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Introduction: Non-Hodgkin lymphomas (NHLs) encompass a wide range of diseases from precancerous states such as monoclonal B-cell lymphocytosis to the rapidly growing Burkitt lymphoma. In 2022, we witnessed two new classifications for these malignant lymphoid tumors: The World Health Organization (WHO) 5th edition Classification of Haematolymphoid Tumours and the International Consensus Classification of Mature Lymphoid Neoplasms (ICC). Areas Covered: Given our improved understanding of the mechanisms underlying lymphomagenesis at the molecular level, several novel agents have been or are being actively developed, including targeted therapies and immunotherapies. Therefore, this review features new and developing first-line pharmacotherapies in NHL. It is organized by the mechanism of action of the drug with the relevant key trials highlighted. Expert opinion: We provide an overview of the development of curative combination chemotherapies for lymphomas, and then discuss the importance of working on a unified classification for these tumors. We discuss resistance to targeted therapies, particularly with the continuous use of Bruton tyrosine kinase inhibitors, how to sequence T-cell therapies (bispecific T-cell engagers and chimeric antigen receptor therapy), and the impact of financial toxicity. We also review possible strategies to increase cure rates at lower costs, with less toxicity, and while promoting global health. [ABSTRACT FROM AUTHOR]

Background: In the landscape of metastatic soft tissue sarcoma (mSTS) treatment, anthracyclines have shown efficacy; however, their associated toxicity imposes significant limitations, especially in frail elderly patients with mSTS who are highly susceptible to severe adverse effects. In this context, trabectedin, due to its distinct pharmacological profile and safety profile, may represent an interesting alternative being demonstrated to be active in treating mSTS. These features hold particular significance for elderly and unfit patients with mSTS, where balancing treatment benefits with potential adverse effects represents the pivotal objective. Methods: The investigation was focused on a specific group of 11 elderly patients with mSTS aged =70, all undergoing first-line treatment with trabectedin, and it was supported by comprehensive pharmacokinetic and pharmacodynamic studies. Among these patients, 9 out of 11 started the treatment at a dose of 1.5 mg/m2. Results: The primary objective of this investigation is to highlight trabectedin as a valuable first-line treatment option for elderly and unfit patients with mSTS. Additionally, this investigation seeks to explore whether higher administered doses of trabectedin can enhance clinical outcomes while maintaining the same toxicity profiles. The median progression-free survival (PFS) was 77 days (95% CI, 53-89), the median overall survival (OS) was 397 days (95% CI, 66-2,102), while the overall toxicity of grade 3-4 severity amounted to 43%. Conclusion: These findings provide new insights into the clinical outcomes and toxicity associated with trabectedin in an elderly patient population, enhancing our understanding of better treatment approaches for a specific population of patients with mSTS. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. Methods: This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. Conclusions: Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality. [ABSTRACT FROM AUTHOR]

ROS1 rearrangements are considered rare in non-small-cell lung cancer (NSCLC). This retrospective real-world study aimed to evaluate first-line treatment with crizotinib, a tyrosine kinase inhibitor (TKI) standard of care vs. new generation ROS1 anti-cancer agents. Forty-nine ROS1-expressing NSCLC patients, diagnosed with advanced metastatic disease, were included. Molecular profiling using either FISH/CISH or NGS was performed on tissue samples. Twenty-eight patients were treated with crizotinib, while fourteen patients were administered newer drugs (entrectinib, repotrectinib) and seven patients received platinum-doublet chemotherapy in a first-line setting. Overall response rate and disease control rate for the crizotinib and entrectinb/repotrectinib cohort were 68% and 82% vs. 86% and 93%, respectively. Median progression free survival was 1.6 years (95% CI 1.15–2.215) for the crizotinib treatment vs. 2.35 years for the entrectinib/repotrectinib cohort (95% CI 1.19–3.52). Central nervous system progression was noted in 20% and 25% of the crizotinib and entrectinib/repotrectinib cohorts, respectively. This multi-center study presents real-world treatment patterns of ROS1 NSCLC population, indicating that crizotinib exhibited comparable results to entrectinib/repotrectinib in a first-line setting, although both response rate and survival was numerically longer with treatment with newer agents. [ABSTRACT FROM AUTHOR]

Background: The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)‐positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first‐line therapy. However, with the development of newer treatment regimens, there is a lack of evidence regarding which is the optimal treatment strategy. The aim of this network meta‐analysis was to evaluate the efficacy and safety of first‐line regimens for advanced HER2‐positive breast cancer by indirect comparisons. Methods: A systematic review and Bayesian network meta‐analysis were conducted. The PubMed, EMBASE, and Cochrane Library databases were searched for relevant articles published through to December 2023. The hazard ratio (HR) and 95% credible interval (CrI) were used to compare progression‐free survival (PFS) between treatments, and the odds ratio and 95% CrI were used to compare the objective response rate (ORR) and safety. Results: Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed. Compared with the traditional trastuzumab and docetaxel regimen, PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen (HR: 0.41, 95% CrI: 0.22–0.75) and the pertuzumab and trastuzumab plus docetaxel regimen (HR: 0.65, 95% CrI: 0.43–0.98). Consistent with the results for PFS, the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen. The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR. Comparable results were found for grade ≥3 AE rates of ≥10%. Conclusions: Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first‐line therapy for patients with HER2‐positive breast cancer. [ABSTRACT FROM AUTHOR]

Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFRL858R mutation caused by c.2573 T > G, have been identified in non‐small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFRL858R (N = 124), EGFRL858Q/M (N = 17), or classical EGFRL858R mutations (N = 348). The comparison of molecular features was performed using treatment‐naïve tumor tissues. Survival benefits and resistance mechanisms of first‐line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFRL858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFRL858R. Concomitant EGFRL861Q mutations were enriched in NSCLCs with EGFRL858Q/M (p < 0.01), with cooccurrence in those carrying EGFRL858M. Patients with uncommon EGFRL858R experienced improved progression‐free survival (PFS) compared to those with classical EGFRL858R (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41–0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti‐vascular therapy (HR: 0.55, 95% CI: 0.39–0.77). Furthermore, EGFRL858Q/M patients showed enhanced first‐line PFS (vs. classical EGFRL858R, HR: 0.26, 95% CI: 0.10–0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFRL858R and classical EGFRL858R had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first‐line EGFR TKIs than those with the classical EGFRL858R. [ABSTRACT FROM AUTHOR]

