Which medical disciplines diagnose and treat melanoma in Europe in 2019? A survey of experts from melanoma centres in 27 European countries.

BACKGROUND AND OBJECTIVES: The incidence of melanoma is increasing. This places significant burden on societies to provide efficient cancer care. The European Cancer Organisation recently published the essential requirements for quality melanoma care. The present study is aimed for the first time to roughly estimate the extent to which these requirements have been met in Europe. MATERIALS AND METHODS: A web-based survey of experts from melanoma centres in 27 European countries was conducted from 1 February to 1 August 2019. Data on diagnostic techniques, surgical and medical treatment, organization of cancer care and education were collected and correlated with national health and economic indicators and mortality-to-incidence ratio (MIR) as a surrogate for survival. Univariate linear regression analysis was performed to evaluate the correlations. SPSS software was used. Statistical significance was set at P < 0.05. RESULTS: The MIR was lower in countries with a high health expenditure per capita and with a higher numbers of general practitioners (GPs) and surgeons (SURG) per million inhabitants. In these countries, GPs and dermatologists (DER) were involved in melanoma detection; high percentage of DER used dermatoscopy and were involved in the follow-up of all melanoma stages; both medical oncologists (ONC) and dermato-oncologists administered systemic treatments; and patients had better access to sentinel lymph node biopsy and were treated within multidisciplinary tumour boards. CONCLUSION: Based on these first estimates, the greater involvement of GPs in melanoma detection; the greater involvement of highly trained DER in dermatoscopy, dermatosurgery, follow-up and the systemic treatment of melanoma; and the provision of ongoing dermato-oncology training for pathologists, SURG, DER and ONC are necessary to provide an optimal melanoma care pathway. A comprehensive analysis of the melanoma care pathway based on clinical melanoma registries will be needed to more accurately evaluate these first insights.

Update of survival and cost of metastatic melanoma with new drugs: Estimations from the MelBase cohort.

PURPOSE: Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. METHODS: Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. RESULTS: Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95%confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95%CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. CONCLUSION: This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability.

Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study.

Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. ClinicalTrials.gov: NCT01689519.

More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments.

BACKGROUND: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). MATERIALS AND METHODS: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. RESULTS: The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines. CONCLUSIONS: Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry.

Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT).

BACKGROUND: Genomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS. PATIENTS AND METHODS: An open-label prospective phase II trial ('PREDICT') in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma. RESULTS: Of 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS- populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS- patients. The median time-to-treatment failure was 2.7/2.4 months (GS+/GS-). There was one complete response (GS-) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile. CONCLUSION: Treatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS- and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study.This study is registered at www.clinicatrials.gov NCT00942162.

Comparators, study duration, outcome measures and sponsorship in therapeutic trials of psoriasis: update of the EDEN Psoriasis Survey 2001-2006.

BACKGROUND: Several new therapeutic options for psoriasis have been tested in clinical trials in recent years. Choice of comparator, study duration and outcome measures are critical for interpreting application of trial results to clinical practice. OBJECTIVES: We examined whether these trial aspects have changed substantially in recent years in comparison with the past. METHODS: A systematic search and evaluation of all randomized controlled trials (RCTs) for psoriasis published from January 2001 up to December 2006 in 14 leading medical and dermatological journals, compared with those published from 1977 to 2000. RESULTS: There were 140 RCTs of psoriasis in the period 2001-2006 and 249 in the period 1977-2000. The proportion of placebo-controlled studies increased from 44.6% to 69.3%. The median study duration increased from 7 weeks to 12 weeks. The proportion of studies adopting the Psoriasis Area and Severity Index score as an outcome increased from 30.6% to 57.7%, while the number of studies incorporating a quality of life measure increased from only one (0.4%) to 12 studies (7.7%). The proportion of studies sponsored by pharmaceutical companies increased from 61.0% to 73.7%. CONCLUSIONS: Despite the increased number of new options, the number of head-to-head comparative trials has decreased and most trials focus on short-term effects, probably reflecting the increased influence of industrial sponsorship on the research agenda.

[Therapeutic modalities and economic assessment in the treatment of superficial basal cell carcinomas and multiple actinic keratoses by French dermatologists]. / Evaluation médico-économique de la prise en charge des carcinomes basocellulaires superficiels et des kératoses actiniques multiples par les dermatologues français.

