eyelid tumors are uncommon and represent 5 - 10% of all skin cancers . basal cell carcinoma ( bcc )
is the most common histological type representing 90% of all cases followed by squamous cell carcinoma ( scc ) , and less frequently by sebaceous cell carcinoma ( sbcc ) , merkel cell tumor and melanoma .
the most common localization are the lower eyelid ( 50 - 60% ) and medial canthus ( 25 - 30% ) .
basal cell carcinoma are slow growing tumors with a metastatic rate ranging from 0.003 to 0.5% but they can be locally invasive infiltrating the lid margin or the lachrymal glands producing functional disability [ 2 , 3 ] .
squamous cell carcinoma are more aggressive than bcc : about 5% are metastatic and in these patients 5-year survival rate is only 25 - 40% .
many treatment approaches are available : surgery , radiotherapy , cryotherapy , curettage , electrodissection , photodynamic therapy , and laser ablation .
surgery is considered the gold standard therapy , and the treatment aims are definitive tumor control and preservation of the functional structures [ 6 , 7 , 8 ] .
radiotherapy is also a good alternative if preservation of functional structures is not possible with surgery .
brachytherapy ( bt ) might be a better therapeutic option due to intrinsic advantages , including high radiation dose concentration into the tumor and rapid dose fall - off at target periphery with optimal sparing of normal tissues in these sensitive structures in shorter treatment time . despite the potential interest about the bt in the treatment of these tumors , randomized controlled trials , systematic reviews and/or metanalyses are lacking in literature .
therefore , the aim of this review was to systematically evaluate the available literature on local control and functional cosmetic outcome after bt of non melanoma skin cancer ( nmsc ) of eyelids .
a systematic search strategy of the bibliographic data - bases pubmed , scopus , and cochrane library from the earliest possible date through october 13 , 2015 was performed [ 9 , 10 , 11 ] .
the search strategy was based on the following terms : (  eyelid neoplasms[mesh terms ] or (  eyelid[all fields ] and  neoplasms[all fields ] ) or 
eyelid neoplasms[all fields ] or (  eyelid[all fields ] and  cancer[all fields ] ) or
[ all fields ] ) and (  brachytherapy[mesh terms ] or  brachytherapy[all fields ] ) . to avoid missing relevant studies we chose this strategy with high sensitivity but low specificity .
type of studies : we included human studies of any design ( randomized , prospective , retrospective studies ) and case series with exception of case reports .
types of participants : studies reporting on patients with a diagnosis of non melanoma skin cancer of eyelid based on histological evaluation were included .
type of interventions : eligible intervention included bt in nmsc of eyelid independently of technique , dose , dose rate , and treatment setting ( curative or adjuvant ) .
the secondary outcomes were acute - late toxicity and functional cosmetic results independently of used scales .
two independent authors ( rf , gm ) screened citations at the abstract level to identify potentially relevant studies and case series .
potentially eligible citations were retrieved for full - text review , with disagreements resolved by a third author ( agm ) .
we obtained the following information from each report : author identification , year of publication , medical center , study design characteristics , study population , bt technique , delivered dose , total treatment time , local control , toxicity , and functional cosmetic outcome . in the studies where
overall treatment time was not reported it was calculated based on dose rate and total dose .
scottish intercollegiate guidelines network ( sign ) criteria was used to classify the quality of evidence .
type of studies : we included human studies of any design ( randomized , prospective , retrospective studies ) and case series with exception of case reports .
types of participants : studies reporting on patients with a diagnosis of non melanoma skin cancer of eyelid based on histological evaluation were included .
type of interventions : eligible intervention included bt in nmsc of eyelid independently of technique , dose , dose rate , and treatment setting ( curative or adjuvant ) .
the secondary outcomes were acute - late toxicity and functional cosmetic results independently of used scales .
two independent authors ( rf , gm ) screened citations at the abstract level to identify potentially relevant studies and case series .
