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Safety and efficacy of infertility treatment after conservative management of borderline ovarian tumors: A preliminary report
FERTILITY AND STERILITY威 VOL. 82, NO. 3, SEPTEMBER 2004
INFERTILITY
Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Safety and efficacy of infertility treatment after conservative management of borderline ovarian tumors: a preliminary report Sozos J. Fasouliotis, M.D., Owen Davis, M.D., Glenn Schattman, M.D., Steven D. Spandorfer, M.D., Isaac Kligman, M.D., and Zev Rosenwaks, M.D. Center for Reproductive Medicine and Infertility, Weill Medical College at Cornell University, New York, New York
Objective: To evaluate the safety and efficacy of infertility treatment in a group of patients after conservative management of borderline ovarian tumors. Design: Retrospective study. Setting: University IVF unit. Patient(s): Five patients with previous conservative treatment of borderline ovarian tumor. Intervention(s): Seventeen IVF cycles. Main Outcome Measure(s): Recurrence, IVF outcome. Result(s): At the time of diagnosis, the mean age of the patients was 32.2 ⫾ 6.9 years. The mean time elapsed between the initial diagnosis of a borderline tumor and the performance of IVF was 42.2 months. After IVF, the mean number of oocytes retrieved was 7.9 ⫾ 4.0 with a mean fertilization rate of 57.1% and a mean number of 3.1 ⫾ 1.4 day 3 embryos transferred. Six pregnancies were achieved in three of the five patients with a pregnancy rate per retrieval of 37.5% and per transfer of 42.9%. The mean follow-up time that elapsed since the first IVF cycle was 39.2 months (range 9 –78 months). One patient had three recurrences 13, 27, and 43 months after her first IVF cycle, all of which remained histologically serous borderline tumor. All patients were without evidence of disease at the time of last follow-up. Conclusion(s): At a mean follow-up time of 39.2 months, our results suggest that IVF may be considered for patients with conservatively treated borderline tumors. Furthermore, overall IVF success rates were very satisfactory, suggesting no perceptible negative impact of prior borderline ovarian neoplasia on pregnancy rates after IVF. (Fertil Steril威 2004;82:568 –72. ©2004 by American Society for Reproductive Medicine.) Key Words: Borderline ovarian tumors, in vitro fertilization, conservative management
Received September 30, 2003; revised and accepted February 4, 2004. Reprint requests: Sozos J. Fasouliotis, M.D., Center for Reproductive Medicine and Infertility, Weill Medical College at Cornell University, 505 East 70 Street, HMT 3rd Floor, New York, New York 10021 (FAX: 212-746-8860; E-mail: sjf2002@med. cornell.edu). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2004. 02.114
568
Ovarian tumors of borderline malignancy constitute approximately 10%–15% of all epithelial malignancies of the ovary (1). In the past, these tumors were treated aggressively, similar to their invasive counterparts. However, recently, after the recognition of their intermediate status between benign and malignant ovarian tumors in terms of histology, clinical behavior, and prognosis, as well as the younger mean age of the patients at the time of diagnosis, more conservative therapeutic approaches have been adopted (2). Thus, patients with ovarian tumors of low malignant potential usually undergo conservative surgery preserv-
ing what appears to be normal ovarian tissue and allowing for future reproduction. Spontaneous conceptions have been reported after conservative surgery (3–5); however, ovulation induction is often required for these patients to conceive (6). The role of ovulation induction in the natural history of borderline tumor of the ovary is still debated. Several studies have suggested a potential link between the use of fertility drugs and borderline ovarian tumors (7–9), whereas other studies failed to find such an association (6, 10). Data regarding the safety of assisted reproduction on the long-term health of surviving
TABLE 1 Patients’ demographics and surgical findings. Age at diagnosis (y)
Gravidity at diagnosis
Parity at diagnosis
Stage
1
40
3
0
IA
Serous
2
22
0
0
IA
Serous
3
32
0
0
IA
Endometrioid
4
30
0
0
IC
Serous
5
37
2
0
IA
Mucinous
Patient
Histology
Surgical treatment Laparotomy L Cystectomy Laparotomy L USO Laparotomy L USO Laparoscopy L Cystectomy Laparoscopy L Cystectomy
Note: L ⫽ left; USO ⫽ unilateral salpingo-oophorectomy. Fasouliotis. IVF and borderline ovarian tumors. Fertil Steril 2004.
patients who have undergone conservative management are limited, yet physicians should strive to provide appropriate counseling to this young population of patients. The aim of this study is to assess the safety and efficacy of infertility treatment in a group of patients after conservative management of borderline ovarian tumors.
