ESMO study on the availability and accessibility of biomolecular technologies in oncology in Europe.

BACKGROUND: Access to biomolecular technologies has become an essential requirement to ensure optimal and timely treatment of patients with cancer. This study sought to provide a comprehensive overview of the availability and accessibility of biomolecular technologies to patients, the status of their use and prescription, barriers to access, and potential economic issues related to cost and reimbursement. MATERIALS AND METHODS: A total of 201 field reporters from 48 European countries submitted data through an electronic survey tool between July and December 2021. The survey methodology mirrored that from previous ESMO studies addressing the availability and accessibility of antineoplastic medicines, in Europe and worldwide. The preliminary data were posted on the ESMO website for open peer-review, and amendments were incorporated into the final report. RESULTS: Overall, basic single-gene techniques are widely available, whereas access to advanced biomolecular technologies, including large next-generation sequencing panels and complete genomic profiles, is highly heterogeneous. In most countries, advanced biomolecular technologies remain largely inaccessible in clinical practice, are limited to clinical trials or basic research, and associated with progressively increasing cost as the technique becomes more advanced. Differences also exist regarding national sequencing initiatives or molecular tumour boards. The most important barriers to multiple versus single-gene sequencing techniques are the reimbursement of the test (59% versus 24%), and the availability of a suitable medicine, either through reimbursement of treatment (48% versus 30%), off-label treatment (52% versus 35%), or clinical trial enrolment (53% versus 39%). CONCLUSIONS: Cost and availability of both treatment and test are the two main factors limiting patients' access to advanced biomolecular technologies and as a consequence to innovative anticancer strategies. In the era of precision medicine, tackling the accessibility to biomolecular technologies is a key step to reduce inequalities to transformative cancer care.

Streamlining clinical research: an ESMO awareness call to improve sponsoring and monitoring of clinical trials.

BACKGROUND: During recent years, the burden of bureaucracy in clinical research has increased dramatically, adversely impacting the activity of investigators and clinical research teams. Although compliance with the Declaration of Helsinki, the guidelines for Good Clinical Practice (GCP), and other applicable regulations remains unquestionable, their overinterpretation and substitution by the internal operating procedures of sponsors and Contract Research Organizations (CROs) have increased the administrative burden. A survey conducted by the European Society for Medical Oncology (ESMO) Clinical Research Observatory (ECRO) among 940 investigators confirmed that they considered that the administrative burden in clinical research is excessive; that administrative procedures could be reduced without affecting the safety and the rights of the patients and the quality of the data; and that bureaucracy represents an obstacle for clinical research. METHODS: A panel of physicians with extensive experience in clinical research, composed by members of the ECRO and the ESMO Scientific Medical and Public Policy divisions, analyzed clinical trial procedures related to administrative workflow, pharmacovigilance, and medical care. RESULTS: The panel identified situations that generate debate between investigators and sponsors/CROs and selected real clinical scenarios that exemplify such situations. The panel discussed and proposed specific recommendations for those situations, based on GCP. CONCLUSIONS: This initiative aspires to streamline clinical research procedures and to become a platform for discussion among all clinical trial stakeholders, with the aim of promoting the sustainability of clinical research and the care of cancer patients.

Influence of different blanching methods on colour, ascorbic acid and phenolics content of broccoli.

Lack of nutrients in cooking water, high energetic costs, high water consumption and recycling are some drawbacks of vegetable blanching. Those disadvantages could be bypassed using microwave blanching. Three blanching methods (microwave, boiling water and steaming) were compared in this study in order to determine their effects on some functional properties of broccoli. In addition, the thermal damage on broccoli colour was evaluated. The effectiveness of each blanching process was performed measuring the lost of peroxidase activity, that results more rapidly in microwaves and steam treatments (50 and 60 s respectively) than in boiling water treatment (120 s). The colour indexes did not allow to discriminate a significant difference among treatments. The increase of treatment time caused a vitamin C decrease in samples blanched by boiling water and steam; this trend was not observed in microwaved samples. The phenols content did not significantly vary depending both on type and on time of treatment.

Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations.

Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add-on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy and safety of safinamide, an α-aminoamide with dopaminergic and nondopaminergic mechanisms, as add-on to l-dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression-Change (CGI-C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI-C were significantly greater in both safinamide groups versus placebo. There were no significant between-group differences for incidences of treatment-emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l-dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia.

Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson's disease.

