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Assessment of male fertility in patients with Hodgkin's lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials
original article
Annals of Oncology 19: 1795–1801, 2008 doi:10.1093/annonc/mdn376 Published online 9 June 2008
Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials M. Sieniawski1,2*, T. Reineke2, A. Josting1,2, L. Nogova1,2, K. Behringer1,2, T. Halbsguth1,2, M. Fuchs1,2, V. Diehl2 & A. Engert1,2 Received 29 April 2008; accepted 2 May 2008
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 4· cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (COPP/ABVD) (91%), 8· bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP) baseline (93%) and 8· BEACOPP escalated (87%) compared with 2· 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
introduction 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], longterm 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. *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: [email protected]
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.
materials and methods 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.
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Department of Internal Medicine; 2German Hodgkin Study Group, University Hospital Cologne, Cologne, Germany
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1
original article
Annals of Oncology
semen analysis
Table 1. Patient treatment
a
Post-treatment (n = 112)
202
112
2 3
2 1
8
12
10
6
8
6
4
1
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 lg/l.
statistical analysis 3 12
6 3
19
13
29
17
20
4
26
15
28
18
1 0 1 1
0 0 0 1
1 0 3 2
0 0 2 0
4
1
5
2
1
1
4
1
7
–
RT-IF on bulk/residual mass. RT-EF, extended field radiotherapy; RT-IF, involved field radiotherapy; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP/ABV/ IMEP, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, ifosfamide, methotrexate, etoposide, prednisone.
1796 | Sieniawski et al.
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 · 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.
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 pretreatment 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).
results 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 pretreatment 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. pre-treatment semen analysis The median sperm concentration in patients before therapy was 22.7 · 106/ml (average 39.5 · 106/ml; range 0.0–365.0). The
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Total HD4 RT-EF 40 Gy RT-EF 30 Gy + IF 10 Gy HD5 2· COPP/ABVD + RT-EF 30 Gy (bulk 10 Gy) 2· COPP/ABV/IMEP + RT-EF 30 Gy (bulk 10 Gy) HD6 4· COPP/ABVD + RT-IF bulk/residual mass 4· COPP/ABV/IMEP + RT-IF bulk/residual mass HD7 RT-EF 40 Gy 2· ABVD + RT-EF 40 Gy HD8 2· COPP/ABVD + RT-EF 30 Gy (bulk 10 Gy) 2· COPP/ABVD + RT-EF 30 Gy (bulk 10 Gy) HD9 4· COPP/ABVD + RT-IF bulk/residual mass 8· BEACOPP baseline + RT-IF bulk/residual mass 8· BEACOPP escalated + RT-IF bulk/residual mass HD10 4· ABVD + RT-IF 30 Gy 4· ABVD + RT-IF 20 Gy 2· ABVD + RT-IF 30 Gy 2· ABVD + RT-IF 20 Gy HD11 4· ABVD + RT-IF 30 Gy 4· ABVD + RT-IF 20 Gy 4· BEACOPP baseline + RT-IF 30 Gy 4· BEACOPP baseline + RT-IF 20 Gy HD12 4· BEACOPP escalated + 4· BEACOPP escalated + RT-IFa 4· BEACOPP escalated + 4· BEACOPP escalated 4· BEACOPP escalated + 4· BEACOPP baseline + RT-IFa 4· BEACOPP escalated + 4· BEACOPP baseline Unknown
Pre-treatment (n = 202)
original article
Annals of Oncology
Table 2. Drugs and schedules used Treatment protocol Treatment regimen for ABVD Doxorubicin Bleomycin Vinblastine Dacarbazine
Procarbazine Prednisone Doxorubicin Bleomycin Vinblastine Dacarbazine Treatment regimen for COPP/ABV/IMEP Cyclophosphamide Vincristine Procarbazine Prednisone Doxorubicin Bleomycin Vinblastine Ifosfamid Methotrexate Etoposide Prednisone Treatment regimen for BEACOPP baseline Bleomycin Etoposide Doxorubicin Cyclophosphamide Vincristine Procarbazine Prednisone Treatment regimen for BEACOPP escalated Bleomycin Etoposide Doxorubicin Cyclophosphamide Vincristine Procarbazine Prednisone
25 10 6 375
650 1.4; maximum 2 mg 100 40 25 10 6 375
Route
Schedule
i.v. i.v. i.v. i.v.
Days 1 + 15 Days 1 + 15 Days 1 + 15 Days 1 + 15 Repeat on day 29
i.v. i.v.