MATERIALS AND METHODS Patients Retrospective review of our records revealed that during the period 1997–2003, five patients with a previously diagnosed and conservatively treated borderline tumor of the ovary underwent IVF. Conservative treatment was defined as a surgical procedure with conservation of the uterus and salvage of at least a portion of one ovary. The International Federation of Gynecology and Obstetrics classification was used for staging. None of the patients received adjuvant therapy pre- or postoperatively. Table 1 summarizes the patients’ demographics and surgical findings. At the time of diagnosis, the mean age of the patients was 32.2 ⫾ 6.9 years, the mean number of gestations was 1.0, and all patients were nulliparous. The etiology of infertility was as follows: tubal (2), combined tubal/male (1), tubal/endometriosis (1) and idiopathic (1). All patients were evaluated and counseled by a gynecological oncologist before undergoing IVF and signed informed clinical consent. Because of the retrospective nature of the study and its descriptive character no institutional review board approval was requested.
was achieved. Women not treated with luteal leuprolide acetate began stimulation on day 2 of their treatment cycle. Ovarian stimulation was then effected with a combination of gonadotropins (hMG or recombinant FSH), using a stepdown protocol. Human chorionic gonadotropin was administered (3,300 –10,000 IU) when at least two follicles reached or exceeded 16 –17 mm mean diameter as measured by transvaginal ultrasound. Oocytes were harvested by transvaginal ultrasound-guided follicular puncture 35–36 hours after hCG administration. Conventional oocyte insemination or micromanipulation was performed as indicated. The best morphologically appearing embryos were transferred into the uterine cavity approximately 72 hours after retrieval. The number of embryos transferred was dependent on maternal age, according to our standard protocol. In general, no more than 2–3 embryos were transferred to patients under 34 years of age, patients 34 –39 years of age received up to 3– 4 embryos, and patients 40 years and older underwent transfer of up to 4 –5 embryos when available. Methylprednisolone (16 mg/day) and tetracycline (250 mg every 6 hours) were administered for 4 days to all patients commencing on the day of oocyte retrieval. Progesterone supplementation was initiated on the third day after hCG administration (25–50 mg IM/day) and was continued until the sonographic assessment of the pregnancy at 47–51 days of gestation as determined by the day of oocyte insemination (day 14). Sonograms were performed using transvaginal techniques (11).
In Vitro Fertilization
Follow-up
Patients were treated with standard ovulation induction protocols and underwent IVF– embryo transfer as previously described (11). In brief, most women were treated with luteal phase leuprolide acetate (Lupron; Tap Pharmaceuticals, Deerfield, IL), 0.5–1 mg SC daily until ovarian suppression
All patients after conservative management of a borderline ovarian tumor were followed by a gynecological oncologist and underwent clinical examination, CA-125 monitoring, and transvaginal ultrasound scan every 3 months during the first year of the procedure and every 6 months thereafter.
FERTILITY & STERILITY威
569
TABLE 2 In vitro fertilization outcome and recurrence.
Patient 1 2 3 4 5
Time from surgery until 1st IVF (mo)
IVF cycles
Time of F/U from 1st IVF cycle (mo)
Recurrence
Pregnancy outcome
6 132 60 10 3
9 1 1 5 1
78 9 12 75 22
No Recurrence before IVF No Three recurrences after 1st IVF cycle No
SABX2, TB — TB TBX2 —
Note: F/U ⫽ follow-up; SAB ⫽ spontaneous abortion; TB ⫽ term birth. Fasouliotis. IVF and borderline ovarian tumors. Fertil Steril 2004.
This same diagnostic protocol was carried out in all patients after the performance of IVF, regardless of the outcome of the IVF cycle. No patients were lost during the follow-up period.
Statistical Methods
All data are presented as mean ⫾ SD. Range of values is presented in parentheses, where appropriate.
RESULTS In Vitro Fertilization Outcome The mean time elapsed between the initial diagnosis of a borderline ovarian tumor and the performance of IVF was 42.2 months (Table 2). The patients in aggregate underwent a total of 17 IVF cycles. Their mean basal day 3 FSH and E2 levels were 8.4 ⫾ 2.3 mIU/mL and 21.8 ⫾ 6.9 pg/mL (range 5–11.3 mIU/mL and 16.8 –33.8 pg/mL, respectively) suggesting the presence of adequate ovarian reserve regardless of the extent of the initial conservative surgery, whereas the mean peak E2 level on the day of hCG administration was 1,493 ⫾ 558 pg/mL (range 964 –2,135 pg/mL) showing normal ovarian response. One cycle was cancelled at the patient’s request. The mean total number of oocytes and mature oocytes retrieved was 7.9 ⫾ 4.0 (range 1–15) and 5.7 ⫾ 3.4 (range 0 –7.7), respectively, whereas a total of 72/126 oocytes were fertilized with a mean fertilization rate of 57.1% (range 0 – 83.3%). All embryo transfers were performed on day 3 after retrieval with a mean number of 3.1 ⫾ 1.4 (range 1–5) embryos replaced. Six pregnancies were achieved in three of the five patients with a pregnancy rate per retrieval of 37.5% and per transfer of 42.9%. Four pregnancies (three singletons and one twin pregnancy) ended in normal term deliveries of healthy infants, whereas two resulted in miscarriages (Table 2). In all cases, cesarean section was performed for obstetrical indications, during which the ovaries and the abdominal and pelvic cavity were evaluated and were found to be normal without any suspicious findings. 570
Fasouliotis et al.
