Cutaneous malignant melanoma mortality in Andalusia from 1979 to 2018. Toward new perspectives?

     Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ Esta es la versión aceptada del artículo publicado en: This is a accepted manuscript of a paper published in: Dermatologic Therapy (2021): 2021 DOI: https://doi.org/10.1111/dth.14715 Copyright: 2020 Wiley Periodicals LLC. El acceso a la versión publicada del artículo puede requerir la suscripción de la revista. Access to the published version may require subscription. “This is the peer reviewed version of the following article: Ortiz-Álvarez, Juan, Durán-Romero, Antonio José, Hernández-Rodríguez, Juan Carlos, SendínMartín, Mercedes, Conejo-Mir Sánchez, Julián, Pereyra-Rodríguez, JoséJuan (2021), Cutaneous malignant melanoma mortality in Andalusia from 1979 to 2018. Towards new perspectives? . Dermatologic Therapy, V. 34, Nº 1. which has been published in final form at https://doi.org/10.1111/dth.14715 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited." 1  TITLE PAGE Title: Cutaneous malignant melanoma mortality in Andalusia from 1979 to 2018. Towards new perspectives? Short title: MELANOMA MORTALITY IN ANDALUSIA Keywords: epidemiology, melanoma, mortality Word count: Manuscript words: 2591; Tables: 2; Figures: 3 Authors: Juan Ortiz-Álvarez1, Antonio José Durán-Romero1 Juan Carlos Hernández-Rodríguez1 Mercedes Sendín-Martin1 Julian Conejo-Mir1,2 José Juan Pereyra Rodriguez1,2 1Dermatology Department. Hospital Universitario Virgen del Rocío, Sevilla, España 2Medicine Department. Universidad de Sevilla, España Corresponding author: José Juan Pereyra Rodriguez1,2 1Dermatology Department, Hospital Universitario Virgen del Rocío 2Medicine Department. Universidad de Sevilla, España Avda. Manuel Siurot S/N 41013-Sevilla, España Mail: [email protected] Authors Contribution Statement  Dr. Ortiz-Álvarez has contributed to the conception and design of the manuscript, data collection, data analysis and interpretation and redaction, revision and approval of the manuscript.  Dr. Duran-Romero has contributed to the conception and design of the manuscript, data collection, data analysis and interpretation and redaction, revision and approval of the manuscript.  Dr. Hernández-Rodríguez has contributed to data collection and redaction, revision and approval of the manuscript.  Dr. Sendin-Martin has contributed to data collection and redaction, revision and approval of the manuscript.  Dr. Conejo-Mir has contributed to the redaction, revision and approval of the manuscript. 2   Dr. Pereyra-Rodriguez has contributed to the conception and design of the manuscript, data collection, data analysis and interpretation and redaction, revision and approval of the manuscript. Financial aid: This work has not received any financial assistance for its realization Conflict of interests:  Dr. Ortiz-Álvarez has nothing to disclose.  Dr. Duran-Romero has nothing to disclose.  Dr. Hernández-Rodríguez has nothing to disclose.  Dr. Sendin-Martin has nothing to disclose.  Dr. Conejo-Mir has nothing to disclose.  Dr. Pereyra-Rodriguez has nothing to disclose. The data that support the findings of this study are available from Instituto Nacional de Estadística.. Restrictions apply to the availability of these data, which were used under license for this study. Data are available www.ine.es with the permission of Instituto Nacional de Estadística. 3  ABSTRACT Background and objectives: malignant melanoma accounts for 80% of deaths due to skin cancer. Its incidence is globally increasing. However, melanoma mortality seems to be decreasing. The aim of this study was to analyse mortality rates due to melanoma in Andalusia between 1979 and 2018. Material and methods: deaths due to melanoma and mid-year population in Andalusia were collected from the National Institute of Statistics. Age-adjusted mortality rates were calculated for overall population and for each sex and age group. Regression models were used to calculate significant points of change. Sex-ratio and the independent effects of age, period and cohort were also analysed. Results: age-adjusted mortality due to melanoma rose from 0,61 to 1,94 deaths per 100.000 from 1979 to 2018 for the overall population. A significant change