Annals of Oncology Advance Access originally published online on June 9, 2008
Annals of Oncology 2008 19(10):1795-1801; doi:10.1093/annonc/mdn376
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supportive care |
Assessment of male fertility in patients with Hodgkin's lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials
1 Department of Internal Medicine
2 German Hodgkin Study Group, University Hospital Cologne, Cologne, Germany
* Correspondence to: Dr M. Sieniawski, Department of Internal Medicine, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Tel: +49-221-4785933; Fax: +49-221-4783778; E-mail: michal.sieniawski{at}ncl.ac.uk
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Abstract |
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Background: Infertility is one of the most significant side-effects in long-term survivors of successfully treated Hodgkin's lymphoma (HL).
Patients and methods: The fertility status was assessed in male HL patients enrolled into trials of the German Hodgkin Study Group from 1988 to 2003.
Results: In pre-treatment analysis (n = 202), 20% of patients had normozoospermia, 11% azoospermia and 69% had other dyspermia. In post-treatment analysis (n = 112), 64% of patients had azoospermia, 30% other dyspermia and 6% normozoospermia (P < 0.001). Azoospermia was observed in 90% of patients treated with chemotherapy alone, 67% of those treated with combined modality and 11% of those treated with radiotherapy alone (P < 0.001). Azoospermia was more frequent after 4x cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (COPP/ABVD) (91%), 8x bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP) baseline (93%) and 8x BEACOPP escalated (87%) compared with 2x COPP/ABVD (56%; P = 0.003). There was a statistically significant difference in post-treatment follicle-stimulating hormone (FSH) levels between patients with azoospermia and those with preserved spermatogenesis (P = 0.001).
Conclusions: Depending on the treatment received, male HL patients are at high risk of infertility after treatment. FSH might be used as surrogate parameter for male fertility in future studies.
Key words: chemotherapy, follicle-stimulating hormone, Hodgkin's lymphoma, male fertility
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introduction |
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Since prognosis of patients with Hodgkin's lymphoma (HL) has improved substantially over the last decades [1–3] and most HL patients are young with an average age of 32 years [4], long-term side-effects of treatment are becoming increasingly important. Particularly, infertility after treatment presents a high psychosocial burden for young patients. A recent report revealed that 51% of men with cancer expressed their wish to preserve their capacity for procreation in the future, including 77% of men who were still childless when their cancer was diagnosed [5]. Several analyses have investigated the fertility status in male HL patients. Chemotherapy regimens, which include alkylating agents such as cyclophosphamide and procarbazine, were particularly associated with infertility [6–8]. Interestingly, the majority of male patients with HL were shown to have inadequate sperm quality even before treatment [9]. However, there is still little information on the fertility of male patients treated in large, prospective trials.
The present study investigates the pre- and post-treatment fertility status of male HL patients treated within prospectively randomised trials of the German Hodgkin Study Group (GHSG). Fertility status was correlated with clinical and biological features at the time of diagnosis as well as the treatment regimen received.
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materials and methods |
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patient selection and study design
Fertility status was assessed in male patients with histologically confirmed first diagnosis of HL. All patients analysed were enrolled into the clinical trails HD4–HD12 and registered in the GHSG database from 1988 to 2003. Patients in early stage were treated within the prospectively randomised trials HD4, HD7 and HD10. Patients in intermediate stage were enrolled in HD5, HD8 and HD11. Patients in advanced stage were treated within trials HD6, HD9 and HD12. The design of the different trials and treatment given are shown in Tables 1 and 2. Consent forms, on the basis of the institutional review board guidelines, were signed by each patient. For the fertility analysis, the age of patients was restricted to <60 years. Patients whose fertility status was assessed after the end of the treatment had to be free of HL.
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semen analysis
Semen samples were evaluated for sperm volume, sperm count, sperm forward motility and morphological criteria of spermatozoa according to World Health Organisation guidelines. The nomenclature of pathologic patterns of ejaculate followed Eliasson's classification of dyspermia [10]. Conditions of disturbed sperm quality included oligozoospermia (i.e. sperm concentration <20 x 106/ml), asthenozoospermia (i.e. sperm with forward motility <50%) and theratozoospermia (i.e. sperm with normal morphology <30%). Combined severe damages were defined as oligoasthenoteratozoospermia syndrome (disturbance of all three variables), or azoospermia, i.e. the complete absence of spermatozoa in ejaculate.
hormonal analysis
Follicle-stimulating hormone (FSH), luteinising hormone (LH) and testosterone were measured by commercial radioimmune assays. Normal laboratory ranges are as follows: FSH 1–7 U/l, LH 2–10 U/l and testosterone 3.5–8.6 µg/l.