Objective: Both camrelizumab plus paclitaxel and carboplatin (CTC) and sintilimab plus gemcitabine and cisplatin or carboplatin (SGP) have been approved by the National Medical Products Administration of China (NMPA) for the first-line treatment of local advanced or metastatic sqNSCLC. However, the comparison of the two treatments as first-line treatments in efficacy or pharmacoeconomics has barely been studied. To deeply understand the costs and outcomes of the two treatments, this work directly compared the cost-effectiveness for the first-line treatment of local advanced or metastatic squamous NSCLC in the Chinese mainland. Methods: A network meta-analysis was first performed based on the three clinical trials, namely, CameL-Sq, ORIENT-12, and C-TONG1002, to compare the clinical benefits of the two treatments. The Weibull approximation was applied to further calculate the life expectancy of the two treatments. The partitioned survivalmodel (PSM) was next established, and one-way sensitivity analysis and probabilistic sensitivity analysis were also performed to evaluate the stability of the underlying parameter values and assumptions within the model. Results: CTC treatment gained 0.68 QALYs and cost $14,764. SGP treatment gained 0.54 QALYs and cost $14,584. The CTC arm gained 0.14 additional QALYs and cost $179 more than the SGP arm, and the ICERs was $1,269/QALY, which was lower than one-fold GDP per capita in the Chinese mainland ($12,734 GDP per capita in 2022). In probabilistic sensitivity analysis, when the WTP ranged from $12,734-38,202 (1-3 folds, 2022 GDP per capita in China), the CTC group had higher probabilities than the SGP group for being cost effective, which ranged from 85.65% to 88.38%. Conclusion: From the perspective of the payers, camrelizumab plus chemotherapy was cost-effective compared with sintilimab plus chemotherapy for the first-line treatment of local advanced or metastatic squamous NSCLC in the Chinese mainland. [ABSTRACT FROM AUTHOR]

Objective: Selecting between programmed cell death ligand 1 (PD-L1) inhibitor or programmed cell death 1 (PD-1) inhibitor plus chemotherapy as first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) patients urgently needs to be answered. Methods: Eligible phase 3 randomized clinical trials evaluating regimens based on PD-1/PD-L1 inhibitors as first-line treatment in ES-SCLC patients were systematically searched on the PubMed and Cochrane Library databases and major international conferences from 01/01/2018 to 18/09/2023. The individual patient data (IPD) were recuperated from the Kaplan–Meier curves of the overall survival (OS) and progression-free survival (PFS) of the included studies using the IPDfromKM method. The reconstructed data were pooled into unified arms, including the PD-L1 inhibitor plus chemotherapy group (PD-L1 group), PD-1 inhibitor plus chemotherapy group (PD-1 group), and PD-1 (L1) inhibitor and chemotherapy plus other (anlotinib group, tiragolumab group, and tremelimumab group). Subsequently, the PD-L1 group was indirectly compared with the other groups. A standard statistical analysis was conducted using the “survival” package for the time-to-event endpoint. The primary outcomes were the OS and PFS of the PD-L1 group and the PD-1 inhibitor group. The secondary outcomes included safety and the 12- and 24-month restricted mean survival time (RMST) of the PD-L1 group and PD-1 group. Results: A total of 9 studies including 11 immunotherapy cohorts were included. No significant difference in PFS (hazard ratio [HR]: 0.96, 95% confidence interval [CI]: 0.86–1.06), OS (HR: 0.94, 95% CI: 0.84–1.05), and 12-month and 24-month RMST for OS (P = 0.198 and P = 0.216, respectively) was observed between the PD-L1 group and the PD-1 group. In contrast, the anlotinib group showed significantly better OS (HR: 0.70, 95% CI: 0.55–0.89), PFS (HR: 0.69, 95% CI: 0.58–0.83), and RMST for OS compared to the PD-L1 group. The tiragolumab group showed similar efficacy to the PD-L1 group. However, the tremelimumab group exhibited inferior efficacy than the PD-L1 group. The incidence of ≥grade 3 treatment-emergent adverse events (TEAEs) was significantly higher in the PD-1 group compared to the PD-L1 group (85.4% vs. 69.6%, P <.001), whereas the incidence of irAEs was similar between the two groups. Conclusion: This reconstructed IPD analysis revealed that PD-1 inhibitors plus chemotherapy achieved similar efficacy to PD-L1 inhibitors plus chemotherapy as first-line treatment in ES-SCLC patients, whereas PD-L1 inhibitors plus chemotherapy had a better safety profile. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and safety of first-line therapy with palbociclib in a Spanish cohort treated after palbociclib approval. Methods: PALBOSPAIN is an observational, retrospective, multicenter study evaluating real-world patterns and outcomes with 1 L palbociclib in men and women (any menopausal status) with advanced HR+/HER2– BC diagnosed between November 2017 and November 2019. The primary endpoint was real-world progression-free survival (rw-PFS). Secondary endpoints included overall survival (OS), the real-world response rate (rw-RR), the clinical benefit rate, palbociclib dose reduction, and safety. Results: A total of 762 patients were included. The median rw-PFS and OS were 24 months (95% CI 21–27) and 42 months (40-not estimable [NE]) in the whole population, respectively. By cohort, the median rw-PFS and OS were as follows: 28 (95% CI 23–39) and 44 (95% CI 38-NE) months in patients with de novo metastatic disease, 13 (95% CI 11–17) and 36 months (95% CI 31–41) in patients who experienced relapse < 12 months after the end of ET, and 31 months (95% CI 26–37) and not reached (NR) in patients who experienced relapse > 12 months after the end of ET. rw-PFS and OS were longer in patients with oligometastasis and only one metastatic site and those with non-visceral disease. The most frequent hematologic toxicity was neutropenia (72%; grade ≥ 3: 52.5%), and the most common non-hematologic adverse event was asthenia (38%). Conclusion: These findings, consistent with those from clinical trials, support use of palbociclib plus ET as 1 L for advanced BC in the real-world setting, including pre-menopausal women and men. Trial registration number: NCT04874025 (PALBOSPAIN). Date of registration: 04/30/2021 retrospectively registered. [ABSTRACT FROM AUTHOR]

Abstract Background This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. Methods This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. Conclusions Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

ROS1 rearrangements are considered rare in non-small-cell lung cancer (NSCLC). This retrospective real-world study aimed to evaluate first-line treatment with crizotinib, a tyrosine kinase inhibitor (TKI) standard of care vs. new generation ROS1 anti-cancer agents. Forty-nine ROS1-expressing NSCLC patients, diagnosed with advanced metastatic disease, were included. Molecular profiling using either FISH/CISH or NGS was performed on tissue samples. Twenty-eight patients were treated with crizotinib, while fourteen patients were administered newer drugs (entrectinib, repotrectinib) and seven patients received platinum-doublet chemotherapy in a first-line setting. Overall response rate and disease control rate for the crizotinib and entrectinb/repotrectinib cohort were 68% and 82% vs. 86% and 93%, respectively. Median progression free survival was 1.6 years (95% CI 1.15–2.215) for the crizotinib treatment vs. 2.35 years for the entrectinib/repotrectinib cohort (95% CI 1.19–3.52). Central nervous system progression was noted in 20% and 25% of the crizotinib and entrectinib/repotrectinib cohorts, respectively. This multi-center study presents real-world treatment patterns of ROS1 NSCLC population, indicating that crizotinib exhibited comparable results to entrectinib/repotrectinib in a first-line setting, although both response rate and survival was numerically longer with treatment with newer agents.

