Adherence, persistence and treatment switching in psoriasis.

Aim: This study aims to investigate drug utilization patterns in the treatment of psoriasis (PsO) from 1 to 5 years in a real-life setting with Adalimumab (Ada), Etanercept (Eta), Ustekinumab (Ust), Golimumab (Gol), Ixekizumab (Ixe), Secukinumab (Sec) and Apremilast (Apr). Materials & methods: Data from an observational study were used to calculate adherence using the Proportion of Days Covered (PDC) method and persistence. Results & conclusion: Treatment adherence was found to be good for all the drugs studied across all years of analysis, while persistence was suboptimal, showing a marked decrease from the third year of study onward. In the treatment of PsO, greater attention needs to be paid to treatment persistence.

This summary explains that when a patient follows their doctor's medication instructions and continues using the same medication over time to treat a condition like psoriasis, they can expect safer and more effective outcomes. This study examined these aspects to assess how different medications perform over the long term and to explore ways to improve their prescription. The findings highlight that the main issue is not so much in following instructions but in continuing to use the same medication throughout the treatment duration. Raising awareness among healthcare professionals about these issues is crucial to help patients maintain consistent therapy over time and improve their care pathway.

A real-world multicentre evaluation of atezolizumab plus platinum-etoposide chemotherapy as first-line treatment in patients with extensive-stage small cell lung cancer in Italy.

INTRODUCTION: The aim of this study was to analyze real-life data from a cohort of adult patients receiving atezolizumab in combination with carboplatin and etoposide for first-line treatment of ES-SCLC, in order to assess relative dose intensity (RDI), time-to-treatment discontinuation (TTD), time-to-treatment failure (TTF), progression-free survival (PFS), overall survival (OS) of treatments as well as the correlation between these outcomes. METHODS: An observational retrospective study was conducted. All patients treated with atezolizumab combined with carboplatin and etoposide for first-line treatment of ES-SCLC were included. Median TTD, TTF, PFS and OS were calculated in our cohort of patient by the Kaplan Meier method. RESULTS: The curves obtained with the Kaplan Meier method of TTF and TTD are substantially similar, indicating a good concordance of the information extracted by the two different data sources. This tendency was confirmed also when the TTD versus PFS curves were compared. The median OS registered was 11.8 months. Patients with no liver metastases showed a longer median time of OS than patients with liver metastases. The mean value of RDI for the entire cohort was 87.4%. CONCLUSIONS: Our study showed that TTD, calculated from the administration data is a useful proxy of TTF as registered in the clinical chart. TTD is a real-world outcome that can be used to demonstrate the efficacy of drugs used for administered therapies. It can be used as an end point for RWE studies, where the evaluation is less structured and standardized.

The lack of head-to-head randomised trials and the consequences for patients and national health service: The case of non-small cell lung cancer.

INTRODUCTION: To introduce a drug to the market, it's not mandatory for it to be more effective and safer than the current treatment for the same condition. Consequently, head-to-head studies between the two best treatments for the same condition are not required, and this could result in a lack of information for patients, clinicians, and decision-makers. This study aims to evaluate the presence of head-to-head studies among the drugs used for the treatment of non-small cell lung cancer (NSCLC). METHODS: Taking into account the National Comprehensive Cancer Network (NCCN) guidelines updated to 2022, which list all available treatments for each NSCLC subtype, the search engine Pubmed and the platform clinicaltrials.gov were consulted to find all completed and ongoing head-to-head studies among various treatments for NSCLC. RESULTS: Among the anti-EGFR (epidermal growth factor receptor) drugs, 7 studies were found, with 6 completed and 5 registrational for drug commercialisation. No completed study to date has compared osimertinib and afatinib. For anti-ALK (anaplastic lymphoma kinase) drugs, 7 studies were found, with 5 completed. Alectinib, brigatinib, and lorlatinib have no completed comparison studies, but all were compared with crizotinib. Among various immunotherapy-based regimens, 5 studies were found, with only 1 completed. Therapeutic regimens based on pembrolizumab, atezolizumab, or the combination of nivolumab/ipilimumab have not been compared in studies published to date. CONCLUSION: There are few head-to-head studies comparing treatments for NSCLC; there are no such studies between the latest generation of drugs. Consequently, ambiguous areas exist due to the lack of comparative studies among the available evidence, preventing the clinician's choice of the most effective treatment and risking the patient receiving suboptimal therapy. Simultaneously, the price of the drug cannot be determined correctly, relying only on indirect evaluations from different trials. To dispel this uncertainty, it would be desirable to initiate a process that brings together the demands derived from clinical practice and clinical research to provide clinicians and patients with the best possible evidence.

