Identifying optimal ALK inhibitors in first- and second-line treatment of patients with advanced ALK-positive non-small-cell lung cancer: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy, safety and effects on quality of life of different ALK-inhibitors for global and Asian patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). METHODS: The included RCTs were identified through a systematic search of PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and major cancer conferences. The assessment of progression-free survival (PFS), intracranial PFS, overall survival (OS), and patient-reported outcomes (PROs) was carried out using restricted mean survival time (RMST) model, fractional polynomial model and Royston-Parmar model. Time-invariant hazard ratio (HR) models were also used to validate and supplement the primary analysis. Objective response rate (ORR) and adverse events with any grade, grade 3-5 were assessed through a Bayesian network meta-analysis. The primary measures for OS, PFS, and PROs were HR and RMST. The odds ratio was the metric for evaluating safety, ORR, 12-month PFS rate, 24-month OS rate, and the 12-month non-deterioration rate of PROs. Subgroup analyses based on patient characteristics were performed. RESULTS: A total of fourteen studies (ten for first-line, four for second-line) consisting of nine treatments (chemotherapy, crizotinib, alectinib [600mg BID], low-dose alectinib [300mg BID], brigatinib, ceritinib, ensartinib, envonalkib, and lorlatinib) were included. In the first-line setting, alectinib showed a significant advantage over crizotinib and had the longest OS among all ALK-inhibitors. Compared to crizotinib, lorlatinib had the best efficacy regarding PFS for global patients, followed closely by alectinib and brigatinib. For Asian patients, alectinib significantly improved PFS compared to other treatments. In second-line, alectinib had the highest PFS for patients pretreated with crizotinib, followed by brigatinib, ceritinib and chemotherapy. Alectinib, irrespective of the dose, was the safest first-line option, whereas lorlatinib, brigatinib, and ceritinib showed poorer safety profiles. Alectinib was also the safest ALK-inhibitor for crizotinib-resistant patients. Brigatinib had the best performance in terms of PROs. CONCLUSIONS: Considering both efficacy and safety, alectinib appears to be the preferable treatment in first-line and second-line, particularly for Asian patients.

Impacts of systemic treatments on health-related quality of life for patients with metastatic colorectal cancer: a systematic review and network meta-analysis.

OBJECTIVE: There is limited evidence of comparative results among different treatments regarding impacts of Health-Related Quality of Life (HRQoL) for patients with metastatic colorectal cancer (mCRC). We aimed to compare efficacy of systemic treatments on HRQoL among patients with mCRC. METHODS: We collected randomized controlled trials (RCTs) reported in English up until July 2023, from databases including PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and prominent conference databases, for this Bayesian network meta-analysis. Phase 2 or 3 trials that evaluated at least two therapeutic regimens were included. Primary outcomes were short-term and long-term mean changes in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) scores. Secondary outcome was mean change in EQ-5D health utility scores. Mean differences (MDs) with 95% confidence intervals (CIs) were used as effect size. Subgroup analysis was performed based on whether patients received systemic treatments before. We conducted various sensitivity analyses, including differentiating between chemotherapy types, and analyzed patient cohorts with non-specified gene expression levels as well as those with target KRAS expression statuses. The current systematic review protocol was registered on PROSPERO (CRD42023453315 and CRD42023420498). RESULTS: Immunotherapy and targeted therapy significantly improved HRQoL over chemotherapy, with MDs of 9.27 (95% CI: 3.96 to 14.6) and 4.04 (95% CI: 0.11 to 7.94), respectively. Monotherapy significantly outperformed both combination therapy (MD 5.71, 95%CI 0.78 to 10.63) and no active treatment (MD 3.7, 95%CI 1.41 to 6.01) regarding GHS/QoL in the short-term. Combining targeted therapy with chemotherapy did not improve HRQoL. Focusing on HRQoL, cetuximab excelled when gene expression baselines were unspecified. Subgroup and sensitivity analyses upheld these robust findings, unaffected by model or patient baseline characteristics. Evidence from clinical trials without specific gene level data suggested that monotherapies, especially targeted therapies such as cetuximab, demonstrated superiority in HRQoL. For KRAS wild-type patients, no significant HRQoL differences emerged between chemotherapy, targeted therapy, or their combination.. CONCLUSIONS: Targeted therapies and immunotherapy demonstrate superior HRQoL benefits, monotherapy such as cetuximab is associated with significant improvements as compared to combination therapy. However, tailoring these results to individual gene expression profiles requires more evidence.

A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer.