BACKGROUND AND PURPOSE: Safinamide is an α-aminoamide with both dopaminergic and non-dopaminergic mechanisms of action in Phase III clinical development as a once-daily add-on to dopamine agonist (DA) therapy for early Parkinson's disease (PD). METHODS: Study 017 was a 12-month, randomized, double-blind, placebo-controlled pre-planned extension study to the previously reported Study 015. Patients received safinamide 100 or 200 mg/day or placebo added to a single DA in early PD. The primary efficacy endpoint was the time from baseline (Study 015 randomization) to 'intervention', defined as increase in DA dose; addition of another DA, levodopa or other PD treatment; or discontinuation due to lack of efficacy. Safinamide groups were pooled for the primary efficacy endpoint analysis; post hoc analyses were performed on each separate dose group. RESULTS: Of the 269 patients randomized in Study 015, 227 (84%) enrolled in Study 017 and 187/227 (82%) patients completed the extension study. Median time to intervention was 559 and 466 days in the pooled safinamide and placebo groups, respectively (log-rank test; P = 0.3342). In post hoc analyses, patients receiving safinamide 100 mg/day experienced a significantly lower rate of intervention compared with placebo (25% vs. 51%, respectively) and a delay in median time to intervention of 9 days (P < 0.05; 240- to 540-day analysis). CONCLUSIONS: The pooled data from the safinamide groups failed to reach statistical significance for the primary endpoint of median time from baseline to additional drug intervention. Post hoc analyses indicate that safinamide 100 mg/day may be effective as add-on treatment to DA in PD.

Essential cancer medicines: adding feasibility to the magnitude of clinical benefit value chain.

BACKGROUND: Cancer is a global public health problem, requiring efficient health system investments to deliver sustainable impact on population health. Access to medicines is a critical component of health systems, having a crucial role in delivering therapeutic benefits. Since 1977, the World Health Organization (WHO) has published a Model List of Essential Medicines (EML) that includes key health interventions for the prevention and control of conditions of public health relevance. Essential medicines are selected for inclusion in the EML based on the evidence of efficacy, safety, therapeutic value, and the potential to impact population health. With the rapid changes in the therapeutic landscape of cancer treatment with new medicine approvals, there is a critical need to select and prioritise specific cancer interventions based on their intrinsic value. MATERIALS AND METHODS: The European Society for Medical Oncology (ESMO) has developed a decisional methodology based on a threshold with a minimum set of technical specifications and a consensus-based procedure for decisions to select candidate cancer medicines to be submitted to the WHO for consideration for the WHO EML. RESULTS: ESMO recognises the WHO EML as an important reference guide for medicines that all countries should include in their national EMLs. Cancer medicines on the WHO EML are used in the treatment of the majority of cancers, and are recommended in the evidence-based ESMO Clinical Practice Guidelines that medical oncologists use to treat patients. ESMO's submissions to the WHO EML in 2019 and 2021 and their respective outcomes are presented in the manuscript. CONCLUSION: Due to the rising costs associated with newly available therapies, structured, reproducible, and field-tested tools to evaluate the added clinical benefit from these therapies need to be implemented in pre-selecting potential candidate medicines to be included in the WHO EML. ESMO is proud to collaborate closely with WHO on this important global public health initiative.

Off-label despite high-level evidence: a clinical practice review of commonly used off-patent cancer medicines.

INTRODUCTION: Off-label use of medicines is generally discouraged. However, several off-patent, low-cost cancer medicines remain off-label for indications in which they are commonly used in daily practice, supported by high-level evidence based on results of phase III clinical trials. This discrepancy may generate prescription and reimbursement obstacles as well as impaired access to established therapies. METHODS: A list of cancer medicines that remain off-label in specific indications despite the presence of high-level evidence was generated and subjected to European Society for Medical Oncology (ESMO) expert peer review to assess for accountability of reasonableness. These medicines were then surveyed on approval procedures and workflow impact. The most illustrative examples of these medicines were reviewed by experts from the European Medicines Agency to ascertain the apparent robustness of the supporting phase III trial evidence from a regulatory perspective. RESULTS: A total of 47 ESMO experts reviewed 17 cancer medicines commonly used off-label in six disease groups. Overall, high levels of agreement were recorded on the off-label status and the high quality of data supporting the efficacy in the off-label indications, often achieving high ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores. When prescribing these medicines, 51% of the reviewers had to implement a time-consuming process associated with additional workload, in the presence of litigation risks and patient anxiety. Finally, the informal regulatory expert review identified only 2 out of 18 (11%) studies with significant limitations that would be difficult to overcome in the context of a potential marketing authorisation application without additional studies. CONCLUSIONS: We highlight the common use of off-patent essential cancer medicines in indications that remain off-label despite solid supporting data as well as generate evidence on the adverse impact on patient access and clinic workflows. In the current regulatory framework, incentives to promote the extension of indications of off-patent cancer medicines are needed for all stakeholders.

