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International Journal of Cancer Aug 2014Gastrointestinal (GI) events have been described with sorafenib, sunitinib and pazopanib in cancer patients. We performed an up-to-date meta-analysis to determine the... (Meta-Analysis)
Meta-Analysis Review
Gastrointestinal (GI) events have been described with sorafenib, sunitinib and pazopanib in cancer patients. We performed an up-to-date meta-analysis to determine the incidence and relative risk (RR) in patients with cancer treated with these agents. PubMed databases were searched for articles published till May 2013. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 6,447 patients were available for the meta-analysis; 2,260 had renal cell carcinoma (RCC) and 4,187, 1,691 non-small cell lung cancers, 599 hepatocellular cancers, 1,066 breast cancers, 165 neuroendocrine tumors, 304 gastrointestinal stromal tumors and 362 soft tissue sarcomas. Diarrhea was the most common GI event. When stratified by tumor type (RCC vs. non-RCC), the difference among the incidences of GI events was significant for diarrhea (p < 0.001) and vomiting (p = 0.006), that resulted higher in RCC patients. In RCC patients, sorafenib registered the lower incidence and RR of all grades GI events. The difference was statistically significant for sorafenib versus sunitinib-related all and high-grade events (p < 0.001) and for sorafenib versus pazopanib all grades GI events (p < 0.001) and high-grade anorexia (p < 0.001). Treatment with VEGFR TKIs sorafenib, sunitinib and pazopanib is associated with a significant increase in the risk of GI events in patients with cancer, and frequent clinical monitoring should be emphasized when managing these three and newer VEGFR TKIs.
Topics: Adverse Drug Reaction Reporting Systems; Carcinoma, Renal Cell; Clinical Trials as Topic; Diarrhea; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Incidence; Indazoles; Indoles; Liver Neoplasms; Neoplasms; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Vomiting
PubMed: 24127298
DOI: 10.1002/ijc.28544 -
Anthracycline, Gemcitabine, and Pazopanib in Epithelioid Sarcoma: A Multi-institutional Case Series.JAMA Oncology Sep 2018Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to...
IMPORTANCE
Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease.
OBJECTIVE
To report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES.
DESIGN, SETTING, AND PARTICIPANTS
Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria.
EXPOSURES
All patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib.
MAIN OUTCOME AND MEASURES
Response was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines).
RESULTS
Overall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months.
CONCLUSIONS AND RELEVANCE
This is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.
Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Pyrimidines; Remission Induction; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Sarcoma; Sulfonamides; Young Adult; Gemcitabine
PubMed: 29800950
DOI: 10.1001/jamaoncol.2018.0219 -
The Oncologist Jan 2018Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for...
BACKGROUND
Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin.
MATERIALS AND METHODS
From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method.
RESULTS
Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months.
CONCLUSION
The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS.
IMPLICATIONS FOR PRACTICE
This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Indazoles; Male; Middle Aged; Prognosis; Pyrimidines; Retrospective Studies; Sarcoma, Alveolar Soft Part; Sulfonamides; Survival Rate; Trabectedin
PubMed: 28754721
DOI: 10.1634/theoncologist.2017-0161 -
Acta Medica Indonesiana Oct 2016In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has provided a new hope and significantly enhanced the prognosis... (Review)
Review
In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has provided a new hope and significantly enhanced the prognosis of the disease. Three class of targeted therapy were developed, including multi-targeted tyrosine kinase inhibitors (TKI), the mammalian target of rapamycin (mTOR) complex-1 kinase inhibitors, and the humanized antivascular endothelial growth factor (VEGF) monoclonal antibody. Hence, the objective of this article was to critically examine the current evidence of targeted therapy treatment for patients with mRCC. In the majority of trials evaluating targeted therapy, patients were stratified according to Memorial Sloan Kattering Cancer Center (MSKCC) risk model and the recommendation of targeted treatment based on risk features. In first-line setting (no previous treatment), sunitinib, pazopanib, or bevacizumab plus IFN-α were recommended as treatment options for patient with favorable- or intermediate- risk features and clear cell histology. Patients who progressed after previous cytokine therapy would have sorafenib or axitinib as treatment options. Clear-cell mRCC with favorable- or intermediate- risk features and failure with first-line TKI therapy might be treated with sorafenib, everolimus, temsirolimus or axitinib. However, the current evidence did not show the best treatment sequencing after first-line TKI failure. In patients with poor-risk clear-cell and non-clear cell mRCC, temsirolimus was the treatment option supported by phase III clinical trial. In addition, several new drugs, nowadays, are still being investigated and waiting for the result of phase II or III clinical trial, and this might change the standard therapy for mRCC in the future.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib
PubMed: 28143997
DOI: No ID Found -
PharmacoEconomics Mar 2019The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011. (Review)
Review
BACKGROUND
The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011.
OBJECTIVE
The objective of this study was to perform an updated review by synthesizing economic studies related to the treatment of RCC that have been published since the previous review.
