Innovations in fertility preservation for patients with gynecologic cancers

MODERN TRENDS Edward E. Wallach, M.D. Associate Editor Innovations in fertility preservation for patients with gynecologic cancers Wen-Shiung Liou, M.D., a,c O. W. Stephanie Yap, M.D., a John K. Chan, M.D., a and Lynn M. Westphal, M.D. b Divisions of a Gynecologic Oncology and b Reproductive Endocrinology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Palo Alto, California; and c Department of Obstetrics and Gynecology, Veteran General Hospital, Kaohsiung, Taiwan Objective: To review options for fertility preservation in women with gynecologic cancers. Design: Literature review. Result(s): We discuss the data regarding cancer treatment and fertility outcomes and current controversies for women with gynecologic cancers. Conclusion(s): Gynecologic cancers represent 12% 15% of cancers affecting women, and 21% of these are diagnosed in women of reproductive age. Current advances in our understanding of these diseases, along with improved multimodality treatment, allow for consideration of fertility options. For some women with gynecologic cancers, fertility-sparing treatment might be appropriate. (Fertil Steril 2005;84:1561 73. 2005 by American Society for Reproductive Medicine.) Key Words: Fertility preservation, gynecologic cancers, cervix, ovary, endometrium, assisted reproductive technologies Progress in preserving reproductive function in patients with gynecologic malignancies has been made owing to advances in surgical techniques, molecular pathology, and combinedtreatment modalities. These developments have allowed identification of patients who can benefit from a conservative approach without compromising long-term outcome. Although the majority of gynecologic cancers are diagnosed in older women, 21% occur in women of reproductive age (1). A small but growing number of these women seek alternatives to standard treatments so as to preserve fertility. In addition, advances in assisted reproductive technology have allowed some women to achieve pregnancy when otherwise impossible. This article will review the literature and discuss fertility-sparing procedures in carefully selected women with gynecologic cancers and their subsequent reproductive and treatment outcomes. CERVICAL CANCER Recent data show that 10% 15% of cervical cancers are diagnosed in women of childbearing age (2). Despite an Received February 9, 2005; accepted April 7, 2005. Reprint requests: Lynn M. Westphal, M.D., Stanford University School of Medicine, Department of Obstetrics and Gynecology, 300 Pasteur Drive, Stanford, California 94305-5317 (FAX: 650-723-7737; E-mail: lynnw@stanford.edu). overall decline in the incidence of invasive cervical cancer, there is a trend toward a rise in the rate of adenocarcinoma in U.S. women aged 30 years (3). Traditionally, invasive cervical cancer has been treated by radical hysterectomy or radiation therapy. A less radical approach simple hysterectomy or therapeutic conization of the cervix is possible to consider in microinvasive cervical cancers. Microinvasive Cervical Cancer Stage IA1. The concept of microinvasive cervical cancer was introduced in 1927 by Mestwerdt (4). The basis for this classification was to identify a subset of patients with early cervical carcinoma who had a favorable prognosis. Nodal and parametrial involvement are rare in these patients, and the risk of relapse after conservative treatment is 0.5% (5, 6). Standard treatment for International Federation of Gynecology and Obstetrics (FIGO) stage IA1 disease is a simple hysterectomy without nodal dissection or, in select cases, conization of the cervix (7). Although lymphovascular space invasion (LVSI) does not affect staging, its presence has typically precluded use of these less-radical surgical approaches. Stage IA1 squamous cell cancer of the cervix can be treated with conization, with the following caveats: negative margin, absence of LVSI, and normal endocervical curettage. Data on the conservative management of microinvasive 0015-0282/05/$30.00 Fertility and Sterility Vol. 84, No. 6, December 2005 doi:10.1016/j.fertnstert.2005.03.087 Copyright 2005 American Society for Reproductive Medicine, Published by Elsevier Inc. 1561

adenocarcinoma are limited, however. With respect to stage IA1 adenocarcinomas with negative margins, investigators have reported encouraging data on treatment with cervical conization alone in two small series. In one of the series, none of five women with either adenocarcinoma or adenosquamous carcinomas had recurred with 6 20 months of follow-up (8). None had LVSI. McHale et al. (9) treated four women with stage IA1 adenocarcinoma conservatively, and none recurred with a median follow-up of 48 months. Therefore, given current data, cold knife conization can be an option for a wellinformed patient willing to accept the risk of possible recurrence. In this setting, the patient should also realize that although fertility is usually not affected by conization, the risk of spontaneous second-trimester loss and prematurity are greater (10). It is important, when therapeutic cervical conization for FIGO stage IA1 disease is performed, that the specimen be removed in a single piece to facilitate histopathologic evaluation. Diathermy loop excision should not be used as a diagnostic or therapeutic modality for microinvasive lesions because it is known frequently to produce a fragmented specimen, making evaluation of the margins and depth of invasion difficult. Stage IA1 with LVSI and stage IA2. Patients with FIGO stage IA1 with LVSI and stage IA2 disease have a 5% 9% risk of lymph node metastasis. Standard management has been either a radical or modified