Secondary Amenorrhea After Hodgkin’s Lymphoma Is Influenced by Age at Treatment, Stage of Disease, Chemotherapy Regimen, and the Use of Oral
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《临床肿瘤学》
the First Department of Internal Medicine, University Hospital Cologne, and the German Hodgkin Lymphoma Study Group, Cologne, Germany
Department of Gynecologic Endocrinology and Reproductive Medicine, University of Innsbruck, Innsbruck, Austria
ABSTRACT
PURPOSE: Long-term survivors of successfully treated Hodgkin’s lymphoma (HL) are at risk for late complications. Among these, infertility for female patients is of major importance. The subject of this analysis is to evaluate the menstrual status after HL therapy.
PATIENTS AND METHODS: From 1994 to 1998, the German Hodgkin’s Lymphoma Study Group conducted clinical trials for early-, intermediate-, and advanced-stage HL (trials HD7 to HD9) involving a total of 3,186 patients. A survey was carried out to evaluate the menstrual status after therapy. The following factors were assessed concerning their influence on amenorrhea: age, treatment, stage, and the use of oral contraceptives during chemotherapy.
RESULTS: A total of 405 women aged younger than 40 years answered the study questions. After a median follow-up of 3.2 years, 51.4% of the women receiving eight cycles of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) had continuous amenorrhea. Amenorrhea was significantly more frequent after dose-escalated BEACOPP compared with doxorubicin, bleomycin, vinblastine, and dacarbazine; cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; or standard BEACOPP (P = .0066). Amenorrhea after therapy was most pronounced in women with advanced-stage HL (P < .0001), in women older than 30 years at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002).
CONCLUSION: Most women who are treated for advanced-stage HL experience amenorrhea after therapy. Amenorrhea is significantly more frequent in women with advanced-stage HL receiving eight cycles of dose-escalated BEACOPP and in women older than 30 years at first treatment. Furthermore, the data show a statistical association between the use of oral contraceptives and return of menstrual cycle, which is subject to further investigation.
INTRODUCTION
Over the last 40 years, the prognosis of patients with advanced-stage Hodgkin’s lymphoma (HL) has changed from an incurable disease to long-term remission rates of more than 60%. Depending on stage at diagnosis, more than 80% of patients with HL can be cured with first-line treatment.1 Consequently, the survival of patients of reproductive age has increased significantly. Therefore, carefully conducted analyses of long-term toxicities in young adults after cancer treatment are becoming increasingly important.
Therapeutic strategies of most recent clinical trials in HL aim at balancing efficacy against acute and chronic toxicities. Among the late sequelae of HL treatment, such as organ dysfunction, secondary malignancies, and psychosocial problems, infertility is of major importance for young patients. Because most patients are diagnosed in the third decade of life,2 many young female patients of childbearing age are affected.
Organ dysfunctions are mostly cardiac and pulmonary.3-6 Secondary malignancies developing after treatment for HL include acute myeloid leukemia and myelodysplastic syndrome,7 non-HL,8 and solid tumors.9-12 The cumulative risk of solid tumors has been shown to be higher than the risk of secondary acute myeloid leukemia and myelodysplastic syndrome or non-HL10 and is enhanced even 30 years after initial treatment.13
Male patients treated with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD) showed azoospermia rates of up to 86%.14 However, the majority of patients suffer from disease-related gonadal dysfunction, such as oligo-, astheno-, or teratospermia, before the initiation of treatment.15,16 Today, semen analysis and cryoconservation before treatment of HL is a standard procedure.
In contrast to male patients, little is known about the gonadal function of female patients. The main aim of the present analysis was to determine possible risk factors, such as age at treatment, chemotherapeutic regimen, stage of disease, and protection with oral contraceptives, associated with the extent of amenorrhea in young female patients after HL treatment.
PATIENTS AND METHODS
Patient Selection
Patients between the age of 15 and 75 years (except for the German Hodgkin’s Lymphoma Study Group [GHSG] HD9 trial: patients not older than 65 years) had to have biopsy-proven HL at diagnosis to be eligible for random assignment. Histology was reviewed by the GHSG Expert Pathologists Panel. Eligibility criteria before study enrollment included adequate organ function (as defined by a creatinine clearance > 60 mL/min, serum transaminases < 3x normal, and bilirubin < 2 mL/dL), left ventricular ejection fraction greater than 0.45, forced expiratory volume in 1 second or diffusion capacity of carbon monoxide greater than 60% of predicted, Karnofsky performance score greater than 60, and WBC count greater than 3,500/μL, hemoglobin level greater than 8 g/dL, and platelets greater than 100,000/μL. Patients were required to test negative for antibodies against HIV and to be free of active infection. Consent forms, based on the institutional review board guidelines, were signed by each patient. The present analysis of the menstrual status of all female patients recorded in the GHSG trial database is based on the analysis of May 2004.
