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Cryopreservation, semen use and the likelihood of fatherhood in male hodgkin lymphoma survivors , an eortc gela lymphoma group cohort study

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  • 1. Hum. Reprod. Advance Access published December 17, 2013 Human Reproduction, Vol.0, No.0 pp. 1 –9, 2013 doi:10.1093/humrep/det430 ORIGINAL ARTICLE Infertility Cryopreservation, semen use and the likelihood of fatherhood in male Hodgkin lymphoma survivors: an EORTC-GELA Lymphoma Group cohort study 1 Department of Internal Medicine, ZH 4A 35, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands Department of Obstetrics and Gynaecology, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The ´ Netherlands 3Cancers & Preventions U 1086 INSERM, University of Caen-Basse Normandie, 14076 Caen Cedex 5, France 4Department of Radiotherapy, ZNA Middelheim-University Hospital Antwerp, University of Antwerp, BE 2020 Antwerp, Belgium 5BioTICLA EA-4656, University of Caen-Basse Normandie, 14076 Caen Cedex 5, France 6Division of Medical Oncology A, National Cancer Institute, 33081 Aviano (PN), Italy 7Department of Radiotherapy, Champalimaud Cancer Centre, 1400-038 Lisbon, Portugal 8European Organization for Research and Treatment of Cancer, BE 1200 Brussels, Belgium 9Department of Haematology, Erasmus MC University Medical Centre, 3015 CE Rotterdam, The Netherlands 10Department of Radiotherapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands 11Department of Radiotherapy, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands 12Department of Medicine, Institut de Cancerologie Gustave Roussy, 94805 Villejuif, France 13Department of General Medical Oncology, UZ Gasthuisberg, BE 3000 Leuven, Belgium 14Department of Haematology, Centre Henri Becquerel, 76038 Rouen Cedex 1, France 15Department of Haematology, Centre Francois Baclesse, 14000 Caen, ¸ ´ ˆ France 16Department of Haematology, Institut Bergonie, 33000 Bordeaux, France 17Department of Haematology, Hopital Saint Louis APHP, 75475 Paris Cedex10, France 18Radiotherapeutic Institute Friesland, 8934 AD Leeuwarden, The Netherlands 19Department of Haematology, ´ ´ Centre Leon Berard, 69008 Lyon, France 20Department of Radiation Oncology, University Medical Centre Utrecht, 3584 CX Utrecht, ˆ ´ The Netherlands 21Department of Haematology, Hopital Henri Mondor, 94000 Creteil, France 22Department of Haematology, Centre ´ Hospitalier Lyon Sud, 69310 Pierre Benite, France 23Department of Radiotherapy, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands 24 Department of Haematology, Centre Hospitalier Universitaire de Dijon, 21000 Dijon, France 25Department of Haematology, Centre Hospitalier Universitaire UCL Mont Godinne Dinant, Yvoir, Belgium 26Department of Haematology, Radboud University Nijmegen Medical ´ ´ ˆ Centre, 6500 HB Nijmegen, The Netherlands 27Centre de Traitement des Donnees du Canceropole Nord-Ouest, Centre Francois Baclesse, ¸ 14076 Caen Cedex 5, France 28Department of Haematology, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands 2 *Correspondence address. Tel: +31 20 444 43 09; E-mail: m.vanderkaaij@vumc.nl Submitted on June 25, 2013; resubmitted on October 11, 2013; accepted on November 5, 2013 † Both shared last authorship. ‡ See Supplementary data. & The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com Downloaded from http://humrep.oxfordjournals.org/ by guest on December 30, 2013 M.A.E. van der Kaaij1,*, J. van Echten-Arends2, N. Heutte3, P. Meijnders4, E. Abeilard-Lemoisson5, M. Spina6, E.C. Moser7, A. Allgeier8, B. Meulemans8, P.J. Lugtenburg9, B.M.P. Aleman10, E.M. Noordijk11, ´ C. Ferme12, J. Thomas13, A. Stamatoullas14, C. Fruchart15, H. Eghbali16, 17, W.G.J.M. Smit18, C. Sebban 19, J.K. Doorduijn9, J.M. Roesink 20, P. Brice I. Gaillard21, B. Coiffier22, M.L.M. Lybeert23, O. Casasnovas24, ´ M. Andre25, J.M.M. Raemaekers26, M. Henry-Amar27,†, and J.C. Kluin-Nelemans28,† for the European Organisation for Research and ´ Treatment of Cancer Lymphoma Group and the Groupe d’Etude des Lymphomes de l’Adulte‡
