1 Department of Obstetrics and Gynecology, Pamukkale University Medical Center, 20100 Denizli and 2 Department of Psychiatry, Hacettepe University School of Medicine, 06200 Ankara, Turkey
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Pamukkale University Medical Center, 20100 Denizli, Turkey. e-mail: msoysal{at}superonline.com
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Abstract |
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Key words: anastrozole/endometriosis/goserelin
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Introduction |
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Recently, the molecular basis for the local treatment of endometriosis using an aromatase inhibitor has been discussed (Bulun et al., 1998, 1999
, 2001
, 2001
; Takayama et al., 1998
; Zeitoun et al., 1999
). According to these authors, the existence of two additional extraovarian sources of endogenous estrogen is probably an important reason for the high rate of failures during follow-up among patients using GnRH analogues. The first source is the peripheral aromatization of adrenal androgens and the second is the inflammation-induced aromatization in the endometriotic foci itself. GnRH analogues are ineffective in both of these estrogen production sites. Aromatase inhibitors are not able to inhibit ovarian function in premenopausal women and thus they are not able to create the desired almost complete hypoestrogenic milieu. The authors postulated that the addition of aromatase inhibitors to GnRH analogues in premenopausal patients could increase the disease-free interval by inhibiting both the ovarian and above-mentioned two important extraovarian sources of estradiol (E2).
Given this background, to test the clinical significance of this new hypothesis related to the two-drug adjuvant regimen, we conducted a prospective randomized study. We tried to answer the question whether anastrozole (Arimidex 1 mg; Astra-Zeneca, Macclesfield, UK), a third-generation aromatase inhibitor, in conjunction with the GnRH analogue goserelin (Zoladex 3.6 mg; Astra-Zeneca) could lower the recurrence rates and thus extend the symptom-free interval with acceptable morbidity as compared to goserelin alone after conservative surgery in severe endometriosis cases.
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Materials and methods |
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Interventions
In patients with a clinical suspicion of severe endometriosis, baseline grading of symptoms and physical findings was performed before the surgery according to the previously developed and widely used multidimensional scale (Biberoglu and Behrman, 1981). In this scale, symptoms of dysmenorrhoea, dysparenuia and pelvic pain were each scored by the patient, and the physical findings of pelvic tenderness and indurations were each scored by the physician as: none (0 point), minimal (1 point), moderate (2 points) or severe (3 points). The sum of these variables compromised the Total Pelvic Symptom Score (TPSS). In this trial, TPSS is considered to be the subjective clinical indicator of the disease severity at baseline and during the follow-up period of the study. After grading the TPSS as the sum of the symptoms and physical findings, all patients were subjected to diagnostic laparoscopy. Laparoscopy with histological proof was the ultimate tool to diagnose endometriosis at baseline. Laparoscopy is also considered to be the objective clinical indicator of disease severity and it was programmed in the luteal phase of the cycle. Among patients who had rASRM scores >40, the diagnosis of severe endometriosis was made and we attempted a thorough conservative surgery either by laparoscopy or laparotomy.
After the thorough conservative surgery, patients were considered eligible for the post-surgical medical therapy trial. Exclusion criteria included further desire for childbearing, any treatment for endometriosis within the previous 3 months, any concomitant disease that can be an established cause of chronic pelvic pain (inflammation sequela, myoma, pelvic congestion, adenomyosis, etc.), osteopenia or osteoporosis at bone mineral density (BMD) measurements according to the World Health Organization (1994) and any concomitant disease that can be a contraindication to goserelin or anastrozole.
In all patients, we prescribed 600 mg elemental Ca and 400 IU vitamin D (b.i.d.) in a commercially available medication (Cal D Vita; Roche, Basel, Switzerland). The first group of patients received anastrozole 1 mg/day plus s.c. depot injections of 3.6 mg goserelin every 4 weeks for 24 weeks with the first injection given in the first late luteal week of the menstrual cycle before discharge. The second group of patients received a placebo tablet in addition to the above-mentioned goserelin regimen for 24 weeks. Patients were evaluated at 24 weeks of medical treatment, and at 6, 12, 18 and 24 months after the end of medical treatment.
Objectives and outcomes
The main objective of this trial was to assess the clinical efficacy of anastrozole in conjunction with goserelin as compared to goserelin alone in the adjuvant setting. Thus the primary outcome measures of this trial were (i) the recurrence rate and (ii) the impact of allocated treatments on TPSS during the follow-up period of 24 months after the end of medical treatment.
