Is high dose rate brachyhtherapy in a 2x6Gy dose an effective treatment for keloid?

          Is  high  dose  rate  brachyhtherapy   in  a  2x6Gy     dose  an  effective  treatment   for  keloid?     S.C.  STOKMANS  -­‐  1746626   ...
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        Is  high  dose  rate  brachyhtherapy   in  a  2x6Gy     dose  an  effective  treatment   for  keloid?     S.C.  STOKMANS  -­‐  1746626     S.C.  Stokmans    

 

        Auteur:    S.C.  Stokmans  –  studentnummer:  1746626  /  [email protected]   Stagebegeleider:     F.B.  Niessen  –  afd.  Plastische  chirurgie  VUMC  /  [email protected]   Stagecoordinator:     M.  Mullender  –  afd.  Plastische  chirurgie  VUMC  /  [email protected]   Commissielid  WVS:   S.M.  Peerdeman  –  afd.  Neurochirurgie  VUMC  /  [email protected]       Stageduur:  22  weken  (wetenschappelijke  stage  zonder  keuzestage)  

 

Is  high  dose  rate  brachyhtherapy  in  a  2x6Gy  dose  an  effective  treatment  for  keloid?       Abstract   Background:   The   aim   of   this   retrospective   study   was   to   assess   the   efficiency   of   keloidectomy   followed   by   high   dose   rate   (HDR)   brachytherapy   in   the   treatment   of   keloids.     Methods  and  materials:  Twenty-­‐eight  patients  with  in  total  35  keloids  who  were   treated  in  the  VU  medical  center  between  2003  and  2009  with  keloidectomy  followed  by   high  dose  rate  brachytherapy  were  included  in  the  study.  Patients  received  a  total  dose   of  12Gy  in  2  fractions  of  6  Gy.  The  first  fraction  was  administered  within  4  hours  after   surgery  and  the  second  dose  within  24  hours  after  the  first.  Recurrence  was  defined  as  a   visible  presence  of  a  new  keloid  at  the  location  that  was  previously  treated.     Results:   Twenty-­‐five   patients   with   32   keloids   completed   the   treatment   according   to   protocol.   After   a   follow-­‐up   of   2.3   years,   1   keloid   (3.1%)   recurred.   All   signs   and   symptoms   improved   after   therapy   and   few   side   effects   were   observed;   mainly   skin   pigmentation  changes  which  occurred  in  six  patients.     Conclusion:  Excision  followed  by  high  dose  rate  brachytherapy  administered  in  a  2x6Gy   dose  is  an  efficient  and  safe  treatment  modality  for  patients  suffering  from  keloids.   Recurrence  rate  in  this  study  is  3.1%,  and  except  for  hyper-­‐  and  hypopigmentation  very   few  side  effects  occur.  The  treatment  modality  is  safe  and  efficient  and  patients  have   very  good  cosmetic  results  and  a  high  satisfaction.  

 

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Introduction   A  keloid  scar  is  a  benign  fibrous  cutaneous  tumour  that  arises  as  a  result  of  abnormal   healing  of  the  dermis  (1).  The  lesion  does  not  improve  over  time  and  exceeds  the   boundaries  of  the  wounded  area  by  infiltrating  into  the  surrounding  normal  tissue,  but   does  not  spread  beyond  the  dermis,  making  it  a  benign  disease  (2,3,4).  Keloids  show   some  similarities  with  hypertrophic  scars  although  hypertrophic  scars  do  not  exceed  the   boundaries  of  the  original  wound  and  tend  to  regress  over  time  (1,6)  (table  1).  Excision   can  be  used  as  a  treatment  for  hypertrophic  scars  but  keloidectomy  shows  80-­‐100%   recurrence  rate  (5,1).     Table  1:  differences  between  hypertrophic  scars  and  keloids  (6)  

Hypertrophic  scar   Develop  soon  (weeks)  after  trauma   Do  not  exceed  boundaries  wounded   area   Regress  spontaneously  over  time   Surgery  can  be  a  curative  treatment  

Keloid   May  develop  months  or  years  after   trauma   Infiltrating  normal  surrounding  tissue   No  spontaneous  regression  over  time   Surgery  is  contra  indicated.  No   curative  treatment  yet.     Associated  with  dark  skin  