IVF and borderline ovarian tumors
Recurrence One patient had a recurrence in the contralateral ovary 3 years after her initial diagnosis of a serous borderline tumor and before undergoing any fertility treatment. Due to her previous unilateral salpingo-oophorectomy, the recurrence was managed conservatively with ovarian cystectomy. Histological examination of the removed tissue revealed serous borderline ovarian tumor identical to the primary. Eight years after, the patient underwent an unsuccessful IVF cycle and currently remains without any evidence of disease (Table 2). The mean follow-up time that elapsed since the first IVF cycle was 39.2 months (Table 2). There was only one case of recurrence (20%) diagnosed in our patients (Table 2) after IVF treatment. Specifically, this patient had three recurrences 13, 27, and 43 months after her first IVF cycle and 23, 37, and 53 months after the initial diagnosis of a serous borderline tumor. Conservative surgery with bilateral ovarian cystectomies was performed in each case and pathology reports revealed serous borderline tumor, which in this case also was identical to the primary tumor. After her last recurrence, she underwent two successful IVF cycles, which ended in two normal pregnancies and the delivery of three healthy infants. No disease-related deaths occurred in our series and all patients were without evidence of disease at the time of last follow-up.
DISCUSSION The rate of ovarian tumor diagnosis has increased significantly in the past decades with 8.7% of invasive epithelial tumors and 31.8% of the borderline epithelial tumors occurring in patients under the age of 40 years (12). Although this increase in the rate of diagnosis of ovarian tumors in women of reproductive age may be attributed to advances in health provision and the development of sensitive diagnostic methods including ultrasonography, significant medical, as well as, media attention has been focused on the potential assoVol. 82, No. 3, September 2004
ciation between infertility, ovulation induction drugs, and ovarian tumors.
cant change in survival rates compared with radical treatment (3–5, 12, 25).
Whittemore et al. (13) in a collaborative analysis of 12 case-control studies conducted during the period 1956 –1986, reported that the risk of invasive ovarian cancer was increased among women who had used fertility drugs and, in particular, for nulliparous women. Also, Rossing et al. (14), who examined the risk of ovarian tumors in a cohort of 3,837 women evaluated for infertility between 1974 and 1985, showed that prolonged use of clomiphene (⬎12 months) might increase the risk of a borderline or invasive ovarian tumor.
The reproductive performance of women who underwent conservative surgery for borderline ovarian tumors was found to be adequate, and spontaneous pregnancies with good outcomes have been reported. Also, no relationship between pregnancy and recurrence has been demonstrated (3–5, 12, 25). However, some patients who were diagnosed with a borderline ovarian tumor and underwent conservative treatment will require evaluation and treatment for infertility. Appropriate counseling to these patients regarding the safety and efficacy of ovarian stimulation is difficult to provide because of the scarcity of information, which is mainly based on case reports.
However, more recent data have provided reassuring evidence on the absence of a strong association between fertility drugs and subsequent risk of developing invasive epithelial ovarian cancer (7, 15–18). Furthermore, Ness et al. (19), in a recent pooled analysis of case control studies concluded that infertility per se, but not the use of fertility medications, elevates the overall risk of ovarian cancer. Several studies that examined the role of ovulation induction in the development of borderline ovarian tumors reported a possible positive association (7–9, 14, 19). Although the pathogenic mechanisms for this effect remain largely unknown, it has been suggested that it is more likely to be related to hormonal than genetic factors (20). Estrogen receptor expression was recently demonstrated in borderline tumors, providing a theoretical explanation for possible tumor promotion in patients undergoing ovulation induction treatments during which high E2 levels are attained (21). Other studies, however, failed to find such an association, and attributed positive findings to surveillance or diagnostic bias, as women who undergo fertility-related treatments are examined more frequently (22). Also, the absence of a reasonable time span between the diagnosis of infertility, the application of ovulation induction treatments, and the diagnosis of a borderline tumor further decreases the likelihood of a causal relationship (6). Although the data regarding the possible association between fertility drugs and borderline ovarian tumors remain inconclusive, it is widely accepted that these tumors represent a different entity from their invasive counterparts, with studies consistently demonstrating their favorable prognosis with an overall 10-year survival rate of 83%–91% (23). The less aggressive behavior of these tumors and the fact that they appear in younger women has led to a more conservative, fertility-sparing approach to therapy, even for patients with advanced stages of disease (24). Several studies evaluated the efficacy of this approach and concluded that it offers a safe solution for borderline tumors of the ovary. Recurrence is noted significantly more often after this type of treatment, but virtually all cases of recurrent disease can be detected with close follow-up and thus treated accordingly. Importantly, there was no signifiFERTILITY & STERILITY威
