Surgical treatment of endometriosis: a prospective randomized double-blinded trial comparing excision and ablation

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1 Surgical treatment of endometriosis: a prospective randomized double-blinded trial comparing excision and ablation Martin Healey, M.D., W. Catarina Ang, M.B., B.S., and Claudia Cheng, M.B., B.S. Royal Women s Hospital, Melbourne, Victoria, Australia Objective: To compare reduction of pain following laparoscopy after ablation or excision of endometriosis. Design: A prospective, randomized, double-blind study. Setting: Endometriosis and pelvic pain clinic at a university teaching hospital. Patient(s): Women of reproductive age presenting with pelvic pain and visually proved endometriosis. Intervention(s): Subjects completed a questionnaire rating their various pains using visual analogue scales (VASs). After visual identification subjects were assigned randomly to treatment with ablation or excision by supervised training gynecologists as primary surgeon. Follow-up questionnaires at 3, 6, 9, and 12 months documented pain levels. Main Outcome Measure(s): Change in overall pain VAS score at 12 months after operation. Result(s): There was no significant difference in reduction in overall pain VAS scores at 12 months when comparing ablation and excision. Conclusion(s): This study has not been able to demonstrate a significant difference in pain reduction between ablation and excisional treatments. Nonsignificant trends suggest that a larger study may find a difference in outcomes looking at dyspareunia or dyschezia. (Fertil Steril Ò 2010;94: Ó2010 by American Society for Reproductive Medicine.) Key Words: Endometriosis, excision, ablation, laparoscopy, pelvic pain Endometriosis occurs in approximately 70% of patients with chronic pelvic pain (1). There are medical and surgical treatment options for endometriosis. However, surgery is required to diagnose the condition, and surgical treatment of endometriosis often is used when medical treatment fails or produces unacceptable side effects or if fertility is desired (as most medical treatment will suppress ovulation). Initial treatment of endometriosis by pioneers such as Sampson (2) and Cullen (3) involved surgical excision of diseased tissue with use of scalpels and scissors. The advent of laparoscopy resulted in a less morbid means of diagnosis for endometriosis. This was followed by innovative use of both laser and diathermy via laparoscopic instrumentation to ablate endometriosis. More recently, steady improvement in both laparoscopic instrumentation and surgical technique has led to the use of scissors, laser, diathermy, and even ultrasound (4) as cutting tools for endometriosis excision. Wood and Maher (5), in presenting outcome data from 20 subjects undergoing laparoscopic peritoneal endometriosis excision, called for controlled trials comparing such excision with ablation techniques. At present gynecologists performing laparoscopic treatment of endometriosis tend to be divided into those who ablate and those who excise. Increasingly claims are being made within the popular Received November 9, 2009; revised and accepted February 18, 2010; published online March 31, M.H. has nothing to disclose. W.C.A. has nothing to disclose. C.C. has nothing to disclose. Supported by grants from the Australian Gynaecological Endoscopy Society Research Foundation, the L.E.W. Carty Charitable Fund, and the Royal Women s Hospital Foundation. Presented in part at the 10th World Endometriosis Conference, Melbourne, Victoria, Australia, March 11 14, Reprint requests: Martin Healey, M.D., 24 Erin St., Richmond, Victoria 3145, Australia (FAX: ; mghealey@optusnet. com.au). press and on the Internet that one method is better than the other. Unfortunately, the medical literature does not provide evidence to either support or refute such claims (6). The current study aims to inform this discussion in part by comparing the effects of these two treatment methods on subject pain scores. In contrast to surgical treatment of general endometriosis, the treatment specifically of endometriomas already has been assessed in a number of prospective randomized trials. These studies have been the subject of a Cochrane meta-analysis, which concluded that excision of endometriomas result in better symptom relief and lower recurrence rates than treatment with drainage and ablation (7). MATERIALS AND METHODS This study was a prospective randomized double-blinded trial aiming to assess for superiority between two laparoscopic treatments of endometriosis. The null hypothesis was that there was no difference in overall pain visual analogue scale (VAS) scores between the two treatment groups at 1 year after operation. The site of this study was a university teaching hospital. Operators for this study were gynecology trainees. They