Melanoma In Europe Research Articles

Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors.

For several decades the incidence of cutaneous malignant melanoma (CMM) steadily increased in fair-skinned, indoor-working people around the world. Scientists think poor tanning ability resulting in sunburns initiate CMM, but they do not understand why the incidence continues to increase despite the increased use of sunscreens and formulations offering more protection. This paradox, along with lower incidences of CMM in outdoor workers, although they have significantly higher annual UV doses than indoor workers have, perplexes scientists. We found a temporal exponential increase in the CMM incidence indicating second-order reaction kinetics revealing the existence of 2 major risk factors. From epidemiology studies, we know one major risk factor for getting CMM is poor tanning ability and we now propose the other major risk factor may be the Human Papilloma Virus (HPV) because clinicians find β HPVs in over half the biopsies. Moreover, we uncovered yet another paradox; the increasing CMM incidences significantly correlate with decreasing personal annual UV dose, a proxy for low vitamin D3 levels. We also discovered the incidence of CMM significantly increased with decreasing personal annual UV dose from 1960, when it was almost insignificant, to 2000. UV and other DNA-damaging agents can activate viruses, and UV-induced cytokines can hide HPV from immune surveillance, which may explain why CMM also occurs in anatomical locations where the sun does not shine. Thus, we propose the 2 major risk factors for getting CMM are intermittent UV exposures that result in low cutaneous levels of vitamin D3 and possibly viral infection.

STAT3 Single Nucleotide Polymorphism rs4796793 SNP Does Not Correlate with Response to Adjuvant IFNα Therapy in Stage III Melanoma Patients.

Interferon alpha (IFNα) is approved for adjuvant treatment of stage III melanoma in Europe and the US. Its clinical efficacy, however, is restricted to a subpopulation of patients while side effects occur in most of treated patients. Thus, the identification of predictive biomarkers would be highly beneficial to improve the benefit to risk ratio. In this regard, STAT3 is important for signaling of the IFNα receptor. Moreover, the STAT3 single-nucleotide polymorphism (SNP) rs4796793 has recently been reported to be associated with IFNα sensitivity in metastatic renal cell carcinoma. To translate this notion to melanoma, we scrutinized the impact of rs4796793 functionally and clinically in this cancer. Interestingly, melanoma cells carrying the minor allele of rs4796793 were the most sensitive to IFNα in vitro. However, we did not detect a correlation between SNP genotype and STAT3 mRNA expression for either melanoma cells or for peripheral blood lymphocytes. Next, we analyzed the impact of rs4796793 on the clinical outcome of 259 stage III melanoma patients of which one-third had received adjuvant IFNα treatment. These analyses did not reveal a significant association between the STAT3 rs4796793 SNP and patients’ progression free or overall survival when IFNα treated and untreated patients were compared. In conclusion, STAT3 rs4796793 SNP is no predictive marker for the efficacy of adjuvant IFNα treatment in melanoma patients.

Melanoma in Europe: North meets South, East meets West

Melanoma incidence and the number of deaths have increased steadily in most European countries and the trend is expected to continue. However, the melanoma burden is unequally distributed across the Continent, with important variations of melanoma incidence, mortality and survival between European regions. According to recent estimates the incidence rates are nine-fold higher in Western than in Central and Eastern Europe (CEE). In contrast, mortality rates are fairly similar, whereas several countries in CEE report the lowest melanoma survival. As effective treatment in advanced stages of melanoma remains elusive, the high disparities in tumor burden and prognosis between European countries are likely related to the large differences of early detection and management of primary tumors. More accurate data on the epidemiological situation and the patterns of access to health care of melanoma patients in CEE countries are needed. Improving patients’ education for early detection and sun safety, enhancing physicians’ training and motivation together with implementation of functional systems of melanoma reporting and registration are priorities across the Continent.

