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Marco Chiumente,1 Mauro De Rosa,2 Andrea Messori,2 Enrica Maria Proli3 1Scientific Direction, SIFaCT – Italian Society for Clinical Pharmacy and Therapeutics, Milan, 2Board of directors, SIFaCT - Italian Society for Clinical Pharmacy and Therapeutics, Milan, 3Hospital Pharmacy, Policlinico Umberto I, Rome, Italy Background and purpose: Epidemiological studies on uterine fibroids (UFs) are mostly based on surveys or analyses of small samples of patients. In 50% of women, the quality of life is worsened by disease-related symptoms; furthermore, treatments imply a remarkable health care cost. The aim of this observational study was to analyze a large sample of Italian patients with UFs and to assess the epidemiology, the appropriateness of treatments, and the consumption of disease-related resources. Methods: Data were collected through a data-linkage technique from five administrative databases. Women aged between 18 and 55 years and resident in three local health authorities (north–central–south Italy) were selected over the period from 1st January 2009 to 31st December 2015. The inclusion criteria were a surgical procedure with diagnosis of UFs or a pharmacological treatment with gonadotropin-releasing hormone (GnRH) analogs or ulipristal acetate. Besides the overall descriptive analysis, two comparisons were evaluated: surgery versus no surgery and treatment with GnRH analogs versus ulipristal acetate. Results: A total of 5,665 women with UFs were selected from an overall population of 2,400,000 people. In the north, 73.6% of patients underwent surgery, as opposed to only 16.7% in the south; 70% of surgeries were hysterectomies. The average cost per patient was €3,249 (duration of follow-up = up to 7 years). The southern district had the highest number of drug prescriptions; in particular, 49% of patients took >10 packages of GnRH analogs. Conclusion: This study is the first on this topic conducted in Italy using a large sample size. The analysis of resource consumption revealed a high heterogeneity in the choice of drug treatments by gynecologists (especially in the south); in the north, marked variations were seen in the rates of surgery. The long-term use of GnRH was inappropriate. Keywords: observational study, leiomyoma, ulipristal acetate, gonadotropin-releasing hormone, costs and cost analysis

OBJECTIVE: The purpose of this study was to review the effectiveness of immune checkpoint inhibitors (ICIs) in the first-line treatment of advanced non-small cell lung carcinoma with wild-type epidermal grow factor receptor (EGFR) or anaplastic lymphoma kinase. MATERIALS AND METHODS: After a standard literature search, we identified all randomized studies published on this issue. Our first inclusion criterion was the use of pembrolizumab, nivolumab, atezolizumab or durvalumab in the treatment arm versus chemotherapy in the control arm. The second criterion was the availability of information on overall survival at 2 years. The restricted mean survival time (RMST) was used to analyze the survival curves and rank the treatments. RESULTS: From the eligible studies, we selected 5 randomized trials that met our inclusion criteria. These trials studied a total of 11 cohorts of patients in whom the treatment arm received ICI as monotherapy (n=3) or in combination with either chemotherapy (n=2) or other monoclonal antibodies (n=1). All the control groups (n=5) received chemotherapy. Pembrolizumab (alone or in combination) showed improvement in overall survival compared with controls, but with borderline statistical significance. Nivolumab, atezolizumab and durvalumab failed to demonstrate any survival advantage. Overall, the RMSTs provided more conservative results than those previously reported using the hazard ratio. In comparing the values of RMST across treatments, pembrolizumab combined with chemotherapy ranked first. CONCLUSIONS: Our results summarized the efficacy of these treatments and showed that only pembrolizumab can have a role as the firstline treatment of NSCLC. These findings are at variance with those previously reported using the hazard ratio as the outcome measure. [ABSTRACT FROM AUTHOR]

Objective: In a scenario of new expensive cancer therapies entering the market, strategies of optimisation and cost containment are crucial in oncology care. Better management of drug waste and centralization of drug preparation can be effective strategies to achieve these goals. The aim of this work is to describe the economic management of a high cost anticancer drug (ipilimumab) in some Italian reference centres. Methods: This was an observational, multicentred study in which economical and clinical data of 21 cancer centres (418 patients) were collected during the enrollment period from February 2013 to August 2014. The follow-up period ended in July 2015. Results: Participants purchased 10.7% more vials of ipilimumab than necessary for compounding. The results were variable among centres, and only five centres had a deviation lower than 5% between the drug purchased and the drug prescribed. Hospitals applying the drug day reached a statistically significant residual of drug effectively used compared to the amount prescribed (P = 0.018). Consequently, the price for treating a model patient was significantly lower in those hospitals (median spare of 7456 euro per patient). Conclusions: This study demonstrated that the careful management of drug waste and the application of drug-day, through a proper selection of vial and the ability to use the leftover drug, can generate economic savings. However, tailoring the drug stock to clinical need is still an open issue which deserves further analysis. [ABSTRACT FROM AUTHOR]