No  association  with  skin  colour     Etiology   Men  and  women  are  equally  affected  although  it  seems  clinically  that  women  are  more   affected  (7).  This  higher  clinical  incidence  is  probably  due  to  a  higher  rate  of  ear  piercing   amongst  women,  and  because  women  are  more  cosmetic  concerned  and  more  likely  to   seek  help  in  case  of  a  keloidal  lesion  (8,9).  Incidence  is  higher  in  dark  skinned   individuals,  (between  5  and  15  times  more  frequent)  and  relatively  young  people  are   mainly  affected  (the  second  to  third  decade  is  most  affected)(1,7,10,11).  Younger   individuals  are  more  exposed  to  traumas,  have  a  higher  collagen  turnover  and  a  higher   skin  tension  (3.12).     Keloids  are  more  frequent  on  the  anterior  chest,  shoulders,  ear  lobules,  upper  arms  and   cheeks,  and  far  less  frequent  on  the  eyelids,  genitalia,  palms,  soles,  cornea  and  mucous   membranes  (1).  More  than  50%  of  all  keloid  cases  have  a  positive  family  history,  and   familial  keloid  is  associated  with  formation  of  keloids  in  multiple  sites  (13).  They  tend  to   have  a  genetic  predisposition  and  likely  to  evolve  aberrant  interactions  of  one  or  more   genes  or  gene  pathways  (14,15).     Keloids  can  cause  major  physical  complaints,  mainly  pain  and  pruritus,  and  can  carry  a   major  physiological  burden  as  well.  This  impairs  the  quality  of  life  (16,17,18,19).     Pathology   Keloids  arise  from  an  excessive  deposit  of  collagen  in  the  dermis  and  subcutaneous   tissues  after  even  the  smallest  skin  injury  in  predisposed  individuals  (20).    

 

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The  precise  pathomechanism  is  unclear,  but  it  seems  that  keloids  are  caused  by  a   derailment  in  the  wound  healing  process  causing  excessive  scar  tissue  formation  (1).   Normal  wound  healing  can  be  grouped  into  three  different  phases.  The  inflammatory   phase,  the  proliferative  or  granulation  phase,  and  the  maturation  or  remodelling  phase   (3,20).  In  which  phase  keloid  formation  takes  place  is  unknown.  Some  researchers  think   it  occurs  in  the  inflammatory  phase,  but  others  argue  for  the  remodelling  phase,  since   keloids  can  occur  even  years  after  wound  closure  (1).   Histologically,  keloids  are  characterized  by  hypo  cellular  collagen  bundles,  organized  in   swirls  comprising  closely  bound  fibrils.  In  comparison  with  normal  scars  the  collagen   fibres  are  larger  and  thicker  and  the  keloidal  fibroblasts  produce  as  much  as  20  times   more  collagen  than  normal  scar  fibroblasts.  The  collagen  type  I  to  III  ratio  is  also   elevated  (3,7,20,21,22,23).   This  abnormal  collagen  turnover  might  be  caused  by  increased  density  of  keloidal   fibroblasts  (12,22,23).  On  top,  these  keloidal  fibroblasts  persist  longer  in  the  scar  (due   to  less  apoptosis)  and  show  a  greater  capacity  to  proliferate  and  produce  high  levels  of   collagen,  elastin,  fibronectin  and  proteoglycans  and  overproduce  certain  grow  factors   (4,7,10,11,12,24).  This  overproduction  might  be  caused  by  the  higher  responsiveness  of   keloid  fibroblasts  to  certain  proteins  such  as  transforming  growth  factor  ß  (TGF-­‐  ß)  and   insuline  like  growth  factor-­‐1  (9).  These  proteins  are  responsible  for  more  collagen   synthesis  and  prevent  collagen  breakdown  (11).   It  is  not  yet  demonstrated  if  the  keloid  fibroblasts  are  abnormal  themselves,  or  if  the   keloid  fibroblasts  are  intrinsically  normal  responding  to  abnormal  extracellular  signals.   Evidence  is  directing  towards  the  latter  (17,25).       Skin  or  wound  tension  is  considered  a  critical  role  in  the  formation  of  keloids  as  well   (26).  Skin  tension  can  cause  fibroblast  proliferation  and  therefore  an  upregulation  of   collagen  production.  Keloids  develop  more  frequent  in  areas  of  high  wound  tension,   such  as  the  back  or  extremities  (27).  However,  the  importance  of  wound  tension  is   questionable  since  keloids  develop  frequently  as  well  in  areas  with  very  low  wound   tension,  such  as  the  ear  lobules  and  appear  rarely  on  the  soles  and  palms  where  the   wound  tension  is  significant  (21).       Treatment   No  single  treatment  modality  has  proven  widely  effective,  although  multiple  treatment   modalities  are  used.  (18,21,28)  These  include  silicone-­‐based  therapy  (29,30)  with  a   relief  of  complaints  in  60-­‐100%  of  cases,  intralesional  steroids  (31,35)  with  a  recurrence   rate  between  9-­‐50%  ,  pressure  therapy  (31)  with  an  60-­‐85%  success  rate,  laser  therapy   (26,32,33)  with  recurrence  rates  between  16-­‐94%,  cryotherapy  (22)  with  51-­‐76%   response  and  antineoplastic  agents  (12,23,34).  Up  to  now  no  curative  treatment  is   found,  merely  due  to  the  unknown  pathogenesis.  Monotherapy  is  insufficient  in  many  

