Hum. Reprod. Advance Access originally published online on December 16, 2005
Human Reproduction 2006 21(4):1070-1075; doi:10.1093/humrep/dei434
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Long-term conservative therapy for endometrial adenocarcinoma in young women
Department of Obstetrics & Gynecology, School of Medicine, Niigata University, Niigata city, Niigata, Japan
1 To whom correspondence should be addressed at: Department of Obstetrics & Gynecology, School of Medicine, Niigata University, 1-757 Asahimachi-Dori, Niigata city, Niigata 951-8510, Japan. E-mail: yahatat{at}med.niigata-u.ac.jp
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Abstract |
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BACKGROUND: To evaluate the efficacy and safety of long-term conservative therapy with medroxyprogesterone acetate (MPA) for endometrial carcinoma in young patients who had experienced failure after initial therapy or relapse, we reviewed the clinical and pathologic records of eight patients diagnosed with well-differentiated endometrial adenocarcinoma without myometrial invasion who were treated with MPA for over 6 months because of treatment failure or relapse. RESULTS: The average duration of MPA treatment was 22 months. All patients were followed-up for a mean of 76.5 months. Seven patients responded to initial MPA treatment within a period of 14 months (mean, 7.9 months). All these patients experienced relapse and the mean time to relapse was 11.6 months (range, 4–33 months). All six patients with relapse were treated with additional treatments of MPA, and all but one responded to this treatment within a period of 16 months (mean, 8.0 months). Six patients ultimately underwent hysterectomy. All presented well-differentiated endometrioid adenocarcinomas without extrauterine disease. Three became pregnant and two delivered full-term normal infants. No patient died of the disease. CONCLUSION: Although lesions are expected to disappear with prolonged MPA treatment, this form of progestin therapy is hazardous because recurrence occurs frequently. Only strictly selected patients should therefore be indicated for long-term MPA treatment and careful evaluation before and after treatment should be performed.
Key words: conservative therapy/endometrial adenocarcinoma/medroxyprogesterone acetate
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Introduction |
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Although most endometrial carcinomas occur around or after menopause, 20–25% are diagnosed prior to menopause and 2–14% occur in women under 40 years of age (Gallup and Stock, 1984
; Evans-Metcalf et al., 1998; Patsner, 2000). Endometrial carcinomas in younger patients are usually well-differentiated (G1) early-stage endometrioid adenocarcinoma at diagnosis. The prognosis of G1 endometrioid adenocarinoma without myometrial invasion is excellent, with the 5-year survival rate after primary therapy exceeding 93% (Creasman et al., 1987). The standard therapy for endometrial carcinoma consists of staging laparotomy with total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic and aortic lymphadenectomy. However, there is an alternative treatment option for young patients who wish to preserve potential fertility.
A limited number of reports have suggested that to preserve fertility, young patients with endometrial carcinoma might be treated conservatively with progestin (Kim et al., 1997; Kung et al., 1997; Randall and Kurman, 1997; Sardi et al., 1998; Shibahara et al., 1999; Kaku et al., 2001; Wang et al., 2002; Ramirez et al., 2004). It has been reported that the efficacy of progestin therapy is relatively high (57–75%) and the rate of relapse low (0–29%) (Kim et al., 1997; Randall and Kurman, 1997; Sardi et al., 1998; Jobo et al., 2000; Jadoul and Donnez, 2003), but follow-up in these studies is limited. Although the optimal duration of progestin treatment is unclear, the absence of a response after 3 months of treatment is often considered failure. Patients experiencing failure undergo hysterectomy; however, in some patients, prolonged treatment is required because of the need for fertility preservation. Moreover, some patients need additional treatment for relapse. We analysed the outcomes of eight young patients with endometrial carcinoma treated with long-term medroxyprogesterone acetate (MPA) treatment because of failure or relapse and followed-up for up to 118 months (mean, 76.5 months).
