ࡱ> sr!( 23/ 0LDTimes New Roman,v0,0$@ .  @n?" dd@  @@`` 3G]       0AA@)g4=d=dD0ppp@  <4BdBdp̨0ʚ;ʚ;<4ddddpkd0\g43d3dD0Pp@ pp{9___PPT10 pp62___PPT9/ 0? %O <fLondon IDEAS Cancer Genetics Workshop 26 April 2006 8Shirley Hodgson - POET StudyPOETPrevention of Endocrine Tumours  &#Previous aliases  d PUNCH (prevention of uterine neoplastic change in HNPCC) PETALS (Prevention of endocrine tumours)&   = Endometrial Cancer (EC)Fifth most common cancer in the UK Type 1 endometriod adenocarcinoma, develops from endometrial hyperplasia, hormone responsive Type 2 in atrophic endometrium, estrogen independent>+ P EC Incidence and Survival  Lifetime risk 2% in general population Age at diagnosis 55-65y; 1% diagnosed before 50y Overall 5-year survival rate 65-82%; Stages 1A and 1B 91%; Stages lllA-C 50%&   '$Endometrial cancer in HNPCC  Vasen et al.: 125 women from HNPCC families: median age at diagnosis 48y (27-72y) 61% had a second primary cancer 5y survival rate 88% (82% for sporadic)  (%Cancer pathway in HNPCC  j2 patients with EH but no EC 3 patients with EH and EC Loss of HNPCC protein in AEH (Berends et al 2001)&W    )& EC in HNPCC   Average age at diagnosis 46.8y Mainly MSH2 mutation carriers Mean age at diagnosis of non-endometrioid cancers 46.4y; stage 1 tumours 47.5y, stage ll and lll tumours 46.0y. Non-endometrioid cancers all in MSH2 2 cases with AEH had EC at hysterectomy tZ   9       ? *' EC in HNPCC  F86.0% endometrioid 97.6% in sporadic cases <50y; 96.2% in sporadic EC +MLH1 methylation Nonendometrioid tumours: clear cell ca.(3); papillary serous ca. (3); malig. mixed mullerian (1) Crohn s-like lymphoid reaction with lymphangio-invasion, poorly differentiated$Z$   V     7          !  Surveillance   Transvaginal ultrasound annually from 35y; sensitivity up to 80% Pipelle endometrial biopsy annually (? Reserve for those with endometrial thickness >5mm postmenopausally) Conflicting evidence for efficacyZZ   6  R  % Hormonal prevention  Estrogens promote type 1 EC development Progestogens inhibit EC development Mirena IUS releases 20mcg/d levonorgestrel locally and is known to reduce endometrial thickness and inhibit hyperplasia and atypia (e.g.with Tamoxifen))       R       /* Mirena IUS  Causes a thin inactive endomtrium with decidualisation of the stroma and atrophy of the glands. Has been reported to cause regression of EC but EC has been reported in a woman with Mirena.t       q   0) Pilot Studies  35 women with HNPCC on surveillance 32 had pipelle biopsy: 30 sufficient for histology. 26 (81%) had mild discomfort 5 (16%) moderate discomfort 1 (3%) severe discomfort &+  y 1+ Pilot Studies  c15 women with HNPCC, average 42y age (24-56y) Pipelle (11 prolif.,1 secretory,1 menstrual). Mirena IUS inserted (9 mild, 4 moderate, 2 severe discomfort); one removed for early bleeding; 7 had spotting, 7 had no vaginal bleeding. Mirena IUS removed at 6 months: 8 biopsies showed pseudodecidualisation of endometrium. 