Department of Obstetrics and Gynaecology, Royal Surrey County Hospital, Guildford, United Kingdom

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1 FERTILITY AND STERILITY Vol. 62, No.4, October 1994 Copyright c 1994 The American Fertility Society Printed on acid-free paper in U. S. A. Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis* Christopher J. G. Sutton, M.B., B.Chir.t Simon P. Ewen, M.B., Ch.B. Naomi Whitelaw, M.B., B.S. Patricia Haines, B.Sc. (Hons) Department of Obstetrics and Gynaecology, Royal Surrey County Hospital, Guildford, United Kingdom Objective: To assess the efficacy of laser laparoscopic surgery in the treatment of pain associated with minimal, mild, and moderate endometriosis. Design: A prospective, randomized, double-blind, and controlled clinical study. Setting: Royal Surrey County Hospital, Guildford, United Kingdom, a referral center for the laser laparoscopic treatment of endometriosis. Patients: Sixty-three patients with pain (dysmenorrhoea, pelvic pain, or dyspareunia) and minimal to moderate endometriosis. Interventions: The patients were randomized at the time of laparoscopy to laser ablation of endometriotic deposits and laparoscopic uterine nerve ablation or expectant management. Pain symptoms were recorded subjectively and by visual analogue scale. The women were unaware of the treatment allocated as was the nurse who assessed them at 3 and 6 months after surgery. Main Outcome Measure: Improvement or resolution of pain symptoms assessed subjectively and by visual analogue score. Results: Laser laparoscopy results in statistically significant pain relief compared with expectant management at 6 months after surgery. Sixty-two and a half percent of the lasered patients reported improvement or resolution of symptoms compared with 22.6% in the expectant group. Results were poorest for minimal disease and, if patients with mild and moderate disease only are included, 73.7% of patients achieved pain relief. There were no operative or laser complications. Conclusions: Laser laparoscopy is a safe, simple, and effective treatment in alleviating pain symptoms in women with stages I, II, and III endometriosis. Fertil Steril1994;62: Key Words: Endometriosis, pelvic pain, laser laparoscopy Endometriosis is one of the most common gynecological disorders and is found in 10% to 25% of women undergoing laparotomy (1) and in a far higher proportion in women having a diagnostic laparoscopy. Although most published studies relate to infertility (2), the leading complaints from women Received November 26, 1993; revised and accepted May 12, * Supported by Birthright Research Grant (Ref:S3/90), Royal College of Obstetricians and Gynaecologists, London and Laserscope, Cwmbran, United Kingdom. t Reprint requests: Christopher J. G. Sutton, Consultant Gynaecologist, Royal Surrey County Hospital, Egerton Road, Guildford, Surrey, United Kingdom (FAX: ). suffering from this condition relate to pain. Even in the minimal and mild stages of the revised American Fertility Society (AFS) classification (3), dysmenorrhoea is reported in approximately 70% of women and intermenstrual pelvic pain and deep dyspareunia is reported in approximately 25% of women (4). Medical therapy has been the traditional therapeutic approach, although the observations of Evers (5), showing that the endometrial implants return within 2 months after cessation of a 6-month course of danazol, suggest that the suppressive effects of these drugs is often only temporary. For this reason there has been a discernable trend 696 Sutton et al. Laser laparoscopy for endometriosis

2 towards primary surgical treatment, and technological advances in laparoscopic surgery in recent years have allowed the surgeon to treat the disease at the same time the diagnosis is made. Laser laparoscopic ablation of endometrial deposits and associated adhesions has been one of the most exciting areas of development in endometriosis therapy since it was first reported by Bruhat (6). The published studies of laser laparoscopy for the treatment of endometriosis have claimed success in relieving pain in 60% to 70% of cases with very low morbidity (7-10). However, all of these studies are either retrospective or uncontrolled (11). The placebo effect of any treatment, especially those associated with new high-technology inventions such as lasers, can be significant, therefore the prospective, randomized, controlled trial with a sham (no treatment) arm is the cornerstone of clinical research and pivotal for determining the future treatment of endometriosis (12). This study was approved by the hospital Ethics Committee but they reasonably felt that it was unethical to withhold treatment from patients in severe