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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 -
Clinical Genitourinary Cancer Jun 2017This systematic review and meta-analysis was accomplished with the purpose of evaluating the risk of encountering selected hair changes in patients with cancer receiving... (Comparative Study)
Comparative Study Meta-Analysis Review
Risk of Distinctive Hair Changes Associated With Pazopanib in Patients With Renal Cell Carcinoma (RCC) Versus Patients Without RCC: A Comparative Systematic Review and Meta-analysis.
OBJECTIVE
This systematic review and meta-analysis was accomplished with the purpose of evaluating the risk of encountering selected hair changes in patients with cancer receiving pazopanib.
METHODS
We favored relevant prospective randomized phase II and III trials that assessed pazopanib in patients with cancer, depicting various hair-related changes, as eligible for inclusion.
RESULTS
After elimination of ineligible studies, a total of 11 clinical trials were regarded as eligible for the meta-analysis. The relative risk of all-grade alopecia and hair color changes was 1.75 (95% confidence interval, 1.33-2.31; P < .0001) and 4.54 (95% confidence interval, 3.67-5.62; P < .00001), respectively. Subgroup analyses of hair color changes according to the type of cancer treated revealed significant differences between renal cell carcinoma and non-renal cell carcinoma studies (P = .01).
CONCLUSIONS
Our meta-analysis has established that pazopanib-based treatment can be significantly correlated to an elevated risk of all grade alopecia and hair color changes compared with controls.
Topics: Alopecia; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Hair Color; Humans; Indazoles; Kidney Neoplasms; Male; Prospective Studies; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides
PubMed: 28189432
DOI: 10.1016/j.clgc.2016.12.018 -
Pazopanib: Evidence review and clinical practice in the management of advanced renal cell carcinoma.BMC Pharmacology & Toxicology Nov 2018Pazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics...
BACKGROUND
Pazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics of pazopanib and see how these aspects are linked to clinical practice.
METHODS
A non-exhaustive systematic review was conducted according to the three topics. No publication restrictions were imposed and the selected languages were Spanish and English. After that, a summary of the main results and findings of the review was presented and discussed during three meetings (one for each topic) with 13 medical oncologists that usually treat mRCC. At these meetings, a questionnaire on the first-line use of pazopanib in clinical practice was also drawn up. After the meetings, the questionnaire was completed by 60 specialist medical oncologists in renal cancer.
RESULTS
The efficacy and safety of pazopanib have been demonstrated in several clinical trials, and subsequently confirmed in studies in real-world clinical practice. In addition to its clinical benefit and good safety profile, quality of life results for pazopanib, which compare favorably to sunitinib, make it a good option in the first-line treatment of patients. Special populations have been included in studies conducted with pazopanib, and it is safe for use in elderly patients, poor functional status, kidney failure, and mild or moderate hepatic impairment, and in patients with concomitant cardiovascular disease. The results of the questionnaire have shown that pazopanib is perceived as an effective drug, in which quality of life (QoL) outcomes are valued above all.
CONCLUSIONS
This paper offers a comprehensive and critical summary of efficacy, tolerability, and pharmacokinetics of pazopanib in the treatment of mRCC. Pazopanib is an effective treatment with an acceptable safety profile. Its QoL and tolerability results offer certain advantages when compared with other therapeutic alternatives, and its use appears to be safe in different patient profiles.
Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Quality of Life; Sulfonamides; Treatment Outcome
PubMed: 30477570
DOI: 10.1186/s40360-018-0264-8 -
Clinical Genitourinary Cancer Apr 2015Two mTOR inhibitors, TEM and EVE, proved to be active in mRCC but have never been compared in a prospective trial. We aimed to compare their effectiveness in mRCC... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Two mTOR inhibitors, TEM and EVE, proved to be active in mRCC but have never been compared in a prospective trial. We aimed to compare their effectiveness in mRCC patients previously treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor, and performed a systematic review and meta-analysis of available evidence.
MATERIALS AND METHODS
The MEDLINE/PubMed database was reviewed for studies that compared EVE with TEM from January 2006 to May 2014. Summary hazard ratio (HR) for overall survival (OS) and time to treatment failure (TTF) were calculated using random and fixed effects models depending on the heterogeneity of included studies. Statistical heterogeneity was assessed using the χ(2) test, and inconsistency was quantified with the I(2) statistic. Publication bias was evaluated using the Begg and Egger test.