Nijman et al. (26) described a patient who was diagnosed with serous borderline tumor stage IIIa after two unsuccessful IVF cycles. Six months after unilateral oophorectomy the patient underwent two more IVF cycles, the last of which was successful leading to the delivery of a healthy female child and with the patient being without any evidence of disease. Mantzavinos et al. (27) followed two patients, also treated with unilateral salpingo-oophorectomy, for 5 years since their first IVF attempt, which was performed 3 and 6 months after surgery, and reported no evidence of recurrence. One patient conceived after the first IVF attempt delivering a healthy infant, whereas the other patient conceived after the second IVF attempt, a pregnancy that, however, ended in a miscarriage. Two more cases of successful pregnancies after IVF in women with advanced stage borderline tumor of the ovary were also described. Follow-up that lasted 2.5 and 5 years revealed no evidence of disease (28, 29). Beiner et al. (30) described seven patients who underwent IVF therapy after the diagnosis and conservative management of borderline ovarian tumor. The mean follow-up time since the first course of IVF treatment until the time of last follow-up was 50 months. Four of these patients developed a recurrence, two patients before and two after IVF treatment (44 and 50 months, respectively). All recurrences were of borderline histology and were treated conservatively. In five patients, IVF treatment was successful leading to the delivery of six healthy infants. All patients were reported to be without evidence of disease at the time of last follow-up. Our results confirm these findings and provide additional evidence for the efficacy of IVF for patients with borderline tumors who underwent conservative fertility-sparing disease management. The overall IVF success rates were very satisfactory with a pregnancy rate per retrieval of 37.5% and per transfer of 42.9%. Although the small number of patients included in this study, as well as the variability in their age do not allow a direct comparison of their outcomes with our general IVF results, the pregnancy rates achieved suggest no perceptible negative impact of prior borderline ovarian neoplasm on pregnancy rates after IVF. 571
Although no definite conclusions can be drawn regarding the safety of infertility treatment in this group of patients, mainly because of the retrospective character of our study, and because of the small number of patients included, our results show that within a follow-up period of 39.2 months, IVF after the diagnosis of a borderline ovarian tumor does not appear to affect survival. We encountered a 20% recurrence rate after IVF treatment, similar to the rate reported for patients who underwent conservative treatment without any subsequent fertility therapy (3, 12). The recurrence occurred in a patient initially diagnosed with borderline ovarian tumor stage IC, confirming previous studies reporting that more advanced stages of disease have a higher risk of recurrence (25). Moreover, this patient, as the majority of patients who have recurrence of disease after conservative treatment, had borderline tumor histologically identical to the primary ovarian tumor, enabling the continuation of conservative management (1– 6, 30) and IVF therapy, which was decided each time after thorough discussion with the patient, her gynecological oncologist, and the reproductive endocrinologist. Nevertheless, the decision to pursue multiple IVF cycles in such patients with repeated recurrence of borderline ovarian tumors warrants further investigation. In conclusion, current available data suggest that IVF may be considered for patients with borderline tumors who underwent conservative fertility-sparing disease management. At present, there is no evidence of any adverse effect of pregnancy on the course of borderline tumor of the ovary. All patients should receive detailed counseling regarding the potential risks and require close follow-up during and after IVF therapy. References 1. Trope CG, Kristensen G, Makar A. Surgery for borderline tumor of the ovary. Semin Surg Oncol 2000;19:69 –75. 2. Morice P, Camatte S, Wicart-Poque F, Atallah D, Rouzier R, Pautier P, et al. Results of conservative management of epithelia malignant and borderline ovarian tumours. Hum Reprod Update 2003;9:185–92. 3. Donnez J, Munschke A, Berliere M, Pirard C, Jadoul P, Smets M, et al. Safety of conservative management and fertility outcome in women with borderline tumors of the ovary. Fertil Steril 2003;79:1216 –21. 4. Seracchioli R, Venturoli S, Colombo FM, Govoni F, Missiroli S, Bagnoli A. Fertility and tumor recurrence rate after conservative laparoscopic management of young women with early-stage borderline ovarian tumors. Fertil Steril 2001;76:999 –1004. 5. Camatte S, Rouzier R, Boccara-Dekeyser J, Pautier P, Pomel C, Lhomme C, et al. Prognosis and fertility after conservative treatment for ovarian tumors of limited malignity: review of 68 cases. Gynecol Obstet Fertil 2002;30:583–91. 6. Gotlieb WH, Flikker S, Davidson B, Korach Y, Kopolovic J, BenBaruch G. Borderline tumors of the ovary: fertility treatment, conservative management, and pregnancy outcome. Cancer 1998;82:141– 6. 7. Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 1996;65:13– 8.
572
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IVF and borderline ovarian tumors
8. Harris R, Whittemore AS, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. III. Epithelial tumors of low malignant potential in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:1204 –11. 9. Parazzini F, Negri E, La Vecchia C, Moroni S, Polatti A, Chiaffarino F, et al. Treatment for fertility and risk of ovarian tumors of borderline malignancy. Gynecol Oncol 1998;68:226 – 8. 10. Kashyap S, Davis OK. Ovarian cancer and fertility medications: a critical appraisal. Semin Reprod Med 2003;21:65–72. 11. Spandorfer SD, Avrech OM, Colombero LT, Palermo GD, Rosenwaks Z. Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection. Hum Reprod 1998;13:334 – 8. 12. Ayhan A, Celik H, Taskiran C, Bozdag G, Aksu T. Oncologic and reproductive outcome after fertility-saving surgery in ovarian cancer. Eur J Gynaecol Oncol 2003;24:223–32. 13. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:1212–20. 14. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771– 6. 15. Franceschi S, La Vecchia C, Negri E, Guarneri S, Montella M, Conti E, et al. Fertility drugs and risk of epithelial ovarian cancer in Italy. Hum Reprod 1994;9:1673–5. 16. Venn A, Watson L, Lumley J, Giles G, King C, Healy D. Breast and ovarian cancer incidence after infertility and in vitro fertilisation. Lancet 1995;346:995–1000. 17. Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Infertility, fertility drugs, and invasive ovarian cancer: a case-control study. Fertil Steril 1997;67:1005–12. 18. Parazzini F, Negri E, La Vecchia C, Moroni S, Franceschi S, Crosignani PG. Treatment for infertility and risk of invasive epithelial ovarian cancer. Hum Reprod 1997;12:2159 – 61. 19. Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002;155:217–24. 20. Shushan A, Paltiel O, Schenker JG. Induction of ovulation and borderline ovarian cancer—the hormonal connection? Eur J Obstet Gynecol Reprod Biol 1999;85:71– 4. 21. Abu-Jawdeh GM, Jacobs TW, Niloff J, Cannistra SA. Estrogen receptor expression is a common feature of ovarian borderline tumors. Gynecol Oncol 1996;60:301–7. 22. Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Ovarian stimulation and borderline ovarian tumors: a case-control study. Fertil Steril 1998;70:1049 –55. 23. Crispens MA. Borderline ovarian tumours: a review of the recent literature. Curr Opin Obstet Gynecol 2003;15:39 – 43. 24. Camatte S, Morice P, Pautier P, Atallah D, Duvillard P, Castaigne D. Fertility results after conservative treatment of advanced stage serous borderline tumour of the ovary. BJOG 2002;109:376 – 80. 25. Morris RT, Gershenson DM, Silva EG, Follen M, Morris M, Wharton JT. Outcome and reproductive function after conservative surgery for borderline ovarian tumors. Obstet Gynecol 2000;95:541–7. 26. Nijman HW, Burger CW, Baak JP, Schats R, Vermorken JB, Kenemans P. Borderline malignancy of the ovary and controlled hyperstimulation, a report of 2 cases. Eur J Cancer 1992;28A:1971–3. 27. Mantzavinos T, Kanakas N, Genatas C, Papadias K, Zourlas PA. Five years’ follow-up in two patients with borderline tumours of the ovary hyperstimulated by gonadotrophin therapy for in-vitro fertilization. Hum Reprod 1994;9:2032–3. 28. Hoffman JS, Laird L, Benadiva C, Dreiss R. In vitro fertilization following conservative management of stage 3 serous borderline tumor of the ovary. Gynecol Oncol 1999;74:515– 8. 29. Hershkovitz R, Lunenfeld E, Piura B, Pak I, Leiberman JR, Yanai-Inbar I, et al. Ovulation induction in three infertile patients with ovarian borderline tumor. Isr J Obstet Gynecol 1998;9:271–5. 30. Beiner ME, Gotlieb WH, Davidson B, Kopolovic J, Ben-Baruch G. Infertility treatment after conservative management of borderline ovarian tumors. Cancer 2001;92:320 –5.
Vol. 82, No. 3, September 2004
INFERTILITY
Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Safety and efficacy of infertility treatment after conservative management of borderline ovarian tumors: a preliminary report Sozos J. Fasouliotis, M.D., Owen Davis, M.D., Glenn Schattman, M.D., Steven D. Spandorfer, M.D., Isaac Kligman, M.D., and Zev Rosenwaks, M.D. Center for Reproductive Medicine and Infertility, Weill Medical College at Cornell University, New York, New York
Objective: To evaluate the safety and efficacy of infertility treatment in a group of patients after conservative management of borderline ovarian tumors. Design: Retrospective study. Setting: University IVF unit. Patient(s): Five patients with previous conservative treatment of borderline ovarian tumor. Intervention(s): Seventeen IVF cycles. Main Outcome Measure(s): Recurrence, IVF outcome. Result(s): At the time of diagnosis, the mean age of the patients was 32.2 ⫾ 6.9 years. The mean time elapsed between the initial diagnosis of a borderline tumor and the performance of IVF was 42.2 months. After IVF, the mean number of oocytes retrieved was 7.9 ⫾ 4.0 with a mean fertilization rate of 57.1% and a mean number of 3.1 ⫾ 1.4 day 3 embryos transferred. Six pregnancies were achieved in three of the five patients with a pregnancy rate per retrieval of 37.5% and per transfer of 42.9%. The mean follow-up time that elapsed since the first IVF cycle was 39.2 months (range 9 –78 months). One patient had three recurrences 13, 27, and 43 months after her first IVF cycle, all of which remained histologically serous borderline tumor. All patients were without evidence of disease at the time of last follow-up. Conclusion(s): At a mean follow-up time of 39.2 months, our results suggest that IVF may be considered for patients with conservatively treated borderline tumors. Furthermore, overall IVF success rates were very satisfactory, suggesting no perceptible negative impact of prior borderline ovarian neoplasia on pregnancy rates after IVF. (Fertil Steril威 2004;82:568 –72. ©2004 by American Society for Reproductive Medicine.) Key Words: Borderline ovarian tumors, in vitro fertilization, conservative management
Received September 30, 2003; revised and accepted February 4, 2004. Reprint requests: Sozos J. Fasouliotis, M.D., Center for Reproductive Medicine and Infertility, Weill Medical College at Cornell University, 505 East 70 Street, HMT 3rd Floor, New York, New York 10021 (FAX: 212-746-8860; E-mail: sjf2002@med. cornell.edu). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2004. 02.114
568
Ovarian tumors of borderline malignancy constitute approximately 10%–15% of all epithelial malignancies of the ovary (1). In the past, these tumors were treated aggressively, similar to their invasive counterparts. However, recently, after the recognition of their intermediate status between benign and malignant ovarian tumors in terms of histology, clinical behavior, and prognosis, as well as the younger mean age of the patients at the time of diagnosis, more conservative therapeutic approaches have been adopted (2). Thus, patients with ovarian tumors of low malignant potential usually undergo conservative surgery preserv-
ing what appears to be normal ovarian tissue and allowing for future reproduction. Spontaneous conceptions have been reported after conservative surgery (3–5); however, ovulation induction is often required for these patients to conceive (6). The role of ovulation induction in the natural history of borderline tumor of the ovary is still debated. Several studies have suggested a potential link between the use of fertility drugs and borderline ovarian tumors (7–9), whereas other studies failed to find such an association (6, 10). Data regarding the safety of assisted reproduction on the long-term health of surviving
TABLE 1 Patients’ demographics and surgical findings. Age at diagnosis (y)
Gravidity at diagnosis
Parity at diagnosis
Stage
1
40
3
0
IA
Serous
2
22
0
0
IA
Serous
3
32
0
0
IA
Endometrioid
4
30
0
0
IC
Serous
5
37
2
0
IA
Mucinous
Patient
Histology
Surgical treatment Laparotomy L Cystectomy Laparotomy L USO Laparotomy L USO Laparoscopy L Cystectomy Laparoscopy L Cystectomy
Note: L ⫽ left; USO ⫽ unilateral salpingo-oophorectomy. Fasouliotis. IVF and borderline ovarian tumors. Fertil Steril 2004.