pain due to stage IV disease, particularly because our previous experience had shown 80% pain relief in this group, most of whom had failed to respond to medical therapy (13). The aim of this study was to assess the efficacy of laser laparoscopy by the established scientific method of a prospective, randomized, double-blind, controlled trial comparing the results of those women with minimal to moderate endometriosis (AFS stages I to III) who were treated by the laser and those in the sham arm who had diagnostic laparoscopy alone. MATERIALS AND METHODS The study population was recruited from women seen in the gynecological outpatient clinic with pain suggestive of endometriosis who had been advised to undergo a diagnostic laparoscopy. To be included in the study women were neither pregnant nor lactating, were between 18 and 45 years of age, and had not received any treatment (medical or surgical) for endometriosis in the previous 6 months. The study was explained in detail and informed consent was obtained. Before the laparoscopy, patients were asked to record the intensity of their pain on a 10-cm linear analogue scale (14) marked from 0 to 10: 0 representing no pain at all and 10 representing the worst pain they had experienced in their life. Between March 1990 and February 1993, 74 women with pain and found to have stage I to III endometriosis of the revised AFS classification (3) were recruited. At the time of laparoscopy, treatment was allocated randomly (computer-generated randomization sequence) to laser or expectant management. Laser treatment included vaporization of all visible endometriotic implants, adhesiolysis, and uterine nerve transection with the C0 2 laser (NIC; Sigmacon, Herriots Wood, United Kingdom) or the potassium-titanyl-phosphate laser (Laserscope, Cumbran, United Kingdom) using a triple puncture technique as described previously (9). No treatment intervention was carried out in the women allocated expectant management, although it was necessary to remove the serosanguinous fluid from the Pouch of Douglas to perform a thorough inspection of the pelvic peritoneum. Patients were not informed of which treatment they had been allocated, with all the women having the same number of incisions (three). Patients were followed up at 3 and 6 months after surgery by im independent observer (research nurse) who also was unaware of the treatment that had been allocated. Patients were asked to complete a visual analogue score at each visit and asked how their pain had changed subjectively. At 6 months follow-up, the randomization code was broken and, if the patient had received expectant management, laser laparoscopy was offered. Efficacy was based on changes in the symptoms of dysmenorrhoea, dyspareunia, and pelvic pain reported subjectively and by visual analogue scale. The differences reported in pain relief between the laser-treated and expectant groups at 3 and 6 months follow-up were analyzed using the Fisher Exact test. The difference in visual analogue score between baseline and 3 months and baseline and 6 months was compared using the Mann-Whitney U test. This is a nonparametric test based on ranks, which does not require the differences to follow any particular distribution. To compare results of laser treatment for the three different stages of endometriosis, the x 2 test for trend was used. RESULTS Of 7 4 women who entered the study, 63 (32 laser, 31 expectant) completed the study to the 6-month follow-up visit. Of 11 patients for whom all data were excluded, 2 became pregnant before the final visit, 5 were started on hormonal contraception by their family doctor during the follow-up period, 1 Vol. 62, No.4, October 1994 Sutton et al. Laser laparoscopy for endometriosis 697

3 BQ, ~Laser c:::::::j Expectant 9 G> ~ 8.:: ~ 7 "'!!! 0 "' c: a; Laser --o-- Expectant Before Figure 2 Median visual analogue pain scores (with time). Figure 1 Proportion of patients with pain symptom alleviation at all stages. developed a psychiatric illness (depression), and 3 were lost to follow-up. The patient characteristics in both groups were not significantly different, with mean age 29 years (range 18 to 42 years) in the laser group and 29.5 years (range 19 to 40 years) in the women managed expectantly. The mean parity was 0.6 and 0.64 in the two groups, respectively. Clinical staging of endometriosis was similar in both groups (minimal: 13 versus 16; mild: 16 versus 12; moderate: 3 versus 3). Five of 32 (15%) women in the laser group had received previous medical treatment for endometriosis compared with 4 of 31 (13%) patients managed expectantly. None of the patients had undergone previous laser laparoscopy. At 3 months after surgery, 18 of 32 (56%) in