Study Design: HD7 to HD9
A total of 3,186 patients were enrolled onto the clinical trials HD7 to HD9 and registered in the GHSG database. These trials were performed between 1993 and 1998. In the HD7 study for early stages of disease (clinical stage [CS]/pathologic stage [PS] I and II without risk factors), patients were randomly assigned to either radiotherapy in extended-field (EF) technique (30 Gy + 10 Gy to involved sites, arm A) or two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) followed by EF radiotherapy (arm B).17 Patients in CS IA/B or IIA with at least one risk factor (large mediastinal mass, extranodal disease, massive splenic involvement, elevated erythrocyte sedimentation rate, and involvement of > two lymph node areas), in stage IIB with elevated erythrocyte sedimentation rate and/or involvement of more than two lymph node areas, or in CS IIIA without any risk factor were enrolled onto the HD8 trial.18 Treatment in both arms consisted of two cycles of COPP/ABVD followed by either 30 Gy of radiotherapy in EF technique and an additional 10 Gy on initial tumor bulk (arm A) or 30 Gy of radiotherapy in involved-field technique and an additional 10 Gy on initial bulky disease (arm B). The HD9 trial included patients (15 to 65 years) in CS IIB or IIIA with risk factors as well as all CS/PS IIIB and CS/PS IV patients. Patients were randomly assigned to receive four cycles of COPP/ABVD (arm A), eight cycles of standard bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP; arm B), or eight cycles of increased-dose BEACOPP (arm C). Radiotherapy was applied after eight cycles of chemotherapy to sites of initial bulky disease (30 Gy) or residual disease after chemotherapy (40 Gy).19
Menstrual Status
Menstrual status after treatment was evaluated by contacting 608 female patients by means of a newly developed survey who were enrolled onto the HD7 to HD9 trials of the GHSG (Fig 1). Age at first treatment was between 16 and 40 years, and patients had to have signed written informed consent that allowed us to address them for questions related to their initial treatment. A total of 405 women (66.6%) answered the questions. Questions referred to the menstrual status before and after therapy (eg, "Was your cycle regular before therapy?", "How was your cycle during therapy?", "Did your menstruation resume after therapy? When?", and "If your menstruation returned after therapy, did it stop again after some time?") and the use of oral contraceptives during treatment. Amenorrhea was defined as having no menstrual bleeding after therapy and at the time of the survey. The median observation time was 3.2 years after treatment (minimum, 7 months; maximum, 6.3 years).
Statistics
Demographics and disease characteristics were summarized using descriptive statistics. Mean, standard deviation, minimum, median, and maximum were calculated for numerical parameters; absolute and relative frequencies were calculated for categoric variables. Logistic regression models were used to evaluate the influence of multiple factors (age at first treatment, stage of disease, chemotherapy regimen, and use of oral contraceptives during chemotherapy) on the extent of amenorrhea. Univariable analyses for each factor were calculated for each trial, and then P values for the comparison of all clinical trials were performed. All P values are to be interpreted in an exploratory sense. Statistical analysis was performed with SAS Version 8.2 (SAS Institute, Cary, NC). The data were last updated in May 2004.
RESULTS
Patient Characteristics
A total of 405 (66.6%) of 608 potential candidates answered the questions. Of these women, 58 had been randomly assigned to the HD7 trial (arm A, n = 32; arm B, n = 26), 188 had been assigned to the HD8 trial (arm A, n = 94; arm B, n = 94), and 159 had been assigned to the HD9 trial (arm A, n = 32; arm B, n = 53; arm C, n = 74). The median observation time after treatment was 3.2 years (range, 7 months to 6.3 years). At the time of HL diagnosis, most of the patients (60.5%) were younger than 30 years old. There were 14.3% of patients with early-stage, 46.4% with intermediate-stage, and 39.3% with advanced-stage HL (Table 1). Combined-modality treatment was the most commonly used treatment in all groups. Chemotherapy consisted of ABVD (HD7), alternating COPP/ABVD (HD8 and HD9), and standard and dose-escalated BEACOPP (HD9; Table 2). Cyclophosphamide and procarbazine were administered in the COPP/ABVD and BEACOPP regimens. Treatment consisting of radiotherapy alone was rare and administered only to 32 (7.9%) of 405 patients.
Menstrual Status Before Therapy
Menstruation before therapy was regular in 89.6% of patients. Only 7.9% of all women reported an irregular cycle; 0.5% of women were menopausal; and for 2.0% of women, menstrual cycle before therapy was unknown.
Oral Contraceptives During Therapy
Overall, there were 54.8% of women who did not take oral contraceptives during chemotherapy (Table 3). Fifty-three percent of women enrolled onto the HD7 trial (arm A) took oral contraceptives during treatment for HL, whereas 58.3% of women in arm B did not, (Table 4). In the HD8 trial, there were 39.1% of women in arm A and 44.2% of women in arm B on oral contraceptives (Table 5). In HD9, 28.6% (arm A), 44.0% (arm B), and 31.8% (arm C) of women took oral contraceptives during therapy (Table 6). P = .228 for the comparison of all clinical trials (unknown status excluded; Table 3). In the group of patients younger than 30 years old, there was an equal amount of women who took (46.5%) and who did not take (46.5%) oral contraceptives. Most women older than 30 years (67.5%) did not take oral contraceptives during treatment.