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Subjects and methods |
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Eight patients with endometrial adenocarcinoma who received over 6 months of conservative treatment with high-dose MPA because of failure (no response within 3 months of initial treatment) or relapse were included in this study. The standard protocol of MPA treatment and follow-up is shown in Figure 1. All women were treated between 1995 and 2004 in our department and presented with International Federation of Obstetrics and Gynecology grade 1 uterine endometrioid adenocarcinoma as shown by total endometrial curettage before treatment. To exclude myometrial invasion and extrauterine spread of the disease, magnetic resonance imaging (MRI) and transvaginal ultrasonography (TVUS) were performed before treatment. All were given oral 600 mg of MPA three times daily as an initial treatment for 3 months, complying with their strong wish for fertility preservation. Histological examinations were conducted by total endometrial curettage after the initial treatment. Regression was indicated if the endometrial curettage showed normal endometrium or hyperplasia without atypia. Patients who did not show regression after 3 months of MPA treatment were given additional MPA depending on the patients’ intention. Total endometrial curettage was repeated after 3 months of additional MPA, and MPA treatment was continued for those who still did not show regression. Myometrial invasion and extrauterine spread of disease were evaluated by MRI and TVUS every 6 months. No more conservative treatment was given when myometrial invasion or extrauterine spread of disease was suspected. Follow-up endometrial biopsies were performed every 3 months after regression of disease. Relapse was indicated if a lesion that initially regressed following treatment reappeared. Patients who experienced relapses were given additional MPA depending on the patients’ intention. Written informed consent, especially concerning the risk of tumour progression, was obtained from all patients prior to commencing the treatment. Coagulant variables, thrombin–antithrombin complex (TAT) and fibrin/fibrinogen-degradation product (FDP)-D-dimer, were measured every 3 months during MPA treatment. Adverse effects were also evaluated. No patients were lost to follow-up; the mean follow-up was 76.5 months (range, 21–118 months). The outcome of treatment, pregnancy, and disease status at follow-up were evaluated.
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Results |
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Clinical findings of eight patients treated with long-term MPA are summarized in Table I. The mean age of the patients was 31.9 years (range, 26–37 years). All had a medical history of irregular menstruation and none had borne a child. All eight cases had positive oestrogen and progesterone receptor statuses, except one with negative progesterone receptor (case 3). The mean duration of MPA treatment performed was 22 months (range, 7–41 months). No patients showed myometrial invasion by MRI and TVUS before starting MPA treatment.
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The treatment and follow-up outcomes of these patients are summarized in Table II and Figure 2. Among seven patients who did not show any response within 3 months of initial MPA treatment, six (85.7%) responded to additional treatment of MPA. The mean time to response was 8.7 months (range, 4–14 months). One patient (case 6) did not show any response during 30 months of MPA treatment. All seven patients who initially responded to treatment experienced relapses. The mean time to relapse was 11.6 months (range, 4–33 months). Although surgical therapy was recommended in these patients, six patients requested to undergo further fertility sparing therapy with MPA. Five patients (83.3%) responded to the secondary treatment of MPA for relapse. The mean time to response was 8.4 months (range, 4–16 ). Four patients showed relapse after secondary resolution of the disease. The mean time to secondary relapse was 25.0 months (range, 8–58 months). MPA was administered again for all these patients. Three patients (75%) responded to the third treatment of MPA. The mean time to response was 8.0 months (range, 6–12 months).
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Adverse effects were also evaluated in these eight patients. One patient complained of weight gain. No elevation of coagulant variables (TAT and FDP-D-dimer) was observed, and no thrombophlebitis or pulmonary emboli were noted in all eight patients.
Among the four patients who expressed a desire to become pregnant after resolution of the disease, seven pregnancies were achieved in three patients; two viable infants were delivered (both singleton pregnancies). Assisted reproductive technology (artificial insemination with husband’s sperm [AIH]) or IVF was implemented for all pregnancies. Mean duration to first pregnancy after resolution of the disease was 2.5 months (range, 1–4 months). Both patients who delivered a baby at term had recurrence. The times to recurrence were 11 and 28 months after delivery, respectively.
Six patients were ultimately treated by hysterectomy. All had grade 1 endometrioid adenocarcinomas without extrauterine disease. Although four patients revealed no myometrial invasion by the pathology of the surgical specimens, myometrial invasion was seen in two patients with diagnosis of stage 1b (case 2) and stage 2a (case 6). A total of 13 months of MPA treatment was given to case 2. Hysterectomy and bilateral oophorectomy with pelvic lymphnode sampling were performed because of secondary relapse, and microscopical invasion (1 mm) to myometrium was found. The patient has been disease-free for 58 months since surgery. Case 6 showed no response during 30 months of MPA treatment. MRI and TVUS did not show myometrial invasion or uterine cervical involvement of the disease at any point during treatment. The patient underwent total abdominal hysterectomy and bilateral oophorectomy with pelvic lymphnode sampling. The pathology of the specimen showed residual carcinoma with myometrial invasion and uterine cervical glandular involvement. The patient has been disease-free for 16 months since surgery.