ADA_ETA_BIO2021: real-world evaluation of adherence, persistence, and cost-effectiveness of originator and biosimilar biologic drugs in the treatment of rheumatoid arthritis: a multicenter study in Italy.

OBJECTIVES: The objective was to assess the adherence, persistence, and costs of bDMARDs through a multicentre study of nine Italian hospital pharmacies. METHODS: The drugs analysed were Abatacept, Adalimumab, Certolizumab, Etanercept, Golimumab and Tocilizumab.Adult subjects with Rheumatoid Arthritis were considered in the analysis.In this study, we calculated the following metrics: Adherence to treatment was evaluated as dose-intensity, which is the ratio between the amount of medication received and probably taken by the patient at home (Received Daily Dose, RDD) and the amount prescribed by the clinician (Prescribed Daily Dose, PDD). Persistence was calculated as the number of days between the first and last dispensing of the same drug. Lastly, costs were assessed based on persistence to treatment and normalized for adherence. RESULTS: Adherence to treatment was found to be above 0.8 for all drugs studied. The median persistence for a 5-year treatment period was 1.4 years for Abatacept, 1.7 years for Adalimumab, 1.8 years for Certolizumab, 1.4 years for Etanercept, 1.3 years for Golimumab, and 1.6 years for Tocilizumab. CONCLUSIONS: This multicentre retrospective observational study of bDMARDs used in the treatment of RA showed that, for all the drugs studied, there was no problem with adherence to treatment but rather a difficulty in maintaining treatment with the same drug over time.

Time to treatment discontinuation in first-line non-small cell lung carcinoma: an overview.

OBJECTIVE: Time To Discontinuation (TTD) is defined as the time from the start of treatment to the end of treatment, usually occurring due to loss of efficacy or occurrence of adverse events. It has become an important surrogate efficacy endpoint especially in real-world studies due to its correlation with endpoints such as Progression Free Survival (PFS). The aim of the study is to conduct a literature review of all studies reporting TTD in first-line therapy of Non-Small Cell Lung Cancer (NSCLC). METHODS: All articles that reported TTD for any first-line treatment of NSCLC as of 30 June 2022 were extracted from the PubMed search engine. From these articles, the drugs, study type, and TTD values were extracted. A descriptive analysis of the studies was made, dividing the TTD by subgroup according to the type of treatment (traditional chemotherapy, target therapy, immunotherapy) and study design (clinical trials, real world studies). RESULTS: Fifty-five studies were considered for the analysis, of which 12 were published in 2021; 28 were clinical trials and 27 were real-world studies. Thirty of the studies considered involved conventional chemotherapy and expressed TTD values from 1.4 to 4.5 months, 5 of the studies considered involved immunotherapy with TTD values from 2.1 to 7.4 months and 18 of the studies considered target therapy, with TTD values from 4 to 31 months. The clinical trials reported TTD values from 1.4 to 16 months and the real-world studies from 2 to 31 months. CONCLUSION: Studies reporting TTD are increasing, most notably real-world studies. Given the increasing importance of TTD as an efficacy endpoint, it becomes critical to measure and monitor it in various therapeutic settings such as NSCLC. This is the first study to review all TTD values of drugs used in first-line NSCLC.

Available information about paediatric use of onco-haematological drugs authorized by EMA since 2016.