Days 1 + 8 Days 1 + 8
p.o. p.o. i.v. i.v. i.v. i.v.
Days 1–14 Days 1–14 Days 29 + 43 Days 29 + 43 Days 29 + 43 Days 29 + 43 Repeat on day 57
800 1.4; maximum 2 mg 100 40 40 10 6 1000 30 100 40
i.v. i.v.
Day 1 Day 1
p.o. p.o. i.v. i.v. i.v. i.v. i.v. i.v. p.o.
Days 1–10 Days 1–15 Day 15 Day 15 Day 15 Days 29–33 Day 31 Days 29 + 31 Days 29 + 35 Repeat on day 43
10 100 25 650 1.4; maximum 2 mg 100 40
i.v. i.v. i.v. i.v. i.v.
Day 8 Days 1–3 Day 1 Day 1 Day 8
p.o. p.o.
Days 1–7 Days 1–14 Repeat on day 22
10 200 35 1250 1.4; maximum 2 mg 100 40
i.v. i.v. i.v. i.v. i.v.
Day 8 Days 1–3 Day 1 Day 1 Day 8
p.o. p.o.
Days 1–7 Days 1–14 Repeat on day 22
ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP/ABV/IMEP, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, ifosfamide, methotrexate, etoposide, prednisone; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone.
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Table 3. Patient characteristics Pretreatment (n = 202) Age median (range) Ann Arbor stage, n (%) I/II III/IV Risk factors, n (%) Erythrocyte sedimentation rate ‡30 B symptoms Large mediastinal mass Extranodal disease Three or more lymph node areas involved Risk group, n (%) early stagea intermediate stageb advanced stagec
Post-treatment (n = 112)
26 (16–58)
27 (16–52)
111 (55) 91 (45)
69 (62) 43 (38)
97 (48)
48 (43)
90 48 30 140
(45) (24) (15) (69)
51 25 16 79
23 (11) 75 (37) 104 (51)
(46) (25) (16) (71)
13 (11) 50 (45) 49 (44)
a
Early stage—CS IA–IIB without risk factors. Intermediate stage—CS IA–IIB with at least one risk factor: large mediastinal mass, extranodal disease, massive splenic involvement, elevated erythrocyte sedimentation rate and involvement of three or more lymph nodes areas; CS IIB with elevated erythrocyte sedimentation rate or/and involvement of three or more lymph nodes areas. c Advanced stage—CS IIB with large mediastinal mass and/or extranodal disease; CS III and CSIV. b
Table 4. Results of sperm analysis before and after treatment PrePostP valuea treatment, treatment, n (%) n (%) Normozoospermiaa 40 (20) Azoospermiaa 23 (11) Other dyspermiaa 139 (69) Severe damage 28 (14) (oligoasthenoteratozoospermia) 50 (25) Combined damage (oligoasthenozoospermia, oligoteratozoospermia, asthenoteratozoospermia) 51 (25) Single damage (oligozoospermia, asthenozoospermia, theratozoospermia)
7 72 33 7
(6) (64) (30) (6)
P < 0.001 P < 0.001 P < 0.001
14 (13)
12 (11)
a
Fisher’s exact test.
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Treatment regimen for COPP/ABVD Cyclophosphamide Vincristine
Dose (mg/m2)
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).
original article
Annals of Oncology
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 lg/l (average 7.96 lg/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).
Table 6. Results of hormone analysis before and after treatment Pretreatment, n (%)
Table 5. Results of sperm analysis and treatment Treatment
Chemotherapy alone (n = 10) Radiotherapy alone (n = 9) Combined modality (n = 93) ABVD (n = 4) 2· COPP/ABVD (n = 48) 4· COPP/ABVD (n = 11) 4· BEACOPP baseline (n = 2) 8· BEACOPP baseline (n = 15) 8· BEACOPP escalated (n = 23) a
Azoospermia, P valuea No azoospermia, n (%) n (%) 1 8 31 4 21 1 2 1 3
(10) (89) (33) (100) (44) (9) (100) (7) (13)
9 1 62 0 27 10 0 14 20
(90) (11) (67) (0) (56) (91) (0) (93) (87)
P < 0.001
P = 0.030
P = 0.480
Fisher’s exact test. ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone.