BACKGROUND: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 -) advanced breast cancer is a prevalent subtype among postmenopausal women. Despite the growing number of randomized clinical trials (RCTs) exploring this topic, the efficacy and safety of first-line and second/further-line treatments remain uncertain. Accordingly, our aim was to conduct a comprehensive evaluation of the efficacy and safety of these therapies through network meta-analysis. METHODS: RCTs were identified by searching Pubmed, Embase, and major cancer conferences. The efficacy of interventions was assessed using the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), while safety was indicated by the incidence of any grade adverse events (AEs), grade 3-5 AEs, AEs leading to treatment discontinuation, and AEs leading to death. Both time-variant HRs fractional polynomial models and time-invariant HRs Cox-proportional hazards models were considered for handling time-to-event data. Safety indicators were analyzed using Bayesian network meta-analysis. Additionally, subgroup analyses were conducted based on patient characteristics. RESULTS: A total of 41 RCTs (first-line 17, second/further-lines 27) were included in the analysis. For first-line treatment, the addition of Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy significantly improved therapeutic efficacy in terms of both PFS and OS, demonstrating the best performance across all mechanisms. Specifically, the combination of Abemaciclib and Letrozole demonstrated the most favorable performance in terms of PFS, while Ribociclib plus Fulvestrant yielded the best outcomes in OS. Incorporating the immune checkpoint inhibitor Avelumab into the regimen with CDK4/6 inhibitors and selective estrogen receptor degraders significantly enhanced both PFS and OS in second-line or later treatments. Regarding safety, endocrine monotherapy performed well. Regarding safety, endocrine monotherapy performed well. There is mounting evidence suggesting that most CDK4/6 inhibitors may demonstrate poorer performance with respect to hematologic AEs. However, additional evidence is required to further substantiate these findings. CONCLUSIONS: CDK4/6 inhibitors, combined with endocrine therapy, are pivotal in first-line treatment due to their superior efficacy and manageable AEs. For second/further-line treatment, adding immune checkpoint inhibitors to CDK4/6 inhibitors plus endocrine therapy may produce promising results. However, to reduce the results' uncertainty, further trials comparing these novel treatments are warranted. TRIAL REGISTRATION: Registration number: PROSPERO (CRD42022377431).

QALY-type preference and willingness-to-pay among end-of-life patients with cancer treatments: a pilot study using discrete choice experiment.

PURPOSE: Quality-adjusted life-year (QALY) is a dominant measurement of health gain in economic evaluations for pricing drugs. However, end-of-life (EoL) patients' preference for QALY gains in life expectancy (LE) and quality of life (QoL) during different disease stages remains unknown and is seldom involved in decision-making. This study aims to measure preferences and willingness-to-pay (WTP) towards different types of QALY gain among EoL cancer patients. METHODS: We attributed QALY gain to four types, gain in LE and QoL, respectively, and during both progression-free survival (PFS) and post-progression survival (PPS). A discrete choice experiment including five attributes (the four QALY attributes and one cost attribute) with three levels each was developed and conducted with 85 Chinese advanced non-small cell lung cancer patients in 2022. All levels were set with QALY gain/cost synthesised from research on anti-lung cancer drugs recently listed by Chinese National Healthcare Security Administration. Each respondent answered six choice tasks in a face-to-face interview. The data were analysed using mixed logit models. RESULTS: Patients valued LE-related QALY gain in PFS most, with a relative importance of 81.8% and a WTP of $43,160 [95% CI 26,751 ~ 59,569] per QALY gain. Respondents consistently preferred LE-related to QoL-related QALY gain regardless of disease stage. Patients with higher income or lower education levels tended to pay more for QoL-related QALY gain. CONCLUSION: Our findings suggest a prioritised resource allocation to EoL-prolonging health technologies. Given the small sample size and large individual heterogeneity, a full-scale study is needed to provide more robust results.

Sotorasib versus Docetaxel for treatment of US and Chinese patients with advanced non-small-cell lung cancer with KRAS p.G12C-mutated: A cost-effectiveness analysis to inform drug pricing.

BACKGROUND: The cost-effectiveness of sotorasib and its reasonable price in the United States (US) and China remain unknown. Our objective was to estimate the price at which sotorasib could be economical as second-line treatment for advanced non-small-cell lung cancer patients with Kirsten rat sarcoma viral oncogene homolog p.G12C-mutation in 2 countries. METHODS: We conducted an economic evaluation from the perspective of US and Chinese payers. To analyze US patients, we built a partitioned survival model. However, since we lacked Asian-specific overall survival data, we created a state transition model for the Chinese patients. We obtained patients' baseline characteristics and clinical data from CodeBreaK200, while utilities and costs were gathered from public databases and published literature. We calculated costs (US dollar), life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. We conducted price simulation to guide pricing strategies. Additionally, we assessed the reliability of our results through sensitivity analyses, scenario analyses, and subgroup analyses. RESULTS: The incremental cost-effectiveness ratios of sotorasib compared to docetaxel were $1501,852 per quality-adjusted life-years (QALY) in the US and $469,106/QALY in China, respectively, which meant sotorasib was unlikely to be economical at the currently available price of $20,878 (240 × 120 mg) in both countries. Price simulation results revealed that sotorasib would be preferred at a price lower than $1400 at the willingness-to-pay threshold of $37,376 in China and a price lower than $2220 at the willingness-to-pay threshold of $150,000 in the US. Sensitivity, scenario, and subgroup analyses showed that these conclusions were generally robust, the model was most sensitive to the utilities of progression-free survival and post-progression survival. CONCLUSIONS: Sotorasib could potentially be a cost-effective therapy in the US and China following price reductions. Our evidence-based pricing strategy can assist decision-makers and clinicians in making optimal decisions. However, further analysis of budget impact and affordability is needed.