Treatment patterns and outcomes among patients diagnosed with unresectable stage III or IV melanoma in Europe: A retrospective, longitudinal survey (MELODY study)

BackgroundMELanoma treatment patterns and Outcomes among patients with unresectable stage III or stage IV Disease: a retrospective longitudinal surveY (MELODY), the first multicountry, observational survey in patients with advanced melanoma, aimed to quantify the impact of existing treatment strategies by capturing information on treatment patterns and clinical outcomes. Patients and methodsPatients attending a participating site between 1st July 2005 and 30th June 2006 with ⩾2months follow-up were eligible. Data were retrieved retrospectively from advanced melanoma diagnosis until 1st May 2008. Treatment data were collected by line of therapy and response and progression-free survival data by line of systemic treatment. Overall survival (OS) was evaluated for all treated patients. ResultsAmong all patients screened, 776 were eligible for this analysis. Median OS from the date of advanced disease diagnosis was 16.4months. After excluding patients diagnosed prior to 1st July 2005 to account for any bias resulting from patient selection, the 12-month survival rate and median OS from the start date of second-line treatment was 28.8% and 6.8months, respectively. Survival was lower in patients with brain metastases, elevated lactate dehydrogenase levels and more advanced disease. Rates of complete/partial tumour response were 15% and 7% in patients treated with first- and second-line systemic therapy, respectively. ConclusionsDespite receiving first- and second-line treatment, most patients with advanced melanoma have short survival times and poor prognoses, reinforcing the need for new treatments.

Side effects of systemic oncological therapies in dermatology

The discovery of specific gene mutations, termed "driver mutations", in different tumors has brought personalized medicine into the focus of cancer treatment. Targeted treatment agents generally are administered orally and have a tolerable adverse event profile; they have become widely used in both inpatient and outpatient settings. The approval of the selective BRAF inhibitor vemurafenib (Zelboraf®) as first-line therapy of metastatic melanoma in Europe in February 2012 as well as the increasing use of MEK inhibitors within clinical trials confronts dermatologists and oncologists with a new spectrum of side effects. Knowledge of these possible adverse events and their management will be crucial for optimized patient care. This article offers an overview of the most important adverse events of currently employed dermato-oncologic therapeutic agents.

Sentinel lymph node biopsy for melanoma is becoming a consensus: a national survey of French centres involved in melanoma care in 2008

The role of sentinel lymph node (SLN) biopsy in melanoma care remains controversial and is not included in most guidelines for the management of melanoma in Europe. To evaluate the practice of SLN biopsy for melanoma. In 2008, a self-administered questionnaire was mailed to physicians in 49 hospitals in France. Questionnaires were returned by 34 (69.3%). A median number of 90 new cases of melanoma were treated each year per centre. SLN biopsy was performed routinely in 21 (61.7%) centres. The practice of SLN biopsy for melanoma was recommended in the local guidelines in 53% of centres. The proportion of patients reported as undergoing SLN biopsy for melanoma was significantly higher in centres with local guidelines than in centres without local guidelines (33.4 ± 21.4% vs. 13.1 ± 21.8%; P = 0.003). Where the local guidelines recommended SLN biopsy (n = 21), it was advocated in the case of Breslow thickness ≥1.0 mm (76%) and/or ulceration of the primary melanoma (38%) and/or histological regression of the primary melanoma (24%). Our study may be considered representative of SLN practice in France. Contrary to current national guidelines for melanoma care in France, SLN biopsy is routinely recommended in the majority of centres. Our study shows that the practice of SLN biopsy for melanoma is increasingly performed in patients with intermediate Breslow melanoma.

