II Department of Obstetrics and Gynecology, University of Milano, Milan, Italy1To whom correspondence should be addressed at: II Department of Obstetrics and Gynecology, Clinica `L. Mangiagalli', Via Commenda 12, 20122, Milano, Italy.
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Abstract |
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Key words: endometriosis/gonadotrophin-releasing hormone analogue/laparoscopy
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Introduction |
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At present, little is known about the post-operative effects of these medical therapies and results from the few randomized controlled trials are often contradictory (Telimaa et al., 1987; Parazzini et al., 1994
; Hornstein et al., 1997
; Bianchi et al., 1999
; Vercellini et al., 1999
). Specifically, two studies have emphasized a potential role of a short-term therapy with gonadotrophin-releasing hormone (GnRH) analogue after surgery in improving pain relief (Hornstein et al., 1997
; Vercellini et al., 1999
) while others failed to observe such an improvement (Telimaa et al., 1987
; Parazzini et al., 1994
; Bianchi et al., 1999
). In the present study, we have evaluated the effects of a post-operative regimen of GnRH analogue in women with pelvic pain symptoms who underwent laparoscopic conservative surgery for endometriosis stage IIIIV. This was studied in a randomized trial in which no post-surgical therapy was compared with a protocol consisting of a post-operative course of 3 months of GnRH analogue. The primary objective was to assess whether this surgical/medical combined approach could produce a significantly longer relief of pain symptoms. The between-group differences in both objective disease recurrence and pregnancy rates among women wanting children were also evaluated.
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Materials and methods |
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The laparoscopic procedures were performed according to the technique described by Cook and Rock (Cook and Rock, 1991). All patients were under the care of three of the authors (M.B., S.B. and M.C.). Approval for this study was granted by the local Human Institutional Investigation Committee. Written consent was obtained from each woman before study entry.
Randomization was achieved at the time of post-operative control (7 days after surgery) so that a definitive histological diagnosis of endometriosis was available. This randomization was performed according to a computer-generated list unknown to the physicians. Eight out of 97 women who were eligible for randomization refused to enter the study. Forty-four patients were randomized to receive an i.m. injection of GnRH analogue leuprolide acetate depot (3.75 mg) every 4 weeks for 8 weeks (three injections). Treatment began on day 1 or 2 of the first menstrual flow after surgery. Forty-five women were allocated to receive no post-operative treatment and were used as controls (Figure 1).
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After surgery, patients underwent a standard gynaecological and pelvic ultrasonography every 6 months. On each occasion, the occurrence of any pregnancy was recorded and any pain symptoms were evaluated using the two scales.
Statistical analysis was performed using Student's t-test for independent samples and 2 analysis to compare basal characteristics of the two groups. Recurrence of pain symptoms and recovery of fertility were analysed by the product-limit method and the curves of the two groups were compared with the log-rank test. The event dates considered were the date of operation and the date of first menstruation associated with moderate or severe pain or the last menstruation before a positive pregnancy test, since the operation. P < 0.05 was considered significant in all comparisons. The sample size used in our study allowed us to exclude, at the usual level of study power (80% chance at a 5% level of significance), a two-fold lower pain recurrence rate in the treated group.
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Results |
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Frequencies of pregnancies, pain and clinical recurrence and the need for second surgery are shown in Table II. During the follow-up, five (33%) of the 15 women who wanted children and who were allocated the GnRH analogue and six (40%) of the 15 given no treatment became pregnant (not significant): the respective cumulative pregnancy rates at 18 months were 38 and 40% (log rank test, not significant). Moderate/severe pelvic pain recurred during the follow-up in 10 (23%) of the 44 women with pelvic pain allocated the GnRH analogue and 11 (24%) of the 45 allocated no treatment; the cumulative pain recurrence rates at 18 months were 23 and 29% respectively (log rank test, not significant) (Figure 2
). No statistically significant differences in time to recurrence of pain symptoms between the two groups were observed. Four women (9%) treated with GnRH analogue and four (9%) who received no treatment had objective disease recurrence as demonstrated by gynaecological examination and/or pelvic ultrasonography (not significant). Finally, two patients allocated to the GnRH analogue group, underwent repeat operations (not significant). In these cases, surgery was decided on due to both the ultrasonographic evidence of an endometriotic cyst and the recurrence of pain symptoms. The diagnosis of endometriosis was confirmed at histological examination.