Estimating the cost-effectiveness threshold of advanced non-small cell lung cancer in China using mean opportunity cost and contingent valuation method.

OBJECTIVES: Monetizing health has sparked controversy and has implications for pricing strategies of emerging health technologies. Medical insurance payers typically set up thresholds for quality-adjusted life years (QALY) gains based on health productivity and budget affordability, but they rarely consider patient willingness-to-pay (WTP). Our study aims to compare Chinese payer threshold and patient WTP toward QALY gain of advanced non-small cell lung cancer (NSCLC) and to inform a potential inclusion of patient WTP under more complex decision-making scenarios. METHODS: A regression model was constructed with cost as the independent variable and QALY as the dependent variable, where the regression coefficients reflect mean opportunity cost, and by transforming these coefficients, the payer threshold can be obtained. Patient WTP was elicited through a contingent valuation method survey. The robustness of the findings was examined through sensitivity analyses of model parameters and patient heterogeneity. RESULTS: The payer mean threshold in the base-case was estimated at 150,962 yuan (1.86 times per capita GDP, 95% CI 144,041-159,204). The two scenarios analysis generated by different utility inputs yielded thresholds of 112,324 yuan (1.39 times per capita GDP) and 111,824 yuan (1.38 times per capita GDP), respectively. The survey included 85 patients, with a mean WTP of 148,443 yuan (1.83 times per capita GDP, 95% CI 120,994-175,893) and median value was 106,667 yuan (1.32 times the GDP per capita). Due to the substantial degree of dispersion, the median was more representative. The payer threshold was found to have a high probability (98.5%) of falling within the range of 1-2 times per capita GDP, while the robustness of patient WTP was relatively weak. CONCLUSIONS: In China, a country with a copayment system, payer threshold was higher than patient WTP, indicating that medical insurance holds significant decision-making authority, thus temporarily negating the need to consider patient WTP.

Cost-effectiveness analysis of atezolizumab in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen: a United Kingdom health care perspective.

Background: Cost-effectiveness of atezolizumab, as a treatment for advanced non-small-cell lung cancer (NSCLC) patients who cannot receive a platinum-containing regimen,was still unknown. Our objective was to evaluate the cost-effectiveness of atezolizumab vs. chemotherapy in this indication from the perspective of UK healthcare system. Methods: From the global, randomised, open-label, phase III IPSOS trial, clinical inputs and patient characteristics were obtained. A partitioned survival model with three health states was built: Progression-free survival, progressed disease and death. A lifetime time horizon was applied, with an annual discount rate of 3.5%. Additionally, the willingness-to-pay threshold of £50,000/QALY was utilized. Primary outcomes were quality-adjusted life-year (QALY), costs, and incremental cost-effectiveness ratio (ICER). Sensitivity, scenario, and subgroup analyses were used to assess the reliability of base-case results. Price simulations were carried out in order to provide information for the pricing strategy at specific willingness-to-pay threshold. Results: In the base-case analysis, atezolizumab resulted in a gain of 0.28 QALYs and an ICER of £94,873/QALY compared to chemotherapy, demonstrating no cost-effectiveness. Price simulation results revealed that atezolizumab would be preferred at a price lower than £2,215 (a reduction of 41.8%) at the willingness-to-pay threshold of £50,000. Sensitivity, scenario and subgroup analyses revealed these conclusions were generally robust, the model was most sensitive to the price of atezolizumab and subsequent medication. Furthermore, atezolizumab was found to be more cost-effective for patients displaying a positive PD-L1 expression, with an ICER of £72,098/QALY as compared to chemotherapy. Conclusion: Atezolizumab is not cost-effective for patients with advanced NSCLC ineligible for platinum-containing regimen, potential price reduction is necessary.

Cost-effectiveness and potential budget impact of non-pharmacological interventions for early management in prehypertensive people: an economic evaluation for China.

BACKGROUND: Non-pharmacological interventions (NPIs) could be considered in the early management of prehypertensive population. This study aimed to evaluate the potential cost-effectiveness of NPIs and the budget impact of implementing NPIs on prehypertensive population in China and provide evidence of chronic disease management innovation for decision-makers. METHODS: Five NPIs including usual care, lifestyle, strengthen exercise, relaxation, and diet therapy were selected based on the practice of hypertension management in China. A nine-state Markov model was constructed to evaluate the lifetime costs and health outcomes of five NPIs and a non-intervention group from the perspective of Chinese healthcare system. The effectiveness of NPIs was obtained from a published study. Parameters including transition probabilities, costs and utilities were extracted or calculated from published literature and open-access databases. Sensitivity analyses were conducted to test the uncertainty of all parameters. The impact of duration of intervention was considered in scenario analyses. A budget impact analysis (BIA) was conducted to evaluate the total cost and the medical cost saving of a hypothetical nationwide implementation of potential cost-effective NPI in prehypertensive people. Management strategies including focusing on patients with specific ages or different CVE risk levels, and different duration of implementation were taken into consideration. RESULTS: Strengthen exercise was the most cost-effective intervention with a probability of 78.1% under the given WTP threshold. Our results were sensitive to the cost of interventions, and the utility of prehypertension and hypertension. The duration of implementation had limited impact on the results. BIA results showed that the program cost was hefty and far more than the medical cost saving with the course of simulation time. Applying management strategies which focused on individual characteristics could largely reduce the program cost despite it remained higher than medical cost saving. CONCLUSIONS: Strengthen exercise was a potential NPI that can be considered in priority for early management in prehypertensive population. Although early management can acquire medical cost saving, the related program cost can be quite hefty. Precise strategies which may help reduce the cost of early management should be taken into consideration in program design.