INTRODUCTION: To date, no prospective studies have been conducted in France describing the management of actinic keratoses (AK) and superficial basal cell carcinomas (sBCC). The aim of the present study was to describe the therapeutic modalities for AK and sBCC adopted by French dermatologists and to determine the direct annual medical costs. PATIENTS AND METHODS: This was a prospective, observational study conducted in France between January and June 2004 in a random selection of representative dermatologists (n=202). The first 5 adult patients seen for one or more sBCCs and the first patient with at least 4 AKs over a period of four non-consecutive weeks were included in the study. The following data were recorded using a standardized questionnaire at inclusion: date of birth, gender, habitat, professional activity, social insurance regimen, site, number and maximum size of lesions. The therapeutic modalities, the physicians involved and the laboratory examinations during the 3 months following diagnosis were recorded prospectively. Medical management costs were calculated taking into account the usual parameters (e.g. French nomenclature of medical acts). RESULTS: 512 patients with sBCC (mean age: 69 years; sex-ratio M/F: 0.92) were included in the study. sBCC was isolated in 80% of cases, measured less than 2 cm in 90%, and was located on the head/neck in 51% and on the trunk in 37%. Histological confirmation of diagnosis of BCC was obtained in 85% of cases. Treatment comprised surgical excision in 70% of cases, cryotherapy in 13%, topical therapy in 7% and curettage/electrodessication in 4%. Clinical follow-up was performed in 79% of cases. The mean cost per patient over 3 months was 139 euros (CI95%: 125-153). In addition, 226 patients with AK (mean age: 76 years; sex-ratio M/F: 2.1) were included in the study. AKs were located on the head/neck in 74% of cases and on the trunk in 6%. Treatment consisted of cryotherapy in 92% of cases. The mean cost per patient over 3 months was calculated at 85 euros (CI95%: 71-99). An on-site audit of 5% of the investigators gave a concordance rate of 98.8%. DISCUSSION: This is the first study conducted in France to evaluate both the medical approach and treatment costs of sBCC and AK. Finally, the mostly surgical treatment of sBCC observed is in accordance with the recent French ANAES guidelines. When extrapolating the results of the present study, the annual cost of treatment of sBCC by French dermatologists may be estimated at between 10.2 and 10.6m euros.

Economic analysis of adjuvant therapy with interferon alpha-2a in stage II malignant melanoma.

Using the trial demonstrating that interferonalpha-2a (IFNalpha-2a) is efficacious as adjuvant therapy in stage II melanoma, we evaluate its outcomes and economic consequences. Using rates observed in the 5-year trial and published figures, survival and Q-TWIST (Time Without Symptoms and Toxicity) were extrapolated to a 10-year and lifetime horizon. Cost analysis was performed using the trial's data, published literature and experts' opinions from the perspective of the French Sickness Funds. Patients in the IFNalpha-2a-group have an additional 0.26 years in life-expectancy over a 5-year time period (P=0.046), 0.67 years over a 10-year period and 2.59 years over a lifetime. Cost per life-year-gained was estimated at approximately 14400 after 5 years, 6635 after 10 years and 1716 over a lifetime. Assuming that there is an improvement in disease-free survival only, cost is 26147 per Q-TWIST. Cost-effectiveness of IFNalpha-2a in stage II melanoma compares favourably with estimates for widely used therapies in the oncological field.

[Experience in the screening of melanoma]. / Expériences de dépistage du mélanome.

Melanoma is theoretically an ideal model for prevention campaigns. However a detailed analysis of this model shows that we do not yet have reliable tools to identify the high risk population and that prevention campaigns have a limited impact. However, any campaign which can increase the notoriety of melanoma in the public can probably improve early diagnosis. Detailed evaluation of messages and cost-effectiveness ratio of campaigns is needed.

Cost-effectiveness of surveillance of stage I melanoma. A retrospective appraisal based on a 10-year experience in a dermatology department in France.

BACKGROUND: There is no agreement about surveillance after resection of a stage I melanoma. OBJECTIVE: We assessed the cost-effectiveness of this surveillance. METHODS: Out of 912 patients with stage I (and Clark's level > or = II) melanoma examined from 1981 to 1991, only 528 were regularly followed in our department. RESULTS: 115 out of 528 relapsed; 33% were detected by the patient himself, 16% by the referring physician and 39% were detected in our department. Chest X-ray or abdomen ultrasonography revealed only 10% of relapses; CT scans were useless. There was a huge gap between the cost-effectiveness of clinical examinations and radiology. The time between relapse and the last check-up in our department was less than 4 months in one third of the metastases. CONCLUSIONS: In stage I melanoma, only clinical examination is really cost-effective in the detection of metastases. However, many metastases are likely to become prominent between two examinations if patients are examined less than 3 times a year. A progressive decrease in frequency is thus not advisable, until the risk is considered low enough to stop follow-up.

[Campaign of early detection of melanoma in the Provence-Alpes-Côte-d'Azur area 1989. Lessons of an experience]. / Campagne de détection précoce du mélanome dans la région Provence-Alpes-Côte d'azur-Corse en 1989. Leçons d'une expérience.

The prognosis of melanoma is closely related to tumor thickness at the time of surgical excision. Thickness depends on the duration of disease before diagnosis. This underlines the importance of information campaigns to promote early diagnosis of melanoma. The purpose of this study was to estimate the cost and effectiveness of a media campaign for the early screening of malignant melanoma (MM) at national level. This trial, the first of its kind in France, was conducted in the spring of 1989 in the Provence-Alpes-Côte d'Azur-Corse region. The campaign combined an effort to inform and heighten awareness in the medical community and the broadcast of an information movie for the general population on a regional TV channel. Following the campaign, the number of MM diagnosed in a representative selection of pathology laboratories increased significantly compared with the same period of the previous year: + 108 p. 100 over the 10 first weeks, + 47.6 p. 100 over 6 months. This increase was mostly for MM of low thickness (less than 1 mm) which have a good prognosis: + 74 p. 100 over 6 months. However MM distribution by thickness was not significantly different from one year to the next. Although the number of added cost generated by this campaign could not be precisely determined, these positive initial results argue for a national prevention campaign based on the lessons of this experience.