1. Surgical Treatment of Endometriosis: When is it worth the risk?
Tommaso Falcone MD
Cleveland Clinic Foundation

2. Attestation Disclosure to Audience Department of Obstetrics and Gynecology Grand Rounds February 5,2009 Tommaso Falcone, MD Surgical Treatment of Endometriosis
In accordance with the standards of the Accreditation Council for Continuing Medical Education (ACCME), all speakers are asked to disclose any real or apparent conflicts of interest or discussion of off-label use of product(s) or device(s). The ACCME also requires disclosure of any commercial support.
Today’s speaker disclosed: Consultant with Gynesonics.
Today’s speaker has one slide for off-label or investigational use(s) of a product or device: an off label use of the Mirena IUD/letrzole.
There was no commercial support for this program

3. Learning Objectives This session will:
Enable a physician to assess the outcome (pain relief or pregnancy) of surgical treatment for endometriosis.
Enable a physician to evaluate the value of postoperative medical therapy
Familiarize the physician with the different surgical techniques used to treat endometriosis

4. Symptoms & Signs of advanced endometriosis
Chapron et al 2005
“Presurgical diagnosis of posterior deep infiltrating endometriosis based on a standardized questionnaire”
Painful defecation during menses
Severe dyspareunia
Previous surgery for endometriosis

5. Diagnostic work-up
History ( dysmenorrhea, dyspareunia & noncyclic pelvic pain)
Physical exam: adnexal mass, non mobile uterus or cul-de-sac nodularity.
CA-125
Meta-analysis
Sensitivity of 28 % showed a specificity of 90%
Sensitivity of 50% showed a specificity of 72%

6. Role of Imaging
Transvaginal ultrasound has a high sensitivity & specificity in the diagnosis of ovarian endometriotic cyst
MR & CT have no added advantage
Trans-rectal ultrasound may have some value for recto-vaginal endometriosis (Fedele et al Obstet & Gynecol 1998)
Imaging has a low sensitivity & specificity for non-ovarian endometriosis

7. Imaging for advanced endometriosis
Ghezzi et al 2005
Ultrasound
Detection of “kissing ovaries” at ultrasound is strongly associated with severe endometriosis

9. Histologic diagnosis Mettler et al JSLS 2003
Histologic confirmation in visually identified endometriosis: 54%
“red” lesions: 100%
“black” lesions: 92%
“white” lesions:31%
Sites: least probable on the ovary, bowel serosa, bladder peritoneum

17. Treatment: Infertile Patient

20. Treatment effect
Treatment effect large enough to be clinically relevant?
Number needed to treat (NNT): number of subjects that must be treated to achieve one more outcome with intervention than control
NNT=1/Risk difference
Risk difference: Event rate treated group- Event rate control

21. Treatment effect Canadian study Italian study
N=172 treated & N=169 untreated
PR% 29% treated & 17% untreated
NNT= 1/.12=8.3
NNT=9, 95 % CI, 5,33
Italian study
N=54 treated & N=47 no treatment
PR% 22% & 28%

22. Treatment Effect
Canadian study PR for pregnancies more than 20 weeks of gestation, Italian study reported any pregnancies
Combine the studies for pregnancies over 20 weeks: 27% (treated) & 18% ( non treated): NNT=12 ( 95% CI 6,112)
20% prevalence of endometriosis
60 diagnostic laparoscopies to get an extra pregnancy

23. Moderate-Severe Endometriosis: Result of surgery
Candiani et al 1991
206 patients/15 studies: MFR:3%; CPR:47%
Luciano et al 1992:
MFR 6.7%; CPR 70%
Busacca et al J Am Ass Gyn L 1999
Prospective study; MFR: 2.4%; CPR 24 months 57%

24. Stage III&IV Endometriosis Pagidas et al Fertility & Sterility 1996

25. Stage III&IV endometriosis
After initial unsuccessful operative procedure to restore fertility , IVF-ET appears to be a superior alternative to re-operation

26. Impact of endometriosis on IVF outcome: Meta-analysis
22 studies ( 2377 with endometriosis & 4383 without endometriosis); Barnhart et al F&S 2002
Stage I & II- 21 % per cycle ( control 27.7%)
Decrease in implantation & fertilization rates
Stage III & IV –13.8 % per cycle ( control 27.7%)
Decrease in the number of oocytes retrieved

27. Endometriomas Drainage has a high recurrence rate
Need to excise the cyst
Cochrane database 2005 Hart R et al
Excision of cyst associated with a reduced rate of recurrence; reduced symptom recurrence and increased spontaneous pregnancy rates compared with ablative surgery