Economic evaluation of five first-line PD-(L)1 inhibitors for treating non-squamous non-small cell lung cancer in China: A cost-effectiveness analysis based on network meta-analysis.

Background and objective: Non-small cell lung cancer (NSCLC) is one of the most malignant cancer types that causes substantial economic burden in China. This study aimed to evaluate the cost-effectiveness of five first-line anti-PD-(L)1 treatments, including sintilimab, camrelizumab, atezolizumab, pembrolizumab and sugemalimab with each combined with chemotherapy, for treating advanced non-squamous NSCLC (nsq-NSCLC) from Chinese healthcare system perspective. Methods: Clinical data were obtained from the following clinical trials, namely, ORIENT-11, CameL, IMpower132, KEYNOTE-189 and GEMSTONE-302. A network meta-analysis was performed based on fractional polynomial models. We constructed a partitioned survival model with a three-week cycle length and a lifetime horizon to derive the incremental cost-effectiveness ratio (ICER). We performed one-way sensitivity analysis and probablistic sensitivity analysis to test the robustness. Additionally, two scenario analyses were undertaken to investigate the impact of Patient Assistant Program on the economic conclusion and to explore potential uncertainty associated with population representativeness of the global trial. Results: Compared with camrelizumab + chemotherapy, sugemalimab + chemotherapy and atezolizumab + chemotherapy were dominated, and the ICERs generated from sintilimab + chemotherapy and pembrolizumab + chemotherapy were $15,280.83/QALY and $159,784.76/QALY, respectively. Deterministic sensitivity analysis showed that uncertainty around ICERs was mainly driven by HR related parameters derived from NMA and drug price. The probablistic sensitivity analysis suggested that camrelizumab treatment was cost-effective at a willingness-to-pay threshold of 1-time GDP per capita. When the threshold was set as 3-time GDP per capita, sintilimab strategy demonstrated the excellent cost-effective advantage. Sensitivity analysis proved the reliability of base-case results. Results from two scenario analyses indicated that the primary finding was robust. Conclusion: In current context of Chinese healthcare system, sintilimab + chemotherapy appeared to be cost-effective for the treatment of nsq-NSCLC compared with sugemalimab, camrelizumab, pembrolizumab as well as atezolizumab combined with chemotherapy.

Effectiveness and cost-effectiveness analysis of 11 treatment paths, seven first-line and three second-line treatments for Chinese patients with advanced wild-type squamous non-small cell lung cancer: A sequential model.

Background: A total of 11 treatment sequences for advanced wild-type squamous non-small cell lung cancer are recommended by Chinese Society of Clinical Oncology Guidelines, consisting of seven first-line and three second-line treatments. Five of these treatments were newly approved in China between 2021 and 2022. We evaluated the effectiveness and cost-effectiveness of these strategies from the Chinese healthcare system perspective. Methods: Network meta-analysis with non-proportional hazards was used to calculate the relative efficacy between interventions. A sequential model was developed to estimate costs and quality-adjusted life years (QALY) for treatment sequences with first-line platinum- and paclitaxel-based chemotherapy (SC) with or without nedaplatin, tislelizumab, camrelizumab, sintilimab, sugemalimab or pembrolizumab, followed by second-line docetaxel, tislelizumab or nivolumab. SC and docetaxel were used as comparators for first-line and second-line treatments, respectively. QALY and incremental cost-effectiveness ratio (ICER) were used to evaluate effectiveness and cost-effectiveness, respectively. Cost-effective threshold was set as USD 19,091. Subgroup analysis was conducted to determine the best first-line and second-line therapy. Results: Pembrolizumab + SC, followed by docetaxel (PED) was the most effective treatment sequence. QALYs for patients received SC, nedaplatin + SC, tislelizumab + SC, sintilimab + SC, camrelizumab + SC, sugemalimab + SC, pembrolizumab + SC followed by docetaxel were 0.866, 0.906, 1.179, 1.266, 1.179, 1.266, 1.603, 1.721, 1.807; QALYs for SC, nedaplatin + SC followed by tislelizumab were 1.283, 1.301; QALYs for SC, nedaplatin + SC followed by nivolumab were 1.353, 1.389. Camrelizumab + SC, followed by docetaxel (CAD) was the most cost-effective. Compared to SC with or without nedaplatin, tislelizumab, or sintilimab followed by docetaxel, ICERs of CAD were USD 12,276, 13,210, 6,974, 9,421/QALY, respectively. Compared with nedaplatin or SC followed by tislelizumab, the ICERs of CAD were USD 4,183, 2,804/QALY; CAD was dominant compared with nedaplatin or SC followed by nivolumab; The ICER of sugemalimab + SC followed by docetaxel and PED were USD 522,023, 481,639/QALY compared with CAD. Pembrolizumab + SC and camrelizumab + SC were the most effective and cost-effective first-line options, respectively; tislelizumab was the most effective and cost-effective second-line therapy. Tislelizumab used in second-line was more effective than first-line, no significant differences between their cost-effectiveness. Sensitivity and scenario analysis confirmed robustness of the results. Conclusions: PED and CAD are the most effective and cost-effective treatment sequence, respectively; pembrolizumab + SC and camrelizumab + SC are the most effective and cost-effective first-line choice, respectively; tislelizumab is the most effective and cost-effective second-line choice.

