Cost-effectiveness of immune checkpoint inhibitors in the treatment of non-small-cell lung cancer as a second line in Taiwan.

Objectives: To evaluate the cost-effectiveness of immune checkpoint inhibitors versus docetaxel in patients with advanced non-small-cell lung cancer. Methods: A Markov model was constructed to simulate the clinical outcomes and costs of advanced non-small-cell lung cancer. Clinical outcomes data were derived from randomized clinical trials. Drug acquisition cost and other health resource use were obtained from the claim data of a tertiary hospital and the National Health Insurance. The outcome was an incremental cost-effectiveness ratio expressed as cost per quality-adjusted life year gained. One-way and probabilistic sensitivity analyses were performed to evaluate the uncertainty of the model parameters. Results: In the base case, patients treated with immunotherapies in the second line were associated with higher costs and higher mean survival. The incremental costs per quality-adjusted life year gained for pembrolizumab, nivolumab, or atezolizumab compared to docetaxel were NT$416,102, NT$1,572,912 and NT$1,580,469, respectively. Conclusion: The results showed that pembrolizumab was more cost effective than nivolumab and atezolizumab compared with docetaxel as a second-line regimen for patients with previously treated advanced non-small-cell lung cancer at willingness to pay threshold in Taiwan.

Plain language summary Lung cancer is the first leading cause of cancer death in Taiwan. About 75% of patients have advanced disease at the time of diagnosis (stage III/IV) with a median survival of 13.2 months. Most non-small-cell lung cancer (NSCLC) patients are usually diagnosed at a late stage. The conventional chemotherapy, surgery or radiation regimens may not be of significant benefits. Fortunately, newer immunotherapies or targeted therapies have improved the 5-year survival rates of advanced NSCLC from 15 to 50% with high cost. This study aimed to assess if the newer targeted therapies are cost effective and provide 'value for money' compared with chemotherapy in NSCLC patients with advanced stage. A cost­effectiveness model was created based on the data from the real-world and published phase III randomized controlled trials. The results showed that pembrolizumab is more cost effective than nivolumab and atezolizumab compared with docetaxel as a second-line regimen for patients with previously treated advanced NSCLC at willingness to pay threshold in Taiwan.

Cost-effectiveness and drug wastage of bevacizumab biosimilar with or without chemotherapy for platinum-resistant recurrent ovarian cancer.

INTRODUCTION: The cost-effectiveness of adding bevacizumab biosimilar with or without chemotherapy (CT) and drug wastage in treating platinum-resistant recurrent ovarian cancer (PRrOC) was assessed. METHODS: A three-state partitioned-survival model to compare the clinical and economic outcomes in the treatment of patients with PRrOC from a Taiwan healthcare prospective, extrapolated to two years based on data obtained from the JGOG3023 clinical trial. The primary outcomes of the model were incremental cost-effectiveness ratios (ICERs). RESULTS: In the base-case scenario, using vials of bevacizumab biosimilar (Bevbiol) plus chemotherapy, the ICER was (new Taiwan dollar) NT$ 4,555,878 per QALY gained. The incremental cost savings of an incremental 2.02 QALYs were NT$ 1,605,828 if weight-based Bevbiol plus chemotherapy were used, but the ICER remained high at the willingness-to-pay (WTP) threshold. If the cost of Bevbiol were reduced to 50% per vial, adding it to CT would be cost-effective at an acceptable WTP threshold of NTD 2,994,200, with an ICER of NT$ 2,975,484. CONCLUSIONS: Bevacizumab biosimilars in mg/kg dosage form with chemotherapy are still not cost-effective in Taiwan, but using weight-based dosing will reduce drug waste and save treatment costs.

Comparative Efficacy and safety of new targeted therapies and immunotherapies for metastatic triple negative breast cancer: a network meta-analysis.

