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Depósi o de in es igación de la Uni e sidad de Se illa
h ps://idus.us.es/
Es a es la e sión acep ada del a ículo publicado en:
This is a accep ed manusc ip o a pape published in:
De ma ologic The apy (2021): 2021
DOI: h ps://doi.o g/10.1111/d h.14715
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Access o he published e sion may equi e subsc ip ion.
“This is he pee e iewed e sion o he ollowing a icle: O iz-Ál a ez, Juan,
Du án-Rome o, An onio José, He nández-Rod íguez, Juan Ca los, Sendín-
Ma ín, Me cedes, Conejo-Mi Sánchez, Julián, Pe ey a-Rod íguez, José-
Juan (2021), Cu aneous malignan melanoma mo ali y in Andalusia om
1979 o 2018. Towa ds new pe spec i es? . De ma ologic The apy, V. 34, Nº
1. which has been published in inal o m a h ps://doi.o g/10.1111/d h.14715
. This a icle may be used o non-comme cial pu poses in acco dance wi h Wiley
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TITLE PAGE
Ti le: Cu aneous malignan melanoma mo ali y in Andalusia om 1979 o 2018.
Towa ds new pe spec i es?
Sho i le: MELANOMA MORTALITY IN ANDALUSIA
Keywo ds: epidemiology, melanoma, mo ali y
Wo d coun :
Manusc ip wo ds: 2591; Tables: 2; Figu es: 3
Au ho s:
Juan O iz-Ál a ez1,
An onio José Du án-Rome o1
Juan Ca los He nández-Rod íguez1
Me cedes Sendín-Ma in1
Julian Conejo-Mi 1,2
José Juan Pe ey a Rod iguez1,2
1De ma ology Depa men . Hospi al Uni e si a io Vi gen del Rocío, Se illa, España
2Medicine Depa men . Uni e sidad de Se illa, España
Co esponding au ho :
José Juan Pe ey a Rod iguez1,2
1De ma ology Depa men , Hospi al Uni e si a io Vi gen del Rocío
2Medicine Depa men . Uni e sidad de Se illa, España
A da. Manuel Siu o S/N
41013-Se illa, España
Mail: pe3 ey [email protected]
Au ho s Con ibu ion S a emen
 D . O iz-Ál a ez has con ibu ed o he concep ion and design o he manusc ip ,
da a collec ion, da a analysis and in e p e a ion and edac ion, e ision and
app o al o he manusc ip .
 D . Du an-Rome o has con ibu ed o he concep ion and design o he
manusc ip , da a collec ion, da a analysis and in e p e a ion and edac ion,
e ision and app o al o he manusc ip .
 D . He nández-Rod íguez has con ibu ed o da a collec ion and edac ion,
e ision and app o al o he manusc ip .
 D . Sendin-Ma in has con ibu ed o da a collec ion and edac ion, e ision and
app o al o he manusc ip .
 D . Conejo-Mi has con ibu ed o he edac ion, e ision and app o al o he
manusc ip .
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 D . Pe ey a-Rod iguez has con ibu ed o he concep ion and design o he
manusc ip , da a collec ion, da a analysis and in e p e a ion and edac ion,
e ision and app o al o he manusc ip .
Financial aid: This wo k has no ecei ed any inancial assis ance o i s ealiza ion
Con lic o in e es s:
 D . O iz-Ál a ez has no hing o disclose.
 D . Du an-Rome o has no hing o disclose.
 D . He nández-Rod íguez has no hing o disclose.
 D . Sendin-Ma in has no hing o disclose.
 D . Conejo-Mi has no hing o disclose.
 D . Pe ey a-Rod iguez has no hing o disclose.
The da a ha suppo he indings o his s udy a e a ailable om Ins i u o Nacional
de Es adís ica.. Res ic ions apply o he a ailabili y o hese da a, which we e used
unde license o his s udy. Da a a e a ailable www.ine.es wi h he pe mission o
Ins i u o Nacional de Es adís ica.
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ABSTRACT
Backg ound and objec i es: malignan melanoma accoun s o 80% o dea hs due o
skin cance . I s incidence is globally inc easing. Howe e , melanoma mo ali y seems o
be dec easing. The aim o his s udy was o analyse mo ali y a es due o melanoma in
Andalusia be ween 1979 and 2018.
Ma e ial and me hods: dea hs due o melanoma and mid-yea popula ion in Andalusia
we e collec ed om he Na ional Ins i u e o S a is ics. Age-adjus ed mo ali y a es we e
calcula ed o o e all popula ion and o each sex and age g oup. Reg ession models we e
used o calcula e signi ican poin s o change. Sex- a io and he independen e ec s o
age, pe iod and coho we e also analysed.
Resul s: age-adjus ed mo ali y due o melanoma ose om 0,61 o 1,94 dea hs pe
100.000 om 1979 o 2018 o he o e all popula ion. A signi ican change o ends was
de ec ed a ound 1994 when, a e a s eady ise om 1979, mo ali y a es s abilized up o
he end o he pe iod s udied. The ci ed inc ease was mo e p onounced in >64 yo males.
