Programmed death-1 (PD-1) inhibitors combined with chemotherapy have become a standard first-line treatment for advanced oesophageal squamous cell carcinoma (ESCC). Given the high costs associated with immunotherapy, evaluating the cost-effectiveness of different PD-1 inhibitors in the Chinese healthcare setting is essential for guiding treatment decisions and policy development.

A cost-effectiveness analysis was conducted comparing six PD-1 inhibitors-sintilimab, toripalimab, tislelizumab, camrelizumab, serplulimab, and pembrolizumab-combined with chemotherapy for first-line treatment of advanced ESCC. A partitioned survival model was used to calculate incremental cost-effectiveness ratios (ICERs) from healthcare system perspective, with a willingness-to-pay (WTP) threshold set at $36,598.19 per quality-adjusted life year (QALY). Sensitivity analyses were performed to evaluate the robustness of the results.

The ICERs for toripalimab, camrelizumab, pembrolizumab, serplulimab, sintilimab, and tislelizumab were $32,356.79/QALY, $48,410.64/QALY, $312,743.54/QALY, $121,200.84/QALY, $29,663.42/QALY, and $35,304.33/QALY, respectively. Sintilimab, toripalimab, and tislelizumab were below the WTP threshold. Among all regimens, the top three in life years (LYs) gained were toripalimab, serplulimab, and tislelizumab. Sensitivity analysis showed that utility values and drug prices were key factors influencing ICERs. Probabilistic analysis indicated that toripalimab, sintilimab, and tislelizumab had the highest probabilities of being cost-effective, at 83.1%, 81.4%, and 70.0%, respectively.

Sintilimab, toripalimab, and tislelizumab are the most cost-effective PD-1 inhibitors when combined with chemotherapy for the first-line treatment of advanced ESCC in China, with ICERs below the WTP threshold. While all six PD-1 inhibitors demonstrated clinical benefits, pembrolizumab and serplulimab were less favourable from a cost-effectiveness standpoint. Sensitivity analysis confirmed that drug prices and utility values are significant determinants of cost-effectiveness.

The treatment paradigm for gastroesophageal cancers is evolving with immune checkpoint inhibitors (ICIs) as first-line therapy, making it crucial to understand their efficacy across patient subgroups, especially concerning PD-L1 expression. We performed a meta-analysis of Phase III randomized controlled trials targeting the effectiveness of ICIs with or without chemotherapy for advanced/metastatic HER2-negative gastroesophageal adenocarcinoma (GEA) or esophageal squamous cell carcinoma (ESCC). Kaplan-Meier (KM) curves of all-comer populations and subgroups according to reported PD-L1 cut-offs were extracted from published reports. Using KMSubtraction algorithm, unreported PD-L1 subgroup survival data were reconstructed by utilizing published KM survival curves. Thirteen first-line phase III RCTs involving 11,795 patients with GEA or ESCC were included. For GEA, ICI with or without chemotherapy showed longer OS in patients with PD-L1 combined positive score ≥1 (HR 0.77, 95 % confidence intervals [CI] 0.71-0.83 for ICI plus chemotherapy; HR 0.86, 95 %CI 0.75-1.01 for ICI alone) compared to chemotherapy alone, showing less benefits in low PD-L1 subgroups. ICI, with or without chemotherapy displayed survival benefits among PD-L1 tumor proportion score ≥1 % for ESCC (HR 0.62, 95 %CI 0.52-0.74 for ICI plus chemotherapy; HR 0.67, 95 %CI 0.54-0.84 for ICI alone) compared to chemotherapy alone. ICI combinations were similarly beneficial for Asian and global patients with GEA or ESCC. In conclusion, this meta-analysis, which includes unreported PD-L1 subgroups show benefit of ICIs with or without chemotherapy as a first-line treatment for advanced gastroesophageal cancers, particularly among patients with high PD-L1 expression.

Mitral valve (MV) repair for infective endocarditis (IE) has proven to be a good and safe option, but current trends favor replacement; the available data, in addition, don't allow to reach a general consensus on the preferred first-line approach. The present metanalysis, aimed to compare short- and long-term outcomes between MV repair (MVRep) and MV replacement (MVR) in patients with IE. A search of PubMed was conducted on 30th August 2024, yielding 120 results. (PROSPERO CRD: CRD42023490612). Four additional suitable studies were identified and added from Embase and Medline (via Ovid). Statistical analyses were performed using RStudio, SPSS, and RevMan. Pseudoindividual patient data were extracted from Kaplan-Meier curves by converting the graphical plots into raw data coordinates through WebPlotDigitizer. A total of 21 studies were eligible for inclusion. The 16-year reconstructed analysis revealed that patients undergoing MVRep have higher survival compared to the MVR group (HR: 1.41, 95% Cl: 1.30-1.53, p < 0.001). Moreover, IE recurrence was significantly lower in MVRep (95% CI, RR:0.46, 12 = 41%, p = 0.03). Reoperation rates, however, were similar between MVRep and MVR (95% CI, RR: 0.78, 12 = 0%, p = 0.27). In-hospital mortality was similar between the groups (95% CI, RR:0.40, 12 = 34%, p = 0.07). In conclusion, MV repair should be favored over replacement in IE when there is no evidence of local extension of the infections and if valve leaflets have not degenerated. This approach is associated with improved overall survival and a reduced risk of IE recurrence, making it particularly advantageous for younger patients.

Radical cystectomy (RC) is the guideline-recommended gold standard of curative treatment for muscle-invasive bladder cancer (MIBC). Trimodality therapy (TMT) has recently emerged as a viable alternative treatment, aiming to improve long term survival and bladder preservation rates.

A systematic literature search was conducted on PubMed, Embase, Scopus and CENTRAL for randomized trials or covariate-matched studies comparing RC versus TMT for MIBC. A graphical reconstructive algorithm was used to obtain overall survival (OS) and cancer-specific survival (CSS) of individual patients, which was then pooled under random-effects individual patient data (IPD) meta-analysis using Cox-models to determine hazard ratios (HRs) and 95% CI.

Altogether, 11 studies, comprising mostly cT2-T4, node-negative, nonmetastatic MIBC, were analyzed. Across 9 studies (6780 patients), TMT was associated with lower OS versus RC (shared-frailty HR = 1.14, 95% CI, 1.08-1.21, P < 0.001). Estimated OS at 1, 5 and 10 years was 86%, 47% and 18% respectively for TMT, and 86%, 57% and 22% for RC. Across 8 studies (4,776 patients), TMT was associated with lower CSS versus RC (shared-frailty HR = 1.09, 95% CI, 1.01-1.18, P = 0.024). Estimated CSS at 1, 5 and 10 years was 92%, 62% and 29% respectively for TMT, and 94%, 72% and 29% respectively for RC.

In the absence of large trials, our meta-analysis of studies of the next-highest quality of evidence suggests that RC may still confer OS and CSS benefit over TMT in MIBC. RC should remain the standard of care for nonmetastatic MIBC while TMT remains a valid alternative for carefully selected and informed patients.

Self-expanding valves (SEV) and balloon-expandable valves (BEV) for transcatheter aortic valve implantation (TAVI) have their own features. There is a growing interest in long-term outcomes with the adoption of lifetime management in younger patients. To evaluate late outcomes in TAVI with SEV versus BEV, we performed a study-level meta-analysis of reconstructed time-to-event data published by May 31, 2023. We found no statistically significant difference in all-cause death after TAVI with SEV versus BEV. Randomized controlled trials are warranted to validate our results.