  • 2. 2 van der Kaaij et al. study question: How does the successful cryopreservation of semen affect the odds of post-treatment fatherhood among Hodgkin lymphoma (HL) survivors? summary answer: Among 334 survivors who wanted to have children, the availability of cryopreserved semen doubled the odds of posttreatment fatherhood. what is known already: Cryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Little is known about what proportion of patients achieve successful semen cryopreservation. To our knowledge, neither the factors which influence the occurrence of semen cryopreservation nor the rates of fatherhood after semen has been cryopreserved have been analysed before. study design, size, duration: This is a cohort study with nested case –control analyses of consecutive Hodgkin survivors treated between 1974 and 2004 in multi-centre randomized controlled trials. A written questionnaire was developed and sent to 1849 male survivors. participants/materials, setting, methods: Nine hundred and two survivors provided analysable answers. The median age at treatment was 31 years. The median follow-up after cryopreservation was 13 years (range 5–36). main results and the role of chance: Three hundred and sixty-three out of 902 men (40%) cryopreserved semen before the limitations, reasons for caution: Data came from questionnaires and so this study potentially suffers from response bias. We could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate due to lack of dates of semen utilization. We do not have detailed information on either the techniques used in cryopreserved semen utilization or the number of cycles needed. ´ study funding/competing interests: Lance Armstrong Foundation, Dutch Cancer Foundation, Rene Vogels Stichting, no competing interests. Key words: fertility / male / cryopreservation / lymphoma / Hodgkin Introduction Cryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Hodgkin lymphoma (HL) is the fourth most common cancer in men aged 15 – 39 in the Western world (International Agency for Research on Cancer, 2008) with high cure rates of 80 – 90%, making fertility concerns extremely relevant. Oncofertility counselling is becoming more and more established for patients about to undergo cancer chemotherapy (Sheth et al., 2012). Little is known about the proportion of patients with cancer who cryopreserve semen (Walschaerts et al., 2007), and most papers come from single fertility centres and have limited follow-up (van Casteren et al., 2008; Crha et al., 2009). Since 1964, the European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group, from 1993 on in collaboration ´ with the Groupe d’Etude des Lymphomes de l’Adulte (GELA), has treated HL patients uniformly in successive clinical trials. Since the early 1970s, cryopreservation before gonadotoxic treatment has been available. In 2009 a Life Situation Questionnaire (LSQ) was sent to survivors with—amongst others—questions related to cryopreservation, fertility and fatherhood. Here, we present data on a large representative sample of HL survivors treated consecutively since 1974, with consequently long-term follow-up. We investigated the number of men who cryopreserved semen before treatment (freeze rate) and demographic and treatment factors influencing occurrence of semen cryopreservation. We also investigated the number of men who used their cryopreserved semen (use rate) and the influence of the availability of cryopreserved semen on whether or not men succeeded in achieving fatherhood. Materials and Methods Survivors A total of 3399 male HL patients from 13 European countries were included in eight consecutive randomized EORTC-GELA clinical trials between 1974 and 2004 (Table I). Detailed protocols of the H2– H9 trials have been published (Raemaekers et al., 2002). Patients were treated for histologically proven, newly diagnosed HL. Most therapy regimens consisted of chemotherapy, often combined with radiotherapy. In 2008, current addresses were collected for survivors alive at last