statistical analysis
Demographics and disease characteristics were summarised using descriptive statistics. The Fisher's exact test and Mann–Whitney test were used to investigate differences in proportions and means, respectively. The different predictive factors and fertility status were evaluated by both univariate and multivariate regression analysis. Risk factors tested in pre-treatment and post-treatment were clinical stage (I/II versus III/IV), B symptoms, large mediastinal mass, extranodal involvement, erythrocyte sedimentation rate <30 versus 
30, three or more lymph nodes areas involved and risk group (early versus intermediate versus advanced stage). Other predictive factors included in the pre-treatment evaluation were FSH, LH and testosterone. In the post-treatment evaluation, treatment regimes (radiotherapy alone versus chemotherapy alone versus combined modality), chemotherapy regimes [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP) versus other chemotherapy and cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (COPP/ABVD) versus other chemotherapy] and pre-treatment sperm quality were also tested. If not otherwise indicated, BEACOPP included all variants of schedule such as BEACOPP escalated or BEACOPP baseline and COPP/ABVD included COPP/ABVD or cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, ifosfamide, methotrexate, etoposide, prednisone (COPP/ABV/IMEP). Statistical analysis was carried out with SAS version 8.2 (SAS Institute, Cary, NC).
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patient characteristics
In all, 243 patients were enrolled in this analysis; 131 patients were examined before treatment, 71 patients before and after the treatment and 41 patients were examined after treatment only. Thus, the pre-treatment evaluation group consisted of 202 patients and post-treatment evaluation group of 112 patients. The median age was 26 years (range 16–58) in the pre-treatment and 27 years (range 16–52) in the post-treatment evaluation group. There was no difference between both groups with regards to Ann Arbor stage or risk factors. The patient characteristics are shown in Table 3.
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pre-treatment semen analysis
The median sperm concentration in patients before therapy was 22.7 x 106/ml (average 39.5 x 106/ml; range 0.0–365.0). The median percentage of sperms with normal motility was 32 (average 36.2; range 0–93) and the median percentage of sperms with normal morphology was 42 (average 42.3; range 0–95). Only 20% of patients had a normal sperm analysis. Azoospermia was observed in 11% of patients and other dyspermia in 69% (Table 4).
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post-treatment semen analysis
Of the 112 patients analysed after treatment, 72 patients were analysed once, 32 twice and eight patients had multiple analyses. The median time of sperm analysis after the end of treatment was 17.4 months (range 1–94 months). The median sperm concentration was 0.0 x 106/ml (average 8.3 x 106/ml; range 0.0–95.0). The majority of patients (64%) had azoospermia with 30% having other form of dyspermia. A normal sperm analysis was found in 6% of patients (Table 4). The differences in sperm quality before and after treatment were statistically significant (P < 0.001) (Table 4). There was no difference in age between fertile patients and those with azoospermia.
The median time to recovery of spermatogenesis for all patients was 27 months. Among the patients with recovery, the onset of spermatogenesis was observed in 18% of patients during the first year after treatment, 23% during the second year, 25% during the third year and 35% after the third year.
Patients treated with radiotherapy alone had the best chance of retaining fertility, with only one patient having azoospermia (n = 11). In contrast, 1 of 10 patients treated with chemotherapy alone was fertile after treatment. In the group treated with combined modality, 67% (62 of 93) of patients were azoospermic (P < 0.001). Among four patients treated with ABVD, all had preserved spermatogenesis after treatment. The infertility rate in patients treated with 2x COPP/ABVD was 56% and statistically lower as compared with those in patients treated with 4x COPP/ABVD (91%); P = 0.03. Interestingly, there was no statistically significant difference between the group of patients treated with 8x BEACOPP baseline (93%) and the group treated with 8x BEACOPP escalated (87%); P = 0.480. Only two patients were treated with 4x BEACOPP baseline and none of them were azoospermic. Table 5 shows the results of sperm analysis for each treatment group.
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comparison of pre- and post-treatment semen analysis
Pre-treatment and post-treatment sperm counts were available for 71 patients. In all but nine, patients the sperm count decreased (61 patients) or remained unchanged (one patient).
Before treatment, in the group with improvement of sperm count, two patients had azoospermia and seven had other forms of dyspermia. After treatment, two patients showed normozoospermia and seven other dyspermia. The median age in this group was 25 years (range 21–39), and there was no difference in age of patients as compared with all patients. Three of these patients were treated with radiotherapy only, three with COPP/ABVD, two with BEACOPP and one with ABVD.