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Follicle-stimulating hormone (normal values 1.0–7.0 U/l) Total <1.0 1.0–7.0 >7.0 Luteinising hormone (normal values 2.0–10.0 U/l) Total <2.0 2.0–10.0 >10.0 Testosterone (normal values 3.5–8.6 lg/l) Total <3.5 3.5–8.6 >8.6
Posttreatment, n (%)
P valuea
P < 0.001 151 5 114 32
(100) (3) (76) (21)
63 0 13 50
(100) (0) (21) (79) P = 0.4114
125 10 108 7
(100) (8) (86) (6)
51 2 44 5
(100) (4) (86) (10) P = 0.0862
101 16 66 19
(100) (16) (65) (19)
40 12 25 3
(100) (30) (63) (7)
a
Fisher’s exact test.
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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 · 106/ml (average 8.3 · 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 2· COPP/ABVD was 56% and statistically lower as compared with those in patients treated with 4· COPP/ABVD (91%); P = 0.03. Interestingly, there was no statistically significant difference between the group of patients treated with 8· BEACOPP baseline (93%) and the group treated with 8· BEACOPP escalated (87%); P = 0.480. Only two patients were treated with 4· BEACOPP baseline and none of them were azoospermic. Table 5 shows the results of sperm analysis for each treatment group.
original article
Annals of Oncology
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).
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.
discussion The following findings emerge from this study: (i) most patients with HL have inadequate semen quality before
Figure 1. Pre-treatment (A) follicle stimulating hormone (FSH), (B) luteinising hormone (LH) and (C) testosterone level in patients without and with azoospermia (P = 0.052, 0.87 and 0.277, respectively). Post-treatment (D) follicle stimulating hormone (FSH), (E) luteinising hormone (LH) and (F) testosterone level in patients without and with azoospermia (P = 0.001, 0.05 and 0.827, respectively).
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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 lg/l (average 5.38 lg/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 2· COPP/ABVD and 4· COPP/ABVD and between patients treated with 8· BEACOPP baseline and 8· BEACOPP escalated (Table 7). 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).
original article
Annals of Oncology
Table 7. Results of hormone analysis and treatment Treatment
Normal Abnormal P valuea values, n (%)values, n (%)
4 44 2 30 4 7 7
(80) (85) (33) (88) (80) (100) (88)
0 7 0 3 1 0 2
(0) (17) (0) (12) (20) (0) (29)
3 12 0 6 2 4 3
(60) (37) (0) (35) (40) (57) (43)
P = 0.013
P = 0.517 P = 0.533
P = 0.419
P = 0.538 P = 0.231
P = 0.237
P = 0.620 P = 0.500
a
Fisher’s exact test. COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone.
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,
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Follicle-stimulating hormone (n = 63) Chemotherapy alone (n = 5) 1 (20) Combined modality (n = 52) 8 (15) Radiotherapy alone (n = 6) 4 (67) 2· COPP/ABVD (n = 34) 4 (13) 4· COPP/ABVD (n = 5) 1 (20) 8· BEACOPP baseline (n = 7) 0 (0) 8· BEACOPP escalated (n = 8) 1 (12) Luteinising hormone (n = 51) Chemotherapy alone (n = 5) 5 (100) Combined modality (n = 42) 35 (83) Radiotherapy alone (n = 4) 4 (100) 2· COPP/ABVD (n = 25) 22 (88) 4· COPP/ABVD (n = 5) 4 (80) 8· BEACOPP baseline (n = 7) 7 (100) 8· BEACOPP escalated (n = 7) 5 (71) Testosterone (n = 40) Chemotherapy alone (n = 5) 2 (40) Combined modality (n = 32) 20 (63) Radiotherapy alone (n = 3) 3 (100) 2· COPP/ABVD (n = 17) 11 (65) 4· COPP/ABVD (n = 5) 3 (60) 8· BEACOPP baseline (n = 7) 3 (43) 8· BEACOPP escalated (n = 7) 4 (57)
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 4· COPP/ ABVD (91%), 8· BEACOPP baseline (93%) and 8· BEACOPP escalated (87%) than in patients receiving 2· COPP/ABVD (56%; P = 0.003). There was no difference between patients who received 8· BEACOPP escalated compared with those treated with 8· BEACOPP baseline (P = 0.48) but there was a difference between patients receiving 2· COPP/ABVD and 4· 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].