of trends was detected around 1994 when, after a steady rise from 1979, mortality rates stabilized up to the end of the period studied. The cited increase was more pronounced in >64 yo males. From the end of the 2000s there was a decrease in mortality rates to date in all population groups, producing a period effect. Conclusions: A stabilization in melanoma mortality rates was observed in Andalusia from 1994 with a decrease in some groups at the beginning of the 21st century. Trends observed in Andalusia don’t differ substantially from those in Spain. The development of new therapies and an earlier diagnosis may have an influence in those changes. Studies that compare differences between Spanish regions are needed to define better prevention strategies. 4  BACKGROUND The incidence of malignant melanoma, unlike other malignant neoplasms, is increasing, with global incidence rates of 11.5 and 11.3 per 100,000 persons-years in men and women respectively (1). Multiple meta-analyses have established key risk factors, among which are intermittent sun exposure and history of sunburn (especially in early ages), skin phototype or family history (2). Although it accounts for 80% of skin cancer deaths (3), its previously feared death rates appear to be trending downward according to recent studies. This decrease may be due to various factors. In this way, multiple primary and secondary prevention strategies seem to have a positive effect in younger cohorts. The aim is to detect earlier stages, thereby increasing survival (4,5). However, the great paradigm shift in the approach to melanoma is given by the emergence at the end of the 2000s of the so-called immunotherapy, a new therapy directed against regulators of the immune response. The appearance of drugs against cytotoxic T lymphocytes antigen 4 (CTLA-4: Ipilimumab, funded since 2012) (6,7) followed by therapies against programmed death receptor type 1 (PD-1: Pembrolizumab and Nivolumab, funded since 2016) have led to a considerable increase in survival in patients with locally advanced or metastatic melanoma (7–9). Also in this decade, therapies aimed at proteins of the MAP kinase pathway expressed by the tumor emerged, such as B-RAF (Vemurafenib and Dabrafenib, funded since 2012 and 2013 respectively) and MEK (Cobimetinib and Trametinib, funded since 2016) (7). With regard to melanoma mortality trends in Spanish territory, a decrease in ageadjusted mortality rates has been observed in last years, especially in the younger 5  subgroups (22-44 years). On the other hand, the mortality rate in people over 65 seems to increase in the latest reports published up to 2016 in both sexes (4). Nevertheless, to date there are no published data on the trends in mortality rates of malignant melanoma in Andalusia. This is a region of Spain with particular characteristics such as high insolation with a significant part of the population dedicated to activities carried out in the open air such as livestock, fishing or agriculture. Therefore, with this study we seek to evaluate the evolution of mortality from this neoplasm in Andalusia in the period 1979-2018, observing the possible changes in trends in relation to the arrival of new therapies. To our knowledge, this is first study to analyse melanoma mortality in Andalusia for such a long period, and it may be useful to compare the differences in mortality between regions of Spain and Europe in subsequent studies. 6  MATERIAL AND METHOD Following the methodology established in previous studies on melanoma mortality, such as those carried out by Cayuela et al. or (10–12), more recently, by Gutiérrez-González et al. (4), death certificates and population data in the middle of the year were obtained for the period 1979-2018 through the National Institute of Statistics (INE) of Spain (http://www.ine.es). These data, obtained by a third party (code ES0002 / 2020), are provided free of charge and its use authorised for the realization of this study with a commitment to cite the source. Through microdata provided from the Death Certificates, all those who died between 1979 and 2018 in Andalusia due to malignant melanoma were selected (codes ICD 8 and ICD9: 172; ICD 10: C43). The mortality rate by age was computed, establishing