Metastatic castration-resistant prostate cancer (mCRPC) presents a challenge for clinicians in determining the optimal treatment sequence because of the lack of direct head-to-head comparisons, which is further complicated by the now-widespread use of androgen receptor pathway inhibitors (ARPIs) in metastatic hormone-sensitive prostate cancer (mHSPC).

This study is a Bayesian network meta-analysis (NMA) intended to provide a comprehensive evaluation and comparison of the efficacy of mCRPC treatments across different treatment lines.

We performed a systematic search of ClinicalTrials.gov, extracted information, assessed the risk of bias, and reconstructed missing outcomes. We performed an NMA to evaluate treatment efficacy for overall survival (OS) and progression-free survival (PFS) in first and subsequent lines. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) NMA guidelines and was registered with PROSPERO (CRD42024499607).

The NMA included 43 trials with 33,494 patients. ARPI-based therapies, particularly in combination with poly(ADP-ribose) polymerase inhibitors, demonstrated the most significant benefits for OS and PFS in first-line mCRPC treatment, followed by chemotherapy regimens. However, ARPI re-treatment showed limited effectiveness in subsequent lines, leading to weaker OS and PFS benefits.

This NMA highlights the superiority of ARPI-based therapies and chemotherapies as first-line options for mCRPC while emphasizing the need for treatment class switching after ARPI failure. To refine treatment sequencing and enable precision care, future research should integrate individual participant data to better address patient-level heterogeneity and identify biomarkers for personalized therapy.

Recently published large-scale randomised controlled trials (RCTs) have questioned the efficacy of preventive interventions in individuals at clinical high risk for psychosis (CHR-P). We conducted a systematic review and meta-analysis to include this new evidence and provide future directions for the field. We followed the PRISMA guidelines and a pre-registered protocol, with a literature search conducted from inception to November 2023. We included RCTs that collected data on psychosis transition (the primary outcome) in CHR-P. Secondary outcomes were symptoms severity and functioning. Investigated time points were 6,12,24,36, and +36 months. We used odd ratios (ORs) and standardised mean differences (SMD) as summary outcomes. Heterogeneity was estimated with the Higgins I2. Twenty-four RCTs, involving 3236 CHR-P individuals, were included. Active interventions were Cognitive Behavioural Therapy (CBT), family-focused therapy, Integrated Psychological Therapy, antipsychotics, omega-3 fatty acids, CBT plus risperidone, minocycline, and other non-pharmacological approaches (cognitive remediation, sleep-targeted therapy, brain stimulation). Results showed no evidence that any of the investigated active interventions had a sustained and robust effect on any of the investigated outcomes in CHR-P, when compared to control interventions, including CBT on transition to psychosis at 12 months (9 RCTs; OR: 0.64; 95% CI: 0.39-1.06; I2: 21%; P = 0.08). These results highlight the need for novel treatment approaches in CHR-P. Future studies should consider the heterogeneity of this clinical population and prioritise stratification strategies and bespoke treatments.

There has been much controversy regarding the order in which cytoreductive nephrectomy (CN) and systemic therapy (ST) are applied for patients with metastatic renal cell carcinoma (mRCC). We aimed to investigate the role of deferred CN (dCN) in mRCC, particularly in the current era of immunotherapy. A systematic literature search was conducted on PubMed, Embase, and Scopus for studies comparing dCN versus any non-dCN strategy, in any temporal sequence, with the provision of Kaplan-Meier curves for overall survival (OS). A graphical reconstructive algorithm was used to obtain OS of individual patients, which was then pooled under random-effects individual patient data (IPD) meta-analysis using Cox-models to determine hazard ratios (HRs) and 95% CI. Altogether, 12 studies (5,350 patients) were analyzed. dCN (ST followed by CN) was associated with significantly improved OS over nondeferred CN (CN followed by ST, ST alone, or CN alone) (HR = 0.60, 95% CI, 0.53-0.67, P < 0.001). Subgroup comparisons restricted to studies comparing dCN versus upfront CN (uCN, CN then ST) were also in favor of dCN (HR = 0.69, 95% CI, 0.61-0.78, P < 0.001), even among those in which immunotherapy as ST was used in all patients (HR = 0.57, 95% CI, 0.39-0.84, P = 0.005). In mRCC patients suitable for CN, dCN is associated with significantly improved OS over nondeferred CN strategies, including uCN. Although limited by inclusion of nonrandomized studies and immortal time bias, this meta-analysis strengthens existing guidelines to offer dCN to surgically fit patients who do not progress on ST in the current age of immunotherapy.

Liver transplant (LT) for transplant oncology (TO) indications is being slowly adopted worldwide and has been recommended to be incorporated cautiously due to concerns about mid-long-term survival and its impact on the waiting list.

We conducted 4 systematic reviews of all series on TO indications (intrahepatic cholangiocarcinoma and perihilar cholangiocarcinoma [phCC]) and liver metastases from neuroendocrine tumors (NETs) and colorectal cancer (CRLM) and compared them using patient-level meta-analyses to data obtained from the United Network for Organ Sharing (UNOS) database considering conventional daily-practice indications. Secondary analyses were done for specific selection criteria (Mayo-like protocols for phCC, SECA-2 for CRLM, and Milan criteria for NET). A total of 112,014 LT were analyzed from 2005 to 2020 from the UNOS databases and compared with 345, 721, 494, and 103 patients obtained from meta-analyses on intrahepatic cholangiocarcinoma and phCC, and liver metastases from NET and CRLM, respectively. Five-year overall survival was 53.3%, 56.4%, 68.6%, and 53.8%, respectively. In Mantel-Cox one-to-one comparisons, survival of TO indications was superior to combined LT, second, and third LT and not statistically significantly different from LT in recipients >70 years and high BMI.

Liver transplantation for TO indications has adequate 5-year survival rates, mostly when performed under the selection criteria available in the literature (Mayo-like protocols for phCC, SECA-2 for CRLM, and Milan for NET). Despite concerns about its impact on the waiting list, some other LT indications are being performed with lower survival rates. These oncological patients should be given the opportunity to have a definitive curative therapy within validated criteria.

Using pharmacokinetics (PK)-guided 5-fluorouracil (5-FU) for metastatic colorectal cancer (mCRC) improves overall survival (OS) and decreases toxicity, yet its value for money in the Australian setting is unknown. Our study assesses the cost-effectiveness of PK vs. body surface area (BSA) dosing of 5-FU for patients with mCRC.

We developed a semi-Markov model with four health states to compare PK-guided dosing within a FOLFOX regimen vs. BSA-guided dosing for mCRC patients from an Australian healthcare system perspective. Transition probabilities were derived from fitted survival models, with utility values obtained directly from published studies. We calculated direct healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs), and included both one-way and probabilistic sensitivity analyses.

BSA-guided FOLFOX provided 1.291 QALYs at a cost of $36 379, compared with PK-guided FOLFOX which delivered 1.751 QALYs at a cost of $32 564. Therefore, PK-guided dosing emerges as the dominant strategy offering both better health outcomes and lower costs. The variables that had the greatest impact on the overall ICER were the adverse event rates in the BSA and PK groups, model time horizon, utility of progression-free survival and PREDICT assay cost. Our univariate and multivariate sensitivity analysis confirmed that the ICER for PK FOLFOX consistently remained below $50 000 per QALY across all tested variables.

PK dose management of 5-FU-based chemotherapy in mCRC patients appears to be a cost-saving strategy in Australia. However, our model estimates are drawn from limited, low-quality evidence. Further evidence from randomized controlled trials (RCTs), directly comparing PK-based to BSA-based dosing across a variety of current regimens, is needed to address our model's uncertainties.

