registry and ASCO meeting library. After exclusion of ineligible studies, a total of 12 clinical trials were considered eligible for the meta-analysis, including six sunitinib studies, four cediranib studies and two axitinib studies. Patients treated with these agents had a significantly increased risk of all-grade hypothyroidism and the relative risk (RR) of all-grade hypothyroidism was 3.59 (95% CI = 2.40-5.38, p ≤ 0.0001). Exploratory subgroup analysis showed no effect of tumor types or agent used on the RR of hypothyroidism. Our meta-analysis has demonstrated that these three agents are associated with a significantly increased risk of all-grade hypothyroidism; with no difference - on subgroup analysis - between sunitinib and cediranib. Clinicians should be aware of these risks and perform regular thyroid function monitoring.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Humans; Hyperthyroidism; Hypothyroidism; Neoplasms; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor
PubMed: 24927771
DOI: 10.1586/14737140.2014.929501 -
Critical Reviews in Oncology/hematology Mar 2014The use of vascular-endothelial growth factor (VEGF) antibody bevacizumab is associated with an increased risk of gastrointestinal (GI) perforation, but the incidence... (Meta-Analysis)
Meta-Analysis Review
Risk of gastrointestinal perforation in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis.
BACKGROUND
The use of vascular-endothelial growth factor (VEGF) antibody bevacizumab is associated with an increased risk of gastrointestinal (GI) perforation, but the incidence and risk of GI perforation associated with vascular endothelial growth factor tyrosine-kinase inhibitors (VEGFR-TKIs) has not been well described. We conduct a systematic review and meta-analysis of published trials to evaluate the overall incidence and risk of GI perforation associated with VEGFR-TKIs.
METHODS
Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to March 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating VEGFR-TKIs in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.
RESULTS
A total of 5352 patients with a variety of solid tumors from 20 clinical trials were included in our analysis. The incidence of GI perforation was 1.3% (95%CI: 0.8-2.0%) among patients receiving VEGFR-TKIs, with a mortality of 28.6% (15.0-47.6%). Patients treated with VEGFR-TKIs did not significantly increase the risk of GI perforation compared with patients treated with control medication, with an OR of 2.99 (95%CI: 0.85-10.53, p=0.089). Sub-group analysis showed that the incidence of GI perforation did not significantly vary with tumor types, VEGFR-TKIs and treatments regimens. No evidence of publication bias was observed.
CONCLUSIONS
The use of VEGFR-TKIs dose not significantly increase the risk of GI perforation in comparison with the controls. Further studies are recommended to investigate this association and the risk differences among different tumor types, VEGFR-TKIs or treatment regimens.
Topics: Humans; Intestinal Perforation; Neoplasms; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor
PubMed: 24182420
DOI: 10.1016/j.critrevonc.2013.10.002 -
Journal of Cancer Research and Clinical... Nov 2013Patients with metastatic renal cell carcinoma (mRCC) and a good performance status typically receive an anti-vascular endothelial growth factor receptor (VEGFR) TKI... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patients with metastatic renal cell carcinoma (mRCC) and a good performance status typically receive an anti-vascular endothelial growth factor receptor (VEGFR) TKI (sunitinib or pazopanib) as initial therapy. Upon disease progression or intolerance, there are four orally administered agents approved in the second-line setting (including cytokine-refractory). However, head-to-head comparative trial data are limited. In this study, an indirect statistical comparison of safety and efficacy was undertaken between axitinib, sorafenib, pazopanib and everolimus in second-line therapy mRCC.
METHODS
A systematic review of major databases was conducted from January 2005 to June 2013 for randomized controlled trials (RCTs) evaluating at least one of the four agents in second-line mRCC. Bayesian mixed treatment comparison models were fitted to assess relative effectiveness on multiple endpoints such as objective response rates, dose-limiting grade III/IV toxicities, treatment discontinuations and progression-free survival (PFS).
RESULTS
Four RCTs met the inclusion criteria. All four agents seem able to induce tumor shrinkage and to provide patients with a clinically meaningful PFS benefit. Axitinib was superior to pazopanib [hazard ratio (HR) 0.64; 95 % credible interval (95 % Crl) 0.42-0.96] and sorafenib (HR 0.70; 95 % Crl 0.57-0.87) in terms of PFS. However, axitinib was associated with an elevated risk of fatigue and to a lesser extent stomatitis.
CONCLUSIONS
Keeping in mind the caveats associated with cross-trial statistical comparisons, axitinib provides superior PFS relative to pazopanib and sorafenib. Everolimus, an mammalian target of rapamycin inhibitor, is mechanistically distinct from the other agents and remains a useful option for patient's post-anti-VEGFR TKI failure.
Topics: Antineoplastic Agents; Axitinib; Bayes Theorem; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides
PubMed: 24037486
DOI: 10.1007/s00432-013-1510-5