Optimal treatment of premature ovarian failure after treatment for Hodgkin s lymphoma is often withheld

Acta Obstetricia et Gynecologica. 2006; 85: 997 1002 ORIGINAL ARTICLE Optimal treatment of premature ovarian failure after treatment for Hodgkin s lymphoma is often withheld SYLVIA I. VERSCHUUREN 1, JISKA J. SCHAAP 1, MARS B. VAN T VEER 2, THEO STIJNEN 3, CURT W. BURGER 1 & ANCA C. ANSINK 1 1 Department of Gynecologic Oncology, University Medical Center Rotterdam, 3015 GD, 2 Department of Hematology, University Medical Center Rotterdam, 3075 EA, and 3 Department of Epidemiology & Biostatistics, University Medical Center Rotterdam, 3000 DR Rotterdam, The Netherlands Abstract Background. The purpose of this study is to determine: 1. the effect of treatment for Hodgkin s lymphoma on ovarian function, and 2. the interventions to relieve postmenopausal symptoms. Methods. Seventy-seven consecutive patients treated between 1989 and 2003 in the Rotterdam region for Hodgkin s lymphoma stages I and II were approached for this study. A questionnaire consisting of 45 questions was carried out to evaluate premature menopausal symptoms, hormonal replacement therapy and use of, menstrual cycle, and subsequent pregnancies. Results. After informed consent 67 patients were willing to participate in the study and 66 patients filled in a questionnaire. After antitumor treatment 13 patients developed treatment-related premature ovarian failure, 35 patients had a spontaneous cycle, and 18 patients could not be classified as they used hormonal. Women who developed treatment-related premature ovarian failure had a significantly higher mean age at the start of treatment for Hodgkin s lymphoma than women who remained premenopausal (p B/0.002). Only 6 of these 13 women (46%) received hormonal substitution. In all, 21 women conceived after antitumor treatment, and 28 children were born. All pregnancies were the result of spontaneous conception. Conclusions. The effect of antitumor treatment for Hodgkin s lymphoma on ovarian function is age dependent (odds ratio of 1.18 per year). There is a striking inconsistency regarding the management of ovarian protection before and during antitumor treatment. Premenopausal women who undergo therapy for Hodgkin s lymphoma should be offered hormonal substitution therapy after loss of ovarian function. Key words: Premature ovarian failure, Hodgkin s lymphoma, antitumor treatment, fertility, GnRH-a Abbreviations: HL: Hodgkin s lymphoma, POF: premature ovarian failure, GnRH-a: gonadotrophin-releasing hormone agonist, EORTC: European Organisation for Research and Treatment of Cancer, HRT: hormone replacement therapy The peak incidence of Hodgkin s lymphoma (HL) is in the third decade of life, making the disease the most common malignancy in the population aged between 15 and 24 years. As the introduction of aggressive antitumor treatment in young patients has brought long-term disease-free survival ( /90%) after HL, quality of life has become an important issue (1 3). For young women treated with multiple agent chemotherapy in their fertile age, preservation of fertility and future fertility is an important aspect of quality of life. The aim of this study was to investigate retrospectively the effect of treatment for HL on ovarian function, and the use of hormone replacement therapy (HRT) to control postmenopausal symptoms. Furthermore we investigated the potential impact of age at the start of treatment of HL. Methods We conducted a population-based study of all women in the Rotterdam region treated for HL Correspondence: A.C. Ansink, Erasmus MC, Daniel den Hoed Oncology Center, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands. E-mail: a.ansink@erasmusmc.nl (Received 25 October 2005; accepted 8 March 2006) ISSN 0001-6349 print/issn 1600-0412 online # 2006 Taylor & Francis DOI: 10.1080/00016340600677043

998 S.I. Verschuuren et al. stage I and II from 1989 until 2003. Eligibility criteria were female patients with HL who were not treated with bone marrow transplantation, aged between 18 and 45, premenopausal at the time of primary treatment, and who had no history of other malignancies. The protocol was approved by the medical ethical board of the Erasmus Medical Center. The patients studied were treated within three European Organisation for Research and Treatment of Cancer (EORTC) trials (H7, H8, and H9). Treatment schedules were according to one of these three protocols (4). A validated questionnaire (5) consisting of 45 questions was sent to all eligible women preceded by information on the study and an informed consent form. Questions dealt with premature menopausal symptoms (such as amenorrhea, oligomenorrhea, hot