Menstrual Status After Therapy
The high rate of other for menstrual status after therapy is a result of the fact that many women chose to continue oral contraceptives after therapy, and therefore, it could not be determined whether a normal menstrual cycle resumed after therapy. A total of 80 women took oral contraceptives at the time of the survey. Additionally, the group of other also included irregular cycles, meaning that the menstrual cycle has returned after therapy but is still not regularly occurring within the expected period of time. In summary, other in this analysis comprises women not answering the question, women having an irregular cycle at the time of the survey, and women not knowing whether their menstrual bleeding is only a result of the use of oral contraceptives or hormonal replacement therapy. The menstrual status was evaluated in the time frame after therapy and at the time of the survey.
Menstrual Status After Therapy According to Treatment
For all women replying to the survey, menstrual cycle after therapy was regular in 38.0%, whereas a total of 19.3% of women experienced amenorrhea (Table 7). Nevertheless, differences were seen according to treatment arm. More women after treatment for early-stage favorable (HD7) and early-stage unfavorable (HD8) HL reported regular menstrual cycle after therapy (HD7: arm A = 84.6%, arm B = 88.9%, Table 8; HD8: arm A = 88.6%, arm B = 84.0%, Table 9). In advanced stages, 54.6% of women treated with four cycles of COPP/ABVD, 32.4% of women treated with standard-dose BEACOPP, and 66.7% of women treated with eight cycles of dose-escalated BEACOPP experienced amenorrhea after treatment (P = .005; Table 10). Altogether, 38.5% (n = 156) of all women included in the analysis (n = 405) received subdiaphragmatic irradiation. Most of these women were treated within the HD8 (arm A, n = 84) and the HD7 trials (arms A and B, n = 52). In the group of women experiencing amenorrhea after treatment (n = 78), only 15.4% (n = 12) received subdiaphragmatic irradiation; whereas in the group of women having a regular cycle after therapy (n = 154), 35.7% (n = 55) received irradiation below the diaphragm.
Menstrual Status After Therapy Related to Age at First Treatment
When considering age at first treatment, regular cycle was more common in women treated for early-stage favorable and early-stage unfavorable HL (Tables 11 and 12). Interestingly, amenorrhea among women in early unfavorable stages was higher in women aged older than 30 years at first treatment compared with women younger than 30 years old (HD8 arm A: < 30 years = 7.7% v 30 years = 16.7%; HD8 arm B: < 30 years = 8.3% v 30 years = 23.1%; Table 13). More women older than 30 years treated for advanced-stage HL with four cycles of alternating COPP/ABVD or eight cycles of standard BEACOPP experienced amenorrhea compared with women younger than 30 years (COPP/ABVD: 30 years = 66.7%; standard BEACOPP: 30 years = 53.3%; Table 14). When treatment consisted of eight cycles of dose-escalated BEACOPP, amenorrhea was most pronounced in patients older than 30 years (95.0%), whereas only 5.0% of women in this group documented a regular cycle after therapy (Table 14). In contrast to the other groups, amenorrhea was also high in women aged younger than 30 years after eight cycles of dose-escalated BEACOPP (51.4%; Table 14).
Impact of Oral Contraceptives During Chemotherapy
Overall, amenorrhea was higher in women not taking oral contraceptives compared with women on oral contraceptives during therapy (44.1% v 10.1%, respectively; P < .0001; Tables 15 and 16). For patients with early-stage favorable and early-stage unfavorable HL, amenorrhea in women who did not take oral contraceptives was higher, but this was not statistically significant (Tables 17, 18, and 19). The highest rate of amenorrhea was seen in women treated for advanced-stage HL with no oral contraception during therapy. Of women enrolled onto the HD9 trial with treatment consisting of four cycles of COPP/ABVD or eight cycles of dose-escalated BEACOPP, 73.3% and 73.7% of women experienced amenorrhea, respectively (P = .046 for the comparison of arms A, B, and C; Table 20).
Prognostic Factors for Amenorrhea After Treatment
Multivariate analysis was performed evaluating the following factors for their influence on amenorrhea: age, chemotherapeutic regimen, stage, and the use of oral contraceptives during chemotherapy. For this analysis, only women with known menstrual status after therapy, use of oral contraceptives during therapy, and age were included (n = 214). Amenorrhea was significantly higher in women receiving eight cycles of dose-escalated BEACOPP than in women treated with ABVD alone, COPP/ABVD, or standard BEACOPP (P = .0066). Moreover, amenorrhea after therapy was higher in women with advanced-stage HL (P < .0001), in women older than 30 years of age at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002; Table 21).
DISCUSSION
This study investigated the menstrual status of 405 female HL patients treated within the GHSG studies HD7 to HD9 in early, intermediate, and advanced disease stages. The following findings emerge from this analysis. First, there was a clear correlation between dose-intensity and amenorrhea. The highest rate of amenorrhea was seen in the dose-escalated arm of the HD9 trial (66.7% in arm C v 32.4% in arm B v 54.6% in arm A; P = .005). The multivariate analysis demonstrates that eight cycles of dose-escalated BEACOPP were more toxic than eight, four, or two cycles of the other regimens. This effect was also evident when dose-escalated BEACOPP was compared with standard-dose BEACOPP or COPP/ABVD (P = .0066). Additionally, stage of disease had an influence on the extent of amenorrhea and was more pronounced in women with advanced-stage HL (P < .0001).