Hypoxemia in thoracoscopic lung resection surgery using a video double-lumen tube versus a conventional double-lumen tube: A propensity score-matched analysis.

Background: Malposition of the double-lumen tubes (DLTs) may lead to hypoxemia during one-lung ventilation (OLV). Video double-lumen tubes (VDLTs) enable continuous observation of DLT position and avoid displacement. We aimed to investigate whether VDLTs could reduce the incidence of hypoxemia during OLV compared with conventional double-lumen tubes (cDLT) in thoracoscopic lung resection surgery. Methods: This was a retrospective cohort study. Adult patients who underwent elective thoracoscopic lung resection surgery and required VDLTs or cDLTs for OLV at Shanghai Chest Hospital from January 2019 to May 2021 were included. The primary outcome was the incidence of hypoxemia during OLV between VDLT and cDLT. Secondary outcomes included bronchoscopy use, the degree of PaO2 decline, and arterial blood gas indices. Results: A total of 1,780 patients were finally analyzed in propensity score-matched cohorts (VDLT vs. cDLT 1:1 n = 890). The incidence of hypoxemia decreased from 6.5% (58/890) in cDLT group to 3.6% (32/890) in VDLT group (Relative Risk [RR]: 1.812, 95% CI: 1.19-2.76, p = 0.005). The use of bronchoscopy was reduced by 90% in VDLT group (VDLT 10.0% (89/890) vs. cDLT 100% (890/890), p < 0.001). PaO2 after OLV was 221 [136.0-325.0] mmHg in cDLT group compared to 234 [159.7-336.2] mmHg in VDLT group, p = 0.003. The percentage of PaO2 decline was 41.4 [15.4-61.9] % in cDLT group, while it was 37.7 [8.7-55.9] % in the VDLT group, p < 0.001. In patients who suffered from hypoxemia, there were no significant differences in arterial blood gas indices or the percentage of PaO2 decline. Conclusion: VDLTs reduce the incidence of hypoxemia and the use of bronchoscopy during OLV compared with cDLTs. VDLT may be a feasible option for thoracoscopic surgery.

Impact of Extrapolation Model Choices on the Structural Uncertainty in Economic Evaluations for Cancer Immunotherapy: A Case Study of Checkmate 067.

OBJECTIVES: The aim of this study was to compare the performance of different extrapolation modeling techniques and analyze their impact on structural uncertainties in the economic evaluations of cancer immunotherapy. METHODS: The individual patient data was reconstructed through published Checkmate 067 Kaplan Meier curves. Standard parametric models and six flexible techniques were tested, including fractional polynomial, restricted cubic splines, Royston-Parmar models, generalized additive models, parametric mixture models, and mixture cure models. Mean square errors (MSE) and bias from raw survival plots were used to test the model fitness and extrapolation performance. Variability of estimated incremental cost-effectiveness ratios (ICERs) from different models was used to inform the structural uncertainty in economic evaluations. All indicators were analyzed and compared under cut-offs of 3 years and 6.5 years, respectively, to further discuss model impact under different data maturity. R Codes for reproducing this study can be found on GitHub. RESULTS: The flexible techniques in general performed better than standard parametric models with smaller MSE irrespective of the data maturity. Survival outcomes projected by long-term extrapolation using immature data differed from those with mature data. Although a best-performing model was not found because several models had very similar MSE in this case, the variability of modeled ICERs significantly increased when prolonging simulation cycles. CONCLUSIONS: Flexible techniques show better performance in the case of Checkmate 067, regardless of data maturity. Model choices affect ICERs of cancer immunotherapy, especially when dealing with immature survival data. When researchers lack evidence to identify the 'right' model, we recommend identifying and revealing the model impacts on structural uncertainty.

Serplulimab Plus Chemotherapy vs Chemotherapy for Treatment of US and Chinese Patients with Extensive-Stage Small-Cell Lung Cancer: A Cost-Effectiveness Analysis to Inform Drug Pricing.