BACKGROUND: The treatment options available to children with cancer are limited. This is why for more than 10 years, the European Medicine Agency (EMA) has stated that all drugs to be marketed must be tested on the paediatric population in accordance with the Paediatric Investigation Plan (PIP). The objective of this study is to make a cross sectional analysis of the information related to the use of cancer drugs authorised on the European market in the paediatric population. METHOD: The European Public Assessment Reports and PIPs have been considered. The following data were extracted for onco-haematological drugs approved since 2016: paediatric indications, information about the paediatric population in the Summary of Product Characteristics (SmPC) and presence and characteristics of PIPs. A descriptive analysis of the characteristics of the drugs was made from the point of view of the paediatric population. RESULTS: Forty-eight drugs with onco-haematological indications have been authorised for marketing since 2016, 7 (15%) of these have paediatric indications. Two (4%) drugs have no paediatric indication but have information related to the paediatric population within SmPC. Forty-one (85%) drugs have no reference to the paediatric population in SmPC. Seventeen (35%) drugs out of 48 do not have PIPs and 11 have been granted a waiver to present the results of paediatric studies. The other 19 active ingredients have a total of 28 PIPs. CONCLUSION AND RELEVANCE: Most of the onco-haematological drugs approved by EMA since 2016 have neither paediatric indications nor mentions about paediatric use in SmPC. PIPs represent an opportunity, but demand for the paediatric population is still huge.

Medication adherence reporting in pivotal clinical trials: overview of oral oncological drugs.

OBJECTIVES: To assess how and to what extent adherence to medication is reported in pivotal clinical trials of oral cancer drugs. METHODS: All drugs authorised by the European Medicines Agency from 1 January 2014 to 31 December 2019 were considered for analysis. For each pivotal trial we extracted the journal of publication, phase of the study, posology, mention of adherence within the main text of the published article or additional material and the terms in which the adherence was reported. RESULTS: Thirty drugs were included in the analysis from 56 clinical trials. Eleven articles (19.6%) contained a mention of medication adherence in the main document, 26 (46.4%) in the supplementary material and 19 (33.9%) did not contain any reference to adherence. Seven studies reported medication adherence between the results, expressed as number of patients discontinuing treatment for non-compliance and mean or median percentage. CONCLUSIONS: Medication adherence in pivotal clinical trials of oral oncological drugs is poorly represented. There should be a greater level of reporting in the results and it should be included among the minimum set of recommendations in reporting health research.

A multicentre study with real-world data of the use of palbociclib in the treatment of breast cancer: Treatment duration correlates with dose reductions.

OBJECTIVE: Palbociclib, a highly selective reversible CDK4-6 kinase inhibitor, is indicated in combination with an aromatase inhibitor or in combination with fulvestrant in women who had received prior endocrine treatment. Studies have demonstrated the efficacy of palbociclib in combination with fulvestrant in increasing progression-free survival in patients who relapsed or progressed on previous endocrine therapy, or in combination with aromatase inhibitor in patients who had not received previous treatments. We analysed the prescribing patterns of palbociclib in real practice correlating it with the evidence of treatment-related toxicity management and to time-to-treatment discontinuation and treatment adherence. METHODS: For the observational, retrospective study, data were collected from five Italian hospital centres that prescribed palbociclib between April 2017 and April 2020. Each centre provided data derived from an administrative database of adult patients treated with palbociclib for the two therapeutic indications.Treatment adherence was calculated using the proportion of days covered method while time-to-treatment discontinuation was defined as the difference between the first and last date treatment was administered plus the days ideally covered by the last date treatment was given. RESULTS: There were 375 patients enrolled during the study period, of whom 159 were treated with palbociclib and aromatase inhibitor and 216 were treated with palbociclib and fulvestrant. The time-to-treatment discontinuation was 8.9 months in the case of P + f (95% CI: 7.1-12.7) and 13.7 months in the case of P + ia (95% CI: 8.9-17.5). In both cohorts, treatments that received at least one dose reduction had a statistically higher time-to-treatment discontinuation than those without dose reduction (17.7 months vs. 9.2 and 16.6 vs. 7.4).The mean adherence in our study was 0.9 and remained high in treatments with one dose reduction (0.83) and this with two dose reductions (0.87). CONCLUSION: Based on these findings, it appears that the management of toxicities through reducing doses, as required by the Summary of Product Characteristics, results in a better outcome in terms of therapy duration, and therefore time to failure due to progression or toxicity.