Second, as expected, amenorrhea occurred significantly more often in women older than 30 years of age at treatment (P = .0065). This was most pronounced in arm C of the HD9 trial (95.0% in arm C v 53.3% in arm B v 66.7% in arm A; P = .012).
Third, for women who did not take oral contraceptives during treatment, amenorrhea rates were higher compared with women who took oral contraceptives (P = .0002). In the HD9 trial, more women not taking oral contraceptives during therapy experienced amenorrhea (arm A, 73.3%; arm B, 43.5%; and arm C, 73.7%; P = .046). This statistical correlation has to be interpreted carefully and needs further investigation. Especially in early-stage favorable patients, where no high rate of amenorrhea was expected, and in early-stage unfavorable patients, the correlation was not statistically significant. The role of oral contraceptives remains uncertain.
Because of the high overall survival rates achieved in HL, this disease can be regarded as a model for the development of gonadal protection in cancer patients. Several authors analyzed the rates of infertility in young HL patients or patients with other malignancies after chemotherapy and radiotherapy. Most reports demonstrate that the extent of ovarian failure depends on the drugs used, dosage, and age at first treatment. Women of older age at first treatment had a significantly lower likelihood of ovarian recovery than women with younger age.14,20-26 A study of 2,498 cancer survivors found a higher resistance of the ovary to the effects of alkylating agents compared with the resistance of the testes. Additionally, infertility associated with radiation therapy below the diaphragm was observed.22 The mechanism of chemotherapy-induced gonadal damage still needs to be better characterized. For alkylating agents, a direct dose-dependent cytotoxic effect has been described. Acute toxicity reduces the number of follicles, whereas chronic toxicity affects the quality of follicles, resulting in early atresia.27 In addition, an early onset of menopause in female patients after treatment for childhood cancer is documented.28 Recent findings suggest that the biologic ovarian age in childhood cancer survivors is approximately 10 years higher than their chronologic age.29
The variety of multiagent regimens used for the treatment of different malignancies made careful analysis of the extent of gonadotoxicity difficult. Other important variables are the number of cycles given, dose and total dose, and age at treatment. Among single agents, cyclophosphamide and procarbazine are most commonly considered to induce gonadal damage.30,31 The cyclophosphamide, methotrexate, and fluorouracil regimen in patients with breast cancer induces amenorrhea in 68% of patients.32 Goldhirsch et al24 demonstrated an increase in amenorrhea after cyclophosphamide, methotrexate, and fluorouracil related to the number of cyclophosphamide courses. In contrast, the cisplatin, vincristine, methotrexate, bleomycin alternating with dactinomycin, cyclophosphamide, and etoposide regimen used for the treatment of germ cell tumors has a low risk of chemotherapy-induced infertility (18%).33
In a retrospective analysis of 103 women treated for HL, only 20 pregnancies were observed.21 After treatment with mechlorethamine, vincristine, procarbazine, and prednisone, only 17 of 44 women maintained regular menses,25 and a persistent amenorrhea was documented in 11 of 24 women.26 Elevated gonadotropin levels were shown in 53% of young female patients at a mean age of 13.0 years after chlorambucil, vinblastine, procarbazine, and prednisolone.34 After eight cycles of alternating COPP/ABVD, premature ovarian failure was described in 17 of 22 patients.14 A more recent analysis including a total of 84 female patients with HL and non-HL treated with at least three cycles of chemotherapy reported that 34 women (40.5%) had premature ovarian failure.20 In contrast, after ABVD alone, chemotherapy-induced ovarian failure is much more unlikely, especially when women are of young age at treatment.35-37
The prevention of ovarian failure in young women with oral contraceptives and gonadotropin-releasing hormone agonistic analogs (GnRHa) is a result of the decline of serum gonadotropin levels inhibiting follicular growth in the ovary. Some authors did not find a protective effect in nine women taking oral contraceptives during chemotherapy.25 The protection of fertility with the application of GnRHa or oral contraceptives during chemotherapy has been reported in the literature.38,39 Although this concept is appealing, it has never been investigated in a randomized trial so far. Hence, the GHSG has started a randomized phase II trial (Protection of Ovarian Fertility) for the reduction of ovarian failure with the use of GnRHa and oral contraceptives in young women treated with intensive chemotherapy for advanced-stage HL. The aim of the trial is to define a standard cotreatment for the reduction of infertility rates in young female patients during chemotherapy for HL.
On the basis of the results of pregnancy outcome in long-term survivors after childhood cancer, no overall increased risk for congenital malformations in offspring has been reported.21,40,41 For women, cryopreservation of ovarian tissue before treatment and its reimplantation after cancer treatment is of current debate.42,43 The first success has recently been reported.44,45However, a risk of disease transmission with reimplantation of ovarian tissue has been detected in mice.46 Taken together, our study indicates a possible protective effect of oral contraceptives in younger women undergoing gonadotoxic chemotherapy.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported in part by the Deutsche Krebshilfe, the Bundesministerium für Bildung und Forschung, and the Kompetenznetz Maligne Lymphome.