radical hysterectomy with pelvic lymph node dissection (7). More recently, on the basis of data from retrospective studies, conization or simple hysterectomy has been performed (11, 12). Yaegashi et al. (11) treated 22 patients who had tumors with 3 5-mm depth of invasion and horizontal spread of 3.3 9.8 mm conservatively (conization or simple hysterectomy) with no adjuvant treatment. None showed LVSI, and no relapses were observed after a median follow-up of 66.5 months. Girardi et al. (12) reviewed 69 patients with small stage IB tumors and a median tumor TABLE 1 Patients and tumor characteristics for vaginal radical trachelectomy. Study (reference) Characteristic Mathevet (23) (n 96) Plante et al. 2004 (24) (n 72) Steed and Covens 2003 (25) (n 93) Shepherd et al. 2001 (27) (n 30) Burnett et al. 2003 (19) (n 19) Schlaerth et al. 2003 (17) (n 10) Age (y) 32 (22 43) 31 (22 42) 30 (25 46) N/A 30 (23 41) 31 (22 44) Stage IA1 13 4 39 0 0 0 IA2 14 23 22 0 1 8 IB1 56 43 31 30 18 2 IB2 1 0 1 0 0 0 IIA 7 2 0 0 0 0 IIB 5 0 0 0 0 0 Histologic type Squamous 76 42 42 21 10 4 Adenocarcinoma 19 26 44 8 9 5 Adenosquamous 0 3 0 1 0 1 Small cell 1 (neuroendocrine) 1 (neuroendocrine) 0 0 0 0 Others 0 0 0 0 0 0 Lymphovascular space invasion No 69 58 62 N/A 17 9 Yes 27 14 31 N/A 2 1 Size (cm) 2 75 64 85 29 19 10 2 21 8 8 1 0 0 Abandoned trachelectomies 13/108 (12) 10/82 (12) 0/93 (0) 4/30 (18) 2/21 (10) 2/12 (17) Note: Data are presented as n (%) or median (range). N/A not applicable. Liou: Fertility preservation for gynecologic cancers. 1562 Liou et al. Fertility preservation for gynecologic cancers Vol. 84, No. 6, December 2005

volume of 270 mm. Depth of invasion exceeded 5 mm in 16 patients (23%), and the tumor width was 7 mmin61 (81%). Twenty-seven patients were treated conservatively, and none developed recurrent disease with a follow-up period of 2 35 years. Stage IB1. The conventional treatment of women with stage IB cervical cancer consists of either radical hysterectomy and bilateral pelvic lymph node dissection or external beam irradiation with local brachytherapy (13). Both techniques result in the loss of fertility for patients with invasive cervical carcinoma. Radical trachelectomy with or without lymph node dissection, as a fertility-sparing option, has been described for early-stage invasive cervical cancer that would otherwise have been treated by radical hysterectomy. Radical Trachelectomy This procedure can be performed by either an abdominal or vaginal approach in conjunction with laparoscopy. In 1994, Dargent et al. (14) first presented a radical vaginal trachelectomy with laparoscopic pelvic lymphadenectomy approach to remove the affected part of the cervix and the parametrium, leaving the body of the uterus intact. His initial experience has now been expanded and performed by others (15 19). The procedure starts with the performance of a laparoscopic pelvic lymphadenectomy. Nodal status is evaluated by frozen section. If lymph nodes are negative, the surgery proceeds to the trachelectomy. Briefly, the radical vaginal trachelectomy consists of a vaginotomy, paravaginal and paracervical dissection, ligation of the descending branch of the uterine artery, ureterolysis, and transection of the distal cervix (16). The goal is to leave approximately 1 cm of proximal cervix below the isthmus (17). A cerclage is then placed in the remaining cervix with a large permanent suture (no. 1 Ethibond, Prolene, or Mersilene; Ethicon,) and the vaginal mucosa sutured to the circumference of the cervical stump. The final specimen is checked thoroughly, particularly at the endocervical margin, and submitted to the pathology laboratory for frozen section. A clear margin of 5 8 mm is considered adequate; otherwise more endocervix is removed, or a complete radical vaginal hysterectomy is performed (18, 20). We reviewed the most recently published series of radical vaginal trachelectomy from France (21 23), Quebec (20, 24), Toronto (16, 25, 26), London (27), and the United States (17, 19). Table 1 summarizes patient and tumor characteristics. A total of 320 twenty patients are included, with comparable outcomes in all series. The majority of lesions was squamous cell cancers, stage IB1 or less, measured 2 cm, and did not have LVSI. Covens et al. (16) also compared the recurrence rate in patients treated by trachelectomy with two matched controls treated by radical hysterectomy. No significant differences in recurrence-free survival were identified between groups. Conversion to laparotomy has been reported, with a rate of 0 17% (24), for lymph nodes metastasis (19, 24), more extensive endocervical extension (17, 19, 24), repair of bladder injury (21), and for control of bleeding (21, 24). The overall morbidity was low, with the most frequent complications related to the laparoscopic portion of the procedure. Three patients had transient nerve injuries (two obturator and one peroneal) (19). Table 2 summarizes the oncologic outcomes after trachelectomy. The mean follow-up time was 23 76 months in these series. The overall incidence of recurrence was 4.7% (15 of 320 patients). Sixty percent of recurrences occurred in women with lesions 2 cm, and 50% were in those with LVSI (28). Dargent et al. (22) reported a 19% recurrence rate TABLE 2 Oncologic outcome of vaginal radical trachelectomy. Study (reference) Mathevet (23) (n 96) Plante et al. 2004 (24) (n 72) Steed and Covens 2003 (25) (n 93) Shepherd et al. 2001 (27) (n 30) Burnett (19) (n 19) Schlaerth (17) (n 10) Follow-up (mo) 76 (4 176) 60 (6 156) 30 (1 103) 23 (1 64) 32 (8 81) 48 (28 84) Pelvic node 21 32 (11 107) N/A N/A 23 (11 38) 23 (9 40) count Positive nodes 3 1 1 2 1 0 Recurrence 5 (5.2) a 3 (4.2) a 7 (7.5) 0 0 0 Deaths 4 (4.2) a 2 (2.8) a 4 (4.3) 0 0 0 Note: Data are presented as n (%) or median (range). N/A not applicable. a One patient with neuroendocrine histology. Liou: Fertility preservation for gynecologic cancers. Fertility and Sterility 1563