the laser-treated group reported that their pain was better or improved compared with 15 of 31 ( 48%) in the expectant group. This difference is not statistically significant (z = 0.37, P = 0.35, Fisher Exact test). However, at the 6-month follow-up, 20 of 32 (62.5%) in the laser group were better, which was significantly different from 7 of 31 (22.6%) in the expectant group (z = 2.92, P < 0.01, Fisher Exact test) (Fig. 1). The median value of visual analogue scores related to time are illustrated in Figure 2. At 3 months the median decrease in pain score was 2.6 for the laser group and 1.2 for the expectant group; this was not significant (P = 0.9, Mann-Whitney U test). When the decrease in pain score from baseline to 6 months is analyzed, the median decrease was 2.85 for the laser group and 0.05 for the expectant group. This difference was significant (P = 0.01, Mann Whitney U test). When successful outcome after laser laparoscopy is analyzed by stage, it can be seen that results are poorest for stage I and best for stage III, as illustrated in Figure 3. When pain relief and stage are analyzed using the x 2 test for trend, at 3 months the trend was not quite significant (P = 0.06), however, at 6 months the trend between pain relief and stage was significant (P = 0.03). If patients with stage I disease are excluded, then 14 of 19 (73. 7%) patients experienced pain relief at 6 months after laser laparoscopy compared with 3 of 15 (20%) in the group managed expectantly. At the time of writing, 16 women who underwent expectant management of endometriosis at the time of laparoscopy have undergone a second-look laparoscopy at 6 to 12 months after the original operation. The mean AFS score was 7.8 at the time of initial laparoscopy and 9.1 at the second look. Three of these patients had progressed to a more severe stage of disease. In no women had the staging spontaneously improved. To date, a secondlook laparoscopy has been performed in five women who continued to complain of pain despite randomization to laser treatment at their laparoscopy. In three women there was no evidence of any residual endometriosis and in the other two endometriosis Stage I D Stage II fii!'ji Stage Ill Figure 3 Proportion of patients with pain symptom alleviation related to stage of endometriosis. 698 Sutton et al. Laser laparoscopy for endometriosis

4 had returned in new sites not lasered previously. There were no laparoscopic or laser complications in any of the women enrolled in this study. DISCUSSION This study has shown that at 6 months follow-up, laser laparoscopy for pain in patients with minimal to moderate endometriosis results in statistically significant pain relief compared with expectant management. This confirms that laser laparoscopy is an effective treatment of endometriosis. In this study, 62.5% of patients were better 6 months after the laser laparoscopy. This is not as good as the 70% pain relief that we reported previously from a retrospective study of 181 patients with all stages of endometriosis (9), although if only stages II and III are included it was remarkably similar. There may be two explanations for this. First, there inevitably is a placebo effect of surgery for pain, which can be seen clearly in this study at 3 months but not at 6 months. A placebo effect previously has been reported to improve dysmenorrhoea in up to 30% of patients treated, however, this improvement did not last longer than 3 months (4), which accorded with our own findings. It is recognized that placebo procedures that make use of apparently sophisticated technical equipment have generated high positive response rates where pain is concerned and that demonstrating faith in a chosen treatment (in front of your patient) increases the chance of good pain control (15). In addition to a placebo effect, there may be some mechanism whereby a laparoscopy alone results in temporary improvement of pain symptoms. To accomplish a thorough inspection of the pelvic peritoneal surface, it is necessary to remove the serosanguinous fluid that is invariably found in patients with endometriosis. This fluid contains high concentrations of pain-mediating substances, particularly prostaglandin F, and the mere removal of this fluid until it inevitably reaccumulates during subsequent menstrual cycles could alleviate pain symptoms (16, 17). In our study, 48% of women in the expectant group reported improvement or absence of pain 3 months after the laparoscopy. This also has been the experience of other surgeons; Fedele et al. (18), in a placebo-controlled study of the efficacy of buserelin acetate, recently reported a spontaneous remission of dysmenorrhoea, partial or complete, after diagnostic laparoscopy in