Fertility after conservative treatment for borderline ovarian tumors: A French multicenter study

Fertility after conservative treatment for borderline ovarian tumors: a French multicenter study Raffaèle Fauvet, M.D.,a,b Christophe Poncelet, M.D., Ph.D., Joëlle Boccara, M.D., Philippe Descamps, M.D.,c Eric Fondrinier, M.D.,b and Emile Daraï, M.D., Ph.D.a a Service de Gynécologie, Hôpital Tenon, AP-HP, Paris; b Service d’Oncologie Chirurgicale, Centre Paul Papin; and c Service de Gynécologie, Centre Hospitalier Universitaire, Angers, France

Objective: To examine fertility outcomes and determinants of fertility after conservative surgery for women with borderline ovarian tumors. Design: Retrospective multicenter study. Setting: Thirteen specialized gynecologic units and one cancer center. Patient(s): In a study of women with borderline ovarian tumors, 162 of 360 women underwent conservative surgery; from these 162, we compared epidemiologic, surgical, and histological parameters between 21 women who conceived and 44 women who failed to conceive. Intervention(s): Conservative surgery for borderline ovarian tumors. Main Outcome Measure(s): Fertility results and outcome. Result(s): Women undergoing conservative treatment were significantly younger and more likely to be nulliparous. Tumor size was significantly smaller in the conservative treatment group. Thirty pregnancies occurred in 21 (32.3%) of the 65 women who wished to conceive after conservative treatment. Twenty-seven pregnancies were spontaneous, whereas three occurred after ovarian stimulation and IUI (one case) or IVF (2 cases). Women who conceived did not differ from women who did not conceive in terms of the tumor recurrence rate or the mean time to recurrence (39.6 ⫾ 28.2 and 22.9 ⫾ 14.9 months, respectively). Age at initial treatment was the only determinant of fertility. Conclusion(s): Despite a high recurrence rate, our results confirm that conservative surgery for women with borderline ovarian tumors is an acceptable option and that fertility is preserved in nearly one third of cases. (Fertil Steril威 2005;83:284 –90. ©2005 by American Society for Reproductive Medicine.) Key Words: Borderline ovarian tumor, conservative treatment, fertility, recurrence

First described by Taylor in 1929 (1), low-malignantpotential ovarian tumors (borderline ovarian tumors) were accepted as a distinct diagnostic category by the International Federation of Gynecology and Obstetrics (FIGO) (2) and the World Health Organization (3) in the early 1970s. Borderline ovarian tumors account for 10%–20% of all ovarian epithelial tumors and in one third of cases are diagnosed before 40 years of age, raising issues regarding the use of conservative surgery to spare fertility (4, 5). Guidelines for surgical treatment of borderline ovarian tumors are similar to those for ovarian cancer and include peritoneal washing, hysterectomy with bilateral salpingooophorectomy, omentectomy, and multiple peritoneal biopsy (6). However, several reports have shown the feasibility of conservative treatment: the risk of recurrence is acceptable, recurrences can be treated surgically, and overall survival is not negatively affected (7–11). Encouraging fertility data have been reported after conservative treatment of both early- and advanced-stage borderline ovarian tumors (9,

Received April 3, 2004; revised and accepted October 11, 2004. Reprint requests: Emile Daraï, M.D., Ph.D., Service de GynécologieObstétrique, Hôpital Tenon, 4 rue de la Chine, Paris 75020, France (FAX: 33-1-56-01-73-17; E-mail: [email protected]).

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12–15). However, little is known regarding the determinants of fertility in this setting. We therefore sought to identify epidemiologic, surgical, or histologic parameters influencing fertility after conservative treatment of borderline ovarian tumors. MATERIALS AND METHODS From January to December 2001, we conducted a retrospective multicenter study of 360 women treated for borderline ovarian tumors from 1990 to 2000 in 13 specialized gynecologic units and one cancer center in France. For this retrospective study, institutional review board approval was not required. The histologic type was established by review of hematoxylin-eosin–stained slides, essentially as recommended by FIGO (6). The following histologic criteria were used to identify borderline tumors: [1] stratification of the epithelial lining of the papillae, with microscopic papillary projections or tufts arising from the epithelial lining of the papillae, [2] nuclear atypia, [3] mitotic activity, [4] intracystic clusters of free-floating cells, and [5] absence of stromal invasion. We did not exclude patients with borderline serous ovarian tumors exhibiting micropapillary features, patients

Fertility and Sterility姞 Vol. 83, No. 2, February 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.