Trends in incidence of cutaneous malignant melanoma in Europe: analysis of population based cancer registry data

Trends in incidence of cutaneous malignant melanoma in Europe: analysis of population based cancer registry data

Melanoma vaccines: The problems of local immunosuppression

The incidence of cutaneous melanoma in Europe is rising, and the disease is incurable once metastases occur. Because melanoma expresses antigens that can be specifically recognized by the immune system, and because this disease occasionally undergoes spontaneous regression mediated by anti-tumor immunity, a number of different melanoma vaccines have been developed and tested clinically. Although most such vaccines show efficacy in vitro and an ability to stimulate anti-melanoma immune responses in blood, they have proved disappointing in clinical practice. It has become increasingly clear that the interaction between melanoma and the immune system is determined locally, within the tumor or draining lymph nodes. It is now clear that melanoma cells have the ability to anergize the immune system by inducing an immunosuppressive microenvironment that may explain the inability of systemic vaccines to alter patient outcomes. This subversion of the immune system involves alteration of dendritic cell (DC) function by tumor-derived cytokines, leading to the generation of suppressive and regulatory T lymphocytes. Successful melanoma vaccination probably requires therapeutic neutralization of the immunosuppressive microenvironment, which will require greater understanding of the molecular mechanisms used by the tumor to promote immunosuppression. Nevertheless, if these problems can be overcome, it seems likely that the efficacy of melanoma vaccines could be greatly enhanced.

Survival in Patients With Uveal Melanoma in Europe

To estimate survival in patients in whom uveal melanoma was diagnosed between January 1, 1983, and December 31, 1994, in Europe. Survival analysis of data from 32 cancer registries in 16 European countries adhering to the European Cancer Registry for 5788 patients with uveal melanoma diagnosed between January 1, 1983, and December 31, 1994, with follow-up to 1999. Five-year relative survival was 68.9% overall and remained stable with the period of diagnosis. Relative excess risk of death was 2.45 (95% confidence interval [CI], 2.10-2.86) in patients aged 75 years or older compared with patients aged 54 years or younger and was slightly higher in male patients (relative excess risk, 1.10; 95% CI, 1.02-1.19) than in female patients. Survival was similar in Nordic countries (relative excess risk, 1.03; 95% CI, 0.87-1.21) compared with the United Kingdom (reference country) and was lower in eastern and western European countries (1.26; 1.05-1.52, and 1.25; 0.90-1.60, respectively) compared with the reference country. In this large series of patients with uveal melanoma, 5-year relative survival remained stable with the introduction of conservative treatment in individuals in whom uveal melanoma was diagnosed between 1983 and 1994. We found differences in survival between sexes and in European areas that should be investigated in studies that consider tumor characteristics at the individual level.

Epidemiology of conjunctival melanocytic neoplasms

Abstract Purpose To summarise the epidemiology of conjunctival melanocytic neoplasms. Methods Review of population‐based data on 85 patients with primary conjunctival melanoma (CM) and recently published literature. Results CM accounts for 5‐7% of ocular melanoma in Europe. Its age‐adjusted incidence has increased 2‐fold in North Europe (Finland, from 0.40 to 0.80/million) and North America (USA, from 0.27 to 0.54) during the last 25 y. In both regions, age‐adjusted incidence is higher in men. Different rates between regions result from differences in registries, ethnicity and solar radiation. Age‐adjusted incidence of CM is 3‐fold in non‐Hispanic Caucasians and 2‐fold in Hispanics relative to Asians, African Americans and American Indians; among non‐Hispanic Caucasians it increases 2.5‐fold from 48 deg. (e.g. Paris) to 21 deg. (e.g. Mecca) of latitude. CM is rare below 30 y of age (age‐specific incidence, 0.06) but increases steadily thereafter (0.48, 1.05 and 1.57 for 30‐49, 50‐70 and >70 y, respectively). Median age at diagnosis is 58‐60 y. Most CM arise in limbal (57‐64%) followed by bulbar (12‐13%), palpebral (7‐9%) and caruncular (3%) conjunctiva. Tumor‐specific 5‐and 10‐y mortality estimates are 14‐20% and 29‐38%, respectively. Non‐limbal location, increasing tumor thickness and local recurrence are consistently associated with higher mortality. Clinically detectable primary acquired melanosis (PAM) and nevus precede or accompany CM in 57‐61% and 7‐23% of patients, respectively. Median age at diagnosis of PAM is 56 y. The risk of malignant change is not precisely known and depends heavily on subtype of PAM, ranging from 10 to 90%. Conclusion Recent studies provide epidemiological data on CM which are remarkably consistent. The epidemiology of conjunctival nevi and PAM is less precisely known.