Background: Renal cell carcinomas (RCCs) are renal parenchymal neoplasms that contribute to <5% of cancer cases worldwide. Within the diverse group of renal tumours, clear cell carcinoma is the most common subtype. The recommended first-line treatment for metastatic disease is a tyrosine kinase inhibitor given either as monotherapy or in combination with an immune checkpoint inhibitor, based on improved survival outcomes. These endpoints are not only influenced by the initial risk stratification but also by certain variables such as the neutrophil-to-lymphocyte (NLR) ratio. Methods: A retrospective review was conducted to evaluate the progression-free survival (PFS) with first-line treatment in patients with metastatic RCC treated at our institute from the year 2017-2021. We also investigated the association of PFS with both Memorial Sloan Kettering Cancer Center risk groups and the pretreatment NLR ratio. Results: Overall, 35 patients were enrolled after fulfilling the eligibility criteria. Of these, 25 patients received Pazopanib, 5 patients were treated with Sunitinib and the remaining patients were administered Pembrolizumab with Axitinib. Two-thirds of the study population belonged to the intermediate-risk group. The median PFS for all participants was 16 months. Among the overall population, patients in the favourable-risk group demonstrated superior PFS. Patients with elevated pretreatment NLR experienced shorter PFS compared to the patients with low to normal NLR. Conclusion: This review highlights the prognostic significance of initial risk stratification and pretreatment NLR in predicting the response to first-line treatment in metastatic RCC patients. As this is a comprehensive study emphasizing the outcomes of metastatic RCC in Pakistan, it fills a void in the literature by providing invaluable perspectives on the real-world outcomes of patients. This not only enhances our understanding of disease management in this region but also lays the foundation for future investigations. [ABSTRACT FROM AUTHOR]

Objectives: No head-to-head trials had been performed to estimate the relative effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). We aimed to perform a systematic review and network meta-analysis to evaluate the comparative effectiveness of various systemic treatment agents for patients with mCRPC. Methods: A comprehensive literature search was conducted for abstracts and full-text articles from the database's inception through April 27, 2023. The study concentrated on assessing radiographic progression-free survival (rPFS) for both overall and homologous recombination repair mutation (HRRm) population, with overall survival (OS) as the secondary measure. Under the Bayesian framework, the overall effect was pooled using the fixed-effects model in base case analysis. Scenario analysis using restricted mean survival time (RMST) methods was performed to test the robustness of the results. Results: Nine studies with 6,830 patients and 8 unique treatment options were included. Network meta-analysis demonstrated that talazoparib in combination with enzalutamide (TALA + ENZA; overall population, hazard ratio [HR], 0.20; 95% credible interval [CrI]: 0.16–0.26; RMST, 3.51; 95% confidence interval [CI] 2.46–4.60; HRRm population, HR, 0.15; 95% CrI: 0.09–0.23; RMST, 4.14; 95% CI 2.84–5.39) was superior to other treatments in the first-line setting in terms of rPFS. The results of Bayesian framework and RMST models showed consistent efficacy ranks. When extrapolated to overall survival benefit, within the Bayesian framework, olaparib plus abiraterone acetate and prednisone (OLAP + AAP) achieved the highest OS benefit for the overall population, which was not statistically significant when compared to TALA + ENZA. However, TALA + ENZA achieved the highest OS benefit at 3 years by applying RMST. Conclusions: We suggest that talazoparib in combination with enzalutamide is probably a preferred treatment agent for the overall population and HRRm patients with mCRPC. Given the limitations of network framework and the modeling assumptions undertaken to finalize the analyses, results should be cautiously interpreted. [ABSTRACT FROM AUTHOR]

Purpose: The treatment of the advanced non-small cell lung cancer (NSCLC) with KRAS mutation has been closely paid more attention. The aim of this study is to investigate the efficacy of different first-line regimens in advanced KRAS-mutated non-small cell lung cancer. Methods: In our retrospective study, we collected patients with advanced NSCLC with KRAS mutation in Zhejiang Cancer Hospital between January 2015 and May 2023. We analyzed the benefit of different first-line therapy according to theraputic methods and the differential effect of the same treatment method among KRAS-mutated subtypes. We divided the patients into group A (A1, chemotherapy alone; A2, immunotherapy alone) and group B (B1, chemotherapy plus immunotherapy; B2, chemotherapy combined with antiangiogenic therapy; B3, chemotherapy combined with immunotherapy plus antiangiogenic therapy). The Kaplan–Meier survival curve was used to reflect the PFS and OS of different methods. The objective response rate (ORR) and the disease control rate (DCR) were used to evaluated the response. Results: We enrolled 227 patients including eighty-two with KRAS G12C mutation. The ORR and DCR of first-line treatment in the overall population were 32.2% and 80.6% respectively. The median PFS was 6.7 months and the median OS was 17.4 months for the overall population. The PFS of the Group B was significantly better than that of the Group A (7.7 months vs 5.4 months, P = 0.003), while no significant difference in OS was observed (19.4 months vs 15.0 months, P = 0.077). In the Group B, chemotherapy combined immunotherapy with antiangiogenic therapy showed better PFS than chemotherapy plus immunotherapy (14.1 months vs 7.7 months, P = 0.049), and OS also showed that tendency of difference (31.9 months vs 19.3 months, P = 0.158). There was no statistically significant difference between KRAS G12C and non-G12C mutation according to first-line treatment methods, whereas patients with TP53 co-mutation showed a better survival benefit (OS, 23.7 vs 12.5 months, P = 0.023). Conclusion: In the first-line treatment, combination regimen has advantages over single regimen. Among them, chemotherapy combined with immunotherapy plus antiangiogenic therapy can achieve significant efficacy benefits. [ABSTRACT FROM AUTHOR]

Background: Metastatic triple-negative breast cancer (mTNBC) is an aggressive histological subtype with poor prognosis. Several first-line treatments are currently available for mTNBC. This study conducted a network meta-analysis to compare these first-line regimens and to determine the regimen with the best efficacy. Methods: A systematic search of PubMed, EMBASE, the Cochrane Central Register of Controlled Bases, and minutes of major conferences was performed. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were analyzed via network meta-analysis using the R software (R Core Team, Vienna, Austria). The efficacy of the treatment regimens was compared using hazard ratios and 95% confidence intervals. Results: A total of 29 randomized controlled trials involving 4607 patients were analyzed. The ranking was based on the surface under the cumulative ranking curve. Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR. For programmed death-ligand 1 (PD-L1) and breast cancer susceptibility gene (BRCA) mutation-positive tumors, atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib was superior to docetaxel plus capecitabine. No significant difference was observed among the treatments in OS. Neutropenia, diarrhea, and fatigue were common serious adverse events. Conclusion: Cisplatin combined with nab-paclitaxel or paclitaxel is the preferred first-line treatment for mTNBC. For PD-L1 and BRCA mutation-positive tumors, atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option. Neutropenia, diarrhea, and fatigue are frequently occurring serious adverse events.

