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Biological & Pharmaceutical Bulletin 2023Pazopanib is one of recommended treatment for metastatic renal cell carcinoma (RCC). Despite its effectiveness, patients often difficult to continue pazopanib treatment...
Pazopanib is one of recommended treatment for metastatic renal cell carcinoma (RCC). Despite its effectiveness, patients often difficult to continue pazopanib treatment due to adverse events (AEs). We established an ambulatory care pharmacy practice that enables pharmacist-urologist collaboration to manage patients with RCC. This study evaluated the usefulness of this collaborative management. We retrospectively reviewed the medical records of 51 consecutive patients with metastatic RCC receiving pazopanib at the Kobe City Medical Center General Hospital between April 2014 and December 2020. Our collaborative management was implemented in October 2016. The time to pazopanib discontinuation was compared between patients who started pazopanib before (n = 30) and after (n = 21) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with pazopanib discontinuation. In the collaborative management, the oncology pharmacists had a total of 245 face-to-face patient consultations, and provided 286 suggestions [according to supportive care in pazopanib treatment (214 suggestions) were most frequent], and 236 (82.5%) were accepted by urologists. The median time to discontinuation (6.1 months vs. 2.4 months, p = 0.024) was significantly longer in the after group. Multivariate analysis showed that collaborative management (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.26-0.88, p = 0.017), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at pazopanib initiation (HR 3.87, 95% CI 1.47-9.13, p = 0.008) were significantly associated with pazopanib discontinuation. These results suggested that, compared to conventional management, collaborative management is effective at prolonging the time to pazopanib discontinuation.
Topics: Humans; Carcinoma, Renal Cell; Pharmacists; Urologists; Kidney Neoplasms; Retrospective Studies; Treatment Outcome; Indazoles; Angiogenesis Inhibitors
PubMed: 37532558
DOI: 10.1248/bpb.b22-00917 -
Cost-Effectiveness of the First Line Treatment Options For Metastatic Renal Cell Carcinoma in India.JCO Global Oncology Feb 2023Tyrosine kinase inhibitors such as sunitinib and pazopanib are the mainstay of treatment of metastatic renal cell carcinoma (mRCC) in India. However, pembrolizumab and...
PURPOSE
Tyrosine kinase inhibitors such as sunitinib and pazopanib are the mainstay of treatment of metastatic renal cell carcinoma (mRCC) in India. However, pembrolizumab and nivolumab have shown significant improvement in the median progression-free survival and overall survival among patients with mRCC. In this study, we aimed to determine the cost-effectiveness of the first-line treatment options for the patients with mRCC in India.
METHODS
A Markov state-transition model was used to measure the lifetime costs and health outcomes associated with sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab among patients with first-line mRCC. Incremental cost per quality-adjusted life-year (QALY) gained with a given treatment option was compared against the next best alternative and assessed for cost-effectiveness using a willingness to pay threshold of one-time per capita gross-domestic product of India. The parameter uncertainty was analyzed using the probabilistic sensitivity analysis.
RESULTS
We estimated the total lifetime cost per patient of ₹ 0.27 million ($3,706 US dollars [USD]), ₹ 0.35 million ($4,716 USD), ₹ 9.7 million ($131,858 USD), and ₹ 6.7 million ($90,481 USD) for the sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab arms, respectively. Similarly, the mean QALYs lived per patient were 1.91, 1.86, 2.75, and 1.97, respectively. Sunitinib incurs an average cost of ₹ 143,269 ($1,939 USD) per QALY lived. Therefore, sunitinib at current reimbursement rates (₹ 10,000 per cycle) has a 94.6% probability of being cost-effective at a willingness to pay threshold of 1-time per capita gross-domestic product (₹ 168,300) in the Indian context.
CONCLUSION
Our findings support the current inclusion of sunitinib under India's publicly financed health insurance scheme.
Topics: Humans; Carcinoma, Renal Cell; Sunitinib; Cost-Benefit Analysis; Kidney Neoplasms; Nivolumab; Ipilimumab
PubMed: 36795991
DOI: 10.1200/GO.22.00246 -
Cancer Chemotherapy and Pharmacology Aug 2018This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth...