 

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cases  and  combination  therapy  has  preference  (1).  Overall,  normally  excision  is  followed   by  one  of  the  treatment  modalities  mentioned  above  (28,35).       Brachytherapy   Many  studies  have  shown  the  efficacy  of  radiotherapy  in  the  treatment  of  keloids  with   far  better  results  than  the  treatment  modalities  mentioned  before.  External  radiation   therapy  shows  a  recurrence  rate  between  12-­‐27%  (2,41,45),  and  brachytherapy  shows   even  lower  recurrence  rates,  between  3,4  and  23,6%  (24,36,37,40).   Guix  et  al.  (36)  treated  147  patients  with  a  keloidectomy  followed  by  high  dose  rate   brachytherapy  from  1991  to  1998.  A  total  dose  of  12Gy  was  given  in  four  fractions  of   300cGy.  The  first  fraction  was  administered  30-­‐60  minutes  post-­‐surgery,  and  the  other  3   fractions  followed  within  the  next  24  hours.  A  3,4%  recurrence  rate  and  a  good  or   excellent  cosmetic  result  was  found  in  130  patients.  A  recurrence  rate  of  3,4%  is  very   low,  but  this  might  be  due  to  patient  selection  bias,  since  most  patients  in  this  study   came  to  the  plastic  surgeon  with  a  small  scar.   Veen  et  al.  (37)  used  three  different  high  dose  rate  brachytherapy  schemes  in  their   group  of  35  patients;  38  keloids  were  treated  first  with  1  x  6Gy  and  2x  4Gy  the  next  day,   7  keloids  were  treated  with  3x  6Gy,  and  9  keloids  were  treated  with  1  x4  Gy  first  and  2x   3Gy  the  next  day.  The  first  dose  was  administered  within  6  hours  after  surgery,  and  the   two  additional  fractions  were  given  the  next  day  with  an  interval  of  at  least  6  hours.   One  recurrence  occurred  in  the  first  group,  and  4  in  the  third  group.  The  3x6Gy  group   gave  the  best  result,  with  a  0%  recurrence  rate.  Their  overall  recurrence  rate  was  3,5%,   although  the  groups  were  very  small.   De  Lorenzi  et  al.  (38)  treated  24  patients  with  30  keloids.  They  found  that  the  thickness   of  the  keloid  after  therapy  was  reduced  with  more  than  2mm,  a  significant  decrease.   79,1%  of  their  patients  had  no  pain  or  irritation  after  treatment,  and  79,2%  would   recommend  the  treatment  to  other  patients.     VU  medical  centre  study   In  the  VU  medical  centre  brachytherapy  is  applied  since  2002  and  clinically  good  results   are  obtained.  The  given  dose  HDR  brachytherapy  is  2x6Gy.  This  dose  scheme  has  not   been  described  before  (2,17,24,31,39,40,41).  Guix  (36)  described  a  total  dose  of  12Gy   too,  but  then  in  a  3x4Gy  scheme.     In  the  VU  medical  centre  the  first  dose  is  administered  within  4  hours  after  surgery,  and   the  next  dose  within  24  hours  after  the  first  dose.  Our  hypothesis  is  that  time  between   first  dose  and  surgery  is  very  important,  although  some  articles  report  otherwise.   (38,37)   We  evaluated  this  treatment  modality  retrospectively  to  determine  its  effectiveness  in   treating  keloids.      

 

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Material  and  Methods     Between  2003  and  2009  a  total  of  48  patients  with  keloid  were  treated  with   keloidectomy  followed  by  high  dose  rate  (HDR)  brachytherapy  at  the  Plastic  Surgery   and  Radiotherapy  department  of  the  VU  University  medical  centre,  Amsterdam,  the   Netherlands.  All  patients  had  received  unsuccessful  therapy  before.     The  patients  were  located  for  follow  up  in  2011.  Mean  follow  up  time  was  2.3  years  and   ranged  from  1.5  to  8  years.  All  patients  were  invited  by  telephone  and  letter  to  attend   for  a  consultation.  Two  patients  refused  cooperation,  14  patients  were  untraceable  and   4  patients  made  an  appointment  but  didn’t  show  up  and  refused  to  make  another   appointment.  Finally  28  patients  with  35  keloids  were  included  in  the  study.     Patient  characteristics   Twenty-­‐eight  patients  showed  up  for  re-­‐examination  by  a  researcher  at  the  department   of  Plastic  Surgery.  Mean  age  at  consultation  was  38.6  years  (18-­‐85  years).  There  were  9   (32.1%)  male  patients  and  19  (67.9%)  females.  Eleven  patients  were  caucasian  (39.3%)   and  17  patients  dark  skinned.  See  table  2  for  more  patients’  characteristics.     The  treatment  and  the  study  characteristics  were  clearly  explained  to  all  patients.       Table  2  Patient  characteristics  