Aim: This study assessed real-world treatment in patients with metastatic urothelial carcinoma (mUC) in Germany. Materials & methods: Patients diagnosed with mUC from 2015 to 2019 were identified in two claims databases: AOK PLUS and GWQ. Results: 3226 patients with mUC were analyzed; 1286 (39.9%) received systemic treatment within 12 months of diagnosis (platinum-based chemotherapy: 64.2%). Factors associated with receiving treatment were: younger age, male sex, less comorbidity and recent diagnosis. In AOK PLUS and GWQ populations, unadjusted median overall survival (interquartile range) from diagnosis in treated patients was 13.7 (6.8–32.9) and 13.8 (7.1–41.7) months, and in untreated patients was 3.0 (1.2–10.8) and 3.6 (1.2–18.8) months, respectively. Conclusion: A significant proportion of patients with mUC in Germany receive no systemic treatment. Plain language summary What is this article about? This article reports the results from a study in Germany between 2015 and 2019 that investigated how advanced bladder cancer that has spread to other organs was treated and how long people lived after diagnosis. The study looked at systemic therapies, which means treatments that affect the entire body. What were the results? Only 40% of people diagnosed with advanced bladder cancer received systemic treatment within the first 12 months. Of those who did receive systemic treatment, the majority received combination therapy that included a chemotherapy drug containing platinum (64%). Systemic treatment was more likely to be given to people who were younger, less sick, male, or more recently diagnosed. After 12 months, 56% of treated people were still alive, compared with 26% of people without treatment. On average, people who received systemic treatment lived for about 14 months, while people without systemic treatment lived for only 3 to 4 months. What do the results of the study mean? Many people with advanced bladder cancer in Germany do not receive systemic treatment. People who receive treatment are likely to live longer than those who do not receive treatment. This study sought to explore real-world treatment rates, treatment patterns, and outcomes in patients with metastatic urothelial carcinoma (mUC) in Germany. Patients in Germany with an incident mUC diagnosis from 2015 to 2019 were identified in two claims databases (AOK PLUS and GWQ) covering ≈8 million patients. Of 3226 patients with mUC identified, 1892 (58.6%) did not receive systemic treatment, 1286 (39.9%) received systemic treatment within the first 12 months after diagnosis and 48 (1.5%) received systemic treatment ≥12 months after diagnosis. Among treated patients, 825 (64.2%) received platinum-based chemotherapy, 322 (25.0%) received non-platinum chemotherapy, and 139 (10.8%) received immunotherapy. Factors associated with a higher likelihood of receiving systemic treatment within 12 months included younger age, lower comorbidity score, more recent diagnosis and male sex. The probability of survival at 12 months after diagnosis in the treated and untreated cohorts was 56.1 and 26.1%. The probability of survival at 12 months after diagnosis for patients receiving platinum-based chemotherapy, non-platinum chemotherapy, or immunotherapy was 60.4, 49.4 and 46.8%, respectively. Unadjusted median OS from diagnosis in the AOK PLUS and GWQ populations in treated patients was 13.7 (interquartile range [IQR], 6.8–32.9) and 13.8 months (IQR, 7.1–41.7) months, and in untreated patients was 3.0 (IQR, 1.2–10.8) months and 3.6 months (IQR, 1.2–18.8), respectively. These findings suggest that a substantial proportion of patients with mUC in Germany remained undertreated during the study period. [ABSTRACT FROM AUTHOR]

Objectives: HER2 is an infrequently mutated driver gene in non‐small cell lung cancer (NSCLC). At present, there has been no comprehensive large‐scale clinical study to establish the optimal first‐line treatment strategy for advanced lung adenocarcinoma (LUAD) with HER2‐Mutant. Besides that, the effectiveness and safety of pyrotinib, a pan‐HER inhibitor, in the context of NSCLC are still undergoing investigation. Materials and Methods: In this study, we conducted a retrospective data collection of HER2‐Mutated advanced LUAD who received first‐line treatment and pyrotinib between May 2014 and June 2023. Patients treated with chemotherapy, chemotherapy + immune checkpoint inhibitors (ICIs), chemotherapy + bevacizumab and pyrotinib in first‐line treatment. Furthermore, we collected data on the efficacy and safety of pyrotinib in these patients after disease progression. The main endpoint of the study was progression‐free survival (PFS). Results: In the final analysis, 89 patients were included in the first‐line cohort and 30 patients were included in the pyrotinib cohort. In the first‐line treatment cohort, chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib exhibited notable survival benefits compared to chemotherapy (median PFS: 9.87 vs. 7.77 vs. 7.10 vs. 5.40 months, p‐value < 0.05). Furthermore, patients with a first‐line treatment PFS of less than 6 months may potentially benefit from subsequent treatment with pyrotinib (median PFS: 7.467 vs. 3.000, p‐value = 0.0490). Conclusions: In the first‐line treatment of HER2‐Mutant LUAD, regimens involving combinations like chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib may confer enhanced survival advantages compared to chemotherapy. Nevertheless, no significant distinctions were observed among these three treatment strategies, underscoring the imperative to identify biomarkers for the discerning selection of suitable therapeutic modalities. Moreover, patients with suboptimal response to first‐line treatment may potentially derive more benefit from pyrotinib. [ABSTRACT FROM AUTHOR]

Objective The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA). Design This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment. Methods Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality. Results Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P <.01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P =.03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P <.01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P =.04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline. Conclusion In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori eradication failure influences its antibiotic resistance. Aims: This study aimed to evaluate the effect of previous treatment failures on it, including the changes in the antibiotic resistance rates, minimal inhibitory concentration (MIC) distributions, and resistance patterns. Materials and Methods: This single‐center retrospective study included 860 primary isolates and 247 secondary isolates. Antibiotic susceptibility testing was performed for amoxicillin, metronidazole, clarithromycin, levofloxacin, furazolidone, tetracycline, and rifampicin. The demographic data and detailed regimens were collected. Results: The primary resistance rates to amoxicillin, metronidazole, clarithromycin, levofloxacin, tetracycline, rifampin, and furazolidone were 5.93%, 83.84%, 28.82%, 26.28%, 0.35%, 1.16%, and 0%, while secondary were 25.10%, 92.31%, 79.76%, 63.16%, 1.06%, 3.19%, and 0%, respectively. The resistance rates to amoxicillin, metronidazole, clarithromycin, and levofloxacin increased significantly with the number of treatment failures accumulated, and showed a linear trend. The proportion of primary and secondary multidrug‐resistant (MDR) isolates were 17.79% and 63.16%, respectively. The MIC values of amoxicillin, clarithromycin, and levofloxacin were elevated significantly with medication courses increased. Conclusion: The prevalence of amoxicillin, clarithromycin, levofloxacin, and metronidazole resistance would increase rapidly following first‐line treatment failure, as well as the MIC values of them. Clinicians should pay great attention to the first‐line treatment to cure H. pylori infection successfully. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the relative efficacy and safety of first-line treatment options for metastatic castration-resistant prostate cancer (mCRPC). Methods: We systematically searched electronic databases, including PubMed and Web of Science, for studies published from their inception to April 3rd, 2023. Inclusion criteria were: 1) Completed Phase III or IV randomized controlled trials (RCTs) registered on ClinicalTrials.gov; 2) Patients with a confirmed diagnosis of mCRPC who had not previously received chemotherapy or novel endocrine therapies. We conducted a network meta-analysis using R software (version 3.4.0). Network graphs and risk of bias graphs were generated using Stata 14.0 and RevMan 5.4, respectively. The primary outcome was overall survival (OS), and the secondary outcome was the incidence of severe adverse events (SAEs). Results: Seven RCTs encompassing 6,641 patients were included. The network meta-analysis revealed that both docetaxel+prednisone (DP) and cabazitaxel +prednisone (CP) significantly improved OS compared to abiraterone. Compared to placebo, DP showed comparable results to both cabazitaxel 20 mg/m^2 +prednisone (C20P) and cabazitaxel 25 mg/m^2+prednisone (C25P) in terms of OS. For SAEs, both DP and C20P were superior to C25P, with no statistical difference between C20P and DP. The probability ranking plots indicated that C25P ranked highest for OS, while DP ranked highest for SAEs. Conclusions: Based on our network meta-analysis, we recommend cabazitaxel 20 mg/m^2+prednisone (C20P) as the primary choice for first-line management of mCRPC, followed by DP. Enzalutamide and abiraterone are suggested as subsequent options. Radium-223 may be considered for patients presenting with bone metastases. [ABSTRACT FROM AUTHOR]