PURPOSE
This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and β, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma.
EXPERIMENTAL DESIGN
Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted.
RESULTS
The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response.
CONCLUSIONS
The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted.
Topics: Administration, Metronomic; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Indazoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Neoplasm Staging; Paclitaxel; Progression-Free Survival; Pyrimidines; Sulfonamides
PubMed: 29943192
DOI: 10.1007/s00280-018-3624-6 -
Indian Journal of Cancer 2021In metastatic soft tissue sarcoma (M-STS), pazopanib has demonstrated promising activity; however, there is dearth of data from lower and middle income countries. It is...
BACKGROUND
In metastatic soft tissue sarcoma (M-STS), pazopanib has demonstrated promising activity; however, there is dearth of data from lower and middle income countries. It is important to explore the feasibility (toxicity, acceptance), efficacy (response rates, survival), and optimal dose requirement of pazopanib in M-STS in India.
METHODS
All patients who received pazopanib for M-STS in 2013-2018 in Tata Memorial Centre were included. Institutional ethics committee approval was obtained. Assessment for response with contrast computed tomography scans was done as per the response evaluation criteria in solid tumors (RECIST) 1.1 criteria. Pazopanib was continued until progression or unacceptable toxicity. Clinical benefit rates and survival were evaluated by Kaplan-Meier method. All statistical calculations were done using SPSS version 21.0.
RESULTS
Seventy-two consecutive patients with a median follow-up of 17 (4-40) months were included in this study. Median lines of prior therapy were 2 (0-2). Among 50 evaluable patients, there were 12/50 (24%) partial responses, 25/50 (50%) stable disease, and 15/50 (30%) progressive disease. Median progression-free survival was 5 (95% confidence interval (CI) 3-6.9) months and median overall survival was 11 (95% CI 6.8-15.2) months. Adverse effects (G2/G3) in patients: hand foot syndrome-28%, hyperbilirubinemia/transaminitis-10%, diarrhea-20%, hypertension-17%, hypothyroidism-15%, anemia-6%, and fatigue-17%. Notably, 40% patient required dose reduction and median dose was 600 (200-800) mg daily.
CONCLUSION
Pazopanib was found a feasible treatment option for M-STS in India with internationally comparable outcomes. However, significant patients required dose modifications, and median tolerated dose was lower than the standard 800 mg dose. This novel finding merits confirmation in larger cohorts for reproducibility.
Topics: Adult; Aged; Angiogenesis Inhibitors; Female; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Survival Analysis; Young Adult
PubMed: 33753596
DOI: 10.4103/ijc.IJC_314_19 -
Frontiers in Oncology 2020Pediatric patients with relapsed or refractory sarcomas have poor outcome and need novel therapies that provide disease control while maintaining an acceptable quality...
Pediatric patients with relapsed or refractory sarcomas have poor outcome and need novel therapies that provide disease control while maintaining an acceptable quality of life. The safety of vincristine, irinotecan, and pazopanib (VIPaz) association has not yet been published in this population. A chart review was conducted in children and adolescents with relapsed or refractory bone and soft tissue sarcomas who received VIPaz in our institution. One hundred sixty-six patients with a diagnosis of soft or bone sarcoma were admitted to our hospital in the period between March 2015 and August 2018, 30 were relapsed or resistant. Seventeen out of 30 resistant or relapsed patients (median age, 14 years) received 114 VIPaz cycles (median six cycles per patient, range 1-17). Sixteen courses (15%) resulted in gastrointestinal toxicity with Grade two diarrhea; 35 courses (30%) resulted in Grade ≥3 neutropenia. One patient presented Grade two hypothyroidism after nine courses, and another one had Grade two hyperbilirubinemia after 12 courses. Two and five patients required a 25% dose reduction of irinotecan (because of diarrhea) and pazopanib (because of neutropenia four and hyperbilirubinemia 1), respectively. No patient experienced heart failure, hypertension, nor posterior reversible encephalopathy syndrome. Pneumothorax was not reported in any case even in lung metastatic patients. After two and four VIPaz cycles, we observed one complete response (CR), five partial responses (PRs), seven stable diseases (SDs), and four progressive diseases (PDs). With a median follow-up of 15 months (range 3-32), five out of 17 (29%) patients were alive, and four patients were in continuous CR after 12 VIPaz cycles. The VIPaz regimen might be a safe option in children and adolescents with relapsed or refractory sarcomas otherwise unable to be enrolled in other clinical trials; on the other hand, the efficacy of pazopanib observed cannot be sustained from the current study.
