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.

Twelve ESMO Congress 2022 breakthroughs: practicing oncologists' perceptions and potential application on presented data.

BACKGROUND: During the European Society for Medical Oncology (ESMO) Congress 2022, outcome data of a great number of clinical trials were presented. For the attending medical oncologist, it is important to structure these data in a way that facilitates a trade-off between treatment burden and benefit. MATERIALS AND METHODS: To illustrate this, we carried out a narrative non-systematic review of 12 selected oral presentations with potential impact on future daily practice, focusing on trial methodology, possible study flaws, reported clinical benefit and implementability. RESULTS: The selected presentations encompassed 10 phase III trials, 1 randomized phase II trial and 1 phase II trial. In 7 out of 12 trials, quality of life and/or patient-reported outcomes had been evaluated. None of the trials, which reported progression-free survival (PFS) data, provided information, which could exclude informative censoring bias. In none of the trials reporting overall survival (OS) data, potential flaws due to undesirable crossover and imbalance between study groups regarding post-progression treatments were addressed. For the 11 reviewed randomized trials, the ESMO-Magnitude of Clinical Benefit Scale (MCBS) grade achieved with the new intervention was calculated based on the presented data. The MCBS grade varied from 1 to 5. CONCLUSIONS: Our review confirms the high-quality standard of current cancer research and the clinical relevance of the research questions answered. However, during presentation of PFS and/or OS data, factors known to affect PFS and OS analysis should be structurally addressed. In order to keep cancer care affordable and sustainable, it could be considered to include an ESMO-MCBS threshold in the drug appraisal process of regulatory authorities.

11 ESMO 2021 breakthroughs: practicing oncologist's perceptions on data presentation.

BACKGROUND: The European Society for Medical Oncology (ESMO) 2021 conference provided a high number of randomized phase III trial reports, many of which were claimed to be practice changing. Given the short time available for conference presentations, results and conclusions tend to have greatest priority with less time remaining for study background and study methodology. PURPOSE: On behalf of the ESMO Practicing Oncologists Working Group, 11 potentially practice-changing reports were selected and screened for three main questions: (i) Did the investigators provide sufficient details with regard to Patients and Methods to make the results comprehensible? (ii) Were there any reasons to consider bias? (iii) To which extent did the results presented translate to clinical benefit? RESULTS: In 2 out of 11 trials, the study design presented differed considerably from the study design described at ClinicalTrials.gov. Allocation concealment was not carried out in 6 out of 11 trials. In none of the trials reporting progression-free survival was informative censoring considered an issue. In none of the trials reporting overall survival was desirable crossover considered an issue. Defined trial outcome measures depicted at ClinicalTrials.gov, which could boost or weaken the ESMO-Magnitude of Clinical Benefit Scale score, were often lacking in the presentation. Study success was claimed in a heterogeneous manner, which was often not clearly linked to overall clinical benefit. CONCLUSION: ESMO conference presentations can inform the scientific community and catalyze further research but cannot replace the full papers in peer-reviewed journals, which are needed to estimate the thoroughness of the results, the overall impact on clinical benefit and the consequences for future treatment guidelines.

Impact of COVID-19 on social media as perceived by the oncology community: results from a survey in collaboration with the European Society for Medical Oncology (ESMO) and the OncoAlert Network.