were supervised by consultant gynecologists with specific expertise in the particular treatment to which the subject was assigned randomly. The gynecologist would complete the operation if the trainee did not have the necessary expertise. Subjects were women recruited from an outpatient setting with pain symptoms suggestive of endometriosis (dysmenorrhea, deep dyspareunia, or cyclic pelvic pain) who had been booked for an operative laparoscopy. Recruitment occurred between July 2001 and September To be included subjects had to provide informed consent, speak English, not be using or planning to use continuous hormonal therapy, and be R18 years of age. At laparoscopy each recruited subject s pelvis and abdomen were assessed for the presence of visible endometriosis. Subjects were excluded if [1] there was no obvious endometriosis or [2] there was obvious endometriosis involving the muscle levels of bowel, bladder, or ureter. For the first year of each consultant s involvement in the study a second consultant was present to 2536 Fertility and Sterility â Vol. 94, No. 7, December /$36.00 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 FIGURE 1 Flowchart of participants flow from recruitment to 12 months after operation. Patients Recruited N=335 Not Suitable N=157 At Laparoscopy Suitable for Study N=178 Ablation N=89 Randomized Excision N=89 Initial Exclusions N=0 Randomization envelope lost N=1 N=4 Pre-operation questionnaires not returned N=3 Exclusions by 12 months N=25 12 month questionnaires not returned N=21 N=5 Pregnancy N=4 N=1 Further surgery N=2 N=6 Continuous hormonal treatment N=5 Ablation N=49 Comparison Groups at 12 months Excision N=54 ensure consistency in diagnosis. Each subject s endometriosis was scored and staged with use of the revised American Fertility Society (AFS) system (8) and also using the superficial/deep categorization (9) at the end of the operation. Randomization of subjects occurred intraoperatively at the time of surgery once endometriosis was diagnosed visually and after evaluation of the pelvis confirmed no involvement of rectal, ureteric, or bladder muscle. Treatment of all recognized endometriosis then was performed by a trainee gynecologist while supervised and assisted by the consultant gynecologist with expertise in the chosen treatment method. The power calculation assumed a base reduction in overall pain VAS score of 3.7 (estimated from the reduction in mean VAS pain score at 6 months in Sutton s study in 1994 [1]); a clinically significant difference between groups being a change of VAS score of 1.0; an SD of 2.0; and a power of 80% and alpha value of 5%. The calculated sample size was N ¼ 49 in each group. To allow for wastage a sample size of 120 (60 in each group) was chosen. Because an interim analysis demonstrated a subject loss of 35% at 1 year, the sample size was increased to 180 to compensate. Treatment randomization was performed with use of a computer random number generator, and the results were placed in consecutively numbered opaque envelopes. Both the subjects and the medical staff performing follow-up care were blinded to the type of treatment. A questionnaire assessing pain types and severity was completed by subjects before surgery and then every 3 months for a year. Pain severity was measured by use of VASs made up of a 10-cm line marked with no pain at the left end and worst imaginable pain at the right end. The VAS lines were measured to the nearest millimeter. Scores were presented as a range from 0 to 10. Occurrence of further surgery, pregnancy, or use of continuous hormonal therapy was noted. Data were entered on a Microsoft Access 2000 database (Microsoft, Redmond, WA). Analysis of the data was performed with use of SPSS version 11.5 (SPSS, Inc., Chicago, IL) and Epi Info version (Centers for Disease Control and Prevention, Atlanta, GA). Proportions were compared with c 2 testing. Continuous variables were compared with use of the t-test for independent variables and Welch s t-test if the assumption of equal variance was not met. Medians were used to describe revised AFS scores, and comparison was with the Mann-Whitney U test. Differences were considered significant if P<.05. This study was approved by the Research and Ethics Committees of the Royal Women s Hospital, Melbourne. RESULTS A total of 335 subjects were recruited and underwent laparoscopy. Of these 178 subjects were assigned randomly to ablation (N ¼ 89) and excision (N ¼ 89). Of the 157 subjects not randomized, Fertility and Sterility â 2537