potentially eligible citations were retrieved for full - text review , with disagreements resolved by a third author ( agm ) .
we obtained the following information from each report : author identification , year of publication , medical center , study design characteristics , study population , bt technique , delivered dose , total treatment time , local control , toxicity , and functional cosmetic outcome . in the studies where
overall treatment time was not reported it was calculated based on dose rate and total dose .
scottish intercollegiate guidelines network ( sign ) criteria was used to classify the quality of evidence .
through a process of screening the title and the abstract , 9 articles were identified [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ] .
after full text , review of 3 articles on skin cancer bt were excluded because eyelid tumors data were not reported separately [ 16 , 17 , 18 ] .
the characteristics of these studies included in the review are summarized in table 1 [ 13 , 14 , 15 , 19 , 20 , 21 ] .
no randomized controlled trials or case control studies were founded . of the selected studies , 1 was prospective   while the others were retrospective reports [ 13 , 15 , 19 , 20 , 21 ] .
because of high risk of confusion or bias , all studies were classified to provide a level of evidence graded as 3 according to sign classification .
flow chart of systematic search and review process summary of studies where brachytherapy was used in non melanoma skin cancer of eyelid scc  squamous cell carcinoma , bcc  basal cell carcinoma , sbcc  sebaceous cell carcinoma , hdr  high - dose - rate , ldr  low - dose - rate , mcc  merkel cell carcinoma , pni  perineural invasion summary of outcome of 5 studies included in our review
nr  not reported , lc  local control in 1 patient was not possible to evaluated functional and cosmetic outcome in all studies , interstitial bt with ir source was the used technique . both low - dose - rate ( ldr ) in 3 studies [ 13 , 14 , 19 ] and high - dose - rate ( hdr ) in the other 3 studies [ 15 , 20 , 21 ] were used .
the overall treatment time did not exceed 1 week [ 13 , 14 , 15 , 19 , 20 , 21 ] . in the ldr group ,
biopsy was performed in 131 lesions and the results were : 85% bcc , 14.5% scc , and 0.5% adenocarcinoma .
tumor size was < 2 cm in 79.5% of cases , and 2 - 5 cm in 20% . according to histotype ,
the delivered dose was 60 gy for bcc and 70 gy for scc , with a dose rate ranging from 65 to 90 cgy / h .
reported the results of 60 patients , 51 patients with primary unresected carcinoma , 5 patients with local recurrence , and 4 patients treated with postoperative bt .
mean delivered dose was 65 gy ( range 51 - 70 gy ) with dose rate ranging from 50 to 60 cgy / h . with a mean follow - up of 92 months ,
local failure rate was 3.3% in previously untreated lesions ( 2 patients with t2 carcinoma ) .
conill et al . reported the results of 24 tumors involving the eyelid tarsal structure treated with curettage and bt .
the delivered dose was 40 gy with a mean dose rate 73 cgy / h .
the reported local control rate was 91.6% . in the hdr group , two institution were in india [ 15 , 20 ] and one in portugal . in india ,
the most common eyelid tumors are scc and sbcc , which are considered to be more aggressive .
forty five nmsc of eyelid were included and treated with different total dose and fractionation [ 15 , 20 , 21 ] .
reported the results of 20 patients with different histotype ( 50% scc , 40% sbcc and 10% bcc ) .
overall , 5-year local control rate was 75.6% ( scc : 90% ; sbcc : 57.1% ; bcc : 50% ) .
the median tumor size was 11 mm but 3 patients were t4 . delivered dose ranged from 21 gy in 7 fractions to 35 gy in 10 fractions ( twice daily fractionation with 6 - 8 hours gap ) .
no local recurrences were reported but two patients had nodal recurrence 6 months after interstitial bt .
the last study reported the results of 17 patients , where bt was delivered in different setting ( curative : 2 patients , postoperative : 12 patients , salvage after surgery : 3 patients ) .
the median total dose was 42.75 gy ( range : 32 - 50 gy ) with a median of 10 fractions ( range : 9 - 11 fractions ) , twice daily fractionation with 6 hours gap .