Results from the phase III Keynote-024 clinical trial established pembrolizumab monotherapy as the first-line standard of care for patients with metastatic NSCLC who have PD-L1 expression ≥ 50%, EGFR , and ALK wild-type tumors. However, given the differences between patients treated in routine clinical practice and those treated in a clinical trial, real-world data are needed to confirm the treatment benefit in standard practice. Given the lack of data on large cohorts of patients with long follow-ups, we designed an observational retrospective study of patients with metastatic NSCLC who were treated with pembrolizumab, starting from its reimbursement eligibility until December 2020. The primary endpoints were PFS and OS, determined using the Kaplan-Meier method. Response and safety were also evaluated. We followed 880 patients (median follow-up: 35.1 months) until February 2022. Median PFS and OS were 8.6 months (95% CI: 7.6-10.0) and 25.5 months (95% CI: 21.8-31.6), respectively. We also found that ECOG PS, PD-L1 expression, and habitual smoking were prognostic factors for PFS, while age, sex, ECOG PS, habitual smoking and histology had an impact on OS. Multivariable analysis confirms the prognostic role of PD-L1 for PFS and of ECOG for both PFS and OS. 39.9% of patients reported an adverse event, but only 6.3% of patients discontinued therapy due to toxicity. Our results suggest a long-term benefit of pembrolizumab in the first-line setting, as well as a safety profile consistent with the results of Keynote-024 . Many collected variables appear to influence clinical outcome, but results from these exploratory unadjusted analyses should be interpreted with caution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be constructed as a potential conflict of interest.

Introduction: The phase III Keynote-189 trial established a first-line treatment combining pembrolizumab with pemetrexed and platinum as a standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) without known EGFR and ALK driver mutations and independent of programmed cell death ligand 1 (PD-L1) expression. However, in Italy, eligibility for the National Health Service payment program is limited to patients with PD-L1 <50%. The PEMBROREAL study assesses the real-world effectiveness and safety of pembrolizumab in patients eligible for the National Health Service payment program., Methods: PEMBROREAL is a retrospective, observational study on patients with NSCLC who started pembrolizumab combined with pemetrexed and platinum within the reimbursability time window, considered as December 2019 to December 2020. The primary endpoints were to assess progression-free survival (PFS) and overall survival (OS; using the Kaplan-Meier method), response to therapy, and tolerability., Results: Until February 2022, 279 patients (median follow-up: 19.7 months) have been observed. The median PFS was 8.0 months (95% confidence interval: 6.5-9.2). OS was not reached, but we can estimate a 12- to 24-month survival rate for the combined treatment: 66.1% and 52.5%, respectively. PD-L1 expression and Eastern Cooperative Group (ECOG) Performance Status were both associated with PFS and OS. Overall, only 44.4% of patients reported an adverse event, whereas toxicity led to a 5.4% discontinuation rate., Conclusion: The results of the PEMBROREAL study have shown that the combined treatment of pembrolizumab with pemetrexed and platinum is effective for metastatic non-squamous NSCLC, even for patients with PD-L1 levels below 50%, despite the differences in patient demographics and pathological features compared to the Keynote-189 study. The adverse events reported during the study were more typical of chemotherapy treatment rather than immunotherapy, and physicians were able to manage them easily., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cafaro, Foca, Nanni, Chiumente, Coppola, Baldo, Orzetti, Enrico, Ladisa, Lerose, Nardulli, Maiolino, Gradellini, Gasbarro, Carrucciu, Provasi, Cappelletto, Pasqualini, Vecchia, Veraldi, De Francesco, Crinò, Delmonte and Masini.)

Background: Deprescribing is an important intervention across different settings in medicine, but the literature supporting such a practice is still conflicting. Therefore, we aimed to capture the breadth of outcomes reported and assess the strength of evidence of the use of deprescribing for health outcomes., Methods: Umbrella review of systematic reviews of the use of deprescribing searching in Medline, Scopus, and Web of Science until 01 November 2023. The grading of evidence was carried out using the GRADE for intervention studies, whilst data regarding systematic reviews were reported as narrative findings., Results: Among 456 papers, 12 systematic reviews (six with meta-analysis) for a total of 231 RCTs and 44,193 patients were included. In any setting, deprescribing was able to significantly reduce the number of total and of potentially inappropriate medications (PIMs) in older patients (low certainty of evidence) and to reduce the proportion of participants potentially having several or PIMs (moderate certainty of evidence). In community, supported by a high certainty of evidence, deprescribing was not more effective than standard care in decreasing injurious falls, any falls or number of fallers. In nursing home, deprescribing was associated with a significantly lower PIMs than standard care (very low certainty of evidence). In end-of-life situations, deprescribing significantly reduced mortality rate of approximately 41% (high certainty of evidence)., Conclusions: Deprescribing is a promising intervention across different settings and situations, but a notable gap in the literature concerning its effects on substantial outcomes still exists., Competing Interests: Declaration of Competing Interest none., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and chemo-free regimens. Our objective was to analyze all recent trials evaluating these treatments and to compare them in terms of efficacy. We applied the Shiny method, an artificial intelligence technique, to analyze Kaplan-Meier curves and reconstruct patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and subjected to indirect head-to-head treatment comparisons. The endpoint was progression-free survival (PFS). Based on 432 reconstructed patients, eight trials were analyzed. The survival data from these trials were pooled into three types of treatments: (i) treatments based on tyrosine kinase inhibitors (TKIs) combined with reduced-intensity chemotherapy (denoted as TKICHE); (ii) TKIs associated with steroids with no chemotherapy (TKISTE); (iii) chemotherapy-free combinations of blinatumomab plus TKIs (TKIBLI). According to the Shiny method, the three PFS curves were reported in a single Kaplan-Meier graph and subjected to survival statistics. In terms of PFS, TKIBLI ranked first, TKICHE second, and TKISTE third; the differences between these three regimens were statistically significant. This multi-treatment Kaplan-Meier graph, generated through the Shiny method, summarized the current evidence on these treatments in both qualitative and quantitative terms.