The optimal radiation dose of definitive concurrent chemoradiotherapy (dCCRT) for esophageal cancer (EC) has always been a concern in radiation oncology and has remained controversial for several decades, we performed a meta-analysis based on individual patient data (IPD) to explore the optimal dose.

Randomized clinical trials (RCTs) comparing high-dose radiotherapy (HD-RT,≥59.4 Gy) with standard-dose radiotherapy (SD-RT, 50 Gy/50.4 Gy) were identified. Graphical reconstructive algorithms were employed to extract time-to-event outcomes from Kaplan-Meier curves presented in the original RCTs. Using reconstructed individual patient data, summary overall survival (OS), progression-free survival (PFS) and locoregional progression-free survival (LRPFS) for HD-RT versus SD-RT were recalculated. Hazard Ratios (HRs) of OS, PFS and LRPFS reported were also pooled by the fixed or random effects model.

Six RCTs, including 1722 patients, were included. IPD for OS, PFS, and LRPFS were from 1287, 462, and 722 patients, respectively. Overall, HD-RT had no significant benefits in 3-year OS (RR = 1.00, P = 0.990), 3-year progression-free survival (PFS) (RR = 0.96, P = 0.320) and 3-year locoregional progression-free survival (LRPFS) (RR = 0.88, P = 0.204), compared with SD-RT. Consistent with above results, the pooled HRs of OS, PFS and LRPFS for HD-RT versus SD-RT were 0.99 (P = 0.854), 0.94 (P = 0.628) and 0.91 (P = 0.410), respectively. However, HD-RT had higher grade ≥ 3 treatment-related adverse effects (TRAEs) (OR = 1.26, P = 0.025). Subgroup analyses were also performed based on the RT techniques, histology, size of the RT target, dose-escalation mode, and stage editions. We found that dose escalation, even in subgroups, did not benefit long-term survival but resulted in a higher incidence of grade ≥ 3 TRAEs.

The results provide robust evidence that corroborates current guidelines and supports the clinical practice of employing SD-RT. Additionally, it provides implications for the feasibility of further research into novel drug combinations (e.g., immunotherapy) rather than radiation dose escalation.

Based on the results of KEYNOTE-048 (NCT02358031), first-line standard-of-care treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) includes pembrolizumab alone or with platinum and fluorouracil (5-FU). Results from the single-arm KEYNOTE-B10 (NCT04489888) showed promising antitumor activity and a manageable safety profile offering an alternative pembrolizumab and chemotherapy regimen (KN-B10), with paclitaxel replacing 5-FU. With KEYNOTE-B10 being a non-comparative trial, this study aims to estimate the comparative efficacy of KN-B10 versus alternative first-line systemic treatments for R/M HNSCC via an indirect treatment comparison analysis.

A systematic literature review (October 2023) identified six connected randomized controlled trials with similar eligibility criteria to KEYNOTE-B10. Interventions included cetuximab + platinum + 5-FU (EXTREME), cetuximab + cisplatin + docetaxel (TPEx), pembrolizumab + platinum + 5-FU (KN-048), platinum + 5-FU, cisplatin + paclitaxel, cisplatin, 5-FU, and methotrexate. To connect KEYNOTE-B10 to the network, individual patient-level data were weighted to match the population characteristics of the most similar trial in the network (KEYNOTE-048). The comparative efficacy of KN-B10 versus other interventions was estimated via fixed-effect Bayesian network meta-analyses. Due to violations of the proportional-hazards assumption, fractional polynomials were used to model overall survival (OS) and progression-free survival (PFS).

For objective response, KN-B10 was comparable to EXTREME and TPEx and more efficacious than all other identified treatments (range of odds ratios [ORs]: 1.69-11.75), including KN-048 (OR: 1.69; 95% credible interval: 1.01-2.81). For OS and PFS, KN-B10 was comparable to EXTREME (with improvements in OS after month 12), TPEx, and KN-048. KN-B10 improved OS versus platinum + 5-FU (range of time-varying hazard ratios: 0.60-0.18; months 9-60), cisplatin + paclitaxel (0.53-0.24; 9-36), cisplatin (0.59-0.32; 6-24), 5-FU (0.58-0.20; 6-36), and methotrexate (0.61-0.07; 6-60). KN-B10 improved PFS versus platinum + 5-FU (0.60-0.31; 3-36).

The improved or comparable efficacy of KN-B10 versus alternative first-line interventions in terms of relevant clinical outcomes, as shown in this study, supports its recommendations for the treatment of R/M HNSCC.

The prognosis of Heart failure with preserved ejection fraction (HFpEF) is significantly impacted by the existence and severity of comorbidities. Recent studies highlight the right ventricle (RV) as a crucial player in heart failure pathophysiology. However, there are still gaps in understanding how right ventricular dysfunction (RVD) affects long-term outcomes in patients with heart failure with preserved ejection fraction (HFpEF).

In this systematic review and meta-analysis, a comprehensive search was conducted to identify studies investigating RVD as the predictor of the composite outcome of All-cause death, cardiac death, and hospitalization for HF in patients with HFpEF published until October 2024. RVD was defined as the deviation of at least one measurement of RV function from the recommended normal range based on modality and the normal ranges established in each study. Time and survival probability were extracted for each Group (HFpEF patients with and without RVD) in each of the Kaplan-Meier curves. Individual patient data were reconstructed by processing the extracted time points, survival probabilities, and the number of patients at risk in a two-stage approach. The restricted mean survival time (RMST) was also calculated as the area under the survival curve for each group.

Seven studies met the inclusion criteria, comprising 1936 individuals, of which 555 patients had RVD. The pooled prevalence of RVD among HFpEF was 41.2% (95% CI: 36.5; 45.9). Patients with RVD had a significantly higher risk of adverse outcomes compared to those without RVD, with an HR of 2.28 (95% CI, 1.95; 2.68, p-value < 0.001) in the eight-year follow-up after the RVD diagnosis. The one-year landmark analysis revealed that the majority of the event-free survival disparity between patients with RVD and those without arises from the first year after an RVD diagnosis. Patients with RVD also had shorter event-free survival. (ΔRMST = -2.127 years, 95% CI, -2.383; -1.872, p-value < 0.001).

The development of RVD in HFpEF is linked to significantly increased composite outcomes of all-cause death and HF hospitalization and shorter event-free survival.

Time-to-event data is commonly used in non-inferiority clinical trials. While the hazard ratio is a popular summary measure in this context, the difference in restricted mean survival time has been theoretically shown to increase power and interpretability. This study aimed to empirically compare the power of the hazard ratio, difference in survival and difference in restricted mean survival time for non-inferiority clinical trials with a time-to-event outcome recently published in key clinical journals.

Sixty-five non-inferiority trials with a time-to-event outcome were included from two literature searches. Individual patient data were reconstructed and reanalysed. The hazard ratio, difference in survival and difference in restricted mean survival time were estimated under proportional hazards, using a Cox model for the hazard ratio and a flexible parametric survival model for the latter two summary measures. The latter measures were additionally estimated non-parametrically. Margin conversion was done using observed data in the control arm. Empirical power was defined as the proportion of trials that rejected the null hypothesis.

Difference in restricted mean survival time gave a potential power advantage over the hazard ratio with an empirical power increase of 7.7 ( - 5.4 , 20.7 ) percentage points, and consistently outperformed difference in survival. Difference in survival was more powerful than the hazard ratio, but while difference in restricted mean survival time showed an empirical power advantage even when estimated non-parametrically, this was not generally true for difference in survival. Sub-group analyses consistently showed similar results. Results were more variable when converting margins under an exponential distribution, highlighting the importance of correct margin conversion.

