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Targeted Oncology May 2024Targeting of angiogenesis has become a major therapeutic approach for the treatment of various advanced cancers. There are many unresolved questions on the toxicity of...
BACKGROUND
Targeting of angiogenesis has become a major therapeutic approach for the treatment of various advanced cancers. There are many unresolved questions on the toxicity of anti-angiogenic tyrosine kinase inhibitors (TKIs).
OBJECTIVE
We performed a meta-analysis to assess the toxicity prevalence of the different anti-angiogenic TKIs among cancer patients and in subpopulations of interest including patients with renal cell carcinoma.
PATIENTS AND METHODS
We searched the MEDLINE and Cochrane Library databases to November 2023. Clinical trials were eligible if they set out to report the grade ≥3 toxicities related to one of the seven currently approved anti-angiogenic TKIs as monotherapies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was applied with PROSPERO (CRD42023411946).
RESULTS
The 421 eligible studies included a total of 56,895 cancer patients treated with anti-angiogenic TKI monotherapy. Twenty-four different cancer types were identified, mainly renal cell carcinoma (41.9% of the patients). The anti-angiogenic TKI was sorafenib (34.5% of the patients), sunitinib (30.5%), regorafenib (10.7%), pazopanib (9.4%), cabozantinib (7.7%), axitinib (4.3%), and lenvatinib (2.9%). The pooled prevalence of grade 3 and 4 toxicities was 56.1% (95% confidence interval 53.5-58.6), with marked between-study heterogeneity (I = 96.8%). Toxicity profiles varied considerably depending on the type of TKI, the cancer type, and the specific patient characteristics. In particular, Asian patients and elderly people had higher prevalences of severe toxicities, with pazopanib being the best-tolerated drug. For patients treated with sunitinib, particularly those with metastatic RCC, there was no significant difference in terms of toxicity according to the regimen schedule.
CONCLUSIONS
This meta-analysis highlights the toxicity profiles of anti-angiogenic TKI monotherapies, and thus enables high-level recommendations for the choice of anti-angiogenic TKIs on the basis of the patient's age, ethnicity, comorbidities, and comedications, for personalized treatment.
PubMed: 38761350
DOI: 10.1007/s11523-024-01067-8 -
European Urology Nov 2018Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal... (Meta-Analysis)
Meta-Analysis
CONTEXT
Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC).
OBJECTIVE
To systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3-4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC.
EVIDENCE ACQUISITION
A critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed. We identified reports and reviewed them according to the Consolidated Standards of Reporting Trials and Standards for the Reporting of Diagnostic Accuracy Studies criteria. Of eight full-text articles that were eligible for inclusion, five studies (two of five were updated analyses) were retained in the final synthesis. Study characteristics were abstracted and the number needed to treat (NNT) per trial was estimated.
EVIDENCE SYNTHESIS
The three randomized controlled phase III trials included the following comparisons: sunitinib versus placebo or sorafenib versus placebo (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma [ASSURE] study, n=1943), sunitinib versus placebo (S-TRAC, n=615), and pazopanib versus placebo (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy study, n=1135). The NNT ranged from 10 (S-TRAC) to 137 (ASSURE study). The pooled analysis showed that VEGFR-targeted therapy was not statistically significantly associated with improved DFS (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.82-1.03, p=0.16) or OS (HR: 0.98, 95% CI: 0.84-1.15, p=0.84) compared with the control group. The adjuvant therapy group experienced significantly higher odds of grade 3-4 AEs (OR: 5.89, 95% CI: 4.85-7.15, p<0.001). In exploratory analyses focusing on patients who started on the full-dose regimen, DFS was improved in patients who received adjuvant therapy (HR: 0.83, 95% CI: 0.73-0.95, p=0.005).
CONCLUSIONS
This pooled analysis of reported randomized trials did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high-risk local or regional fully resected RCC. Improvement in DFS may be more likely with the use of full-dose regimens, pending further results. However, adjuvant treatment was associated with high-grade AEs.
PATIENT SUMMARY
Vascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life and comes at the expense of potentially significant side effects.
Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Disease Progression; Disease-Free Survival; Humans; Kidney Neoplasms; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Nephrectomy; Progression-Free Survival; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Risk Factors; Signal Transduction; Time Factors; Vascular Endothelial Growth Factor A
PubMed: 29784193
DOI: 10.1016/j.eururo.2018.05.002 -
BMC Urology Jun 2019Conflicting evidence exists regarding the effect of hypertension on the prognosis of metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Conflicting evidence exists regarding the effect of hypertension on the prognosis of metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). This study aimed to assess the predictive value of TKIs-induced hypertension in patients with mRCC.
METHODS
This study was registered in PROSPERO (CRD42019129593). PubMed, Embase, Web of Science and the Cochrane Library database were searched with terms: "renal cell carcinoma", "hypertension", "blood pressure", "tyrosine kinase inhibitor", "sunitinib", "axitinib", "sorafenib" and "pazopanib" until March 21, 2019. Hazard Ratios (HR) and 95% confidence intervals (CI) for progression-free survival (PFS) or overall survival (OS) were extracted and analyzed with Stata 15.0 software. Heterogeneity was assessed using the I value. Meta-regression, subgroup analysis and sensitivity analysis were also performed to explore heterogeneity. Publication bias was assessed with funnel plots and precisely assessed by Egger's and Begg's tests. The quality of evidence of outcomes was generated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).
RESULTS
A total of 4661 patients from 22 studies were included in the study. The results showed that the increase of blood pressure was an effective predictor for longer PFS (HR = 0.59, 95% CI: 0.48-0.71, p < 0.001; I = 77.3%) and OS (HR = 0.57, 95% CI: 0.45-0.70, p < 0.001; I = 77.4%) of patients with mRCC. Subgroup analysis revealed that patients receiving sunitinib and pazopanib could have longer PFS and OS.
CONCLUSIONS
This study indicated that TKIs-induced hypertension may be a good predictor for better prognosis of patients with mRCC receiving TKIs treatment, especially using sunitinib or pazopanib.
Topics: Carcinoma, Renal Cell; Disease-Free Survival; Humans; Hypertension; Kidney Neoplasms; Prognosis; Protein Kinase Inhibitors; Survival Rate
PubMed: 31174518
DOI: 10.1186/s12894-019-0481-5 -
European Archives of... Apr 2024To evaluate literature evidences about the efficacy and safety of anti-angiogenesis agents plus chemoradiotherapy versus chemoradiotherapy in the treatment of locally... (Review)
Review
PURPOSE
To evaluate literature evidences about the efficacy and safety of anti-angiogenesis agents plus chemoradiotherapy versus chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma.
METHODS
The relevant literature was systematically searched from the date of establishment to April 2023 in PubMed, Embase, Web of Science, The Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biological Medicine, Wanfang and VIP database. Search terms included: Nasopharyngeal Neoplasms, Angiogenesis inhibitors, Endostar, Anlotinib, Apatinib, Bevacizumab, Sunitinib, Pazopanib, Chemoradiotherapy. The literature was strictly screened according to the inclusion and exclusion criteria, and 8 eligible studies were finally included in our meta-analysis (4 randomized controlled trials and 4 retrospective studies).
RESULTS
A total of 642 patients were included, with 316 in the anti-angiogenesis agents plus chemoradiotherapy group and 326 in the chemoradiotherapy group. The results of our meta-analysis showed that compared with chemoradiotherapy group, the complete response rate (RR = 1.35, 95% CI 1.05-1.74, P = 0.02), objective response rate (RR = 1.26, 95% CI 1.12-1.43, P = 0.0002) in the anti-angiogenesis agents plus chemoradiotherapy group were significantly improved. In terms of safety, there was a higher incidence of cardiac arrhythmia (RR = 3.63, 95% CI 1.16-11.37, P = 0.03) and hypertension (RR = 1.85, 95% CI 1.04-3.27, P = 0.004) in the anti-angiogenesis agents plus chemoradiotherapy group, while no statistically significant differences were reported in other adverse reactions (all P > 0.05).
CONCLUSION
Compared with chemoradiotherapy, anti-angiogenesis agents plus chemoradiotherapy could bring more benefits in terms of short-term efficacy, particularly by notably improving both complete response rate and objective response rate, and overall adverse reactions were acceptable. Anti-angiogenesis agents plus chemoradiotherapy may provide a promising direction for the treatment of locally advanced nasopharyngeal carcinoma.