A Regional Survey on Merkel Cell Carcinoma: A Plea for Uniform Patient Journey Modeling and Diagnostic-Therapeutic Pathway.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer that usually affects the elderly and immunosuppressed in sun-exposed areas. Due to its rarity, it is frequently unrecognized, and its management is not standardized across medical centers, despite the more recent availability of immunotherapy, with avelumab as first-line treatment improving the prognosis even in advanced stages of disease. We conducted a purpose-designed survey of a selected sample of physicians working in the Lazio region, in Italy, to assess their awareness and knowledge of MCC as well as their perspective on assisted diagnostic and therapeutic pathways. The Lazio region, and in particular Rome, is one of the most important academic and non- academic center in Italy dedicated to the diagnosis and treatment of skin cancer. A total of 368 doctors (including 100 general practitioners, 72 oncologists, 87 dermatologists, 59 surgeons, and 50 anatomopathologists) agreed to be part of this survey. Surgeons, oncologists, and dermatologists thought themselves significantly more updated on MCC than primary care physicians, but more than half of the interviewees are interested in CCM training courses and training with clearer and more standardized care pathways. Significant differences have been reported from survey participants in terms of multidisciplinary team set up for MCC management. The identification of specialized centers and the improvement of communication pathways among different specialties, as well as between patients and physicians, could be very beneficial in improving patients' journey modeling and starting a uniform diagnostic and therapeutic pathway for MCC patients in the new era of immunotherapies.

Topical chlormethine gel in the treatment of mycosis fungoides: A single-center real-life experience and systematic review of the literature.

Gel formulation of chlormethine (CG) has gained a preeminent role among therapies available for mycosis fungoides (MF). To evaluate the frequency of use of CG for MF treatment and to determine the limits and potentialities of CG in a real-world setting. A systematic review of articles published prior to October 2021 was performed. Articles were included in the review if a full-text English version was available. MEDLINE (PubMed), Scopus, and Web of Science were each queried from their date of inception with the following terms: "mechlorethamine gel", "chlormethine gel", and "mycosis fungoides". The reference lists of the studies retrieved were searched manually. Moreover, this study included all consecutive patients with different stages of MF (from IA to IIB) who started treatment with CG gel between July 2020 and May 2021. Data of the literature were compared to our single-center real-life experience. Of the surveyed literature, 11 publications were included in the final analysis describing a total of 548 patients with MF. Eleven patients with a median (standard deviation) age of 66 years (15.1) were enrolled and followed up, receiving CG (0.02% chlormethine HCl). Response to treatment resulted higher (90.1%) in our study population than in other real-world experiences published in literature. This systematic review supports the role of CG for MF treatment, showing its limits and potentialities. Our single-center real-life experience revealed an elevated percentage of clinical response with high safety and tolerance, demonstrating its versatile use with dose and application rate adaptability.

Preventing drug vial wastage and reducing expenditure associated with injectable cancer drugs: International oncology pharmacy survey.