Background: The epidermal growth factor receptor (EGFR) ex20ins mutation, as a rare subtype of mutation, has gradually attracted attention. Its heterogeneity is high, its prognosis is extremely poor, and the efficacy of existing traditional treatment plans is limited. In this study, we aimed to evaluate efficacy of high dose furmonertinib as a first-line treatment for EGFR ex20ins-positive NSCLC. Methods: This is a retrospective, multi-center, non-interventional study. From May 2021 to March 2023, 9 NSCLC patients with EGFR ex20ins were enrolled. Efficacy and safety of 160 mg furmonertinib were evaluated. Objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and treatment related adverse events (TRAEs) were assessed. Results: Of the evaluated patients, six patients experienced partial remission (PR), two patients experienced stable disease (SD) and one patient experienced progress disease (PD). Data indicated 66.7% ORR and 88.9% DCR. The median progression free survival (PFS) was 7.2 months (95% CI: 6.616 - 7.784). Besides, a longgest PFS with 18 months was found in one pa t ient with p.H773_V774insGTNPH mutation. No ≥ level 3 adverse events have been found. Conclusions: The study proved the potential efficacy of 160mg furmonertinib in patients with advanced NSCLC with EGFR ex20ins. Meanwhile, 160mg furmonertinib had a good safety profile. [ABSTRACT FROM AUTHOR]

Aim: Real-world adverse event (AE) data are limited for first-line (1L) treatments in advanced non-small-cell lung cancer (NSCLC). Methods: Using Flatiron Health Spotlight data, information for a pre-specified list of AEs was abstracted and described among patients with advanced NSCLC receiving 1L nivolumab + ipilimumab (NIVO + IPI), NIVO + IPI + chemotherapy and other approved immuno-oncology (IO) therapy + chemotherapy combination therapies. Results: Fatigue, pain, dyspnea, weight loss, decreased appetite, diarrhea, nausea/vomiting, cough, constipation and rash were the most common AEs. Rates of AEs were generally numerically similar across the three cohorts. The majority of patients received treatment for AEs and approximately one fourth of the patients had hospitalization due to their AEs. Conclusion: The real-world safety experiences of patients treated with 1L NIVO + IPI-based regimens were in general similar to those treated with other approved IO + chemotherapy combination therapies. Immuno-oncology (IO) therapies boost the immune system to fight cancer cells and have been approved to treat non-small-cell lung cancer (NSCLC). The IO combination of nivolumab + ipilimumab (NIVO + IPI) is approved to treat NSCLC that has spread to other parts of the body or come back and at least 1% of the tumor cells express a protein called PD-L1; NIVO + IPI is also approved in combination with a short course chemotherapy, independent of tumor PD-L1 expression. While NIVO + IPI-based regimens are generally safe, some patients experienced side effects during the clinical trial. However, there is limited information on the side effects of these treatments in a real-world setting. This study analyzed data on side effects from a de-identified database of patients with advanced NSCLC who were treated with NIVO + IPI, NIVO + IPI + chemotherapy, or other approved IO + chemotherapy combinations based on information obtained from physicians' notes in clinical practice settings. The most common side effects among patients in all groups were tiredness, pain, shortness of breath, weight loss, decreased appetite, diarrhea, nausea/vomiting, cough, constipation and rash. The rates at which the side effects occurred were numerically similar regardless of the specific treatment that patients received. Approximately one-quarter of patients in each treatment group were hospitalized because of a side effect. These results show that in a real-world setting, NIVO + IPI-based regimens have similar safety to other IO + chemotherapy combinations when used as a first treatment for NSCLC that has spread or come back. [ABSTRACT FROM AUTHOR]

Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. #NCT02900443. [Display omitted] • Limited efficacy and tolerability of standard prednisolone and azathioprine combination therapy in autoimmune hepatitis. • Mycophenolate mofetil combined with prednisolone is effective as first-line therapy for achieving biochemical remission. • Mycophenolate mofetil has a more favourable tolerability profile than azathioprine. [ABSTRACT FROM AUTHOR]

Objective Digital self-management programs are increasingly used in the management of osteoarthritis (OA). Little is known about heterogeneous patterns in response to these programs. We describe weekly pain trajectories of people with knee or hip OA over up to 52-week participation in a digital self-management program. Methods Observational cohort study among participants enrolled between January 2019 and September 2021 who participated at least 4 and up to 52 weeks in the program (n  = 16 274). We measured pain using Numeric Rating Scale (NRS 0–10) and applied latent class growth analysis to identify classes with similar trajectories. Associations between baseline characteristics and trajectory classes were examined using multinomial logistic regression and dominance analysis. Results We identified 4 pain trajectory classes: "mild-largely improved" (30%), "low moderate-largely improved" (34%), "upper moderate-improved" (24%), and "severe-persistent" (12%). For classes with decreasing pain, the most pain reduction occurred during first 20 weeks and was stable thereafter. Male sex, older age, lower body mass index (BMI), better physical function, lower activity impairment, less anxiety/depression, higher education, knee OA, no walking difficulties, no wish for surgery and higher physical activity, all measured at enrolment, were associated with greater probabilities of membership in "mild-largely improved" class than other classes. Dominance analysis suggested that activity impairment followed by wish for surgery and walking difficulties were the most important predictors of trajectory class membership. Conclusions Our results highlight the importance of reaching people with OA for first-line treatment prior to developing severe pain, poor health status and a wish for surgery. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate whether the efficacy and safety of PD-1 inhibitors combined with chemotherapy in the treatment of patients with esophageal squamous cell carcinoma (ESCC) with distant metastasis in the real world are as effective and safe as in clinical trials. Patients and methods: From July 2019 to July 2023, a total of 422 patients with distant metastasis of ESCC were included and divided into the PD-1 inhibitor combined chemotherapy group (PC group) and the chemotherapy alone group (C group) according to the treatment regimen. There were 278 patients in the PC group and 144 patients in the C group. The primary endpoint of this study was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: The objective response rate (ORR) and disease control rate (DCR) of the PC group were 44.60% (124/278) and 91.00% (253/278), respectively, which were 18.9% and 3.5% higher than those of the C group. The median PFS and median OS of the PC group were significantly better than those of the C group (median PFS: 6.5 vs. 5.5 months, P < 0.001; median OS: 16.6 vs. 13.9 months, P = 0.002). Further univariate and multivariate Cox analysis showed that the Eastern Cooperative Oncology Group performance status (ECOG PS) score and the number of metastatic sites were potential predictors of PFS in PC patients. The combination of PD-1 inhibitors with cisplatin and paclitaxel (TP) was more beneficial for patients with PFS compared to the combination of cisplatin and fluorouracil (PF). Furthermore, the presence of bone metastasis, body mass index (BMI), and lymphocyte-to-monocyte ratio (LWR) before treatment may be potential predictive factors for patient OS. The adverse reactions that occurred in the PC group can be tolerated or alleviated after both prevention and active treatment. Conclusions: The combination of PD-1 inhibitors and chemotherapy as first-line treatment for ESCC patients with distant metastasis still has good efficacy and safety compared to clinical trials in the real world. [ABSTRACT FROM AUTHOR]