DPSEEA Use in an Environment and Health Information System: UV and Melanoma in Europe

ISEE-397 Objective: Using the DPSEEA model and the available results of the data collected in 26 European countries this case study aims to delineate ways to improve and harmonize policy as well as exposure and health data collection, assessment and monitoring, concerning the issue of UV excessive exposure and melanoma prevention. Material and Methods: Two indicators have been developed in the WHO-ENHIS project. “Incidence of melanoma” gives an impression of melanoma rates and trends. “Policies to reduce children's exposure to UV” assesses the current UV protection policy situation in European countries. The use of the DPSEEA model (Driving Forces - Pressures - State - Exposure - Effects - Actions) allows to identify key issues that have to be monitored according the international prevention program recommendations and currently available knowledge concerning UV exposure, melanoma risk, and their social determinants. Results: In European countries, development of public health policies on UV protection and exposure reduction has so far been a rather heterogeneous process with major differences between countries. Parallel tendencies show the melanoma incidence concerning differences in geographic distribution and temporal evolution. Comparing the results show major opportunities to improve and harmonize policies concerning this issue among European countries. On the basis of the available information, it is possible to identify the key issues in the process of the evolution of the public health problem that have to be monitored and to propose possible indicators. Conclusions: Improving and harmonizing UV exposure assessment and evaluation of exposure determinants in European countries is the first further step. UV indicators, exposure (E) and pressure (P) in the first place, should be further developed according to the DPSEEA model. This case study indicates the need for a standardized environmental health information system at the European scale.

Incidence of Uveal Melanoma in Europe

To estimate incidence rates of uveal melanoma in Europe from 1983 to 1994. Incidence analysis of data from cancer registries adhering to the European Cancer Registry-based study on survival and care of cancer patients (EUROCARE) (cases diagnosed from 1983 to 1994). Data of 6673 patients with ocular melanoma (as defined by International Classification of Diseases for Oncology morphology codes 8720 to 8780 [melanoma] and International Classification of Diseases 9 (ICD9) codes 190.0 [iris and ciliary body], 190.5 [retina], 190.6 [choroid], and 190.9 [unspecified ocular location]) from 33 cancer registries of 16 European countries. Incidence rate ratios (IRRs) were obtained from a multilevel Poisson regression model. Incidence rates and IRRs associated with demographic and geographic variables. Standardized incidence rates increased from south to north across registries, from a minimum of <2 per million in registries of Spain and southern Italy up to >8 per million in Norway and Denmark. The inclusion of tumors with unspecified ocular location (code 190.9) increased incidence rates in most United Kingdom registries, but not in the other geographic areas, where this code was seldom used for uveal melanomas. Incidence increased noticeably up to age 55 (IRR, 1.46 per 5 years; 95% confidence interval [CI], 1.36-1.57) but leveled off after age 75 (IRR, 0.99 per 5 years; 95% CI, 0.93-1.05), with intermediate levels midway (IRR, 1.18 per 5 years; 95% CI, 1.12-1.23). It was also higher in males (IRR, 1.22; 95% CI, 1.16-1.28). Rates were stable during the study period, but a cohort effect was evidenced, accounting for higher incidence rates in people born during the period 1910 to 1935 (P = 0.005). Incidence increased with latitude (P = 0.008), which explained most differences in rates among areas. In this large series of uveal melanomas, we found stable incidence during the years 1983 to 1994. The north-to-south decreasing gradient supports the protective role of ocular pigmentation. European ophthalmologists should develop guidelines to standardize the coding of tumors treated conservatively using the ICD classification to improve the registration and surveillance of uveal melanoma by cancer registries.