PURPOSE: Our objective was to determine what vial sharing techniques and other strategies were being used globally to reduce wastage from partially used single-use drug vials, what barriers are preventing these strategies being employed, and what savings are being achieved. METHODS: A survey, comprising 19 questions, was distributed to the membership of the International Society of Oncology Pharmacy Practitioners and British Oncology Pharmacy Association. Questions asked included how parenteral cancer drugs are obtained and prepared, what vial sharing strategies are used, what means are employed to extend stability, how prepared products are reused and what cost savings are achieved. RESULTS: In all, 74 responses were received from 20 countries, most from the United Kingdom. Some manufacturing is done by 60.8% of institution, with 41.9% making all products. Vial sharing strategies, for frequently used drugs, were employed in 53% of cases. Barriers preventing vial sharing being used included government legislation, USP 797 guidelines, and health insurance companies. Extension of stability was possible for 70.2% of centres. Most respondents reported reduction in cytotoxic and biological waste, and alleviation of drug shortages from vial sharing utilisation. Cost savings were achieved in 74% of cases and was significant in one third. CONCLUSIONS: The survey has determined that drug vial wastage and expenditure can be reduced, and vial sharing facilitates this. International collaboration plus the assistance of governments and the pharmaceutical industry is vital in achieving this aim. These findings can hopefully guide oncology pharmacy in establishing appropriate strategies to reduce wastage internationally.

Randomized clinical trials and real life studies: Comparison of baseline characteristics of patients in oral target therapies for renal cell carcinoma.

INTRODUCTION: Pivotal Randomized Controlled Trials (RCTs) constitute scientific evidence in support of therapeutic choices when a drug is authorized in the market. In RCTs, patients are selected in a rigorous manner, in order to avoid bias that may influence efficacy assessments. Therefore, patients who take the drug in Real Life Studies (RLSs) are not the same as those participating in RCTs, which, in turn, leads to low data transferability from RCTs to RLS. The objective of this study was to evaluate the differences between RCTs and RLS, in terms of patient baseline characteristics. MATERIALS AND METHODS: Our study includes all oral target therapies for RCC (Renal Cell Carcinoma) marketed in Europe before March 31, 2019. For each treatment, we considered both RCTs and RLSs, the former gathered from Summary of Product Characteristics published on the European Medicine Agency (EMA) website, and the latter yielded by our search in relevant literature. For each drug considered, we then compared the baseline characteristics of patients included in the RCT samples with those of the samples included in the RLSs using the Chi-squared and Mann-Whitney tests. RESULTS: We considered six medicines, for a total of 9 pivotal RCTs and 31 RLSs. RCTs reported the same type of patient baseline characteristics, whereas RLSs are more varied in reporting. Some patient baseline characteristics (metastases, previous treatments, etc.) were significantly different between RCTs and RLs. Other characteristics, such as ECOG Performance Status, brain metastases, and comorbidities, liver and kidney failure, are comprised in exclusion criteria of RCTs, though are included in RLS.Discussion and Conclusion: While evaluating equal treatments for the same indications, RCTs and RLSs do not always assess patients with the same characteristics. It would be necessary to produce evidence from RLSs so as to have an idea of treatment effectiveness in patients groups that are not eligible or underrepresented in RCTs.

[Immunotherapy with nivolumab and pembrolizumab in unresectable or metastatic advanced melanoma: real-life observational study of drug use.] / Immunoterapia con nivolumab e pembrolizumab nel melanoma in fase avanzata non resecabile o metastatico: studio osservazionale in real-life di farmacoutilizzazione.