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Discussion |
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In the present report, eight young patients with endometrial carcinoma underwent long-term conservative treatments with high-dose MPA for over 6 months. We demonstrated the efficacy of long-term MPA treatment both for treatment failure and relapse of the disease.
Endometrial carcinoma, especially in young patients, seems to have a favourable prognosis and is highly hormone dependent. Although hysterectomy has been the mainstay of therapy for endometrial carcinoma, since as early as the late 1969s, progestative treatment has been reported in young patients with well-differentiated endometrial carcinoma (Kempson and Pokorny, 1968). Various studies have shown a relatively high response rate and favourable pregnancy outcomes, although the follow-up in these studies has been limited (mean, 32 months) (Bokhman et al., 1985; Kim et al., 1997; Randall and Kurman, 1997; Duska et al., 2001; Gotlieb et al., 2003).
The absence of a response after 3 months of progestins is often considered treatment failure. Patients experiencing failures usually undergo hysterectomy, but in some patients, longer treatment is needed until the lesion disappears. It is therefore unknown that how long conservative treatment can be continued. In addition, some cases require re-treatment by progestins for relapse during longer follow-up periods. It is also unknown whether fertility sparing therapy should be retried for patients with relapse. In contrast to other reports, patients here were followed up for longer time (mean, 76.5 months) and outcomes of disease and pregnancy were evaluated.
The published initial response rate for the conservative management of well-differentiated endometrial adenocarcinoma for fertility sparing purposes ranges from 50 to 100% (Kempson and Pokorny 1968; Bokhman et al., 1985; Kim et al., 1997; Randall and Kurman, 1997; Duska et al., 2001; Gotlieb et al., 2003). The mean time to response is reportedly 2–6 months with a minimal time to response in most studies of 3 months (Kempson and Pokorny1968; Bokhman et al., 1985; Kim et al., 1997; Randall and Kurman, 1997; Sardi et al., 1998; Jobo et al., 2000; Duska et al., 2001; Kaku et al., 2001; Gotlieb et al., 2003). The absence of a response after 3 months of treatment is often considered failure. In most cases, hysterectomy is performed for patients who did not respond to their initial treatment. In the present study, responses were seen in all but one patient, with a high (87.5%) response rate by continuing MPA treatment for failure. Regression of the disease was seen by 14 months with 8.7 months of mean time to response. Four more patients with early endometrial carcinoma were treated conservatively in our department. After 3 months of MPA treatment the lesion disappeared in one patient, and she has been disease-free for 6 months. Hysterectomy was performed for the remaining three patients in whom the lesion did not disappear. Although the response rate after 3 months of MPA is quite low (16.7%, 2 of a total of 12 patients treated in our department), it is possible that the lesions might disappear with continuing MPA treatment.
The absence of progesterone receptors might be related to the failure of progestin treatment. In this study, one patient with a negative progesterone receptor status (case 3) also responded to 4 months of initial therapy. She underwent two additional MPA treatments for relapses, and responded to 4 and 6 months of MPA treatment. She has remained disease free for 36 months. It has been reported that oestrogen and progesterone receptor expressions are correlated with the success of hormone treatment (Thigpen et al., 1999). The response rate of MPA in patients with advanced or recurrent endometrial carcinoma was 37% for those with a positive progesterone receptor status and 8% for those with a negative progesterone receptor status. Similarly, the response rate was 26% for patients with a positive oestrogen receptor status and 7% for those with a negative oestrogen receptor status. In addition to our findings, a case of oestrogen receptor-negative early endometrial carcinoma who responded to MPA treatment has been described (Kaku et al., 2001). Although regression of the disease is expected even if hormone receptors are negative, careful follow-up is necessary for these patients, and moreover, prolonged treatment is required.
The relapse rates in previous studies have been relatively low (range, 0–29%) (Kim et al., 1997; Randall and Kurman, 1997; Sardi et al., 1998; Jobo et al., 2000). In contrast, we observed a higher relapse rate after remission of the disease by conservative treatment. This difference can be explained, in part, by the long follow-up period of our study. In two recent studies with a long follow-up after remission of the disease, the relapse rate was reported as 46–50% (Wang et al., 2002; Gotlieb et al., 2003). It is possible that the relapse rate increases when patients are observed for a longer follow-up period.