F om he end o he 2000s he e was a dec ease in mo ali y a es o da e in all popula ion
g oups, p oducing a pe iod e ec .
Conclusions: A s abiliza ion in melanoma mo ali y a es was obse ed in Andalusia
om 1994 wi h a dec ease in some g oups a he beginning o he 21s cen u y. T ends
obse ed in Andalusia don’ di e subs an ially om hose in Spain. The de elopmen o
new he apies and an ea lie diagnosis may ha e an in luence in hose changes. S udies
ha compa e di e ences be ween Spanish egions a e needed o de ine be e p e en ion
s a egies.
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BACKGROUND
The incidence o malignan melanoma, unlike o he malignan neoplasms, is
inc easing, wi h global incidence a es o 11.5 and 11.3 pe 100,000 pe sons-yea s in men
and women espec i ely (1). Mul iple me a-analyses ha e es ablished key isk ac o s,
among which a e in e mi en sun exposu e and his o y o sunbu n (especially in ea ly
ages), skin pho o ype o amily his o y (2).
Al hough i accoun s o 80% o skin cance dea hs (3), i s p e iously ea ed dea h
a es appea o be ending downwa d acco ding o ecen s udies. This dec ease may be
due o a ious ac o s. In his way, mul iple p ima y and seconda y p e en ion s a egies
seem o ha e a posi i e e ec in younge coho s. The aim is o de ec ea lie s ages,
he eby inc easing su i al (4,5).
Howe e , he g ea pa adigm shi in he app oach o melanoma is gi en by he
eme gence a he end o he 2000s o he so-called immuno he apy, a new he apy di ec ed
agains egula o s o he immune esponse. The appea ance o d ugs agains cy o oxic T
lymphocy es an igen 4 (CTLA-4: Ipilimumab, unded since 2012) (6,7) ollowed by
he apies agains p og ammed dea h ecep o ype 1 (PD-1: Pemb olizumab and
Ni olumab, unded since 2016) ha e led o a conside able inc ease in su i al in pa ien s
wi h locally ad anced o me as a ic melanoma (7–9). Also in his decade, he apies aimed
a p o eins o he MAP kinase pa hway exp essed by he umo eme ged, such as B-RAF
(Vemu a enib and Dab a enib, unded since 2012 and 2013 espec i ely) and MEK
(Cobime inib and T ame inib, unded since 2016) (7).
Wi h ega d o melanoma mo ali y ends in Spanish e i o y, a dec ease in age-
adjus ed mo ali y a es has been obse ed in las yea s, especially in he younge

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subg oups (22-44 yea s). On he o he hand, he mo ali y a e in people o e 65 seems o
inc ease in he la es epo s published up o 2016 in bo h sexes (4).
Ne e heless, o da e he e a e no published da a on he ends in mo ali y a es
o malignan melanoma in Andalusia. This is a egion o Spain wi h pa icula
cha ac e is ics such as high insola ion wi h a signi ican pa o he popula ion dedica ed
o ac i i ies ca ied ou in he open ai such as li es ock, ishing o ag icul u e. The e o e,
wi h his s udy we seek o e alua e he e olu ion o mo ali y om his neoplasm in
Andalusia in he pe iod 1979-2018, obse ing he possible changes in ends in ela ion
o he a i al o new he apies. To ou knowledge, his is i s s udy o analyse melanoma
mo ali y in Andalusia o such a long pe iod, and i may be use ul o compa e he
di e ences in mo ali y be ween egions o Spain and Eu ope in subsequen s udies.
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MATERIAL AND METHOD
Following he me hodology es ablished in p e ious s udies on melanoma
mo ali y, such as hose ca ied ou by Cayuela e al. o (10–12), mo e ecen ly, by
Gu ié ez-González e al. (4), dea h ce i ica es and popula ion da a in he middle o he
yea we e ob ained o he pe iod 1979-2018 h ough he Na ional Ins i u e o S a is ics
(INE) o Spain (h p://www.ine.es). These da a, ob ained by a hi d pa y (code ES0002 /
2020), a e p o ided ee o cha ge and i s use au ho ised o he ealiza ion o his s udy
wi h a commi men o ci e he sou ce. Th ough mic oda a p o ided om he Dea h
Ce i ica es, all hose who died be ween 1979 and 2018 in Andalusia due o malignan
melanoma we e selec ed (codes ICD 8 and ICD9: 172; ICD 10: C43). The mo ali y a e
by age was compu ed, es ablishing i e-yea age g oups. Age-adjus ed mo ali y a es
we e calcula ed using he di ec me hod o he en i e coun y and s a i ying by sex and
age g oup (<35, 35-64 and> 64 yea s o age), as well as he sex a io, de ined as he
p opo ion o male mo ali y in ela ion o emale. These esul s we e exp essed as dea hs
pe 100.00 pe sons-yea using he new Eu opean s anda d popula ion o 2013 as a
e e ence, in o de o acili a e compa isons wi h o he ecen Eu opean- ocused s udies
(13). To manage and ob ain hese da a, he Epida 3.1®, Mic oso ® Excel and SPSS
S a is ics 25® p og ams we e used.