five-year age groups. Age-adjusted mortality rates were calculated using the direct method for the entire country and stratifying by sex and age group (<35, 35-64 and> 64 years of age), as well as the sex ratio, defined as the proportion of male mortality in relation to female. These results were expressed as deaths per 100.00 persons-year using the new European standard population of 2013 as a reference, in order to facilitate comparisons with other recent European-focused studies (13). To manage and obtain these data, the Epidat3.1®, Microsof® Excel and SPSS Statistics 25® programs were used. Using regression models, both the significant trend change points for mortality rates by sex and age group were calculated, as well as the Annual Average Percentage Change (AAPC). For this, the Joint regression program developed by the Surveillance Research Program of the National Cancer Institute of the United States was used (14), defining the maximum number of joint points at 5. Finally, the independent effects of age, period, and cohort (APC effects) on mortality rates were calculated using the penalty functions proposed by Decarli and La 7  Vecchia, using the GLIM macros provided by the authors for R® software (15). This proposal is based on the Osmond and Gardner models (16), estimating the APC models using Poisson regression. The data were divided into periods of 5 years and five years of age and the goodness of fit of the possible APC models was also compared. 8  RESULTS The global mortality due to melanoma in Andalusia for the first period studied (1979-1983) was 0.61 cases per 100,000 (0.34; 0.87 95% CI), reaching a value of 1.94 cases per 100,000 (1.63; 2.25 95% CI) in the last five years (2014-2018). Stratifying by sex, mortality rose from 0.661 to 2.707 cases per 100,000 in men in these intervals, while in women the increase was less pronounced, going from 0.347 to 1.336 cases per 100,000 (Table 1). In the regression analysis for the total population, a statistically significant change in trend was observed, defining two stages. The first of them, from 1979 to 1994 (AAPC 7.7 with a 95% CI of 5.5-9.9), is characterized by a progressive rise in mortality, followed by a stabilization of it from 1994 to 2018 (AAPC 0.2 with a CI 95% of -0.5-0.9). In this same analysis stratified by sex, a single junction point is seen in both groups that defines two periods of the same duration as in the global analysis. In both groups, the first period is characterized by a progressive ascent. However, while in men an ascent of attenuated slope was appreciated, in women there was a decrease that is maintained until the present time (Table 1). Respecting the age and sex-adjusted analysis, in the subgroup under 34 years of age, a downward trend can be seen globally without appreciating any change in trend both for the analysis of the subgroup as a whole and for men (Figure 1a). On the other hand, in the 35-64 year-old subgroup, an upward trend is observed at the beginning that affects both sexes, producing a point of trend change around 1996-1998, when there was a decrease in mortality rates. Later, mortality rates rose again in the early 2010s in men and if we take into account both sexes (Figure 1b). In women aged 35-64 years, the downward trend continues to this day. Contrary to what happens in the youngest subgroup, in those over 65 years of age, a globally upward trend was observed, in which, both taking into 15  BIBLIOGRAPHY 1. Observatory GC. Lyon: International Agency for Research on Cancer (WHO); c2018-20. 2. Belbasis L, Stefanaki I, Stratigos AJ, Evangelou E. Non-genetic risk factors for cutaneous melanoma and keratinocyte skin cancers: An umbrella review of metaanalyses. J Dermatol Sci ]. 2016;84(3):330–9. 3. Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer . 2018;103:356–87. 4. GutiérrezGonzález E, López-Abente G, Aragonés N, Pollán M, Pastor-Barriuso R, Sánchez MJ, et al. Trends in mortality from cutaneous malignant melanoma in Spain (1982–2016): sex-specific age-cohort-period effects. J Eur Acad Dermatology Venereol. 2019;33(8):1522–8. 5. Erdmann F, Lortet-Tieulent J, Schüz J, Zeeb H, Greinert R, Breitbart EW, et al. International trends in the incidence of malignant melanoma 1953-2008-are recent generations at higher or lower risk? Int J Cancer. 