During this trial, recurrence was defined as symptoms and physical findings suggesting endometriosis with a TPSS of 7 that requires alternative treatment at any time during the follow-up period of 24 months after the end of post-surgical medical treatment. Laparoscopy to diagnose recurrent endometriosis was not considered to be necessary in accordance with the recent literature (Hornstein et al., 1997
; American College of Obstetrics and Gynecology, 1999
; Ling, 1999
; Vercellini et al., 1999
; Winkel, 2000
; Gambone et al., 2002
). Thorough history taking, complete physical and detailed pelvic examination, transvaginal sonography, urinalysis, complete blood count, and endocervical examination to rule out chlamydia and gonococcus were performed to rule out pain syndromes other than endometriosis. The time to initiate alternative treatment was recorded for each patient. Examinations to detect recurrences were scheduled either by the request of the patient (whenever the patients had complaints, they were immediately examined to detect recurrences) or at the time of scheduled follow-up examinations at the immediate end of post-surgical medical treatment (24 weeks exam), and at 6, 12, 18 and 24 months post-surgical medical treatment. Symptoms of TPSS recorded by the patients (dysmenorrhoea, dysparenuia, pelvic pain) were studied as TPSS-Patient (TPSS-P). In each exam, TPSS was re-evaluated by the surgeons and noted for statistical analysis, and the probability of recurrence noted. During the study period we were able to record TPSS at baseline, at 24 weeks post-surgical medical treatment, and at 6, 12, 18 and 24 months post-surgical medical treatment. Whenever a recurrence was detected (TPSS
7), we offered GnRH analogue plus add-back or definitive surgery as second-line treatments.
The secondary outcome measures of this trial were established to evaluate the adverse effects of therapy and were studied in two aspects. The first secondary outcome measure is the impact of treatment on the menopausal quality of life according to the 24-week examination findings and E2 levels throughout the therapy. In order to assess the severity of climacteric symptoms as a measure of quality of life induced by the drug regimens, the modified Greene scale and BlattKupperman Index were used (Greene, 1998; Alder, 1998
). The validity and sensitivity of these scales have been established in climacteric research. These classification systems, though simple, construct a comprehensive measure of the multi-faceted and wide ranging symptom picture presented by the climacteric women. The modified Greene scale was used to determine the severity of vasomotor, somatic, psychological symptoms (anxiety and depression) and loss of sexual interest (Greene, 1998
). The BlattKupperman Index, in contrast, does not assess sexual interest, but vasomotor symptoms are of prime importance in this scale (Alder, 1998
). All patients were instructed to self record the scales at 24 weeks of evaluation during the post-surgical medical treatment. The scales were reviewed and scored by a blinded psychiatrist. In order to assess the impact of treatment regimens on E2 concentrations, blood samples were taken before the second, fourth and sixth goserelin administrations, and free E2 levels were measured.
The second secondary outcome measure is the impact of medical treatment on L1L4 vertebra BMD at 24 weeks of medical therapy and 24 months post-surgical medical treatment. Variables were studied at baseline, at 24 weeks of post-surgical medical treatment and at the end of the study period, i.e. 24 months after the post-surgical medical treatment. The BMD of the lumbar vertebra (L1L4) were measured by dual-energy X-ray absorptiometry with the use of Hologic QRD (Hologic, Waltham, MA). The coefficient of variation of the machine over the study period was 3.5%.
Sample size calculation
In calculating the sample size required, the primary assessment was the recurrence rates. A 31% recurrence rate after laparoscopic reductive surgery and post-surgical treatment with a GnRH analogue has been reported (Hornstein et al., 1997). We expected a decrease in recurrence rates after laparoscopic conservative surgery and post-surgical treatment with anastrozole plus goserelin. A difference of 25% between the allocated treatments was considered significant. To have a 90% chance of detecting such a difference at an overall significance level of 5%, 40 patients for each group were required.
Randomization process and masking
Treatment allocation was performed in accordance with a computer-generated randomization sequence using numbered, opaque, sealed envelopes. The research assistants prescribed the drugs. Neither the surgeons nor the patients were aware of the regimen prescribed during the evaluation of TPSS recurrence during the study period. Randomization code was broken and unblinding occurred at the time of the diagnosis of recurrence.
Statistical methods
StatMate and Prism Software for Windows (Graph Pad) were used in the randomization process, sample size calculation and statistical analysis of this trial.