flushes, sweating, dyspareunia, and depression), hormonal replacement and use of, menstrual cycle, subsequent pregnancies and their outcome, and health status of the children who were born after their mothers treatment for HL. The information obtained from the questionnaires was compared with data from the hospital records. We considered women as suffering from treatmentrelated premature ovarian failure (POF) if they did not resume their spontaneous menstrual cycle within five years after antitumor treatment. We mainly looked at after primary treatment, but we also collected data on after treatment for recurrent disease. A computerized database in SPSS 11.0 was created for the analysis of the data. The yearly odds ratio of treatment-related POF and age at the start of treatment of HL was estimated by using logistic regression. Results From 1989 until 2003, 122 women in the Rotterdam region were treated for HL stage I and II. Forty-five of these women were not eligible for our study. In Table I, the reasons for in- and exclusion are presented. Thus, 77 patients were eligible and they were approached for this study. Ten patients refused to participate. One patient signed a consent form, but did not submit the questionnaire. The median age of the remaining 66 patients was 27 years (range 18 44 years) at the start of treatment for HL. Median follow-up was 10 years (range 13 180 months). Primary antitumor treatment modalities and dosage of radiation are presented in Table II. Seven patients were treated for recurrent disease. Table I. In- and exclusion criteria for 122 women treated for Hodgkin s lymphoma in the Rotterdam region between 1989 and 2003 Included 77 Excluded 45 DOD 11 Age B/18 or /45 years 23 Bone marrow transplantation 4 Second primary malignancy 1 Follow-up time B/10 months 2 Emigration 2 Lost to follow-up 2 DOD, dead of disease Four patients received MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine) and three patients received MOPP (mechlorethamine, vincristine, procarbazine, prednisone). Menopausal status after primary treatment We divided our patient population into three subgroups. Women in group A developed treatmentrelated POF, women in group B remained premenopausal, and women in group C could not be classified. Group A consisted of 8 patients (12%). The median age of the 8 women who developed treatment-related POF was 37 years (range 32 44 years). Group B consisted of 40 patients with a median age of 24 years (range 1842 years) who preserved a spontaneous cycle after antitumor treatment. Group C consisted of 18 patients. It was decided that we could not classify these patients as they used hormonal. None of these women became pregnant after antitumor treatment. The median age of these 18 patients was 28 years (range 18 43 years). Women who developed treatment-related POF had a significantly higher average age at the time they started treatment for HL than women who remained premenopausal (p B/0.002). The yearly odds ratio (1.35) also showed this agedependent association. Menopausal status after secondary treatment Seven women were treated for recurrent disease. As a result of the second treatment, five women developed treatment-related POF. Three of these patients received a combination of chemotherapy and radiotherapy for their primary tumor and chemotherapy alone for the recurrent disease. Four patients were treated with radiotherapy for their primary tumor and with chemotherapy for the recurrence. Two of these patients developed treatment-related POF.

Table II. Primary antitumor treatment of 66 women treated for Hodgkin s lymphoma Treatment of ovarian failure after Hodgkin s lymphoma 999 Chemotherapy Involved field radiation Mantle field radiation Subtotal nodal radiation, supraand infradiaphragmatic Agents Cycles 0 Gy 20 Gy 30 Gy 36 Gy 38 Gy 40 Gy 36 Gy 40 Gy 40 Gy/36 Gy 3 2 5 EBVP 6 2 3 5 2 11 MOPP/ABV 6 7 1 6 MOPP/ABV 4 1 6 4 MOPP/ABV 3 1 BEACOPP 4 1 2 ABVD 6 1 3 EBVP: epirubicin, bleomycin, vinblastine, prednisone; MOPP/ABV: mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine; BEACOPP: cyclophosphamide, doxorubicin, vincristine, bleomycin, etoposide, procarbazine, prednisone; ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine After secondary treatment, group A consisted of 13 patients (20%) with a median age of 34 years (range 1944 years), and group B consisted of 35 patients with a median age of 24 years (range 1842 years). At the start of treatment for HL, the mean age of the women in group A was significantly higher than the age of the women in group B (p B/0.002), with an odds ratio of 1.18 per year (Figure 1). Pregnancies After primary antitumor treatment, 19 patients conceived. Median