Our results empirically corroborate the theoretical advantage of difference in restricted mean survival time over the hazard ratio and difference in survival in non-inferiority clinical trials. This advantage is most apparent when estimation is done under proportional hazards. Choosing a relevant time point at which to evaluate the survival-based summary measures is an important aspect that should be carefully considered. We recommend incorporation of the difference in restricted mean survival time in the design and analysis of non-inferiority clinical trials when clinically justifiable. If appropriate, estimation under proportional hazards is preferable.

For survival studies, pooling hazard ratios (HRs) across multiple clinical trials through meta-analysis is commonly performed to achieve widely accepted and robust conclusions. However, clinical trials sometimes do not report HRs.

We developed a new, simple approach to estimate HRs by reconstructing life tables from Kaplan-Meier (KM) curves, particularly for small clinical trials. First, we extracted the time points and survival rates from the published KM curves. Then, we reconstructed the life table by reverse derivation of its parameters, using time points and survival rates extracted from the KM curves. Finally, we replotted the KM curves using the Kaplan-Meier method and estimated the HRs via the Cox regression method by SPSS software, using the survival data from the reconstructed life table.

The estimated HRs of 3 examples were 0.510 (95% CI 0.272-0.958, P = 0.036), 2.472 (95% CI 1.548-3.949, P < 0.001), and 0.591 (95% CI 0.291-1.199, P = 0.145), compared with the original HRs of 0.51 (95% CI 0.27-0.96, P = 0.04), 2.33 (95% CI 1.45-3.73, P < 0.001), and 0.62 (95% CI 0.31-1.26, P = 0.18), respectively.

This simple approach allows for the estimate of HRs from published KM curves in small survival studies without reported HRs, facilitating their inclusion in meta-analyses. This increases the overall sample size and enhances the reliability of synthesized clinical evidence.

Overall survival (OS) is the standard efficacy endpoint in various solid tumor trials; however, it requires longer follow-up time for assessment than potential intermediate endpoints. This study evaluated radiological progression-free survival (rPFS) as a surrogate for OS in metastatic hormone-sensitive prostate cancer (mHSPC) using aggregate-level data from randomized controlled trials (RCTs).

A systematic literature review identified mHSPC RCTs published through December 2023, reporting hazard ratios for rPFS (HRrPFS) and OS (HROS). Correlation between HRrPFS and HROS was assessed using bivariate random-effects meta-analysis (BRMA). Predictive validity was assessed with leave-one-out cross-validation (LOOCV). The surrogate threshold effect (STE), or minimum rPFS benefit predicting an OS benefit, was estimated using recent mHSPC trial sample sizes. Sensitivity analyses (1) omitted trials that had only one of the endpoints reported, (2) omitted HRs that violated proportional hazards assumptions, (3) omitted trials that allowed cross-over and (4) investigated different assumed values of the within-study correlation.

The primary analysis included 35 treatment comparisons from 31 trials. The estimated rPFS-OS correlation was 0.95 (95 % CrI: 0.75, 1.00). LOOCV confirmed HROS were within 95 % prediction intervals. The estimated STE ranged from 0.55 to 0.71 depending on the trial size being predicted. Sensitivity analyses produced strong but slightly lower correlations (0.87, 0.89, 0.91) than the primary analysis, with full coverage of the reported HROS in cross validation. Increasing within-study correlation slightly reduced between-study correlation.

The derived surrogacy equation enables OS estimation based on reported rPFS benefits in mHSPC, meeting NICE's 95 % surrogate validity threshold. These findings support rPFS as a reliable surrogate for OS, facilitating prediction of OS benefits in future mHSPC trials.

This study aims to compare the survival benefits of perioperative versus neoadjuvant immune checkpoint inhibitors (ICI)-based therapy in patients with resectable non-small cell lung cancer (NSCLC), focusing specifically on those who achieve major pathological response (MPR) or pathological complete response (pCR) following neoadjuvant ICI-based treatment.

s: A systematic literature review was performed using PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases. A trial-level proportional meta-analysis was conducted to compare the two treatment modalities. A patient-level-based analysis was also conducted to obtain more evidence of different perioperative treatment regimens. Cox regression and accelerated failure time models were used to analyze the survival benefits in patients who achieved MPR or pCR for the proper treatment modality.

Twenty-three studies were included in the trial-level proportional meta-analysis, wherein no statistical significance was observed in the 1-, 2-, and 3-year event-free survival (EFS) rates between patients with MPR and pCR receiving perioperative or neoadjuvant ICI-based therapy. The pooled median EFS (mEFS) was 40.1 and 32.1 months in patients with MPR receiving perioperative and neoadjuvant ICI-based therapies, respectively. Meanwhile, the pooled mEFS was 35.4 and 34.2 months in patients with pCR receiving perioperative and neoadjuvant ICI-based therapies, respectively. Multivariable Cox analysis showed that perioperative chemoimmunotherapy was a favorable prognostic factor compared with neoadjuvant chemoimmunotherapy in MPR patients (P = 0.038), but not in those with pCR (P = 0.408).

The EFS were similar among patients with NSCLC who received neoadjuvant and perioperative ICI-based treatment and achieved MPR or pCR. Multivariable Cox analysis indicated that perioperative chemoimmunotherapy was a favorable prognostic factor in patients who achieved MPR after neoadjuvant chemoimmunotherapy, but not in those who reached pCR.

The COMPASSION-15 trial demonstrated that cadonilimab plus chemotherapy (CAD-CHM) confers clinical benefits over placebo plus chemotherapy (PLA-CHM) as a first-line treatment for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, the introduction of cadonilimab substantially elevates treatment costs, and its cost-effectiveness relative to PLA-CHM remains undetermined. This study evaluates the cost-effectiveness of CAD-CHM compared with PLA-CHM from the perspective of the Chinese healthcare system.

A Markov model with three health states was developed to assess the cost-effectiveness of CAD-CHM in HER2-negative advanced G/GEJ adenocarcinoma. Clinical efficacy data were sourced from the COMPASSION-15 trial, while drug costs were calculated based on national tender prices, and additional costs and utility values were extracted from published literature. The analysis encompassed the overall population, as well as subgroups stratified by programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 5 and CPS < 5. Outcomes included total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were conducted to evaluate model robustness.

The ICER of CAD-CHM was $67,378.09 per QALY in the overall population, $48,433.34 per QALY in the PD-L1 CPS ≥ 5 subgroup, and $78,463.86 per QALY in the PD-L1 CPS < 5 subgroup. Key determinants influencing model outcomes included patient weight, cadonilimab cost, and the utility value of progression-free survival. Across all groups, CAD-CHM resulted in an ICER exceeding the willingness-to-pay threshold of $41,511 per QALY, with a 0% probability of cost-effectiveness compared with PLA-CHM.

From the perspective of the Chinese healthcare system, CAD-CHM is not cost-effective as a first-line treatment for HER2-negative advanced G/GEJ adenocarcinoma, either in the overall population or in subgroups stratified by PD-L1 CPS status, compared with chemotherapy alone.