In this study, 15 relapses were observed in seven patients with 15.5 months of mean time to relapse after remission of the disease. Six patients were treated with additional treatment of MPA for initial relapse and five were treated for secondary relapse conservatively again. Response rate and time to response of treatment for initial and secondary relapse is almost equal to the initial treatment for these patients. Thus, relatively high effectiveness could be expected with additional treatment of MPA even for relapse. Two patients recurred after full-term delivery (11 and 28 months after delivery, respectively); relapse after delivery has also been reported in several other studies (Mitsushita et al., 2000; Gotlieb et al., 2003). When definitive treatment was not chosen, long-term follow-up after remission following conservative treatment is needed even after delivery. Patients should be kept under close surveillance to diagnose any possible relapse.
The problems of conservative treatment are progression of the disease during treatment. Extrauterine disease after progestin therapy, such as pelvic lymph node involvement, have been reported in some cases (Kim et al., 1997; Kaku et al., 2001). Ovarian disease is rarely observed in patients with stage 1 disease but reportedly occurs in 5% of cases. It has been reported that 11% of patients aged 45 years or younger have synchronous ovarian malignancies, compared with only 2% of those older than 45 years (Evans-Metcalf et al., 1998). Progestin therapy for endometrial carcinoma therefore entails risks, and consequently, careful diagnosis and counselling with regard to the potential risks with progression of the disease are indispensable when continuing or re-starting treatment. A laparoscopic procedure including adnexal exploration and peritoneal cytology is proposed for patients who desire conservative management in order to verify the absence of extrauterine disease (Morice et al., 2005). This procedure might be helpful for pre-treatment evaluation.
In this study, hysterectomy was performed for six patients after long-term treatment of MPA. Although the lesion was confined to the uterus in all of these patients, deep myometrial invasion was found in one patient (case 6) who had not responded at all during 30 months of MPA treatment. No deep myometrial invasion was found in any other patients who responded to MPA treatment within 14–16 months of initial or secondary MPA treatment. Thus, hysterectomy should be considered when no response is obtained after 14–16 months of MPA treatment.
The optimal dose, duration and regimen for conservative treatment are unclear. The majority of patients are treated with either MPA or megestrol acetate (MGA) with similar results (Kaku et al., 2001; Ramirez et al., 2004). Both MPA and MGA are effective over a variety of dosages and schedules. Other reported cases include treatment with 17
-hydroxyprogesterone caproate, oxyprogesterone acetate, hydroxyprogesterone, norethisterone and tamoxifen with success (Lai et al., 1994; Kimmig et al., 1995; Kim et al., 1997; Randall and Kurman, 1997). Other authors have found a progesterone intrauterine device, a useful treatment option (Van Liedekerke et al., 1998; Montz et al., 2002). The intrauterine release of progestin achieves much higher concentrations in the endometrium than oral administration, and hence might be more efficacious.
An ideal outcome of conservative therapy is the ability to have a baby without compromising their carcinoma outcome. Implementation of assisted reproduction during conservative management has been described in several reports (Kimmig et al., 1995; Ogawa et al., 2001; Pinto et al., 2001; Lowe et al., 2002; Lowe et al., 2003; Yarali et al., 2004). In this study, all patients were nullipara at diagnosis. Of four patients who hoped for a child, three became pregnant (a total of seven pregnancies), and of these, two delivered healthy children. Assisted reproductive technology (i.e. AIH or IVF-embryo transfer) was applied for all pregnancies. The interval to first pregnancy after regression of disease ranged from 1 to 4 months. The timely implementation of assisted reproduction not only increases the chance of successful conception, but it might also decrease the interval to conception. Through appropriate counselling, motivated and carefully selected women might be candidates for long-term conservative therapy supplemented by assisted reproduction. Assisted reproduction should be started as soon as the lesion disappears. Hysterectomy should be recommended after delivery because of the high relapse rate.
Progestin therapy could be a treatment option for young women with well-differentiated endometrial carcinoma. Although these lesions are expected to disappear with prolonged MPA treatment, this form of progestin therapy is hazardous because of the high risk of recurrence. Long-term MPA treatment should therefore be indicated only for patients who are strongly motivated to preserve their fertility and wish to immediately pursue childbearing. Extremely careful evaluation, both before and after treatment, is also required.
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Submitted on July 26, 2005; resubmitted on October 18, 2005; accepted on October 26, 2005.
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