Annals of Oncology
references 1. Rosenberg SA. The management of Hodgkin’s disease: half a century of change. The Kaplan Memorial Lecture. Ann Oncol. 1996; 7: 555–560. 2. Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003; 348: 2386–2395. 3. Bonadonna G, Bonfante V, Viviani S et al. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol. 2004; 22: 2835–2841. 4. Greco RS, Acheson RM, Foote FM. Hodgkin disease in Connecticut from 1935 to 1962. The bimodal incidence curve in the general population and survival in untreated patients. Arch Intern Med. 1974; 134: 1039–1042. 5. Schover LR, Brey K, Lichtin A et al. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J Clin Oncol. 2002; 20: 1880–1889.
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6. Kreuser ED, Xiros N, Hetzel WD, Heimpel H. Reproductive and endocrine gonadal capacity in patients treated with COPP chemotherapy for Hodgkin’s disease. J Cancer Res Clin Oncol. 1987; 113: 260–266. 7. Kulkarni SS, Sastry PS, Saikia TK et al. Gonadal function following ABVD therapy for Hodgkin’s disease. Am J Clin Oncol. 1997; 20: 354–357. 8. Behringer K, Breuer K, Reineke T et al. Secondary amenorrhea after Hodgkin’s lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2005; 23: 7555–7564. 9. Rueffer U, Breuer K, Josting A et al. Male gonadal dysfunction in patients with Hodgkin’s disease prior to treatment. Ann Oncol. 2001; 12: 1307–1311. 10. Eliasson R, Hellinga F, Lubcke F. Empehlungen zur Nomenklatur in der Andrologie. Andrologie 1970; 2: 1257. 11. Vierula M, Niemi M, Keiski A et al. High and unchanged sperm counts of Finnish men. Int J Androl. 1996; 19: 11–17. 12. Auger J, Kunstmann JM, Czyglik F, Jouannet P. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995; 332: 281–285. 13. Chapman RM, Sutcliffe SB, Malpas JS. Male gonadal dysfunction in Hodgkin’s disease. A prospective study. JAMA 1981; 245: 1323–1328. 14. Redman JR, Bajorunas DR, Goldstein MC et al. Semen cryopreservation and artificial insemination for Hodgkin’s disease. J Clin Oncol. 1987; 5: 233–238. 15. Viviani S, Santoro A, Ragni G et al. Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol. 1985; 21: 601–605. 16. Ragni G, Bestetti O, Santoro A et al. Evaluation of semen and pituitary gonadotropin function in men with untreated Hodgkin’s disease. Fertil Steril 1985; 43: 927–930. 17. Huleihel M, Lunenfeld E, Levy A et al. Distinct expression levels of cytokines and soluble cytokine receptors in seminal plasma of fertile and infertile men. Fertil Steril 1996; 66: 135–139. 18. Dousset B, Hussenet F, Daudin M et al. Seminal cytokine concentrations (IL-1beta, IL-2, IL-6, sR IL-2, sR IL-6), semen parameters and blood hormonal status in male infertility. Hum Reprod. 1997; 12: 1476–1479. 19. Schulte HM, Bamberger CM, Elsen H et al. Systemic interleukin-1 alpha and interleukin-2 secretion in response to acute stress and to corticotropin-releasing hormone in humans. Eur J Clin Invest. 1994; 24: 773–777. 20. da Cunha MF, Meistrich ML, Fuller LM et al. Recovery of spermatogenesis after treatment for Hodgkin’s disease: limiting dose of MOPP chemotherapy. J Clin Oncol. 1984; 2: 571–577. 21. Clark ST, Radford JA, Crowther D et al. Gonadal function following chemotherapy for Hodgkin’s disease: a comparative study of MVPP and a seven-drug hybrid regimen. J Clin Oncol. 1995; 13: 134–139. 22. Kreuser ED, Felsenberg D, Behles C et al. Long-term gonadal dysfunction and its impact on bone mineralization in patients following COPP/ABVD chemotherapy for Hodgkin’s disease. Ann Oncol. 1992; 3 (Suppl 4): 105–110. 23. Viviani S, Ragni G, Santoro A et al. Testicular dysfunction in Hodgkin’s disease before and after treatment. Eur J Cancer 1991; 27: 1389–1392. 24. Waxman JH, Terry YA, Wrigley PF et al. Gonadal function in Hodgkin’s disease: long-term follow-up of chemotherapy. Br Med J (Clin Res Ed) 1982; 285: 1612–1613. 25. Bramswig JH, Heimes U, Heiermann E et al. The effects of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin’s disease during childhood or adolescence. Cancer 1990; 65: 1298–1302. 26. Petti N, Anghel G, Schimberni M et al. Successful paternity with microassisted fertilization after total body irradiation-based conditioning for autologous bone marrow transplantation. Hematol J 2003; 4: 285–288. 27. Chan PT, Palermo GD, Veeck LL et al. Testicular sperm extraction combined with intracytoplasmic sperm injection in the treatment of men with persistent azoospermia postchemotherapy. Cancer 2001; 92: 1632–1637.