four studies did not use eye shield [ 13 , 14 , 15 , 19 ] .
one study used a shield conformer from dental prosthesis material   and the other one a lead shielding covered with paraffin to prevent additional dose to healthy tissues of the eye .
edematous reaction , lid erythema , and conjunctivitis were the most common acute toxicity reported , ranging from 12% to 100% of cases [ 14 , 15 , 19 , 20 , 21 ] .
radiodermatitis g1 , g2 , and g3 were reported in one study ( 52% , 12% , and 12% , respectively ) .
also g1 keratitis were reported in 21.7% of cases and some patients required local therapy or systemic therapy .
one study reported hematoma after needle insertion in 46% of patients but was resolved without therapy . in another study , 6 - 8 weeks after the implant , persistent edematous ( 29.6% ) and conjunctival reaction ( 12% ) were observed .
epilation of the treated area was the most common late toxicity reported ranging 65 - 100% [ 13 , 14 , 15 , 21 ] .
pigmentation was reported in four studies ranging from 10% to 47% [ 13 , 15 , 20 , 21 ] and lid fibrosis in two studies ranging from 15% to 18% [ 15 , 21 ] .
other late toxicities reported less frequently were : lacrimal duct stenosis ( range 6.7 - 9.5% ) [ 13 , 19 ] , eyelid fissure impairment ( 5.5 - 12% ) [ 13 , 21 ] , epiphora ( range 5 - 25% ) [ 13 , 19 , 20 ] , unilateral cataract ( 3.3% ) , ectropion ( range 4.4 - 14.2% ) [ 13 , 20 ] , entropion ( 23% ) , conjunctivitis ( 42% ) , keratoconjuctivitis secca ( 46% ) , eyelid malocclusion ( 46% ) , edema ( 18% ) , fibrosis ( 18% ) , pruritus ( 46% ) , hyperlacrimation ( 18% ) , and small corneal ulcer ( 0.6% ) .
recurrent lesions and larger volumes were associated with worse outcomes [ 13 , 21 ] .
functional and cosmetic outcome were reported according to the physicians   or patients judgement , cosmesis after interstitial brachytherapy ( caib ) scale   or not specified [ 14 , 15 ] . only in one study was cosmesis graded and documented using a 6 domain objective scoring criteria ( depigmentation of skin , eyelid dysfunction like ectropion or entropion , dry eye , keratitis , cataract , and glaucoma ) .
functional and cosmetic outcomes were reported in 5 studies and graded as optimal to good / excellent in 68.3 - 100% , respectively [ 14 , 15 , 19 , 20 , 21 ] .
both low - dose - rate ( ldr ) in 3 studies [ 13 , 14 , 19 ] and high - dose - rate ( hdr ) in the other 3 studies [ 15 , 20 , 21 ] were used .
the overall treatment time did not exceed 1 week [ 13 , 14 , 15 , 19 , 20 , 21 ] . in the ldr group ,
biopsy was performed in 131 lesions and the results were : 85% bcc , 14.5% scc , and 0.5% adenocarcinoma .
tumor size was < 2 cm in 79.5% of cases , and 2 - 5 cm in 20% . according to histotype ,
the delivered dose was 60 gy for bcc and 70 gy for scc , with a dose rate ranging from 65 to 90 cgy / h .
reported the results of 60 patients , 51 patients with primary unresected carcinoma , 5 patients with local recurrence , and 4 patients treated with postoperative bt .
mean delivered dose was 65 gy ( range 51 - 70 gy ) with dose rate ranging from 50 to 60 cgy / h . with a mean follow - up of 92 months ,
local failure rate was 3.3% in previously untreated lesions ( 2 patients with t2 carcinoma ) .
conill et al . reported the results of 24 tumors involving the eyelid tarsal structure treated with curettage and bt .
the delivered dose was 40 gy with a mean dose rate 73 cgy / h .