follow-up (n ¼ 1849; Fig. 1). Ethical approval Approval by local Human Investigations Committees was obtained, and we received informed consent from each participant. Questionnaires Survivors from five of the countries (France, Belgium, Netherlands, Italy, Switzerland) received the specially developed LSQ in the language of their country or region. The LSQ addresses parenthood after HL amongst other issues, in more detail than any validated questionnaire (see Supplementary Table SI). If the questionnaire was not returned within 5 weeks, survivors received one reminder letter. Because of the sensitive nature of the questionnaire, no further reminders were sent. Downloaded from http://humrep.oxfordjournals.org/ by guest on December 30, 2013 start of potentially gonadotoxic treatment. The likelihood of semen cryopreservation was influenced by age, treatment period, disease stage, treatment modality and education level. Seventy eight of 363 men (21%) used their cryopreserved semen. Men treated between 1994 and 2004 had significantly lower odds of cryopreserved semen use compared with those treated earlier, whereas alkylating or second-line (chemo)therapy significantly increased the odds of use; no other influencing factors were identified. We found an adjusted odds ratio of 2.03 (95% confidence interval 1.11– 3.73, P ¼ 0.02) for post-treatment fatherhood if semen cryopreservation was performed. Forty-eight out of 258 men (19%) who had children after HL treatment became a father using cryopreserved semen.
  • 3. 3 Cryopreservation in Hodgkin lymphoma survivors Table I Subject characteristics. All men treated (1974– 2004) Not included Included ............................................................................................................................................................................................. No. of men (%) 3399 2497 (73) 902 (27) 1493 (44) 1138 (46) 355 (39) The Netherlands 1273 (37) 829 (33) 444 (49) Belgium 351 (10) 281 (11) 70 (8) Other 282 (8) 249 (10) 33 (4) Country France Age at start of the treatment, median (range) 32 (8– 73) 32 (8–73) 31 (15– 69) ≤29 years 1460 (43) 1053 (42) 30–39 years 878 (26) 639 (26) 239 (27) ≥40 years 1061 (31) 805 (32) 256 (28) 433 (48) 407 (45) Not known Not known Age at reply LSQ, median (range), years N/A N/A 48 (24– 84) Follow-up duration, median (range), years N/A N/A 13 (5–36) 1974– 1983 534 (16) 443 (18) 91 (10) 1984– 1993 990 (29) 776 (31) 224 (25) 1994– 2004 1875 (55) 1288 (52) 587 (65) I and II 2795 (82) 2025 (81) 770 (85) III and IV 132 (15) Period of treatment Disease stage 604 (18) 472 (19) Initial treatment only 2702 (79) 1915 (77) 787 (87) Chemotherapy 2216 (79) 1559 (62) 657 (73) Radiotherapy None 289 (9) 228 (9) 61 (7) Above diaphragm 1666 (49) 1145 (46) 521 (58) Abdominal RT 630 (19) 453 (18) 177 (20) Inguinal RT 117 (3) 89 (4) 28 (3) 697 (21) 582 (23) 115 (13) Not known 266 (29) b First- and second-line treatment Education levelc Low Not known Middle 295 (33) High 327 (36) Data are n (%) unless stated otherwise. Due to rounding, percentages may exceed or fall short of 100%. N/A means not applicable. LSQ means life situation questionnaire. a Children before treatment yes/no was unknown for three males. b Second-line treatment varying from radiotherapy to high-dose chemotherapy and haematopoietic stem cell transplantation. c Education level was unknown for 14 males. Semen cryopreservation and utilization were evaluated based on the following questions: ‘Before treatment, did you cryopreserve (freeze) your semen? If yes, did you use it?’