for patients with tumors 2 cm and a 25% recurrence rate for patients with tumors 2 cm along with depth of invasion 1 cm. Morice et al. (28) reported the first centropelvic (involving the preserved uterus) recurrence after radical vaginal trachelectomy. The previous published cases of recurrence were either parametrium (four cases), pelvic sidewall (two cases), pelvic nodes (one case), para-aortic nodes (three cases), supraclavicular nodes (one case), adrenal (one case), lung and liver (one case), or intra-abdominal (two cases) (24, 26, 28). Five recurrences were noted in Dargent s latest series (22); four of five had lesions 2 cm. The one recurrence with tumor 2cmwas stage IB1 with neuroendocrine histology. However, these recurrence rates are comparable to those reported for patients undergoing radical hysterectomy (16, 29). Several reports have suggested criteria for considering a radical trachelectomy (20 23, 28, 30). They include [1] desire to preserve fertility, [2] no clinical evidence of impaired fertility, [3] Stage IA2 or IB, [4] lesion size 2 cm, [5] no adenocarcinoma histology, [6] no capillary space involvement, [7] limited endocervical involvement on colposcopic examination, [8] no pelvic nodal disease, and [9] no deep stromal infiltration. However, Schlaerth et al. (17) concluded that adenocarcinoma histology is not a contraindication to radical vaginal trachelectomy, on the basis of 5 of 10 patients who were managed successfully without evidence of disease during a mean follow-up period of 47.6 months. Indeed, 35% of patients (112 of 320) who underwent a radical trachelectomy had an adenocarcinoma (see Table 1); the histologic type (with the exception of the neuroendocrine tumor) had no influence on the outcome of patients (17, 22). Interestingly, of the women who attempted to conceive in the Covens et al. series (16), five had a prior history of infertility, yet three became pregnant spontaneously. Therefore, a history of infertility should not necessarily exclude patients from this procedure. Table 3 shows that the majority of women have been successful in conceiving after trachelectomy. Altogether, 148 pregnancies in 97 women have been reported, resulting in 93 live births. Covens et al. (16) reported that all women in their series became pregnant within 12 months of attempting to conceive. Bernardini et al. (31) reported a median time to conception of 6 months (range, 1 62 months) in their series. TABLE 3 Obstetric outcome of vaginal radical trachelectomy. Study (reference) Mathevet (23) (n 96) Plante et al. 2004 (24) (n 72) Steed and Covens 2003 (25) (n 93) Shepherd et al. 2001 (27) (n 30) Burnett (19) (n 19) Schlaerth (17) (n 10) Attempt to 42 42 39 13 4 4 conceive Total no. 56 (33) 48 (31) a 22 (18) 14 (8) 4 (3) 4 (4) pregnancies (no. of women) Live birth 34 28 18 9 2 2 Neonatal N/A 2 0 0 0 0 death First trimester 9 8 2 3 0 0 miscarriage Voluntary 3 2 0 0 0 0 abortion Second 8 2 2 1 1 2 trimester miscarriage Unable to conceive 9 N/A 9 3 N/A N/A Note: Data are presented as n, unless otherwise specified. N/A not applicable. a Eight patients with ongoing pregnancy. Liou: Fertility preservation for gynecologic cancers. 1564 Liou et al. Fertility preservation for gynecologic cancers Vol. 84, No. 6, December 2005

Because cervical incompetence is related to the amount of cervix surgically removed, the risks of second trimester miscarriage, preterm premature rupture of membranes (PPROM), PROM, premature labor, and prematurity after trachelectomy are significant. In Bernardini s series (31), 5 of 18 pregnancies developed PPROM with subsequent premature delivery. Shephard et al. (27) reported that 7 of 9 pregnancies resulted in premature live births. Two other series (20, 21) have also identified PROM and the resulting labor as problematic in this patient population. Dargent et al. (21) have proposed complete closure of the cervix during pregnancy with a technique, called early total cervical occlusion, previously described by Saling in 1981 (32) for patients with habitual abortions. Only 1 of the 6 patients who underwent this procedure had premature labor, as compared with 6 of 21 patients before the routine use of the Saling procedure. Sentinel Node Work on evaluating the sentinel node for parametrial spread of disease in cervical cancer has just begun (33). The concept holds that the sentinel node is the first node in the lymphatic system that drains the primary tumor site. If the sentinel node does not contain tumor metastasis, all other nodes should be free of disease (34). Its identification and subsequent pathological processing might therefore help reduce the number of patients undergoing extensive lymphadenectomy. Sentinel node biopsy has been proved to be a feasible and reliable technique for assessing lymph node status in breast cancer and melanoma. In cervical cancer, Dargent et al. (35) reported a 100% sentinel node detection rate in 35 patients who were evaluated laparoscopically with sufficient injection of blue violet dye. A procedure failure rate of 14.5% was attributed to an insufficient quantity of dye being injected. Others have found a higher detection rate with combination technetium-99m-labeled nanocolloid and blue dye injection (36). ENDOMETRIAL CANCER Although endometrial cancer is usually a disease of postmenopausal women, 2% 14% of cases occur in women aged 45 years (37). The diagnosis of endometrial carcinoma in a young woman is