the reported local control rate was 91.6% . in the hdr group , two institution were in india [ 15 , 20 ] and one in portugal . in india ,
the most common eyelid tumors are scc and sbcc , which are considered to be more aggressive .
forty five nmsc of eyelid were included and treated with different total dose and fractionation [ 15 , 20 , 21 ] .
reported the results of 20 patients with different histotype ( 50% scc , 40% sbcc and 10% bcc ) .
overall , 5-year local control rate was 75.6% ( scc : 90% ; sbcc : 57.1% ; bcc : 50% ) .
the median tumor size was 11 mm but 3 patients were t4 . delivered dose ranged from 21 gy in 7 fractions to 35 gy in 10 fractions ( twice daily fractionation with 6 - 8 hours gap ) . no local recurrences were reported but two patients had nodal recurrence 6 months after interstitial bt .
the last study reported the results of 17 patients , where bt was delivered in different setting ( curative : 2 patients , postoperative : 12 patients , salvage after surgery : 3 patients ) .
the median total dose was 42.75 gy ( range : 32 - 50 gy ) with a median of 10 fractions ( range : 9 - 11 fractions ) , twice daily fractionation with 6 hours gap .
four studies did not use eye shield [ 13 , 14 , 15 , 19 ] .
one study used a shield conformer from dental prosthesis material   and the other one a lead shielding covered with paraffin to prevent additional dose to healthy tissues of the eye .
edematous reaction , lid erythema , and conjunctivitis were the most common acute toxicity reported , ranging from 12% to 100% of cases [ 14 , 15 , 19 , 20 , 21 ] .
radiodermatitis g1 , g2 , and g3 were reported in one study ( 52% , 12% , and 12% , respectively ) .
also g1 keratitis were reported in 21.7% of cases and some patients required local therapy or systemic therapy .
one study reported hematoma after needle insertion in 46% of patients but was resolved without therapy . in another study , 6 - 8 weeks after the implant , persistent edematous ( 29.6% ) and conjunctival reaction ( 12% ) were observed .
epilation of the treated area was the most common late toxicity reported ranging 65 - 100% [ 13 , 14 , 15 , 21 ] .
pigmentation was reported in four studies ranging from 10% to 47% [ 13 , 15 , 20 , 21 ] and lid fibrosis in two studies ranging from 15% to 18% [ 15 , 21 ] .
other late toxicities reported less frequently were : lacrimal duct stenosis ( range 6.7 - 9.5% ) [ 13 , 19 ] , eyelid fissure impairment ( 5.5 - 12% ) [ 13 , 21 ] , epiphora ( range 5 - 25% ) [ 13 , 19 , 20 ] , unilateral cataract ( 3.3% ) , ectropion ( range 4.4 - 14.2% ) [ 13 , 20 ] , entropion ( 23% ) , conjunctivitis ( 42% ) , keratoconjuctivitis secca ( 46% ) , eyelid malocclusion ( 46% ) , edema ( 18% ) , fibrosis ( 18% ) , pruritus ( 46% ) , hyperlacrimation ( 18% ) , and small corneal ulcer ( 0.6% ) .
recurrent lesions and larger volumes were associated with worse outcomes [ 13 , 21 ] .
functional and cosmetic outcome were reported according to the physicians   or patients judgement , cosmesis after interstitial brachytherapy ( caib ) scale   or not specified [ 14 , 15 ] . only in one study was cosmesis graded and documented using a 6 domain objective scoring criteria ( depigmentation of skin , eyelid dysfunction like ectropion or entropion , dry eye , keratitis , cataract , and glaucoma ) .
functional and cosmetic outcomes were reported in 5 studies and graded as optimal to good / excellent in 68.3 - 100% , respectively [ 14 , 15 , 19 , 20 , 21 ] .
the aims of treatment is definitive tumor control with functional preservation of anatomical structures [ 6 , 7 , 8 ] .
radiotherapy is an effective alternative in patients where surgery might be associated with functional or cosmetic deficits or in patients unfit because of comorbidities .
