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Health Technology Assessment... Jan 2018Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them.
OBJECTIVE
To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta, Pfizer Inc., NY, USA), cabozantinib (Cabometyx, Ipsen, Slough, UK), everolimus (Afinitor, Novartis, Basel, Switzerland), nivolumab (Opdivo, Bristol-Myers Squibb, NY, USA), sunitinib (Sutent, Pfizer, Inc., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy.
DATA SOURCES
A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals.
REVIEW METHODS
A fixed-effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values.
RESULTS
Four RCTs ( = 2618) and eight non-RCTs ( = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of £45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of £126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus.
LIMITATIONS
Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS.
CONCLUSIONS
The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost-effectiveness.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42016042384.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Clinical Trials as Topic; Cost-Benefit Analysis; Everolimus; Humans; Kidney Neoplasms; Models, Econometric; Nivolumab; Pyridines; Quality-Adjusted Life Years; Sunitinib; Technology Assessment, Biomedical; Vascular Endothelial Growth Factor A
PubMed: 29393024
DOI: 10.3310/hta22060 -
International Braz J Urol : Official... 2018We conducted a systematic review and meta-analysis of the literature on the efficacy of the targeted therapies in the treatment of advanced RCC and, via an indirect... (Meta-Analysis)
Meta-Analysis Review
We conducted a systematic review and meta-analysis of the literature on the efficacy of the targeted therapies in the treatment of advanced RCC and, via an indirect comparison, to provide an optimal treatment among these agents. A systematic search of Medline, Scopus, Cochrane Library and Clinical Trials unpublished was performed up to Jan 1, 2015 to identify eligible randomized trials. Outcomes of interest assessing a targeted agent included progression free survival (PFS), overall survival (OS) and objective response rate (ORR). Thirty eligible randomized controlled studies, total twentyfourth trails (5110 cases and 4626 controls) were identified. Compared with placebo and IFN-α, single vascular epithelial growth factor (receptor) tyrosine kinase inhibitor and mammalian target of rapamycin agent (VEGF(r)-TKI & mTOR inhibitor) were associated with improved PFS, improved OS and higher ORR, respectively. Comparing sorafenib combination vs sorafenib, there was no significant difference with regard to PFS and OS, but with a higher ORR. Comparing single or combination VEGF(r)-TKI & mTOR inhibitor vs BEV + IFN-α, there was no significant difference with regard to PFS, OS, or ORR. Our network ITC meta-analysis also indicated a superior PFS of axitinib and everolimus compared to sorafenib. Our data suggest that targeted therapy with VEGF(r)-TKI & mTOR inhibitor is associated with superior efficacy for treating advanced RCC with improved PFS, OS and higher ORR compared to placebo and IFN-α. In summary, here we give a comprehensive overview of current targeted therapies of advanced RCC that may provide evidence for the adequate targeted therapy selecting.
Topics: Carcinoma, Renal Cell; Disease-Free Survival; ErbB Receptors; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A
PubMed: 29211397
DOI: 10.1590/S1677-5538.IBJU.2017.0315 -
Critical Reviews in Oncology/hematology Dec 2017A systematic review was conducted to illustrate the bleeding risks associated with targeted therapies used in the treatment of metastatic renal cell carcinoma (mRCC).... (Review)
Review
A systematic review was conducted to illustrate the bleeding risks associated with targeted therapies used in the treatment of metastatic renal cell carcinoma (mRCC). Eligible studies included phase II, III, or IV clinical trials using pazopanib, sunitinib, cabozantinib, lenvatinib, everolimus, temsirolimus, bevacizumab, axitinib, and/or sorafenib in the setting of mRCC. Types of bleeding event(s), bleeding event frequency, and incidence of thrombocytopenia were collected from the relevant articles. ClinicalTrials.gov was also searched for incidence of "Serious bleeding adverse effects" reported in these trials. The incidences of bleeding events ranged from 1 to 36%, and incidences of thrombocytopenia ranged from 2 to 78%. Available serious bleeding adverse events ranged from 1 to 7%. The highest percentage of bleeding incidences were seen with bevacizumab, while the lowest percentage of bleeding incidences were seen with axitinib. All of the included trials were of high quality per Jadad scoring.
Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Hemorrhage; Humans; Incidence; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Thrombocytopenia
PubMed: 29198329
DOI: 10.1016/j.critrevonc.2017.10.014 -
International Journal of Clinical... Oct 2017The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib,... (Meta-Analysis)
Meta-Analysis
The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23-1.66; p < 0.00001) and high-grade (≥grade 3) fatigue (1.97; 95% CI1.44-2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.