3 TABLE 1 Comparison of demographic variables on included subjects at 12 months (ablation N [ 49 vs. excision N [ 54). P value Age (y) 28 (6.5) 28 (6.4).78 Weight (kg) 75 (70) 66 (14).38 Children 0.2 (0.5) 0.4 (0.9).15 a Times pregnant 0.7 (1.2) 0.7 (1.0).97 Smoker 25/54 23/49.95 Cigarettes per day 5.7 (7.6) 4.9 (7.0).56 Relatives with E 13/54 13/49.77 Past surgery for E 14/54 16/49.45 Past medications for E 20/54 12/49.17 Note: E ¼ endometriosis. a Equal variance not assumed. 20 had endometriosis involving rectum, bladder, or ureter muscularis; 36 had possible endometriosis confirmed on histology; and 101 did not have endometriosis. There were 20 initial study violations. One subject s randomization was lost, seven subjects did not return the preoperation questionnaire, six subjects had a progestinreleasing device inserted during or after the laparoscopy, five subjects had disease too severe for the study and so had incomplete treatment, and one subject was treated partly by excision when randomized to ablation. The subjects with a missing randomization envelope or preoperation questionnaire were excluded from analysis (n ¼ 8). The remainder were included as this was an intention to treat study (ablation N ¼ 85 and excision N ¼ 85). There were additional exclusions of subjects who did not return the 12-month postoperation questionnaire, pregnant subjects, and subjects who had further medical or surgical treatment for endometriosis. Figure 1 summarizes the number of subjects recruited in this study, their participation, and rates of exclusion. Demographic variable data for the included subjects at the 12- month postoperation analysis are shown in Table 1. No significant differences were found when demographic factors and preoperation VAS pain scores were compared between subjects included at the 12-month analysis and those excluded. The number of subjects with revised AFS stage I endometriosis for ablation and excision groups respectively was 18 and 10, stage II was 24 and 28, stage III was 6 and 9, and stage IV was 0 and 4. Four subjects had not been staged. Median revised AFS scores (95% confidence interval) were 10 (2 53) for the excision group and 7 (1 33) for the ablation group. This difference was significant (P¼.014), Using the superficial/deep classification, 28/53 (53%) of the excision group and 11/49 (22%) of the ablation group had deep infiltrating endometriosis (significantly different P¼.002). Of the excision group 46/53 (87%) subjects had positive histology for endometriosis. When stratified on disease depth, 19/26 (76%) of superficial disease and 27/28 (96%) of deep disease had positive histology. The reduction of VAS score from preoperation to 12 months after operation has been used for comparison between the ablation and excision groups. This helped to reduce any effect differences in preoperation scores between the two groups might have had. These data are shown in Tables 2 and 3. Dyspareunia, rectal pain, and defecation pain all show a nonsignificant trend toward a greater reduction in the excision group. Subjects were stratified on the basis of revised AFS stage (stages 1 and 2, stages 3 and 4). No significant differences were found in reductions in VAS scores between the excision and ablation groups within these strata. Subjects also were stratified on the basis of the superficial/deep classification. Again, no differences were found in changes in VAS scores between the two treatment groups. In particular, no differences were noted in VAS score changes between subjects with deep endometriosis undergoing excision and ablation. DISCUSSION Laparoscopy has revolutionized the diagnosis and treatment of endometriosis. Magnification allows better recognition, while modern instrumentation has allowed effective disease treatment, with the advantages of swifter recovery and fewer complications. Energy sources used to treat endometriosis include diathermy, laser, and ultrasound. The choice of instrument, technique, and energy source varies according to a surgeon s preference, which may be dictated by prior training, as well as availability. Generally, surgical treatment may be divided into ablation or excision techniques. The ability to treat endometriosis laparoscopically either by ablation or by excision has led inevitably to polarization of operators to support one treatment method or the other. There is evidence for symptomatic relief with use of excisional treatment. Abbott et al. (10) performed a placebo-controlled blinded crossover trial comparing laparoscopic endometriosis excision with placebo in 39 subjects. They found that by 6 months 80% of the excision group had symptom improvement compared with only 32% in the placebo group. Abbott et al. (11) also published a cohort study that included the subjects mentioned above. Follow-up varied from 2 to 5 years and demonstrated continuing reduction from baseline pain scores. Their subject group included 41% with revised AFS stage IV disease. In contrast, Jarrell et al. (12) performed a placebocontrolled trial of endometriosis excision in 30 subjects and found a significant reduction in symptoms in both cases and controls but no difference between the