Both K.Be. and K.Br. contributed equally to this study.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Department of Gynecologic Endocrinology and Reproductive Medicine, University of Innsbruck, Innsbruck, Austria
ABSTRACT
PURPOSE: Long-term survivors of successfully treated Hodgkin’s lymphoma (HL) are at risk for late complications. Among these, infertility for female patients is of major importance. The subject of this analysis is to evaluate the menstrual status after HL therapy.
PATIENTS AND METHODS: From 1994 to 1998, the German Hodgkin’s Lymphoma Study Group conducted clinical trials for early-, intermediate-, and advanced-stage HL (trials HD7 to HD9) involving a total of 3,186 patients. A survey was carried out to evaluate the menstrual status after therapy. The following factors were assessed concerning their influence on amenorrhea: age, treatment, stage, and the use of oral contraceptives during chemotherapy.
RESULTS: A total of 405 women aged younger than 40 years answered the study questions. After a median follow-up of 3.2 years, 51.4% of the women receiving eight cycles of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) had continuous amenorrhea. Amenorrhea was significantly more frequent after dose-escalated BEACOPP compared with doxorubicin, bleomycin, vinblastine, and dacarbazine; cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; or standard BEACOPP (P = .0066). Amenorrhea after therapy was most pronounced in women with advanced-stage HL (P < .0001), in women older than 30 years at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002).
CONCLUSION: Most women who are treated for advanced-stage HL experience amenorrhea after therapy. Amenorrhea is significantly more frequent in women with advanced-stage HL receiving eight cycles of dose-escalated BEACOPP and in women older than 30 years at first treatment. Furthermore, the data show a statistical association between the use of oral contraceptives and return of menstrual cycle, which is subject to further investigation.
INTRODUCTION
Over the last 40 years, the prognosis of patients with advanced-stage Hodgkin’s lymphoma (HL) has changed from an incurable disease to long-term remission rates of more than 60%. Depending on stage at diagnosis, more than 80% of patients with HL can be cured with first-line treatment.1 Consequently, the survival of patients of reproductive age has increased significantly. Therefore, carefully conducted analyses of long-term toxicities in young adults after cancer treatment are becoming increasingly important.
Therapeutic strategies of most recent clinical trials in HL aim at balancing efficacy against acute and chronic toxicities. Among the late sequelae of HL treatment, such as organ dysfunction, secondary malignancies, and psychosocial problems, infertility is of major importance for young patients. Because most patients are diagnosed in the third decade of life,2 many young female patients of childbearing age are affected.
Organ dysfunctions are mostly cardiac and pulmonary.3-6 Secondary malignancies developing after treatment for HL include acute myeloid leukemia and myelodysplastic syndrome,7 non-HL,8 and solid tumors.9-12 The cumulative risk of solid tumors has been shown to be higher than the risk of secondary acute myeloid leukemia and myelodysplastic syndrome or non-HL10 and is enhanced even 30 years after initial treatment.13
Male patients treated with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD) showed azoospermia rates of up to 86%.14 However, the majority of patients suffer from disease-related gonadal dysfunction, such as oligo-, astheno-, or teratospermia, before the initiation of treatment.15,16 Today, semen analysis and cryoconservation before treatment of HL is a standard procedure.
In contrast to male patients, little is known about the gonadal function of female patients. The main aim of the present analysis was to determine possible risk factors, such as age at treatment, chemotherapeutic regimen, stage of disease, and protection with oral contraceptives, associated with the extent of amenorrhea in young female patients after HL treatment.
PATIENTS AND METHODS
Patient Selection
Patients between the age of 15 and 75 years (except for the German Hodgkin’s Lymphoma Study Group [GHSG] HD9 trial: patients not older than 65 years) had to have biopsy-proven HL at diagnosis to be eligible for random assignment. Histology was reviewed by the GHSG Expert Pathologists Panel. Eligibility criteria before study enrollment included adequate organ function (as defined by a creatinine clearance > 60 mL/min, serum transaminases < 3x normal, and bilirubin < 2 mL/dL), left ventricular ejection fraction greater than 0.45, forced expiratory volume in 1 second or diffusion capacity of carbon monoxide greater than 60% of predicted, Karnofsky performance score greater than 60, and WBC count greater than 3,500/μL, hemoglobin level greater than 8 g/dL, and platelets greater than 100,000/μL. Patients were required to test negative for antibodies against HIV and to be free of active infection. Consent forms, based on the institutional review board guidelines, were signed by each patient. The present analysis of the menstrual status of all female patients recorded in the GHSG trial database is based on the analysis of May 2004.