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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.
original article
Annals of Oncology 19: 1795–1801, 2008 doi:10.1093/annonc/mdn376 Published online 9 June 2008
Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials M. Sieniawski1,2*, T. Reineke2, A. Josting1,2, L. Nogova1,2, K. Behringer1,2, T. Halbsguth1,2, M. Fuchs1,2, V. Diehl2 & A. Engert1,2 Received 29 April 2008; accepted 2 May 2008
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 4· cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (COPP/ABVD) (91%), 8· bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP) baseline (93%) and 8· BEACOPP escalated (87%) compared with 2· 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
introduction 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], longterm 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. *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: [email protected]
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.
materials and methods 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.
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Department of Internal Medicine; 2German Hodgkin Study Group, University Hospital Cologne, Cologne, Germany
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1
original article
Annals of Oncology
semen analysis
Table 1. Patient treatment
a
Post-treatment (n = 112)
202
112
2 3
2 1
8
12
10
6
8
6
4
1
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 lg/l.
statistical analysis 3 12
6 3
19
13
29
17
20
4
26
15
28
18
1 0 1 1
0 0 0 1
1 0 3 2
0 0 2 0
4
1
5
2
1
1
4
1
7
–
RT-IF on bulk/residual mass. RT-EF, extended field radiotherapy; RT-IF, involved field radiotherapy; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP/ABV/ IMEP, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, ifosfamide, methotrexate, etoposide, prednisone.
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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 · 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.
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 pretreatment 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).
results 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 pretreatment 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. pre-treatment semen analysis The median sperm concentration in patients before therapy was 22.7 · 106/ml (average 39.5 · 106/ml; range 0.0–365.0). The
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Total HD4 RT-EF 40 Gy RT-EF 30 Gy + IF 10 Gy HD5 2· COPP/ABVD + RT-EF 30 Gy (bulk 10 Gy) 2· COPP/ABV/IMEP + RT-EF 30 Gy (bulk 10 Gy) HD6 4· COPP/ABVD + RT-IF bulk/residual mass 4· COPP/ABV/IMEP + RT-IF bulk/residual mass HD7 RT-EF 40 Gy 2· ABVD + RT-EF 40 Gy HD8 2· COPP/ABVD + RT-EF 30 Gy (bulk 10 Gy) 2· COPP/ABVD + RT-EF 30 Gy (bulk 10 Gy) HD9 4· COPP/ABVD + RT-IF bulk/residual mass 8· BEACOPP baseline + RT-IF bulk/residual mass 8· BEACOPP escalated + RT-IF bulk/residual mass HD10 4· ABVD + RT-IF 30 Gy 4· ABVD + RT-IF 20 Gy 2· ABVD + RT-IF 30 Gy 2· ABVD + RT-IF 20 Gy HD11 4· ABVD + RT-IF 30 Gy 4· ABVD + RT-IF 20 Gy 4· BEACOPP baseline + RT-IF 30 Gy 4· BEACOPP baseline + RT-IF 20 Gy HD12 4· BEACOPP escalated + 4· BEACOPP escalated + RT-IFa 4· BEACOPP escalated + 4· BEACOPP escalated 4· BEACOPP escalated + 4· BEACOPP baseline + RT-IFa 4· BEACOPP escalated + 4· BEACOPP baseline Unknown
Pre-treatment (n = 202)
original article
Annals of Oncology
Table 2. Drugs and schedules used Treatment protocol Treatment regimen for ABVD Doxorubicin Bleomycin Vinblastine Dacarbazine
Procarbazine Prednisone Doxorubicin Bleomycin Vinblastine Dacarbazine Treatment regimen for COPP/ABV/IMEP Cyclophosphamide Vincristine Procarbazine Prednisone Doxorubicin Bleomycin Vinblastine Ifosfamid Methotrexate Etoposide Prednisone Treatment regimen for BEACOPP baseline Bleomycin Etoposide Doxorubicin Cyclophosphamide Vincristine Procarbazine Prednisone Treatment regimen for BEACOPP escalated Bleomycin Etoposide Doxorubicin Cyclophosphamide Vincristine Procarbazine Prednisone
25 10 6 375
650 1.4; maximum 2 mg 100 40 25 10 6 375
Route
Schedule
i.v. i.v. i.v. i.v.