Background: Pembrolizumab (PEM) and tislelizumab (TIS), in combination with chemotherapy, have demonstrated significant clinical benefits in first-line treatment of advanced non-small cell lung cancer (NSCLC). However, no head-to-head clinical trial has yet compared these two treatments., Methods: We conducted a literature search of randomized trials, in which TIS plus chemotherapy or PEM plus chemotherapy were studied for the first-line treatment of NSCLC. Randomized design and the endpoint of progression-free survival (PFS) were the inclusion criteria for our analysis. Adjusted indirect comparison between TIS and PEM was performed by application of the IPDfromKM-Shiny method. This method is based on the reconstruction of individual patient data from Kaplan-Meier curves. Outcomes in terms of PFS were expressed as hazard ratio (HR) with 95% and 90% confidence interval (CI)., Results: Data were extracted from five randomized trials involving nearly 2,000 participants. In comparing PEM plus chemotherapy (n=748) or TIS plus chemotherapy (n=462) vs. chemotherapy alone (n=782), the Shiny method found a significant advantage in terms of PFS (HR =0.5856, 95% CI: 0.4986-0.6876 for TIS; HR =0.5573, 95% CI: 0.4969-0.6251 for PEM), thus confirming the results of the original trials. The indirect comparison of PEM plus chemotherapy vs. TIS plus chemotherapy showed a substantial equivalence between these two regimens (HR =0.952; 95% CI: 0.775-1.168; 90% CI: 0.801-1.130) suggesting an acceptable degree of equivalence according to regulatory criteria. Medians were 8.89 months for PEM combination, 7.97 months for TIS combination, and 5.69 for the controls., Conclusions: The PFS of TIS combined with chemotherapy was similar to that of PEM combined with chemotherapy. Based on the HR with 90% CI, these two agents met an equivalence criterion for PEM vs. TIS ranging from -19.9% to +13.0%.

Background: Recently, numerous combination therapies based on immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors have been proposed as first-line treatments for advanced renal cell carcinoma (aRCC). Our study aimed to compare the efficacy of these combination regimens by the application of an innovative method that reconstructs individual patient data., Methods: Six phase III studies describing different combination regimens for aRCC were selected. Individual patient data were reconstructed from Kaplan-Meier (KM) curves through the "Shiny method". Overall survival (OS) and progression-free survival (PFS) were compared among combination treatments and sunitinib. Results were summarized as multi-treatment KM curves. Standard statistical testing was used, including hazard ratio and likelihood ratio tests for heterogeneity., Results: In the overall population of aRCC patients, pembrolizumab + lenvatinib showed the longest median PFS and was expected to determine the longest OS. Pembrolizumab + axitinib, nivolumab + cabozantinib and nivolumab + ipilimumab were similar in terms of PFS, but pembrolizumab + axitinib also demonstrated a better OS. Our subgroup analysis showed that sunitinib is still a valuable option, whereas, in intermediate-poor risk patients, pembrolizumab + axitinib and nivolumab + ipilimumab significantly improve OS compared to sunitinib., Conclusion: The Shiny method allowed us to perform all head-to-head indirect comparisons between these agents in a context in which "real" comparative trials have not been performed.

In the area of evidence-based medicine, the IPDfromKM-Shiny method is an innovative method of survival analysis, midway between artificial intelligence and advanced statistics. Its main characteristic is that an original software investigates the Kaplan-Meier graphs of trials so that individual-patient data are reconstructed. These reconstructed patients represent a new form of original clinical material. The typical objective of investigations based on this method is to analyze the available evidence, especially in oncology, to perform indirect comparisons, and determine the place in therapy of individual agents. This review examined the most recent applications of the IPDfromKM-Shiny method, in which a new web-based software-published in 2021-was used. Reported here are 14 analyses, mostly focused on oncological treatments. Indirect comparisons were based on overall survival or progression free survival. Each of these analyses provided original information to compare treatments with one another and select the most appropriate depending on patient characteristics. These analyses can also be useful to assess equivalence from a regulatory viewpoint. All investigations stressed the importance of heterogeneity to better interpret the evidence generated by IPDfromKM-Shiny investigations. In conclusion, these investigations showed that the reconstruction of individual patient data through this online tool is a promising new method for analyzing trials based on survival endpoints. This new approach deserves further investigation, particularly in the area of indirect comparisons.