BACKGROUND: The COVID-19 pandemic has impacted all aspects of modern-day oncology, including how stakeholders communicate through social media. We surveyed oncology stakeholders in order to assess their attitudes pertaining to social media and how it has been affected during the pandemic. MATERIALS AND METHODS: A 40-item survey was distributed to stakeholders from 8 July to 22 July 2020 and was promoted through the European Society for Medical Oncology (ESMO) and the OncoAlert Network. RESULTS: One thousand and seventy-six physicians and stakeholders took part in the survey. In total, 57.3% of respondents were medical oncologists, 50.6% aged <40 years, 50.8% of female gender and mostly practicing in Europe (51.5%). More than 90% of respondents considered social media a useful tool for distributing scientific information and for education. Most used social media to stay up to date on cancer care in general (62.5%) and cancer care during COVID-19 (61%) given the constant flow of information. Respondents also used social media to interact with other oncologists (78.8%) and with patients (34.4%). Overall, 61.1% of respondents were satisfied with the role that social media was playing during the COVID-19 pandemic. On the other hand, 41.1% of respondents reported trouble in discriminating between credible and less credible information and 30% stated social networks were a source of stress. For this reason, one-third of respondents reduced its use during the COVID-19 pandemic. Regarding meeting attendance, a total of 59.1% of responding physicians preferred in-person meetings to virtual ones, and 51.8% agreed that virtual meetings and social distancing could hamper effective collaboration. CONCLUSION: Social media has a useful role in supporting cancer care and professional engagement in oncology. Although one-third of respondents reported reduced use of social media due to stress during the COVID-19 pandemic, the majority found social media useful to keep up to date and were satisfied with the role social media was playing during the pandemic.

Professional burnout in European young oncologists: results of the European Society for Medical Oncology (ESMO) Young Oncologists Committee Burnout Survey.

BACKGROUND: Burnout in health care professionals could have serious negative consequences on quality of patient care, professional satisfaction and personal life. Our aim was to investigate the burnout prevalence, work and lifestyle factors potentially affecting burnout amongst European oncologists ≤40 (YOs). METHODS: A survey was conducted using the validated Maslach Burnout Inventory (MBI) and additional questions exploring work/lifestyle factors. Statistical analyses were carried out to identify factors associated with burnout. RESULTS: Total of 737 surveys (all ages) were collected from 41 European countries. Countries were divided into six regions. Results from 595 (81%) YOs were included (81% medical oncologists; 52% trainees, 62% women). Seventy-one percent of YOs showed evidence of burnout (burnout subdomains: depersonalization 50%; emotional exhaustion 45; low accomplishment 35%). Twenty-two percent requested support for burnout during training and 74% reported no hospital access to support services. Burnout rates were significantly different across Europe (P < 0.0001). Burnout was highest in central European (84%) and lowest in Northern Europe (52%). Depersonalization scores were higher in men compared with women (60% versus 45% P = 0.0001) and low accomplishment was highest in the 26-30 age group (P < 0.01). In multivariable linear regression analyses, European region, work/life balance, access to support services, living alone and inadequate vacation time remained independent burnout factors (P < 0.05). CONCLUSIONS: This is the largest burnout survey in European Young Oncologists. Burnout is common amongst YOs and rates vary across Europe. Achieving a good work/life balance, access to support services and adequate vacation time may reduce burnout levels. Raising awareness, support and interventional research are needed.

A new approach for rapid and reliable enumeration of circulating endothelial cells in patients.

BACKGROUND: Mature circulating endothelial cells (CECs) are surrogate markers of endothelial damage/dysfunction. A lack of standardized assays and consensus on CEC phenotype has resulted in a wide variation of reported CEC numbers (4-1300 per mL). OBJECTIVES: Given the need for a quick, reliable, robust and validated CEC assay at an affordable price, we present a novel approach to enumerate CECs using a multi-parameter flow cytometric (FCM) method without immunological pre-enrichment. METHODS: CECs were defined as CD34+, CD45neg, CD146+ and DNA+ events based on the immunophenotype of endothelial cells from vein-wall dissections. As CECs express high levels of CD34, we based our assay on absolute CD34 counts after analyzing all CD34 positive events in a total blood volume of 4 mL needed for a precise enumeration of CECs at a frequency of < 1 cell µL(-1). RESULTS: The endothelial origin of CECs was confirmed by morphology, immunohistochemistry and gene expression. The new FCM assay was tested in parallel with a validated assay (i.e. CellSearch). CEC levels ranged from 4 to 79 CEC mL(-1) in healthy individuals and were significantly higher in patients with advanced solid malignancies (P = 0.0008) and in patients with hematological malignancies (P < 0.0001). CONCLUSIONS: This flow cytometric method should be useful as a fast and economical assay to enumerate and characterize CECs.

Circulating tumour cells and circulating endothelial cells as biomarkers in oncology.