Study Design: HD7 to HD9
A total of 3,186 patients were enrolled onto the clinical trials HD7 to HD9 and registered in the GHSG database. These trials were performed between 1993 and 1998. In the HD7 study for early stages of disease (clinical stage [CS]/pathologic stage [PS] I and II without risk factors), patients were randomly assigned to either radiotherapy in extended-field (EF) technique (30 Gy + 10 Gy to involved sites, arm A) or two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) followed by EF radiotherapy (arm B).17 Patients in CS IA/B or IIA with at least one risk factor (large mediastinal mass, extranodal disease, massive splenic involvement, elevated erythrocyte sedimentation rate, and involvement of > two lymph node areas), in stage IIB with elevated erythrocyte sedimentation rate and/or involvement of more than two lymph node areas, or in CS IIIA without any risk factor were enrolled onto the HD8 trial.18 Treatment in both arms consisted of two cycles of COPP/ABVD followed by either 30 Gy of radiotherapy in EF technique and an additional 10 Gy on initial tumor bulk (arm A) or 30 Gy of radiotherapy in involved-field technique and an additional 10 Gy on initial bulky disease (arm B). The HD9 trial included patients (15 to 65 years) in CS IIB or IIIA with risk factors as well as all CS/PS IIIB and CS/PS IV patients. Patients were randomly assigned to receive four cycles of COPP/ABVD (arm A), eight cycles of standard bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP; arm B), or eight cycles of increased-dose BEACOPP (arm C). Radiotherapy was applied after eight cycles of chemotherapy to sites of initial bulky disease (30 Gy) or residual disease after chemotherapy (40 Gy).19
Menstrual Status
Menstrual status after treatment was evaluated by contacting 608 female patients by means of a newly developed survey who were enrolled onto the HD7 to HD9 trials of the GHSG (Fig 1). Age at first treatment was between 16 and 40 years, and patients had to have signed written informed consent that allowed us to address them for questions related to their initial treatment. A total of 405 women (66.6%) answered the questions. Questions referred to the menstrual status before and after therapy (eg, "Was your cycle regular before therapy?", "How was your cycle during therapy?", "Did your menstruation resume after therapy? When?", and "If your menstruation returned after therapy, did it stop again after some time?") and the use of oral contraceptives during treatment. Amenorrhea was defined as having no menstrual bleeding after therapy and at the time of the survey. The median observation time was 3.2 years after treatment (minimum, 7 months; maximum, 6.3 years).
Statistics
Demographics and disease characteristics were summarized using descriptive statistics. Mean, standard deviation, minimum, median, and maximum were calculated for numerical parameters; absolute and relative frequencies were calculated for categoric variables. Logistic regression models were used to evaluate the influence of multiple factors (age at first treatment, stage of disease, chemotherapy regimen, and use of oral contraceptives during chemotherapy) on the extent of amenorrhea. Univariable analyses for each factor were calculated for each trial, and then P values for the comparison of all clinical trials were performed. All P values are to be interpreted in an exploratory sense. Statistical analysis was performed with SAS Version 8.2 (SAS Institute, Cary, NC). The data were last updated in May 2004.
RESULTS
Patient Characteristics
A total of 405 (66.6%) of 608 potential candidates answered the questions. Of these women, 58 had been randomly assigned to the HD7 trial (arm A, n = 32; arm B, n = 26), 188 had been assigned to the HD8 trial (arm A, n = 94; arm B, n = 94), and 159 had been assigned to the HD9 trial (arm A, n = 32; arm B, n = 53; arm C, n = 74). The median observation time after treatment was 3.2 years (range, 7 months to 6.3 years). At the time of HL diagnosis, most of the patients (60.5%) were younger than 30 years old. There were 14.3% of patients with early-stage, 46.4% with intermediate-stage, and 39.3% with advanced-stage HL (Table 1). Combined-modality treatment was the most commonly used treatment in all groups. Chemotherapy consisted of ABVD (HD7), alternating COPP/ABVD (HD8 and HD9), and standard and dose-escalated BEACOPP (HD9; Table 2). Cyclophosphamide and procarbazine were administered in the COPP/ABVD and BEACOPP regimens. Treatment consisting of radiotherapy alone was rare and administered only to 32 (7.9%) of 405 patients.
Menstrual Status Before Therapy
Menstruation before therapy was regular in 89.6% of patients. Only 7.9% of all women reported an irregular cycle; 0.5% of women were menopausal; and for 2.0% of women, menstrual cycle before therapy was unknown.
Oral Contraceptives During Therapy
Overall, there were 54.8% of women who did not take oral contraceptives during chemotherapy (Table 3). Fifty-three percent of women enrolled onto the HD7 trial (arm A) took oral contraceptives during treatment for HL, whereas 58.3% of women in arm B did not, (Table 4). In the HD8 trial, there were 39.1% of women in arm A and 44.2% of women in arm B on oral contraceptives (Table 5). In HD9, 28.6% (arm A), 44.0% (arm B), and 31.8% (arm C) of women took oral contraceptives during therapy (Table 6). P = .228 for the comparison of all clinical trials (unknown status excluded; Table 3). In the group of patients younger than 30 years old, there was an equal amount of women who took (46.5%) and who did not take (46.5%) oral contraceptives. Most women older than 30 years (67.5%) did not take oral contraceptives during treatment.