RESULTS
Four studies were included in the meta-analysis; data of 937 patients were available: 545 received EVE and 392 TEM. Among the included patients, 863 [92%] were treated with sunitinib and 74 [8%] with pazopanib or sorafenib as first-line therapy. In the overall population, treatment with EVE decreased the risk of death by 26% over TEM (HR, 0.74; 95% confidence interval [CI], 0.59-0.93; P = .008). The TTF was evaluable in 692 patients; in this group, treatment with EVE decreased the risk of treatment failure by 30% (HR, 0.70; 95% CI, 0.56-0.88; P = .002). No significant heterogeneity or publication bias was found for OS and TTF.
CONCLUSION
In this analysis, we compared EVE with TEM as second-line therapy in mRCC, and report a significant difference between mTOR inhibitors, even if these results need to be confirmed in a prospective trial.
Topics: Carcinoma, Renal Cell; Databases, Bibliographic; Everolimus; Humans; Kidney Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome
PubMed: 25160521
DOI: 10.1016/j.clgc.2014.07.006 -
Frontiers in Pharmacology 2022Multiple targeted therapeutics are available for radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), but it remains unclear which treatment is optimal to...
Multiple targeted therapeutics are available for radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), but it remains unclear which treatment is optimal to achieve long-term survival. A systematic search of the PubMed, Embase, and ClinicalTrials.gov databases was conducted to identify eligible randomized controlled trials (RCTs) comparing the efficacy and safety of targeted treatments for patients with RAIR-DTC from inception to April, 2022. Data were extracted by following the recommendations of the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. We calculated the odds ratio (OR) or hazard ratio (HR), its corresponding 95% credible intervals (CrI), and the surface under the cumulative ranking curve (SUCRA) to indicate ranking probability using Bayesian network meta-analyses. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade 3 or higher adverse events. A total of 12 eligible RCTs involved 1,959 patients and 13 treatments: apatinib, cabozantinib, anlotinib, nintedanib, lenvatinib, lenvatinib with low dose (LD), sorafenib, sorafenib plus everolimus, donafenib (200 mg), donafenib (300 mg), pazopanib (continuous), pazopanib (intermittent), and vandetanib. Pooled analyses indicated that targeted therapeutics significantly prolonged PFS and OS in patients with RAIR-DTC (0.31, 0.21-0.41; 0.69, 0.53-0.85, respectively) compared with placebo. Network meta-analyses indicated that lenvatinib showed the most favorable PFS, with significant differences versus sorafenib (0.33, 0.23-0.48), vandetanib (0.31, 0.20-0.49), nintedanib (0.30, 0.15-0.60), and placebo (0.19, 0.15-0.25), while apatinib was most likely to be ranked first for prolonging OS with a SUCRA of 0.90. Lenvatinib showed the highest ORR (66%, 61%-70%), followed by anlotinib (59%, 48%-70%) and apatinib (54%, 40%-69%). Lenvatinib caused the most adverse events of grade 3 or higher, followed by lenvatinib (LD) and apatinib. Different toxicity profiles of individual treatment were also revealed. This network meta-analysis suggests that lenvatinib and apatinib were associated with the best progression-free survival and overall survival benefits, respectively, for patients with RAIR-DTC, compared with other targeted therapeutics. Patients who received lenvatinib or apatinib also had more grade 3 or higher adverse events. : [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=302249], identifier [CRD42022302249].
PubMed: 36091770
DOI: 10.3389/fphar.2022.933648 -
Cancers Oct 2022Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about... (Review)
Review
Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of these drugs in pediatric patients is partially assessed. The aim of this study was to evaluate the safety of AADs in pediatric patients with solid tumors. Clinical trials and observational studies were searched in PubMed, ISI Web of Science, and ClinicalTrials database For each included study, adverse events (AEs) were extracted. A meta-analysis was conducted by pooling proportions of AEs using a random intercept logistic regression model. Seventy studies were retrieved. Most part were clinical trials (55 out of 70), and only fifteen observational studies were found. Overall, proportion of serious and non-serious AEs of AADs used as monotherapy was 46% and 89%, respectively. Proportions of serious AEs varied among drugs: sunitinib, 79%; lenvatinib, 64%; sorafenib, 48%; ramucirumab, 41%; pazopanib, 30%; and vandetanib, 27%. A higher proportion of non-serious hematological AEs was found in the patients receiving pazopanib with respect to sunitinib and lenvatinib. The safety profile of AADs has been extensively investigated for mostly drugs in phase I and II trials and is limited to acute toxicities. Overall, one out of two patients using AAD drugs in monotherapy experienced a serious AE despite proportions varied per single drugs. When AADs were combined with standard chemotherapy, the proportion of AEs varied in relation to the single combinations.