the only randomized trial comparing radiotherapy versus surgery in patients with bcc of the face was published by avril et al . in 1997 .
basal cell carcinoma of eyelid represented 19% of surgery group and 20% of radiotherapy group .
interstitial bt was performed with ir - wires afterloaded with a dose of 65 - 70 gy delivered over a period of 5 - 7 days .
superficial contact therapy ( 50 kv ) was delivered in two sessions , each delivering 18 - 20 gy with a 2-week interval .
basal cell carcinoma of less than 2 cm in the largest diameter were treated with this technique .
conventional radiotherapy ( 85 - 250 kv ) was delivered with 60 gy total dose in treatment fractions ranging from 2 to 4 gy . in the radiotherapy group ,
55% were treated with interstitial bt , 33% with contact therapy , and 12% with conventional radiotherapy .
the 4-year actuarial failure rate was 7.5% in the radiotherapy group compared with 0.7% in the surgery group .
however , no analysis of outcomes according the treatment site or radiotherapy technique was performed .
only few studies are available in literature regarding the use of bt in eyelid nmsc . in all studies ,
the patients population was very heterogeneous in terms of histology , treatment aim ( curative or adjuvant ) , dose rate ( ldr and hdr ) , total dose , and follow up time [ 13 , 14 , 15 , 19 , 20 , 21 ] .
the level of evidence was low ( 3 in all studies according to sign criteria ) .
it is difficult to make a comparison because in 5/6 studies , lc was reported in terms of crude rate .
therefore , these results are probably influenced by the follow - up length [ 13 , 14 , 19 , 20 , 21 ] .
the only study reporting actuarial lc is the one of azad et al .   and
this difference may explain the lower results . among the authors reporting the crude rate , conill et al .  
had slightly lower results ( lc : 91.6% ) compared to the others ( 94.1 - 100% ) [ 13 , 20 , 21 ] .
this might indicate that the use of curettage ( performed by conill ) did not produces benefits in terms of disease control .
it should also be noted that conill , among the studies based on ldr [ 13 , 14 , 19 ] , is the one with the lowest total delivered dose .
only 4 studies reported the used acute toxicity score [ 14 , 19 , 20 ] .
edema was reported in three studies [ 13 , 14 , 15 ] with variable incidence ( 29.6 - 100% ) [ 13 , 14 ] .
conjunctival erythema or conjunctivitis was reported in 3 studies [ 13 , 14 , 19 ] and in the other two studies the site of erythema was not specified ( skin ?
daly et al . reported the lowest incidence of edema and conjunctival erythema ( 29.6% and 12% , respectively ) .
it is not clear whether it is a real difference or if the authors   reported only the most obvious cases .
other toxicities were reported in individual studies , 21.7% of keratites   and 29% of epiphora .
therefore , due to inhomogeneous and non - standardized reporting of acute toxicity , the identification of potential predictors of short term side - effects between the different studies results was difficult .
only 3 studies reported the used late toxicity score [ 14 , 20 , 21 ] .
epilation was reported in 4 studies [ 13 , 14 , 15 , 21 ] ranging from 65 to 100% .
the lowest value was reported by mareco et al . where a correlation between v100 ( volume of the tissue that receives 100% of the prescription dose ) and v150 ( volume of the tissue that receives 150% of the prescription dose ) , and epilation was observed .
v100  2 cm and v150  1 cm were associated with higher epilation frequency .
epiphora was reported in 2 studies with the same incidence ( 5% ) [ 15 , 19 ] as well as lacrimal duct stenosis , which was reported in 2 studies with a similar incidence ( 6.7 - 9.5% ) [ 13 , 19 ] .
pigmentation changes was reported in 4 studies [ 13 , 15 , 20 , 21 ] ( incidence 10 - 47% ) and impairment of eyelid fissure in 2 studies ( incidence 5.5 - 12% ) [ 13 , 21 ] .