Menstrual Status After Therapy
The high rate of other for menstrual status after therapy is a result of the fact that many women chose to continue oral contraceptives after therapy, and therefore, it could not be determined whether a normal menstrual cycle resumed after therapy. A total of 80 women took oral contraceptives at the time of the survey. Additionally, the group of other also included irregular cycles, meaning that the menstrual cycle has returned after therapy but is still not regularly occurring within the expected period of time. In summary, other in this analysis comprises women not answering the question, women having an irregular cycle at the time of the survey, and women not knowing whether their menstrual bleeding is only a result of the use of oral contraceptives or hormonal replacement therapy. The menstrual status was evaluated in the time frame after therapy and at the time of the survey.
Menstrual Status After Therapy According to Treatment
For all women replying to the survey, menstrual cycle after therapy was regular in 38.0%, whereas a total of 19.3% of women experienced amenorrhea (Table 7). Nevertheless, differences were seen according to treatment arm. More women after treatment for early-stage favorable (HD7) and early-stage unfavorable (HD8) HL reported regular menstrual cycle after therapy (HD7: arm A = 84.6%, arm B = 88.9%, Table 8; HD8: arm A = 88.6%, arm B = 84.0%, Table 9). In advanced stages, 54.6% of women treated with four cycles of COPP/ABVD, 32.4% of women treated with standard-dose BEACOPP, and 66.7% of women treated with eight cycles of dose-escalated BEACOPP experienced amenorrhea after treatment (P = .005; Table 10). Altogether, 38.5% (n = 156) of all women included in the analysis (n = 405) received subdiaphragmatic irradiation. Most of these women were treated within the HD8 (arm A, n = 84) and the HD7 trials (arms A and B, n = 52). In the group of women experiencing amenorrhea after treatment (n = 78), only 15.4% (n = 12) received subdiaphragmatic irradiation; whereas in the group of women having a regular cycle after therapy (n = 154), 35.7% (n = 55) received irradiation below the diaphragm.
Menstrual Status After Therapy Related to Age at First Treatment
When considering age at first treatment, regular cycle was more common in women treated for early-stage favorable and early-stage unfavorable HL (Tables 11 and 12). Interestingly, amenorrhea among women in early unfavorable stages was higher in women aged older than 30 years at first treatment compared with women younger than 30 years old (HD8 arm A: < 30 years = 7.7% v 30 years = 16.7%; HD8 arm B: < 30 years = 8.3% v 30 years = 23.1%; Table 13). More women older than 30 years treated for advanced-stage HL with four cycles of alternating COPP/ABVD or eight cycles of standard BEACOPP experienced amenorrhea compared with women younger than 30 years (COPP/ABVD: 30 years = 66.7%; standard BEACOPP: 30 years = 53.3%; Table 14). When treatment consisted of eight cycles of dose-escalated BEACOPP, amenorrhea was most pronounced in patients older than 30 years (95.0%), whereas only 5.0% of women in this group documented a regular cycle after therapy (Table 14). In contrast to the other groups, amenorrhea was also high in women aged younger than 30 years after eight cycles of dose-escalated BEACOPP (51.4%; Table 14).
Impact of Oral Contraceptives During Chemotherapy
Overall, amenorrhea was higher in women not taking oral contraceptives compared with women on oral contraceptives during therapy (44.1% v 10.1%, respectively; P < .0001; Tables 15 and 16). For patients with early-stage favorable and early-stage unfavorable HL, amenorrhea in women who did not take oral contraceptives was higher, but this was not statistically significant (Tables 17, 18, and 19). The highest rate of amenorrhea was seen in women treated for advanced-stage HL with no oral contraception during therapy. Of women enrolled onto the HD9 trial with treatment consisting of four cycles of COPP/ABVD or eight cycles of dose-escalated BEACOPP, 73.3% and 73.7% of women experienced amenorrhea, respectively (P = .046 for the comparison of arms A, B, and C; Table 20).
Prognostic Factors for Amenorrhea After Treatment
Multivariate analysis was performed evaluating the following factors for their influence on amenorrhea: age, chemotherapeutic regimen, stage, and the use of oral contraceptives during chemotherapy. For this analysis, only women with known menstrual status after therapy, use of oral contraceptives during therapy, and age were included (n = 214). Amenorrhea was significantly higher in women receiving eight cycles of dose-escalated BEACOPP than in women treated with ABVD alone, COPP/ABVD, or standard BEACOPP (P = .0066). Moreover, amenorrhea after therapy was higher in women with advanced-stage HL (P < .0001), in women older than 30 years of age at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002; Table 21).
DISCUSSION
This study investigated the menstrual status of 405 female HL patients treated within the GHSG studies HD7 to HD9 in early, intermediate, and advanced disease stages. The following findings emerge from this analysis. First, there was a clear correlation between dose-intensity and amenorrhea. The highest rate of amenorrhea was seen in the dose-escalated arm of the HD9 trial (66.7% in arm C v 32.4% in arm B v 54.6% in arm A; P = .005). The multivariate analysis demonstrates that eight cycles of dose-escalated BEACOPP were more toxic than eight, four, or two cycles of the other regimens. This effect was also evident when dose-escalated BEACOPP was compared with standard-dose BEACOPP or COPP/ABVD (P = .0066). Additionally, stage of disease had an influence on the extent of amenorrhea and was more pronounced in women with advanced-stage HL (P < .0001).