PubMed: 36358734
DOI: 10.3390/cancers14215315 -
European Journal of Endocrinology May 2015Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC... (Meta-Analysis)
Meta-Analysis Review
Therapy of endocrine disease: response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and meta-analysis.
CONTEXT
Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients.
METHODS
All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand-foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported.
RESULTS
In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33-64)%, and was 17 (95% CI 12-24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14-77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34-46)% and 27 (95% CI 22-32)% respectively. Clinical benefit was found in 53 (95% CI 48-59)% of DTC patients on sorafenib, and in 84 (95% CI 79-88)% and 55 (95% CI 49-61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity.
CONCLUSION
The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.
Topics: Antineoplastic Agents; Humans; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Thyroid Neoplasms
PubMed: 25572389
DOI: 10.1530/EJE-14-0788 -
Expert Review of Clinical Pharmacology Aug 2016Cabozantinib (XL184) is an oral inhibitor of multiplereceptor tyrosine kinases including mesenchymal-epithelial transition factor (MET) and vascular endothelial growth... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Cabozantinib (XL184) is an oral inhibitor of multiplereceptor tyrosine kinases including mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2). Hypertension is one of its major side effects, but the incidence rate and overall risk has not been systematically studied. We thus conducted this meta-analysis to investigate the overall incidence and risk of developing hypertension in cancer patients treated with cabozantinib.
AREAS COVERED
Pubmed, Embase and oncology conference proceedings were searched for relevant studies. Eligible studies were phase II and III prospective clinical trials of cabozantinib in cancer patients with data on hypertension available. A total of 1,514 patients (cabozantinib, 1083; control, 431) with a variety of solid tumors from 8 prospective clinical trials were included for the meta-analysis. The use of cabozantinib was associated with significantly increased risk of developing all grade (RR 5.48; 95%CI, 3.76-7.99; p < 0.001) and high grade (5.09; 95% CI: 2.71-9.54, p < 0.001) hypertension in comparison with controls. Additionally, the risk of high grade hypertension with cabozantinib was substantially higher than other four approved VEGFR-TKIs (sorafenib, sunitinib, vandetanib and pazopanib). Expert commentary: Cancer patients receiving cabozantinib have an increased risk of developing hypertension. Close monitoring and management of hypertension are recommended.
Topics: Anilides; Antineoplastic Agents; Clinical Trials as Topic; Humans; Hypertension; Incidence; Neoplasms; Protein Kinase Inhibitors; Pyridines; Risk
PubMed: 27181268
DOI: 10.1080/17512433.2016.1190269 -
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 -
Journal of the American Academy of... Nov 2013Pruritus has been anecdotally described in association with targeted cancer therapies. The risk of pruritus has not been systematically ascertained. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pruritus has been anecdotally described in association with targeted cancer therapies. The risk of pruritus has not been systematically ascertained.
OBJECTIVE
A systematic review and meta-analysis of the literature was conducted for axitinib, cetuximab, dasatinib, erlotinib, everolimus, gefitinib, imatinib, ipilimumab, lapatinib, nilotinib, panitumumab, pazopanib, rituximab, sorafenib, temsirolimus, tositumomab, vandetanib, and vemurafenib.
METHODS
Databases from PubMed, Web of Science (January 1998 through July 2012), and American Society of Clinical Oncology abstracts (2004 through 2012) were searched. Incidence and relative risk of pruritus were calculated using random- or fixed-effects model.
RESULTS
The incidences of all-grade and high-grade pruritus were 17.4% (95% confidence interval 16.0%-19.0%) and 1.4% (95% confidence interval 1.2%-1.6%), respectively. There was an increased risk of all-grade pruritus (relative risk 2.90 [95% confidence interval 1.76-4.77, P < .001]) and variation among different drugs (P < .001).
LIMITATIONS
The reporting of pruritus may vary, resulting from concomitant medications, comorbidities, and underlying malignancies. We found a higher incidence of pruritus in patients with solid tumors, concordant with those targeted therapies with the highest pruritus incidences.
CONCLUSION
There is a significant risk of developing pruritus in patients receiving targeted therapies. To prevent suboptimal dosing and decreased quality of life, patients should be counseled and treated against this untoward symptom.
Topics: Drug Eruptions; Humans; Molecular Targeted Therapy; Neoplasms; Pruritus
PubMed: 23981682
DOI: 10.1016/j.jaad.2013.06.038