Normozoospermia was diagnosed in 20 patients before treatment with only two retaining normal sperm analysis after completion of treatment, most patients (11) showed azoospermia and seven manifested various other forms of dyspermia. In this group, 12 patients received COPP/ABVD, seven BEACOPP and one patient ABVD.
pre-treatment hormonal analysis
Availability of hormone serum levels before treatment was as follows: FSH 151 patients, LH 125 and testosterone 101 patients. The median serum levels were FSH 4.5 U/l (average 5.7 U/l; range 0.3–54.4), LH 4.4 U/l (average 4.99 U/l; range 0.5–21.0) and testosterone 4.4 µg/l (average 7.96 µg/l; range 0.5–70.3). Normal levels for FSH, LH and testosterone were found in 76%, 86% and 65% of patients, respectively (Table 6).
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Regarding pre-treatment hormone levels and sperm count, there were no differences in the number of patients with azoospermia between the patients with normal and abnormal FSH, LH and testosterone levels (P = 0.126, 0.668 and 0.596, respectively). Additionally, there was a trend in difference of average FSH level between patients with azoospermia and those without azoospermia (P = 0.052); (Figure 1A, but there was no difference in pre-treatment average LH and testosterone levels between both groups of patients (P = 0.087 and 0.277) (Figure 1B and C).
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post-treatment hormonal analysis
After treatment, serum levels were available from 63 patients for FSH, 51 for LH and 40 for testosterone. The median levels were FSH 14.2 U/l (average 14.77 U/l, range 2.1–47.5); LH 4.6 U/l (average 5.17 U/l, range 0.5–13.9) and testosterone 4.49 µg/l (average 5.38 µg/l, range 2.32–24.5). Comparing hormone levels pre- and post-treatment, 79% of patients had abnormal FSH levels after treatment. This difference was statistically significant (P < 0.001). Normal LH and testosterone serum levels were found in 86% and 63% of patients, respectively. There was no significant difference between the pre- and post-treatment LH and testosterone values (P = 0.4114 and 0.0862, respectively) (Table 6). Patients who had been treated with radiotherapy alone faired better than those receiving chemotherapy or combined modality treatment. These differences were significant for FSH (P = 0.013) but not for LH (P = 0.419) or testosterone (P = 0.237). Patients treated with COPP/ABVD had slightly better post-treatment hormonal status than those patients treated with BEACOPP; these differences were, however, not significant (Table 7). There were no differences in post-treatment hormone levels between patients treated with 2x COPP/ABVD and 4x COPP/ABVD and between patients treated with 8x BEACOPP baseline and 8x BEACOPP escalated (Table 7).
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Regarding the post-treatment hormone levels and fertility status, 23% of patients showed azoospermia in the group with normal FSH levels. In contrast, the majority of patients with abnormal FSH level were azoospermic (78%; P = 0.001). Additionally, the average FSH level in the group with azoospermia was significantly higher than in the group without azoospermia (P = 0.001) (Figure 1D). The correlation between sperm count and LH or testosterone levels was not as pronounced. In the group with normal LH and testosterone levels, 70% and 64% of patients had azoospermia, whereas azoospermia was confirmed in 86% and 80% of patients with abnormal LH and testosterone levels, respectively (P = 0.0657 and 0.4774). There was a trend in average post-treatment LH levels between the group with and without azoospermia (P = 0.05) (Figure 1E). In contrast, there was no difference in post-treatment testosterone level between both groups of patients (P = 0.813) (Figure 1F).
predictive factors
In the pre-treatment analysis, there were no predictive factors for normal sperm quality. By contrast, extranodal involvement (P < 0.001), stage (P < 0.001), treatment with chemotherapy (P < 0.001) and BEACOPP (P = 0.005) were significant predictive factors for azoospermia in the univariate analysis with none of these factors significant in Cox regression multivariate analysis.
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discussion |
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The following findings emerge from this study: (i) most patients with HL have inadequate semen quality before treatment; (ii) the majority of patients become azoospermic after treatment and recovery of spermatogenesis depends on the treatment received and (iii) FSH levels appear to correlate with the fertility status after treatment.
The majority of HL patients had inadequate semen quality before treatment with 11% having azoospermia and 69% other forms of dyspermia. In addition, sperm concentration and percentage of sperms with normal motility and morphology were lower as compared with the healthy male population [11, 12]. Similar results were reported in other studies where HL patients were investigated [9, 13–15]. Serum levels of FSH, LH and testosterone before treatment were normal in most patients and did not correlate with sperm quality as shown previously [9, 16]. The underlying mechanism of infertility in HL patients is still unknown. Possible factors are damage in germinal epithelium and disturbances in the hypothalamic—hypophysial axis as well as the impact of cytokines on spermatogenesis [9, 17–19].
We report testicular dysfunction in the majority of patients after treatment, with 64% of patients being azoospermic. Infertility was at least in part related to the type of treatment received. The highest rate of infertility was observed among those treated with chemotherapy alone (90%). In this group, all patients had advanced disease and were treated with intensified regimens. In the group of patients receiving combined modality treatment, 67% were azoospermic after treatment. The present study showed that by contrast to chemotherapy, radiotherapy only had the least impact on male fertility, with 11% of patients being azoospermic after treatment. However, all patients in this group had limited disease and no B symptoms.