, again v150  1 cm seemed to be correlated with the frequency of late toxicities .
ectropion was reported in 2 studies ( 5 - 14.2% ) [ 19 , 20 ] and 1 study reported the eversion of the lower lid in 4.4% of patients .
other late toxicities reported in individual studies were unilateral cataract , entropion , conjunctivitis , keratoconjunctivitis sicca , eyelid malocclusion , hyperlacrimation , and small corneal ulcer with incidences of 3.3% , 23% , 42% , 46% , 46% , 18% , and 0.6% , respectively .
cosmetic outcome was reported in 5 studies [ 14 , 15 , 19 , 20 , 21 ] .
it should be noted that in this trial the prescribed dose was the highest between the analyzed trials .
recurrent lesions [ 13 , 21 ] and higher volumes receiving the prescribed dose were associated with worst cosmetic outcomes .
the aims of treatment is definitive tumor control with functional preservation of anatomical structures [ 6 , 7 , 8 ] .
radiotherapy is an effective alternative in patients where surgery might be associated with functional or cosmetic deficits or in patients unfit because of comorbidities .
the only randomized trial comparing radiotherapy versus surgery in patients with bcc of the face was published by avril et al . in 1997 .
basal cell carcinoma of eyelid represented 19% of surgery group and 20% of radiotherapy group .
interstitial bt was performed with ir - wires afterloaded with a dose of 65 - 70 gy delivered over a period of 5 - 7 days .
superficial contact therapy ( 50 kv ) was delivered in two sessions , each delivering 18 - 20 gy with a 2-week interval .
basal cell carcinoma of less than 2 cm in the largest diameter were treated with this technique .
conventional radiotherapy ( 85 - 250 kv ) was delivered with 60 gy total dose in treatment fractions ranging from 2 to 4 gy . in the radiotherapy group ,
55% were treated with interstitial bt , 33% with contact therapy , and 12% with conventional radiotherapy .
the 4-year actuarial failure rate was 7.5% in the radiotherapy group compared with 0.7% in the surgery group .
however , no analysis of outcomes according the treatment site or radiotherapy technique was performed .
only few studies are available in literature regarding the use of bt in eyelid nmsc . in all studies ,
the patients population was very heterogeneous in terms of histology , treatment aim ( curative or adjuvant ) , dose rate ( ldr and hdr ) , total dose , and follow up time [ 13 , 14 , 15 , 19 , 20 , 21 ] .
the level of evidence was low ( 3 in all studies according to sign criteria ) .
it is difficult to make a comparison because in 5/6 studies , lc was reported in terms of crude rate .
therefore , these results are probably influenced by the follow - up length [ 13 , 14 , 19 , 20 , 21 ] .
the only study reporting actuarial lc is the one of azad et al .   and
this difference may explain the lower results . among the authors reporting the crude rate , conill et al .  
had slightly lower results ( lc : 91.6% ) compared to the others ( 94.1 - 100% ) [ 13 , 20 , 21 ] .
this might indicate that the use of curettage ( performed by conill ) did not produces benefits in terms of disease control .
it should also be noted that conill , among the studies based on ldr [ 13 , 14 , 19 ] , is the one with the lowest total delivered dose .
only 4 studies reported the used acute toxicity score [ 14 , 19 , 20 ] .
edema was reported in three studies [ 13 , 14 , 15 ] with variable incidence ( 29.6 - 100% ) [ 13 , 14 ] .
conjunctival erythema or conjunctivitis was reported in 3 studies [ 13 , 14 , 19 ] and in the other two studies the site of erythema was not specified ( skin ?
daly et al . reported the lowest incidence of edema and conjunctival erythema ( 29.6% and 12% , respectively ) .
it is not clear whether it is a real difference or if the authors   reported only the most obvious cases .
other toxicities were reported in individual studies , 21.7% of keratites   and 29% of epiphora .
therefore , due to inhomogeneous and non - standardized reporting of acute toxicity , the identification of potential predictors of short term side - effects between the different studies results was difficult .