patients who have undergone conservative management are limited, yet physicians should strive to provide appropriate counseling to this young population of patients. The aim of this study is to assess the safety and efficacy of infertility treatment in a group of patients after conservative management of borderline ovarian tumors.
MATERIALS AND METHODS Patients Retrospective review of our records revealed that during the period 1997–2003, five patients with a previously diagnosed and conservatively treated borderline tumor of the ovary underwent IVF. Conservative treatment was defined as a surgical procedure with conservation of the uterus and salvage of at least a portion of one ovary. The International Federation of Gynecology and Obstetrics classification was used for staging. None of the patients received adjuvant therapy pre- or postoperatively. Table 1 summarizes the patients’ demographics and surgical findings. At the time of diagnosis, the mean age of the patients was 32.2 ⫾ 6.9 years, the mean number of gestations was 1.0, and all patients were nulliparous. The etiology of infertility was as follows: tubal (2), combined tubal/male (1), tubal/endometriosis (1) and idiopathic (1). All patients were evaluated and counseled by a gynecological oncologist before undergoing IVF and signed informed clinical consent. Because of the retrospective nature of the study and its descriptive character no institutional review board approval was requested.
was achieved. Women not treated with luteal leuprolide acetate began stimulation on day 2 of their treatment cycle. Ovarian stimulation was then effected with a combination of gonadotropins (hMG or recombinant FSH), using a stepdown protocol. Human chorionic gonadotropin was administered (3,300 –10,000 IU) when at least two follicles reached or exceeded 16 –17 mm mean diameter as measured by transvaginal ultrasound. Oocytes were harvested by transvaginal ultrasound-guided follicular puncture 35–36 hours after hCG administration. Conventional oocyte insemination or micromanipulation was performed as indicated. The best morphologically appearing embryos were transferred into the uterine cavity approximately 72 hours after retrieval. The number of embryos transferred was dependent on maternal age, according to our standard protocol. In general, no more than 2–3 embryos were transferred to patients under 34 years of age, patients 34 –39 years of age received up to 3– 4 embryos, and patients 40 years and older underwent transfer of up to 4 –5 embryos when available. Methylprednisolone (16 mg/day) and tetracycline (250 mg every 6 hours) were administered for 4 days to all patients commencing on the day of oocyte retrieval. Progesterone supplementation was initiated on the third day after hCG administration (25–50 mg IM/day) and was continued until the sonographic assessment of the pregnancy at 47–51 days of gestation as determined by the day of oocyte insemination (day 14). Sonograms were performed using transvaginal techniques (11).
In Vitro Fertilization
Follow-up
Patients were treated with standard ovulation induction protocols and underwent IVF– embryo transfer as previously described (11). In brief, most women were treated with luteal phase leuprolide acetate (Lupron; Tap Pharmaceuticals, Deerfield, IL), 0.5–1 mg SC daily until ovarian suppression
All patients after conservative management of a borderline ovarian tumor were followed by a gynecological oncologist and underwent clinical examination, CA-125 monitoring, and transvaginal ultrasound scan every 3 months during the first year of the procedure and every 6 months thereafter.
FERTILITY & STERILITY威
569
TABLE 2 In vitro fertilization outcome and recurrence.
Patient 1 2 3 4 5
Time from surgery until 1st IVF (mo)
IVF cycles
Time of F/U from 1st IVF cycle (mo)
Recurrence
Pregnancy outcome
6 132 60 10 3
9 1 1 5 1
78 9 12 75 22
No Recurrence before IVF No Three recurrences after 1st IVF cycle No
SABX2, TB — TB TBX2 —
Note: F/U ⫽ follow-up; SAB ⫽ spontaneous abortion; TB ⫽ term birth. Fasouliotis. IVF and borderline ovarian tumors. Fertil Steril 2004.
This same diagnostic protocol was carried out in all patients after the performance of IVF, regardless of the outcome of the IVF cycle. No patients were lost during the follow-up period.
Statistical Methods
All data are presented as mean ⫾ SD. Range of values is presented in parentheses, where appropriate.