BACKGROUND: Serplulimab is a potential valuable therapy, while patients, physicians, and decision-makers are uncertain about the cost-effectiveness of this novel drug and its corresponding reasonable price. This study aimed to simulate the price at which serplulimab was cost-effective as first-line therapy for United States (US) and Chinese extensive-stage small-cell lung cancer (ES-SCLC) patients. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of US and Chinese payers. Baseline characteristics of patients and critical clinical data were obtained from ASTRUM-005. Costs and utilities were collected from open-access databases and published literature. Cumulative costs (in US dollars), life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were measured and compared. Price simulation was conducted to inform the pricing strategy at the given willingness-to-pay (WTP) threshold. The robustness of the model was assessed via sensitivity analyses and scenario analyses; subgroup analyses were also included. RESULTS: Base-case analysis indicated that serplulimab ($818.16/100 mg) would be cost-effective in the US at the WTP threshold of $150,000, with improved effectiveness of 0.61 QALYs and an additional cost of $64,918 (ICER $106,757). Serplulimab ($818.16/100 mg, patient assistance program considered) was cost-effective in China, with improved effectiveness of 0.58 QALYs and an increased overall cost of $19,369 (ICER $33,392). The price simulation results indicated that serplulimab was favored in the US when the price was less than $762.11/100 mg and $1261.57/100 mg at the WTP threshold of $100,000 and $150,000, respectively; it was cost-effective at the WTP threshold of $38,184 when the price was less than $373.37/100 mg in China. Sensitivity analyses revealed that the above results were stable. Subgroup analysis results indicated an overall trend for subgroups with better survival advantages to have a higher probability of cost-effectiveness, despite serplulimab not being cost-effective in some subgroups. CONCLUSIONS: Serplulimab might be a valuable and cost-effective therapy in both the US and China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about the budget impact and affordability for patients is needed.

Cost-effectiveness analysis of sintilimab vs. placebo in combination with chemotherapy as first-line therapy for local advanced or metastatic oesophageal squamous cell carcinoma.

Objective: Results of Orient 15 indicated the health benefits to patients with local advanced or metastatic oesophageal squamous cell carcinoma (OSCC). This study aimed to evaluate the cost-effectiveness of sintilimab plus chemotherapy in treating OSCC from the perspective of Chinese healthcare system. Methods: A partitioned survival model was constructed to evaluate the cost-effectiveness of sintilimab plus chemotherapy vs. chemotherapy in treating OSCC. Baseline characteristics of patients and key clinical data were extracted from Orient 15. Costs and utilities were collected from published studies and open-access databases. Costs, quality-adjusted life-years (QALYs), life-years gained, and incremental cost-effectiveness ratios (ICER) were chosen as economic outcome indicators. We also performed sensitivity analyses and subgroup analyses to verify the stability of results. Results: Combination therapy provided additional 0.84 QALYs and 1.46 life-years with an incremental cost of $25,565.48 than chemotherapy, which had an ICER of $30,409.44 per QALY. The probabilistic sensitivity analysis indicated that combination therapy had a 98.8% probability of cost-effectiveness at the willingness-to-pay threshold (WTP) of $38,184 per QALY. Deterministic sensitivity analysis showed that model outcomes were sensitive to the utilities of progression-free survival and progression disease. The subgroup analysis revealed that combination therapy was cost-effective in patients with high expression of PD-L1 and several specific subgroups. Conclusion: In this economic evaluation, sintilimab plus chemotherapy was likely to be cost-effective compared with chemotherapy in the first-line therapy of advanced OSCC from the perspective of Chinese healthcare system. Our findings may provide evidence for clinicians to make optimal decisions in clinical practice and for decision-makers to evaluate the cost-effectiveness of sintilimab.

Role of EGFR expressed on the granulosa cells in the pathogenesis of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrinological disorders affecting between 6 to 20% of reproductive aged women. However, the etiology of PCOS is still unclear. Epidermal growth factor receptor (EGFR) plays a critical role in the growth and development of ovarian follicles. In our previous study, we showed that the expression level of EGFR was significantly higher in the cumulus granulosa cells from women with PCOS than that of normal women, suggesting that EGFR may play a potential role in the pathogenesis of PCOS. The present study further evaluated the association between EGFR and PCOS through both in clinical observation and animal experiments. We firstly validated the differential expression of EGFR in cumulus granulosa cells between PCOS patients and normal subjects by qRT-PCR and immunofluorescence staining. Then we generated a mouse model (n=20) of PCOS by injecting dehydroepiandrosterone (DHEA). The PCOS mice were then injected with an E corpus GFR inhibitor (AG1478) (n=10), which significantly improved the sex hormone levels in the estrous cycle stage, and the serum levels of LH, FSH and testosterone were compared with the PCOS mice without EGFR inhibitor treatment (n=10). Decreasing the expression level of EGFR in the PCOS mice also improved the ovulatory function of their ovaries which was indicated by the multifarious follicle stage in these mice as compared with the PCOS mice without EGFR inhibitor treatment. Also, the number of corpopa lutea were higher in the control group and the EGFR inhibitor treated group than in the PCOS group. The sex hormone levels and reproductive function were not significantly different between the control mice and the PCOS mice treated with the EGFR inhibitor. Our results demonstrated that EGF/EGFR signaling affected the proliferation of cumulus granulosa cells, oocyte maturation and meiosis, and played a potential role in the pathogenesis of PCOS. Therefore, the selective inhibition of EGFR may serve as a novel strategy for the clinical management of PCOS.

A systematic review and network meta-analysis of first-line immune checkpoint inhibitor combination therapies in patients with advanced non-squamous non-small cell lung cancer.