0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2004.10.009

TABLE 1 Epidemiologic characteristics of women undergoing conservative vs. radical treatment for borderline ovarian tumors. Characteristic

Conservative group (n ⴝ 162)

Radical group (n ⴝ 198)

P

35.5 ⫾ 13.1 1.3 ⫾ 1.6 0.9 ⫾ 1.2 87 (53.7) 16 (9.9) 24

55.7 ⫾ 13.0 2.1 ⫾ 1.7 1.8 ⫾ 1.5 44 (22.2) 120 (60.6) 20

⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 NS

17 3

11 11

NS

26/82 (31.7) 95 ⫾ 332 9.7 ⫾ 6.2

61/138 (44.2) 126 ⫾ 367 11.9 ⫾ 7.8

.06 NS ⬍.009

59 6 9 20 1 67

46 14 2 35 8 93

Age (y) Gravidity Parity Nulliparous Menopausal History of infertility (n ⫽ 44) Previous history of surgery Cystectomy Unilateral salpingooophorectomy Preoperative serum levels CA125 ⬎ 35 IU/mL CA125 (IU/mL) Tumor size (cm) Circumstance of diagnosis Pelvic pain Menometrorrhagia Infertility Abdominal mass Urinary symptoms Routine examination

NS

Note: Data are presented as mean ⫾ standard deviation or n (%). NS ⫽ not significant. Fauvet. Fertility and borderline ovarian tumor. Fertil Steril 2005.

with mucinous borderline tumors with features of intraepithelial carcinoma, and patients with microinvasion. The histologic diagnosis of borderline ovarian tumor was performed on ovarian lesion. Surgical treatment was considered conservative when one ovary and the uterus were respected. Conservative ovarian treatment consisted of unilateral cystectomy, unilateral salpingo-oophorectomy, unilateral salpingo-oophorectomy plus contralateral cystectomy, or bilateral cystectomy. Surgical treatment was considered nonconservative when bilateral salpingo-oophorectomy was performed. The initial surgery was considered a complete staging operation when all peritoneal surfaces were carefully inspected and peritoneal washing, random or oriented multiple biopsies, and infracolonic omentectomy were performed. Systematic appendectomy was also a criterion for complete staging of mucinous borderline tumors. Initial surgical staging was considered incomplete in all other cases, independently of the radical or conservative nature of treatment. Disease was staged as recommended by FIGO (6). For this analysis, the complete or incomplete nature of initial staging was not taken into account when forming the Fertility and Sterility姞

conservative and radical treatment groups. Information regarding subsequent fertility was obtained from the hospital records, physicians, and patients. When assessing fertility after conservative treatment, we distinguished between women who expressed the desire to conceive and those who stated they did not wish to conceive. Only women aged ⬍43 years who had at least 12 months of postsurgical follow-up were included. For statistical analysis, the ␹2 test and Student’s t test were used. P values of ⬍.05 were considered significant. RESULTS The epidemiologic characteristics of the women with borderline ovarian tumors, according to the conservative or radical nature of treatment, are shown in Table 1. Among the 360 women with borderline tumors, 210 (58.4%) did not have an intraoperative histologic examination. Intraoperative histologic examination was performed in 150 patients (41.6%). This led to the diagnosis of a borderline tumor in 97 patients (64.7%) and showed a benign tumor or a carcinoma or failed to distinguish between a borderline 285

TABLE 2 Epidemiologic characteristics of women who conceived and women who did not conceive after conservative treatment for borderline ovarian tumors. Characteristic

Women who conceived (n ⴝ 21)

Women who did not conceive (n ⴝ 44)

P

84.8 ⫾ 52.1 26.7 ⫾ 5.6 0.5 ⫾ 0.9 0.4 ⫾ 0.9 17/21 3/21

60.6 ⫾ 46.0 32.3 ⫾ 6.5 1.2 ⫾ 1.5 0.7 ⫾ 1.1 28/44 13/44

NS .001 NS NS NS NS

2 0

0 2

NS

1/6 25.5 ⫾ 15.0 11.4 ⫾ 5.2 4 1 13 3 0

14/26 107.0 ⫾ 151.7 10.4 ⫾ 7.7 12 3 16 10 3

NS NS NS

Follow-up (mo) Age (y) Gravidity Parity Nulliparous History of infertility (n ⫽ 44) Previous history of ovarian surgery Cystectomy USO Preoperative serum levels CA125 ⬎ 35 IU/mL CA125 (IU/mL) Tumor size (cm) UC Bilateral cystectomy USO USO ⫹ wedge biopsy UC ⫹ USO