A multicentre epidemiological study on sunbed use and cutaneous melanoma in Europe

A large European case–control study investigated the association between sunbed use and cutaneous melanoma in an adult population aged between 18 and 49 years. Between 1999 and 2001 sun and sunbed exposure was recorded in 597 newly diagnosed melanoma cases and 622 controls in Belgium, France, The Netherlands, Sweden and the UK. Fifty three precent of cases and 57% of controls ever used sunbeds. The overall adjusted odds ratio (OR) associated with ever sunbed use was 0.90 (95% CI: 0.71–1.14). There was a South-to-North gradient with high prevalence of sunbed exposure in Northern Europe and lower prevalence in the South (prevalence of use in France 20%, OR: 1.19 (0.68–2.07) compared to Sweden, prevalence 83%, relative risk 0.62 (0.26–1.46)). Dose and lag-time between first exposure to sunbeds and time of study were not associated with melanoma risk, neither were sunbathing and sunburns (adjusted OR for mean number of weeks spent in sunny climates >14 years: 1.12 (0.88–1.43); adjusted OR for any sunburn >14 years: 1.16 (0.9–1.45)). Host factors such as numbers of naevi and skin type were the strongest risk indicators for melanoma. Public health campaigns have improved knowledge regarding risk of UV-radiation for skin cancers and this may have led to recall and selection biases in both cases and controls in this study. Sunbed exposure has become increasingly prevalent over the last 20 years, especially in Northern Europe but the full impact of this exposure on skin cancers may not become apparent for many years.

Seasonal variation in the occurrence of cutaneous melanoma in Europe: influence of latitude. An analysis using the EUROCARE group of registries

The aim of our study was to analyse seasonal variations in melanoma incidence in Europe. Data from 28 117 cutaneous melanoma cases reported during 1978–1993 to the EUROCARE group of registries were analysed. There is a clear summer peak in incidence in Western countries (summer–winter ratio: 1.31 P < 0.0001; Nam’s test), which was not observed in Central Europe (ratio: 1.06; P = 0.0699). The amplitude of seasonality is higher for females (ratio = 1.38, 95% Confidence Interval (CI) [1.31–1.44]) than for males (ratio = 1.21 95%CI [1.14–1.29]). It is also higher for upper and lower limbs (1.44 and 1.46, respectively), than for head and neck or trunk regions (1.09 and 1.20, respectively). The amplitude of seasonality also varies with latitude and increases with time: in a linear regression adjusting for age, gender and anatomical localisation, the date of diagnosis was significantly closer to summer solstice with decreasing latitude ( P = 0.0005) and for more recent year of diagnosis ( P = 0.0123). The effect of latitude on the amplitude of the seasonal variation in melanoma incidence in Europe may be an indicator of ultraviolet B (UVB) exposure. Furthermore, an increase in intentional sun exposure could lead to an increase in melanoma promotion and thus to an increase in the amplitude of seasonal variation.

Mortality from cutaneous malignant melanoma in Europe. Has the epidemic levelled off?

Trends of mortality from cutaneous malignant melanoma (CMM) between 1960 and 1999 in several European countries and the European Union (EU) as a whole have been reviewed, using death certification data for skin cancer available from the World Health Organization. Separate analyses were performed for young (i.e., age 20-44 years) and middle-aged (i.e., age 45-64 years) adults, among whom around 80-90% of skin cancer deaths are attributable to CMM. After steady rises between 1960 and 1990, skin cancer rates among young adults have tended to decline since the mid-1990s in several European countries, with a fall of 14% in men and of 11% in women in the EU as a whole. In middle-aged adults, the trends were less favourable, although mortality started to level off since the mid-1990s. Thus, our data provide further evidence of an improvement of CMM mortality trends in recent years in several European countries. The particularly favourable trends in young people suggest that a further decline in mortality from CMM in Europe is likely to occur within the next few years.