typically associated with a hyperestrogenic state. Up to 25% of these cases occur in patients with polycystic ovarian syndrome. The majority of young women with endometrial cancer have a well-differentiated adenocarcinoma that is often estrogen receptor positive and has no or minimal myometrial invasion (38). These patients have an excellent prognosis, with a cure rate exceeding 95% (39). The standard therapy for endometrial carcinoma consists of a staging laparotomy with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Conservative treatment with high-dose medroxyprogesterone acetate has recently been described in premenopausal women with endometrial carcinoma who have a strong desire to maintain their fertility (40). Earlier work by Bokhman et al. (41) showed that a short preoperative course of progestin therapy before hysterectomy could reverse up to 24% of the well-differentiated carcinomas. Most conservative therapies are based on the hormonal sensitivity of endometrial cancer and the presence of estrogen, P, and GnRH receptors (42). Progestational Agents From several small series, investigators have reported on the use of progestational agents in young women with endometrial adenocarcinoma and atypical complex hyperplasia (38, 43, 44). The most frequently used progestins are megestrol acetate at 40 160 mg/day and medroxyprogesterone acetate at 200 600 mg/day. Response rates vary from 83% to 94% for atypical hyperplasia and from 57% to 75% for endometrial adenocarcinoma (38, 43). Randall and Kurman (38) reported one of the larger series, in which 16 of 17 women (94%) with complex atypical hyperplasia and 9 of 12 (75%) with well-differentiated endometrial cancer were successfully treated with high-dose progestins. The median length of treatment required to achieve disease regression was 9 months (38). Most responses occurred in the first 3 6 months of treatment, and close monitoring with dilatation and curettage was performed at regular intervals, usually every 3 to 6 months. In the Gotlieb et al. series (45), 13 patients responded within a mean time of 3.5 months, with a mean follow-up of 82 months. Six of these patients recurred with a median time of 40 months (range, 19 358 months), and 4 were treated with a second course of progestins and had complete histologic responses. Nine healthy infants were born, and all patients show no evidence of recurrence. Some investigators have successfully prolonged treatment in partial responders to 1 year and achieved complete reversal (46). Long-term treatment with high-dose progestins, however, is associated with increased risk of phlebitis (5% 10%) (47). Concerns about conservative treatment relate to treatment failure and delayed definitive therapy that might have implications on prognosis. In atypical hyperplasia, a recurrence rate of 13% was observed, whereas in endometrial adenocarcinoma, the recurrence rate varied from 11% to 50% (38, 43 45). Kim et al. (43) described 3 of 13 patients (23%) with apparent initial responses to progestins who subsequently developed recurrences. One patient was retreated with megestrol acetate but was later found to have adenocarcinoma after a hysterectomy. The second patient underwent a hysterectomy but had extrauterine spread of disease and received postoperative radiation and progestin therapy. At 27 months after surgery, she was alive with disease. The third patient was retreated with progestin, with no further follow-up available. Similarly, in a report by Vinker et al. (48), a patient with a well-differentiated adenocarcinoma ultimately underwent a radical hysterectomy after 4 months of unsuccessful progestin treatment and required adjuvant radiotherapy for disease Fertility and Sterility 1565

invading one third of the myometrium. Conversely, Randall and Kurman (38) reported on the successful retreatment with progestin of one patient with a recurrence of endometrial cancer who eventually conceived and delivered a healthy infant. Several investigators have reported on obstetric outcomes after conservative treatment of endometrial carcinoma. Kim et al. (43) reported that 3 patients had successful pregnancies in the 21 patients they treated or found in the literature. Jadoul et al. (49) described 26 patients aged 40 years (range, 15 38 years) who underwent conservative treatment of endometrial adenocarcinoma and had subsequent pregnancies. Thirty-one pregnancies were reported in 26 patients, and at least 17 pregnancies occurred in 15 women after ovarian stimulation or IVF (55%) (49). In another series, investigators described 4 infertile women (2 with stage I grade 1 endometrial carcinoma, 2 with complex hyperplasia with atypia) who were successfully treated with progestins. Successful pregnancy outcomes were achieved in 3 of the 4 women with ART (50). Table 4 summarizes the outcome of conservative treatment of endometrial carcinoma (38, 43 45, 51). Whereas earlier studies reported only an occasional patient with synchronous uterine corpus and ovarian tumors, more recent investigations have indicated a significant incidence of simultaneous endometrial and ovarian neoplasms (16% 29%) (37, 52 54). Gitsch et al. (37) found five cases of simultaneous primary ovarian neoplasms in his series of 17 women aged 45 years, for a 29% incidence, compared with a 4.6% incidence (11 of 237) in older patients. Results from another study suggested that nulliparity, which occurs with a higher prevalence in younger women who develop endometrial cancer, is an independent risk factor for the development of synchronous ovarian malignancies (52). Women with both uterus and ovaries remaining will, therefore, need monitoring of the ovaries as well. GnRH Agonists Literature