2013;132(2):385–400. 6. O’Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): A novel strategy for the treatment of melanoma and other malignancies. Cancer. 2007;110(12):2614–27. 7. Ministerio de Sanidad C y BS. BIFIMED: Buscador de la Información sobre la situación de financiación de los medicamentos [Internet]. [cited 2020 Aug 18]. Available from: https://www.mscbs.gob.es/profesionales/medicamentos.do 8. Robert C, Schachter J, Long G V., Arance A, Grob JJ, Mortier L, et al. 16  Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. 9. Robert C, Soria JC, Eggermont AMM. Drug of the year: Programmed Death-1 receptor/Programmed Death-1 Ligand-1 receptor monoclonal antibodies. Eur J Cancer . 2013;49(14):2968–71. 10. Cayuela A, Rodríguez-Domínguez S, Lapetra-Peralta J, Conejo-Mir JS. Has mortality from malignant melanoma stopped rising in Spain? Analysis of trends between 1975 and 2001. Br J Dermatol. 2005;152(5):997–1000. 11. Cayuela A, Rodríguez-Domínguez S, Vigil E, Conejo-Mir JS. Effect of age, birth cohort and period of death on skin melanoma mortality in Spain, 1975 through 2004. Int J Cancer. 2008;122(4):905–8. 12. Cayuela A, Cayuela L, Rodríguez-Domínguez S, Lorente AI, Rodríguez de la Borbolla M. Is melanoma mortality declining in Spain? Analysis of trends from 1975 to 2016. Br J Dermatol. 2018;179(4):991–2. 13. Eurostat. Revision of the European Standard Population. 2013. 128 p. 14. Institute NC. Joinpoint Regression Program, Version 4.2.0.2, Statistical Methodology and Applications Branch, Surveillance Research Program. 2015. 15. Decarlia A, La Vecchia C, Malvezzi M, Micciolo R. An R package for fitting age, period and cohort models. Epidemiol Biostat Public Heal. 2014;11(4):e 9977-1-12. 16. Osmond C, Gardner MJ. Age, period and cohort models applied to cancer mortality rates. Stat Med. 1982;1(3):245–59. 17. Durán‐Romero AJ, Sendín‐Martin M, Conejo‐Mir J, Pereyra‐Rodriguez JJ. 17  Cutaneous malignant melanoma mortality in Spain from 1979 to 2018. Trends and new perspectives in the immunotherapy era. J Eur Acad Dermatology Venereol. 2020 Oct 8. doi: 10.1111/jdv.16983. Epub ahead of print. PMID: 33030772. 18. De Vries E, Willem Coebergh J. Cutaneous malignant melanoma in Europe. Eur J Cancer. 2004;40(16):2355–66. 19. Arnold M, Holterhues C, Hollestein LM, Coebergh JWW, Nijsten T, Pukkala E, et al. Trends in incidence and predictions of cutaneous melanoma across Europe up to 2015. J Eur Acad Dermatology Venereol. 2014;28(9):1170–8. 20. Sáenz S, Conejo-Mir J, Cayuela A. Epidemiología del melanoma en España. Actas Dermosifiliogr. 2005;96(7):411–8. 21. Pastushenko I. Incidencia y mortalidad del cáncer cutáneo en Espa ña : revisión sistemática y metaanálisis. Actas dermosifiliogríaficas . 2016;107(4):318–28. 22. Galceran J, Uhry Z, Marcos-Gragera R, Borràs J, Van Eycken E, Henau K, et al. Trends in net survival from skin malignant melanoma in six European Latin countries: Results from the SUDCAN population-based study. Eur J Cancer Prev. 2017;26(Trends in cancer net survival in six European Latin Countries: the SUDCAN study):S77–84. 23. Gardner LJ, Strunck JL, Wu YP, Grossman D. Current controversies in earlystage melanoma: Questions on incidence, screening, and histologic regression. J Am Acad Dermatol . 2019;80(1):1–12. 24. Argenziano G, Albertini G, Castagnetti F, Pace B De, Lernia V Di, Longo C, et al. Early diagnosis of melanoma : what is the impact of dermoscopy ? 18  2012;25(1):403–9. 25. Rosendahl C, Williams G, Eley D, Wilson T, Canning G, Keir J, et al. The impact of subspecialization and dermatoscopy use on accuracy of melanoma diagnosis among primary care doctors in Australia. J Am Acad Dermatol . 2012;67(5):846–52. 26. Conejo-Mir JS. Campañas de prevención del melanoma. Piel. 2002;17(10):457– 65. 27. Conejo-Mir J, Bravo J, Díaz-Pérez JL, Fernández-Herrera J, Guillén C, Martí R, et al. Día del Euromelanoma. Resultados en España de las campañas de 2000, 2001 y 2002. Actas Dermosifiliogr . 2005;96(4):217–21. 28. Sattar J, Kartolo A, Hopman WM, Lakoff JM, Baetz T. The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population. J Geriatr Oncol . 2019;10(3):411–4. 