Days 1 + 15 Days 1 + 15 Days 1 + 15 Days 1 + 15 Repeat on day 29
i.v. i.v.
Days 1 + 8 Days 1 + 8
p.o. p.o. i.v. i.v. i.v. i.v.
Days 1–14 Days 1–14 Days 29 + 43 Days 29 + 43 Days 29 + 43 Days 29 + 43 Repeat on day 57
800 1.4; maximum 2 mg 100 40 40 10 6 1000 30 100 40
i.v. i.v.
Day 1 Day 1
p.o. p.o. i.v. i.v. i.v. i.v. i.v. i.v. p.o.
Days 1–10 Days 1–15 Day 15 Day 15 Day 15 Days 29–33 Day 31 Days 29 + 31 Days 29 + 35 Repeat on day 43
10 100 25 650 1.4; maximum 2 mg 100 40
i.v. i.v. i.v. i.v. i.v.
Day 8 Days 1–3 Day 1 Day 1 Day 8
p.o. p.o.
Days 1–7 Days 1–14 Repeat on day 22
10 200 35 1250 1.4; maximum 2 mg 100 40
i.v. i.v. i.v. i.v. i.v.
Day 8 Days 1–3 Day 1 Day 1 Day 8
p.o. p.o.
Days 1–7 Days 1–14 Repeat on day 22
ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP/ABV/IMEP, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, ifosfamide, methotrexate, etoposide, prednisone; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone.
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Table 3. Patient characteristics Pretreatment (n = 202) Age median (range) Ann Arbor stage, n (%) I/II III/IV Risk factors, n (%) Erythrocyte sedimentation rate ‡30 B symptoms Large mediastinal mass Extranodal disease Three or more lymph node areas involved Risk group, n (%) early stagea intermediate stageb advanced stagec
Post-treatment (n = 112)
26 (16–58)
27 (16–52)
111 (55) 91 (45)
69 (62) 43 (38)
97 (48)
48 (43)
90 48 30 140
(45) (24) (15) (69)
51 25 16 79
23 (11) 75 (37) 104 (51)
(46) (25) (16) (71)
13 (11) 50 (45) 49 (44)
a
Early stage—CS IA–IIB without risk factors. Intermediate stage—CS IA–IIB with at least one risk factor: large mediastinal mass, extranodal disease, massive splenic involvement, elevated erythrocyte sedimentation rate and involvement of three or more lymph nodes areas; CS IIB with elevated erythrocyte sedimentation rate or/and involvement of three or more lymph nodes areas. c Advanced stage—CS IIB with large mediastinal mass and/or extranodal disease; CS III and CSIV. b
Table 4. Results of sperm analysis before and after treatment PrePostP valuea treatment, treatment, n (%) n (%) Normozoospermiaa 40 (20) Azoospermiaa 23 (11) Other dyspermiaa 139 (69) Severe damage 28 (14) (oligoasthenoteratozoospermia) 50 (25) Combined damage (oligoasthenozoospermia, oligoteratozoospermia, asthenoteratozoospermia) 51 (25) Single damage (oligozoospermia, asthenozoospermia, theratozoospermia)
7 72 33 7
(6) (64) (30) (6)
P < 0.001 P < 0.001 P < 0.001
14 (13)
12 (11)
a
Fisher’s exact test.
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Treatment regimen for COPP/ABVD Cyclophosphamide Vincristine
Dose (mg/m2)
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).
original article
Annals of Oncology
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 lg/l (average 7.96 lg/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).
Table 6. Results of hormone analysis before and after treatment Pretreatment, n (%)
Table 5. Results of sperm analysis and treatment Treatment
Chemotherapy alone (n = 10) Radiotherapy alone (n = 9) Combined modality (n = 93) ABVD (n = 4) 2· COPP/ABVD (n = 48) 4· COPP/ABVD (n = 11) 4· BEACOPP baseline (n = 2) 8· BEACOPP baseline (n = 15) 8· BEACOPP escalated (n = 23) a
Azoospermia, P valuea No azoospermia, n (%) n (%) 1 8 31 4 21 1 2 1 3
(10) (89) (33) (100) (44) (9) (100) (7) (13)
9 1 62 0 27 10 0 14 20
(90) (11) (67) (0) (56) (91) (0) (93) (87)
P < 0.001
P = 0.030
P = 0.480
Fisher’s exact test. ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone.