28. Endometriomas Jones & Sutton 39.5% PR/12 months
Most studies have shown no impact on endometriomas on IVF outcome
ESHRE recommendation: remove endometrioma >= 4 cm

29. Endometrioma surgery:Impact on IVF
Potential for decreased oocyte recovery
Outcome is dependent on technique
Minimize damage to the surrounding tissue

30. Treatment of Infertility:Medical Suppressive therapy
Meta-analysis
No benefit to pregnancy rates

31. Pain Management

32. Laser Laparoscopy vs Expectant Management Sutton et al Fertil Steril 1994
74 women ( Stage I-III)
Prospective randomized double blind
Significant pain relief compared to expectant management
Non response rate was 38 %
Results were poorest for Stage I

36. RCT scope excision of endo
Abbott et al F&S 2004
RCT-placebo trial
Immediate surgery group- 80 % response rate at 6 months
Far fewer stage I endometriosis
Delayed surgery group-30 % response rate at 6 months (placebo effect)

37. Recurrence Rate Sutton’s trial F&S 1994
Follow-up( 1 year) after RCT: Treated Group that Improved
10% recurrence rate
Subsequent surgery showed endometriosis
Abbott et al Human Reproduction 2003
135 patients Kaplan –Meier survival curve
Average follow up 3.2 years ( 2-5 years)
36 % probability of further surgery
32 % had no endometriosis

38. Reoperation free survival
Reoperation-Free Survival Estimates are Shown for Groups Defined by Surgery Type and Ovary Preservation
1.0 .8 .6
Reoperation free survival .4
Laparoscopy
Hysterectomy (ovaries preserved)
Hysterectomy (ovaries removed) .2 1 2 3 4 5 6 7
Years
Cleveland Clinic experience. Surgical Treatment of Endometriosis. Obstet Gynecol 2008.

39. Reoperation-Free Survival Stratified by Potential Factors Affecting Outcome
2 Years 5 Years 7 Years HR Versus
Factor Frequency (95% CI) (95% CI) (95% CI) (95% CI) Reference Overall
Overall ( ) 70.2 ( ) 63.1 ( ) NA
Surgery type Laparoscopic ( ) 54.1 ( ) 45.7 ( ) 1.0 <.001 Hysterectomy ( ) 89.2 ( ) 84.6 ( ) 0.20 ( ) <.001
Ovaries involved No ( ) 71.6 ( ) 64.5 ( ) Yes ( ) 68.8 ( ) 61.6 ( ) 1.12 ( ) .64
Colon involved No ( ) 72.9 ( ) 65.3 ( ) Yes (73.4) 65.2 ( ) 59.1 ( ) 1.21 ( ) .42
Disease stage I ( ) 70.6 ( ) 66.5 ( )
II ( ) 67.1 ( ) 58.5 ( ) 0.98 ( ) III ( ) 80.8 ( ) 73.3 ( ) 0.66 ( ) IV ( ) 67.9 ( ) 61.1 ( ) 0.97 ( ) .93
Race Other ( ) 63.8 ( ) 54.3 ( ) White ( ) 71.5 ( ) 65.1 ( ) 0.67 ( ) .15
Surgery age (y) ( ) 39.0 ( ) 31.7 ( ) 1.0 < ( ) 72.0 ( ) 62.0 ( ) 0.39 ( ) < or older ( ) 85.8 ( ) 83.5 ( ) 0.15 ( ) <.001

40. Reoperation-Free Survival Stratified by Potential Factors Affecting Outcome
2 Years 5 Years 7 Years HR Versus
Factor Frequency (95% CI) (95% CI) (95% CI) (95% CI) Reference Overall
Ages Overall ( ) 39.0 ( ) 31.7 ( ) NA Laparoscopy ( ) 33.3 ( ) 27.8 ( ) NA ovaries preserved
Ages Overall ( ) 72.0 ( ) 62.0 ( ) NA Laparoscopy ( ) 58.0 ( ) 43.8 ( ) ovaries preserved Hysterectomy ( ) 95.2 ( ) 89.6 ( ) 0.13 ( ) ovaries preserved Hysterectomy ( ) 85.7 ( ) 85.7 ( ) 0.23 ( ) ovaries removed
Ages 40 and older Overall ( ) 85.8 ( ) 83.5 ( ) NA Laparoscopy ( ) 76.2 ( ) 76.2 ( ) ovaries preserved Hysterectomy ( ) 80.4 ( ) 64.3 ( ) 1.00 ( ) ovaries preserved Hysterectomy ( ) 96.0 ( ) 96.0 ( ) 0.14 ( ) ovaries removed