. The number of children before and after HL therapy was obtained from the following LSQ question: ‘How many children alive at birth have you fathered? Please specify the numbers before and after HL’. The use of fresh or cryopreserved semen with artificial reproductive techniques was also registered. Out of 1849 survivors who were approached, 927 (50%) returned the questionnaires with a signed informed consent form. Semen cryopreservation was done at local laboratories allied with the hospitals where patients were treated. Patients were treated for HL between 1974 and 2004. During those years, no uniform protocols or inter-laboratory quality control systems were available. Selection of survivors For the current analysis, we included all men aged 15 and older at treatment who had completed the LSQ questions on cryopreservation and parenthood (n ¼ 913). Analysis was done on treatment actually received, not on an intention-to-treat basis (n ¼ 902; Fig. 1). Eleven men were excluded from analysis: five received multiple chemotherapy regimens (protocol violation) and for six the treatment information was incomplete. Definitions Information on education level and presence and number of biological children before and after treatment was provided by the LSQ questionnaire. Education level was grouped into low, middle and high: low comprised Downloaded from http://humrep.oxfordjournals.org/ by guest on December 30, 2013 Children before treatmenta
  • 4. 4 van der Kaaij et al. primary school and the lower level of secondary school [corresponding to ISCED levels (Organisation for Economic Co-operation and Development, 1999) 0, 1 and 2]; middle comprised the higher levels of secondary school (ISCED levels 3 and 4) and high comprised higher education, polytechnic and university (ISCED levels 5 and 6). Statistical analysis A cohort analysis was performed. Univariable analyses of factors influencing occurrence of semen cryopreservation (freeze rate) or subsequent fatherhood chances were performed using the x 2 test or Fisher’s exact test, as appropriate. All multivariable analyses were performed using logistic regression analysis. Variables entered for the use of cryopreservation (freeze rate) were country of residence (the Netherlands, France, other with other comprising Belgium, Italy and Switzerland), age at treatment (15 –29, 30– 39, ≥40 years), presence of children before treatment (no, yes), treatment period (1974– 1983, 1984 – 1993, 1994 – 2004), clinical stage (I– II or III – IV), chemotherapy (no, yes; if yes, non-alkylating chemotherapy, alkylating chemotherapy), radiotherapy (none, above diaphragm only, below diaphragm), second-line therapy (no, yes) and education level (low, middle, high). Variables entered for cryopreserved semen utilization (use rate) were country of residence (the Netherlands, France, Belgium, Italy), age at treatment (15– 29, 30 – 39, ≥40 years), presence of children before treatment (no, yes), treatment period (1974– 1983, 1984 –1993, 1994 – 2004), education level (low, middle, high), alkylating chemotherapy (no, yes), radiotherapy (none, above diaphragm only, below diaphragm) and second-line therapy (no, yes). Variables for fatherhood chances were age at treatment, alkylating chemotherapy (no, yes), radiotherapy (none, above diaphragm only, below diaphragm), second-line therapy (no, yes) and education level (low, middle, high). Both a complete model containing all potential confounders and a final model are presented. For the final model, a backward stepwise selection procedure was used with P , 0.1 for addition to the model and P ≥ 0.15 for rejection from the model. Results were expressed as odds ratios (ORs) with their 95% confidence interval (CI). All statistical tests were two-sided and statistical significance was defined as a P-value ,0.05. Data were collected at the EORTC Headquarters, Brussels. Stata Statistical Software version 10.1 (StataCorp., College Station, Texas) was used for analysis. Results Characteristics of the survivors included in the analysis (n ¼ 902) compared with all men included in the EORTC trials from 1974 to 2004 (n ¼ 3399) are provided (Table I). Among the 902 men included, the median age at treatment start was 31 years (range 15 –69). The median follow-up was 13 years (range 5 –36). A non-responders analysis performed to compare those who did not return the questionnaires with Downloaded from http://humrep.oxfordjournals.org/ by guest on December 30, 2013 Figure 1 Selection of males included in the analysis. HL is Hodgkin lymphoma.