INTRODUCTION: In Italy, the monoclonal antibodies nivolumab and pembrolizumab are subjected to the AIFA monitoring registries for the indication "advanced melanoma (unresectable or metastatic) in adults". These two drugs have the same eligibility criteria, and they are indicated until failure due to progression or toxicity; both of these drugs have also undergone dosage changes from pro/kg to flat dose. In this observational study, also based on clinical eligibility parameters, we wanted to investigate the rwTTD, definitive and temporary suspensions, as well as dose modifications. METHODS: We enrolled patients who started a treatment with nivolumab or pembrolizumab and were admitted to the Regina Elena National Cancer Institute in the period between 01/01/2016 and 31/12/2018. Treatments were followed up to 31/01/2021. Data were collected from the AIFA monitoring registries and from local therapy monitoring databases. We used the Kaplan-Meier method to estimate rwTTD, and the differences between sample subgroups were evaluated using the Log-Rank Test. RESULTS: In the 123 patients enrolled, the rwTTD was 11.67 months (IC 95%: 7,93-17,27). On average, about one out of five patients stopped the therapy before 2 months. The treatments suspended for at least 45 consecutive days and then resumed were 49 (47.6%) with rwTTD= 26.4 months (95% CI 17.3-43.6), significantly higher (p=0.008) compared to treatments suspended for less than or equal to 45 days (rwTTD= 8.4 months (95% CI 4.3-17.1). Dosage changes of nivolumab from pro/kg to flat dose ended in percentage ranging from -23.8% to +56.9%, mean +7.2%. In the case of pembrolizumab, the transition to the flat dose led to variations between +22% and +81.8%, average +39.9%. DISCUSSION AND CONCLUSIONS: Patients who temporarily stopped the treatment had a median rwTTD that is three times higher than patients who stopped permanently and had at least 45 days of therapy. Other studies suggest that patients who had immunological response and side effects, then had better PFS and OS than those without side effects. It is confirmed that it is therefore important to manage toxicities and then resume treatment, whenever possible. In patients who switched to a flat dose, there was an evident increase in the dose administered, especially for pembrolizumab.

Adherence, persistence and efficacy of dasatinib and nilotinib in the treatment of patients resistant or intolerant to imatinib with chronic myeloid leukemia in chronic phase: an Italian multicenter study over two years in real life.

BACKGROUND: The use of dasatinib and nilotinib in the treatment of patients with chronic myeloid leukemia represents a valid therapeutic option for patients resistant or intolerant to imatinib. In this multicentre study, adherence, persistence and efficacy in real life over two years of treatment were evaluated. MATERIALS AND METHODS: Adherence to treatment was calculated as the ratio between the dose received and the prescribed dose. The dose received was calculated using pharmacy refill data. The persistence with treatment was calculated as the difference between the end and the beginning of the treatment. Efficacy was assigned as Progression-Free Survival (PFS) and Events-Free Survival (EFS) and represented through the Kaplan-Meier curve. RESULTS: The number of patients analysed was 117, 70 treated with dasatinib and 47 with nilotinib. Adherence to treatment for dasatinib and nilotinib at two years was 0.91 and 0.82 respectively. Persistence at two years was 77% while the PFS was 92% for both drugs in the study. CONCLUSION: Adherence to the treatment calculated over two years showed a superiority of dasatinib over nilotinib. Nevertheless, the efficacy in terms of PFS and EFS is superimposable between the two drugs in the study.

Cancer drugs for solid tumors approved by the EMA since 2014: an overview of pivotal clinical trials.

INTRODUCTION: The European Medicine Agency (EMA) authorizes the marketing of drugs, with the authorization being full, conditional or issued under exceptional circumstances. Usually the efficacy and safety of drugs must be demonstrated in at least 2 well-controlled trials, but this rule is not always observed. The objective of the trial is to provide an overview of the pivotal trials of cancer drugs authorized for marketing in Europe since 2014. MATERIALS AND METHODS: From the technical data sheets of each drug authorized by the EMA between January 1, 2014 and May 31, 2019, we evaluated the relative pivotal trial(s) in terms of the following characteristics: number of patients, masking, trial phase, number of arms, primary endpoint(s), presence of subgroup analysis, quality of life as endpoint, and value of statistical p. The results provided us with the total number of trials, which we then divided into trials for orphan and non-orphan drugs. RESULTS: We considered 38 medicines, 6 of which were classified as orphans, for a total of 96 pivotal trials. Four drugs had conditional authorization, 1 was authorized under exceptional circumstances. Seventeen drugs underwent only 1 pivotal trial to support marketing authorization. Most of the trials were phase 3 and open-label, with 2 arms. Most trials considered the progression-free survival (PFS) as the primary endpoint, less than 30% of trials consider OS as a primary endpoint, and less than 40% of trials reported quality of life. The p values, with very few exceptions, were below 0.05. CONCLUSIONS: The rule of 2 well-controlled trials was complied with in just over 50% of the authorized drugs, and even when there was only 1 pivotal trial supporting the authorization, the trial itself may not have been necessarily well-controlled; the authorization was revoked for a drug because the trial did not confirm the benefits expected from confirmatory trials; while for 2 drugs, the evidence of efficacy yielded by the trials was not considered exhaustive. Considering that sometimes clinical authorization trials do not provide complete data on safety and efficacy, it would be perhaps appropriate to gather more pre-marketing evidence or leverage post-marketing data to complete the available information and have greater certainty.