Characteristic   Median  age  at  follow  up  (range)   Sex   Females     Males   Location   Ear  Lobules     Sternum     Shoulders     Head     Retro-­‐Auriculair     Upper  Back     Other     Limb      Abdomen     Thorax   Etiology   Post-­‐Operative     Ear  Piercing     Trauma     Unknown     Acne     Insect  Bite   Width  pre-­‐treatment(range)   Width  post-­‐treatment  (range)   Length  pre-­‐treatment(range)   Length  post-­‐treatment  (range)  

Frequency  (Percent)     38.6   (18-­‐85)     19   (67.9)     9   (32.1)     13   (37.1)     7     (20.0)     3     (8.6)     3     (8.6)     2     (5.7)     2     (5.7)     2     (5.7)     1     (2.9)     1     (2.9)     1     (2.9)     10     (28.6)     7     (20.0)     6     (17.1)     6     (17.1)     5     (14.3)     1     (2.9)     2,19     (0,5-­‐10)     0,99     (0,0-­‐6,0)     5,24     (1,0-­‐24)     5,49    (0,0-­‐24,0)  

*N=28  

 

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Outcome  measures   During  follow  up  a  researcher  at  the  Department  of  Plastic  Surgery  re-­‐examined  the   keloid  location(s).  First  outcome  measure  is  recurrence.   The  researcher  and  the  patients  independently  rated  the  therapeutic  response  using  the   Patient  and  Observer  Scar  Assessment  Scale  (POSAS)  and  the  Vancouver  Scar  Scale   (VSS).  The  reason  to  use  both  the  VSS  and  the  POSAS  are  the  higher  validity  and   reliability  obtained.  Both  scale  measure  roughly  the  same  characteristics,  but  the  inter-­‐ rater  reliability  is  higher  when  used  both  (42).  See  Table  3.1  and  3.2.       Table  3.1:  Patient  and  Observer  scar  assessment  scale  

    Table  3.1:  The  POSAS  scale  incorporates  both  observer  and  patient  scar  ratings.  The  results  were  obtained   after  the  therapy.  The  POSAS  scale  consists  of  the  Observer  Scar  Assessment  Scale  (OSAS)  and  the  Patient   Scar  Assessment  Scale  (PSAS).  In  the  OSAS  scale  the  observer  scores  the  vascularity,  pigmentation,  thickness,   relief,  pliability,  surface  area  and  overall  opinion.  Each  characteristic  can  be  scored  between  1  and  10,  with  1   representing  normal  and  10  as  the  worst  scar  imaginable.  The  OSAS  is  combined  with  the  Patient  Scar  

 

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Assessment  Scale  (PSAS),  which  contains  six  items:  scar-­related  pain,  itchiness,  colour,  stiffness,  thickness  and   irregularity.  The  patient  can  also  score  between  1  and  10.  The  PSAS  and  OSAS  items  obtain  a  total  score   ranging  from  7  to  70  in  each  scale.    

  Table  3.2  Vancouver  Scar  Scale  

  Table  3.2:  The  VSS  scores  four  physical  characteristics  of  the  scar:  pigmentation,  vascularity,  pliability  and   height,  and  each  variable  include  ranked  subscales  that  are  summed  to  obtain  a  total  score  ranging  from  0  to   14,  with  0  representing  normal  skin.      

The  symptoms  of  pain,  pruritis,  burning  sensation,  functional  discomfort,  dysesthesia,   movement  induction  and  psychological  impairment  before  and  after  treatment  were   assessed  and  scored  on  a  visual  analogue  scale  (VAS)  0-­‐10.     The  researcher  took  a  picture  of  the  keloid  during  the  follow  up  session.  The  pictures   were  scored  by  an  experienced  plastic  surgeon  with  the  observer  scale  of  the  POSAS  (the   OSAS),  excluding  the  pliability  criteria.  The  professional  scored  between  6-­‐60,  6   representing  a  normal  scar.  To  compare  the  VSS,  the  PSAS  and  the  OSAS  and  the  scores   were  converted  to  percentages.     Keloid  sizes  (with  and  length)  were  measured  before  and  after  treatment,  to  obtain  the   average  reduction  (or  increase)  of  the  keloid.    