Background: In patients with advanced melanoma, immune-checkpoint inhibitors (ICIs) represent the mainstay for first line treatment. Recently, relatlimab+nivolumab was proposed as a new combination therapy. This review was aimed at summarizing the current data of effectiveness for ICIs. Progression-free survival (PFS) was the endpoint of our analysis., Methods: After a standard literature search, Phase II/III studies comparing different ICI regimens in previously untreated advanced melanoma patients were analyzed. Patient-level data were reconstructed from Kaplan-Meier curves by application of the IPDfromKM method. These reconstructed datasets were used to perform indirect comparisons between treatments. Standard statistical testing was used, including hazard ratio and medians. A secondary analysis employed the restricted mean survival time., Results: Six trials were included in our analysis. Information on PFS from these trials was pooled according to the following treatments: nivolumab or pembrolizumab as monotherapy, or in combination with ipilimumab, and relatlimab + nivolumab. Pembrolizumab+ipilimumab showed significantly better PFS compared with the other treatments; nivolumab+ipilimumab ranked second; the other treatments showed a similar survival pattern., Conclusions: The picture of comparative effectiveness resulting from our analysis is complex. The IPDfromKM method is advantageous because it accounts for the length of follow-up but loses the balance between treatment group and controls determined by randomization. Based on indirect comparisons, the combination of pembrolizumab+ipilimumab showed a particularly high efficacy, and so deserves further investigation. While the effect of between-trial differences in inclusion criteria plays an important role, our results do not support the proposal of relatlimab+nivolumab as a new standard of care., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: When COVID-19 pandemic started, Italian hospital pharmacists faced multiple challenges and change their work practices., Objectives: The aim of this study was to describe the impact of COVID-19 emergency on pharmaceutical care provided by pharmacists during the first wave of the pandemic. Issues related to pharmacist's involvement in the pandemic management were: changes in activities, support received by authorities and pharmacists' own perceived role in the Health System., Methods: A cross-sectional study based on a web survey was conducted between May and June 2020 collecting information from pharmacists, members of Italian Society of Clinical Pharmacy and Therapeutics. 113 (11.4%) completed the questionnaire. The cohort was divided in 2 arms: pharmacists who worked in severely COVID-19 affected areas (High Spread Regions) and those employed in less affected areas (Low Spread Regions)., Results: The changes in pharmacy work settings reflected the increase of logistics area and non-sterile clinical galenic, and reduction of clinical tasks. The most demanding challenge was referred to shortages of medical devices and drugs, 61/113 pharmacists reported difficulty in obtaining products compliant to quality standards. National Institutions and Regional Governments provided a greater perceived support. More than 50% of participants felt that their role did not change if compared to other health professionals., Conclusions: Despite some limitations related to their clinical activity, pharmacists played a crucial role in supplying personal protective equipment, medical devices and medications to improve health outcomes during this emergency. The results may guide pharmacists in future actions to improve the management of the pandemic.

In recent years, new treatments have been studied for relapsed-refractory multiple myeloma (RRMM), including two CAR-T products and a variety of non-CAR-T agents. Since direct comparisons between these innovative treatments are not available, indirect comparisons can be of interest. Reconstruction of individual patient data from Kaplan-Meier graphs (e.g., according to the Shiny method) has been the subject of numerous reports that have fully validated their performance. In the present systematic review, we evaluated six treatments proposed for RRMM, including two CAR-T products (ciltacabtagene autoleucel and idecabtagene vicleucel) and four treatments not based on a CAR-T (melflufen plus dexamethasone, isatuximab plus dexamethasone, selinexor, and belantamab). The endpoint was overall survival (OS). Our results showed statistically significant differences in OS across these treatments. In particular, ciltacabtagene autoleucel showed better OS than idecabtagene vicleucel. As regards non-CAR-T treatments, the ranking in OS was headed by isatuximab plus dexamethasone, followed by belantamab, selinexor, and melflufen plus dexamethasone. In conclusion, while the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons have offered some original clues to interpret the results of OS published in these studies.