Anti-PD-1 immunotherapy in advanced metastatic melanoma: State of the art and future challenges.

Immunotherapy with immune checkpoint inhibitors, such as anti-PD-1 drugs, is an area in increasing development for its efficacy and advantages in the treatment of advanced metastatic melanoma. In fact, immunotherapy has been the target of several and recent studies in different types of cancer, namely in melanoma, a globally growing threat. Contributing to the increasing incidence of this cancer is climate change, particularly global warming of the past century, which has increased the tendency to spend more time outdoors and, consequently, exposure to sunlight and ultraviolet radiation. Among the most relevant risk factors for melanoma is the increase in ultraviolet radiation due to ozone layer depletion, one of the main factors responsible for the incidence of new cases. Anti-PD-1 agents like Nivolumab and Pembrolizumab allow a more effective treatment, enhancing the duration of the responses to therapy and prolonging the survival of the patient. However, recent studies about safety and tolerability have stated that, although these drugs present less adverse effects and toxicity, they may lead to specific autoimmune-mediated adverse events. Overall, immunotherapy with anti-PD-1 agents represents a highly promising area in the treatment of some types of cancer such as melanoma.

Dosage adjustments in pivotal clinical trials with oral targeted therapies in solid tumors conducted in Europe.

PURPOSE: The aim of this study was to evaluate in what measure is dosage adjustment particularly prevalent in pivotal clinical trials of oral targeted therapy drugs approved by the European Medicine Agency as of July 31, 2018, for the treatment of solid tumors. METHODS: We performed a search on the official EMA site on human medicines, using as Keyword Search the ATC Code L01X (other antineoplastic agents); from the list of drugs results, we subsequently excluded antineoplastic drugs for hematological diseases, as well as refused and withdrawn drugs. For all analyzed drugs, we recorded full dosages, dose adjustments with relative reduction percentage, reason for the adjustments, number of patients included in the trial, percentage of patients who reduced their dosage or temporarily discontinued therapy, cause of dose reduction, and presence or absence of reference to a clinical outcome in patients who reduced their dose or discontinued therapy. RESULTS: We considered 74 pivotal trials on 29 target therapies, of which 56 (76%) provide information on dosage reduction, 41 (55%) on therapy suspension, and 29 (39%) on the dose taken by the sample. Trials that provide information on dosage adjustment include reduction and suspension data widely used to manage side effects; they concern, respectively, 32 and 44% of the samples considered. No trial results take account of the possible role of adjustment in clinical outcomes. CONCLUSION: It would be advisable for pivotal clinical trials to give more relevance to dose management, which is a widely used tool for the management of adverse events in clinical practice. To date, such information is lacking.

[Appropriate use of trastuzumab in Lazio Region: therapeutic scenarios and estimation of possible savings for the Regional Health Service.] / Utilizzo appropriato del trastuzumab nel Lazio: scenari terapeutici e stima del possibile risparmio per il Servizio Sanitario Regionale.