Circulating tumour cells (CTC) and circulating endothelial cells (CEC) are considered promising biomarkers for tumour aggressiveness and vascular damage. Their number in the blood of cancer patients has already demonstrated to be of prognostic and predictive value in several studies. In addition, the molecular characterization of these cells may provide novel insight in the growth and dissemination of cancer, and help the development of new anti-neoplastic drugs. Therefore, many attempts have been made to reliably detect these extremely rare cells in the blood. In this review, we address the detection, applicability and results from clinical trials for both CTC and CEC.

Circulating endothelial cells, circulating tumour cells, tissue factor, endothelin-1 and overall survival in prostate cancer patients treated with docetaxel.

PURPOSE: We investigated whether serum markers of angiogenesis endothelin-1 (ET-1) and tissue factor (TF), and/or markers of vascular damage such as circulating endothelial cells (CECs), or their relative changes during treatment, were prognostic for overall survival (OS) in castration resistant prostate cancer (CRPC) patients. Additionally, we combined these markers with circulating tumour cells (CTCs) to construct a predictive nomogram for treatment outcome. PATIENTS AND METHODS: One hundred and sixty two CRPC patients treated with a docetaxel containing regimen had blood drawn before and at 2-5 weeks and 6-8 weeks after treatment start. Prospectively determined CTC and CEC levels, and retrospectively measured serum concentrations of ET-1 (pg/mL) and TF (pg/mL) were evaluated to determine their prognostic value for OS. RESULTS: Baseline CEC, TF and ET-1 were not prognostic for OS. A > or = 3.8-fold increase in CEC 2-5 weeks after treatment initiation was associated with decreased OS (median 10.9 versus 16.8 months; P=0.015), as was any decrease in TF levels compared to baseline levels (median 11.9 versus 21.5 months; P=0.0005). As previously published, baseline and CTC counts > or = 5 at 2-5 weeks were also predictive of decreased OS. Combining CTC with changes in TF and CEC 2-5 weeks after treatment initiation yielded four groups differing in OS (median OS 24.2 versus 16.0 versus 11.4 versus 6.1 months; P<0.0001). CONCLUSION: CEC, CTC and TF levels alone and combined can predict early on OS in CRPC patients treated with docetaxel-based therapy. A prospective study to confirm the use of these markers for patient management is needed.

Circulating endothelial cells in oncology: pitfalls and promises.

Adequate blood supply is a prerequisite in the pathogenesis of solid malignancies. As a result, depriving a tumour from its oxygen and nutrients, either by preventing the formation of new vessels, or by disrupting vessels already present in the tumour, appears to be an effective treatment modality in oncology. Given the mechanism by which these agents exert their anti-tumour activity together with the crucial role of tumour vasculature in the pathogenesis of tumours, there is a great need for markers properly reflecting its impact. Circulating endothelial cells (CEC), which are thought to derive from damaged vasculature, may be such a marker. Appropriate enumeration of these cells appears to be a technical challenge. Nevertheless, first studies using validated CEC assays have shown that CEC numbers in patients with advanced malignancies are elevated compared to healthy controls making CEC a potential tool for among other establishing prognosis and therapy-induced effects. In this review, we will address the possible clinical applications of CEC detection in oncology, as well as the pitfalls encountered in this process.

Supraglottic laryngectomy: short- and long-term functional results.

A supraglottic laryngectomy offers the possibility of resection of a large portion of the larynx leaving the true vocal cords. From 57 supraglottic laryngectomies performed between 1971 and 1984 in the Department of Otolaryngology and Head and Neck Surgery of the University of Nijmegen, the 5- and 10-year actuarial survival rates were 80% and 59%, respectively. The deaths after 5 years were not directly related to the original tumour. The functional results with respect to the voice were excellent. In this study particular attention has been paid to the postoperative results with regard to swallowing and aspiration. More than half of the patients (56%) had occasional complaints of aspiration, especially when taking liquids. It is concluded that supraglottic laryngectomy is an excellent alternative, especially for the treatment of extensive supraglottic tumours without involvement of the true vocal cords.