only 3 studies reported the used late toxicity score [ 14 , 20 , 21 ] .
epilation was reported in 4 studies [ 13 , 14 , 15 , 21 ] ranging from 65 to 100% .
the lowest value was reported by mareco et al . where a correlation between v100 ( volume of the tissue that receives 100% of the prescription dose ) and v150 ( volume of the tissue that receives 150% of the prescription dose ) , and epilation was observed .
v100  2 cm and v150  1 cm were associated with higher epilation frequency .
epiphora was reported in 2 studies with the same incidence ( 5% ) [ 15 , 19 ] as well as lacrimal duct stenosis , which was reported in 2 studies with a similar incidence ( 6.7 - 9.5% ) [ 13 , 19 ] .
pigmentation changes was reported in 4 studies [ 13 , 15 , 20 , 21 ] ( incidence 10 - 47% ) and impairment of eyelid fissure in 2 studies ( incidence 5.5 - 12% ) [ 13 , 21 ] .
, again v150  1 cm seemed to be correlated with the frequency of late toxicities .
ectropion was reported in 2 studies ( 5 - 14.2% ) [ 19 , 20 ] and 1 study reported the eversion of the lower lid in 4.4% of patients .
other late toxicities reported in individual studies were unilateral cataract , entropion , conjunctivitis , keratoconjunctivitis sicca , eyelid malocclusion , hyperlacrimation , and small corneal ulcer with incidences of 3.3% , 23% , 42% , 46% , 46% , 18% , and 0.6% , respectively .
cosmetic outcome was reported in 5 studies [ 14 , 15 , 19 , 20 , 21 ] .
it should be noted that in this trial the prescribed dose was the highest between the analyzed trials .
recurrent lesions [ 13 , 21 ] and higher volumes receiving the prescribed dose were associated with worst cosmetic outcomes .
it is difficult to make a comparison because in 5/6 studies , lc was reported in terms of crude rate .
therefore , these results are probably influenced by the follow - up length [ 13 , 14 , 19 , 20 , 21 ] .
the only study reporting actuarial lc is the one of azad et al .   and
this difference may explain the lower results . among the authors reporting the crude rate , conill et al .  
had slightly lower results ( lc : 91.6% ) compared to the others ( 94.1 - 100% ) [ 13 , 20 , 21 ] .
this might indicate that the use of curettage ( performed by conill ) did not produces benefits in terms of disease control .
it should also be noted that conill , among the studies based on ldr [ 13 , 14 , 19 ] , is the one with the lowest total delivered dose .
only 4 studies reported the used acute toxicity score [ 14 , 19 , 20 ] .
edema was reported in three studies [ 13 , 14 , 15 ] with variable incidence ( 29.6 - 100% ) [ 13 , 14 ] .
conjunctival erythema or conjunctivitis was reported in 3 studies [ 13 , 14 , 19 ] and in the other two studies the site of erythema was not specified ( skin ?
daly et al . reported the lowest incidence of edema and conjunctival erythema ( 29.6% and 12% , respectively ) .
it is not clear whether it is a real difference or if the authors   reported only the most obvious cases .
other toxicities were reported in individual studies , 21.7% of keratites   and 29% of epiphora .
therefore , due to inhomogeneous and non - standardized reporting of acute toxicity , the identification of potential predictors of short term side - effects between the different studies results was difficult .
only 3 studies reported the used late toxicity score [ 14 , 20 , 21 ] .
epilation was reported in 4 studies [ 13 , 14 , 15 , 21 ] ranging from 65 to 100% .
the lowest value was reported by mareco et al . where a correlation between v100 ( volume of the tissue that receives 100% of the prescription dose ) and v150 ( volume of the tissue that receives 150% of the prescription dose ) , and epilation was observed .
v100  2 cm and v150  1 cm were associated with higher epilation frequency .
epiphora was reported in 2 studies with the same incidence ( 5% ) [ 15 , 19 ] as well as lacrimal duct stenosis , which was reported in 2 studies with a similar incidence ( 6.7 - 9.5% ) [ 13 , 19 ] .
pigmentation changes was reported in 4 studies [ 13 , 15 , 20 , 21 ] ( incidence 10 - 47% ) and impairment of eyelid fissure in 2 studies ( incidence 5.5 - 12% ) [ 13 , 21 ] .