Topics: Anilides; Axitinib; Fatigue; Humans; Imidazoles; Indazoles; Neoplasms; Odds Ratio; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Receptors, Vascular Endothelial Growth Factor
PubMed: 28733794
DOI: 10.1007/s10147-017-1167-1 -
European Journal of Clinical... Oct 2017We performed a meta-analysis to systematically review the gastrointestinal (GI) events (diarrhea, nausea, vomiting, anorexia) of five newly approved (after 2011)... (Meta-Analysis)
Meta-Analysis Review
Risk of gastrointestinal events with newly approved (after 2011) vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a meta-analysis of randomized controlled trials.
PURPOSE
We performed a meta-analysis to systematically review the gastrointestinal (GI) events (diarrhea, nausea, vomiting, anorexia) of five newly approved (after 2011) VEGFR-TKIs in cancer patients.
METHODS
The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with cabozantinib, vandetanib, lenvatinib, regorafenib, and axitinib were retrieved and the systematic evaluation was conducted.
RESULTS
Forty-one randomized controlled trials and 10,860 patients were included. Current analysis suggested that the use of these agents increased the risk of all-grade and high-grade GI events, and the diarrhea was the most common GI events. The risk of all-grade and high-grade GI events varies significantly within drug types, tumor types, and VEGFR-TKIs-based regimens.
CONCLUSION
The available data suggested that the use of the five newly approved VEGFR-TKIs may increase risk of GI events in cancer patients. Physicians and patients should be aware of these risks and frequent monitoring and careful management should be emphasized when managing these VEGFR-TKIs.
Topics: Antineoplastic Agents; Gastrointestinal Diseases; Humans; Neoplasms; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Risk
PubMed: 28710508
DOI: 10.1007/s00228-017-2299-y -
The Cochrane Database of Systematic... May 2017Partial nephrectomy and radical nephrectomy are the relevant surgical therapy options for localised renal cell carcinoma. However, debate regarding the effects of these... (Review)
Review
BACKGROUND
Partial nephrectomy and radical nephrectomy are the relevant surgical therapy options for localised renal cell carcinoma. However, debate regarding the effects of these surgical approaches continues and it is important to identify and summarise high-quality studies to make surgical treatment recommendations.
OBJECTIVES
To assess the effects of partial nephrectomy compared with radical nephrectomy for clinically localised renal cell carcinoma.
SEARCH METHODS
We searched CENTRAL, MEDLINE, PubMed, Embase, Web of Science, BIOSIS, LILACS, Scopus, two trial registries and abstracts from three major conferences to 24 February 2017, together with reference lists; and contacted selected experts in the field.
SELECTION CRITERIA
We included a randomised controlled trial comparing partial and radical nephrectomy for participants with small renal masses.
DATA COLLECTION AND ANALYSIS
One review author screened all of the titles and abstracts; only citations that were clearly irrelevant were excluded at this stage. Next, two review authors independently assessed full-text reports, identified relevant studies, evaluated the eligibility of the studies for inclusion, assessed trial quality and extracted data. The update of the literature search was performed by two independent review authors. We used Review Manager 5 for data synthesis and data analyses.
MAIN RESULTS
We identified one randomised controlled trial including 541 participants that compared partial nephrectomy to radical nephrectomy. The median follow-up was 9.3 years.Based on low quality evidence, we found that time-to-death of any cause was decreased using partial nephrectomy (HR 1.50, 95% CI 1.03 to 2.18). This corresponds to 79 more deaths (5 more to 173 more) per 1000. Also based on low quality evidence, we found no difference in serious adverse events (RR 2.04, 95% CI 0.19 to 22.34). Findings are consistent with 4 more surgery-related deaths (3 fewer to 78 more) per 1000.Based on low quality evidence, we found no difference in time-to-recurrence (HR 1.37, 95% CI 0.58 to 3.24). This corresponds to 12 more recurrences (14 fewer to 70 more) per 1000. Due to the nature of reporting, we were unable to analyse overall rates for immediate and long-term adverse events. We found no evidence on haemodialysis or quality of life.Reasons for downgrading related to study limitations (lack of blinding, cross-over), imprecision and indirectness (a substantial proportion of patients were ultimately found not to have a malignant tumour). Based on the finding of a single trial, we were unable to conduct any subgroup or sensitivity analyses.
AUTHORS' CONCLUSIONS
Partial nephrectomy may be associated with a decreased time-to-death of any cause. With regards to surgery-related mortality, cancer-specific survival and time-to-recurrence, partial nephrectomy appears to result in little to no difference.
