Background : Borderline and early invase ovarian tumors frequently occur in young women and are treated by conservative surgery. The presence of associated infertility raises the question of a possible ovarian stimulation or A.R.T. Methods : Between June and December 1997, all French public and private A.R.T. centres were contacted by two letters, and in some cases by phone. A questionnaire was sent to collect information on ovarian stimulation or IVF in woman previously treated for borderline or early invasive ovarian tumor. Results : 24 cycles of simple stimulation in 7 women achieved only one term pregnancy (14.2%). In 22 women, 45 cycles were stimulated with the purpose of performing an IVF.
Eight clinical pregnancies resulted in the birth of 12 children. There were no tumor recurrences. The mean duration of the follow-up was 46.7 ± 36 months after the last ovarian stimulation and 114.7 ± 80 months after the initial treatment of the ovarian tumor. Conclusions : Apart from cases in which contralateral ovariectomy or potentially sterilizing chemotherapy are planned in the short-term, a minimum follow-up period appears to be desirable. Specific information of the patient on the oncological risks of ovarian stimulation is essential.
Her written consent is compulsory. ICSI appears to be the most effective method. Only long-term follow-up will make it possible to determine whether ovarian stimulation can be considered as an acceptable alternative in these patients.
Borderline ovarian tumors constitute 4 to 14% of all ovarian carcinomas.1 They occur before the age of 40 years in 30% to 50% of cases, and 85% of cases are discovered during stage 1 of the disease.2 Their very favourable prognosis (93% 5-year survival rate, 90% 10-year survival rate at stage 1) frequently allows treatment by unilateral adnexectomy alone in young women.3-4 In cases of an invasive ovarian tumor in young woman, conservative surgery is generally limited to stage 1 with a favourable histological grade, after the patient has been fully informed. After the initial treatment and after verification of the absence of recurrence, permission for natural procreation is the logical consequence of this therapeutic approach, especially as pregnancy reduces the risk of ovarian cancer.5-10
A case study of 39 borderline ovarian tumors showed 22 spontaneous pregnancies in 15 patients (38.5%) with a mean follow-up of 69 months, with no unfavourable consequences either during the course of the pregnancy or on the development of the ovarian disease.11 In an other study of 56 cases of invasive tumors treated conservatively, 20 patients (35.7%) were able to conceive spontaneously and gave birth to 17 children, with a mean follow-up of 7 years.12 However, the presence of associated infertility can raise the question of a possible ovarian stimulation or A.R.T..
Several rare cases of ovarian stimulation have been reported in the literature after conservative treatment for borderline or invasive ovarian tumors.13-16 Several pregnancies were obtained, but in one case a uterine recurrence was observed, and most importantly one woman died 7 months after ovarian stimulation, following extensive recurrence of an invasive lesion. 13-15 However, we must emphasize that this tumor was initially a stage 1c, grade 3 tumor, possibly associated with peritoneal dissemination prior to ovarian stimulation. Based on our practice, we decided to conduct a multicentre survey in French A.R.T. centres and to collect a maximum of analogous cases, in order to analyse the modalities and results of infertility treatment, and to more precisely define the conditions under which this practice could be regarded as acceptable.
Materials and method :
Between June and December 1997, we contacted all French public and private A.R.T. centres by two letters, and in some cases by phone. The following question was asked : have you already had to perform simple ovarian stimulation or in vitro fertilization in a woman previously treated for a borderline or early invasive ovarian tumor? In the case of a positive reply, a questionnaire was sent to the centre to collect information about each case. The first part of the questionnaire recorded the patient's age at the time of cancer management, her gestational status and parity, the presence of a family history of ovarian tumor, the histological type of ovarian tumor, its FIGO stage and grade, the type of operation and associated chemotherapy. The second part of the questionnaire concerned the patient's fertility before and after treatment of the ovarian tumor, the probable cause of infertility, its primary or secondary nature, its duration, the timing of ovarian stimulation in relation to surgery and its modalities : simple stimulation or IVF, number of cycles treated, number of oocytes, embryos and pregnancies obtained. The last part indicated the presence or absence of recurrences of the ovarian tumor, their treatment and the total duration of the follow-up.
Twenty-one (21.6%) of the 97 centres questioned replied that they had previously performed ovarian stimulation or A.R.T. after treatment of a known borderline or early invasive ovarian tumor. A total of 26 cases were collected. The mean age of the patients was 24.2 ± 7.4 years (18-34 years) at the time of diagnosis of the ovarian tumor and 32.3 ± 5.5 years (24-38 years) at the time of ovarian stimulation. The total number of pregnancies before treatment was 0.38 ± 0.88 (0-4), and the number of children was 0.17 ± 0.48 (0-3).