Objective: Immune therapies such as teplizumab and antithymocyte globulin (ATG) offer promise in delaying type 1 diabetes (T1D). However, growing availability of automated insulin delivery (AID) systems for insulin management may alter the cost-effectiveness of these therapies. Immune therapies may become more cost-effective when paired with AID instead of conventional insulin management. Meanwhile, as immune therapies delay T1D for only a short period, effective AID may reduce the economic value of prevention. This study provides the first cost-effectiveness analysis of the interplay between immune therapies and AID systems. Methods: Using microsimulation modeling, we examined the cost-effectiveness of six alternative prevention-treatment strategies defined by a combination of three preventive immune therapies (teplizumab, ATG, or no therapy) and two insulin management strategies (AID or conventional insulin management). Effectiveness was measured by quality-adjusted life years (QALYs). Costs were estimated from a payer perspective. Results: Among the six strategies considered, preventive ATG therapy followed by AID was the most cost-effective. It entailed $394,250 in lifetime costs and yielded 19.13 QALYs. These costs were lower and QALY gains higher than those with strategies that did not involve immune therapy or AID. Preventive teplizumab therapy followed by AID generated 0.25 more QALYs than ATG therapy followed by AID, albeit at an additional cost of $153,670, resulting in an incremental cost-effectiveness ratio of $369,890/QALY. Conclusions: Preventive ATG therapy followed by AID after T1D onset can be a potentially cost-effective approach. In the absence of randomized clinical trials for ATG in the prevention space, findings in this study assume that ATG is at least half as efficacious as teplizumab. The optimal prevention-treatment strategy will ultimately depend on payers' ability to negotiate prices for teplizumab and further evidence on efficacy of ATG in preventing T1D.

Matching adjusted indirect comparisons (MAICs) were performed to compare the efficacy of cilta-cel versus elotuzumab + pomalidomide + dexamethasone (EloPd), isatuximab + carfilzomib + dexamethasone (IsaKd), isatuximab + pomalidomide + dexamethasone (IsaPd), and selinexor + bortezomib + dexamethasone (SVd) in patients with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior therapy and are lenalidomide-refractory.

Unanchored MAICs were performed using individual patient-level data (IPD) for all apheresed patients randomized to the cilta-cel arm of CARTITUDE-4 (n = 208) and published arm-level data for EloPd from ELOQUENT-3 (n = 60), IsaKd from IKEMA (lenalidomide-refractory subgroup, n = 57), IsaPd from ICARIA-MM (n = 154), and SVd from BOSTON (lenalidomide-refractory subgroup, n = 53). Eligibility criteria from each comparator trial were applied to the cilta-cel arm IPD, and further imbalances in patient characteristics were adjusted by weighting the cilta-cel patient data to match the reported baseline characteristics of the comparator trials. Comparative efficacy was estimated for overall response rate, very good partial response or better (≥ VGPR) rate, complete response or better (≥ CR) rate, progression-free survival (PFS), and overall survival (OS).

After adjustment, cilta-cel patients were significantly more likely to achieve an overall response versus EloPd, IsaPd, and SVd, and were significantly more likely to achieve ≥ VGPR and ≥ CR versus all comparators. Cilta-cel patients also had significant reductions in the risk of disease progression or death (PFS) versus all comparators: 64% versus EloPd, 49% versus IsaKd, 69% versus IsaPd, and 62% versus SVd. Similarly, cilta-cel patients had significant improvements in OS for all feasible comparisons: 52% versus EloPd, 58% versus IsaPd, and 60% versus SVd.

Cilta-cel patients demonstrated clinically meaningful benefits over EloPd, IsaKd, IsaPd, and SVd for response and survival outcomes, highlighting its superiority over alternative treatment options for patients with RRMM who have received at least one prior therapy and are refractory to lenalidomide.

Metastatic urothelial carcinoma (mUC) is challenging to treat, with 37% of patients failing first-line therapy. Effective second-line treatments, like Erdafitinib, are crucial. This study evaluates the cost-effectiveness of Erdafitinib as a second-line treatment for mUC from US and Chinese payer perspectives.

A Markov model was developed to project costs, life years, and quality-adjusted life years (QALYs) over lifetime. Data were collected from December 2023 to December 2024 for up-to-date estimates and were obtained from literature, health databases, and clinical trials.. The model was run to project long-term outcomes for both the United States and China.

In the United States, Erdafitinib provides an additional 0.467 QALYs at a cost of $238,294.2 per QALY, which exceeds the $150,000 per QALY willingness-to-pay threshold. For China, when the cost of Erdafitinib is below $6.9 or $14 per milligram, there is a 90% probability that its incremental cost-effectiveness ratio will be below $38,223 or $84,966 per QALY, respectively.

From the perspective of U.S. payers, Erdafitinib as a second-line treatment for mUC is not cost-effective. From the perspective of China, the cost-effectiveness of Erdafitinib is highly sensitive to its price, which could provide a reference for healthcare reimbursement negotiations.

Immune checkpoint inhibitors (ICIs) + chemotherapy became standard her2-GC first line treatment.

The aim of this study is to investigate whether ICIs + chemo provides benefit for patients with low programmed death-ligand 1 (PD-L1) expression.

This study is a systematic review and meta-analysis.

We searched PubMed, Embase, Web of Science, and Cochrane Library as well as the 2019 to 2024 Annual Meetings of the European Society for Medical Oncology, the American Association for Cancer Research, the American Society of Clinical Oncology (ASCO), and the ASCO Symposium on Gastrointestinal Oncology (ASCO-GI) and the ClinicalTrials.gov database.

This systematic review included phase III randomized controlled trials comparing first-line immunotherapy combined with chemotherapy versus chemotherapy alone in advanced gastric cancer. KMSubtraction was used to estimate survival data for those trials that did not report data for the PD-L1 low-expression population.

We included a total of nine randomized clinical trials. In patients with combined positive score (CPS) < 1 and CPS < 5, monoclonal antibody + chemotherapy did not show an improvement in overall survival (OS) or progression-free survival (PFS) (CPS < 1 OS: hazard ratio (HR) = 0.91, 95% CI: 0.77-1.08; PFS: HR = 0.88, 95% CI: 0.73-1.07. CPS < 5 OS: HR = 0.92, 95% CI: 0.79-1.08; PFS: HR = 0.78, 95% CI: 0.53-1.14). However, in trials using dual antibodies, patients with PD-L1 CPS < 5 achieved improvements in PFS (HR = 0.64, 95% CI: 0.52-0.80). In trials using tumor area positivity (TAP) scoring, the subgroup with TAP < 5% did not achieve benefits in OS or PFS from immunotherapy plus chemotherapy (OS: HR = 0.92, 95% CI: 0.75-1.13; PFS: HR = 0.91, 95% CI: 0.74-1.13).

Our study results indicate that in the first-line treatment of advanced gastric cancer, monoclonal antibody combined with chemotherapy does not provide a survival benefit compared to chemotherapy alone for patients with low PD-L1 expression. However, it is noteworthy that in the COMPASSION-15 trial, patients with CPS < 5 achieve significant improvements in OS and PFS, which may be related to the bispecific antibodies and needs to be validated by further studies.

This study was registered in PROSPERO (CRD42024568972).

This study compared the costs and effectiveness of angiotensin receptor neprilysin inhibitor (ARNI) with angiotensin-converting enzyme inhibitor (ACEI) for the heart failure with reduced ejection fraction population from the Malaysian Ministry of Health's perspective.

A 3-state Markov model, with a monthly cycle, was constructed to estimate the lifetime healthcare costs, quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER) of ARNI and ACEI. The monthly baseline risks for all-cause mortality and heart failure (HF) hospitalization were estimated from the PARADIGM-HF trial and age-adjusted to the Malaysian population. The treatment effects were obtained from the PARADIGM-HF trial. All-cause mortality risks from hospitalization, utility values, and costs were derived from local studies. All costs were adjusted to 2023. The ICER was compared with Malaysian Ringgit (RM) 55 426 per QALY (one gross domestic product per capita).