  • 5. 5 Cryopreservation in Hodgkin lymphoma survivors Table II Factors influencing whether semen was cryopreserved (freeze rate). Semen cryo-preservation, n (%) No cryo-preservation, n (%) P-value Complete model aOR (95% CI; P-value) Final model aOR (95% CI; P-value) ............................................................................................................................................................................................. No. of males (%) 363 (40) 539 (60) France 174 (48) 181 (36) The Netherlands 161 (44) 283 (53) 19 (5) 51 (9) Italy 9 (2) 22 (4) Switzerland 0 Country Belgium P , 0.001 1.00 1.00 0.72 (0.48–2.07; P ¼ 0.11) 0.24 (0.13–0.45; P , 0.001)d 0.30 (0.17– 0.53; P , 0.001)d 2 (,1) Age at start of the treatment Median (range) ≤29 years 26 (15– 46) 38 (15–69) P , 0.001 149 (28) 1.00 1.00 30–39 years 93 (26) 146 (27) 0.23 (0.15–0.34; P , 0.001) 0.22 (0.15– 0.33; P , 0.001) ≥40 years 12 (3) 244 (45) 0.01 (0.01–0.02; P , 0.001) 0.01 (0.01– 0.02; P , 0.001) Children before treatmenta 85 (23) 348 (65) P , 0.001 1.00 (0.97–1.02; P ¼ 0.79) — Age at reply LSQ, median (range), years 40 (24– 64) 54 (24–84) N/A N/A N/A Follow-up duration, median (range), years 12 (5–35) 14 (5– 36) N/A N/A N/A P , 0.001 Period of treatment 1974– 1983 15 (4) 76 (14) 1.00 1.00 1984– 1993 75 (21) 149 (28) 3.64 (1.80–7.37; P , 0.001) 4.10 (2.05– 8.20; P , 0.001) 1994– 2004 273 (75) 314 (58) 8.93 (4.48–17.83; P , 0.001) 10.63 (5.41–20.89; P , 0.001) 319 (88) 451 (84) 1.00 1.00 44 (12) 88 (16) 0.52 (0.27–0.99; P ¼ 0.048) 0.54 (0.32– 0.92; P ¼ 0.02) Initial treatment only 309 (85) 478 (89) Chemotherapy 291 (80) 366 (68) P , 0.001 4.94 (2.52–9.69; P , 0.001) 4.26 (2.55– 7.13; P , 0.001) P , 0.001 1.00 — Disease stage I and II III and IV P ¼ 0.08 Radiotherapy None Above diaphragm Below diaphragm 25 (7) 36 (7) 228 (63) 293 (54) 0.82 (0.40–1.70; P ¼ 0.60) 0.98 (0.46–2.08; P ¼ 0.96) 56 (15) 149 (28) 54 (15) 61 (11) P ¼ 0.12 1.94 (1.12–3.36; P ¼ 0.02) 2.03 (1.18– 3.49; P ¼ 0.01) 63 (17) 203 (38) P , 0.001 1.00 1.00e Middle 127 (35) 168 (31) 1.44 (0.90–2.31; P ¼ 0.13) High 167 (46) 160 (30) 1.98 (1.25–3.16; P ¼ 0.004) First- and second-line treatmentb Education levelc Low 1.60 (1.11– 2.30; P ¼ 0.01) Due to rounding, percentages may exceed or fall short of 100%. N/A means not applicable; aOR means adjusted odds ratio; CI means confidence intervals. LSQ means life situation questionnaire. a Children before treatment yes/no was unknown for three males. b Second-line treatment varying from radiotherapy to high-dose chemotherapy and haematopoietic stem cell transplantation. c Education level was unknown for 14 males. d Belgium, Italy and Switzerland were taken together; in the final model France and the Netherlands were taken together as the reference category. e In the final model low and middle education were taken together as the reference category. Downloaded from http://humrep.oxfordjournals.org/ by guest on December 30, 2013 258 (71)
  • 6. 6 van der Kaaij et al. Table III Characteristics of males who did and did not use cryopreserved semen. All who cryopreserved Used cryopreserved semen Did not use cryopreserved semen ............................................................................................................................................................................................. No. of men (%) 363 78 (21) 285 (79) France 174 (48) 34 (44) 140 (49) The Netherlands 161 (44) 38 (49) 123 (43) 19 (5) 4 (5) 15 (5) 9 (2) 2 (3) 7 (2) Country Belgium Italy Age at start of the treatment median (range) 26 (15 –46) 27 (16– 