on the use of GnRH agonists in the medical management of endometrial carcinoma is limited. Two case reports and one small series on GnRH agonist treatment have been published (49, 55, 56). In the case reports, two patients had well-differentiated endometrial adenocarcinoma and were treated with 3 months of GnRH agonists. After 3 months of GnRH agonist therapy, the endometrium was found to be normal in both patients. Long-term follow-up was not reported. In the Jadoul and Donnez series (49), seven patients (aged 27 38 years) were treated with 3 months of GnRH agonist. Five patients had grade I endometrial carcinoma, and two had complex atypical hyperplasia. Two patients showed persistent atypical hyperplasia and were treated for an additional 1 and 3 months, respectively. At the end of this treatment one patient had complex nonatypical hyperplasia, and the other had atypical simple hyperplasia. Both women became pregnant without delay, one spontaneously and the other with IVF. Of the seven patients in this series, six had been referred for infertility evaluation, and five patients conceived with IVF. One patient suffered a miscarriage, but the remaining patients delivered live infants. The most serious side effect of GnRH agonists is bone loss that is related to length of treatment. In general, up to 6 months of GnRH agonist treatment is believed to cause minimal, reversible bone loss. Significant bone loss might occur if treatment is extended beyond 6 months. Outside the United States, add-back therapy with tibolone has been proposed to reduce bone loss in women treated with GnRH agonists for a long period. To date, no data exist regarding TABLE 4 Outcome of conservative treatment of endometrial adenocarcinoma with progestins. Study (reference) n Treatment Duration Regression (n) Recurrence (n) Pregnancy (n) Kim et al. (cases) 7 Megestrol acetate 3mo 4 2 0 1997 (43) (160 mg/d) Kim et al. 1997 (literature 14 Megestrol acetate Up to 1 y 9 1 3 review) (43) or MPA Randall and Kurman 12 Megestrol acetate 3 18 mo 9 1 3 1997 (38) or MPA Kaku et al. 2001 (44) 12 MPA 200 800 mg/d 2 14 mo 9 2 2 Wang et al. 2002 (51) 9 Megestrol acetate N/A 8 4 4 and/or tamoxifen Gotlieb (45) 13 Megestrol acetate or MPA 3.5 mo 13 6 3 Note: MPA medroxyprogesterone acetate; N/A not applicable. Liou: Fertility preservation for gynecologic cancers. 1566 Liou et al. Fertility preservation for gynecologic cancers Vol. 84, No. 6, December 2005

the safety of this additive treatment with tibolone and GnRH in conservatively managed endometrial cancer patients. P-Containing Intrauterine Device Some women with early endometrial cancer might not be able to take or tolerate systemic P therapy. For these individuals, local delivery of P to the endometrium could induce the desired antineoplastic effect, thereby avoiding any associated adverse systemic reactions. The efficacy of a P-containing intrauterine device (IUD) in treating well-differentiated early stage (IA) endometrial carcinoma is unclear. Its feasibility was explored in a study by Montz et al. (57), who treated 12 women with stage IA1 endometrial cancer at high risk of perioperative complications with a P-containing IUD. They were observed for up to 36 months, with biopsies of endometrium negative in 7 of 11 at 6 months and in 6 of 8 at 12 months. No IUD-related complications occurred except for expulsion. Results of this study suggest that continuous intrauterine administration of P can eliminate FIGO grade 1 endometrioid carcinoma in some patients. However, the risk of undetected residual invasive disease exists. In this series, none of the 5 patients with 12 months (and up to 3 years) of intrauterine P therapy have evidence of hyperplasia or cancer. In conclusion, hormone therapy alone for early-stage, low-grade endometrial carcinoma in young women has been reported but remains controversial. Comprehensive guidelines for selection, treatment, and follow-up are not yet established. A number of issues remain to be clarified including [1] consensus regarding optimal progestational agent, dose, and duration of treatment, [2] the optimal surveillance schedule and type of surveillance (e.g., regular dilatation and curettage with or without sonography), [3] a maintenance regimen to prevent recurrent cancer in women after reversal of the adenocarcinoma, [4] the value of imaging studies and surgical interventions, such as laparoscopic staging, as proposed by Sardi et al. (58), to exclude metastatic disease, [5] the safety of ART, and [6] recommendations with regard to hysterectomy after completion of childbearing. Despite the issues raised above, to date 101 patients have undergone primary treatment with progestational agents for well-differentiated endometrial adenocarcinoma (45). A careful clinical approach is warranted, with therapy tailored to the individual circumstance. Assisted reproductive technologies do not seem to adversely impact prognosis. OVARIAN CANCER Invasive Epithelial Carcinoma Epithelial ovarian carcinoma (EOC) is the fourth leading cause of cancer death in women and the second most common gynecologic cancer (59). It is primarily a disease of postmenopausal women. Nevertheless, an estimated 3% 17% of EOCs occur in women aged 40 years (60 62). Likewise, 7% to 8% of all malignant stage I epithelial tumors of the ovary occur in women aged 35 years (63). Standard management of EOC involves primary surgical staging and debulking, including total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy, pelvic and para-aortic lymph node dissection, peritoneal biopsies, and washings of the pelvis and abdomen. Adjuvant chemotherapy might be recommended depending on the stage of disease, histology, and tumor