 

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Technique   Surgery   During  the  keloidectomy,  as  much  scar  tissue  is  removed  as  possible.  Mostly  all  keloidal   tissue  can  be  removed,  but  sometimes  some  keloidal  tissue  is  left  for    cosmetic  reasons.   This  occurs  especially  on  the  ears,  to  prevent  abnormal  cosmetics  and  hearing  loss.   After  surgery,  a  metal  tipped  Varisource  catheter  (150  cm)  is  positioned  between  the   dermal  edges  of  the  wound.  The  wound  edges  need  to  be  maximal  approximated  to  lie   directly  against  the  catheter.  At  the  level  of  in  and  outcome  of  the  catheter  at  the  end  and   beginning  of  the  scar  the  catheter  needs  to  be  fixed  on  the  skin  using  adhesive  tape.  The   catheter  must  follow  exactly  the  shape  of  the  scar  and  must  be  at  least  one  centimetre   longer  than  the  scar  to  avoid  under  dosage  at  the  extremities  of  the  scar.  (see  fig.  1)   The  catheter  must  be  kept  intact  without  any  kinking  and  cutting  or  slicing.       HDR  Brachytherapy   Within  4  hours  of  the  operation  the  patient  is  transferred  to  the  Radiotherapy   department  for  the  two  HDR  brachytherapy  sessions.  The  catheter  is  loaded  over  the   whole  wound  course  with  a  dose  of  6Gy  at  0,5  cm  around  the  axis  of  the  catheter.  Within   24  hours  after  the  first  fraction  the  second  6Gy  is  administered.  A  total  dose  of  12Gy  is   administered  in  two  days.     After  the  second  fraction  the  catheter  is  removed,  together  with  the  radioactive  material.   The  stitches  are  removed  ten  days  post  surgery.     Fig  1:  The  fixed  Varisource  Catheter  after  keloidectomy.  

        Statistics   Data  analysis  was  performed  using  the  software  program  IBM  SPSS  statistics  version   18.0  for  Mac.   A  dependent  t-­‐test  is  performed  to  compare  the  VAS  scores  before  and  after  treatment.     Descriptive  statistical  analyses  were  used  to  assess  outcomes.    A  p-­‐value  <  0,05  was   considered  statistically  significant.     Recurrence  was  defined  as  a  visible  presence  of  new  keloid  at  the  location  that  was   previously  treated.      

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Results     During  the  follow  up  period  (mean  2,3  years  ranging  1.5-­‐8  years),  3  out  of  35  keloids   recurred  (8.6%).  Thirty-­‐two  keloids  totally  disappeared  after  the  high  dose  rate   brachyhtherapy.     Three  patients  were  not  treated  following  protocol.  Although  these  three  patients  did   not  follow  protocol,  they  were  included  in  the  descriptive  statistics.  Two  of  those   patients  showed  a  recurrence.  One  patient  had  an  overnight  dislocation  of  the  catheter.   Instead  of  the  6Gy  HDR  brachytherapy,  she  underwent  an  extern  radiation  therapy  of   6,6Gy  at  day  2.  She  did  not  develop  a  recurrence.  Both  other  patients  not  treated   following  protocol  did,  however,  recur.  One  patient  had  an  overnight  dislocation  and  did   not  receive  any  treatment  at  day  two,  so  was  only  treated  with  one  dosis  of  6Gy  HDR   brachyhtherapy.  The  other  patient  whit  a  recurrence  received,  due  to  a  technical   deficiency,  a  lower  dose  HDR  brachytherapy  during  his  second  session.     When  the  patients  not  treated  according  to  protocol  are  excluded,  only  1  out  of  32   keloids  recurred  (3.13%).     Patients  rated  the  symptoms  associated  with  the  keloid  using  the  VAS  score  with  a  grade   from  0-­‐10.  Pain,  pruritus,  movement  induction,  burning  sensation,  physical  burden,   functional  discomfort  and  dysesthesia  were  evaluated  before  and  after  treatment.   The  initial  signs  and  symptoms,  as  well  as  their  responses  to  the  treatment,  are  shown  in   table  4.       Table  4:  Signs  and  symptoms  before  and  after  treatment  

    Signs  and  symptoms   Pain   Pruritus   Movement  induction   Burning  Sensation   Physical  Burden   Functional  Discomfort   Dysesthesie   N=35,  (*)  =  significant    

Before   treatment   Mean  (SD)   5.60  (3.77)   6.89  (2.72)   0.57  (1.99)   1.03  (2.76)   3.51  (3.94)   2.11  (3.53)   4.43  (3.91)      

   After      treatment   Mean  (SD)   Significance   1.17  (2.18)   0.06   1.37  (2.58)   0.06   0.06  (0.24)   0.03*   0.14  (0.85)   0.008*   0.97  (2.23)   0.001*   0.43  (1.65)   0.003*   1.31  (2.54)   0.005*          

    Pruritus  followed  by  pain  and  physical  burden  were  the  most  common  symptoms   observed.  All  signs  and  symptoms  improved  after  therapy  and  except  for  pain  and   pruritus  all  improvement  is  significant.      