29. Consejeria de Agricultura Ganaderia Pesca y Desarrollo Sostenible (Junta de Andalucía). Insolación y temperatura [Internet]. [cited 2020 Aug 9]. Available from: http://www.juntadeandalucia.es/medioambiente/site/portalweb/menuitem.7e1cf4 6ddf59bb227a9ebe205510e1ca/?vgnextoid=f47996f06f245310VgnVCM100000 1325e50aRCRD&vgnextchannel=23f996f06f245310VgnVCM1000001325e50a RCRD 30. Instituto de Estadística y Crtografía (junta de Andalucía). El Mercado de Trabajo en Andalucía. datos estructurales [Internet]. 2020 [cited 2020 Aug 9]. Available from: https://www.juntadeandalucia.es/institutodeestadisticaycartografia/merctrab/mtIn 19  d02.htm 31. Ministerio de Sanidad. Gasto Sanitario. En: Ministerio de Sanidad. Informe anual del Sistema Nacional de Salud 2018. Madrid: Ministerio de Sanidad; 2019. 32. Simon AE, Forbes LJL, Boniface D, Warburton F, Brain KE, Dessaix A, et al. An international measure of awareness and beliefs about cancer: Development and testing of the ABC. BMJ Open. 2012;2(6):1–8. 33. Marcoval J, Moreno A, Torras A, Baumann E, Graells J, Gallego MI. Changes in incidence of malignant melanoma in the last 19 years in a tertiary hospital on the mediterranean coast. Actas Dermosifiliogr [Internet]. 2008;99(6):464–8. Available from: http://dx.doi.org/10.1016/S1578-2190(08)70290-7 34. Duma N, Abdel‐Ghani A, Yadav S, Hoversten KP, Reed CT, Sitek AN, et al. Sex Differences in Tolerability to Anti‐Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non‐Small Cell Lung Cancer: Are We All Equal? Oncologist. 2019;24(11):1148–55. 35. Giblin A V., Thomas JM. Incidence, mortality and survival in cutaneous melanoma. J Plast Reconstr Aesthetic Surg. 2007;60(1):32–40. 36. Joshi KP, Atwal D, Ravilla R, Tao J, Su J, Makhoul I, et al. Outcomes of immunotherapy in advanced melanoma in relation to age. J Clin Oncol. 2018;36(5_suppl):187–187. 20  LEGENDS Table 1. Trend análisis on anual average percentage change (AAPC) global and stratified by age and sex. Table 2. Goodness-of-fit test for different age, period and cohort specific models of cutaneous malignant melanoma in Andalusia, 1979–2018 Figure 1. Global and age and sex-adjusted mortality rates Figure 2. Sex-ratio adjusted by age groups. Figure 3. Age-period-cohort effect for the whole population and adjusted by sex Figure 1.tiff (Imagen JPEG, 1587 × 1298 píxeles) - Escalado (42 %) https://buzonweb.us.es/correoweb/index.php/login/?_task=mail&_m.. . 1 de 1 28/06/2024, 11:1 8 Figure 2.tiff (Imagen JPEG, 2182 × 1204 píxeles) - Escalado (45 %) https://buzonweb.us.es/correoweb/index.php/login/?_task=mail&_m.. . 1 de 1 28/06/2024, 11:1 8 Figure 3.tiff (Imagen JPEG, 818 × 1348 píxeles) - Escalado (40 %) https://buzonweb.us.es/correoweb/index.php/login/?_task=mail&_m.. . 1 de 1 28/06/2024, 11:1 9 TABLE 1 Trend análisis on annual average percentage change (AAPC) global and stratified by age and sex Both sexes Men Women 1979-1983 ASMR (95% CI) 2014-2018 ASMR (95% CI) JP Period(s) years: AAPC (95% CI) 1979-1983 ASMR (95% CI) 2014-2018 ASMR (95% CI) JP Period(s) years: AAPC (95% CI) 1979-1983 ASMR (95% CI) 2014-2018 ASMR (95% CI) JP Period(s) years: AAPC (95% CI) All 0.61 (0.34;0.87) 1.94 (1.63;2.25) 1 1979-1994: 7.7* (5.5;9.9) 1994-2018: 0.2 (-0.5;0.9) 0.73 (0.26-1.21) 2.71 (2.14-3.27) 1 1979-1994: 8* (5.1-11) 1994-2018: 0.6 (-0.3-1.5) 0.52 (0.21-0.84) 1.34 (0.99-1.68) 1 1979-1994: 7.9* (5.310.5) 1994-2018: -0.6 (-1.4-0.3) <35 years 0.10 (0.01;0.33) 0.10 (0.02;0.30) 0 1979-2018: -0.8* (-2.3;0.7) 0.15 (0.01;0.57) 0.14 (0.02;0.41) 0 1979-2018: -1.3* (-2.70.1) 0.04 (0;020) 0.07 (0;0.32) 0 1979-2018: -1.7* (-1.7-0) 35-64 years 0.56 (0.28;1.01) 1.70 (1.30;2.21) 2 1979-1996: 8.1* (5.9;10.3) 1996-2009: -3.6* (-5.9;-1.2) 2009-2018: 6.9 (4.6;9.3) 0.60 (0.23;1.37) 2.25 (1.61;3.08) 2 1979-1999: 6.9* (4.6-9.3) 1996-2009: -6.1* (-11.2;- 0.8) 2009-2018: 6* (1-11.2) 0.51 (0.17;1.18) 1.16 (0.73;1.81) 1 1979-1996: 7.1* (3.6;10.6) 1996-2018: -2* (-3.5;-0.4) >64 years 1.75 (0.79;3.61) 6.21 (4.96;7.70) 1 1979-1994: 7.4* (4.1;10.8) 1994-2018: 1.2* (0.3;2) 2.19 (0.64;7.23) 8.94 (6.65;11.99) 1 1979-1994: 7.9* (3.412.5) 1994-2018: 1.4* (0.1-2.8) 1.53 (0.51;3.95) 4.27 (2.98;5.98) 0 1979-2018: 1.8* (0.9-2.7) Abbreviations: AAPC (95% CI), annual average percentage change and 95% confidence interval; ASMR, age standardized mortality rate; JP, jointpoint. * = p<0.05