follow-up after antitumor treatment was 5 years (range 313 years). Two patients conceived after treatment for recurrent disease. The two children were born within three and six years after the last treatment. All pregnancies were the result of spontaneous conception (Figure 2). Three women had an ectopic pregnancy. Subsequently, one of these three women gave birth to a healthy child. Predicted probability to develop premature ovarian failure 1.0 0.8 0.6 0.4 0.2 0.0 10 20 30 40 50 Age at the start of treatment for Hodgkin's lymphoma Figure 1. The relation between age at the start of treatment for Hodgkin s lymphoma and the predicted probability of developing premature ovarian failure (POF) for 48 patients. One woman had two miscarriages, but gave subsequently birth to a healthy child. In total, 27 healthy children and one child with Down syndrome were born. One patient was still pregnant at the time of the current analysis. Hormone replacement therapy Hormonal treatment for substitution of loss of ovarian function was prescribed to nine women (Figure 3). HRT according to national guidelines was prescribed to six patients (46%). Three women received oral as HRT, and four patients received no HRT for obscure reasons. All patients of group C used hormonal. Discussion Ovarian failure is a well known consequence of exposing female gonads to antitumor treatment for HL (6 9). Long-term disease-free survival after HL in young patients has improved dramatically ( /90%), therefore quality of life and thus preservation of fertility have become important issues. In accordance with the literature (10,11), treatment for HL has a negative effect on ovarian function. It was demonstrated in our study that 13 (20%) women younger than 45 years developed treatment-related POF. In the current study, women who developed treatment-related POF had a significantly higher average age than women who remained premenopausal. This is compatible with the literature (12,13). The median age in group C was higher than in group B and lower than in group A. Among the patients in group C, some patients probably developed treatment-related POF. However, due to continuous hormonal contraceptive use, this could not be established. Treatment with a gonadotrophin-releasing hormone agonist (GnRH-a) starting two weeks before

1000 S.I. Verschuuren et al. 77 eligible patients treatment for HL After primary treatment 10 no consent form 1 no questionnaire submitted 40 premenopausal 8 postmenopausal 18 unclassified 19 women pregnant 21 women not pregnant 25 children 1 still pregnant 2 ectopic 1 abortion 2 miscarriages 1 child with Down syndrome 24 healthy children After primary and secondary treatment 21 women pregnant 35 premenopausal 13 postmenopausal 18 unclassified 14 women not pregnant 28 children 1 still pregnant 3 ectopic 1 abortion 2 miscarriages 1 child with Down syndrome 27 healthy children Figure 2. Menopausal status and pregnancies of 66 women after primary and secondary* treatment for Hodgkin s lymphoma. *Seven women received secondary treatment for recurrence. chemotherapy appears to be a promising approach to prevent ovarian failure induced by antitumor treatment. However, only one randomized study on this issue has been conducted (14). Pereyra Pacheco et al. (15) have shown that GnRH-a treatment before and during antitumor treatment enhances ovarian function and preserves fertility. Blumenfeld and Eckman (16) have reported on the largest group of females exposed to both cytotoxic drugs and GnRH-a thus far. The rate of POF was 7% in the GnRH-a/chemotherapy group versus 54% in the chemotherapy-alone group. Because of these promising results, it is striking that, to the best of our knowledge, no large multicenter studies have been conducted, although it has been suggested in reviews several times (13). In order to assess the effectiveness of GnRH-a on the protection of ovarian damage properly, such a large multicenter study should be initiated. In recent years, several different techniques to preserve ovarian tissue have been developed (17,18). Several cases of restoration of ovarian function after autotransplantation of cryopreserved ovarian tissue have now been published (1922), and recently three pregnancies due to cryopreserved and returned ovarian tissue were claimed (20 22). However, success rates of this technique are obscure, as it is not known how many failures preceded these three apparently successful cases. Furthermore, two concerns regarding cryopreservation of ovarian tissue should be borne in mind. First, for cryopreservation a laparoscopy is needed. Although the complication rate of this operation is low, it is not negligible. And in addition, laparoscopy implies that the patient will have to submit herself to another procedure within the short time-span that will be filled with numerous diagnostic interventions and counseling procedures before antitumor treatment can start. Secondly, returning cryopreserved ovarian tissue may result in transferring cancer cells back into the patient during the autograft procedure (17). Recent research with mice on this issue was reassuring (23). However, the potential risk