SYSTEMATIC REVIEW REGISTRATION
https://inplasy.com/inplasy-2023-8-0076/ , registration number INPLASY202380076.
PubMed: 38625559
DOI: 10.1007/s00405-024-08545-9 -
Cancer Investigation Aug 2016The present systematic review summarizes current evidence regarding the mechanisms of action, the efficacy, and the adverse effects of tyrosine kinase inhibitors (TKIs)... (Meta-Analysis)
Meta-Analysis Review
The present systematic review summarizes current evidence regarding the mechanisms of action, the efficacy, and the adverse effects of tyrosine kinase inhibitors (TKIs) in ovarian cancer patients. Phase II and III clinical trials were sought in the PubMed database and in the Clinical Trials.gov registry through September 30, 2015. Seventy-five clinical trials regarding TKIs targeting mainly vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, and sarcoma tyrosine kinase (Src) were yielded. The most promising results were noted with cediranib, nintedanib, and pazopanib. However, drawing universal conclusions about the potential integration of TKIs in ovarian cancer therapy remains elusive. Furthermore, emerging challenges and directions for the future research are critically discussed.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; ErbB Receptors; Female; Humans; Molecular Targeted Therapy; Ovarian Neoplasms; Protein Kinase Inhibitors; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Treatment Outcome; src-Family Kinases
PubMed: 27486869
DOI: 10.1080/07357907.2016.1206117 -
European Journal of Cancer (Oxford,... Sep 2021The efficacy of tyrosine kinase inhibitor (TKI)-based therapy after previous immuno-oncology therapy (IO) failure has been addressed before. However, summary efficacy... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The efficacy of tyrosine kinase inhibitor (TKI)-based therapy after previous immuno-oncology therapy (IO) failure has been addressed before. However, summary efficacy estimates have never been generated in these reports. We addressed this void.
MATERIAL AND METHODS
We systematically examined TKI efficacy after IO-failure and generated weighted median progression-free survival (PFS) estimates for Pazopanib, Axitinib, Cabozantinib, Sunitinib. A systematic review according to PRISMA was conducted. PubMed and abstracts were queried. Only studies proving median PFS were included. Weighted medians were computed for each TKI alternative.
RESULTS
Of 245 articles, nine eligible studies were included in the current study with 952 analysed patients. Weighted PFS medians after any previous IO-based therapy were respectively 13.7 (range from 4.6 to 24.4), 8.1 (range from 4.7 to 13.2), 8.5 (range from 4.7 to 15.2) and 6.9 months (range from 2.9 to 11.6) for Pazopanib, Axitinib, Cabozantinib, Sunitinib. Specific second-line weighted PFS median was 14.8 months (range from 5.6 to 24.4), 10.1 months (range from 6.4 to 13.2), 8.7 months (range from 4.7 to 15.2) and 6.0 months (range from 2.9 to 8.0) for Pazopanib, Axitinib, Cabozantinib, Sunitinib, respectively, after first-line IO.
CONCLUSION
Pazopanib results in the longest weighted median PFS, after previous IO-failure, regardless of treatment line, as well as in specific second-line, post-first-line IO failure settings. Pending novel studies, Pazopanib appears to represent the most promising treatment option after prior IO.
Topics: Female; Humans; Kidney Neoplasms; Male; Neoplasm Metastasis; Protein Kinase Inhibitors; Time Factors
PubMed: 34392067
DOI: 10.1016/j.ejca.2021.07.014 -
European Urology Oncology Jun 2018The role of antiangiogenic agents in advanced renal cell carcinoma (RCC) is well established. However, it is still not clear whether this benefit can be extrapolated to...
CONTEXT
The role of antiangiogenic agents in advanced renal cell carcinoma (RCC) is well established. However, it is still not clear whether this benefit can be extrapolated to the adjuvant setting.
OBJECTIVE
To determine the efficacy and safety of antiangiogenic agents in patients with RCC and a high risk of relapse after nephrectomy.
EVIDENCE ACQUISITION
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) evaluating the use of any oral antiangiogenic agent compared to placebo in post-nephrectomy RCC patients. Prespecified data elements were extracted from each trial. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). The overall effect was pooled using the DerSimonian and Laird random-effects models.