No woman had a family history of ovarian cancer, but two women had already received treatment for infertility before the diagnosis of ovarian tumor (borderline stage 1a and 1c). Treatment of the cancer was surgical in 25 cases (TABLE 1), usually by laparoscopy only (56%) and generally consisted of unilateral adnexectomy (88%). In 8 cases, the ovarian tumor was discovered incidentally on the cyst resection specimen. Surgery was completed by chemotherapy in 6 cases (1 borderline tumor, 2 invasive carcinomas, 2 seminomas, 1 immature germ cell tumor) and by radiotherapy in 4 cases of seminoma. One woman presented an ovarian recurrence of thoracic seminoma, and was treated exclusively by radiotherapy and chemotherapy.
The initial ovarian tumor was discoverd at stage 1 in 14 cases out of 16 borderline tumors (87.5%) and in 5 out of 10 invasive cancers (50%) (TABLE II). Twenty-five cases presented an infertility, which was known before the discovery of the cancer in 18 cases (72%), and appeared after treatment of the cancer in 7 cases (28%) (TABLE III). In one other case, the woman did not express an immediate desire for pregnancy, but she lived with her partner and preferred to freeze embryos prior to potentially sterilizing chemotherapy. In 4/26 cases (15.4%), ovarian stimulation was commenced immediately after the initial surgery, before contralateral ovariectomy or chemotherapy.
In the other 22 cases (84.6%), an observation period of 42 ± 60 months (6-88 months) was respected. Prior to IVF, 24 cycles of simple stimulation in 7 women achieved only one term pregnancy (14.2%). During 45 IVF cycles in 22 women, the mean number of ampoules of hMG or FSH (75 IU/ampoule) used was 31.5 ± 11.3 (14-56). Four cycles were cancelled because of an insufficient ovarian response. During the other 41 cycles, the plasma oestradiol level on the day of HCG injection was 1,389.6 ± 972.4 pg/ml (330-3,341). Punction enabled a mean of 8.7 ± 5.2 (1-18) oocytes and a mean of 4.7 ± 3.5 (1-15) embryos to be obtain. Eight clinical pregnancies were obtained : one early spontaneous abortion and 7 term pregnancies, with the birth of 12 children (2 sets of triplets and 1 set of twins) (TABLE IV).
Two thawed embryo transfers and 2 attempts of IVF during a spontaneous cycle failed, but 2 other pregnancies (including a twin pregnancy) resulted from 4 cycles with oocyte donation. No tumor recurrence was demonstrated by imaging techniques, plasma marker assays, or 6 second look operations (one after borderline tumor and 5 after invasive cancer : 2 carcinomas, 1 teratoma, 1 seminoma and 1 complex immature germ cell tumor). The mean duration of the follow-up was 46.7 ± 36 months after the last ovarian stimulation and 114.7 ± 80 months after the initial treatment of the ovarian tumor.
Infertility is a frequent problem after conservative surgical treatment for ovarian tumor. Only 15 out of 39 women (38.5%) with borderline ovarian tumors and 20 out of 56 women with invasive stage 1 tumors obtained at least one spontaneous pregnancy.11-12 In the 25 patients of our series, the cause of infertility was tubal in 11 cases (44%), male in 5 cases (25%), ovarian in 2 cases (8%) and unexplained in 7 cases (28%). Chemotherapy, administered in only 6 cases (24%), therefore did not appear to play an important role. On the other hand, the initial surgery may have been responsible for adhesional sequelae in some cases. But, the main cause seems to be the epidemiological link between ovarian tumor and infertility.6,7
The possible links between ovarian stimulation and the risk of borderline or invasive ovarian tumors remain highly controversial.17 Several studies have suggested an increased risk after ovarian stimulation.6,7,18-20 However, other studies have not demonstrated any increased risk.21-24 In fact, most authors consider that infertility itself is associated with an increased risk of ovarian tumor, while pregnancy provides a protective effect. In our series of 26 cases, the largest reported series to our knowledge, no tumor recurrence was demonstrated even after a follow-up of 46.7 ± 36 months after the last ovarian stimulation. In practice, when ovarian stimulation is considered in this clinical context, certain precautions in our opinion must be respected. Apart from cases in which contralateral ovariectomy or potentially sterilizing chemotherapy are planned in the short-term, a minimum follow-up period appears to be desirable.
It must take into account the patient's age and the characteristics of the ovarian tumor. Recurrences of borderline ovarian tumors are rare, but sometimes occur very late.3-4 We suggest a follow-up period of 12 to 24 months before stimulation. After an invasive the indication for ovarian stimulation always remains highly controversial tumor and should be strictly limited to a few stage 1, grade 1 tumors, for which the mean time for recurrence is 18 months.25 In all cases, it is essential to verify the absence of tumor recurrence before stimulation, by ultrasonography, abdominopelvic CT scan, plasma CA 125 and CEA assays, or even by systematic second look laparoscopy, which should be routinely indicated in this particular context. Specific information of the patient on the oncological risks of ovarian stimulation is essential. Her written consent is compulsory. Simple stimulations and conventional IVF have given only limited success rates in our series. ICSI appears to be more effective, but sample sizes are too limited to allow the systematic use of this technique to be recommended in women who have been previously treated for ovarian tumor.