METHODS
We performed a literature search in PubMed, EMBASE, and the Cochrane Library, covering English-language studies published between June 2010 and August 2018. We categorized these articles by type of analyses [cost-effectiveness analysis (CEA), cost analysis, and cost of illness (COI)] and treatment setting (cancer status and treatment), discussed findings from these articles, and synthesized information from each article in summary tables.
RESULTS
We identified 52 studies from 2317 abstracts/titles deemed relevant from the initial search, including 21 CEA, 23 cost analysis, and 8 COI studies. For localized RCC, costs were found to be positively associated with the aggressiveness of the local treatment. For metastatic RCC (mRCC), pazopanib was reported to be cost effective in the first-line setting. We also found that the economic burden of RCC has increased over time.
CONCLUSION
RCC continues to impose a substantial economic burden to the healthcare system. Despite the large number of treatment alternatives now available for advanced RCC, the cost effectiveness and budgetary impact of many new agents remain unknown and warrant greater attention in future research.
Topics: Carcinoma, Renal Cell; Cost of Illness; Cost-Benefit Analysis; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Time Factors
PubMed: 30467701
DOI: 10.1007/s40273-018-0746-y -
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 -
British Journal of Cancer Aug 2013Tyrosine kinase inhibitors (TKI) such as sunitinib and pazopanib display their efficacy in a variety of solid tumours. However, their use in therapy is limited by the...
BACKGROUND
Tyrosine kinase inhibitors (TKI) such as sunitinib and pazopanib display their efficacy in a variety of solid tumours. However, their use in therapy is limited by the lack of evidence about the ability to induce cell death in cancer cells. Our aim was to evaluate cytotoxic effects induced by sunitinib and pazopanib in 5637 and J82 bladder cancer cell lines.
METHODS
Cell viability was tested by MTT assay. Autophagy was evaluated by western blot using anti-LC3 and anti-p62 antibodies, acridine orange staining and FACS analysis. Oxygen radical generation and necrosis were determined by FACS analysis using DCFDA and PI staining. Cathepsin B activation was evaluated by western blot and fluorogenic Z-Arg-Arg-AMC peptide. Finally, gene expression was performed using RT-PCR Profiler array.
RESULTS
We found that sunitinib treatment for 24 h triggers incomplete autophagy, impairs cathepsin B activation and stimulates a lysosomal-dependent necrosis. By contrast, treatment for 48 h with pazopanib induces cathepsin B activation and autophagic cell death, markedly reversed by CA074-Me and 3-MA, cathepsin B and autophagic inhibitors, respectively. Finally, pazopanib upregulates the α-glucosidase and downregulates the TP73 mRNA expression.
CONCLUSION
Our results showing distinct cell death mechanisms activated by different TKIs, provide the biological basis for novel molecularly targeted approaches.
Topics: Antineoplastic Agents; Autophagy; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Cell Death; Cell Line, Tumor; Cell Survival; Humans; Indazoles; Indoles; Inhibitory Concentration 50; Membrane Potential, Mitochondrial; Necrosis; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Reactive Oxygen Species; Sulfonamides; Sunitinib; Urinary Bladder Neoplasms
PubMed: 23887605
DOI: 10.1038/bjc.2013.420 -
American Journal of Clinical Oncology Jun 2023Patients with recurrent or persistent ovarian cancer often have poor prognoses, and their optimal treatment regimen remains unclear. Inhibition of angiogenesis is a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients with recurrent or persistent ovarian cancer often have poor prognoses, and their optimal treatment regimen remains unclear. Inhibition of angiogenesis is a valuable strategy for treating ovarian cancer, and the drug pazopanib is a potent, multitarget tyrosine kinase inhibitor. However, treatment with pazopanib in combination with chemotherapy remains controversial. We performed a systematic review and meta-analysis to clarify the efficacy and side effects of pazopanib combined with chemotherapy in the treatment of advanced ovarian cancer.
METHODS
The PubMed, Embase, and Cochrane databases were systematically searched for relevant randomized controlled trials published up to September 2, 2022. The primary outcomes of eligible studies included overall response rate (ORR), disease control rate, 1-year progression-free survival (PFS) rate, 2-year PFS rate, 1-year overall survival (OS) rate, 2-year OS rate, and adverse events.
RESULT
Outcomes from a total of 518 recurrent or persistent ovarian cancer patients from 5 studies were analyzed in this systematic review. Pooled results showed that pazopanib plus chemotherapy, when compared with chemotherapy alone, significantly improved the ORR (pooled risk ratio=1.400; 95% CI, 1.062-1.846; P = 0.017) but not the disease control rate, 1-year PFS, 2-year PFS, 1-year OS, or 2-year OS. Moreover, pazopanib increased the risk of neutropenia, hypertension, fatigue, and liver dysfunction.
CONCLUSION
Pazopanib plus chemotherapy improved patient ORR but did not improve survival; it also increased the occurrence of several adverse events. Further large-sample clinical trials are needed to verify these results to guide pazopanib use in patients with ovarian cancer.