5 opted to continue with Mirena IUS..  '    ,         Questions  Does the Mirena IUS prevent EC in HNPCC? What is the age-related risk of atypical endometrial hyperplasia and cancer in HNPCC How effective is surveillance? Satisfaction and compliance Psychological effects Adverse effects?&     Mirena IUS randomised trial  Baseline clinical exam., U/S and biopsy If normal, randomise into Mirena IUS for 4y, or control (with surveillance). U/S and pipelle biopsy annually POMS questionnaire at baseline and 2y Annual questionnaire re hormone exposure, satisfaction and health.@B  6  z  Trial plan  Ascertain women (with an intact uterus) aged between 35-65y: either proven HNPCC mutation carriers, or women with CRC or other HNPCC-related cancer from an Amsterdam-positive family Exclude women on chemotherapy, those planning pregnancy or pregnant, those planning hysterectomy  # "!Outcomes  Detection of AEH or EC. (Path. checked in one centre). Abnormalities on U/S Sensitivity and specificity of screening Adverse effects Psychological parameters Rate of therapeutic hysterectomy   /4 ` ̙33` ` ff3333f` 333MMM` f` f` 3>?" dd@,|?" dd@   " @ ` n?" dd@   @@``PR    @ ` ` p>> $(    6Ϧ P  T Click to edit Master title style! !  0Ѧ   RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  0ئ ``  X*  0ܦ `   Z*  0P `   Z*H  0޽h ? Default Design0 zr (    0tL P   L P*    0ЪL    L R*  d  c $ ?  L  0L  0 L RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  6̲L _P  L P*    6L _  L R*  H  0޽h ? 3380___PPT10.dt  :2(    0\I] Z  ] Z*   6] Z  ] Z*   6] KC ] Z* H  0޽h ? 3380___PPT10.dou % 0(  l  C {Lp L l  C {L `   L H  0޽h ? ̙33y___PPT10Y+D=' = @B +a  P(  l  C LP  L l  C L L H  0޽h ? y___PPT10Y+D=' = @B +a  @ (   l  C LP  L l  C L 0 L H  0޽h ? y___PPT10Y+D=' = @B +a  `\( ? \l \ C 8LP  L l \ C  L L H \ 0޽h ? y___PPT10Y+D=' = @B +a  ( ]g l  C xLP  L l  C 0L L H  0޽h ? y___PPT10Y+D=' = @B +a  (  l  C ,\P  \ l  C \ \ H  0޽h ? y___PPT10Y+D=' = @B +a  (  l  C |\P  \ l  C  \` \ H  0޽h ? y___PPT10Y+D=' = @B +a  (  l  C 8\P  \ l  C  \ \ H  0޽h ? y___PPT10Y+D=' = @B +a  `(  `l ` C |%\P  \ l ` C P&\ \ H ` 0޽h ? y___PPT10Y+D=' = @B +a  @X( c@ Xl X C t1\P  \ l X C 4\P \ H X 0޽h ? y___PPT10Y+D=' = @B +a  `( S l  C :\P  \ l  C :\ \ H  0޽h ? y___PPT10Y+D=' = @B +a  p( `   l  C C\P  \ l  C D\ \ H  0޽h ? y___PPT10Y+D=' = @B +a  (  l  C LJ\P  \ l  C  K\ \ H  0޽h ? y___PPT10Y+D=' = @B +a  x( # xl x C @R\P  \ l x C S\ \ H x 0޽h ? y___PPT10Y+D=' = @B +a  ( > l  C Z\P  \ l  C x[\ \ H  0޽h ? y___PPT10Y+D=' = @B +a  |( j |l | C c\P  \ l | C d\ \ H | 0޽h ? y___PPT10Y+D=' = @B +- &--P\\,(  F @@  @@  04m\@@ HMutation present and/or satisfies Amsterdam/ modified Amsterdam criteriaI 2I  I `  0@ F `    `   0pq\`   ]Satisfies POET criteria 2   `  0`  F 0   @    0u\0  cAgrees to participate in POET 2   `   00P oF P P    l    0Hz\P P  IYes 2   `   0P P@ nF @  l  0~\@ HNo 2   `  0@uF P 0`   8 H :  0(\P 0`  O Randomise 2    `  0P 0 F P  P  0ԇ\P ZProphylactic surgery 2   `  0PzF `   2  0\x TScreening only 2   `  0`F       0,\  .Baseline TVS and pipelle and menstrual history/ 2/ &   `  0 rF  pZ       00\ pZ  LNormal 2   `  0 @P F     % 0   ! 