two groups. There is also evidence for the role of ablative treatment in the landmark study by Sutton et al. (13), who used laser ablation and achieved significant pain reduction for at least 6 months after operation. This study looked at overall pain levels and did not investigate specific pain types such as dysmenorrhea or dyspareunia. There are few descriptive data regarding the technique of performing ablation, including energy modality (bipolar diathermy, monopolar diathermy, ultrasound, and laser), duration of application of energy, power settings, or type of instrument used. The current study did not attempt to address this, instead allowing individual consultants to use their preferred method for ablation. In 2005 a prospective randomized pilot study by Wright et al. (14) was unable to demonstrate a difference between the two surgical methods of laparoscopic endometriosis treatment but suffered from a small sample size (N ¼ 24). The study standardized the type of energy source used and the power settings. This study was specifically limited to patients with mild endometriosis (revised AFS stage I and II), as the authors did not believe that electrocoagulation was a suitable treatment modality for nodular or deep infiltrating disease. In our study, there was a significantly greater proportion of patients assessed as having a higher revised AFS stage and deep 2538 Healey et al. Endometriosis: ablation versus excision Vol. 94, No. 7, December 2010

4 TABLE 2 Comparison of preoperation and postoperation VAS scores (ablation N [ 49 vs. excision N [ 54). preoperation postoperation preoperation postoperation T-test P value a Overall pain 5.5 (2.8) 2.4 (3.1) 6.2 (2.5) 3.2 (3.2).17 Pelvic pain 6.0 (3.0) 3.2 (3.3) 6.8 (1.7) 4.0 (3.2).13 b Period pain 6.4 (2.8) 3.8 (3.3) 7.1 (2.6) 4.8 (3.2).19 Back pain 4.7 (2.8) 3.0 (3.3) 5.5 (2.8) 4.3 (3.3).19 Rectal pain 2.8 (3.4) 1.2 (2.4) 2.3 (2.8) 1.7 (2.4).47 b Thigh pain 2.7 (3.2) 1.8 (2.9) 2.1 (2.7) 1.7 (2.5).26 Abdominal pain 5.3 (3.1) 2.7 (3.4) 5.9 (2.7) 4.0 (3.2).27 Defecation pain 3.6 (3.4) 1.8 (2.8) 2.9 (3.0) 2.3 (3.0).30 Voiding pain 1.2 (1.8) 0.6 (1.5) 1.7 (2.4) 0.9 (1.8).27 Nausea 3.3 (3.0) 1.3 (2.0) 3.2 (2.7) 2.4 (3.0).97 Abdominal bloating 5.9 (2.8) 3.4 (3.2) 5.8 (2.5) 4.1 (3.2).78 Vomit 1.6 (2.4) 0.5 (1.1) 1.4 (2.1) 0.5 (1.4).73 Dyspareunia 5.6 (3.5) 1.9 (2.5) 5.2 (3.3) 3.3 (3.2).56 a T-tests compare preoperation excision and ablation data. b Equal variance not assumed. infiltrating disease in the excisional group compared with the ablation group. Exclusion criteria included endometriotic involvement of viscera such as bowel and bladder, and this occurred at the initial assessment of the pelvis during the diagnostic aspect of the laparoscopy. However, final scoring and staging were completed at the end of the procedure. It is possible that higher scores occurred in the excisional group because some deep infiltrating endometriosis was not obvious until dissection was undertaken. This would mean that such disease would not be identified in the ablative procedure, leading to falsely lower revised AFS scoring. The exclusion criteria of visceral muscle involvement encompass higher revised AFS scores, even though these do not always correlate with degree of pain. Nonetheless, as with Wright et al. (14), there was a concern that ablation would not be effective in treating pain in this group of patients with severe bulky disease. This reflects an ongoing concern that ablation techniques destroy surface disease but leave endometriotic lesions in deep tissue intact and untreated. The current trial is the first adequately powered study that attempts to answer the question Is either ablation or excision superior for treatment of endometriosis-related pain? It has been unable to reject the null hypothesis and so has not proved a difference in overall pain reduction between the two treatments. This is not the same as proving that the two treatments are equal. The assumed SD (in change of overall pain VAS score) used in the sample size calculation for the current study has proved to be smaller than reality, resulting in a smaller than needed sample size. In addition the current study has suffered from a high rate (26%) of subjects failing to complete postoperation questionnaires. This may reflect a low socioeconomic population or alternatively may have been influenced by only partial funding resulting in significant turnover in staff managing subject follow-up. If a further study is done, a larger sample size of approximately 160 subjects per arm would be needed (power 0.8, alpha 0.05, SD 3.1 and 2.9, difference 1.0 not allowing for dropouts), and the design specifically should explore differences in dyspareunia and rectal symptoms between these two treatments (a secondary aim in the current study that was not taken into account when calculating sample size). The