 

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Cosmetic  outcome  was  very  good  in  the  group  without  recurrence  with  a  mean  of  7.94   out  of  10  (SD  2.31,  range  1-­‐10).  The  patients  with  a  recurrence  were  not  as  satisfied   with  the  cosmetic  result;  the  mean  score  was  3,67  out  of  10  (SD  3.06,  range  1-­‐7).   Patient  satisfaction  about  the  treatment  protocol  was  closer  together  when  comparing   the  recurrence  group  and  the  group  without  recurrence.  Patients  without  recurrence   rated  their  satisfaction  with  a  mean  of  8,5  (SD  1.65,  range  2-­‐10)  and  the  patients  with   recurrence  with  a  mean  of  6,67  (SD  4,16  range  2-­‐10).  Dissatisfied  patients  were  mostly   dissatisfied  because  they  were  not  treated  by  the  surgeon  of  their  choice  or  felt  not  fully   prepared  for  the  treatment  protocol.       As  a  result  of  the  brachytherapy  6  patients  observed  to  have  skin  pigmentation  changes;   3  patients  were  diagnosed  with  hypopigmentation  and  3  patients  with   hyperpigmentation.  In  1  case  telangiectasy  was  noted.  Two  patients  suffered  from  a   possibly  brachytherapy  induced  infection  and  2  patients  reported  a  decelerated  wound   healing.  No  other  side  effects  such  as  alopecia  or  skin  fibrosis  were  noted.  (see  table  5).     Table  5:  Side  effects  of  Brachytherapy  

  Frequency   %   Hypopigmentation   3   8,6%   Hyperpigmentation   3   8,6%   Telangiectasia   1   2,9%   Infection   2   5,7%   Decelerated  wound  healing   2   5,7%   Desquamation   2   5,7%   No  side  effects   22   62,9%     All  patients  underwent  previous  therapies.  Corticosteroid  injections  were  used  in  85,7%   of  the  patients,  mostly  Kenacort.  Excision  and  silicone  therapy  was  used  in  60%  of  the   cases.     The  mean  period  between  appearance  of  the  keloid  and  the  first  visit  to  a  medical  doctor   was  2,17  years  (SD  3.40,  range  0-­‐18  years).  The  mean  time  between  the  first   consultation  at  VUmc  and  the  brachytherapy  treatment  was  2,2  years  (SD  3.68,  range  0-­‐ 14  years).  This  is  important  to  distinguish  between  a  keloid  and  a  hypertrophic  scar.   Hypertrophic  scars  regress  over  time,  keloids  do  not.     Main  reason  for  seeking  help  (60,7%)  were  complaints  caused  by  the  keloid,  mainly  pain   and/or  pruritus.  For  21,4  %  of  patients  the  cosmetic  burden  was  the  main  reason  to   seek  treatment  (see  table  6).      

 

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Table  6:  The  main  reasons  for  patients  to  find  help.  

Cosmetic   Complaint  (pain/ pruritus)   Concerned   Other  

      In    table  7,  recurrences  (n=3)  are  compared  with  cases  in  which  no  recurrence  occurred   (n=32).    In  the  comparison  of  the  two  groups,  no  significant  differences  were  observed   using  independent  sample  t-­‐test.       Table  7:  The  recurrence  group  vs  the  no-­recurrence  group       Recurrence   No-­recurrence  group   group   Gender   Male   66.67%   26.92%     Female   33.33%   73.08%   Race   White   33.33%   38.46%     Afro-­‐American   66.67%   53.85%     Other   0%   7.69%     Age   26  (20-­‐30)   39.38  (18-­‐85)   Location   Ear  Lobules   66.67%   34,38%     Sternum   0%   21.88%     Shoulders   0%   9.38%     Genitalia   33.33%   0%     Other   0%   34.38%   Etiology   Ear  Piercing   66.67%   15.63%     Trauma   33.33%   15.63%     Post-­‐operative   0%   31.25%     Other   0%   37.5%   Familiar   Yes   66.67%   38.46%     No   33.33%   61.54%     Width  Before   2.17  (SD  0.29)   2.18  (SD  1.75)     Width  After   1.66  (SD  0.58)   0.92  (SD  1.22)  

 

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Lenght  Before   Lenght  After   PSAS   VSS   OSAS  researcher   OSAS  professional   Cosmetic  Result   Satisfaction  Treatment   Recommend  to  others    

Again  if  neccessary    

Treated  as  protocol    

             