Background and objectives Glofitamab, tafasitamab, loncastuximab tesirine, polatuzumab, and selinexor have been proposed for the treatment of relapsed-refractory diffuse large B-cell lymphoma (DLBCL). We studied the pattern of overall survival (OS) for these five agents. Methods We reconstructed patient-level data from the Kaplan-Meier OS graphs published in five pivotal trials. For this purpose, we used an artificial intelligence technique (the Shiny method). Reconstructed survival curves were subjected to standard statistics to perform cross-trial indirect comparisons; medians and hazard ratios (HRs) with 95% confidence interval (CI) were estimated for each treatment. Results Using glofitamab (a bispecific antibody) as a common comparator, our analysis of OS yielded the following results: a) tafasitamab plus lenalidomide, HR: 0.514 (95% CI: 0.341 to 0.776; P=0.0015); b) polatuzumab vedotin, HR: 0.822 (95% CI: 0.509 to 1.327); c) selinexor, HR: 1.170 (95% CI: 0.852 to 1.603); and d) loncastuximab tesirine, HR: 1.120 (95% CI: 0.868 to 1.659). Medians were estimated as follows: a) tafasitamab plus lenalidomide, 26.5 months (95% CI: 18.9 to NA); b) polatuzumab vedotin, 12.5 months (95% CI: 9.03 to NA); c) glofitamab, 11.7 months (95% CI: 7.96 to 18.0); d) loncastuximab tesirine, 10.2 months (95% CI: 6.97 to 11.6); and e) selinexor, 10.1 months (95% CI: 6.72 to 14.2). Conclusions These comparative results represent an original finding generated by the Shiny method. Although these comparisons are indirect, our analysis offers a useful synthesis of the outcomes of these treatments. According to these results, glofitamab, despite its improved mechanism of action, does not seem to confer any OS advantage compared with the other four treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Messori et al.)

Purpose: Chimeric antigen receptor (CAR) T-cell products (eg, tisagenlecleucel [tisa], axicabtagene ciloleucel [axi]) have been used in patients with relapsed/refractory large B-cell lymphoma (LBCL) and in adult patients with acute lymphoblastic leukemia (ALL). After the recent publication of long-term follow-up data in LBCL, reviewing the evidence on this topic is worthwhile. The aim of the present work was to study the pattern of overall survival (OS) reported for CAR T-cell products in LBLC and ALL., Methods: A standard literature search was performed. OS was studied through an artificial intelligence technique (the Shiny method) that reconstructs individual patient data from published Kaplan-Meier curves. Standard statistics along with indirect comparisons were performed on these reconstructed data. Indirect comparisons focused on CAR T cells versus chemotherapy in LBCL and ALL; tisa and axi were further indirectly compared in LBCL., Findings: Seven trials were included (4 for LBCL, 3 for ALL). Other populations were selected as control groups. The main results of our analysis were: (1) the survival advantage of CAR T cells is greater in adult patients with ALL than in patients with LBCL; and (2) for LBCL, the survival gain is more substantial for axi compared with tisa., Implications: Our results are helpful to define the place in therapy of CAR T cells in these 2 disease conditions and also suggest preliminary estimates of cost-effectiveness. One strength of our analysis is that extensive information was available for the treatment options included in indirect comparisons. The main weakness is the inability of the Shiny method to perform multivariate analyses., Competing Interests: Declaration of Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The clinical choice among recently approved cancer drugs is burdened by the absence of direct comparisons in terms of efficacy across these new agents. In this article we present the IPDfromKM method, an artificial intelligence (AI) application that aims to facilitate the analyses on efficacy based on secondary data., Methods: Seven therapeutic areas were selected in which at least three new agents were recently approved. Kaplan-Meier curves of related clinical trials were digitized. Then, the IPDfromKM method was employed to reconstruct patient-level survival data. This information allowed us to compare selected agents in each therapeutic area and to rank them in terms of efficacy., Results: We identified the most effective treatment in each of the seven selected therapeutic areas. In two cases, immunotherapies, sharing similar mechanisms of actions, were compared highlighting the most effective one. In the remaining cases, our comparison included also the standard of care, which proved to be superior to new agents in patients with osteosarcoma., Discussion: When randomized clinical trials are not available, indirect comparisons can be a valuable source of information. The experience described herein recommends the use of a new method endowed by two important advantages: remarkable speed of analysis and free access to computational tools. In assessing the place in therapy for newly developed agents, this approach can further promote the application of evidence-based principles.