46) 26 (15– 46) 15–29 years 258 (71) 54 (69) 204 (72) 30–39 years 93 (26) 21 (27) 72 (25) ≥40 years 12 (3) 3 (4) 9 (3) a Children before treatment 277 (77) 62 (79) 215 (75) Yes 85 (23) 16 (21) 69 (24) Period of treatment 1974– 1983 15 (4) 8 (10) 7 (2) 1984– 1993 75 (21) 23 (29) 52 (18) 1994– 2004 273 (75) 47 (60) 226 (79) 53 (19) Education levelb Low 63 (17) 10 (13) Middle 127 (35) 32 (41) 95 (33) High 167 (46) 35 (45) 132 (46) 183 (50) 61 (78) 122 (43) 54 (15) 23 (29) 31 (11) Alkylating chemotherapy First- and second-line treatment c Data are n (%) unless stated otherwise. Due to rounding, percentages may exceed or fall short of 100%. a Children before treatment yes/no was unknown for one man. b Education level was unknown for six men. c Second-line treatment varying from radiotherapy to high-dose chemotherapy and haematopoietic stem cell transplantation. those who did indicated few differences. Responders came more often from the Netherlands, less often from recent trials and had less often been treated with non-alkylating chemotherapy and radiotherapy above the diaphragm. Disease stage distribution was similar in responders and non-responders. A total of 363 out of 902 men (40%) had had their semen cryopreserved before starting HL treatment. Men aged between 30 and 39 and men over 40 at start of the treatment had progressively lower odds of cryopreserving their semen compared with younger men (adjusted odds ratio (aOR 0.22; 95% CI 0.15 –0.33; P , 0.001 and aOR 0.01; 95% CI 0.01 –0.02; P , 0.001, respectively). The presence of children before treatment had no effect on the odds of men cryopreserving their semen (Table II). The first semen cryopreservation in our cohort took place in 1974 in the Netherlands. Having a higher disease stage negatively influenced semen cryopreservation odds (aOR 0.54; 95% CI 0.32 –0.92; P ¼ 0.02). Treatment type also influenced the odds of cryopreserving semen: those treated with chemotherapy had an aOR of 4.26 (95% CI 2.55 –7.13; P , 0.001) and those going on to receive second-line treatment for progression or relapse had double odds of cryopreserving their semen (aOR 2.03; 95% CI 1.18 –3.49; P ¼ 0.01). However, scheduled chemotherapy with or without alkylating agents made no difference for the odds of cryopreservation (data not shown). Men with the highest level of education had 60% greater odds of cryopreserving their semen (aOR 1.60; 95% CI 1.11 – 2.30; P ¼ 0.01). Of 363 men who cryopreserved their semen, 78 (21%) used it (Table III). In a multivariable logistic regression analysis model to investigate prognostic factors for semen use (n ¼ 78) in those who cryopreserved (n ¼ 363), none of the variables in Table III (age at start of the treatment, presence of children before treatment, education level, country of residence) were statistically significant except treatment period (1994 –2004 versus those treated earlier). On the other hand, the use rate was clearly influenced by the type of treatment received: survivors treated with alkylating agents had an OR of 9.86 (95% CI 4.58 –21.22; P , 0.001) and those treated with second-line therapy had an OR of 7.50 (95% CI 3.16 –17.83; P , 0.001) after correction for treatment period. Of the 285 who did not use their cryopreserved semen, 134 (47%) have not or not yet tried to father children; 129 (45%) could father children without resorting to the cryopreserved semen; 12 filled in another reason for not using cryopreserved semen (mostly that semen quality was insufficient) and 10 did not specify a reason. Downloaded from http://humrep.oxfordjournals.org/ by guest on December 30, 2013 No
