Pre and post surgical medical therapy Mauro Busacca M.D. Dept of Obstetrics and Gynecology University of Milan- Italy
introduction A disease is an open problem when two conditions are nor satisfied: The knowledge of ethiopatogenesis The absence of recurrence Both these problems are unsolved in endometriosis
Trattamento dell endometriosi recidivante The rate of recurrence of endometriosis after treatment has varied from 2% to 47% in published reports. 423 patients treated with conservative surgical procedures 62 patients underwent reoperation. Recurrence rate, based on findings at reoperation, ranges from 0.9% at one year, to 13.6% in the eighth postoperative year. The cumulative 3- and 5-year recurrence rates were 13.5% and 40.3%, respectively. Severity of disease was not predictive of recurrence Pregnancy did not preclude, but did delay, recurrence. Wheeler JM. Am J Obstet Gynecol 1983; 146(3):247-53
Trattamento dell endometriosi recidivante Cumulative pain recurrence in 740 women with endometriosis
Trattamento dell endometriosi recidivante Recurrence rate after conservative treatment for Deep Endometriosis Author N. OF PTS FU (mos) % Redwine, 2001 67 50 34 Abbot, 2003 135 60 36 Varol, 2003 169 35 36 Fedele, 2004 83 36 34 Redwine DB, Wright JT. Fertil Steril 200;76(2):358-65 Abbott JA et al. Hum Reprod 2003;18(9):1922-7 Varol N et al. J Am Assoc Gynecol Laparosc 2003;10(2):182-9 Fedele et al. Am J Obstet Gynecol 2004;190:1020-4
Actuarial pain recurrence rate (%) 35 30 25 20 15 10 5 0 0 6 12 18 24 30 36 Time (months) Pain recurrence in deep endometriosis Vignali M. J.M.I.G., 2005
Trattamento dell endometriosi recidivante Predictive factors of pain recurrence in 740 patients with stage III-IV Endometriosis Factor Odds ratio (95% CI) Pregnancy 0.3 (0.15-0.65) Age* 2.1 (1.01-4.5) Radicality 0.4 (0.23 0.71) *Age <25 years vs >30 years Busacca M. unpublished data
Rate of pain recurrence Trattamento dell endometriosi recidivante Recurrence of pain according to disease stage at surgery 60 50 40 30 20 10 0 Stage III Stage IV 0 3 6 9 12 15 18 21 24 Time Busacca M et al. J Am Assoc Gynecol Laparosc 1999;6(1):55-8
Risk factors for Recurrence Trattamento dell endometriosi recidivante rafs score of >70 was predictive of requiring further surgery (P = 0.03) Abbott JA et al. Hum Reprod 2003;18(9):1922-7
Pre-operative treatment rationale To reduce the volume of endometriomas To reduce vascularization To facilitate intervention
Impact of preoperative gonadotrpin-realising hormone agonist treatment on laparoscopic excision of ovarian endometriotic cysts Muzii L, Marana R, Caruana P, Mancuso S, Fertil.Steril. 1996 20 patients with unilateral endometrioma underwent operative laparoscopy after 3 month GnRHa treatment,whereas 21 patients underwent laparoscopic excision of endometriomas without preoperative medical treatment. Recurrence rate were evaluated at 1 year follow up ultrasonography. No significant difference was found in: Total operative time Cyst excision time Time needed for cyst capsule stripping Recurrence rate
Group 1: 6 months pre-treatment with GnRH analogues Group 2: prompt surgery
Gynaecological Endoscopy (2001) 10:151-157
Shaw et al, Gynecol Endoscopy 10, 151, 2001 GnRHa + Surgery Group 1 (n=21) Surgery alone Group 2 (n=27) Change in size (pre op) -2.29 cm 1.29 cm.036 Complete excision 72% 73% ns Minimal blood loss 61 ml 60 ml ns Mean operating time 72.2 min 86.4 min ns Moderate and 78% 92% ns high difficulty Recurrence (6 months) 10% 15% ns P
Canbaz MA et al, Eur J Obst Gynecol Rep Biol, 1999 Adhesion Score CONTROL (Group I) 2.7 + 0.26 RINGER L. (Group II) 1.4 + 0.27 LEUPROLIDE (Group III) 0.9 + 0.18 DILUENT (Group IV) 2.5 + 0.34 Group I vs II p <.01 Group I vs III p <.01 Group II vs III ns Group II vs IV p <.05
Pre operative treatment Adverse factors Limited reduction of endometriomas Under-extimation of the process More difficulty in dissection and clivage Delay in operation