All raw data were tested to confirm the Gaussian distribution using the KolmogorovSmirnov test. The cumulative proportion of recurrences by plotting percent recurrences as a function of time was estimated by the method of Kaplan and Meier. The survival curves for each allocated treatment were compared with the log-rank test. The impact of treatment on TPSS as a primary outcome measure is studied in the efficacy-evaluable population; in order to mitigate the bias that would result from the missing data, we carried out the last observation carried forward procedure. In this procedure, a patients last measured response is applied to the subsequent scheduled observations for which data are not available and included in the statistical analysis (Archer and Pickar, 2002). Thus, for example, the TPSS of a patient with recurrence at 17 months is studied in the 18 months scheduled examination. In order to quantify the impact of treatment arms on TPSS during the study period, the non-parametric repeated measures ANOVA (Friedman test) with Dunn as the post-test was used. The differences of treatment effects on TPSS were assessed by the paired t-test and Wilcoxon matched-pairs signed-rank test. In the statistical analysis of the secondary outcome variables, intention-to-treat analysis (Archer and Pickar, 2002
) was used; thus, it included the dropouts for whom data are not available at 24 months after post-surgical medical treatment. P < 0.05 was considered statistically significant.
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Results |
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Adverse events
The impact of treatment regimens on E2 levels and on climacteric symptoms as a measure of quality of life during the treatment period is given in Figure 3. In the repeated measures, one-way ANOVA test done separately for each group, we do not have evidence that free E2 concentrations differed through the therapy period (P = 0.69 for goserelin; P = 0.47 for goserelin plus anastrozole). However, goserelin plus anastrozole lowered E2 concentrations significantly as compared to the goserelin-only regimen (Table V). In contrast, the mean of the differences between the treatment regimens either in terms of modified Greene scale scores or the BlattKupperman index scores as a measure of menopausal quality of life at 24 weeks of evaluation are not statistically significant (Table IV).
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Discussion |
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In a significant proportion of patients, the pain related to endometriosis eventually returns. One explanation for the observed long-term inefficiency of GnRH analogues is the presence of significant E2 production that continues in the adi pose tissue, skin and endometriotic foci per se during the GnRH analogue treatment. Inflammation-induced aromatization in the endometriotic foci itself represents the intra-acrine mechanism of estrogen action in endometriosis. The prostaglandin E2 content, the aberrant expression of aromatase, the presence of 17 HSD Type 1 and the absence of 17
HDS Type 2 collectively raise the local levels of E2 of the ectopic endometrial tissues. Furthermore, GnRH analogues are ineffective to stop peripheral aromatization of androstenedione in adipose tissue and skin fibroblasts; therefore, there is an ongoing peripheral supply of estrone and E2 to the target foci that are rich in 17
HSD Type 1 (Takayama et al., 1998
; Bulun et al., 1998
, 1999
, 2000
, 2001
; Zeitoun et al., 1999
; Vignali et al., 2002
).
In this trial we did not include a placebo group because it seemed unethical to us given the proven effectiveness of GnRH analogues and current practice (Vercellini et al., 1998; American College of Obstetrics and Gynecology, 1999
; Winkel, 1999; Jones and Sutton, 2001
; Gambone et al., 2002
; Vignali et al., 2002
). Therefore, we have chosen goserelin as the standard arm of the trial. We intended to increase the hypoestrogenism by the double-drug regimen both centrally and peripherally. Aromatase inhibitors given alone are not able to completely inhibit ovarian steroidogenesis (Vignali et al., 2002
), and, furthermore, may increase follicular recruitment (Mitwally and Casper, 2001
) and may lead to ovarian stimulation and cyst formation. Given alone they are only sufficiently potent to block extraovarian estrogen production (Dowsett, 1999
; Santen and Harvey, 1999
; Vignali et al., 2002
). However, in the presence of a GnRH analogue which itself results in ovarian inhibition, aromatase inhibitors are effective to achieve near maximal estrogen suppression (Dowsett, 1999
; Santen and Harvey, 1999
). Therefore, in this trial we tested the efficacy of anastrozole in the presence of ovarian inhibition and did not have an anastrozole-only group.
In the experimental arm of this trial, goserelin was used in order to inhibit ovarian steroidogenesis, and anastrozole to inhibit the consequences of peripheral aromatization and the aberrant expression of aromatase in the endometriotic foci.