0\  l&Review in clinic with results and POMS' 2'  ' ` " 0  F    #    $ 0\   :Review annually with TVS +/- pipelle and menstrual chart. ; 2; &   ` % 0  F @J &  2 ' 0\@J ZMirena and screening 2   ` ( 0@@F  p  )  @  * 0Ȩ\ p  .Baseline TVS and pipelle and menstrual history/ 2/ &   ` + 0 @ F    ,    - 0\   ZAbnormal/ suspicious 2   ` . 0  F   /   0 0\  eSubmucous fibroid 2     ` 1 0 rF    2 3 pP  3 0l\   LNormal 2   ` 4 0  F    5  8H  6 0̻\   ZAbnormal/ suspicious 2   ` 7 0  F  pj  8  pj  9 0x\ pj  HRefer to gynaecological oncologist for discussion +/- further managementI 2I  I ` : 0 @` F  @ :  ; I P pC  < 0t\ @ :  {5Review in clinic with results and POMS. Insert Mirena6 26  6 ` = 0 @ 0 F    >  8   ? 0@\   8Review annually with TVS +/- pipelle and menstrual chart9 29 &   ` @ 0  F    A  `   B 0<\ j  HRefer to gynaecological oncologist for discussion +/- further managementI 2I  I ` C 0  RB D s *D  RB E s *D  0RB F s *D  RB G s *D  RB H@ s *D0 RB I s *D0 `RB J s *D@RB K s *D  RB L@ s *D0 p RB M s *D0  RB N s *D00RB O s *D 00 RB P@ s *DRB Q s *DPRB R s *D 00@ RB S s *D0 00 RB T@ s *D0 `0 RB U s *D `` RB V s *D  RB W s *D  RB X s *D  F P @  Y @ P  Z 0\P @  p,If unsuitable for Mirena, then screening arm--  - ` [ 0P @ RB \ s *D p p @ H  0޽h ? ̙33y___PPT10Y+D=' = @B +|$ ##FF3#(  F 0V   V0   0\0V  LEndometrial thickness >12mm in second week of cycle or irregular endometriumMM  M `  00`P F p= k  p k  0$\q= k p,Pipelle within 2-4 weeks if not done already--  - `  0p `F  =    P    0 \-=  =Inadequate. Failure to perform. Atypical hyperplasia or worse>>  > `   0  pF H = [    `  Z    0\H = [  g#Hysteroscopy and endometrial biopsy$$  $ `   0` ` P F  = `    = `   0`\ = ^  AAtypical hyperplasia or worse. Failure to gain entry into cavity.BB  B `  0 ` F } m    }m   0L\} m  g#Review by gynaecological oncologist$$  $ `  0 F V0P  V0P  0]V0P w3Endometrial thickness <12mm in second week of cycle44  4 `  0`PF #  #  0]# rSatisfactory pipelle &    `  0@zF S:   S:   0 ]S:  TAnnual screening   `  0p0 F @     I   0]S   }No abnormality or no curettings  &    `  0@ p zF S *     S*  ! 0]S *  TAnnual screening   ` " 0p   # <]D W {5Management of abnormal results in premenopausal women66 6 F &p $ J % <h]&p VTransvaginal scan    ` & 00pRB '@ s *DzF S *  ( p@p  ) 0 ]S *  TAnnual screening   ` * 0p  RB +@ s *D  RB , s *D  RB - s *DRB . s *DPpRB / s *DpRB 0 s *D` RB 1 s *Dp` RB 2 s *DP  RB 3 s *D`  F &p 4 J 5 < (]&p VMenstrual history   ` 6 00pF   7 V P 8 0-]  `Irregular cycles, IMB or PMB   ` 9 0 RB :@ s *DP F 6`f  ; V6f < <1]6f  Q Regular cycle   ` = 0@`P zF S *  > p@  ? 0T6]S *  TAnnual screening   ` @ 0p  RB A s *D ``pRB B@ s *D@ P0RB C s *D@P`0RB D@ s *D@`RB E s *D@`S F <;]f; Note. 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