Factors affecting the outcome of temporary sacral nerve stimulation for faecal incontinence. The value of the new tined lead electrode.

AIM: Sacral nerve stimulation (SNS) is an effective but expensive treatment for faecal incontinence. About 50% of the patients are unresponsive for unknown reasons, hence knowledge of any factors predictive of success would be highly desirable. The aim of this study was to analyse the potential factors associated with a successful outcome of the temporary test of electrostimulation. METHOD: Eighty-five patients with faecal incontinence were tested for SNS. The cause was idiopathic in 45, iatrogenic or obstetric in 28, spinal lesion or neurological diseases in nine and anal malformation in three patients; 43 were tested with a unipolar electrode and 42 with a quadripolar electrode. The severity of faecal incontinence was evaluated using the American Medical System (AMS) score and Wexner's score. RESULTS: A positive response was obtained in 45 patients (53%); 40 (47%) were implanted with a permanent pulse generator. Responders and nonresponders were comparable in age, duration of incontinence, anal manometry, pudendal nerve terminal motor latency and diabetes. Unipolar electrode test (PNE test) was able to elicit positive responses in 18 of 43 (42%) and the quadripolar in 27 of 42 patients (P < 0.001). Type of incontinence and gender did not affect the success rate. Patients with idiopathic incontinence had a significantly higher response rate (P =0.022). Multivariate regression analysis indicated use of a quadripolar electrode as the only independent variable predicting the success of SNS (OR = 5.58, P = 0.009). CONCLUSION: Use of the quadripolar electrode is the only factor significantly related to the success of SNS.

Distribution of the workforce involved in cancer care: a systematic review of the literature.

BACKGROUND: A skilled health workforce is instrumental for the delivery of multidisciplinary cancer care and in turn a critical component of the health systems. There is, however, a paucity of data on the vast inequalities in cancer workforce distribution, globally. The aim of this study is to describe the global distribution and density of the health care workforce involved in multidisciplinary cancer management. METHODS: We carried out a systematic review of the literature to determine ratios of health workers in each occupation involved in cancer care per 100 000 population and per 100 cancer patients (PROSPERO: protocol CRD42018095414). RESULTS: We identified 33 eligible papers; a majority were cross-sectional surveys (n = 16). The analysis of the ratios of health providers per population and per patients revealed deep gaps across the income areas, with gradients of workforce density, highest in high-income countries versus low-income areas. Benchmark estimates of optimal workforce availability were provided in a secondary research analysis: mainly high-income countries reported workforce capacities closer to benchmark estimates. A paucity of literature was defined for critical health providers, including for pediatric oncology, surgical oncology, and cancer nurses. CONCLUSION: The availability and distribution of the cancer workforce is heterogeneous, and wide gaps are described worldwide. This is the first systematic review on this topic. These results can inform policy formulation and modelling for capacity building and scaleup.

The EMA review of trastuzumab emtansine (T-DM1) for the adjuvant treatment of adult patients with HER2-positive early breast cancer.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate of trastuzumab [a monoclonal antibody against human epidermal growth factor receptor 2 (HER2)] and DM1 (an inhibitor of tubulin polymerisation). It was initially approved in the European Union for the treatment of adult patients with HER2-positive unresectable locally advanced or metastatic breast cancer (BC) who had previously received trastuzumab and taxanes. On 18 December 2019, a variation of the marketing authorisation was approved extending this use to the adjuvant therapy of adult patients with HER2-positive early BC who have residual invasive disease in the breast and/or lymph nodes after neoadjuvant taxane-based and HER2-targeted therapy. A phase III randomised, multicentre, open-label trial compared T-DM1 with trastuzumab as adjuvant therapy in patients with HER2-positive early BC who had received preoperative chemotherapy and HER2-targeted therapy followed by surgery, with a finding of invasive residual disease in the breast and/or axillary lymph nodes. The study met its primary endpoint by showing an increased 3-year invasive disease-free survival rate in the T-DM1 arm (88.3%) compared with the trastuzumab arm (77.0%), with an unstratified hazard ratio of 0.50 (95% confidence interval: 0.39-0.64). There was a higher incidence of hepatotoxicity (37.3% versus 10.6%), thrombocytopenia (28.5% versus 2.4%), peripheral neuropathy (32.3% versus 16.9%), haemorrhage (29.2% versus 9.6%) and pulmonary toxicity (2.8% versus 0.8%) in the T-DM1 arm compared with the control arm. The aim of this manuscript was to summarise the scientific review of the application leading to regulatory approval of this additional indication in the European Union.

Different approaches in the molecular analysis of the SHOX gene dysfunctions.