differentiation. Conservative management of early invasive EOC with reasonable outcomes has been described. McHale et al. (64) suggested that in young women with a well-differentiated serous, mucinous, endometrioid, or mesonephric carcinoma of the ovary, a unilateral salpingo-oophorectomy can be performed. The tumor should be unilateral, well encapsulated, free of adhesions, and not associated with ascites or extra-ovarian spread. Given the 33% incidence of bilaterality in stage I serous tumors of the ovary and a 15% incidence for mucinous lesions, the opposite ovary should be examined carefully. In a separate study, only 2 of 56 women (3.6%) who were treated conservatively recurred in the contralateral ovary (65). In another study, 3 of 56 women (5.3%) who were treated conservatively recurred, as compared with 5 of 43 women (11.6%) who were treated radically in stage I disease (66). The pelvic and para-aortic lymph nodes must be carefully palpated and suspicious nodes removed. It is, however, rare for grade 1 ovarian lesions to metastasize to the retroperitoneal nodes (64). Schilder et al. (67) reported on the outcomes of 52 patients with stage I EOC (42 with stage IA and 10 with stage IC disease) who were managed conservatively. Thirty-eight patients had grade 1, 9 had grade 2, and 5 had grade 3 tumors. Median duration of follow-up was 68 months (range, 6 426 months). Five- and ten-year survival rates were 98% and 93%, respectively. The majority of patients (27 of 33) with stage IA grade 1 cancers did not receive chemotherapy. Nineteen patients received adjuvant chemotherapy (mean, six courses; range, 3 12 courses). Eleven patients with stage IA (26%) and 8 patients with stage IC (80%) disease received adjuvant chemotherapy. Four of the five patients who recurred (8 78 months after surgery) had stage IA cancers and one had stage IC disease. Three patients recurred in the contralateral ovary. One was treated with surgery alone and two with surgery followed by chemotherapy. All three of these patients showed no evidence of disease with a mean follow-up time of 21 months. Two deaths were reported in this series. One patient had a stage IA grade 1 mucinous carcinoma and developed a regional recurrence to the abdominal peritoneum 9 months after unilateral adnexectomy. She was subsequently treated with carboplatin and paclitaxel chemotherapy but died of intraperitoneal carcinomatosis. The second patient had a stage IA grade 2 mucinous carcinoma and developed a Fertility and Sterility 1567

pulmonary metastasis 78 months after initial therapy. Despite chemoradiation she died of disease 19 months later. Previously, Zanetta et al. (65) had reported that among patients with EOC treated conservatively, the risk of recurrence to the contralateral ovary is low. In this study of 99 women, 56 underwent fertility-sparing surgery, and 43 had a more radical procedure. Of the women treated conservatively, 62% had grade 1 tumors, 48% grade 2, and 50% grade 3. With a median follow-up of 7 years, the recurrence rate in both groups was similar 9% (five patients) in the women who underwent fertility-sparing surgery and 12% (five patients) in those who had a more radical procedure. Recurrence correlated with histologic grade: 3.6% for grade 1, 17% for grade 2, and 21% for grade 3 tumors, respectively. Two recurrences (3.6%) involved the residual ovary in the fertility-sparing group. One of the two had stage IA grade 1 tumor that was treated with surgery alone with no evidence of disease. The other had stage IC grade 2 tumor that was treated with surgery and chemotherapy but died of disease. Three of the five recurrences were out of the pelvis; two of the three patients died of disease, with one recurrence in the brain and the other in the lungs and para-aortic nodes. The third recurred in the spleen and underwent a splenectomy and chemotherapy. She remains alive with disease. Conservative treatment might be safe in some women with early EOC who have had an appropriate staging procedure. Indications for adjuvant chemotherapy in patients with stage I EOC treated with unilateral salpingo-oophorectomy are identical to indications for patients managed in the standard manner. Seiden et al (68) reported the first case of a successful pregnancy after high-dose cyclophosphamide, carboplatinum, and paclitaxel chemotherapy with peripheral blood stem cell transplantation in a young woman with ovarian carcinoma. More recent studies (Table 5) indicate successful reproductive attempts in patients treated with conservative surgery with or without chemotherapy (60, 65 67, 69). Low Malignant Potential (Borderline) Tumor A low malignant potential (LMP) tumor is an epithelial ovarian tumor characterized by the absence of destructive stromal invasion, younger age at diagnosis, longer survival, and an earlier stage at presentation compared with its invasive counterpart. Low malignant potential tumors constitute 10% 15% of ovarian carcinomas and tend to occur in women of childbearing age (70). Overall 5-year survival is approximately 90%, with most deaths occurring in the relatively small percentage of patients who present with advanced-stage disease (71, 72). Standard treatment of LMP tumors has been to perform a total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytology, omentectomy, and multiple peritoneal biopsies, including pelvic and para-aortic lymph node sampling. However, given its less aggressive behavior, there has been a trend toward more conservative surgery, comprising staging with unilateral salpingo-oophorectomy or cystectomy in women who desire to retain their reproductive function (73 76). The studies that have examined fertility-sparing surgery in