NS

Note: Data are presented as mean ⫾ standard deviation or n. NS ⫽ not significant; USO ⫽ unilateral salpingooophorectomy; UC ⫽ unilateral cystectomy. Fauvet. Fertility and borderline ovarian tumor. Fertil Steril 2005.

and malignant tumor in 34 patients (22.7%), 3 patients (2%), and 16 patients (10.6%), respectively. Among the 360 women treated for borderline ovarian tumors, 162 (45%) underwent conservative treatment, and 198 (55%) underwent radical treatment.

treatment groups. Recurrences were significantly more frequent in the conservative treatment group (P⫽.0002). No cases of recurrent carcinoma occurred during the period study, and none of the conservatively treated women died of the disease.

The borderline tumors were generally diagnosed after a pelvic mass was found during routine examination or the patient presented with pelvic pain; the diagnostic circumstances did not differ between the conservative and radical treatment groups.

Regarding fertility after conservative treatment, 21 (32.3%) of the 65 conservatively treated women who wished to conceive became pregnant. The epidemiologic characteristics of the women who conceived and those who did not conceive after conservative treatment are shown in Table 2. The two subgroups did not differ according to the mean length of follow-up. The women who conceived were, on average, younger than the women who did not conceive (26.7 ⫾ 5.6 years vs. 32.3 ⫾ 6.5 years; P⫽.001), whereas the two subgroups did not differ according to the proportion of nulliparous women, the history of infertility or ovarian surgery, preoperative tumor marker levels, tumor size, or the type of conservative treatment. In the group of women who did not conceive, 8 patients underwent unsuccessful infertility treatment, including 3 women who required IVF attempts.

Women undergoing conservative treatment were significantly younger (35.5 ⫾ 13.1 years [mean ⫾ SD] vs. 55.7 ⫾ 13.0 years; P⬍.0001) and more likely to be nulliparous (53.7% vs. 22.2%; P⬍.0001) than women who underwent radical surgery. Tumor size was significantly smaller in the conservative treatment group (9.7 ⫾ 6.2 cm vs. 11.9 ⫾ 7.8 cm; P⬍.009). The proportions of women with a history of infertility or surgery for adnexal masses did not differ between the two treatment groups. Elevated preoperative serum CA125 levels were slightly but not significantly more frequent in the radical treatment group than in the conservative treatment group. Recurrences were diagnosed in 27 women (16.6%) and 9 women (4.5%), respectively, in the conservative and radical 286

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Pregnancy outcomes are shown in Table 3. The interval between surgery and conception was 28.6 ⫾ 24.6 months (range, 4 – 89 months). Twenty-one patients had a total of 30 pregnancies. Of the 30 pregnancies, 27 were spontaneous, Vol. 83, No. 2, February 2005

TABLE 3 Pregnancy outcome after conservative treatment for borderline ovarian tumors. Characteristic Patients who conceived Pregnancies Age at conception (y) Time to conceive (mo) Spontaneous pregnancies Induction of ovulation ⫹ IUI IVF First-trimester abortion Elective abortion Term deliveries Live newborns Singletons Twins Vaginal delivery Cesarean section

Data 21 30 29.2 ⫾ 5.2 28.6 ⫾ 24.6 27 1 2 5 8 17 18 16 2 15/17 2/17

Note: Data are presented as mean ⫾ standard deviation or n. Fauvet. Fertility and borderline ovarian tumor. Fertil Steril 2005.