41. Hysterectomy in young women ( less than 30 years of age)
Women under 30 ( compared with women over 40)
80 % felt that hysterectomy had “cured their pain”
18 % had residual symptoms of dyschezia
18 % persistent dysuria
50 % persistent dyspareunia
56 % had a “sense of loss”

44. Postoperative Medical Therapy
Yap C et al Cochrane Database 2004
Ineffective
Reason? The way it was given?
Vercellini et al 2008
Prevent recurrences of endometriomas while on the oral contraceptives.
Sesti F et al 2007
Vitamins, minerals, VSL3 lactic ferments, omega-3 and omega-6 fatty acids

45. Postoperative Medical Treatment
Telimaa et al Gynecol Endocrinol 1987 Danazol or medroxyprogesterone: no significant difference in pain scores
Hornstein et al Fertil Steril 1997
nafarelin 200ug BID; no significant difference in pain scores at 1 year post surgery; number of patients needing re-treatment within 2 years ( 57% placebo group & 31% nafarelin group)

46. Postoperative Medical Treatment
Parazzini et al Am J Obstet Gynecol 1994
Stage III & IV endometriosis
Placebo controlled trial, 3 months treatment nafarelin, no difference in pain scores at 12 months follow-up

47. Prevention of Recurrent Pain
To be effective you have to use them for long periods of time
Why would the effect be protective after discontinuing the drug?

48. Long term treatment of endometriosis
GnRH agonist ( leuprolide)
Treatment extended beyond 6 months if add back therapy used
Add back approved by the FDA: norethindrone 5 mg orally daily
Preservation of bone density
Other add backs:
CEE 0.625mg + MPA 5 mg daily

49. Other medical treatments
Depot-Provera SQ
Levonorgestrel-releasing intrauterine system ( Petta et al HR 2005)off label
Norethindrone mg daily without agonist
Anastrazole and oral contraceptive agent
Off label use

50. New drugs Oral GnRH antagonist SPRM ( asoprisnil)-clinical trials
COX-2 inhibitors
PPAR ( Peroxisome Proliferator Activated Receptors) agonists
TNF alpha inhibitors
HR 2008-RCT-no effect-30 % placebo effect

51. Endometriosis: Persistence after TAH+BSO
Often seen when endometrial implants not excised
Aromatase expressed in endometriotic lesions
Conversion of adrenal androgens to estrogen locally

52. LUNA procedure Randomized controlled trials
Sutton et al Gynaecol Endosc 2001
Vercillini et al Fert & Steril 2003
Proctor et al Cochrane Review, Issue 4, 2002
No evidence that LUNA adds value to conservative surgery for endometriosis associated pain.

57. Presacral neurectomy Tjaden et al Obstet Gynecol 1990
Value for midline pain at the time of menses
Few patients recruited
Zullo F et al AJOG 2003;189:5-10
All stages of endometriosis
141 patients double blind RCT
Improves the cure rate in women who are treated with conservative surgery for severe dysmenorrhea caused by endometriosis
Constipation (14% at 12 months) & Urinary urgency (5%)

58. Excision versus Ablation
Pregnancy rates similar
Pain relief?

65. Rectosigmoid Endometriosis:
Significant bowel symptoms
Colonoscopy or barium enema normal
May show a stricture
Persistent disease after TAH+BSO is usually recto-sigmoid endometriosis

66. Colo-rectal endometriosis
Superficial
Peritoneum
Serosa
Muscularis
Hypertrophy of muscle layer
Infiltration of levator muscles
Mucosa
Uncommon to penetrate the mucosa

67. Rectosigmoid Endometriosis: CCF experience
Journal of the American College of Surgeons: Dec 2002
51 patients (32-39 years of age)
Symptoms:
Dysmenorrhea (85%), dyspareunia(56%),rectal pain(41%),rectal bleeding(14%),bloating(29%), tenesmus(8%)

68. Surgical technique Excision of serosal implants
Disc resection of infiltrating disease
Segmental Bowel resection

73. Segmental Resection: Management of the proximal Bowel
Exteriorize the proximal bowel
Trans-rectally ( no longer used)
Trans-vaginally (occasionally)
Mini-laparotomy (most common)
Disease removed & anvil placed for EEA

77. Outcome Operating time:187 minutes LOS: 2 days
No postop NG tube & all start oral fluids same day
1/3 patients outpatients
7% conversion to laparotomy
Complications: 4 patients
1 Pyosalpinx,1 leak, antibiotic associated diarrhea
1 pneumonia

78. Catamenial Sciatica

79. Diaphragmatic endometriosis

80. Video