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Follicle-stimulating hormone (normal values 1.0–7.0 U/l) Total <1.0 1.0–7.0 >7.0 Luteinising hormone (normal values 2.0–10.0 U/l) Total <2.0 2.0–10.0 >10.0 Testosterone (normal values 3.5–8.6 lg/l) Total <3.5 3.5–8.6 >8.6
Posttreatment, n (%)
P valuea
P < 0.001 151 5 114 32
(100) (3) (76) (21)
63 0 13 50
(100) (0) (21) (79) P = 0.4114
125 10 108 7
(100) (8) (86) (6)
51 2 44 5
(100) (4) (86) (10) P = 0.0862
101 16 66 19
(100) (16) (65) (19)
40 12 25 3
(100) (30) (63) (7)
a
Fisher’s exact test.
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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 · 106/ml (average 8.3 · 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 2· COPP/ABVD was 56% and statistically lower as compared with those in patients treated with 4· COPP/ABVD (91%); P = 0.03. Interestingly, there was no statistically significant difference between the group of patients treated with 8· BEACOPP baseline (93%) and the group treated with 8· BEACOPP escalated (87%); P = 0.480. Only two patients were treated with 4· BEACOPP baseline and none of them were azoospermic. Table 5 shows the results of sperm analysis for each treatment group.
original article
Annals of Oncology
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).
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.
discussion The following findings emerge from this study: (i) most patients with HL have inadequate semen quality before
Figure 1. Pre-treatment (A) follicle stimulating hormone (FSH), (B) luteinising hormone (LH) and (C) testosterone level in patients without and with azoospermia (P = 0.052, 0.87 and 0.277, respectively). Post-treatment (D) follicle stimulating hormone (FSH), (E) luteinising hormone (LH) and (F) testosterone level in patients without and with azoospermia (P = 0.001, 0.05 and 0.827, respectively).
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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 lg/l (average 5.38 lg/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 2· COPP/ABVD and 4· COPP/ABVD and between patients treated with 8· BEACOPP baseline and 8· BEACOPP escalated (Table 7). 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).
original article
Annals of Oncology
Table 7. Results of hormone analysis and treatment Treatment
Normal Abnormal P valuea values, n (%)values, n (%)
4 44 2 30 4 7 7
(80) (85) (33) (88) (80) (100) (88)
0 7 0 3 1 0 2
(0) (17) (0) (12) (20) (0) (29)
3 12 0 6 2 4 3
(60) (37) (0) (35) (40) (57) (43)
P = 0.013
P = 0.517 P = 0.533
P = 0.419
P = 0.538 P = 0.231
P = 0.237
P = 0.620 P = 0.500
a
Fisher’s exact test. COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone.
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,
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Follicle-stimulating hormone (n = 63) Chemotherapy alone (n = 5) 1 (20) Combined modality (n = 52) 8 (15) Radiotherapy alone (n = 6) 4 (67) 2· COPP/ABVD (n = 34) 4 (13) 4· COPP/ABVD (n = 5) 1 (20) 8· BEACOPP baseline (n = 7) 0 (0) 8· BEACOPP escalated (n = 8) 1 (12) Luteinising hormone (n = 51) Chemotherapy alone (n = 5) 5 (100) Combined modality (n = 42) 35 (83) Radiotherapy alone (n = 4) 4 (100) 2· COPP/ABVD (n = 25) 22 (88) 4· COPP/ABVD (n = 5) 4 (80) 8· BEACOPP baseline (n = 7) 7 (100) 8· BEACOPP escalated (n = 7) 5 (71) Testosterone (n = 40) Chemotherapy alone (n = 5) 2 (40) Combined modality (n = 32) 20 (63) Radiotherapy alone (n = 3) 3 (100) 2· COPP/ABVD (n = 17) 11 (65) 4· COPP/ABVD (n = 5) 3 (60) 8· BEACOPP baseline (n = 7) 3 (43) 8· BEACOPP escalated (n = 7) 4 (57)
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 4· COPP/ ABVD (91%), 8· BEACOPP baseline (93%) and 8· BEACOPP escalated (87%) than in patients receiving 2· COPP/ABVD (56%; P = 0.003). There was no difference between patients who received 8· BEACOPP escalated compared with those treated with 8· BEACOPP baseline (P = 0.48) but there was a difference between patients receiving 2· COPP/ABVD and 4· 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].