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Discussion |
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In regard to pain symptoms and disease recurrences, data from the randomized trials on this topic are more controversial. Indeed, in a previous study, we failed to demonstrate additional benefit of a short course of post-operative danazol treatment in preventing pain recurrence (Bianchi et al., 1999); similarly, Parazzini et al. reported that medical treatment with 400 µg/day nasal naferelin for 3 months after surgery did not markedly improve short-term pelvic pain prognosis (Parazzini et al., 1994
). On the other hand, results from three other groups documented some kind of benefit from using an oestrogen-lowering medical regimen after surgery (Telimaa et al., 1987
; Hornstein et al., 1997
; Vercellini et al., 1999
). Specifically, these therapies have been claimed to significantly delay the return of endometriosis symptoms. Hornstein et al. found that 15 out of 49 women treated with GnRH analogue for 6 months required an alternative therapy for recurrent pain compared with 25 out of 44 women allocated to post-operative placebo (Hornstein et al., 1997
). Vercellini et al. using survival analysis, reported that time to symptom recurrence was significantly longer in the GnRH analogue group (Vercellini et al., 1999
). To the contrary, in our study, we failed to document a significant longer relief of pain symptoms in women with symptomatic endometriosis stage IIIIV treated with a 3 month course of post-operative GnRH analogue. The relatively small sample size of our study did not allow the identification of less important effects of treatment. However, advantages associated with this therapy have to be weighed with costs and harmful side-effects; in this context, the use of GnRH analogue should be considered only if it provides a marked improvement in short-term pelvic pain prognosis. The sample size used in our study allows the exclusion, at the usual level of study power (80% chance at a 5% level of significance), a two-fold lower pain recurrence in the GnRH analogue-treated versus the untreated women. Interestingly, since the day of surgery was chosen as a starting point in both groups of women, patients who were allocated to the GnRH analogue group have symptom relief for at least the first 3 months compared with women given no treatment. However, this bias would most likely further increase rather than decrease the benefits of treatment.
Discrepancies among studies on this topic are difficult to explain; three reasons can be postulated. First, therapeutic protocol used in these studies varies and this may account at least for some differences. In our study, an i.m. injection of GnRH analogue depot every 4 weeks was chosen since this protocol appeared to be very simple, and adherence with this method of administration seems high; moreover, a 3 month therapy instead of a 6 month was decided on since it has been reported that a shorter protocol of this drug could be as effective as a longer one, whereas costs and side-effects could be reduced (Hornstein et al., 1995). In this context, it has to be noted that this study is the first report on this topic using this protocol. Second, another controversy may be related to the study design since our trial was not blinded and we did not use placebo. However, it should be noted that none of the available studies have conducted a true double-blinded, placebo-controlled trial; indeed, although such a study design would have been preferable, the frequent side effects observed with oestrogen-lowering medical therapies do not allow its application. At present, we are unable to assess the importance of this aspect in determining pain recurrence and in explaining differences between studies. Nevertheless, considering that we failed to identify a beneficial effect of GnRH analogue in lowering pain recurrence, it is unlikely that this bias may play an important role in our study. Third, the comparison with the other studies may be difficult because of differences in patient's characteristics, disease extension (only cases with advanced stages of the disease were considered in this study), surgical procedures and surgeon's skill. In our study, compliance with the study protocol was complete, surgery was always performed by only three experienced surgeons and the two study groups were comparable in terms of age, reproductive history, pain symptoms and disease stage. Interestingly, pregnancy rates as well as pain recurrence rates are comparable with those reported in the largest review of the literature (Hughes et al., 1993
; Adamson and Pasta, 1994
; Candiani et al., 1995
). Therefore, we estimate that important sources of bias in our trial can be excluded.
In conclusion, the present study does not support the routine post-operative use of a 3 month course of GnRH analogue in women with symptomatic endometriosis stage IIIIV. However, larger series and longer follow-ups are required to identify less important effects of treatment, in particular on the objective disease recurrence rate. Moreover, these data could not rule out that post-surgical GnRH analogue or other oestrogen-lowering medical therapies may be of value in selected patients, particularly those in whom disease has not been completely extirpated. Further trials to identify women who may benefit from these therapies are hence also required.
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Notes |
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References |
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Submitted on February 2, 2001; accepted on July 18, 2001.