these patients have reported acceptable disease outcomes and successful posttreatment pregnancies (74, 75). Rates of recurrence or development of new lesions after conservative treatment seem to be higher than after hysterectomy and bilateral salpingo-oophorectomy, varying from 0 to 33% (77 79). However, the rate of death attributable to disease is equally low in both groups of patients, with frequently successful salvage of relapses (79). Morice et al. (74) reported that tumor recurrence rates after radical surgery, adnexectomy, and cystectomy were 5.7%, 15.1%, and 36.3%, respectively. Given a rate of recurrence between 12% and 37.5% with cystectomy (74, 77), some advocate that TABLE 5 Obstetric outcome with epithelial ovarian cancer patients treated conservatively. Outcome items Study (reference) % successful pregnancy (n achieved/ n attempted) Term deliveries Miscarriage Ectopic pregnancy Elective Congenital terminations anomaly Colombo et al. 1994 (66) 100 (25/25) 16 (one twin) 4 2 4 0 Zanetta et al. 1997 (65) 56 (20/36) 17 4 2 4 0 Duska et al. 1999 (60) 33.3 (2/6) 2 0 1 0 0 Morice et al. 2001 (69) 22.2 (4/18) 3 1 0 0 0 Schilder et al. 2002 (67) 71 (17/24) 26 a 5 0 0 0 Note: Values are n unless otherwise specified. a One patient with ongoing pregnancy. Liou: Fertility preservation for gynecologic cancers. 1568 Liou et al. Fertility preservation for gynecologic cancers Vol. 84, No. 6, December 2005

unilateral adnexectomy is the more appropriate conservative procedure. Gotlieb et al. (73) and investigators of two previous series (77, 80), however, described a similar recurrence rate after cystectomy or adnexectomy (17%, 12%, and 15%, respectively). Women who have serous LMP tumors with noninvasive peritoneal implants have a recurrence risk of 8% 33% (mean, 20%) and a mortality rate of 0 17% (mean, 7%) (81). Those with LMP tumors with invasive implants have a higher recurrence risk (range, 0 83%; mean, 39%) and a higher mortality rate (range, 0 67%; mean, 28%) (82). Fertility outcomes have been excellent after conservative management of both early- and advanced-stage LMP tumors. Twenty-five pregnancies occurred in one study of 12 women who attempted pregnancy after fertility-sparing surgery (75). In the Morice et al. study (74), 14 patients delivered 17 infants. Fifteen were spontaneous conceptions, and four pregnancies were in women who had stage III disease. Similar results were echoed in a recent publication by Camatte et al. (83), who reported on 17 patients who were stage II (6 of 17) and III (11 of 17). Two patients recurred with invasive implants on the peritoneum. No deaths have been reported with a median follow-up time of 60 months. Eight pregnancies resulted in 7 patients, with pregnancy occurring a median of 8 months after the surgical procedure. Six of the pregnancies occurred spontaneously, one after ovarian stimulation and one with IVF. No recurrences were observed after pregnancy. Malignant Germ Cell Tumor Malignant ovarian germ cell tumors (MOGCT) account for 5% of all ovarian malignancies but usually affect women of childbearing age. Eighty percent of cases are diagnosed in women aged 30 years; fortunately, 70% 75% have stage I disease (84, 85). Malignant ovarian germ cell tumors can be divided into two main groups: dysgerminomas and nondysgerminomas. Nondysgerminoma tumors include endodermal sinus tumors, immature teratomas, mixed germ cell tumors, choriocarcinomas, embryonal carcinomas, and polyembryomas. During the mid-1980s, fertility-sparing surgery followed by chemotherapy (except in stage IA dysgerminomas) became the standard of care for early-stage disease and selected advanced stage MOGCTs (86). Evidence suggested equivalent survival outcomes for women treated conservatively as compared with those who received more radical surgery (i.e., bilateral salpingo-oophorectomy with or without hysterectomy) (85, 87 90). Fertility-sparing surgery is also possible in women with advanced stage disease because it is not usually accompanied by contralateral ovarian disease (88 91). Effective chemotherapy has made possible the option of conservative surgery and successful salvage for recurrence in these patients. Virtually all women with MOGCTs will require cisplatin-based adjuvant chemotherapy, except for those with stage IA dysgerminoma and stage I grade 1 immature teratoma (92). Bleomycin, etoposide, and cisplatin is the most widely used regimen today, with an overall survival rate that ranges from 75% for advanced stages to 95% for early stages (84, 91, 93, 94). Only a few studies have evaluated the reproductive outcomes of MOGCT patients after conservative surgery and chemotherapy. Low et al. (91) reported on 74 women with MOGCTs who received conservative surgery and were observed for a mean of 52.1 months. Forty-seven of these women received adjuvant chemotherapy, and 20 attempted to conceive. Of these, 19 were successful (95%), with 14 live births and no malformations. In the Zanetta et al. series (95), 81 of 169 women with MOGCTs (70 dysgerminomas, 28 endodermal sinus tumors, 24 mixed tumors, and 47 immature teratomas) were treated conservatively and received postoperative chemotherapy. Twenty attempted conception, with an 80% success rate (16 women). In the group that did not receive chemotherapy, 100% were successful (12 of 12). Malformations were detected in 3 of 41 conceptions in women who received adjuvant chemotherapy, as compared with 1 of 14 conceptions in women who did not receive chemotherapy. Perrin et al. (96) reported initial amenorrhea in approximately 50% of patients (13 of 29) who received chemotherapy, and 97% of patients had return of normal menstrual function. Seven healthy neonates were