Abstract Background To evaluate the outcomes of first‐line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML‐CP) in real‐world clinical practice. Methods A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. Results Nilotinib‐treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib‐treated patients. However, there was no significant difference in 5‐year overall survival (OS) or progression‐free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib‐treated patients had a higher failure‐free survival (FFS) and event‐free survival (EFS) than imatinib‐treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). Conclusions This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.

BackgroundAdvanced breast cancer (ABC) is a heterogeneous disease with varied prognoses, that is affected by many clinicopathological features. This study aimed to investigate the clinicopathological characteristics, first-line treatment (FLx), and prognostic impact of these features on survival among Syrian patients with ABC.Materials and methodsThis retrospective cohort study included patients with ABC. The association of clinicopathological factors with survival was assessed using Kaplan-Meier curves and the log-rank test, as well as the Cox proportional hazards regression model to calculate the hazard ratio (HaR).ResultsA total of 423 patients with ABC were included in the study, with a median age (range) of 47 years (23-82). 83% of metastases were metachronous. Most patients (91.8%) received chemotherapy as the FLx. The median progression-free survival (PFS) and overall survival (OS) of all the patients were 7 and 16 months, respectively. The median PFS was associated with four factors, which were time of metastasis (adjusted HaR=1.861, 95% CI 1.420-2.438, P

This study aimed to identify the most effective first-line treatment for patients with metastatic colorectal cancer based on overall survival, identify the most commonly used treatment, and generate a meaningful ranking among all available treatments based on their relative effectiveness. Researchers used the ANOVA parametrization method to fit the second-order fractional polynomial network meta-analysis with a random-effect model. Using a non-proportional hazards network meta-analysis, 46 treatments were compared by considering a combination of direct and indirect evidence extracted from clinical trial studies. Included in the review were 46 trials involving 21350 patients. Between January 2000 and January 2023, researchers conducted a thorough search through Embase, PubMed/Medline, and Scopus. To undertake a secondary analysis of this data, we recreate individual patient data from published Kaplan-Meier (K-M) survival curves and assess the accuracy of that reconstruction. A random-effects model was used to evaluate the pooled overall survival and hazard ratio with a 95 percent confidence interval. The predicted survival curves for the network meta-analysis showed that GOLFIG and FOLFOX + Cetuximab treatments have higher survival, respectively. Our results provide moderate quality evidence and comparative effective estimates for various available first-line treatments for metastasis colorectal cancer based on network meta-analysis.

BackgroundIn the landscape of metastatic soft tissue sarcoma (mSTS) treatment, anthracyclines have shown efficacy; however, their associated toxicity imposes significant limitations, especially in frail elderly patients with mSTS who are highly susceptible to severe adverse effects. In this context, trabectedin, due to its distinct pharmacological profile and safety profile, may represent an interesting alternative being demonstrated to be active in treating mSTS. These features hold particular significance for elderly and unfit patients with mSTS, where balancing treatment benefits with potential adverse effects represents the pivotal objective.MethodsThe investigation was focused on a specific group of 11 elderly patients with mSTS aged ≥70, all undergoing first-line treatment with trabectedin, and it was supported by comprehensive pharmacokinetic and pharmacodynamic studies. Among these patients, 9 out of 11 started the treatment at a dose of 1.5 mg/m2.ResultsThe primary objective of this investigation is to highlight trabectedin as a valuable first-line treatment option for elderly and unfit patients with mSTS. Additionally, this investigation seeks to explore whether higher administered doses of trabectedin can enhance clinical outcomes while maintaining the same toxicity profiles. The median progression-free survival (PFS) was 77 days (95% CI, 53–89), the median overall survival (OS) was 397 days (95% CI, 66–2,102), while the overall toxicity of grade 3–4 severity amounted to 43%.ConclusionThese findings provide new insights into the clinical outcomes and toxicity associated with trabectedin in an elderly patient population, enhancing our understanding of better treatment approaches for a specific population of patients with mSTS.

Background and purpose: First-line treatment (education, exercise) for patients with hip and knee osteoarthritis (OA) aims to reduce pain and improve function. We aimed to compare progression to joint replacement within 5 years between responders and non-responders to first-line treatment for hip and knee OA, respectively. Methods: This observational study included data for 30,524 knee OA and 13,787 hip OA patients from the Swedish Osteoarthritis Register, linked with the Swedish Arthroplasty Register, Statistics Sweden, and the Swedish Prescribed Drug Register. The primary prognostic factor was change in pain between baseline and 3-month follow-up, measured on a numeric rating scale (0–10, best to worst) where an improvement of ≥ 2 was classified as responder and ≤ 1 as non-responder. The main outcome was progression to joint replacement surgery within 5 years, assessed using baseline adjusted multivariable Cox regression analyses. Results: At 5 years, in hip OA, 35% (95% confidence interval [CI] 32.2–37.2) of the responders and 48% (CI 45.9–49.5) of the non-responders and in knee OA 14% (CI 13.0–15.3) of the responders and 20% (CI 18.8–20.8) of the non-responders had progressed to joint replacement. Being a responder to the treatment was associated with having a lower probability of progression to surgery for both hip OA (hazard ratio [HR] 0.4, CI 0.4–0.5) and knee OA (HR 0.6, CI 0.5–0.6). Conclusion: Patients with hip or knee OA who experienced pain relief after a first-line OA treatment program were less likely to progress to joint replacement surgery.