The infertility rate was higher in patients receiving 4x COPP/ABVD (91%), 8x BEACOPP baseline (93%) and 8x BEACOPP escalated (87%) than in patients receiving 2x COPP/ABVD (56%; P = 0.003). There was no difference between patients who received 8x BEACOPP escalated compared with those treated with 8x BEACOPP baseline (P = 0.48) but there was a difference between patients receiving 2x COPP/ABVD and 4x COPP/ABVD (P = 0.03). All these regimens contain cyclophosphamide and procarbazine cytostatic agents, which are suspected as major contributors to gonadotoxicity. The cumulative dose of cyclophosphamide was 5200 mg/m2 in four cycles COPP/ABVD and eight cycles BEACOPP baseline, 10 000 mg/m2 in eight cycles BEACOPP escalated and 2600 mg/m2 in two cycles COPP/ABVD. In contrast, the doses of procarbazine were the same (5600 mg/m2) in four cycles COPP/ABVD, eight cycles BEACOPP baseline and in eight cycles BEACOPP-escalated regimens but lower (2800 mg/m2) in two cycles COPP/ABVD. These data may suggest the increase in cumulative dose of cyclophosphamide and procarbazine beyond the dose given in two cycles COPP/ABVD may not further contribute to higher rates of infertility, although the number of patients is low. This has been observed by da Cunha et al. [20]; three or fewer cycles of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) resulted in 14% azoospermia as compared with 91% after more than three cycles. The fertility rates reported in this study do not differ significantly from those reported after similar regimens such as mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (MOPP/ABVD) (87%), COPP/ABVD (86%) and chlorambucil, vinblastine, prednisolone, procarbazine, doxorubicin, vincristine, etoposide (95%) [21–23]. Similar rates of azoospermia after treatment were also reported with older regimens such as mechlorethamine, vinblastine, procarbazine, prednisone (MVPP), MOPP cyclophosphamide, vincristine, procarbazine, prednisone (COPP); the majority of patients were infertile: 88% (36 of 41), 86% (25 of 29) and 100% (19 of 19), respectively [6, 15, 24]. Other studies reported that azoospermia was lower when the treatment received did not include alkylating agents [7, 15]. With ABVD, azoospermia was observed in fewer patients, ranging from 0% to 4% [7, 15]. In our cohort, all patients treated with ABVD have preserved spermatogenesis.
The observed improvement of fertility after treatment in some patients suggests that successful therapy for HL can result in restoring spermatogenesis. Pre-treatment impairment of fertility is associated with disease activity, which can be overcome by successful treatment. On the other hand, our study shows that the fertility status at diagnosis does not seem to be predictive for the post-treatment fertility status. This was also suggested by other investigators [14, 23].
Regarding the post-treatment hormone levels, FSH levels were elevated in the majority of patients. In contrast, LH and testosterone levels remained normal in most patients. Similar results were previously reported by others [7, 21] and confirm the hypothesis that the spermatogonia are sensitive, whereas Sertoli and Leyding cells are more resistant to the toxic effects of cytostatic drugs [6, 25]. It was also possible to recognise the correlation between the FSH level and fertility status; therefore, the FSH level may be helpful in the examination of fertility status after treatment.
In our evaluation, we were not able to find significant prognostic factors for normal sperm quality before treatment. In post-treatment analysis, we found extranodal involvement, risk groups, treatment with chemotherapy and BEACOPP significantly predictive for azoospermia in a univariate model. None of these factors, however, were significant in a multivariate model.
The question is whether incomplete sperm production such as oligozoospermia or other forms of dyspermia is of clinical relevance. Since patients with severe oligozoospermia have been reported fathering healthy children [26], this might indeed be the case. More importantly, reduced fertility after chemotherapy can be compensated for by improved assisted reproduction techniques [27].
In conclusion, the main issue of this report was to evaluate the male fertility status in patients with HL treated within clinical trials conducted by one study group. This analysis is the most comprehensive reported for HL in terms of number of male patients included. Importantly, we included patients treated with BEACOPP, a new polychemotherapy regimen particularly used in advance stages. The knowledge of infertility rates after treatment with BEACOPP seems to be very important. This regimen can induce high long-lasting response rates in patients with advance stage of disease, but is associated with toxic effects including infertility. Thus, the patient's future plans regarding family planning should be taken into consideration in discussion before treatment. Additionally, FSH levels appeared to correlate with the fertility status after treatment and this could help in guiding judgement particularly when there is still some resistance of patients to undergo sperm analysis.
Received for publication April 29, 2008. Accepted for publication May 2, 2008.
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