Introduction: Clinical evidence suggests that first-line immune checkpoint inhibitor (ICI) combination therapies can improve survival in patients with advanced non-squamous non-small cell lung cancer (nsq-NSCLC). However, the optimal strategy remains unknown without a systematic comparison of their long-term effects. Methods: We performed a systematic review and network meta-analysis by retrieving up-to-date literature from PubMed® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, Netherlands), MEDLINE® (National Library of Medicine), ClinicalTrials.gov (National Library of Medicine), and major international conference publications. Published studies and abstracts comparing first-line ICI combination therapies with other treatments for patients with advanced nsq-NSCLC were included. Restricted mean survival time (RMST) was measured over 12 months for progression-free survival (PFS) and 18 months for overall survival (OS), and the Royston-Parmar model was used to extrapolate and compare data for the long-term outcomes. Results: We included a total of 11 trials involving 12 therapies and 6,130 patients. Pembrolizumab plus chemotherapy exhibited the best overall survival (OS) benefit at both 18 and 60 months [RMST = 2.95, 95% confidence interval (CI) 1.96 to 3.97; life-years gained over a 5-year period = 2.18 years]. Nivolumab plus bevacizumab plus chemotherapy was found to present the best progression-free survival (PFS) benefit at 12 months (RMST 3.02, 95% CI 2.11 to 3.91), whereas atezolizumab plus bevacizumab plus chemotherapy showed the best PFS benefit at 36 months (life-years gained over 3 years = 1.22 years). Subgroup analyses showed that among patients with programmed death-ligand 1 (PD-L1) expression ≥ 50%, atezolizumab plus chemotherapy and nivolumab plus ipilimumab resulted in superior OS benefits at 18 and 60 months, respectively. Among patients with PD-L1 expression< 1%, pembrolizumab plus chemotherapy was associated with OS benefits at both 18 and 60 months. Sintilimab plus chemotherapy was associated with relatively fewer grade ≥ 3 adverse events than other ICI combination therapies. Conclusion: Our results show that ICI combination therapies showed better survival benefits than chemotherapy. Pembrolizumab plus chemotherapy could provide the best OS benefits to patients with advanced nsq-NSCLC, whereas atezolizumab plus bevacizumab plus chemotherapy could bring the best PFS benefits. The optimal ICI combination therapy varies depending on PD-L1 expression level. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=325005, identifier CRD42022325005.

Identifying optimal PD-1/PD-L1 inhibitors in first-line treatment of patients with advanced squamous non-small cell lung cancer in China: Updated systematic review and network meta-analysis.

Objective: After Gemstone-302 was published in Lancet in January 2022, seven PD-(L)1 inhibitors launched or about to be launched in China, but there are no head-to-head RCTs reporting the comparative efficacy for squamous non-small cell lung cancer (sq-NSCLC). Therefore, we aimed to indirectly compare the efficacy of these treatments to provide evidence for clinical decision and Chinese national reimbursement drug listing. Methods: We collected phase III clinical trials targeted on stage IIIB-IV patients for first-line immunotherapy of sq-NSCLC by systematically searching databases. Relative effects of competing treatments were assessed by Bayesian network meta-analysis and non-parametric restricted mean survival time (RMST) model. Hazard ratio (HR), severe adverse events (SAEs, grade 3-5), progression-free survival (PFS) and overall survival (OS) years were the outcomes. Subgroup analysis was done according to PD-(L)1 expression, smoking, gender, Eastern Cooperative Oncology Group performance status, age and disease stage. Sensitivity analysis using the range of parameters distribution as well as different comparison methods was performed to test the robustness of the results. Results: A total of 7 clinical trials with 2,640 patients were included. For OS, the efficiency (HR, 95%CI) ranks from high to low were sugemalimab (0.48, 0.32-0.73), camrelizumab (0.55, 0.40-0.76), sintilimab (0.56, 0.35-0.90), pembrolizumab (0.71, 0.58-0.87) and atezolizumab (0.88, 0.73-1.05). For PFS, the efficiency ranks from high to low were sugemalimab (0.33, 0.24-0.45), camrelizumab (0.37, 0.30-0.46), tislelizumab (0.53, 0.36-0.79), sintilimab (0.54, 0.42-0.69), toripalimab (0.56, 0.38-0.83), pembrolizumab (0.57, 0.47-0.70) and atezolizumab (0.71, 0.59-0.85). Proportional hazard models and non-proportional hazard models showed consistent efficiency ranks. When extrapolated to long-term survival benefit, under non-proportional hazard ratio, sugemalimab achieved the highest PFS benefit (lifeyears, LYs) in 2 years (1.323), with camrelizumab (1.320), sintilimab (1.243), tislelizumab (1.189), pembrolizumab (0.990) and atezolizumab (0.947) ranking in order; Camrelizumab achieved the highest OS benefit (LYs) in 10 years (2.723), with atezolizumab (2.445) and pembrolizumab (2.397) ranking in order. RMST model showed similar results. In terms of safety, PD-(L)1 inhibitors increased the incidence of SAEs when combined with chemotherapy, sugemalimab and camrelizumab was the safest drugs. Conclusion: Sugemalimab is superior both in HR and long-term survival benefit for Chinese patients with advanced sq-NSCLC.