Summary: Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. Methods: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan–Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. Findings: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48–1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41–0.66, p

Background: This was the first Phase III randomized study comparing an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, to standard-of-care chemotherapy (pemetrexed + carboplatin followed by pemetrexed maintenance) in advanced EGFR-mutated lung cancer. The initial interim analysis showed the superiority of gefitinib over chemotherapy in terms of progression-free survival (PFS), objective response rate (ORR), and safety. Objectives: We aimed to evaluate the long-term outcomes. Our primary endpoint was to evaluate the overall survival (OS) and the secondary endpoints were progression-free survival 2 (PFS2) and duration of response (DOR). Materials and Methods: This was a Phase III open-label, randomized, parallel-group study conducted in the Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India, in patients with EGFR mutation-positive treatment-naïve Stage IIIB or IV lung adenocarcinoma. Patients were randomized to gefitinib (250 mg orally daily) or carboplatin (area under the curve 5) and pemetrexed (500 mg/m2) chemotherapy, followed by maintenance pemetrexed (500 mg/m2). Results: Between February 2012 and April 2016, 290 patients were randomized:145 to each arm. At a median follow-up of 104 months, all 290 (100%) patients had progressed, and 287 (99%) deaths had occurred. The median OS in the gefitinib arm was 19.5 months (95% confidence interval [CI], 16.7-24.8) compared to 22.6 months (95% CI, 19.2-25.2) in the chemotherapy arm; hazard ratio [HR], 1.11; 95% CI, 0.87-1.39; P, 0.423. The median PFS2 in the gefitinib arm was 15.5 months (95% CI, 13.5-18.1) compared to 12.5 months (95% CI, 11.1-14.5) in the chemotherapy arm; HR, 0.86 (95% CI, 0.66-1.13); P, 0.270. The median DOR was improved in the gefitinib arm (7.6 months; 95% CI, 5.45-9.88) compared to 3.9 months (95% CI, 3.49-6.35) in the chemotherapy arm; HR, 0.59; 95% CI, 0.42-0.82; P, 0.002. The 5-year survival was 4.1% in the gefitinib arm versus 6.8% in the chemotherapy arm. Conclusions: This study establishes the advantages of first-line EGFR TKI therapy over chemotherapy in terms of a durable response and numerically superior PFS2. Due to crossover post-progression, there was is no significant difference in OS (Clinical Trials Registry of India number: CTRI/2015/08/006113).

Pediatric low-grade gliomas are the most common brain tumours in childhood and adolescence. Despite the excellent prognosis, pediatric low-grade glioma survivors may suffer from variable long-term complications and may require repeated therapies, implying that this is a chronic disease. The current review describes the European Standard Clinical Practice recommendations for low-grade gliomas at primary diagnosis, that were developed on behalf of SIOPe BTG LGG Working Group within the framework of European Reference Network PaedCan. The manuscript describes the diverse spectrum of pediatric low-grade gliomas in terms of location, age, underlying cancer predisposition syndromes, and special circumstances, such as infantile chiasmatic hypothalamic glioma and diencephalic syndrome, as well as current diagnostic criteria and indications for treatment. Furthermore, it provides current knowledge in histopathology and molecular pathology. Finally, the review focuses on the need for a multidisciplinary approach and treatment indications providing a guide on current treatment modalities, used as first-line therapy in Europe along with information on adverse effects, and follow-up.

Simple Summary: Randomized clinical trials show a survival benefit associated with immuno-molecular therapy (IMT) use in metastatic or recurrent cervical cancer. This study investigated IMT use and survival in stage IVB cervical cancer patients in Commission on Cancer® (CoC)®-accredited facilities. Patients diagnosed with stage IVB cervical cancer in the National Cancer Database and treated with first-line therapy with chemotherapy alone or with radiotherapy ± IMT were studied. Adjusted risks of death were estimated in patients treated with ±IMT after applying a propensity score analysis to balance the clinical covariates. There were 3164 evaluable patients, including 31% who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. In propensity-score-balanced patients, the median survival was 5 months longer with vs. without IMT. The adjusted risk of death was 28% lower following treatment with vs. without IMT. IMT was associated with a consistent survival benefit in real-world patients in (CoC)®-accredited facilities with stage IVB cervical cancer. Purpose: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials. Methods: Patients diagnosed with stage IVB cervical cancer during 2013–2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates. Results: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. Age, insurance, facility type, sites of distant metastasis, and type of first-line treatment were independently associated with using IMT. In propensity-score-balanced patients, the median survival was 18.6 vs. 13.1 months for with vs. without IMT (p < 0.001). The AHR was 0.72 (95% CI = 0.64–0.80) for adding IMT overall, 0.72 for IMT + CT, 0.66 for IMT + CT + EBRT, and 0.69 for IMT + CT + EBRT + ICBT. IMT-associated survival improvements were suggested in all subgroups by age, race/ethnicity, comorbidity score, facility type, tumor grade, tumor size, and site of metastasis. Conclusions: IMT was associated with a consistent survival benefit in real-world patients with stage IVB cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose: Irinotecan has considerable importance in the treatment of metastatic colorectal cancer (mCRC). UDP-glucoronyltransferase (UGT) 1A1 is responsible for the inactivation of SN-38, a metabolite of irinotecan. Depending on UGT1A1 polymorphism, the activity of the UGT enzyme can be reduced leading to more frequent occurrence of adverse events related to irinotecan. The present study aimed to assess the safety and efficacy of different doses of irinotecan adjusted according to UGT1A1 polymorphism. Methods: Thirty-four patients treated with FOLFIRI as first-line treatment for mCRC were included in this study. The irinotecan dosage was adapted on the basis of UGT1A1 polymorphisms: *1/*1 (370 mg/m2); *1/*28 (310 mg/m2), and *28/*28 (180 mg/m2). The incidence of grades 3 and 4 toxicities (neutropenia, febrile neutropenia, and diarrhoea) was recorded. Response was assessed according to the RECIST 1.1 criteria. Results: On the basis of UGT1A1 genotyping, 20 patients were *1/*1 (58.8%), 12 were *1/*28 (35.3%) and 2 were *28/*28 (5.9%). Seven patients experienced at least one severe toxicity, i.e., 21% of the population, amounting to eleven adverse events. Concerning the response rate, 15 patients (44%) had partial or complete response. Conclusion: This study demonstrates that mCRC patients treated with FOLFIRI can tolerate a higher dose of irinotecan than the standard dose, i.e., > 180 mg/m2, on the basis of their UGT1A1 genotype, without increased toxicities. Trial registration: NCT01963182 (registered on 16/10/2013, Clermont-Ferrand, France). [ABSTRACT FROM AUTHOR]