and 3 occurred after ovarian stimulation and IUI (1 case) or IVF (2 cases). The three women requiring fertility treatment had stage Ia, stage Ic, and stage IIIc ovarian disease. Seventeen pregnancies went to term, and the offspring were all normal. Eight elective terminations were performed, for personal reasons. There were five tumor recurrences (23.8%) among the women who conceived. Four occurred after salpingooophorectomy and one after cystectomy (on the ipsilateral ovary). There were 11 recurrences (33.3%) among the women who did not conceive: 5 after cystectomy (on the ipsilateral ovary) and 6 after salpingo-oophorectomy. The recurrence rate did not differ according to conception status. The time to recurrence among women who conceived and those who did not conceive was 39.6 ⫾ 28.2 and 22.9 ⫾ 14.9 months, respectively (P⫽.13). Two of the five recurrences among women who conceived occurred before conception. The women concerned became pregnant after IUI (one case) and IVF (one case). The recurrences in the other three women were diagnosed at sonography at routine follow-up visits 9 months and 4 years after delivery and during the first trimester of pregnancy in the last case, which was treated by laparoscopic cystectomy and was associated with legal abortion. No recurrences were seen in two women who underwent cesarean section for obstetric reasons. Factors potentially influencing fertility after conservative treatment for borderline ovarian tumors are shown in Table Fertility and Sterility姞

4. Only age at diagnosis seemed to have an impact on postsurgical fertility. No pregnancies occurred among women aged ⬎40 years, and the conception rate was higher among women aged ⬍35 years (42%) than among those aged 35– 40 years (20%). The histologic type, disease stage, surgical approach, and type of conservative treatment did not influence subsequent fertility. DISCUSSION This multicenter study confirms that conservative treatment of borderline ovarian tumors, in an attempt to preserve fertility, is an acceptable alternative to radical surgery. One hundred sixty-two women (45%) underwent conservative treatment, a rate far higher than in earlier studies (11, 16 – 19). This difference is probably due to the fact that all our patients were treated after 1990, whereas many previous studies began before conservative management of borderline ovarian tumors was widely accepted (7, 8, 20). Another possible explanation is that radical treatment, particularly for early-stage disease, remains controversial, owing to its modest impact on clinical management and outcome (21, 22). No clear guidelines have been published regarding the selection of women qualifying for conservative treatment of borderline ovarian tumors. In the current study, conservative treatment was mainly offered to young nulliparous women. This is in keeping with the general epidemiologic characteristics of women with borderline ovarian tumors, who are approximately 10 years younger and more often nulliparous than women with frankly malignant ovarian tumors (23). In contrast, a history of infertility and previous surgery for ovarian tumors did not influence the choice of conservative surgery. Since the first reported use of salpingo-oophorectomy for borderline ovarian tumors, published by Tazelaar et al. (20), several investigators (4, 7–10, 19) have confirmed the feasibility of cystectomy, with an acceptable recurrence rate. In the current study, the recurrence rate was higher after conservative surgery than after radical surgery, but none of the patients died of the disease, and no cases of recurrent carcinoma were observed during the study period. The rate of recurrence observed here after conservative treatment is in keeping with previous reports, in which it was as high as 30% (8 –10, 15, 24, 25). Hence, conservative management of borderline ovarian tumors, including the higher risk of relapse, should be discussed with the patient and family. Nearly one third of women wishing to conceive after conservative treatment for borderline ovarian tumor became pregnant in our study. This pregnancy rate is in keeping with previous reports (10, 13, 15, 18, 25) confirming that conservative treatment can spare fertility. Apart from age at diagnosis, we identified no other determinants of fertility after conservative surgery for borderline ovarian tumors, including epidemiologic characteristics, preoperative tumor marker levels, tumor size, the type of conservative treatment, and 287

TABLE 4 Determinants of fertility after conservative treatment for borderline ovarian tumors.

Characteristic Age at diagnosis (y) ⬎40 ⬍ 43 ⱖ35 ⬍ 40 ⬍35 Histology Serous Mucinous Serous and mucinous Disease stage Ia ⬎Ia Laparotomy Laparoscopy Unilateral ovarian surgery Bilateral ovarian surgery (wedge biopsy included) Alive without recurrence Alive with disease Died

Women who conceived (n ⴝ 21)

Women who did not conceive (n ⴝ 44)

0 3 18

7 12 25

.04

11 8 2

26 16 2

NS

18 3 14 7 17 4 20 1 0

32 12 26 18 28 16 41 3 0

P

NS NS NS

NS

Note: Data are presented as n. NS ⫽ not significant. Fauvet. Fertility and borderline ovarian tumor. Fertil Steril 2005.