Cost-effectiveness analysis of camrelizumab plus chemotherapy as first-line treatment for advanced squamous NSCLC in China.

Objective: Results of CameL-sq has revealed the clinical benefits to patients with advanced squamous non-small-cell lung cancer (sq-NSCLC). This study aims to evaluate the cost-effectiveness of camrelizumab plus chemotherapy to treat sq-NSCLC from the perspective of the Chinese healthcare system. Methods: We used a partitioned survival model with a lifetime horizon to evaluate the cost-effectiveness of camrelizumab plus chemotherapy vs. chemotherapy in treating sq-NSCLC. Baseline characteristics of patients and key clinical data were extracted from CameL-sq. Costs and utilities were collected from the open-access database and published literature. Costs, quality-adjusted life-years (QALYs), life-years gained, and incremental cost-effectiveness ratios (ICERs) were chosen as economic outcome indicators. We also performed a sensitivity analysis, subgroup analysis, and scenario analysis to verify the stability of the basic analysis results and explore the results under different scenarios. Results: Combination therapy added 0.47 QALYS and 0.91 life-years with an incremental cost of $6,347.81 compared with chemotherapy, which had an ICER of $13,572 per QALY. The probabilistic sensitivity analysis indicated that camrelizumab plus chemotherapy had a 37.8% probability of cost-effectiveness at a willingness-to-pay threshold (WTP) of 1 time GDP per capital. When WTP was set as 3 times GDP per capital, combination therapy had significant cost-effectiveness. Deterministic sensitivity analysis showed that cost of the best supportive care was the factor with the greatest influence. The subgroup analysis found that combination therapy was associated with cost-effectiveness in several subgroups, namely, patients with disease stage IIIB/IIIC and with PD-L1 tumor proportion score ≤ 1%. Scenario analysis showed that ICER was positively correlated with the price of camrelizumab. Conclusion: In this economic evaluation, camrelizumab plus chemotherapy was unlikely to be cost-effective compared with chemotherapy in the first line therapy of sq-NSCLC from a perspective of the Chinese healthcare system. Reducing the price of camrelizumab and tailoring treatments based on individual patient factors might improve the cost-effectiveness. Our findings may provide evidence for clinicians in making optimal decisions in general clinical practice.

Traffic Flow Prediction and Analysis in Smart Cities Based on the WND-LSTM Model.

Aiming at the problem that the road traffic flow in intelligent city is unevenly distributed in time and space, difficult to predict, and prone to traffic congestion, combined with pattern recognition and big data mining technology, this paper proposes a research method to analyze and mine the daily travel patterns of urban vehicles. This paper proposes a WND-LSTM model, which mainly includes data preprocessing, data modelling, and model implementation, to analyze the similarity of travel patterns in seasonal changes. Combining the data mining results with the data mining results, the daily travel model of road traffic vehicles in intelligent city is established. The results of the case study showed that the WND-LSTM model outperformed ARIMA (88.48%), LR (65.79%), SVR (70.46%), KNN (68.21%), SAEs (66.95%), GRU (68.43%), and LSTM (70.41%) in MAPE, respectively, with an average accuracy improvement of 71.25% (MAPE of 0.651%).

Adverse outcomes of artificial pneumothorax under right bronchial occlusion for patients with thoracoscopic-assisted oesophagectomy in the prone position versus the semiprone position.

Background: There are few studies on the impact of body position on variations in circulation and breathing, and it has not been confirmed whether body position changes can reduce the pulmonary complications of thoracoscopic-assisted oesophagectomy. Methods: A single-center retrospective study included patients undergoing thoracoscopic-assisted oesophagectomy in the prone position or semiprone position between 1 July 2020, and 30 June 2021, at the Shanghai Chest Hospital. There were 103 patients with thoracoscopic-assisted oesophagectomy in the final analysis, including 43 patients undergoing thoracoscopic-assisted oesophagectomy in the prone position. Postoperative pulmonary complication (PPC) incidence was the primary endpoint. The incidence of cardiovascular and other complications was the secondary endpoint. Chest tube duration, patient-controlled anaesthesia (PCA) pressing frequency within 24 h, ICU stay, and the postoperative hospital length of stay (LOS) were also collected. Results: Compared with the semiprone position, the prone position decreased the incidence of atelectasis (12% vs. 30%, P = 0.032). Nevertheless, there were no considerable differences in the rates of cardiovascular and other complications, ICU stay, or LOS (P >0.05). Multivariable logistic regression analysis showed that the prone position (OR = 0.196, P = 0.011), no smoking (OR = 0.103, P <0.001), preoperative DLCO% ≥90% (OR = 0.230, P = 0.003), and an operative time <180 min (OR = 0.268, P = 0.006) were associated with less atelectasis. Conclusions: Our study shows that artificial pneumothorax under right bronchial occlusion one-lung ventilation for patients with thoracoscopic-assisted oesophagectomy in the prone position can decrease postoperative atelectasis compared with the semiprone position.