  • 7. 7 Cryopreservation in Hodgkin lymphoma survivors Concerning child wish, of 902 survivors included, 334 men (37%) wished to have one or more children after treatment (Fig. 2). Of those 334, 128 (38%) did not succeed spontaneously and needed medical help. Cryopreserved semen was available in 99 of 128 cases (77%). Out of these 99, 78 (79%) used the cryopreserved semen, of whom 48 (62%) succeeded in conceiving one or more children. Twenty-seven (35%) did not have any success up till now and 3 (4%) conceived a child spontaneously while having already sought medical help. Among the 258 out of 902 survivors who had a child after treatment, 48 (19%) did so using cryopreserved semen. Of those who tried to have children after treatment (n ¼ 334), 83 of 112 without cryopreserved semen succeeded (74%) and 175 of 222 with cryopreserved semen (79%) succeeded (x 2test P ¼ 0.33; Fisher’s exact test P ¼ 0.34). The chances of fatherhood after treatment doubled [OR 2.03 (95% CI 1.11 –3.73, P ¼ 0.02)] when semen cryopreservation was performed when the influence of alkylating agents (no, yes), age at treatment and second-line treatment (no, yes) was taken into account. Discussion We studied the number of survivors who had cryopreserved semen, the proportion of men who used their cryopreserved semen and the odds of post-treatment fatherhood related to cryopreserved semen availability among HL survivors. Forty per cent of the 902 men who responded to our questionnaire had cryopreserved semen, and one in five had used it. Of the users, a third failed to have a child. Among survivors wishing to have children, availability of cryopreserved semen doubled the chance (OR 2.03) of post-treatment fatherhood in a multivariate analysis. In total, one out of five male HL survivors who had children after treatment did so using cryopreserved semen. The LSQ survey provided detailed data on a large cohort of Hodgkin survivors with sufficiently long follow-up. Outcomes as reported by subjects were used, the most reliable way of assessing fatherhood-related issues. Our study is unique in providing data on the occurrence of semen cryopreservation, including influencing factors. Data are provided on both survivors who did and did not cryopreserve semen for an estimation of the impact of cryopreservation on post-treatment fatherhood. Other studies lack information on those not requesting semen use and fertility treatments (Menon et al., 2009). Unfortunately, we did not collect the date of birth of post-treatment children or the year of utilization of cryopreserved semen. Therefore, we could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate. Out of 1849 questionnaires sent, 927 (50%) were completed. Of the 3399 men included in the trials, 798 (23%) were deceased, 457 (13%) were included in centres or countries that did not participate in this survey and 350 (10%) were lost to follow-up. The explanation for the seemingly ‘low’ response of 50% lies in what is also one of the strengths of this study: its scope. Much happened between a man’s inclusion in the trial between 1974 and 2004 and the start of this survey: physicians moved away or died, hospitals merged, whole departments disappeared, hampering the tracing back of many survivors treated in the past. Due to privacy laws, we were not allowed to track down survivors directly, but Downloaded from http://humrep.oxfordjournals.org/ by guest on December 30, 2013 Figure 2 Child wish, fatherhood and the use of artificial reproductive techniques (ART) among male Hodgkin lymphoma survivors.