BACKGROUND: Several therapies directed at novel targets and also immunotherapies have recently shown promising results in advanced or metastatic TNBC. We aimed to compare the efficacy and safety of these new regimens for advanced or metastatic TNBC (mTNBC). METHODS: The PubMed, Embase, and Cochrane Library electronic databases were searched for phase III randomized trials. We conducted a network meta-analysis to compare the efficacy and safety of new targeted and immunotherapy regimens. Trial quality was assessed using the GRADE method. The comparative outcomes were progression-free survival, overall survival, and G3-4 adverse drug events (ADEs). RESULTS: Thirteen phase III randomized controlled trials were identified in the network meta-analysis. Olaparib significantly improved PFS in comparison with the pembrolizumab plus chemotherapy 1, atezolizumab plus nab-paclitaxel and pembrolizumab regimens. Sacituzumab yielded a significant improvement in OS over immunotherapies, veliparib, and chemotherapy alone, but no significantly superiority over pembrolizumab, olaparib, and talazoparib. The risk of ≥grade 3 ADEs associated with olaparib was significantly lower than the risks associated with the other regimens. CONCLUSION: For mTNBC, sacituzumab had a better effect on overall survival, with comparatively high risk of SAE, whereas olaparib improved progression-free survival with a lower risk of SAE, particularly in those patients with BRCA mutations.

Cost-effectiveness analysis of olaparib and niraparib as maintenance therapy for women with recurrent platinum-sensitive ovarian cancer.

OBJECTIVE: We evaluated the cost-effectiveness of olaparib and niraparib as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer.Methods: A decision analysis model compared the costs and effectiveness of olaparib and niraparib versus placebo for patients with or without germline BRCA mutations. Resource use and associated costs were estimated from the 2020 National Health Insurance Administration reimbursement price list. Clinical effectiveness was measured in progression-free survival per life-years (PFS-LY) based on the results of clinical trials SOLO2/ENHOT-Ov21 and ENGOT-OV16/NOVA. The incremental cost-effectiveness ratio (ICER) was estimated from a single-payer perspective. RESULTS: In the base case, olaparib was the more cost-effective treatment regimen. The ICERs for olaparib and niraparib compared to placebo were NT$1,804,785 and NT$2,340,265 per PFS-LY, respectively. Tornado analysis showed that PFS and the total resource use cost of niraparib regimen for patients without gBRCA were the most sensitive parameters impacting the ICER. The ICERs for both drugs in patients with a gBRCA mutation were lower than in patients without a gBRCA mutation. Probabilistic sensitivity analysis indicated that olaparib was more cost-effective than niraparib at the willingness-to-pay threshold of NT$2,602,404 per PFS life-year gained. CONCLUSION: Olaparib was estimated to be less cost and more effective compared to niraparib as maintenance therapy for patients with recurrent platinum-sensitive ovarian cancer.

Cost-effectiveness of trastuzumab biosimilar combination therapy and drug wastage as first-line treatment for HER2-positive metastatic breast cancer.

BACKGROUND: The rising cost of cancer drug therapy threatens the long-term sustainability of Taiwan National Health Insurance. Cost savings can be achieved through various strategies, e.g., using smaller vial sizes, sharing vials, weight-based dosing, or switching to biosimilars. Here we aimed to examine the cost-effectiveness of a trastuzumab biosimilar combined with docetaxel (TDbiol) for treatment-naïve HER2+ metastatic breast cancer (MBC), and the financial impact of drug wastage. METHODS: A Markov model with three health states was developed to assess the cost-effectiveness of trastuzumab biosimilars plus docetaxel over a 40-month time horizon in patients with HER2+ MBC. Based on the literature and our expert opinion, we assumed similar efficacy between the trastuzumab biosimilar and its reference product. The primary clinical input for the biosimilar was the same as for the reference product in the Catastrophic Patient Database (HV). Health state utilities were derived from the literature, and direct medical costs were obtained from the National Health Insurance Administration (NHIA). RESULTS: In the base-case scenario, the incremental cost-effectiveness ratio (ICER) was NTD 811,050 per QALY gained. One-way sensitivity analyses showed that the model was sensitive to utilities and transition probabilities, but not particularly sensitive to the wastage assumption. In scenario analyses, the ICER was higher when applying the price for trastuzumab reference biologic (branded), than for trastuzumab biosimilar. CONCLUSION: The trastuzumab biosimilar combination regimen is cost-effective and offers significant drug cost savings in Taiwan.