Using eg ession models, bo h he signi ican end change poin s o mo ali y
a es by sex and age g oup we e calcula ed, as well as he Annual A e age Pe cen age
Change (AAPC). Fo his, he Join eg ession p og am de eloped by he Su eillance
Resea ch P og am o he Na ional Cance Ins i u e o he Uni ed S a es was used (14),
de ining he maximum numbe o join poin s a 5.
Finally, he independen e ec s o age, pe iod, and coho (APC e ec s) on
mo ali y a es we e calcula ed using he penal y unc ions p oposed by Deca li and La
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Vecchia, using he GLIM mac os p o ided by he au ho s o R® so wa e (15). This
p oposal is based on he Osmond and Ga dne models (16), es ima ing he APC models
using Poisson eg ession. The da a we e di ided in o pe iods o 5 yea s and i e yea s o
age and he goodness o i o he possible APC models was also compa ed.
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RESULTS
The global mo ali y due o melanoma in Andalusia o he i s pe iod s udied
(1979-1983) was 0.61 cases pe 100,000 (0.34; 0.87 95% CI), eaching a alue o 1.94
cases pe 100,000 (1.63; 2.25 95% CI) in he las i e yea s (2014-2018).
S a i ying by sex, mo ali y ose om 0.661 o 2.707 cases pe 100,000 in men in hese
in e als, while in women he inc ease was less p onounced, going om 0.347 o 1.336
cases pe 100,000 (Table 1).
In he eg ession analysis o he o al popula ion, a s a is ically signi ican change
in end was obse ed, de ining wo s ages. The i s o hem, om 1979 o 1994 (AAPC
7.7 wi h a 95% CI o 5.5-9.9), is cha ac e ized by a p og essi e ise in mo ali y, ollowed
by a s abiliza ion o i om 1994 o 2018 (AAPC 0.2 wi h a CI 95% o -0.5-0.9). In his
same analysis s a i ied by sex, a single junc ion poin is seen in bo h g oups ha de ines
wo pe iods o he same du a ion as in he global analysis. In bo h g oups, he i s pe iod
is cha ac e ized by a p og essi e ascen . Howe e , while in men an ascen o a enua ed
slope was app ecia ed, in women he e was a dec ease ha is main ained un il he p esen
ime (Table 1).
Respec ing he age and sex-adjus ed analysis, in he subg oup unde 34 yea s o
age, a downwa d end can be seen globally wi hou app ecia ing any change in end bo h
o he analysis o he subg oup as a whole and o men (Figu e 1a). On he o he hand,
in he 35-64 yea -old subg oup, an upwa d end is obse ed a he beginning ha a ec s
bo h sexes, p oducing a poin o end change a ound 1996-1998, when he e was a
dec ease in mo ali y a es. La e , mo ali y a es ose again in he ea ly 2010s in men and
i we ake in o accoun bo h sexes (Figu e 1b). In women aged 35-64 yea s, he downwa d
end con inues o his day. Con a y o wha happens in he younges subg oup, in hose
o e 65 yea s o age, a globally upwa d end was obse ed, in which, bo h aking in o
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LEGENDS
Table 1. T end análisis on anual a e age pe cen age change (AAPC) global and s a i ied
by age and sex.
Table 2. Goodness-o - i es o di e en age, pe iod and coho speci ic models o
cu aneous malignan melanoma in Andalusia, 1979–2018
Figu e 1. Global and age and sex-adjus ed mo ali y a es
Figu e 2. Sex- a io adjus ed by age g oups.
Figu e 3. Age-pe iod-coho e ec o he whole popula ion and adjus ed by sex

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TABLE 1 T end análisis on annual a e age pe cen age change (AAPC) global and s a i ied by age and sex
Bo h sexes Men Women
1979-1983
ASMR
(95% CI)
2014-2018
ASMR
(95% CI)
JP Pe iod(s) yea s:
AAPC (95% CI)
1979-1983
ASMR
(95% CI)
2014-2018
ASMR
(95% CI)
JP Pe iod(s) yea s:
AAPC (95% CI)
1979-1983
ASMR
(95% CI)
2014-2018
ASMR
(95% CI)
JP Pe iod(s) yea s:
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* (5.3-
10.5)
1994-2018: -0.6 (-1.4-0.3)
<35 yea s 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* (-2.7-
0.1)
0.04
(0;020)
0.07
(0;0.32) 0 1979-2018: -1.7* (-1.7-0)
35-64 yea s 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 yea s 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* (3.4-
12.5)
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)
Abb e ia ions: AAPC (95% CI), annual a e age pe cen age change and 95% con idence in e al; ASMR, age s anda dized mo ali y a e; JP, join poin .
* = p<0.05