Annals of Oncology
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6. Kreuser ED, Xiros N, Hetzel WD, Heimpel H. Reproductive and endocrine gonadal capacity in patients treated with COPP chemotherapy for Hodgkin’s disease. J Cancer Res Clin Oncol. 1987; 113: 260–266. 7. Kulkarni SS, Sastry PS, Saikia TK et al. Gonadal function following ABVD therapy for Hodgkin’s disease. Am J Clin Oncol. 1997; 20: 354–357. 8. Behringer K, Breuer K, Reineke T et al. Secondary amenorrhea after Hodgkin’s lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2005; 23: 7555–7564. 9. Rueffer U, Breuer K, Josting A et al. Male gonadal dysfunction in patients with Hodgkin’s disease prior to treatment. Ann Oncol. 2001; 12: 1307–1311. 10. Eliasson R, Hellinga F, Lubcke F. Empehlungen zur Nomenklatur in der Andrologie. Andrologie 1970; 2: 1257. 11. Vierula M, Niemi M, Keiski A et al. High and unchanged sperm counts of Finnish men. Int J Androl. 1996; 19: 11–17. 12. Auger J, Kunstmann JM, Czyglik F, Jouannet P. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995; 332: 281–285. 13. Chapman RM, Sutcliffe SB, Malpas JS. Male gonadal dysfunction in Hodgkin’s disease. A prospective study. JAMA 1981; 245: 1323–1328. 14. Redman JR, Bajorunas DR, Goldstein MC et al. Semen cryopreservation and artificial insemination for Hodgkin’s disease. J Clin Oncol. 1987; 5: 233–238. 15. Viviani S, Santoro A, Ragni G et al. Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol. 1985; 21: 601–605. 16. Ragni G, Bestetti O, Santoro A et al. Evaluation of semen and pituitary gonadotropin function in men with untreated Hodgkin’s disease. Fertil Steril 1985; 43: 927–930. 17. Huleihel M, Lunenfeld E, Levy A et al. Distinct expression levels of cytokines and soluble cytokine receptors in seminal plasma of fertile and infertile men. Fertil Steril 1996; 66: 135–139. 18. Dousset B, Hussenet F, Daudin M et al. Seminal cytokine concentrations (IL-1beta, IL-2, IL-6, sR IL-2, sR IL-6), semen parameters and blood hormonal status in male infertility. Hum Reprod. 1997; 12: 1476–1479. 19. Schulte HM, Bamberger CM, Elsen H et al. Systemic interleukin-1 alpha and interleukin-2 secretion in response to acute stress and to corticotropin-releasing hormone in humans. Eur J Clin Invest. 1994; 24: 773–777. 20. da Cunha MF, Meistrich ML, Fuller LM et al. Recovery of spermatogenesis after treatment for Hodgkin’s disease: limiting dose of MOPP chemotherapy. J Clin Oncol. 1984; 2: 571–577. 21. Clark ST, Radford JA, Crowther D et al. Gonadal function following chemotherapy for Hodgkin’s disease: a comparative study of MVPP and a seven-drug hybrid regimen. J Clin Oncol. 1995; 13: 134–139. 22. Kreuser ED, Felsenberg D, Behles C et al. Long-term gonadal dysfunction and its impact on bone mineralization in patients following COPP/ABVD chemotherapy for Hodgkin’s disease. Ann Oncol. 1992; 3 (Suppl 4): 105–110. 23. Viviani S, Ragni G, Santoro A et al. Testicular dysfunction in Hodgkin’s disease before and after treatment. Eur J Cancer 1991; 27: 1389–1392. 24. Waxman JH, Terry YA, Wrigley PF et al. Gonadal function in Hodgkin’s disease: long-term follow-up of chemotherapy. Br Med J (Clin Res Ed) 1982; 285: 1612–1613. 25. Bramswig JH, Heimes U, Heiermann E et al. The effects of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin’s disease during childhood or adolescence. Cancer 1990; 65: 1298–1302. 26. Petti N, Anghel G, Schimberni M et al. Successful paternity with microassisted fertilization after total body irradiation-based conditioning for autologous bone marrow transplantation. Hematol J 2003; 4: 285–288. 27. Chan PT, Palermo GD, Veeck LL et al. Testicular sperm extraction combined with intracytoplasmic sperm injection in the treatment of men with persistent azoospermia postchemotherapy. Cancer 2001; 92: 1632–1637.
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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.
original article