Second, as expected, amenorrhea occurred significantly more often in women older than 30 years of age at treatment (P = .0065). This was most pronounced in arm C of the HD9 trial (95.0% in arm C v 53.3% in arm B v 66.7% in arm A; P = .012).
Third, for women who did not take oral contraceptives during treatment, amenorrhea rates were higher compared with women who took oral contraceptives (P = .0002). In the HD9 trial, more women not taking oral contraceptives during therapy experienced amenorrhea (arm A, 73.3%; arm B, 43.5%; and arm C, 73.7%; P = .046). This statistical correlation has to be interpreted carefully and needs further investigation. Especially in early-stage favorable patients, where no high rate of amenorrhea was expected, and in early-stage unfavorable patients, the correlation was not statistically significant. The role of oral contraceptives remains uncertain.
Because of the high overall survival rates achieved in HL, this disease can be regarded as a model for the development of gonadal protection in cancer patients. Several authors analyzed the rates of infertility in young HL patients or patients with other malignancies after chemotherapy and radiotherapy. Most reports demonstrate that the extent of ovarian failure depends on the drugs used, dosage, and age at first treatment. Women of older age at first treatment had a significantly lower likelihood of ovarian recovery than women with younger age.14,20-26 A study of 2,498 cancer survivors found a higher resistance of the ovary to the effects of alkylating agents compared with the resistance of the testes. Additionally, infertility associated with radiation therapy below the diaphragm was observed.22 The mechanism of chemotherapy-induced gonadal damage still needs to be better characterized. For alkylating agents, a direct dose-dependent cytotoxic effect has been described. Acute toxicity reduces the number of follicles, whereas chronic toxicity affects the quality of follicles, resulting in early atresia.27 In addition, an early onset of menopause in female patients after treatment for childhood cancer is documented.28 Recent findings suggest that the biologic ovarian age in childhood cancer survivors is approximately 10 years higher than their chronologic age.29
The variety of multiagent regimens used for the treatment of different malignancies made careful analysis of the extent of gonadotoxicity difficult. Other important variables are the number of cycles given, dose and total dose, and age at treatment. Among single agents, cyclophosphamide and procarbazine are most commonly considered to induce gonadal damage.30,31 The cyclophosphamide, methotrexate, and fluorouracil regimen in patients with breast cancer induces amenorrhea in 68% of patients.32 Goldhirsch et al24 demonstrated an increase in amenorrhea after cyclophosphamide, methotrexate, and fluorouracil related to the number of cyclophosphamide courses. In contrast, the cisplatin, vincristine, methotrexate, bleomycin alternating with dactinomycin, cyclophosphamide, and etoposide regimen used for the treatment of germ cell tumors has a low risk of chemotherapy-induced infertility (18%).33
In a retrospective analysis of 103 women treated for HL, only 20 pregnancies were observed.21 After treatment with mechlorethamine, vincristine, procarbazine, and prednisone, only 17 of 44 women maintained regular menses,25 and a persistent amenorrhea was documented in 11 of 24 women.26 Elevated gonadotropin levels were shown in 53% of young female patients at a mean age of 13.0 years after chlorambucil, vinblastine, procarbazine, and prednisolone.34 After eight cycles of alternating COPP/ABVD, premature ovarian failure was described in 17 of 22 patients.14 A more recent analysis including a total of 84 female patients with HL and non-HL treated with at least three cycles of chemotherapy reported that 34 women (40.5%) had premature ovarian failure.20 In contrast, after ABVD alone, chemotherapy-induced ovarian failure is much more unlikely, especially when women are of young age at treatment.35-37
The prevention of ovarian failure in young women with oral contraceptives and gonadotropin-releasing hormone agonistic analogs (GnRHa) is a result of the decline of serum gonadotropin levels inhibiting follicular growth in the ovary. Some authors did not find a protective effect in nine women taking oral contraceptives during chemotherapy.25 The protection of fertility with the application of GnRHa or oral contraceptives during chemotherapy has been reported in the literature.38,39 Although this concept is appealing, it has never been investigated in a randomized trial so far. Hence, the GHSG has started a randomized phase II trial (Protection of Ovarian Fertility) for the reduction of ovarian failure with the use of GnRHa and oral contraceptives in young women treated with intensive chemotherapy for advanced-stage HL. The aim of the trial is to define a standard cotreatment for the reduction of infertility rates in young female patients during chemotherapy for HL.
On the basis of the results of pregnancy outcome in long-term survivors after childhood cancer, no overall increased risk for congenital malformations in offspring has been reported.21,40,41 For women, cryopreservation of ovarian tissue before treatment and its reimplantation after cancer treatment is of current debate.42,43 The first success has recently been reported.44,45However, a risk of disease transmission with reimplantation of ovarian tissue has been detected in mice.46 Taken together, our study indicates a possible protective effect of oral contraceptives in younger women undergoing gonadotoxic chemotherapy.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported in part by the Deutsche Krebshilfe, the Bundesministerium für Bildung und Forschung, and the Kompetenznetz Maligne Lymphome.
Both K.Be. and K.Br. contributed equally to this study.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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