BACKGROUND: The availability of subcutaneous (SC) and intravenous (EV) formulations of trastuzumab and the recent release of the biosimilar EV version (10/2018) increase the offer for the treatment of patients with breast or gastric cancer HER2 positive. In this context, it is necessary to build therapeutic scenarios form avalible data in order to estimate the potential savings for the Regional Health Service (RHS) taking into account the appropriateness of use and patient's preferences. AIM: To evaluate the available comparative evidence regarding the effectiveness and safety of the different trastuzumab formulations; to analyze the supply of trastuzumab by type of administration (EV/SC) in Lazio in 2018, identifying the most appropriate use; to hypothesize a cost-effective scenario for the Regional Health Service (SSR) in 2019. Mehods. With the working group formed by clinicians and methodologists, we analysed the evidence of efficacy and safety available to date for the different formulations of trastuzumab, also taking into account the recent availability of biosimilars and with particular regard to the phenomenon of the potential switch between different therapeutic options. In addition, for the year 2019 the available economic impact assessments were also simulated with data from the Lazio Region. Through the datas from direct pharmaceutical products, the transtuzumab cycles supplied in 2018 were identified separately for the available formulations (EV/SC). For each cycle of therapy, starting from the date of delivery, the possible presence of a concomitant treatment (± 2 days) was investigated, tracing the type and method of administration. The treatments (concomitant with trastuzumab) were identified for which there were conflicting modes of administration. In addition, the supply of SC per dispensing structure was evaluated and, on the basis of this information, a scenario of use was hypothesized that takes into account costs and plausible consumption. RESULTS: A review of the literature summarized the available evidence on the efficacy and safety of the use of trastuzumab in the recorded therapeutic indications. The review was discussed with the working group and used to reproduce, at regional level, the estimates of the economic impact of the different therapeutic choices possible with trastuzumab. As regards the data on the use of trastuzumab, in the Lazio Region in 2018, 22,214 treatment cycles were observed (at a cost of 33 million euro) for 2,407 patients; new users accounted for 52.2%. 46.8% of the cycles were administered via SC; the use of the biosimilar was observed from October onwards and involved 143 cycles (0.6%). In 68.4% of the cycles trastuzumab was administered in monotherapy; among the therapies associated with trastuzumab, the most frequent was pertuzumab (n=4,258, 19.2% of the total cycles), followed by paclitaxel (n=1,364, 6.1% of the total cycles). Among the cycles of trastuzumab in concomitant therapy (N=7,022), 17.3% was administered via SC despite the presence of other drugs administered via EV. The prescriptive pattern of trastuzumab was heterogeneous for the different delivery structures. The SC administration presents a variability in the supply from 26% to 70% (interquartile range) and does not seem to be related to the type and volume of activity of the hospital. If the biosimilar EV is expected to account for 55% of consumption by 2019, thus reducing the use of the EV originator to 10% and the SC originator to 35%, savings of more than €7 million. CONCLUSIONS: Through the use data of the different formulations available for trastuzumab and taking into account the prescriptive appropriateness (and patient preferences), it has been possible to identify a SSR scenario of economic convenience due to the greater use of the biosimilar.

Iodixanol versus iopromide in cancer patients: Evidence from a randomized clinical trial.

To assess the safety profile of iso-osmolar contrast medium (CM) versus low osmolar CM in cancer patients with an estimated glomerular filtration rate (eGFR) >60 ml/min. In this multicenter, blind trial of patients seeking a chest-abdomen-pelvis contrast enhanced computed tomography (CT) with iodated CM, participants were centrally randomized to iodixanol or iopromide. Contrast induced nephropathy (CIN) at 24 and/or 72 hr were our primary outcomes. We further considered irreversible CIN, average eGFR percentage variation (%Δ), and adverse events (AEs). Overall, 607 patients were enrolled. Among them, 497 eligible patients were randomized to iodixanol (N: 247) or iopromide (N: 250). No differences emerged by descriptive characteristics. Seven and 3 CIN at 24 hr (p = 0.34) and 8 and 2 CIN at 72 hr (p = 0.11) occurred in the iopromide and iodixanol group, respectively. Within the subgroup of individual patients who developed CIN (N: 17), the event rate was higher in the iopromide arm (p = 0.045). No cases of permanent CIN or significant differences in terms of AEs or GFR %Δ were observed. Our results suggest a more favorable safety profile of iodixanol versus iopromide. Adequately sized trials with similar design are warranted to confirm our findings and clarify the underlying biological mechanisms.