Treatment of ovarian failure after Hodgkin s lymphoma 1001 77 eligible patients treatment for HL After primary treatment 10 no consent form 1 no questionnaire submitted 40 premenopausal 8 postmenopausal 18 unclassified 9 oral 2 continuous 29 no hormonal 2 oral 2 HST 4 no hormonal 15 oral 3 continuous After primary and secondary treatment 35 premenopausal 13 postmenopausal 18 unclassified 7 oral 2 continuous 26 no hormonal 3 oral 6 HST 4 no hormonal 15 oral 3 continuous Figure 3. Menopausal status and hormonal treatment of 66 women after primary and secondary* treatment for Hodgkin s lymphoma. *Seven women received secondary treatment for recurrence. of transferring cancer cells into a cured cancer patient cannot be ruled out completely. In the present study, we did not incorporate questions on cryopreservation as the technique was not available during the entire study period (1989 2003). Despite antitumor treatment, 21 women gave birth to 27 healthy children. Three women had an ectopic pregnancy. In the literature, we could not identify any data on ectopic pregnancy risk after antitumor treatment. It is remarkable that several postmenopausal women in our study were not offered HRT. Some were prescribed hormonal instead of HRT, which is not in line with national and international guidelines, as oral do not contain the appropriate dosage or the appropriate drugs to alleviate postmenopausal symptoms. Furthermore, women with treatment-related POF who use hormonal instead of hormone substitution will have postmenopausal symptoms during the pill-free period (usually one week per month). This will of course result in a reduced quality of life. It was obscure to us why some attending physicians choose to prescribe oral to women with treatment-related POF. Female survivors of HL have a strongly elevated risk of breast cancer when they have been treated with radiation in the area of the breast (24). On the other hand, women who develop treatment-related POF have a reduced risk of breast cancer. Theoretically, HRT could neutralize this reduced risk. Postmenopausal women who use HRT may eventually develop the same risk of breast cancer as women who remained premenopausal after treatment for HL. However, there is no evidence that women who develop treatment-related POF have an increased risk of breast cancer when compared with women who remain premenopausal after this treatment. With this issue in mind, if and how to substitute women who develop treatment-related POF is a matter of debate and possibly of individualization, weighing risk versus quality of life (12,25,26). This applies in particular to women who received irradiation on the breast (24). It is obvious that expert care for iatrogenic postmenopausal symptoms was withheld from several women who underwent intensive antitumor treatment. In group C, all patients used hormonal in order to prevent pregnancy. However, several of these women expressed symptoms compatible with POF in their questionnaire. It is therefore likely that these patients suffered from treatmentrelated POF and inadequate hormone use. Several patients were informed about definitive infertility as a consequence of the antitumor treatment. In contrast

1002 S.I. Verschuuren et al. with this, other patients were prescribed GnRH analogs to protect the ovaries. Remarks made by the patients on the questionnaires revealed a considerably diverging approach by attending physicians. Conclusions The effect of antitumor treatment for HL on ovarian function is age dependent. In our study, this effect was proven by an odds ratio of 1.18 per year (95% CI/ 1.06 1.31) (Figure 1). There is a striking inconsistency regarding the management of ovarian protection before and during antitumor treatment. Protocols for assessment and management of loss of ovarian function after antitumor treatment should be developed and standardized. This should be initiated in a multidisciplinary setting, in collaboration between hematologists and gynecologists. Furthermore, there is an obvious need to conduct multicenter randomized controlled trials on interventions that may prevent the loss of ovarian function after treatment. References 1. Posada MN, Kolp L, Garcia JE. Fertility options for female cancer patients: facts and fiction. Fertil Steril 2001; 75(4): 64753. Review. 