Background & Aims: Systemic therapy is mainly recommended for advanced hepatocellular carcinoma (HCC). Considering the variety of treatments available for HCC, there is a need to understand their relative benefits and risks, especially for the newly approved combination of immune checkpoint inhibitors and vascular endothelial growth factor inhibitors represented by atezolizumab in combination with bevacizumab. A reticulated metaanalysis was used to evaluate the efficacy and safety of atezolizumab-bevacizumab combination therapy compared with other first-line systemic therapies for the treatment of patients advanced HCC. Methods: PubMed, The Cochrane Library, Web of Science, and Embase databases were searched from the time of library construction to 01 December 2022, and the data were extracted and analyzed using Stata16.0 for Meta-analysis. The data were extracted separately, and a meta-analysis was performed using the software Stata16.0. Results: 16 clinical studies with 8,779 subjects were identified from 13,417 records and were used to build the evidence network for all trials. TThe combination therapy of atezolizumab and bevacizumab has the advantage of prolonging the OS of patients when treating advanced HCC [HR=5.71, 95%CI (4.30, 7.12), p<0.05] Also, the combination therapy has the advantage of prolonging the patient's progression free survival [HR=1.60, 95%CI (0.89, 2.49), p<0.05]. Conclusions: Atezolizumab-bevacizumab combination therapy can improve clinical outcomes such as OS and PFS in patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Background: Atezolizumab + bevacizumab represent the current standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, direct comparison with other combination treatments including immune checkpoint inhibitors (ICI) + tyrosine kinase inhibitors (TKIs) are lacking. Objectives: This network meta-analysis (NMA) aims to indirectly compare the efficacy and the safety of first-line systemic therapies for unresectable advanced HCC. Method: A literature search of MEDLINE, Embase, and SCOPUS databases was conducted up to October 31, 2022. Phase 3 randomized controlled trials (RCTs) testing TKIs, including sorafenib and lenvatinib, or ICIs reporting overall survival (OS) and progression-free survival (PFS) were included. Individual survival data were extracted from OS and PFS curves to calculate restricted mean survival time. A Bayesian NMA was performed to compare treatments in terms of efficacy (15- and 30-month OS, 6-month PFS) and safety, represented by grade ≥3 (severe) adverse events (SAEs). The incremental safety-effectiveness ratio as measure of net health benefit was calculated as the difference in SAE probability divided by survival difference between the 2 most effective treatments. Results: Nine RCTs enrolling 6,600 patients were included. Atezolizumab plus bevacizumab showed the highest probability (88%) of achieving the 30-month OS landmark. Lenvatinib showed a probability of 86% of achieving best PFS outcomes. ICI monotherapies ranked as most tolerable. Atezolizumab plus bevacizumab showed the best net health benefit for OS, compared to durvalumab plus tremelimumab. When evaluating the net health benefit for PFS, at a willingness-to-risk threshold of 10% of SAEs for life-month gained, atezolizumab plus bevacizumab was favoured in 78% of cases, while at threshold of 30% of SAEs for life-month gained, lenvatinib was favoured in 76% of cases. Conclusions: Atezolizumab plus bevacizumab is the best treatment in terms of net benefit and therefore it should be recommended as standard of care. Compared to atezolizumab plus bevacizumab, lenvatinib monotherapy had the best net benefit for PFS when physicians and patients are available to accept a higher risk of toxicity. [ABSTRACT FROM AUTHOR]

To evaluate the cost-effectiveness of lorlatinib compared to 1st generation anaplastic lymphoma kinase (ALK) TKI crizotinib, and 2nd generation TKIs alectinib and brigatinib, for previously untreated patients with ALK+ advanced Non-Small Cell Lung Cancer (aNSCLC). A partitioned survival model was locally adapted from a Greek payer perspective over a lifetime horizon. Clinical, safety and utility data were extracted from literature. Direct medical costs reflecting the year 2023 were included in the analysis (€). Model outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). Total cost per patient with lorlatinib, alectinib, crizotinib, and brigatinib was estimated to be €188,205, €183,343, €75,028, and €145,454 respectively. Lorlatinib appeared to yield more LYs and QALYs gained versus alectinib, crizotinib, and brigatinib. Hence, lorlatinib resulted in ICERs of €4,315 per LY gained and €4,422 per QALY gained compared to alectinib, €34,032 per LY gained and €48,256 per QALY gained versus crizotinib and €16,587 per LY gained and €26,271 per QALY gained compared to brigatinib. Lorlatinib provides substantial clinical benefit and appears to be a cost – effective treatment option compared to 1st and 2nd generation TKIs for previously untreated patients with ALK+ aNCSLC in Greece. [ABSTRACT FROM AUTHOR]

Background/Aim: Atezolizumab/bevacizumab (Atez/BV) and lenvatinib (LEN) are the recommended first-line treatments for patients with unresectable hepatocellular carcinoma (HCC). Previous reports have suggested that the tolerability and therapeutic efficacy of LEN could be enhanced by modifying its administration method. Therefore, this study compared the efficacy and safety of Atez/BV, the standard LEN therapy (standard LEN), and modified LEN therapy (modified LEN). Patients and Methods: The overall survival (OS) and the rate of discontinuation due to adverse events (AEs) were compared between groups treated with Atez/BV (n=36), standard LEN (n=30), and modified LEN (n=11). Results: Discontinuation due to AEs was required in 22.2%, 23.3%, and 9.1% of patients in the Atez/BV, standard LEN, and modified LEN groups (p=0.485). The median OS for the Atez/BV, standard LEN, and modified LEN groups was 523 [95% confidence interval (CI)=163-818], 382 (95%CI=330-547), and 604 (95% CI=257-656) days, respectively (log-rank test, p=0.949). Conclusion: Atez/BV and the standard and modified LEN regimens showed comparable efficacy and safety. [ABSTRACT FROM AUTHOR]

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Background: Cryoablation has emerged as a recognized interventional strategy for the treatment of atrial fibrillation (AF). Numerous trials have investigated cryoablation as a first-line therapy for AF. This meta-analysis aimed to evaluate the impact of cryoablation on quality of life (QoL) and safety outcomes compared to antiarrhythmic drugs (AADs) in patients with symptomatic AF. Methods: A comprehensive search of the PubMed, EMBASE, and Cochrane Library databases was conducted for randomized controlled trials (RCTs) comparing cryoablation and AADs as first-line treatments for AF until May 2023. Continuous outcome data were analyzed using mean differences (MDs) with 95% confidence intervals (CIs), and dichotomous outcome data were analyzed using relative risks (RRs) with 95% CIs. The primary outcomes assessed were QoL and serious adverse events. Results: Our analysis included four RCTs involving 928 patients. Cryoablation was associated with a significant improvement in the AF Effect on Quality of Life (AFEQT) score (3 trials; MD 7.46, 95% CI 2.50 to 12.42; p = 0.003; I² = 79%) and EQ-VAS score (2 trials; MD 1.49, 95% CI 1.13 to 1.86; p < 0.001; I² = 0%) compared to AAD therapy. Additionally, cryoablation demonstrated a modest increase in EQ-5D score from baseline compared to AAD therapy, with no statistically significance (2 trials; MD 0.03, 95% CI -0.01 to 0.07; p = 0.07; I² = 79%). Furthermore, the rate of serious adverse events was significantly lower with cryoablation compared to AAD therapy (4 trials; 11.8% vs. 16.3%; RR, 0.73; 95% CI, 0.54-1.00; p = 0.05; I² = 0%). Cryoablation was also associated with a reduction in overall adverse events, incidence of persistent AF, hospitalizations, and additional ablation. However, there was no significant difference in major adverse cardiovascular events and emergency department visits between the two treatment groups. Conclusions: Cryoablation, as a first-line treatment for symptomatic AF patients, significantly improved AF-specific quality of life and reduced serious adverse events, as well as overall adverse events, persistent AF, hospitalizations, and additional ablation compared to AADs. [ABSTRACT FROM AUTHOR]