Topics: Humans; Female; Ovarian Neoplasms; Pyrimidines; Sulfonamides; Indazoles; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36877187
DOI: 10.1097/COC.0000000000000999 -
Frontiers in Endocrinology 2023Aggressive prolactinomas (APRLs) pose a significant clinical challenge due to their high rate of regrowth and potentially life-threatening complications. In this study,... (Review)
Review
INTRODUCTION
Aggressive prolactinomas (APRLs) pose a significant clinical challenge due to their high rate of regrowth and potentially life-threatening complications. In this study, we present a case of a patient with an APRL who had a trial of multiple therapeutic modalities with the aim to provide a review of molecular abnormalities and management of APRLs by corroborating our experience with previous literature.
METHODS
A total of 268 articles were reviewed and 46 were included. Case reports and series, and studies that investigated the molecular and/or genetic analysis of APRLs were included. Special care was taken to include studies describing prolactinomas that would fall under the APRL subtype according to the European Society of Endocrinology guidelines; however, the author did not label the tumor as "aggressive" or "atypical". Addiontionally, we present a case report of a 56-year-old man presented with an invasive APRL that was resistant to multiple treatment modalities.
RESULTS
Literature review revealed multiple molecular abnormalities of APRLs including mutations in and/or deregulation of ADAMTS6, MMP-9, PITX1, VEGF, POU6F2, CDKN2A, and Rb genes. Mismatch repair genes, downregulation of microRNAs, and hypermethylation of specific genes including RASSF1A, p27, and MGMT were found to be directly associated with the aggressiveness of prolactinomas. APRL receptor analysis showed that low levels of estrogen receptor (ER) and an increase in somatostatin receptors (SSTR5) and epidermal growth factor receptors (EGFR) were associated with increased invasiveness and higher proliferation activity. Our patient had positive immunohistochemistry staining for PD-L1, MSH2, and MSH6, while microarray analysis revealed mutations in the CDKN2A and POU6F2 genes. Despite undergoing two surgical resections, radiotherapy, and taking dopamine agonists, the tumor continued to progress. The patient was administered pazopanib, which resulted in a positive response and the patient remained progression-free for six months. However, subsequent observations revealed tumor progression. The patient was started on PD-L1 inhibitor pembrolizumab, yet the tumor continued to progress.
CONCLUSION
APRLs are complex tumors that require a multidisciplinary management approach. Knowledge of the molecular underpinnings of these tumors is critical for understanding their pathogenesis and identifying potential targets for precision medical therapy.
Topics: Male; Humans; Middle Aged; Prolactinoma; Pituitary Neoplasms; Indazoles; POU Domain Factors
PubMed: 37529607
DOI: 10.3389/fendo.2023.1195792 -
Cancer Medicine Nov 2023Personalized dosing based on measurement of individual drug levels and adjusting the dose accordingly can improve efficacy and decrease unnecessary toxicity of...
BACKGROUND
Personalized dosing based on measurement of individual drug levels and adjusting the dose accordingly can improve efficacy and decrease unnecessary toxicity of oncological treatment. For imatinib, sunitinib, and pazopanib, this therapeutic drug monitoring (TDM)-guided dosing is, however, not routinely used, despite accumulating evidence favoring individualized dosing. Therefore, we aimed to identify and quantify (potential) barriers and facilitators in TDM-guided dosing for imatinib, sunitinib, and pazopanib.
METHODS
We performed a mixed methods study among all stakeholders involved: patients, healthcare professionals (HCPs), pharmaceutical companies, and health insurance companies. During the first qualitative part of this study, we performed semi-structured individual interviews and one focus group interview to identify all (potential) barriers and facilitators, and during the second quantitative part of this study, we used a web-based survey to quantify these findings. The interviews addressed the six domains of the implementation of change model of Grol and Wensing: (1) the innovation itself; (2) the HCP; (3) the patient; (4) social context; (5) organizational context; and (6) finances, law, and governance.
RESULTS
In the qualitative study, we interviewed 20 patients, 18 HCPs and 10 representatives of pharmaceutical and health insurance companies and identified 72 barriers and 90 facilitators. In the quantitative study, the survey was responded by 66 HCPs and 58 patients. Important barriers were on the domain of the HCP, such as a lack of experience with TDM (36.4%), on the domain of the patient, such as lack of awareness of TDM (39.7%), and the processing time for measurement and interpretation of the TDM result (40.9%) (organizational domain). Important facilitators were education of HCPs (95.5%), education of patients (87.9%) and facilitating an overview of when and where TDM measurements are being performed (86.4%).
CONCLUSION
We identified and quantified important barriers and facilitators for the implementation of TDM-guided dosing for imatinib, sunitinib, and pazopanib. Based on our results, the implementation strategy should mainly focus on educating both HCPs and patients and on the organizational aspect of TDM.
Topics: Humans; Imatinib Mesylate; Sunitinib; Drug Monitoring; Pharmaceutical Preparations
PubMed: 37902257
DOI: 10.1002/cam4.6663