Topics: Carcinoma, Renal Cell; Cause of Death; Humans; Kidney Neoplasms; Neoplasm Recurrence, Local; Nephrectomy; Randomized Controlled Trials as Topic; Time Factors
PubMed: 28485814
DOI: 10.1002/14651858.CD012045.pub2 -
Cancer Research and Treatment Oct 2017Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer... (Review)
Review
Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Clinical Trials as Topic; Esophageal Neoplasms; Esophagogastric Junction; Humans; Molecular Targeted Therapy; Neoplasm Staging; Protein Kinase Inhibitors; Quality of Life; Receptor, ErbB-2; Stomach Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 28052652
DOI: 10.4143/crt.2016.176 -
European Urology Mar 2017While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown.
OBJECTIVE
To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC.
EVIDENCE ACQUISITION
Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta-analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken.
EVIDENCE SYNTHESIS
The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant.
CONCLUSIONS
This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed.
PATIENT SUMMARY
We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need.
Topics: Anilides; Antineoplastic Agents; Axitinib; Benzimidazoles; Bevacizumab; Carcinoma, Renal Cell; Comparative Effectiveness Research; Disease-Free Survival; Erlotinib Hydrochloride; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Pyrrolidinones; Quinolines; Quinolones; Sirolimus; Sorafenib; Sulfonamides; Sunitinib
PubMed: 27939075
DOI: 10.1016/j.eururo.2016.11.020 -
Critical Reviews in Oncology/hematology Nov 2016Sunitinib, pazopanib, sorafenib, axitinib and bevacizumab are the five recommended antiangiogenic agents in first-line therapy for metastatic renal cell carcinoma... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sunitinib, pazopanib, sorafenib, axitinib and bevacizumab are the five recommended antiangiogenic agents in first-line therapy for metastatic renal cell carcinoma (mRCC). Because these drugs underwent simultaneous clinical development, no direct efficacy and safety comparison was ever conducted, thus preventing optimal therapy choices.
METHODS
We performed a traditional and network meta-analysis to evaluate the efficacy and safety of mRCC-recommended first-line antiangiogenic agents. After a systematic review of Medline and Embase up to July 2014, we identified randomized clinical trials (RCTs) evaluating the outcomes of mRCC patients treated with sunitinib, pazopanib, sorafenib, axitinib and bevacizumab as first-line treatment. Endpoints of interest were response rate, progression-free survival (PFS), overall survival (OS), and safety.
RESULTS
We screened 769 abstracts and included nine RCTs with a total of 4282 patients. In the weighted pooled analysis, first-line antiangiogenic agents showed significant improvement in PFS (HR=0.6; 95% IC, 0.51-0.72) and OS (HR=0.85; 95% IC, 0.78-0.93) compared to control (placebo or interferon-alpha2a (INF)). Network meta-analysis showed no significant differences among antiangiogenic drugs in 6-month PFS, 1-year OS, disease control rate and drug-related safety for all-grade hypertension, diarrhea, weight-loss, nausea or anorexia. However, pazopanib showed a lower incidence of fatigue, anemia and hand foot skin reaction.
CONCLUSIONS
This meta-analysis confirms the benefits of first-line antiangiogenic therapy in mRCC, with an improvement in OS. Sunitinib, pazopanib, axitinib and bevacizumab + INF offer similar efficacy but different safety profiles which can help clinicians to better personalize treatment decisions in patients with mRCC.
Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease Progression; Humans; Kidney Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome
PubMed: 27823651
DOI: 10.1016/j.critrevonc.2016.08.012 -
OncoTargets and Therapy 2016This study was performed to evaluate the comparative efficacy and safety of axitinib and sorafenib in the therapy of metastatic renal cell carcinoma. (Review)
Review
OBJECTIVE
This study was performed to evaluate the comparative efficacy and safety of axitinib and sorafenib in the therapy of metastatic renal cell carcinoma.
MATERIALS AND METHODS
Eligible studies were searched from PubMed, Embase, and Future Medicine databases. The pooled hazard ratios and relative risk ratios (RRs) were calculated by using Stata 12.0 software.
RESULTS
A total of 1,011 patients qualified to participate in this Phase III study that included randomized controlled trials. Meta-analysis results showed that axitinib was more highly and significantly associated with a survival benefit in the independently assessed progression-free survival in comparison to sorafenib. The values of RR of the objective response rate and disease control rate were also significantly different. Results of the analysis of adverse events concerning hypertension and hypothyroidism demonstrated that the values of RR were significantly higher in the axitinib group and lower risks were established in the patients treated with axitinib.
CONCLUSION
Therefore, axitinib was a better treatment option for metastatic renal cell carcinoma treatment than sorafenib, especially after failure of prior systemic therapies. This analysis revealed that axitinib had higher risks of hypertension and hypothyroidism and lower risks of rash and palmar-plantar erythrodysesthesia.
PubMed: 27354814
DOI: 10.2147/OTT.S100706