2. Revel A, Laufer N. Protecting female fertility from cancer therapy. Mol Cell Endocrinol 2002; 187(12): 8391. Review. 3. Falcone T, Attaran M, Bedaiwy MA, Goldberg JM. Ovarian function preservation in the cancer patient. Fertil Steril 2004; 81(2): 24357. Review. 4. Raemaekers J, Kluin-Nelemans H, Teodorovic I, Meerwaldt C, Noordijk E, Thomas J, Glabbeke M, Henry-Amar M, Carde P. The achievements of the EORTC Lymphoma Group. European Organisation for Research and Treatment of Cancer. Eur J Cancer. 2002;/38(Suppl 4):/S10713. 5. Klip H, Burger CW, de Kraker J, van Leeuwen FE; OMEGAproject group. Risk of cancer in the offspring of women who underwent ovarian stimulation for IVF. Hum Reprod 2001; 16(11): 24518. 6. Specht L, Hansen M, Geisler C. Ovarian function in young women in long term remission after treatment for Hodgkin s disease stage I and II. Scand J Haematol. 1984;/32:/26570. 7. Shahin MS, Puscheck E. Reproductive sequelae of cancer treatment. Obstet Gynecol Clin North Am. 1998;/25(2): /423 33. 8. Kreuser ED, Xiros N, Hetzel WD, Heimpel H. Reproductive and endocrine gonadal capacity in patients treated with COPP for Hodgkin s disease. J Cancer Res Clin Oncol. 1987;/113(3):/2606. 9. Kreuser ED, Hetzel WD, Billia DO, Thiel E. Gonadal toxicity following cancer therapy in adults: significance, diagnosis, prevention and treatment. Cancer Treat Rev. 1990;/17(23):/ 16975. 10. Brandt L, Kimby E, Nygren P, Glimelius B. A systemic overview of chemotherapy effects in Hodgkin s disease. Acta Oncol. 2001;/40(2/3):/18597. 11. Bokemeyer C, Schmoll HJ, van Rhee J, Kuczyk M, Schuppert F, Poliwoda H. Long-term gonadal toxicity after the therapy for Hodgkin s and non-hodgkin s lymphoma. Ann Hematol. 1994;/68(3):/10510. 12. Barton C, Waxman J. Effects of chemotherapy on fertility. Blood Rev. 1990;/4(3):/18795. 13. Clark ST, Radford JA, Crowther D, Swindell R, Shalet SM. Gonadal function following chemotherapy for Hodgkin s disease: a comparative study of MVPP and a seven-drug hybrid regimen. J Clin Oncol. 1995;/13(1):/1349. 14. Waxman JH, Ahmed R, Smith D, Wrigley PF, Gregory W, Shalet S, Crowther D, Rees LH, Besser GM, Malpas JS, et al. Failure to preserve fertility in patients with Hodgkin s disease. Cancer Chemother Pharmacol. 1987;/19:/15962. 15. Pereyra Pacheco B, Mendez Ribas JM, Milone G, Fernandez I, Kvicala R, Mila T, Di Noto A, Contreras Ortiz O, Pavlovsky S. Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report. Gynecol Oncol. 2001;/81:/3917. 16. Blumenfeld Z, Eckman A. Preservation of fertility and ovarian function and minimization of chemotherapy-induced gonadotoxicity in young women by GnRH-a. J Natl Cancer Inst Monogr. 2005;/34:/403. 17. Oktay K, Buyuk E. Ovarian transplantation in humans: indications, techniques and the risk of reseeding cancer. Eur J Obstet Gynecol Reprod Biol. 2004;/113(suppl):/457. 18. Radford JA, Lieberman BA, Brison DR, Smith AR, Critchlow JD, Russell SA, Watson AJ, Clayton JA, Harris M, Gosden RG, Shalet SM. Orthotopic reimplantation of cryopreserved ovarian cortical strips after high-dose chemotherapy for Hodgkin s lymphoma. Lancet. 2001;/357(9263):/11725. 19. Schmidt KL, Andersen CY, Loft A, Byskov AG, Ernst E, Andersen AN. Follow-up of ovarian function post-chemotherapy following ovarian cryopreservation and transplantation. Hum Reprod. 2005;/20(12):/353946. Epub 2005 Aug 19. 20. Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, Martinez-Madrid B, van Langendonckt A. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;/364(9443):/140510. Erratum in: Lancet 2004 Dec 4; 364(9450): 2020. 21. Meirow D, Levron J, Eldar-Geva T, Hardan I, Fridman E, Zalel Y, Schiff E, Dor J. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med. 2005;/353(3):/31821. 22. Oktay K, Buyuk E, Veeck L, Zaninovic N, Xu K, Takeuchi T, Opsahl M, Rosenwaks Z. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;/363(9412):/83740. 23. Kim SS, Radford J, Harris M, Varley J, Rutherford AJ, Lieberman B, Shalet S, Gosden R. Ovarian tissue harvested from lymphoma patients to preserve fertility may be safe for autotransplantation. Hum Reprod. 2001;/16:/205660. 24. Van Leeuwen FE, Klokman WJ, Stovall M, Dahler EC, van t Veer MB, Noordijk EM, Crommelin MA, Aleman BM, Broeks A, Gospodarowicz M, Travis LB, Russell NS. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin s disease. J Natl Cancer Inst. 2003;/95(13):/97180. 25. Chapman RM, Sutcliffe SB, Malpas JS. Cytotoxic-induced ovarian failure in Hodgkin s disease. II. Effects on sexual function. JAMA. 1979;/242(17):/18824. 26. Chapman RM. Effect of cytotoxic therapy on sexuality and gonadal function. Semin Oncol. 1982;/9(1):/8494.