PubMed: 32850366
DOI: 10.3389/fonc.2020.01228 -
Medical Hypothesis, Discovery &... 2020Exudative age related macular degeneration (AMD) is related to active choroidal neovascularization (CNV) and formation of disciform scars. Vascular endothelial growth...
Exudative age related macular degeneration (AMD) is related to active choroidal neovascularization (CNV) and formation of disciform scars. Vascular endothelial growth factor (VEGF) mediated choroidal vascular endothelial cell (CVECs) proliferation is characteristic of CNV. Intravitreal injections of bevacizumab, ranibizumab and aflibercept (anti-VEGF monoclonal antibodies) are used to treat exudative AMD. Pazopanib, a tyrosine kinase inhibitor, inhibits neovascularization through blockade of intracellular tyrosine kinase VEGF receptor and platelet-derived growth factor receptor. In this investigation, we evaluated the inhibitory consequences of escalating doses of pazopanib on proliferation of VEGF-enriched CVECs to establish a safe dosage range. VEGF 50 ng/mL) enriched CVECs were treated with escalating doses of pazopanib (10, 50,100 and 250 µM). Cell proliferation rates (WST-1 assay), cell viability (trypan blue exclusion assay), and reactive oxygen species (ROS) levels were measured at 48 hours (h), 72h and 1 week. Intracellular caspase 3 levels and morphological changes were recorded. VEGF enriched CVECs showed a significant decrease in cell proliferation rates after one week of treatment with increasing doses of pazopanib (10, 50,100 and 250 µM) treatment i.e. 87.8%, 43.0%, 38.1% and 9.3% compared to controls (p<0.001). Similarly, trypan blue exclusion assay revealed a decrease in cell viability as 81.8%, 81.0%, 53.4% and 8.7%, respectively (p<0.05). Further, pazopanib actively inhibited proliferation of VEGF-enriched CVECs, with 1.32, 1.92, 1.92 and 4.1-fold increase (p<0.01) in intracellular caspase 3 levels. VEGF-enriched CVECs treated with escalating doses of pazopanib decreased cell viability and increased caspase 3 levels in a time and dose dependent manner.
PubMed: 31976338
DOI: No ID Found -
Journal of Cellular and Molecular... Dec 2022Metastatic disease is the leading cause of death in children suffering from medulloblastoma and a major treatment challenge. The evidence of leptomeningeal dissemination...
Metastatic disease is the leading cause of death in children suffering from medulloblastoma and a major treatment challenge. The evidence of leptomeningeal dissemination defines the most aggressive tumours and is associated with increased mortality; thus, inhibition of migration as a factor involved in the process of metastatic disease is fundamental for the treatment and prevention of metastatic dissemination. Targeting the small Rho GTPases Rac1 has been shown to effectively impair medulloblastoma cell migration in vitro. Yet clinically applicable selective Rac1 inhibitors are still lacking. In view of the pertinent oncogenic role of the PI3K signalling cascade and tyrosine kinase-mediated signalling pathways in medulloblastoma, we explored clinically available targeted therapeutics to this effect. Here, we show that Rac1 is expressed in both the cytoplasm and nucleus in the medulloblastoma cell lines Daoy and MEB-Med-8A representative of two high risk medulloblastoma entities. We demonstrate that activated Rac1 is subject to substantial downmodulation following administration of the clinically available inhibitor of the PI3K pathway Pictilisib (GDC-0941) and the multityrosine kinase inhibitors Pazopanib and Sorafenib. The application of those drugs was associated with reduced mobility of the medulloblastoma cells and alterations of the actin skeleton. Of note, PI3K inhibition reveals the strongest anti-migratory effect in Daoy cells. Thus, our in vitro observations provide new insights into different strategies of blocking Rac1 and inhibiting migration in medulloblastoma employing clinically available agents paving the way for confirmatory studies in in vivo models.