Oocyte donation constitutes an effective alternative in the case of failure and justifies preservation of the uterus whenever possible, even in cases of bilateral ovariectomy.16,26,27 Before or after ovarian stimulation, oral contraception must be prescribed in order to reduce the risk of ovarian cancer. After the desired pregnancies have been obtained or after the definitive discontinuation of infertility treatment, hysterectomy with contralateral adnexectomy should be considered in some cases with an initial invasive or high grade borderline tumor. Only long-term follow-up will make it possible to determine whether ovarian stimulation can be considered as an acceptable alternative in these patients.
ACKNOWLEDGEMENTS : For this multicentric study, data were also obtained from Clinique Ste Thérèse de l'Enfant Jésus AMIENS (Dr BALLOT), Clinique de La Dhuys BAGNOLET (Dr CORNET), Clinique Saint Antoine BOIS-GUILLAUME (Dr AVRIL), Polyclinique CLERMONT-FERRAND (Pr POULY), Centre d'A.M.P. GRENOBLE (Dr SAGE), Centre d'A.M.P. LILLE (Dr BUVAT, Dr MARCOLIN), Centre Hospitalo-universitaire de LYON (Dr BOULIEU), Hôpital de la Conception MARSEILLE (Pr GAMERRE), Centre Hospitalier Arnaud de Villeneuve MONTPELLIER (Pr HEDON), Centre d'A.M.P. MULHOUSE (Dr LAMARCA-ROTH), Clinique Notre-Dame de Grâce NANTES (Dr POUSSET), Hôpital Cochin PARIS (Pr ZORN, Pr DUBUISSON), Hôpital des Diaconesses PARIS (Dr ROUBACH), Hôpital Pitié-Salpétrière PARIS (Dr LEFEBVRE), Polyclinique Courlancy REIMS (Dr GIACOMINI), Centre Oberthür RENNES (Dr PRIOU), Hôpital Jean Rostand SEVRES (Dr BELAISCH-ALLART), Centre d'A.M.P. VALENCE (Dr GILLIOZ). The authors would like to thank all the clinicians for their valuable collaboration.
TABLE I : OVARIAN TUMORS SURGICAL MANAGEMENT (n = 25 cases)
SURGICAL PROCEDURE : n = 25
|- Laparoscopy only : n = 14 (56%) - Laparotomy only : n = 4 (16%) - Laparoscopy followed by laparotomy : n = 7 (28%) |
|OVARIAN SURGERY : n = 25 ||- Unilateral adnexectomy : n = 22 (88%) - Unilateral cystectomy : n = 2 (8%) - Bilateral cystectomy : n = 1 (4%) |
|ASSOCIATED SURGICAL TREATMENTS : n = 7 || - Lymph nodes removal : n = 3 (12%) - Omentectomy : n = 4 (16%) |
TABLE II : OVARIAN TUMORS FIGO STAGE AND HISTOLOGY
|FIGO STAGE |
| || 1a || 1b || 1c || 2a || 2b || 2c || 3 |
|BORDERLINE TUMORS (n = 16) || || || || || || || |
|. SEROUS (n = 10) || 5 || 1 || 2 || - || - || 1 || 1 |
|. MUCINOUS (n = 3) || 3 || - || - || - || - || - || - |
|. MIXED (n = 3) || 2 || - || 1 || - || - || - || - |
|INVASIVE TUMORS (n = 10) || || || || || || || |
|. SEMINOMA (n = 5) || 3 || - || - || 1 || - || - || 1 |
|. EPITHELIAL (n = 3) || 1 || - || 1 || - || - || - || 1 |
|. IMMATURE TERATOMA (n = 1) || 1 || - || - || - || - || - || - |
|. IMMATURE DYSGERMINOMA (n = 1) || - || - || - || - || - || - || 1 |
TABLE III : INFERTILITY FEATURES (n = 25 infertile women)
TYPE OF INFERTILITY
|known before the discovery of the cancer n = 18 (72%) appeared after treatment of the cancer n = 7 (28%) |
|PRIMARY SECONDARY || 12. 6 || 61 |
|TUBAL || 9 || 2 |
|UNEXPLAINED || 4 || 3 |
|MALE || 5 || 0 |
|OVARIAN || 0 || 2 |
TABLE IV : INFERTILITY MANAGEMENT AND RESULTS
INFERTILITY MANAGEMENT PREGNANCIES
| TREATED CYCLES || TERM |
|SIMPLE OVARIAN STIMULATION || 24 || 1 (4,2%) |
|IN VITRO FERTILISATION || || |
|- CONVENTIONAL IVF || 33 || 4 (12,1%) (2 triple) |
|- ICSI procedure || 8 || 3 (37,5%) (1 twin) |
|- thawed embryo transfers || 2 || 0 |
|OOCYTE DONATION AFTER IVF FAILURE || 4 || 2 (50%) (1 twin) |
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1 - Department of Obstetrics and Gynaecology, Bichat-Claude Bernard University, Paris - France 2 - Department of Obstetrics, Gynaecology and Reproductive Medicine, Tenon Hospital and Paris VI University, Paris - France 3 - Department of Obstetrics and Gynaecology, Antoine Béclère Hospital, Clamart - France