Deficit of the short stature homeobox containing gene (SHOX) accounts for 2.15% of cases of idiopathic short stature (ISS) and 50-100% of cases of Leri-Weill dyschondrosteosis (LWD). It has been demonstrated that patients with SHOX deficit show a good response to treatment with GH. Thus, the early identification of SHOX alterations is a crucial point in order to choose the best treatment for ISS and LWD patients. In this study, we analyze the most commonly used molecular techniques for the detection of SHOX gene alterations. multiple ligation-dependent probe amplification analysis appears to represent the gold standard for the detection of deletion involving the SHOX gene or the enhancer region, being able to show both alterations in a single assay.

Fecal incontinence: up to date on pathophysiology and treatment.

This study analyzes the most recent insight into the pathophysiology of fecal incontinence considering each of the factors contributing to the mechanism of fecal continence both during urgency to defecate and in resting state. In fact different types of incontinence are caused by different damage to one or more of these physiologic factors. The second part of the study focuses on the therapeutic choices of fecal incontinence. The recent introduction of sacral nerve electrostimulation and the progressive broadening of its clinical indications is progressively replacing and challenging other traditional surgical techniques because of their disappointing long-term results and because they are much more invasive. An emerging new treatment based on the injection of anal bulking agents is nowadays even more preferred for the less severe cases of fecal incontinence. An increasing number of materials is now proposed by the industry in order to identify the best biocompatible material to be injected trans-anally. Traditional surgery could be reserved for patients non-responding to these new treatments.

A comparative in vitro study of the toxic potency of five inorganic lead compounds on a rat liver epithelial cell line (REL).

Relative insolubility of inorganic Pb compounds is one of the major problems in the evaluation of the toxicological profile of this metal. Different characteristics of Pb-containing solutions may, in fact, alter the biological properties of Pb compounds and influence their toxic potency. To investigate these aspects, we used selected experimental conditions to evaluate and compare the specific biological effects of five inorganic Pb compounds (soluble salts and oxide) on the viability and proliferation rate of a rat liver-derived cell line (REL cells). The study was performed according to classical toxicological criteria (dose- and time-response, reversibility/transience of the effect). Each Pb compound was accurately solubilised and the quantification of the real concentration of Pb(II) ions was performed either on the culture media used for each treatment, or on the extracts of exposed cells. Our study shows that four, out of the five Pb compounds we tested, induce the same dose- and time-related anti-proliferative effects on REL cells, being these effects also reversible, transient and directly related to the intracellular content of the metal. Since the intracellular concentration of the metal and, consequently, its biological effects on REL cells, directly depends on the bioavailability of the Pb(II) cation present in the treatment solutions, our results indicate that, in the experimental procedures aimed to assess the toxic potency of this metal, the solubility of each Pb compound should be carefully evaluated and taken into account.

Modulation of tumor angiogenesis by conditional expression of fibroblast growth factor-2 affects early but not established tumors.

Fibroblast growth factor-2 (FGF2) is a pleiotropic heparin-binding growth factor endowed with a potent angiogenic activity in vitro and in vivo. To investigate the impact of the modulation of FGF2 expression on the neovascularization at different stages of tumor growth, we generated stable transfectants (Tet-FGF2) from the human endometrial adenocarcinoma HEC-1-B cell line in which FGF2 expression is under the control of the tetracycline-responsive promoter (Tet-off system). After transfection, independent clones were obtained in which FGF2 mRNA and protein were up-regulated compared with parental cells. Also, the conditioned medium of Tet-FGF2 transfectants caused proliferation, urokinase-type plasminogen activator up-regulation, migration, and sprouting of cultured endothelial cells. A 3-day treatment of Tet-FGF2 cell cultures with tetracycline abolished FGF2 overexpression and the biological activity of the conditioned medium without affecting their proliferative capacity. Tet-FGF2 cells formed tumors when nude mice received s.c. injections. The administration of 2.0 mg/ml tetracycline in the drinking water before cell transplantation, continued throughout the whole experiment, inhibited FGF2 expression in Tet-FGF2 tumor lesions. This was paralleled by a significant decrease in the rate of tumor growth and vascularization to values similar to those observed in lesions generated by parental HEC-1-B cells. Tetracycline administration 20 days after tumor cell implant, although equally effective in reducing FGF2 expression and inhibiting tumor vascularity, only minimally impaired the growth of established Tet-FGF2 tumors. The results indicate that FGF2 expression deeply affects the initial tumor growth and neovascularization of HEC-1-B human endometrial adenocarcinoma in nude mice. On the contrary, the growth of established tumors appears to be independent of the inhibition of FGF2 expression and decreased vascular density. The possibility that a significant reduction of angiogenesis may not affect the progression of large tumors points to the use of antiangiogenic therapy in early tumor stage.