Topics: Humans; Cell Line, Tumor; Cell Movement; Cerebellar Neoplasms; Medulloblastoma; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; rac1 GTP-Binding Protein; Sorafenib
PubMed: 36377725
DOI: 10.1111/jcmm.17604 -
Journal of Immunology (Baltimore, Md. :... Aug 2022Severe acute respiratory syndrome coronavirus 2, responsible for the severe acute respiratory syndrome known as COVID-19, has rapidly spread in almost every country and...
Severe acute respiratory syndrome coronavirus 2, responsible for the severe acute respiratory syndrome known as COVID-19, has rapidly spread in almost every country and devastated the global economy and health care system. Lung injury is an early disease manifestation believed to be a major contributor to short- and long-term pathological consequences of COVID-19, and thus drug discovery aiming to ameliorate lung injury could be a potential strategy to treat COVID-19 patients. By inducing a severe acute respiratory syndrome-like pulmonary disease model through infecting A/J mice with murine hepatitis virus strain 1 (MHV-1), we show that i.v. administration of pazopanib ameliorates acute lung injuries without affecting MHV-1 replication. Pazopanib reduces cell apoptosis in MHV-1-infected lungs. Furthermore, we also identified that pazopanib has to be given no later than 48 h after the virus infection without compromising the therapeutic effect. Our study provides a potential treatment for coronavirus-induced lung injuries and support for further evaluation of pazopanib in COVID-19 patients.
Topics: Animals; Indazoles; Lung; Lung Injury; Mice; Murine hepatitis virus; Pyrimidines; Sulfonamides; COVID-19 Drug Treatment
PubMed: 35914834
DOI: 10.4049/jimmunol.2100968 -
Diseases (Basel, Switzerland) May 2023The term posterior reversible encephalopathy syndrome (PRES) refers to an acute syndrome characterised by a range of neurological symptoms and posterior transient...
The term posterior reversible encephalopathy syndrome (PRES) refers to an acute syndrome characterised by a range of neurological symptoms and posterior transient changes on neuroimaging. Common clinical presentation includes headache, confusion, visual disturbances, seizures, and focal neurological deficit. With the advancement and increasing availability of neuroimaging, this syndrome is increasingly recognised. There are several underlying causes for PRES, including certain medications. Tyrosine kinase inhibitors (TKIs) such as pazopanib can increase the risk of developing PRES by markedly elevating the blood pressure due to its effect of inhibition of vascular endothelial growth factor receptors (VEGFRs). We are reporting a case of a 55-year-old male patient with the clear cell type of renal cell carcinoma (RCC) who developed PRES within a short period after starting pazopanib therapy. With the effective control of his blood pressure and discontinuation of pazopanib, his typical magnetic resonance imaging (MRI) lesion of PRES resolved in the follow-up scan after four weeks.
PubMed: 37366864
DOI: 10.3390/diseases11020076 -
British Journal of Cancer Sep 2018Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated...
BACKGROUND
Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC.
METHODS
mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods.
RESULTS
Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.
CONCLUSIONS
Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.
Topics: Carcinoma, Transitional Cell; DNA Copy Number Variations; Everolimus; Female; High-Throughput Nucleotide Sequencing; Humans; Indazoles; Kidney Neoplasms; Male; Microtubule-Associated Proteins; Mutation; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 3; Sequence Analysis, DNA; Sulfonamides; Survival Analysis; Treatment Outcome; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein
PubMed: 30220708
DOI: 10.1038/s41416-018-0261-0