RESULTS In Vitro Fertilization Outcome The mean time elapsed between the initial diagnosis of a borderline ovarian tumor and the performance of IVF was 42.2 months (Table 2). The patients in aggregate underwent a total of 17 IVF cycles. Their mean basal day 3 FSH and E2 levels were 8.4 ⫾ 2.3 mIU/mL and 21.8 ⫾ 6.9 pg/mL (range 5–11.3 mIU/mL and 16.8 –33.8 pg/mL, respectively) suggesting the presence of adequate ovarian reserve regardless of the extent of the initial conservative surgery, whereas the mean peak E2 level on the day of hCG administration was 1,493 ⫾ 558 pg/mL (range 964 –2,135 pg/mL) showing normal ovarian response. One cycle was cancelled at the patient’s request. The mean total number of oocytes and mature oocytes retrieved was 7.9 ⫾ 4.0 (range 1–15) and 5.7 ⫾ 3.4 (range 0 –7.7), respectively, whereas a total of 72/126 oocytes were fertilized with a mean fertilization rate of 57.1% (range 0 – 83.3%). All embryo transfers were performed on day 3 after retrieval with a mean number of 3.1 ⫾ 1.4 (range 1–5) embryos replaced. Six pregnancies were achieved in three of the five patients with a pregnancy rate per retrieval of 37.5% and per transfer of 42.9%. Four pregnancies (three singletons and one twin pregnancy) ended in normal term deliveries of healthy infants, whereas two resulted in miscarriages (Table 2). In all cases, cesarean section was performed for obstetrical indications, during which the ovaries and the abdominal and pelvic cavity were evaluated and were found to be normal without any suspicious findings. 570
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Recurrence One patient had a recurrence in the contralateral ovary 3 years after her initial diagnosis of a serous borderline tumor and before undergoing any fertility treatment. Due to her previous unilateral salpingo-oophorectomy, the recurrence was managed conservatively with ovarian cystectomy. Histological examination of the removed tissue revealed serous borderline ovarian tumor identical to the primary. Eight years after, the patient underwent an unsuccessful IVF cycle and currently remains without any evidence of disease (Table 2). The mean follow-up time that elapsed since the first IVF cycle was 39.2 months (Table 2). There was only one case of recurrence (20%) diagnosed in our patients (Table 2) after IVF treatment. Specifically, this patient had three recurrences 13, 27, and 43 months after her first IVF cycle and 23, 37, and 53 months after the initial diagnosis of a serous borderline tumor. Conservative surgery with bilateral ovarian cystectomies was performed in each case and pathology reports revealed serous borderline tumor, which in this case also was identical to the primary tumor. After her last recurrence, she underwent two successful IVF cycles, which ended in two normal pregnancies and the delivery of three healthy infants. No disease-related deaths occurred in our series and all patients were without evidence of disease at the time of last follow-up.
DISCUSSION The rate of ovarian tumor diagnosis has increased significantly in the past decades with 8.7% of invasive epithelial tumors and 31.8% of the borderline epithelial tumors occurring in patients under the age of 40 years (12). Although this increase in the rate of diagnosis of ovarian tumors in women of reproductive age may be attributed to advances in health provision and the development of sensitive diagnostic methods including ultrasonography, significant medical, as well as, media attention has been focused on the potential assoVol. 82, No. 3, September 2004
ciation between infertility, ovulation induction drugs, and ovarian tumors.
cant change in survival rates compared with radical treatment (3–5, 12, 25).
Whittemore et al. (13) in a collaborative analysis of 12 case-control studies conducted during the period 1956 –1986, reported that the risk of invasive ovarian cancer was increased among women who had used fertility drugs and, in particular, for nulliparous women. Also, Rossing et al. (14), who examined the risk of ovarian tumors in a cohort of 3,837 women evaluated for infertility between 1974 and 1985, showed that prolonged use of clomiphene (⬎12 months) might increase the risk of a borderline or invasive ovarian tumor.
The reproductive performance of women who underwent conservative surgery for borderline ovarian tumors was found to be adequate, and spontaneous pregnancies with good outcomes have been reported. Also, no relationship between pregnancy and recurrence has been demonstrated (3–5, 12, 25). However, some patients who were diagnosed with a borderline ovarian tumor and underwent conservative treatment will require evaluation and treatment for infertility. Appropriate counseling to these patients regarding the safety and efficacy of ovarian stimulation is difficult to provide because of the scarcity of information, which is mainly based on case reports.