histologic type. In light of our data, when the diagnosis of unilateral borderline nature of the ovarian lesion is accessible by intraoperative histology, because of the high recurrence rate and the absence of negative impact of salpingooophorectomy on subsequent fertility, it seems logical to recommend a unilateral salpingo-oophorectomy. The vast majority of pregnancies in this study were spontaneous. The mean interval between surgery and conception exceeded 2 years. This long interval could be partly explained by the relatively high proportion of women with postsurgical infertility but also by recommendations given to women who underwent conservative treatment. Previous studies have shown that most recurrences occur during the first 2 years after primary treatment (10, 11, 16), and women are therefore often advised to wait before attempting to conceive. Moreover, the occurrence of postoperative adhesions might interfere on subsequent fallopian tube function. In our study, the time to recurrence (slightly less than 2 years) tended to be less among patients who did not conceive. This might have biased the fertility analysis, because some women who had a recurrence during the first 2 postoperative years might have decided against becoming pregnant. However, there is no evidence that conception during this period increases the risk of recurrence. We found no difference in the recurrence rate between patients who conceived and those who did not conceive. Moreover, among 288

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the five recurrences observed in women who conceived, two were diagnosed before conception, one during the first trimester of pregnancy, and two after delivery. It is therefore difficult to recommend a precise interval before attempting to conceive. Previous studies have also failed to show a relationship between pregnancy and recurrence (13, 15, 18, 24). The live birth rate was in keeping with previous reports (4, 7, 8, 13, 15, 18, 24, 26 –28). The high number of abortions underlines these patients’ mixed feelings, opposing the desire to become pregnant and the fear of relapse after pregnancy. In the study by Morice et al. (18), there were three terminations among the 17 pregnancies occurring after conservative treatment for borderline tumors. In our study, one pregnancy occurred after IUI and two after IVF. Few data are available regarding women who undergo fertility treatment after conservative surgery for borderline ovarian tumors. Reports describing four cases of induced ovulation in this setting (29, 30) mentioned no disease recurrences during a follow-up of 2–5 years. Morice et al. (18) suggested that induction of ovulation should only be offered to women with stage Ia disease. However, in women with advanced-stage borderline tumors, Nijman et al. (30) and Mantzavinos et al. (29) reported the feasibility and safety of IUI or IVF. Abu-Jawdeh et al. (31) reported that estrogen receptor overexpression was a common feature of Vol. 83, No. 2, February 2005

ovarian tumors, theoretically suggesting that the high estrogen levels induced by superovulation might have a negative impact on overall and disease-free survival. However, in a French multicenter study (32) of 16 women with borderline tumors requiring induction of ovulation, five pregnancies were obtained, and no recurrences were observed. Founder mutations in BRCA1 and BRCA2 could be potentially used to select women for conservative surgery and infertility treatment, but previous studies (33–35) have shown that the incidence of BRCA mutations in women with borderline tumors is too low for this purpose. Ovarian cryopreservation could be an alternative to induction of ovulation for women with bilateral or advanced-stage borderline tumors. However, despite encouraging results with ovarian cryopreservation in animal studies (36, 37), no human data have been published. In conclusion, our results confirm that conservative management is a reasonable option for women with borderline ovarian tumors who wish to preserve their fertility. Age at diagnosis seems to be the sole determinant of posttreatment fertility. Our results suggest that approximately one third of women undergoing conservative surgery for borderline ovarian tumors will be able to conceive. Acknowledgments: The authors thank the participating centers: Centre Hospitalier Universitaire Angers (Prof. Descamps); Centre de Recherche et de Lutte contre le Cancer Paul Papin Angers (Dr. Fondrinier); Centre Hospitalier Général Le Mans (Dr. Pillot); Centre Hospitalier Universitaire Lille (Prof. Querleu); Centre Hospitalier Universitaire Marseille (Prof. Blanc); Centres Hospitaliers Universitaires Paris: Hôpital Béclère (Prof. Fernandez), Hôpital Bichat (Prof. Madelenat), Hôpital Cochin (Prof. Chapron), Hôpital de la Pitié-Salpétrière (Prof. Blondon, Prof Darbois), Hôpital SaintAntoine (Prof. Milliez), Hôpital Tenon (Prof. Uzan); Centre Hospitalier Général Roubaix (Prof. Querleu); and Centre Hospitalier Universitaire Strasbourg (Prof. Baldauf, Prof. Nisand).

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