Cost-utility analysis of stereotactic body radiotherapy plus cetuximab in previously irradiated recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: This study aimed to estimate the cost-utility of stereotactic body radiotherapy (SBRT) plus cetuximab for patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. METHODS: We constructed a Markov health-state transition model to simulate costs and clinical outcomes of recurrent squamous cell carcinoma of the head and neck. Model parameters were derived from the published literature and the National Health Insurance Administration reimbursement price list. Incremental cost-effectiveness ratio and the net monetary benefit were calculated from a health payer perspective. The impact of uncertainty was modeled with one-way and probabilistic sensitivity analyses. RESULTS: In the base-case, SBRT plus cetuximab compared to SBRT alone resulted in an ICER of NT$ 840,455 per QALY gained. In the one-way sensitivity analysis, the utility of progression-free state for patients treated with SBRT plus cetuximab or SBRT alone and the cost of progression-free survival for SBRT+Cet were the most sensitive parameters in the model. Probabilistic sensitivity analysis showed that the probability of cost-effectiveness at a willingness-to-pay threshold of NT$ 2,252,340 per QALY was 100% for SBRT plus cetuximab but 0% for SBRT alone. CONCLUSIONS: This study showed that SBRT+Cet was cost-effective and benefited patients with previously irradiated rSCCHN.

Evodiamine stabilizes topoisomerase I-DNA cleavable complex to inhibit topoisomerase I activity.

Evodiamine (EVO), an alkaloidal compound isolated from Evodia rutaecarpa (Juss.), has been reported to affect many physiological functions. Topoisomerase inhibitors have been developed in a variety of clinical applications. In the present study, we report the topoisomerase I (TopI) inhibitory activity of EVO, which may have properties that lead to improved therapeutic benefits. EVO is able to inhibit supercoiled plasmid DNA relaxation catalyzed by TopI. Upon treatment 0-10 microM EVO TopI was depleted in MCF-7 breast cancer cells in a concentration-dependent and time-dependent manner in 0-120 min. A K-SDS precipitation assay was performed to measure the extent of Top I-trapped chromosomal DNA. The ability of EVO to cause the formation of a TopI-DNA complex increased in a concentration-dependent manner, in that the DNA trapped increased by 24.2% in cells treated with 30 microM. The results suggest that EVO inhibits TopI by stabilizing the enzyme and DNA covalent complex.

Network meta-analysis of treatment regimens for inoperable advanced hepatocellular carcinoma with portal vein invasion.

PURPOSE: We assessed the efficacy and safety of different modalities using the network meta-analysis for inoperable hepatocellular carcinoma (HCC) with portal vein invasion. The interested modalities included stereotactic body radiotherapy (SBRT) combined with transarterial chemoembolization (TACE), three-dimensional radiotherapy (3D-RT) combined with hepatic arterial infusion chemotherapy (HAIC) or TACE, TACE plus sorafenib, and use of SBRT, HAIC, sorafenib, and TACE alone. METHODS: PubMed and Cochrane Library electronic databases were systematically searched for eligible studies published up to June 2017. We used network meta-analysis to compare the disease control rate (DCR) and severe adverse events for the eight interested regimens included in this analysis. Study quality was assessed following the Grading of Recommendations, Assessment, Development and Evaluations method. RESULTS: Fifteen studies published between 2010 and 2016 involving a total of 2,359 patients were enrolled in this network meta-analysis. With indirect comparison of DCR and overall safety, the pooled results showed that RT plus HAIC was the most effective regimen in treating advanced HCC with portal vein tumor thrombosis, followed by RT plus TACE. HAIC alone and sorafenib combined with HAIC appeared least effective intervention regimens. The incidence of treatment-related adverse events of grade 3 or 4 occurred less in the patients who received SBRT alone compared with other interested regimens. CONCLUSION: 3D-RT combined with HAIC or TACE showed more favorable treatment responses compared with other regimens in advanced HCC patients with portal vein tumor thrombosis.

Abscopal effect of radiation on bone metastases of breast cancer: A case report.

The abscopal effect is defined as the clearance of distant tumors after applying localized irradiation to a particular tumor site. It has been proposed that a mechanism for the abscopal effect might be the activation of the immune system, which leads to immunogenic tumor cell death. Here, we describe a woman with advanced breast cancer that received modified ablative radiation therapy that targeted her primary breast tumor. She experienced an apparent regression of metastatic mass in the thoracic spine. This case supported the hypothesis that the abscopal effect might be attributable to an activation of the systemic immune response.