Childhood melanoma in Europe since 1978: a population-based survival study

The existence of the EUROCARE database now makes it possible to compare population-based survival for childhood melanoma in different European populations. The database contains verified information, including histological data, from cancer registries in 17 European countries, and as such it represents a particularly important source of survival information on a very rare cancer like childhood melanoma. The aim of the present paper was to describe survival in children with melanoma (MM), by sex, age and subsite, diagnosed during the period 1978–1989, using analysis of the data of the European pool of cases. Five year-survival for childhood MM diagnosed in 1978–1989 in Europe, is relatively good (80%; 95% confidence interval (CI) 47–95 for boys and 78%; 95% CI 58–91 for girls). Analysis by subsite, revealed the survival for MM on the head and neck, legs and arms was generally higher than survival for MM on other cutaneous sites (trunk, neck and scalp). For skin melanomas outcome for girls was better than boys, adjusting for age and sub-site. We suggest that the good survival observed in childhood MM seems to be related to early diagnosis.

Malignant melanoma in Europe: changes in mortality rates (1970-90) in European Community countries.

Reducing mortality, especially premature death, is a major goal of the fight against cancer. In this study, we have analyzed trends in malignant melanoma (MM) mortality in the European Community (EC) as a whole and for each country. The data (obtained from the World Health Organization data bank) have been analyzed for the period 1970-90, by age groups (20-44, 45-64, 65-74, 75+ years). Trends are presented as percentage change of mortality rate for each three-year period in comparison with the rate in the first one (1970-72). The mortality from MM in the EC as a whole increased for both genders (men, +89.2 percent; women, +72.6 percent), with statistically significant trends in all age classes. Northern countries experienced mortality changes about 30 to 50 percent less than the EC average increase. Greater changes were seen in southern European countries, in which recent standardized rates are near to those observed in northern European populations. Among Mediterranean people, the highest increase (more than fourfold) was observed in Spain. The significant increase found for the younger age class makes unlikely the risk of misclassification with other skin cancers. No future decrease in MM mortality in the EC is indicated from these data.

Incidence of malignant melanoma of the skin in Norway, 1955-1989: associations with solar ultraviolet radiation, income and holidays abroad.

Norway has the highest incidence of melanoma in Europe. This study analyses geographical variations in melanoma incidence within Norway and their association with possible aetiological factors. Data on melanoma incidence from the Norwegian Cancer Registry were used to calculate standardized incidence ratios (SIR) for the 19 counties in Norway for each 5-year period from 1955 to 1989. Multiple regression analysis was used to examine the associations between these SIR and local UVB levels, holidays abroad and income. Similar methods were also used to analyse changes in SIR between 1955-1969 and 1985-1989. There was a highly significant association between melanoma incidence and UVB in each of the time periods studied. Income showed a significant positive association in the 1960s and early 1970s but not later. Foreign holidays showed a significant positive association in the 1980s, but not earlier. Changes in melanoma SIR between 1955-1969 and 1985-1989 were significantly positively associated with holidays abroad and negatively with income levels. Melanoma incidence in Norway is closely related to local levels of UVB radiation independently of other factors suggesting that local exposures carry significant risk. Risks would probably increase if ozone depletion led to enhanced UVB flux (estimated as 1.6% rise in incidence for each 1% increase in UVB). By the end of the study period income was no longer a significant factor but holidays abroad had started to have a detectable effect on melanoma incidence.

Cutaneous melanoma in Europe

1Episearch, PO Box 11, Brussels (1050), Belgium; 2INSERM, Centre Léon Bérard, 69373 Lyon Cedex 08, France

Report on consensus meeting of the EORTC melanoma group of educational needs for primary and secondary prevention of melanoma in Europe: Results of a workshop held under the auspices of the EEC Europe Against Cancer Programme in Inssbruck, April 1991

Report on consensus meeting of the EORTC melanoma group of educational needs for primary and secondary prevention of melanoma in Europe: Results of a workshop held under the auspices of the EEC Europe Against Cancer Programme in Inssbruck, April 1991