Despite ARNI being more expensive compared with ACEI, it gained more QALYs, resulting in an ICER of RM46 498 per QALY. One-way sensitivity analyses found that the key model drivers were the relative treatment effects on cardiovascular mortality, duration of treatment effects, and time horizon. Probabilistic sensitivity analysis estimated that ARNI is 66% cost-effective at the cost-effectiveness threshold of RM55 426 per QALY. Subgroup analysis showed that ICER increased with age. Scenario analysis demonstrated that initiation of ARNI alongside sodium-glucose cotransporter-2 inhibitor (SGLT-2i) produces more favorable ICER and ARNI without SGLT-2i.

At the cost-effectiveness threshold of RM55 426 per QALY, ARNI is cost-effective compared with ACEI for the heart failure with reduced ejection fraction population. Expanding patient access to ARNI is likely to improve health outcomes cost-effectively.

A limited number of randomized controlled trials (RCTs) investigated adjuvant chemotherapy in biliary tract cancers (BTCs). Recurrences and deaths are common in the first 2 years and survival remains poor despite adjuvant treatment.

Phase-III RCTs were included comparing adjuvant chemotherapy and observation in resected BTCs. The primary endpoints were recurrence-free (RFS) and overall survival (OS). Proportional hazard results were used for trial-based analyses. Patient data was curated from published Kaplan-Meier curves to analyze short-term (2-year) hazards. The Parmar and generic inverse variance methods were used.

1308 patients in 4 trials (BILCAP, ASCOT, BCAT, PRODIGE-12) were included. Capecitabine (BILCAP) and S-1 (ASCOT) were grouped as 5-FU-based, gemcitabine (BCAT) and gemcitabine-oxaliplatin (PRODIGE-12) were grouped as gemcitabine-based chemotherapy. Adjuvant 5FU-based chemotherapy improved RFS [HR: 0.80 (95 % CI:0.68-0.95), p = 0.012] and OS [HR: 0.78 (95 % CI:0.65-0.94), p = 0.009]. However, gemcitabine-based chemotherapy did not provide benefit in RFS [HR: 0.90 (95 % CI:0.70-1.15), p = 0.428] and OS [HR: 1.03 (95 % CI:0.78-1.36), p = 0.794]. The benefit of 5-FU-based chemotherapy was more apparent in the short-term (2-year hazards) (RFS: [HR: 0.67 (95 %CI:57-0.79), p < 0.001] and OS: [HR: 0.61 (95 % CI:59-0.64), p < 0.001]). However, gemcitabine-based chemotherapy did not provide RFS benefit in the short term either [HR: 0.80 (95 % CI:0.64-0.1.01), p = 0.067] and seemed to be even detrimental for OS [HR: 1.22 (95 % CI:1.14-1.31), p < 0.001] in the first 2 years.

This study confirms using 5FU-based monotherapy in the adjuvant treatment of resected BTCs. The more prominent benefit in the first 2 years emphasizes that more effective adjuvant treatments with sustained long-term benefits are needed. Two-year proportional hazards OS and RFS are proposed here as an additional secondary end-point to consider in future clinical trials. in this setting. Registration ID (PROSPERO): CRD42024614444.

In randomized clinical trials of patients undergoing percutaneous coronary intervention (PCI) for de novo small-vessel coronary artery disease (SV-CAD), paclitaxel-coated balloon (PCB) angioplasty showed mid-term angiographic or clinical non-inferiority to drug-eluting stent (DES) implantation. Nevertheless, these trials have sample size limitations, and the relative safety and efficacy beyond the first year remain uncertain.

The ANDROMEDA study was a collaborative, investigator-initiated, individual patient data meta-analysis comparing 3 year clinical outcomes between PCB angioplasty and DES implantation for the treatment of de novo SV-CAD. Multiple electronic databases (PubMed, Scopus, ScienceDirect, and Web of Science) were searched from May 2010 to June 2024 to identify eligible trials. All the following eligibility criteria were required: (i) random allocations of treatments; (ii) patients with SV-CAD; (iii) treatment with PCB or DES; and (iv) clinical follow-up of at least 36 months. The primary and co-primary endpoints were major adverse cardiac events (MACE) and target lesion failure (TLF), respectively. The protocol was registered with PROSPERO (CRD42023479035).

Individual patient data from three randomized trials, including a total of 1154 patients and 1360 lesions, were combined. At 3 years, PCB was associated with a lower risk of MACE compared with DES [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.47-0.96], due to a lower risk of myocardial infarction and target vessel revascularization. This benefit persisted after multivariable adjustment (HR 0.75, 95% CI 0.58-0.96), but did not reach statistical significance in the two-stage analysis (HR 0.67, 95% CI 0.43-1.04). At the landmark analysis, the risk of MACE between groups was consistent over time. At 3 years, TLF was not significantly different between PCB and DES groups. Reconstructed time-to-event information from a fourth trial was included in a sensitivity analysis (1384 patients and 1590 lesions), showing consistent results in terms of TLF (HR 0.87, 95% CI 0.63-1.20). The comparison between PCB and second-generation DES did not reveal significant differences in 3 year TLF (HR 1.03, 95% CI 0.70-1.50).

In patients undergoing PCI for de novo SV-CAD, PCB angioplasty is associated with a reduction in MACE and a non-significant difference in TLF at 3 year follow-up compared with DES implantation. The restriction of the comparator group to second-generation DES does not alter the main conclusions. Larger trials comparing contemporary devices at a more prolonged follow-up are warranted to confirm these findings.

The aim of this study was to compare the efficacy and safety of endoscopic endonasal approaches (EEA) with craniofacial resection (CFR) for sinonasal cancers invading the skull base, using an unanchored matching-adjusted indirect comparison (MAIC).

A MAIC approach was used to analyse data from two large cohorts: the MUlti-institutional collaborative Study on Endoscopically treated Sinonasal cancers (MUSES) cohort, comprising sinonasal cancer patients treated endoscopically, and a historical CFR cohort reported by Ganly et al. Individual patient data were available only for the first cohort. Patients with olfactory neuroblastomas were excluded. Key prognostic factors were used to match and adjust the two cohorts, minimising selection bias. The primary endpoint was overall survival (OS), with secondary endpoints including recurrence-free survival (RFS), perioperative mortality, complication rates, and resection margins.

A total of 724 EEA-treated and 334 CFR-treated patients were included. EEA showed significantly improved OS before (HR= 2.33, 95 % CI= 1.88-2.87) and after MAIC adjustment (HR= 1.93, 95 % CI= 1.60-2.34). Observed RFS was higher in the EEA group (HR= 1.39, 95 % CI = 1.14-1.69) but no longer differed after adjustment (HR= 1.06, 95 % CI= 0.91-1.23). EEA was associated with significantly better Disease Specific Survival (HR= 1.71, 95 % CI = 1.39-2.13), lower perioperative mortality (OR= 8.12, 95 % CI= 3.45-36.7) and fewer complications than CFR (OR= 3.68, 95 % CI= 2.47-5.42).

In this MAIC study based on the 2 largest cohorts of sinonasal cancer with skull base invasion, EEA offered comparable oncologic outcomes to CFR with reduced morbidity, supporting it as a valid alternative when performed in expert centres.

Several first-line therapeutic strategies have been evaluated alongside platinum-based chemotherapy in advanced or recurrent endometrial cancer (a/rEC). However, the optimal approach remains unclear.

A systematic review was conducted to identify randomized control trials (RCTs) that evaluate first-line therapeutic strategies in a/rEC involving immune checkpoint inhibitors (ICI) and PARP inhibitors (PARPi). A network meta-analysis with a frequentist framework using random-effects and an extracted individual patient data meta-analysis were performed. The primary endpoint was progression-free survival (PFS) by MMR status, p53 status within the MMRp population and PD-L1 status.