Introduction: In recent years, new treatments have been approved for nonmetastatic castration-resistant prostate cancer (M0CRPC). Because direct comparisons between these treatments are not available to guide treatment decisions, indirect comparisons can be of interest., Methods: Our analysis evaluated second-generation hormone treatments proposed for M0CRPC. We searched multiple databases for articles published between 2010 and 2022. Phase-III clinical trials that studied these agents in M0CRPC patients were eligible. Among these, we included trials reporting overall survival (OS) through Kaplan-Meier curves. We performed the reconstruction of individual patient data from Kaplan-Meier graphs, according to the Shiny method, to indirectly compare the efficacy of the different agents. Indirect comparisons included testing for equivalence according to FDA criteria. Confidence intervals (CI) were 95% in all analyses except equivalence testing, where 90%CIs were used., Results: Three studies met these inclusion criteria. Apalutamide (hazard ratio [HR]: 0.75, 95% confidence interval [CI] 0.64-0.88), darolutamide (HR 0.70, 95%CI 0.58-0.84), and enzalutamide (HR 0.77, 95%CI 0.65-0.90) were all significantly more effective than the placebo. Our results showed no difference in OS between any of these three agents, and in testing for equivalence, our estimates of HR met the 0.75-1.33 level., Conclusions: While the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons based on mature OS demonstrated similar efficacy and substantial equivalence among these three second-generation androgen receptor inhibitors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective This paper presents a preliminary experience based on the "one-to-many" approach of the Shiny method. Numerous (or "many") treatments for advanced or metastatic urothelial carcinoma have recently been reviewed. More recently, "one" potentially innovative treatment has been made available. Our analysis was aimed at assessing the benefits of the new treatment in comparison with the alternatives developed previously. Materials and methods The Shiny method was employed to reconstruct patient-level survival data. This information allowed us to compare the Kaplan-Meier (KM) curves of five treatments previously available (i.e., pembrolizumab, nivolumab, atezolizumab, vinflunine, and standard chemotherapy) with the potentially innovative agent represented by enfortumab vedotin. Overall survival was evaluated for each agent. Statistical tests to assess head-to-head indirect comparisons were performed through standard survival analysis. The hazard ratio (HR) was the main parameter. Results In ranking the efficacy across these agents, enfortumab vedotin was first, followed by immune checkpoint inhibitors (ICIs). Standard chemotherapy and vinflunine were the least effective. The remarkable survival results of enfortumab were, to some extent, influenced by the slightly better prognosis of the population enrolled in the enfortumab trial in comparison with patients enrolled in the three ICI trials. Conclusions The experience described herein shows that, when a potential innovative treatment (enfortumab vedotin) is developed in an already investigated area (metastatic urothelial cancer), the Shiny method can be applied according to the "one-to-many" approach. This allows us to quickly assess the place in therapy of the new treatment (the "one") and to evaluate whether the new treatment determines a relevant incremental benefit in comparison with previous treatments (the "many")., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Messori et al.)

Background: In PD-L1-negative patients with advanced non-small-cell lung cancer (NSCLC), conclusive evidence in support of specific treatments remains lacking. Objectives: The efficacy of first-line chemoimmunotherapy versus chemotherapy alone was compared. Methods: Eligible randomized studies that included patients with advanced NSCLC irrespective of PD-L1 status who were treated with chemoimmunotherapy as the first line were identified. Kaplan-Meier curves were extracted and analyzed using restricted mean survival time (RMST). Patient-level data were reconstructed from progression-free survival (PFS) graphs. A Bayesian network meta-analysis (NETMA) was carried out. Results: In five trials selected, chemoimmunotherapy regimens, compared with chemotherapy alone, resulted in an improvement in PFS without statistical significance. In the NETMA, chemoimmunotherapy was found to slightly improve PFS. Conclusion: This analysis showed that the incremental benefit of chemoimmunotherapy versus chemotherapy is limited.

Objectives: The effectiveness of omega-3 fatty acids (PUFAs) in cardiovascular diseases (CVD) remains a matter of debate. The aim of this work was to evaluate PUFAs in the reduction of cardiovascular mortality in primary and secondary prevention of CVD to determine if further original studies are needed or the available data can be considered conclusive., Methods: A meta-analysis was performed according to a dichotomous endpoint followed by a trial-sequential analysis (TSA). Clinical data were identified through a PubMed search based on the following keywords: omega-3 fatty acids; cardiovascular disease; death; and cardiovascular risk. The clinical trials identified by this procedure were subjected to standard meta-analysis and TSA., Results and Conclusions: A total of 11 randomised studies for 100 609 patients were analysed. Our meta-analysis showed a statistically significant reduction in mortality due to cardiovascular issues (RR=0.937; 95% CI: 0.88 to 0.98; P=0.018). The TSA indicated that no further trials are needed to better evaluate the efficacy of PUFAs in preventing death related to CVD., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To collect pilot data on medication disposal practices of unused and expired medications from three cities in three countries. Methods: A cross-sectional survey was conducted in Pittsburgh, United States (US); Turin, Italy; and Kobe, Japan. A convenience sampling was utilized through drug take-back programs in Pittsburgh, US; pharmacy customers in Turin, Italy; and pharmacy students and family members in Kobe, Japan. Descriptive analysis was conducted to assess medications disposal practices including attitudes and beliefs of respondents. Results: The sample included 342 respondents [99 (Pittsburgh, US); 168 (Turin, Italy); and 75 (Kobe, Japan)]. The mean unused and expired medications per patient for Pittsburgh, US was (1.60±2.30 and 0.51±1.54); Turin, Italy (1.69±1.86 and 0.49±1.22) and Kobe, Japan (6.69±8.78 and 0.84±2.26). The major reason for unused medications in Pittsburgh, US (31.3%) was "Medication was as needed"; in Turin, Italy (28.0%) "No longer suffer from the condition"; and in Kobe, Japan (54.7%) "No longer suffer from the condition". The most common reason for expired medications was "No longer suffer from the condition" (Pittsburgh, US 17.2%; Turin, Italy 15.5%; Kobe, Japan 12.0%). The disposal method in Pittsburgh, US was disposing in the toilet (35.4%); returned to the pharmacy in Turin, Italy (51.2%); and disposed the original container in the trash in Kobe, Japan (82.7%). Conclusions: There is a need for counseling protocols regarding proper disposal, which can lead to better adherence, reduction of prescription drug abuse, and less environmental hazards due to improper disposal of prescription medications., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Kamal et al.)