Vitamin D3 Intake Dose and Common Cancer: A Population-Based Case Control Study in a Chinese Population.

Objectives: Epidemiological studies suggest that vitamin D status is associated inversely with risk of common cancers in western populations. This study aimed to investigate whether vitamin D is associated with risk of common cancers in Chinese population. Methods: A population-based retrospective case-control study was conducted analyzing data retrieved from the Catastrophic Illness Patient Databases (CIPD) and longitudinal health insurance database (LHID) from January 1, 2010 to December 31, 2011and January 1, 2000 to December 31, 2011, respectively. Cases were identified as subjects diagnosed with site-specific cancers (International Classification of Diseases, Ninth Revision,) and frequency matched to select controls. Use of vitamin D3 was compared between two groups. Odds ratios (ORs) were employed to quantify the risk associated with exposure to vitamin D3 by logistic regression. Results: There were 1.21% (1961/161806) patients in cases and 0.67 % (1092/161806) patients in controls identified were vitamin D3 users. Overall risk of cancers associated with vitamin D3 users was 1.67 (95% CI:1.55 -1.81). Among these, the risk of kidney cancer and bladder cancer associated with intakes of vitamin D3 were significant (OR 2.59; 95% CI 1.81-3.70; OR 4.97; 95% CI 4.40-5.60) in an adjusted model. In further stratification analysis, we found a statistically significant risk of bladder cancer associated with high intake of vitamin D3. Except this, no statistically significant risk of other site-specific cancers associated with high intake of vitamin D3. Conclusion: Except bladder cancer in stratification analysis, we observed no statistically significant association between high intake of vitamin D3 and other site-specific cancers.

Inhibitory effects of quercetin derivatives on phosphodiesterase isozymes and high-affinity [(3) H]-rolipram binding in guinea pig tissues.

Rolipram has high (PDE4(H)) and low (PDE4(L)) affinities for phosphodiesterase (PDE)-4, respectively. In general, it is believed that inhibitions by PDE4(H) and PDE4(L) are respectively associated with an adverse response and with anti-inflammatory and bronchodilating effects. This has provided a rational basis for designing new compounds with high PDE4(H)/PDE4(L) ratios. In the present study, we attempted to determine the PDE4(H)/PDE4(L) ratios of quercetin (1), qercetin-3-O-methylether (3-MQ, 2), quercetin-3,7,4'-O-trimethylether (ayanin, 3), quercetin-3,7,3',4'-O- tetramethylether (QTME, 4), quercetin-3,5,7,3',4'-O-petamethylether (QPME, 5), quercetin-3,5,7,3',4'-O-pentaacetate (QPA, 6), and quercetin-3-O-methyl-5,7,3',4'-O-tetraacetate (QMTA, 7). The activities of PDE1 approximately 5, which were partially separated from homogenates of guinea pig lungs and hearts, were measured by a two-step procedure using adenosine 3',5'-cyclic monophosphate (cAMP) with [(3) H]-cAMP or guanosine 3',5'-cyclic monophosphate (cGMP) with [(3) H]-cGMP as substrates. The IC(50) values of all of these compounds except quercetin (1), 3-MQ (2), and QMTA (7) on PDE1 approximately 5 inhibition were determined. The anti-inflammatory effects of PDE4 inhibitors were reported to be associated with inhibition of PDE4 catalytic activity. Therefore, these IC(50) values for PDE4 inhibition were taken as the PDE4(L) values. The effective concentration (EC(50)), at which one half of the [(3) H]-rolipram bound to high-affinity rolipram binding sites (HARBSs) of brain cell membranes was replaced, was defined as the PDE4(H) value. In the present results, the PDE4(H)/PDE4(L) ratios of quercetin (1), ayanin (3), and QPME (5) were >30, >19, and 11, respectively (Table 1), which are higher than or equal to that of AWD12-281, the selective PDE4 inhibitor with the greatest potential currently undergoing clinical trials for treating asthma and chronic obstructive pulmonary disease.