EVIDENCE SYNTHESIS
Three RCTs comparing antiangiogenics to placebo among 3693 patients met our inclusion criteria and were used in meta-analyses. Overall, antiangiogenics did not improve DFS (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.78-1.07) or OS (HR 0.99, 95% CI 0.79-1.25). These results persisted when restricting the analysis to patients with clear cell carcinoma and patients with highest risk of relapse. Similarly, sunitinib did not show any improvement in the entire cohort for either DFS (HR 0.89, 95% CI 0.67-1.19) or OS (HR 1.11, 95% CI 0.90-1.37).
CONCLUSIONS
In this meta-analysis, antiangiogenics did not improve OS and DFS over placebo in high-risk RCC after nephrectomy. Further studies are needed to identify the patient population that might derive a benefit from antiangiogenics in the adjuvant setting.
PATIENT SUMMARY
In this article, we found that there is currently insufficient evidence to support the use of oral antiangiogenics in nonmetastatic renal cell carcinoma after nephrectomy. In addition, the use of oral antiangiogenics was associated with a 2.7-fold higher rate of significant side effects compared to placebo.
PubMed: 30345423
DOI: 10.1016/j.euo.2018.03.012 -
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 -
Journal of Ovarian Research 2014As increased angiogenesis has been linked with the progression of ovarian cancer, a number of anti-angiogenic agents have been investigated, or are currently in... (Review)
Review
As increased angiogenesis has been linked with the progression of ovarian cancer, a number of anti-angiogenic agents have been investigated, or are currently in development, as potential treatment options for patients with advanced disease. Bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor, has gained European Medicines Agency approval for the front-line treatment of advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in combination with carboplatin and paclitaxel, and for the treatment of first recurrence of platinum-sensitive ovarian cancer in combination with carboplatin and gemcitabine. We conducted a systematic literature review to identify available efficacy and safety data for bevacizumab in ovarian cancer as well as for newer anti-angiogenic agents in development. We analyzed published data from randomized, controlled phase II/III clinical trials enrolling women with ovarian cancer to receive treatment with bevacizumab. We also reviewed available data for emerging anti-angiogenic agents currently in phase II/III development, including trebananib, aflibercept, nintedanib, cediranib, imatinib, pazopanib, sorafenib and sunitinib. Significant efficacy gains were achieved with the addition of bevacizumab to standard chemotherapy in four randomized, double-blind, phase III trials, both as front-line treatment (GOG-0218 and ICON7) and in patients with recurrent disease (OCEANS and AURELIA). The type and frequency of bevacizumab-related adverse events was as expected in these studies based on published data. Promising efficacy data have been published for a number of emerging anti-angiogenic agents in phase III development for advanced ovarian cancer. Further research is needed to identify predictive or prognostic markers of response to bevacizumab in order to optimize patient selection and treatment benefit. Data from phase III trials of newer anti-angiogenic agents in ovarian cancer are awaited.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Humans; Molecular Targeted Therapy; Neovascularization, Pathologic; Ovarian Neoplasms; Randomized Controlled Trials as Topic
PubMed: 24864163
DOI: 10.1186/1757-2215-7-57 -
Anti-cancer Drugs Jan 2022Pyoderma gangrenosum is a rare ulcerative dermatosis. It may be caused by some drugs, including small molecule tyrosine kinase inhibitors (TKIs). The aim of this study...
Pyoderma gangrenosum is a rare ulcerative dermatosis. It may be caused by some drugs, including small molecule tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the reported evidence of pyoderma gangrenosum associated with the use of these drugs. A systematic electronic literature search of PubMed and Embase was conducted. In these databases, search terms describing pyoderma gangrenosum were combined with TKIs. Fifteen case reports (eight cases associated with sunitinib, two with imatinib, two with ibrutinib, one with gefitinib, one with pazopanib, and one with dabrafenib and trametinib) were identified over the 14 years. The average Naranjo score of these cases is 6.6, which indicates a probable adverse drug reaction. Pyoderma gangrenosum is a probable and reversible drug reaction associated with some TKIs. Detailed medical history can help to prompt diagnosis of drug-induced pyoderma gangrenosum. Clinicians should be aware of TKI-associated pyoderma gangrenosum when caring for the skin of oncologic patients undergoing therapy with kinase inhibitors.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Patient Acuity; Protein Kinase Inhibitors; Pyoderma Gangrenosum
PubMed: 34282745
DOI: 10.1097/CAD.0000000000001140