In patients with paroxysmal atrial fibrillation, cryoballoon ablation (CBA) and radiofrequency ablation (RFA) represent two therapeutic approaches supported by increasing literature. While both these ablation techniques play a role during different stages of the patient's therapeutic pathway, their use as first-line is being increasingly recognized. This scoping review comparatively examined the evidence of effectiveness for these two ablation techniques. Our analysis was limited to the evaluation of the end-point of time to recurrence of atrial fibrillation (or other forms of atrial arrhythmias), which was the primary end-point in most clinical trials. The method used for pooling the information from clinical trials (Shiny method) is original and based on an artificial intelligence (AI) method that reconstructs individual patient data from published Kaplan-Meier time-to-event curves. Because a network meta-analysis has been published on this same clinical material, one objective of the present work was to compare the meta-analytic results with those generated by the Shiny method. A standard literature search was conducted on PubMed/Medline. Only randomized studies comparing CBA versus medical therapy, RFA versus medical therapy, or CBA versus RFA in previously untreated patients were eligible. Trials presenting a Kaplan-Meier curve to present the above-mentioned end-point were included. Patient-level data were reconstructed by application of the Shiny method. These individual patient data were then analyzed by standard statistical testing based on hazard ratio (HR) for risk of recurrence and medians of time to recurrence. Our analysis compared the two ablation treatments and medical therapy. A total of five trials were identified through our literature search. Information from these trials was pooled according to the three treatments (CBA: three trials, n = 365; RFA: two trials, n = 99; medical therapy: five trials, n = 457). CBA showed higher effectiveness than medical therapy (HR, 0.51; 95% confidence interval (CI): 0.38 to 0.67). In comparison with medical therapy, RFA showed a numerical trend that remained far from statistical significance (HR, 0.89; 95% CI: 0.62 to 1.27). Medians for time to recurrence were 14.1 months (95% CI: 10.0 to not reached) for RFA and 11.5 months (95% CI: 9.3 to 25.3) for medical therapy. This parameter was not reached for CBA. The current evidence from five randomized trials suggests that CBA ranks first in effectiveness, followed by RFA and medical therapy. In our comparison between the results generated by the Shiny method with those published in the previous meta-analysis, the Shiny method confirmed its ability to account for the length of follow-up in individual trials, whereas the meta-analytic approach confirmed its ability to account for the effects of randomizations performed in the trials., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Trippoli et al.)

In metastatic triple-negative breast cancer (TNBC), the efficacy of immune checkpoint inhibitors (ICIs) in combination with chemotherapy has been demonstrated in randomized clinical trials (RCTs). Despite this, an indirect comparison is not yet available. Reconstruction of individual patient data from Kaplan-Meier curves allows the indirect comparison of different treatments. We analyzed six overall survival (OS) curves from three RCTs. In patients with ≥1% positivity, atezolizumab was found to determine a significantly better OS than pembrolizumab. As regards pembrolizumab, adopting a threshold of PD-L1 positivity ≥10% (as opposed to ≥1%) improved median survival to a remarkable extent (23.0 vs 15.5 months)., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Di Spazio et al.)

Background: Maintenance therapy using poly (ADP-ribose) polymerase inhibitors (PARPIs) is an important therapeutic option in advanced ovarian cancer after platinum-based chemotherapy., Materials and Methods: We evaluated randomized studies (n = 5) describing the effect of maintenance therapy with PARPIs; they were obtained mainly by searching PubMed. Patient data for the analysis were derived from progression-free survival curves. Restricted mean survival time (RMST) and 95% confidence interval were estimated for individual arms of each trial., Results: The three PARPIs used (olaparib, niraparib, rucaparib) all showed a higher effectiveness than placebo. The gains in progression-free survival were 6 - 8 months., Conclusion: Maintenance therapy studies provide evidence that olaparib, niraparib, rucaparib are effective treatments for advanced ovarian cancer.

Health-related quality of life is frequently included in patient-reported outcomes aimed at evaluating the effectiveness of disease-modifying drugs for multiple sclerosis, but recent data about Italian patients are missing. A multicenter observational and cross-sectional study was performed by students of hospital pharmacy to update existing data on quality of life and to correlate it with the pharmacological and medical history of patients. Quality of life (QoL) was assessed using the MS-QoL54 questionnaire, and the pharmacist collected patients' characteristics, medical and pharmacological history, and Expanded Disability Status Scale (EDSS). Three hundred and forty-nine patients with multiple sclerosis were recruited from 16 centers between May 2018 and June 2019 (median age = 44.1 years; 68.9% women). The composite indexes of physical and mental well-being showed direct correlation with each other (R = 0.826; p < 0.001), and EDSS disability was an independent negative predictor of both indexes (R 2 = 35.08% p < 0.001 and R 2 = 15.74% p < 0.001, respectively). A trend of association between Physical Health Composite Score and different classes of oral disease-modifying drugs (DMDs) was observed. Our study found a decrease in QoL correlated with teriflunomide, which deserves further investigation. This experience demonstrates that joint action between scientific society and students association can be successful in conducting a no-profit multicenter observational study in a real-world setting.

Programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) inhibitors are increasingly used in a variety of solid tumors. In patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer, their efficacy has been demonstrated in recently published phase-II trials. However, an indirect comparison of effectiveness between pembrolizumab, nivolumab, and nivolumab+ipilimumab is not yet available. After a standard literature search, we analyzed four overall survival (OS) curves from three phase-II trials. Individual patient data were reconstructed from each curve using a specific web-based technique (Shiny method). Indirect statistical comparisons were made based on hazard ratio (HR) and restricted mean survival time (RMST). Nivolumab+ipilumumab had a better HR compared with pembrolizumab (0.65, 95% confidence interval [CI], 0.43 to 1.002, p=0.051); the difference being close to statistical significance. In the analysis based on RMST, the combination of nivolumab+ipilimumab showed a significantly longer OS than pembrolizumab (improvement in RMST, 1.08 mos; 95%CI, 0.11 to 2.06; p=0.029). The other two pairwise differences in RMST (nivolumab vs. pembrolizumab and nivolumab+ ipilimumab vs. nivolumab) had a smaller magnitude (0.25 mos, 95%CI, -0.99 to 1.48, and 0.84 mos, 95%CI, -0.40 to 2.07, respectively) and were far from statistical significance. Our results favoring the combination of nivolumab+ipilimumab in metastatic colorectal cancer must be viewed with caution owing to the indirect nature of our statistical comparisons. With this limitation in mind, the magnitude of the incremental benefit for the above combination treatment was estimated to be around one month over a follow-up of 15 months., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2021, Cancanelli et al.)

Introduction: On the basis of two randomized trials, evolocumab and alirocumab have been approved in patients with cardiovascular disease. The evidence on these two agents has been studied through different methods of analysis that span from narrative approaches to network meta-analysis. In the present study, we assessed the performance of a narrative approach combined with the application of the restricted mean survival time (RMST)., Methods: We studied the two pivotal placebo-controlled trials focused on evolocumab and alirocumab. Our original framework of comparative assessment employed the RMST. Our objective was to show that in the context of a narrative review, the RMST can be an efficient although simple tool to make indirect comparisons. The endpoint was event-free survival, expressed in months., Results: For each cohort of patients (13,784 patients administered evolocumab, 9462 patients administered alirocumab, 23,242 controls), we determined the RMST values with 95% confidence intervals (CI) [evolocumab: 33.60 months, 95% CI 33.46-33.74; alirocumab: 34.07 months, 95% CI 33.92-34.22]. These results, along with those of the control groups, were analyzed and interpreted narratively. Univariate statistics were conducted, but no network meta-analysis was performed., Conclusion: The experience presented herein indicates that a framework of evidence assessment focused on the RMST is a worthwhile option. Our study is in line with the growing literature that has recently emphasized the methodological advantages of the RMST.

Introduction: Dose banding is an original approach that manages intravenous (IV) chemotherapy preparation by generating on a weekly basis a series of bags containing scaled dosages of the active agent. These predetermined, fixed dosage bags are intended to replace the traditional bags prepared daily that contain fully individualized dosages., Methods: Three different scenarios were examined: (1) the current method of daily preparation of individualized bags at the hospital pharmacy; (2) the weekly preparation at the hospital pharmacy of non-individualized bags containing discrete, predefined doses covering an adequate range of doses (dose banding); (3) the use of commercial ready-to-use bags based on the same approach of dose banding. The objective of this study was to compare these three different approaches in terms of cost per patient. We considered five cancer drugs (gemcitabine, oxaliplatin, paclitaxel, trastuzumab and 5-fluorouracil) that were suitable for the dose ranging approach. Appropriate dose bands for these five agents were identified. Costs were estimated for each of the three approaches., Results: A total of 13,490 fully individualized bags were studied, which corresponded to the real bags prepared at our institution for these five agents in 2018. Dose banding was predicted to determine savings ranging from €10,998 (-0.84%) for trastuzumab to €169,429.60 (-8.39%) for paclitaxel., Conclusion: The introduction of dose banding can determine economic savings along with other advantages, such as improved work conditions, management reorganization and containment of waste. The pharmaceutical industry can hopefully support these experiences by producing ready-to-use bags in predetermined dosages., Competing Interests: Conflict of interest: The authors have nothing to disclose. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Background: The purpose of this study was to assess the effectiveness of immune checkpoint inhibitors (ICIs) in advanced urothelial carcinoma. Materials & methods: We selected seven cohorts of patients published in four clinical trials. The restricted mean survival time (RMST) was used to analyze survival curves, perform the comparisons and rank the treatments based on their effectiveness. The performance of RMST was compared with that of a network meta-analysis. Results: Three ICIs, vinflunine and best standard care, given as second line, were examined. ICIs significantly improved overall survival compared with best standard care. However, the survival gain was quite limited (up to 2.27 months). Post hoc pairwise comparisons were calculated. Conclusion: Our results summarized the efficacy of these treatments and confirmed the good methodological performance of RMST.