, again v150  1 cm seemed to be correlated with the frequency of late toxicities .
ectropion was reported in 2 studies ( 5 - 14.2% ) [ 19 , 20 ] and 1 study reported the eversion of the lower lid in 4.4% of patients .
other late toxicities reported in individual studies were unilateral cataract , entropion , conjunctivitis , keratoconjunctivitis sicca , eyelid malocclusion , hyperlacrimation , and small corneal ulcer with incidences of 3.3% , 23% , 42% , 46% , 46% , 18% , and 0.6% , respectively .
cosmetic outcome was reported in 5 studies [ 14 , 15 , 19 , 20 , 21 ] .
it should be noted that in this trial the prescribed dose was the highest between the analyzed trials .
recurrent lesions [ 13 , 21 ] and higher volumes receiving the prescribed dose were associated with worst cosmetic outcomes .
in conclusion , evidences from studies comparing the results of bt with other treatments are lacking in literature . furthermore , due to low evidence of the published studies it is challenging to draw any meaningful conclusions about factors correlated with tumor control and toxicity based on available data . some scattered evidence seem to suggest that the association with curettage is not beneficial and that the use of lower doses is associated with a higher incidence of local failure .
moreover , the use of higher doses and higher volumes receiving the prescribed dose seems to be associated with a worse cosmetic outcome while prolonged treatment would produce less late effects at least from the point of view of epilation .
finally , we can conclude that bt in small tumor size ( t  3.5 cm ) or in postoperative treatment of high risk patients ( positive or close margin , perineural invasion ) resulted in high local control rates ( median : 95.2% ) with acceptable - good functional cosmetic outcome ( median : 100% ) , mainly based on retrospective studies [ 13 , 14 , 15 , 19 , 20 , 21 ] .
therefore , prospective controlled trials evaluating not only local control but also functional cosmetic outcome with validated scale are justified .
 purposenon melanoma skin cancers ( nmsc ) of eyelid are uncommon . 
 many treatments approach are available with surgery being considered as the gold standard . 
 radiotherapy is an effective alternative in patients unfit for surgery . 
 brachytherapy ( bt ) might be a better therapeutic option due high radiation dose concentration to the tumor and rapid dose fall - off resulting in normal tissues sparing . 
 the aim of this review is to evaluate local control , toxicity , and functional cosmetic outcome of bt in nmsc of eyelid.material and methodsa systematic search of the bibliographic databases pubmed , scopus , and cochrane library from the earliest possible date through october 2015 was performed . 
 only studies published in english were included.resultssix articles fulfilled the selection criteria and were included in our review . due to high risk of bias , 
 all studies were classified to provide a low level of evidence ( according to scottish intercollegiate guidelines network classification ) . 
 no randomized controlled trials or case control studies were founded . 
 brachytherapy was well tolerated with acceptable toxicity and high local control rates ( median : 95.2% ) . 
 functional and cosmetic outcome were reported in five study as acceptable good functional - cosmetic outcome ( median : 100%).conclusionsto date , few evidences are available on the role of bt in eyelid nmsc , and they show satisfactory results in terms of local control and functional cosmetic outcome . therefore , prospective controlled trials are justified . 
Purpose
Material and methods
Criteria for considering studies to be included in this review
Study selection and quality assessment
Results
Treatment characteristics and local control
Acute-late toxicity and functional cosmetic outcome
Discussion
Treatment of eyelid cancer
Comparisons between analyzed studies
Local control
Acute toxicity
Late toxicity
Cosmetic outcome
Conclusions
Disclosure