However, more recent data have provided reassuring evidence on the absence of a strong association between fertility drugs and subsequent risk of developing invasive epithelial ovarian cancer (7, 15–18). Furthermore, Ness et al. (19), in a recent pooled analysis of case control studies concluded that infertility per se, but not the use of fertility medications, elevates the overall risk of ovarian cancer. Several studies that examined the role of ovulation induction in the development of borderline ovarian tumors reported a possible positive association (7–9, 14, 19). Although the pathogenic mechanisms for this effect remain largely unknown, it has been suggested that it is more likely to be related to hormonal than genetic factors (20). Estrogen receptor expression was recently demonstrated in borderline tumors, providing a theoretical explanation for possible tumor promotion in patients undergoing ovulation induction treatments during which high E2 levels are attained (21). Other studies, however, failed to find such an association, and attributed positive findings to surveillance or diagnostic bias, as women who undergo fertility-related treatments are examined more frequently (22). Also, the absence of a reasonable time span between the diagnosis of infertility, the application of ovulation induction treatments, and the diagnosis of a borderline tumor further decreases the likelihood of a causal relationship (6). Although the data regarding the possible association between fertility drugs and borderline ovarian tumors remain inconclusive, it is widely accepted that these tumors represent a different entity from their invasive counterparts, with studies consistently demonstrating their favorable prognosis with an overall 10-year survival rate of 83%–91% (23). The less aggressive behavior of these tumors and the fact that they appear in younger women has led to a more conservative, fertility-sparing approach to therapy, even for patients with advanced stages of disease (24). Several studies evaluated the efficacy of this approach and concluded that it offers a safe solution for borderline tumors of the ovary. Recurrence is noted significantly more often after this type of treatment, but virtually all cases of recurrent disease can be detected with close follow-up and thus treated accordingly. Importantly, there was no signifiFERTILITY & STERILITY威
Nijman et al. (26) described a patient who was diagnosed with serous borderline tumor stage IIIa after two unsuccessful IVF cycles. Six months after unilateral oophorectomy the patient underwent two more IVF cycles, the last of which was successful leading to the delivery of a healthy female child and with the patient being without any evidence of disease. Mantzavinos et al. (27) followed two patients, also treated with unilateral salpingo-oophorectomy, for 5 years since their first IVF attempt, which was performed 3 and 6 months after surgery, and reported no evidence of recurrence. One patient conceived after the first IVF attempt delivering a healthy infant, whereas the other patient conceived after the second IVF attempt, a pregnancy that, however, ended in a miscarriage. Two more cases of successful pregnancies after IVF in women with advanced stage borderline tumor of the ovary were also described. Follow-up that lasted 2.5 and 5 years revealed no evidence of disease (28, 29). Beiner et al. (30) described seven patients who underwent IVF therapy after the diagnosis and conservative management of borderline ovarian tumor. The mean follow-up time since the first course of IVF treatment until the time of last follow-up was 50 months. Four of these patients developed a recurrence, two patients before and two after IVF treatment (44 and 50 months, respectively). All recurrences were of borderline histology and were treated conservatively. In five patients, IVF treatment was successful leading to the delivery of six healthy infants. All patients were reported to be without evidence of disease at the time of last follow-up. Our results confirm these findings and provide additional evidence for the efficacy of IVF for patients with borderline tumors who underwent conservative fertility-sparing disease management. The overall IVF success rates were very satisfactory with a pregnancy rate per retrieval of 37.5% and per transfer of 42.9%. Although the small number of patients included in this study, as well as the variability in their age do not allow a direct comparison of their outcomes with our general IVF results, the pregnancy rates achieved suggest no perceptible negative impact of prior borderline ovarian neoplasm on pregnancy rates after IVF. 571
Although no definite conclusions can be drawn regarding the safety of infertility treatment in this group of patients, mainly because of the retrospective character of our study, and because of the small number of patients included, our results show that within a follow-up period of 39.2 months, IVF after the diagnosis of a borderline ovarian tumor does not appear to affect survival. We encountered a 20% recurrence rate after IVF treatment, similar to the rate reported for patients who underwent conservative treatment without any subsequent fertility therapy (3, 12). The recurrence occurred in a patient initially diagnosed with borderline ovarian tumor stage IC, confirming previous studies reporting that more advanced stages of disease have a higher risk of recurrence (25). Moreover, this patient, as the majority of patients who have recurrence of disease after conservative treatment, had borderline tumor histologically identical to the primary ovarian tumor, enabling the continuation of conservative management (1– 6, 30) and IVF therapy, which was decided each time after thorough discussion with the patient, her gynecological oncologist, and the reproductive endocrinologist. Nevertheless, the decision to pursue multiple IVF cycles in such patients with repeated recurrence of borderline ovarian tumors warrants further investigation. In conclusion, current available data suggest that IVF may be considered for patients with borderline tumors who underwent conservative fertility-sparing disease management. At present, there is no evidence of any adverse effect of pregnancy on the course of borderline tumor of the ovary. All patients should receive detailed counseling regarding the potential risks and require close follow-up during and after IVF therapy. References 1. Trope CG, Kristensen G, Makar A. Surgery for borderline tumor of the ovary. Semin Surg Oncol 2000;19:69 –75. 2. Morice P, Camatte S, Wicart-Poque F, Atallah D, Rouzier R, Pautier P, et al. Results of conservative management of epithelia malignant and borderline ovarian tumours. Hum Reprod Update 2003;9:185–92. 3. Donnez J, Munschke A, Berliere M, Pirard C, Jadoul P, Smets M, et al. Safety of conservative management and fertility outcome in women with borderline tumors of the ovary. Fertil Steril 2003;79:1216 –21. 4. Seracchioli R, Venturoli S, Colombo FM, Govoni F, Missiroli S, Bagnoli A. Fertility and tumor recurrence rate after conservative laparoscopic management of young women with early-stage borderline ovarian tumors. Fertil Steril 2001;76:999 –1004. 5. Camatte S, Rouzier R, Boccara-Dekeyser J, Pautier P, Pomel C, Lhomme C, et al. Prognosis and fertility after conservative treatment for ovarian tumors of limited malignity: review of 68 cases. Gynecol Obstet Fertil 2002;30:583–91. 6. Gotlieb WH, Flikker S, Davidson B, Korach Y, Kopolovic J, BenBaruch G. Borderline tumors of the ovary: fertility treatment, conservative management, and pregnancy outcome. Cancer 1998;82:141– 6. 7. Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 1996;65:13– 8.
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