Yes   No   Yes   No   Yes   No  

2.5  (SD  0.5)   1.67  (SD  0.58)   51.85  (SD  30.63)   54.77  (SD  8.26)   49.21  (SD  5.72)   29.01  (SD  15.75)   3.67  (SD  3,06)   6.67  (SD  4.16)   33.33%   66.67%   33.33%   66.67%   33.33%   66.67%  

5.5  (SD  5.04)   5.84  (SD  6.23)   17.36  (SD  19.12)   24.28  (SD  17.51)   16.21  (SD  11.56)   18.98  (11.84)   7.94  (SD  2.31)   8.5  (SD  1.65)   91.43%   8.57%   91.43%   8.57%   96.87%   3.13%  

         

 

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Discussion     This  study  shows  that  excision  of  a  keloid  followed  by  high  dose  rate  brachytherapy   represents  an  effective  and  safe  treatment  for  keloids  with  a  low  recurrence  rate  of   3.1%.  The  treatment  is  a  useful  and  effective  method  for  keloid  eradication,  particularly   in  patients  whose  lesions  have  been  resistant  to  other  treatment  modalities.       Niessen  et  al  have  already  largely  discussed  the  necessity  of  complementary  treatment   following  surgery  of  keloids  since  recurrence  without  additional  treatment  is  very  high   (1).   Radiotherapy  in  combination  with  surgery  is  a  valuable  treatment  modality  for  keloidal   scars  and  showed  the  best  results.  It  offers  better  local  control  than  other  treatments,   such  as  silicone  therapy  or  corticosteroid  injections  with  median  recurrence  rates  of   50%  (31,43).  The  exact  mechanism  by  which  radiotherapy  prevents  regrowth  is   unknown,  although  is  it  hypothesized  that  ionizing  radiation  destroys  the  fibroblasts  by   apoptosis  and  these  fibroblasts  are  not  replaced  by  blood  borne  cells  from  distant   tissues.  By  destroying  enough  fibroblasts,  a  balance  between  collagen  production  and   degradation  may  be  created  (44).  The  extracellular  matrix  gene  expression  seems  to  be   affected  as  well  and  it  may  provoke  damage  to  connective  tissue  stem  cells  (1).       Radiotherapy   Many  studies  using  external  radiotherapy  are  described.  Viani  et  al  (2)  treated  the   largest  number  of  patients  so  far.  Six  hundred  and  twelve  patients  with  892  keloids   were  treated  using  a  strontium  90  surface  applicator  after  keloidectomy.  12.4%  patients   showed  a  recurrence.  Ragoowansi  et  al  (41)  treated  80  patients  with  surgical  excision   and  immediate  postoperative  single  fraction  radiotherapy  and  reported  16%  recurrence   after  5  years.  Kovalic  et  al  (45)  treated  113  keloids  with  superficial  X  ray  therapy  in  a   dose  schedule  of  12  Gy  in  three  fractions.  A  recurrence  rate  of  27%  was  found.     Low  dose  rate  Brachytherapy   The  largest  experience  with  low  dose  rate  (LDR)  brachyhterapy  in  the  treatment  of   keloids  was  reported  by  Escarmant  et  al  (46).  In  this  study  855  keloids  were  treated   with  surgical  excision  followed  by  immediate  interstitial  implantation  of  192  Iridium,   reporting  a  21%  recurrence  rate.  This  recurrence  rate  is  about  as  high  as  the  recurrence   rate  obtained  with  external  radiation  therapy  but  the  authors  favour  low  dose  rate   brachytherapy  for  practical  reasons.      Taken  together,  all  of  the  above  mentioned  studies  reported  a  recurrence  rate   approaching  19%  when  keloids  are  treated  with  external  radiotherapy  or  LDR   brachytherapy.    

 