A total of 3210 patients with EC were included. In the MMRp population, the combination (ICI and PARPi) showed a not statistically significant PFS benefit compared with each agent alone. In MMRp p53-abnormal patients (n = 590), combining PARPi and ICI statistically improved PFS compared to ICI alone (HR=0.47, 95 %CI 0.40-0.94) with a numerically better outcome compared to PARPi alone (HR=0.63, 95 %CI 0.26-1.57). No benefit from PARPi was observed in the p53 wild-type MMRp population. PD-L1-positivity (n = 1121) appears to predict more benefit from the addition of ICI and PARPi, with a larger benefit of combination therapy. In the MMRd population (n = 769), the best outcomes were observed with ICI alone, with no additional benefit of PARPi. Grade 3 or greater treatment-related adverse events were seen in 75.1 % patients treated with the combination.

The addition of the combination of ICI and PARPi to platinum-based chemotherapy provides greatest benefit to p53-abnormal MMRp patients. PD-L1 is a potentially useful biomarker with PD-L1-positive tumors more likely to respond to ICI. Implementation of biomarkers is crucial to redefine the treatment paradigm in a/rEC.

Penpulimab is a PD-1 monoclonal antibody recommended for treating squamous non-small cell lung cancer (sqNSCLC) in combination with paclitaxel and carboplatin. This study aimed to assess the cost-effectiveness of penpulimab combined with paclitaxel and carboplatin against paclitaxel plus carboplatin as first-line treatment for locally advanced or metastatic sqNSCLC in China.

A three-state partitioned survival model was constructed using the efficacy outcomes obtained by digitizing the AK105-302 trial and was extrapolated to the lifetime horizon. Data on direct medical costs and utilities was gathered from the literature and commercial databases from the perspective of the Chinese healthcare system. Outcomes included quality-adjusted life years (QALYs), life years (LYs), and the incremental cost-effectiveness ratio (ICER). Sensitivity analysis and scenario analysis were performed to test the model robustness.

The incremental efficacy of penpulimab plus paclitaxel and carboplatin was 0.821 QALYs and 1.176 LYs with an incremental cost of $20,335 compared with paclitaxel plus carboplatin combination therapy. The ICER was $24,778 per QALY, falling below the threshold of three times the per capita gross domestic product of China, a commonly applied benchmark. The results of the one-way sensitivity analysis demonstrated that the ICER values were primarily influenced by the utility of progression-free state and cost of penpulimab. Probabilistic sensitivity analysis showed that penpulimab plus paclitaxel and carboplatin was cost-effective for 98.3% of the cases. Scenario analysis yielded results similar to those of the base-case analysis.

Our analysis suggests that penpulimab plus paclitaxel and carboplatin combination therapy is cost-effective for patients with locally advanced or metastatic sqNSCLC in China.

Camrelizumab plus rivoceranib (camr-rivo) has been shown to significantly improve overall survival (OS) in patients with unresectable or advanced hepatocellular carcinoma (HCC) in the CARES-310 trial. However, the cost-utility of this treatment remains unclear. Therefore, this study evaluated the cost-utility of camr-rivo versus sorafenib as a first-line systemic therapy for patients with unresectable or advanced HCC from the perspectives of the Chinese healthcare system and the United States (US) payers.

Based on the CARES-310 trial, a partitioned survival model was constructed to estimate economic costs and health outcomes over a 10-year lifetime horizon. Drug costs were obtained from the public database, Red Book, and relevant literature. Health utility values were derived from the literature. One-way and probabilistic sensitivity analyses were performed. The willingness-to-pay (WTP) threshold was $36,627.25/QALY in China and $150,000.00/QALY in the United States.

Camr-rivo yielded an additional 0.34 quality-adjusted life years (QALY) compared to sorafenib for patients with unresectable or advanced HCC. The incremental costs in China and the United States were $4,762.10 and $92,700.49, respectively, and the incremental cost-utility ratios (ICURs) were $14,174.40/QALY and $272,852.59/QALY, respectively. Sensitivity analyses indicated that the cost of rivoceranib and camrelizumab had the greatest impact on the ICUR in China and the United States. Scenario analyses showed that a price reduction of approximately 30% for camrelizumab and rivoceranib could make camr-rivo a cost-utility option in the United States.

At the set WTP threshold, camr-rivo is a cost-utility treatment strategy compared to sorafenib as a first-line therapy for patients with unresectable or advanced HCC in China but not in the United States.

Patients with suspected rare diseases often experience lengthy and uncertain diagnostic pathways. This study aimed to estimate the cost-effectiveness of exome sequencing (ES) in different positions in the diagnostic pathway for patients suspected of having a rare genetic disease.

Data collected retrospectively from 305 patients suspected of having a rare genetic disease (RGD), who received clinical-grade ES and participated in the Canadian multicentre Care4Rare-SOLVE study, informed a discrete event simulation of the diagnostic pathway. We distinguished between tests that can lead to the diagnosis of a specific RGD ('indicator tests') and more routine non-RGD diagnostic tests ('non-indicator tests'). Five strategies were considered: no-ES, and ES as 1st, 2nd, 3rd, or 4th test (Tier 1, Tier 2, Tier 3, and Tier 4, respectively), where ES was the final test in the diagnostic pathway if included. Outcomes included the diagnostic yield, time-to-diagnosis, time on the diagnostic pathway, and test costs for each strategy. The cost-effectiveness analysis from a Canadian healthcare system perspective was conducted with diagnostic yield as the primary outcome of interest. Probabilistic analyses and expert-defined scenario analyses quantified uncertainty.

Implementing ES increases the diagnostic yield by 16 percentage points from 20% with no-ES to 36%. Exome sequencing, as the first test (Tier 1), resulted in the shortest time to a diagnosis and the lowest testing cost. Mean testing costs per patient were CAD4347 (95% CI 3925, 4788) for no-ES, CAD2458 (95% CI 2406, 2512) for Tier 1, CAD3851 (95% CI 3684, 4021) for Tier 2, CAD5246 (95% CI 4956, 5551) for Tier 3 and CAD6422 (95% CI 5954, 6909) for Tier 4, with Tier 1 having the highest diagnostic yield at the lowest cost. The scenario analyses yielded results consistent with those of the base case.

Implementing ES to diagnose patients suspected of having a RGD can result in a higher diagnostic yield. Although a limitation of our study was that the yield for the non-ES indicator tests was estimated using expert opinion due to a lack of available data, the results underscore the value of ES as a first-line diagnostic test, offering reduced time to diagnosis and lower overall testing costs.

Despite therapeutic advances, prostate cancer remains lethal for most patients. Accelerated development of novel therapies requires validated surrogate endpoints to circumvent prolonged survival follow-up in phase III trials. This review systematically evaluates intermediate clinical endpoints (ICEs) in prostate cancer to establish methodologically robust alternatives to overall survival (OS). We first synthesized methodological standards for ICE validation. Subsequent analysis encompassed phase III trials (PubMed/Web of Science, Jan. 2025) in metastatic castration-sensitive (mCSPC) and -resistant prostate cancer (mCRPC), requiring: randomization, therapeutic intervention, OS as primary/co-primary endpoint, ≥1 ICE (radiographic progression-free survival (rPFS), milestone survival), and ≥70 participants. Surrogacy was quantified via two-stage meta-analysis, with R2 ≥ 0.7 defining validity. Metastasis-free survival (MFS) is validated for localized disease, enabling trial endpoint substitution. In advanced stages, evidence for ICEs remains critically deficient. Our analysis identifies milestone survival as a promising ICE candidate in mCSPC and mCRPC, demonstrating strong trial-level correlation with OS. Current ICE validation in prostate cancer is disproportionately focused on localized disease, leaving advanced-stage therapeutic development constrained. While milestone survival shows surrogacy potential, endpoint validation remains methodologically challenging even in rigorously designed trials. This work underscores the imperative to accelerate ICE standardization through unified methodological frameworks and collaborative cross-trial analyses.