almost half of the women who did not receive any treatment. The second reason for the poorer results may be because only patients with stages I through III endometriosis were included. It can be seen from the results (Fig. 3) that outcome was poorest for minimal endometriosis, with only 38% reporting improvement at 6 months compared with 69% and 100% for mild and moderate disease. This finding poses an important question-why are the results for minimal disease poor? It may be that in anumber of patients the diagnosis of minimal endometriosis on visual appearance alone could have been incorrect. Many of the atypical peritoneal appearances of endometriosis that are seen do not necessarily represent endometriosis and unfortunately we were not permitted to biopsy these lesions because this would have resulted in cytoreduction of endometriosis and would have interfered with the "no treatment" arm of the study. Furthermore, there is increasing evidence that women who experience pelvic pain secondary to their endometriosis have larger lesions that infiltrate deeper and have more and larger endometriomas (19). This may explain why the results for minimal disease are poor, in that it may not be the endometriosis at all that is responsible for the patients symptoms and that laser ablation of these small lesions will therefore not improve the patients' pelvic pain. It is interesting to note that three of five women who failed to improve after laser laparoscopy in this study did not have endometriosis present at second-look laparoscopy. We recommend that biopsies should be taken in women with apparently minimal endometriosis, to confirm the diagnosis, as this information may be crucial to plan further management of her pelvic pain if treatment fails. Our findings at second-look laparoscopy in patients who received no treatment at the initial operation confirm previously published evidence that endometriosis is a progressive disorder in some patients when left untreated (20, 21). Enthusiasts of medical treatment of endometriosis no longer can claim that laser laparoscopy has not been subjected to a placebo-controlled study. In reality there are only a few placebo-controlled studies of medical regimens for endometriosis, the first of which was published in 1987 (20) and only a few since (18, 21, 22). In a study of buserelin acetate for minimal and mild endometriosis, the drug induced a significant improvement of pain symptoms compared with expectant management, however, the benefit persisted in only half of the patients after withdrawal of the drug (18). In this study, 89% of women experienced unpleasant drug side effects. In a random- Vol. 62, No. 4, October 1994 Sutton et al. Laser laparoscopy for endometriosis 699

5 ized, double-blind study of the efficacy of leuprolide acetate versus placebo, Dlugi et al. (22) reported that there was a recurrence of pelvic pain to pretreatment levels in 54% of patients within 3 months of completing treatment and 91% of those women treated with Lupron depot reported side effects. These studies illustrate the short-term effect of medical treatment, and a significant and unacceptable recurrence of symptoms and endometriotic implants now is well recognized (23). The recurrence rates after medical therapy appear to be higher compared with surgical excision or ablation of the disease based on published data in the literature (23-25). Our findings suggest that laser laparoscopy is an effective treatment of pain due to minimal to moderate endometriosis and appears to be safe in experienced hands. It enables simultaneous diagnosis and treatment, therefore adding little additional cost to those involved with the diagnostic laparoscopy. Furthermore, in our hands, it is extremely safe and we have had no serious complications from the laparoscopic use of laser in over 2,500 patients treated over the past 11 years. In the majority of patients it avoids the need for treatment with expensive hormonal agents, which inevitably are associated with unpleasant side effects and symptom recurrence in a significant number of patients within 3 months of stopping the therapy. We would, however, conclude that in women with apparently minimal endometriosis, laser laparoscopy is less likely to be effective, but still has a role in limiting progression of the disease. Acknowledgment. We thank Mr. Martin Bland, Reader in Statistics, St. Georges Medical School, London, United Kingdom, for his expert statistical guidance. REFERENCES 1. Shaw RW. LHRH analogues in the treatment of endometriosis-comparative results with other treatments. Bail Heres Clin Obstet Gynaecol 1988;2: Adamson GD, Hurd SJ, Pasta DJ, Rodriguez BD. 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