sample size would have to be increased further to reflect the failure of subjects to return follow-up questionnaires in the population being studied. In the current population the 26% failure would require approximately 220 subjects per arm. The nonsignificant trend for greater reduction in pain VAS scores with sex and defecation after excision is consistent with findings by Chapron et al. (15) that linked these symptoms to deep infiltrating endometriosis, the disease suspected of being most likely to be undertreated by an ablation technique. The literature has many case series and even prospective randomized trials where surgery is performed by a single international leader in endometriosis treatment. This results in outcomes that often cannot be extrapolated to the majority of gynecologists. TABLE 3 Reduction in VAS score by 12 months after operation. T-test P value Overall pain 2.9 (3.4) 2.9 (2.9).93 Pelvic pain 2.6 (3.5) 2.7 (2.7).94 Period pain 2.4 (3.9) 2.0 (3.9).69 Back pain 1.6 (3.9) 1.1 (2.9).49 a Rectal pain 1.4 (3.7) 0.5 (2.7).22 Thigh pain 0.9 (2.9) 0.4 (3.0).46 Abdominal pain 2.4 (3.1) 2.0 (3.7).60 Defecation pain 1.8 (3.5) 0.7 (3.1).16 Voiding pain 0.4 (2.3) 0.6 (2.7).70 Nausea 1.7 (2.7) 0.6 (3.6).13 Abdominal bloating 2.4 (3.4) 1.5 (2.8).21 Vomiting 1.1 (2.4) 0.9 (2.3).60 Dyspareunia 3.1 (4.1) 1.8 (4.1).17 a Equal variance not assumed. Fertility and Sterility â 2539

5 In addition, an individual operator s skill set (accumulated often as a result of personal preference) can introduce a significant bias in outcome if comparing a preferred treatment with an unpopular alternative. The current study attempted to negate these effects by making the operators trainees (the usual situation in teaching hospitals) and providing them with supervisors who were advocates for the specific treatment to be performed. Subject outcomes therefore may not be as excellent as some in published studies but truly reflect those achievable by a general gynecologist. In conclusion, this study has shown that general gynecologists are justified in using ablation techniques for treating superficial endometriosis. The results raise the question Is deeply infiltrating endometriosis better treated with excision than ablation?, but as always a further study is needed to answer this. Acknowledgments: This study was achieved as a team effort. Year 1 gynecology trainees recruited subjects. The gynecology laparoscopy fellows (Sharon Moss, Philip Thomas, Annie Leong, Anne Poliness, Alex Eskander, Catarina Ang, Leah Xu, and Claudia Cheng) performed data entry and managed follow-up. The gynecology consultants of the Gynecology 2 Unit (Amber Moore, Huon O Sullivan, Peter Wein, Peter Jurcevic, Kym Jansen, Alex Ades, Martin Healey, and previous fellows) supervised trainees performing the laparoscopic operations central to this study. Three further gynecology consultants (Geoffrey Clarke, Raphael Kuhn, and Jeffrey Tan) supported this study at its inception so that it became reality. REFERENCES 1. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril 2008;90 (5 Suppl):S Sampson JA. Perforating hemorrhagic (chocolate) cysts of the ovary. Arch Surg 1921;3: Cullen TS. The distribution of adenomyomas containinguterine mucosa. Arch Surg 1920;1: Robbins ML. Excision of endometriosis with laparosonic coagulating shears. J Am Assoc Gynecol Laparosc 1999;6: Wood C, Maher P. Peritoneal surgery in the treatment of endometriosis excision or thermal ablation? Aust NZ J Obstet Gynaecol 1996;36: Yeung PP Jr, Shwayder J, Pasic RP. Laparoscopic management of endometriosis: comprehensive review of best evidence. J Minim Invasive Gynecol 2009;16: Hart RJ, Hickey M, Maouris P, Buckett W. Excisional surgery versus ablative surgery for ovarian endometrioma. Cochrane Database Syst Rev 2008;2. CD American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: Fertil Steril 1997;67: Koninckx PR, Martin D. Treatment of deeply infiltrating endometriosis. Curr Opin Obstet Gynecol 1994;6: Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril 2004;82: Abbott JA, Hawe J, Clayton RD, Garry R. The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2 5 year followup. Hum Reprod 2003;18: Jarrell J, Brant R, Leung W, Taenzer P. Women s pain experience predicts future surgery for pain associated with endometriosis. J Obstet Gynaecol Can 2007;29: Sutton CJG, Ewen SP, Whitelaw N, Haines P. Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 1994;62: Wright J, Lotfallah H, Jones K, Lovell D. A randomised trial of excision versus ablation for mild endometriosis. Fertil Steril 2005;83: Chapron C, Barakat H, Frittel X, Dubuisson JB, Breart G, Fauonnier A. Presurgical diagnosis of posterior deep infiltrating endometriosis based on a standardized questionnaire. Hum Reprod 2004;20: Healey et al. Endometriosis: ablation versus excision Vol. 94, No. 7, December 2010