Immune checkpoint inhibitor (ICI)-containing treatment is currently prescribed as first-line treatment for all patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, only 30-45% of patients show no progression within 12 months after treatment start. Various biomarkers are being studied to save costly and potentially harmful treatment in non-responders. We evaluated the cost-effectiveness of implementing a hypothetical predictive biomarker for ICI-containing treatment response compared with standard of care (e.g., no implemented biomarker) for pembrolizumab-containing treatment in patients with advanced NSCLC in the Netherlands.

Standard-of-care-based and predictive-biomarker-based strategies were compared using Markov models for three first-line pembrolizumab-containing treatments depending on a patient's tumor programmed cell death ligand-1 (PD-L1) expression and histology. A Dutch healthcare system perspective was adopted. Assuming a receiver operating characteristic-area under the curve of 1.0 in identifying responders, alternative treatments were offered for non-responders in the predictive-biomarker-based strategy. Parameters and assumptions were based on real-world data from surveys, literature using a targeted search, expert opinion, and registries. Outcomes included differences in costs, survival (life years (LYs)), and survival corrected for health-related quality of life (QoL) quality-adjusted life-years (QALYs) between the predictive-biomarker- and standard-of-care-based strategy.

Implementing a predictive biomarker in pembrolizumab-carboplatin-paclitaxel treatment led to a mean survival reduction of 24 days (- 0.067 LYs) (18 days corrected for QoL (- 0.049 QALYs)), with cost savings of €22,606 compared with standard of care. Pembrolizumab monotherapy and pembrolizumab-pemetrexed-platinum treatments showed survival reductions of 4.5 and 3.9 months, respectively (3.6 and 2.8 months corrected for QoL), with cost savings of €24,345 and €28,456. Sensitivity analyses confirmed consistent cost savings and survival reductions. Survival losses were mainly observed due to the lower survival rates associated with the alternative first-line treatment options available for non-responders in the predictive-biomarker-based strategy within each pembrolizumab-containing treatment regimen. Pembrolizumab-carboplatin-paclitaxel treatment also showed survival gains under certain conditions related to QoL and survival estimates.

Our study highlights the importance of careful de-implementation of ICI-treatments in advanced NSCLC, balancing costs reductions and side effects without comprising survival. In the pembrolizumab-carboplatin-paclitaxel treatment regimen, the survival loss could be considered negligible. Future research should define acceptable tradeoffs and thresholds for de-implementation, considering factors such as survival of alternative treatments and responder classification to guide predictive biomarker implementation and optimize health resource allocation.

Matching-adjusted indirect comparisons (MAICs) can be used in case of cross-trial heterogeneity or availability of only single-arm trials. Although the National Institute for Health and Care Excellence (NICE) provides MAIC-development orientation, many still do not adhere to it. Our goal was to map MAIC oncology studies and whether NICE recommendations were observed.

We included MAIC studies comparing treatments in oncology from 2010. We searched PubMed, Embase, and the Cochrane Library up to October 1, 2024. We analyzed MAIC characteristics such as previous systematic reviews, whether the analysis was anchored or unanchored, selection of variables, and individual patient data (IPD) reporting. We adopted NICE recommendations for the assessment of MAIC studies.

We included 117 MAIC studies, which often explored multiple myeloma (n = 19%) and non-small cell lung cancer (17%) more frequently. Most MAICs were unanchored (72%), with an average of 1.9 comparisons per study. MAIC studies generally reported using pseudo-IPD (69%) but did not report the source of IPD (78%). In general, MAICs did not conduct systematic reviews to select trials for inclusion (66%). The average sample size reduction, in comparison with the original trials, was 44.9%. Only 3 MAICs fulfilled all NICE recommendations. The least reported aspects were the adjustment for all effect modifiers and prognostic variables (for unanchored MAICs), evidence of effect modifier status, and distribution of weights.

Most MAIC models did not follow NICE recommendations. Our review highlights the importance of rigorous methodological standards and thorough reporting of MAIC studies to enhance their credibility.

In this study, we aimed to evaluate the cost-effectiveness of S-1 and oxaliplatin (SOX) plus bevacizumab (Bmab group) compared with SOX plus cetuximab (Cmab group) as a first-line treatment for patients with Kirsten rat sarcoma virus (KRAS) wild-type metastatic colorectal cancer (mCRC) in Japan from the perspective of healthcare payers.

A partitioned survival model was developed using data from the randomized phase II Osaka Multicenter Study Group on Colorectal Cancer-1107 study, which included overall survival, progression-free survival, and treatment regimens for the Bmab and Cmab groups. Treatment costs were estimated from the Japanese medical claims database and the National Health Insurance drug price list. The utilities were derived from the literature. Outcomes were reported as incremental cost, incremental quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The willingness-to-pay (WTP) threshold was set at 7.5 million JPY per QALY. The time horizon of the model was set to 20 years. Sensitivity analyses were conducted to assess the uncertainty of the model for various parameters.

Compared with the Cmab group, the Bmab group had an incremental cost of 911,373 JPY (6,528 USD), an incremental effectiveness of 0.79 QALY, and an ICER of 1,146,745 JPY (8,215 USD) per QALY. One-way sensitivity analysis showed that the cost of progressive disease treatment in the Bmab group had the greatest impact on the ICER. According to the probabilistic sensitivity analysis, the Bmab group had a 94.9% probability of being cost-effective compared with the Cmab group.

Considering a WTP threshold of 7.5 million JPY (approximately 53,700 USD) per QALY, Bmab might be a cost-effective treatment option for patients with KRAS wild-type mCRC in Japan. Further studies on economic evaluations based on personalized drugs and patient selection based on clinical and genetic information are warranted.

Cirrhosis is a progressive form of liver disease associated with significant patient morbidity and mortality. Model for End-Stage Liver Disease (MELD) and Child-Pugh scores are disease severity classification systems that carry predictive value for patients undergoing various procedures. Missing is a granular analysis exploring the association between liver disease severity and clinical outcomes among patients who require cardiac surgery. Our study extracted demographic, periprocedural, and postoperative clinical data for patients with liver cirrhosis undergoing cardiac surgery between 2000 and 2023. Continuous variables were pooled by meta-analysis utilizing a random effects model, and categorical variables were studied using meta-analysis of proportions with logit transformations. The most frequently observed Child-Pugh classification was class A in 60% of patients (95% confidence interval [CI]: 53-67), followed by class B in 33% (95% CI: 27-39) and class C in 4% (95% CI: 2-6). Notably, 30% of patients developed renal failure in the postoperative period (95% CI: 21-39), and overall in-patient mortality occurred in 11% of patients (95% CI: 9-14). There was a significant association between Child-Pugh classification and overall patient survival for 3 years in the postoperative period. No significant relationship was observed between preoperative MELD score and postoperative clinical outcomes. Preoperative Child-Pugh classification is associated with postoperative clinical outcomes among patients undergoing cardiac surgery. More granular data are required to understand the association between MELD scores and postoperative outcomes within the cardiac surgery population.