When we analyzed the KaplanMeier survival curves, we detected a statistically significant advantage in favour of goserelin plus anastrozole as compared to goserelin only, in terms of the median time to detect symptom recurrence (>24 versus 17 months; log-rank test; P = 0.0089). This statistically significant advantage occurred with an RR of 4.3 (95% CI 1.39.8). Three cases out of 40 recurred (TPSS >7) in the goserelin plus anastrozole arm (7.5%), whereas we detected recurrences in 14 cases out of 40 cases in the goserelin-only arm (35%) during the follow-up period of 24 months. Based on these data, the interpretation of KaplanMeier curves indicates that at the end of follow-up, 54.7 versus 10.4%, respectively, of patients were free of recurrence. The median time to detect recurrence in the goserelin treatment arm was 17 months post-treatment. In contrast, the median time to detect recurrence in the goserelin and anastrozole arm was >24 months.
In this trial both treatment protocols proved to be statistically effective in reducing the TPSS; however, we observed a more profound, stable and long-lasting effect of goserelin and anastrozole on TPSS during the study period. Furthermore, the impact of treatment in terms of TPSS and individual symptom score reduction was statistically relevant in favour of goserelin and anastrozole. Based on our data, we argue that almost complete targeted endocrine blockade of estrogen biosynthesis in the adjuvant setting after conservative surgery involving goserelin and anastrozole is superior to the standard approach. This novel approach was associated with a lower rate of recurrence and better, continuous symptom control within the time frame of the study.
The most common adverse effects of GnRH analogues are associated with hypo-estrogenism. Our data clearly demonstrates that anastrozole is a very effective suppressant of E2 concentration even in the presence of the GnRH analogue goserelin. However, it was interesting to note that this combination was tolerated as well as goserelin only in the context of the climacteric quality of life. The mean of the differences between the treatment regimens either in terms of modified Greene scale or the BlattKupperman index scores as measures of climacteric quality of life were not statistically significant. The explanation for this unexpected finding may be our sample size, which is relatively small to study the differences in quality of life or the inefficiency of the arma mentarium available today to detect differences in the menopausal quality of life below a threshold value of E2 or the biological suppression we have detected is not of clinical relevance. Even though not studied in our population, it may also be related to the dynamics of sex hormone-binding globulin and free testosterone in the presence of goserelin and anastrozole, as it theoretically leads to an increase in free testosterone indices.
To our knowledge the impact of double-drug regimen to BMD of women with endometriosis has not been reported in the literature. Both regimens had significant detrimental impact on BMD even after treatment withdrawal. The observed BMD loss was statistically more pronounced at 24 weeks of evaluation in the goserelin plus anastrozole arm. Even though the bone loss did not recover at 24 months of evaluation, none of our patients were osteopenic or osteoporotic according to WHO criteria either at 24 weeks or at 24 months of post-surgical medical treatment evaluation. In our opinion this finding is very important from the clinical standpoint, because for women with no history of fragility fracture, only WHO definitions of osteopenia and osteoporosis are associated with a high risk of fracture (American Association of Clinical Endocrinologists, 2001). Furthermore, the physiological bone loss of 0.5% per year that is evident after the third decade should also be taken into account (Stevenson et al., 1989
). Our statistical results point to a significant loss of BMD in L2L4 at 24 weeks and 24 months of evaluation within each treatment arm; however, the size of the bone loss being significant in favour of goserelin at the end of treatment is not significant at 2 years after treatment. The masking of bone loss with bisphosphonates may be considered; however, this has not been studied in our patients.
In our local practice the costs of a 6-month treatment with goserelin plus anastrozole and goserelin are around US$2500 and 1250, respectively. Even though measuring the cost-effectiveness is beyond the scope of this trial, in the era of managed care medicine the costs of our drugs must be interpreted cautiously with regard to the limited costs and efficacy of their alternatives, particularly progestins with or without estrogens (Vercellini et al., 2003).
In conclusion, we showed that in patients with severe endometriosis after conservative surgery, almost maximal endocrine blockade of estrogen synthesis achieved with anastrozole and goserelin for 6 months as a post-surgical medical treatment is a rational treatment. On the basis of the presented findings, this combination in the adjuvant setting increases the pain-free interval, decreases recurrence rates, and improves symptom control without further deteriorating the menopausal quality of life and bone metabolism. In our opinion, key targets for future development in the treatment of severe endometriosis are (i) further assessment of the potential role of aromatase inhibition in premenopausal patients, (ii) strategies to enhance the degree of hormone suppression for prolonged periods without deteriorating the bone, (iii) investigation of the optimal sequential use of different compounds such as estrogens/progestogens, immunomodulators and anti-inflammatory agents in addition to GnRH analogues and aromatase inhibitors.
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Submitted on April 22, 2003; resubmitted on July 9, 2003; accepted on October 1, 2003.