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High  dose  rate  brachytherapy   Better  results  were  obtained  using  high  dose  rate  (HDR)  brachytherapy.   Brachytherapy’s  biggest  advantages  are  dose  optimatization  and  better  dose   distribution,  rapid  dose  fall  off  and  better  radioprotection.  The  same  dose  of  radiation  is   given  to  the  patient  in  a  shorter  amount  of  time.  Compared  with  external  radiotherapy,   HDR  brachytherapy  involves  less  normal  tissue  in  the  treated  area  and  it’s  costs   compare  favourably  with  those  of  external  radiotherapy.     HDR  Brachytherapy  also  compares  favourably  with  LDR  brachytherapy.  It  is  more   convenient  for  patients  because  there  is  no  need  for  hospitalisation  in  a  shielded  room   and  it  decreases  the  radiation  exposure  for  health  care  workers.  Garg  et  al  (40)  already   proved  the  higher  effectiveness  of  brachytherapy  in  comparision  with  conventional   radiotherapy  showing  that  patients  who  failed  surgery  and  postoperative  external   radiotherapy  had  a  low  recurrence  rate  (12%)  when  treated  with  keloidectomy   following  HDR  Brachytherapy  of  15Gy  in  three  fractions.  The  first  fraction  was  delivered   within  24  hours  after  surgery  and  the  other  two  fractions  were  administered  on  day  two   and  day  three.  Veen  et  al  (37)  used  three  different  HDR  brachytherapy  schemes  in  their   group  of  35  patients.  He  reported  an  overall  recurrence  rate  of  3.5%.  The  first  fraction   was  administered  within  6  hours  after  the  surgery  and  the  next  fractions  were   administered  at  day  two,  with  a  six  hours  interval  between  the  doses.  Guix  et  al  (36)   treated  147  patients  with  four  fractions  of  3Gy.  A  3.4%  recurrence  rate  was  found.  The   first  fraction  administered  within  30-­‐60  minutes  post  surgery  and  the  total  of  4  fractions   were  administered  within  24  hours.     Arnault  et  al  (24)  reported  a  23.6%  recurrence  rate  when  treating  32  patients  with   Iridium  192  brachytherapy  in  an  average  dose  scheme  of  17.9Gy.  The  exact   time/delivery  scheme  was  not  described  in  this  study.       All  these  studies  offered  much  better  local  control  rates  than  did  those  with  other   techniques  like  radiotherapy,  corticosteroid  injections,  silicone  therapy  or  laser  therapy   which  had  a  median  recurrence  rate  of  50%.  Nowadays  surgical  excision  followed  by   radiotherapy  is  considered  the  treatment  of  choice  for  keloid  scars,  especially  keloids   that  recurred  after  previous  therapies.       In  our  series  we  found  a  local  recurrence  rate  of  3.1%  suggesting  that  12Gy  is  a  good   dosage.  Kal  et  al  (47  and  48)  recommend  a  BED  value  of  30  Gy  (for  instance  obtained   with  1x13Gy,  2x8Gy  or  3x6Gy)  for  the  lowest  recurrence  rate.  Our  lower  dose  seems  to   work  as  well  even  resulting  in  a  lower  recurrence  rate  (3.1%  vs.  3.5%)  and  off  course   less  radiance  for  the  patient.  Guix  used  a  total  dose  of  12Gy  too  and  found  3.4%   recurrence,  but  Veen’s  group  (37)  recommends  a  3x  6Gy  scheme  with  3.5%  recurrence.       As  mentioned  above,  not  only  brachytherapy  dose  is  important  but  also  the  time   between  the  surgery  and  the  first  administration  of  the  brachytherapy.  In  the  studies  

 

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mentioned  above,  this  interval  varies  between  30-­‐60  minutes  up  to  within  24  hours   after  surgery.  In  our  study  the  surgery-­‐first  HDR  brachyhtherapy  treatment  interval  is  4   hours  and  our  hypothesis  is  that  the  shorter  the  interval,  the  better  the  result.  Veen  (37)   and  Guix  (36)  both  used  short  intervals,  within  6  hours  and  within  30-­‐60  minutes   respectively,  and  both  studies  had  very  low  recurrence  rates  of  3.5%  and  3.4%.       The  risk  of  carcinogenesis  from  radiation  exposure  is  well  known,  leading  to  a   discussion  about  the  suitability  of  treating  a  benign  disease  with  radiotherapy.  The  use   of  radiation  as  a  therapeutic  modality  in  the  control  of  a  benign  disease  merits  caution,   especially  in  children  and  carcinogenic  sensitive  areas  such  as  the  breasts  and  thyroid   gland.  Extensive  large  studies  of  this  treatment  have  shown  a  0%  carcinogenetic  rate,   despite  theoretical  risks.  Therefore  it  can  be  concluded  that  radiotherapy  is  acceptable   as  keloid  treatment  modality  (49,50).       We  conclude  that  the  results  of  this  study  prove  the  effectiveness  of  HDR  brachytherapy   after  keloidectomy.  The  2x6Gy  scheme  seems  to  be  sufficiently  high  and  the  surgical   technique  used  seems  to  be  adequate.  This  treatment  protocol  has  minimal  side  effects   and  no  serious  complications.       Conclusion   Excision  followed  by  high  dose  rate  brachytherapy  in  a  2x6Gy  dose  is  an  efficient  and   safe  treatment  modality  for  patients  suffering  for  keloids.  Recurrence  rate  is  3.1%  and   except  for  hyper-­‐  and  hypopigmentation  very  few  side  effects  occur.  The  treatment   modality  is  safe  and  efficient  and  patients  have  very  good  cosmetic  results  and  a  high   satisfaction.      

 

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