delivered, and no fetal anomalies were reported. In the Tangir et al. series (97), 64 patients underwent conservative surgery. Subsequently, 38 attempted conception, and 29 achieved at least one pregnancy (76%). Of note, 8 of 10 patients (80%) with advanced disease who were treated conservatively were able to conceive. Table 6 summarizes successful reproductive attempts in patients treated with conservative surgery with or without chemotherapy (91, 95 98). ASSISTED REPRODUCTIVE TECHNOLOGIES Because advances in cancer treatment modalities have resulted in a significant increase in cure rates, many cancer survivors can seriously consider having children (99). Each case is unique and requires a different strategy of fertility preservation given the type of cancer, the chemotherapy regimen, patient age, partner status, and time frame available before onset of treatment. Patients who have time to undergo ovarian stimulation can elect to cryopreserve embryos or oocytes. The long-term effects of ovulation induction on the course of disease or response to treatment remain to be defined (100), especially in women with estrogen-sensitive tumors. Oocyte retrieval can be performed in natural (unstimulated) cycles, but usually no more than one egg is obtained. Tamoxifen has been used for ovulation induction and has been found to increase the number of oocytes retrieved (101). The use of aromatase inhibitors for ovulation induction in patients with estrogen-dependent cancers is another area of investigation (102). Ovulation induction with an aromatase Fertility and Sterility 1569

1570 Liou et al. Fertility preservation for gynecologic cancers Vol. 84, No. 6, December 2005 TABLE 6 Obstetric outcome with malignant ovarian germ cell tumor patients treated conservatively. Study (reference) Outcome items % successful pregnancy (n achieved/ n attempted) Term deliveries Miscarriage Ectopic pregnancy Elective terminations Congenital anomaly Gershenson et al. 75 (12/16) 22 0 0 1 0 1988 (81) Perrin et al. 1999 (96) N/A 8 (7 in chemo group N/A N/A N/A 0 and 1 in non-chemo group) a Low et al. 2000 (91) 95 (19/20), chemo group; N/A, non-chemo group 16 (14 in chemo group and 2 in non-chemo N/A N/A N/A 0 Zanetta et al. 2001 (95) Tangir (97) 80 (16/20), chemo group; 100 (12/12), non-chemo group 76 (25/33), chemo group; 80 (4/5), non-chemo group group) b 26, chemo group; 12, non-chemo group 9, chemo group, 0, non-chemo group Note: Values are n unless otherwise specified. N/A not applicable; chemo chemotherapy. a Two patients with ongoing pregnancy (one in the chemo group, one in the non-chemo group). b Five patients with ongoing pregnancy (four in the chemo group, one in the non-chemo group). Liou: Fertility preservation for gynecologic cancers. N/A 4, chemo group; 2, non-chemo group 3, chemo group; 1, non-chemo group 38 (3 twins) 2 N/A 10 0 (16 available children)

inhibitor and embryo cryopreservation has been reported in a patient with endometrial cancer before radical surgery (103). In patients with endometrial cancer, a P-containing IUD also might be considered. We have used a P-releasing IUD before ovarian stimulation in a patient with endometrial cancer. Embryos were frozen before total abdominal hysterectomy and bilateral salpingo-oophorectomy. This patient used a gestational carrier to have a child, and she is free of disease 5 years after surgery (104). Many patients, however, do not have sufficient time to undergo ovarian stimulation for embryo or oocyte cryopreservation. For these patients, ovarian cryopreservation can be considered. This approach offers the advantage of [1] no need to delay treatment, [2] no need for ovarian hyperstimulation, and [3] ability to be performed in prepubertal girls (105). Orthotopic autologous ovarian transplantation is not novel. Restoration of fertility was reported in an animal model a decade ago (106). However, recent advances in ovarian cryostorage and the development of new orthotopic and heterotopic techniques in humans bring a new dimension to the field (107 110). Two different approaches to transplanting ovarian cortical strips have been developed. One method is pelvic orthotopic transplantation, whereby a natural pregnancy could possibly be achieved if the fallopian tubes are intact and if the ovarian tissue is implanted intraperitoneally. Recently, there was a report of a possible human pregnancy with this technique (109). The other method is the heterotopic technique, whereby ovarian tissue is grafted into the subcutaneous space in the forearm or the abdomen. The tissue is easier to insert and remove this way, but these patients would always require IVF to conceive. The risk of transmitting metastatic cancer cells by ovarian autotransplantation is a concern. Therefore, multiple biopsies need to be performed on the ovary and thorough histologic analysis run to minimize the risk of cryopreserving cancer cells with ovarian tissue (111). Future clinical trials will clarify issues related to the longevity of ovarian grafts, hormone production and ovarian follicle development, possibility and safety of pregnancy, and the safety of autotransplantation in cancer patients. In young women with gynecologic malignancies, fertility issues should be addressed. These alternative treatments are appropriate in a small, highly select group of patients with relatively good prognosis. Individualization of treatment might allow for future fertility. Collaboration between gynecologic oncologists and reproductive endocrinologists might optimize fertility preservation for these patients. REFERENCES 1. Jelfs P, Giles G, Shugg D, Cancer in Australia 1986 1988. Cancer series No. 2. 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