Pain recurrence after combined surgicalmedical treatment Danazol No treatment (n = 31) (n = 29) Pain recurrence 7 (23%) 9 (31%) No pain recurrence 24 (77%) 20 (69%) X square adjusted for stage not significant Bianchi et al. Human Reproduction, 1999
Effects of 3 months therapy with Danazol after laparoscopic surgery for stage III/IV endometriosis: a randomized study S Bianchi, M Busacca, B Agnoli, M Candiani, C Calia, M Vignali Danazol No treatment (n = 36) (n = 41) Infertile patients 11 (31%) 18 (39%) Pregnancy rate 6/11 (55%) 8/16 (50%) at 12 months X square adjusted for stage not significant Bianchi S et al., Human Reproduction, 1999
Postoperative Gonadotropin-Releasing Hormone Analogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: a randomized study M. Busacca, E. Somigliana, S. Bianchi, S. De Marinis, C.Calia, M. Candiani, M. Vignali Controls GnRH analogue Number 45 4 Age (y) 31 (21-38) 28 (20-37) Previous pregnancy 10 (22%) 8 (18%) Stage III of 31 (69%) 28 (64%) endometriosis Stage IV 14 (31%) 16 (36%) Wanting children 15 (33%) 15 (34%) Hum Reprod. 2001 Nov;16(11):2399-402
Postoperative Gonadotropin-Releasing Hormone Analogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: a randomized study M. Busacca, E. Somigliana, S. Bianchi, S. De Marinis, C.Calia, M. Candiani, M. Vignali Controls GnRH analogue Follow-up (m) 20 (10-31) 18 (6-36) Cumulative Pain 29 23 Recurrence Rate at 18 months Cumulative 40 38 Pregnancy Rate at 18 months Objective disease 4 (9%) 4 (9%) recurrence Second surgery 0 2 (5%)
Muzii et al Am J Obst Gynecol 183:588, 2000 Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriosis. A prospective, randomized trial group 1 33 pz e/p follow up clinical and us group 2 35 pt control recurrence group 1 group 2 6,1% 2,9% n.s. pain recurrence 9,1% 17,1% n.s.
Am J Obstet Gynecol 2000;183:588-592
Estroprogestin vs GnRHa plus estroprogestin in the treatment of endometriosis related pelvic pain: a randomized trial Italian Endometriosis Study Group European Journal of Obstet.Gynecol.,1999 Dolore non mestruale( %) E/P GnRHa+E/P Arruolamento 97.9 89.1 8 mesi 42.9 44 12 mesi 38.5 37.9 Multidimensionale Arruolamento 3 2 8 mesi 0 0 12 mesi 0 0
Estroprogestin vs GnRHa plus estroprogestin in the treatment of endometriosis related pelvic pain. Gruppo Italiano per lo Studio dell Endometriosi European Journal of Obste.Gynecol. 1999 E/P GnRHa +E/P Dismenorrea si(%) Arruolamento 97.9 100 8 mesi 38.1 40 12 mesi 35.9 34.8 Multidimensionale Arruolamento 4 3 8 mesi 1 0 12 mesi 2 0
In one small randomized controlled trial (RCT) there was a statistically significant reduction in the recurrence of painful periods in the LNG-IUS group compared with the control group receiving a gonadotrophin-releasing hormone (GnRH) agonist (OR 0.14, 95% CI = 0.02 to 0.75). The proportion of women who were satisfied with their treatment was higher in the LNG-IUS group than in the control group but this difference did not reach statistical difference (OR 3.00, 0.79 to 11.44). There is a need for further welldesigned RCTs of this approach.
Retrograde menses, implantation of endometriotic cells Estrogen sicam-1 MCP-1 EGF Endometriotic implant growth VEGF, IL-6 IL-8, PGF 2 Implant neovascularization IL-1 TNF-a RANTES MCP-1 RANTES Interferon- MF IL-6 T & B lymphocyte activation IL-1 TNF-a Endometrial and/or blastocyst dysfunction (infertility) Autoantibodie s
Journal of Minimally Invasive Gynecology (2008) 15, 62 66
The Cochrane Database of Systematic Reviews The Cochrane Library, Copyright 2005, The Cochrane Collaboration Volume (3), 2005
THERE IS INSUFFICIENT EVIDENCE FROM THE STUDIES IDENTIFIED TO CONCLUDE THAT MEDICAL THERAPY FOR HORMONAL SUPPRESSION IN ASSOCIATION WITH SURGERY FOR ENDOMETRIOSIS IS ASSOCIATED WITH A SIGNIFICANT BENEFIT WITH REGARD TO ANY OF THE OUTCOME IDENTIFIED. PRESURGICAL MEDICAL THERAPY SHOWED SIGNIFICANT IMPROVEMENT IN AFS SCORES IN MEDICAL THERAPY GROUP BUT THIS MAY OR MAY NOT BE ASSOCIATED WITH BETTER OUTCOMES FOR THE PATIENTS