  • 8. 8 73%. Unfortunately, we did not obtain complete information on fertility techniques including number of cycles used in case of cryopreserved semen utilization. The vital role of semen cryopreservation in securing chances of posttreatment fatherhood is underlined by the fact that among those wishing to become fathers after HL treatment, men who had cryopreserved semen had twice greater odds of succeeding compared with those who did not cryopreserve their semen. Twenty-three per cent of men unable to conceive spontaneously did not have cryopreserved semen available and did not become fathers. Information about fertility preservation and access to cryopreservation facilities among cancer patients should be optimized. Supplementary data Supplementary data are available at http://humrep.oxfordjournals.org/. Acknowledgements The authors thank the survivors for their cooperation. The authors thank the European Organization for Research and Treatment of Cancer for permission to use the data from EORTC studies H2–H9 for this research. The contents of this publication and methods used are solely the responsibility of the authors and do not necessarily represent the official views of the EORTC Headquarters. Authors’ roles M.A.E.K.: substantial contributions to conception and design, acquisition of data and analysis and interpretation of data; drafting the article and final approval. J.E.-A. and N.H.: substantial contributions to analysis and interpretation of data; drafting the article and final approval. P.M. and J.M.M.R.: substantial contributions to conception and design and acquisition of data; revising the article critically for important intellectual content and final approval. E.A.-L., M.S., E.C.M., A.A., B.M., P.J.L., B.M.P.A., E.M.N., C.Fe., J.T., A.S., C.Fr., H.E., P.B., W.G.J.M.S., C.S., J.K.D., J.M.R., I.G., B.C., M.L.M. and O.C.: Substantial contributions to acquisition of data; revising the article critically for important intellectual content and final approval. M.A.: substantial contributions to acquisition of data; and final approval. M.H.A. and J.C.K.-N.: substantial contributions to conception and design, acquisition of data and analysis and interpretation of data; drafting the article and final approval. Funding This work was supported by a research grant from the Lance Armstrong Foundation and by a donation from the Dutch Cancer Society through the EORTC Charitable Trust. M.v.d.K. was supported by a travel grant ´ from the Rene Vogels Stichting. Conflict of interest None declared. Downloaded from http://humrep.oxfordjournals.org/ by guest on December 30, 2013 were required to do this via their original treating physician. Many nonresponders were survivors for whom no correct address was found by their former physicians. The only other published estimates of the occurrence of semen cryopreservation (freeze rate) have been provided by Chang et al. (2006), who found only 3% of cancer patients aged 13– 45 years from a single Taiwanese centre cryopreserved semen and by Walschaerts et al. (2007), who found that the freeze rate was 0.79 –1.24 per 100.000 person-years for French HL patients. A study conducted in patients aged 14–30 diagnosed between 1995 and 2005 found a freeze rate of 18% (Neal et al., 2007) and one in patients aged 18 –55 diagnosed between 2002– 2010 yielded a freeze rate of 5% (Sheth et al., 2012). A recent study by (Babb et al. (2012) yielded a freeze rate of 38% in patients who had undergone stem cell transplantation. Finally, a study in recently treated Hodgkin survivors (Behringer et al., 2013) also gave a freeze rate of 38%. We documented a freeze rate of 40%, comparable to the studies by Babb and Behringer, indicating fair-to-good access to cryopreservation facilities for Western European patients treated at university or large general hospitals. This could also reflect the reasonably good semen quality among Hodgkin patients, for instance compared with testicular cancer patients (Gandini et al., 2003; van der Kaaij et al., 2009). We are the first to report on factors influencing whether or not semen is cryopreserved. Not surprisingly, age at treatment is a major factor, with 5-fold lower odds of cryopreservation in those aged 30 –39 when compared with those below 30s, and an aOR of 0.01 for those aged 40 or over, indicating almost no use of cryopreservation facilities in men over 40. A higher education level gives 60% higher odds of using semen cryopreservation, possibly indicating that information to patients about this option could be improved. This view is supported by a recent paper (Salonia et al., 2013) in which the wish to bank sperm was investigated; no differences according to education level were found. Men with higher disease stages had lower odds of cryopreservation. This might be a reflection of the negative influence of advanced-stage HL on semen quality that has been shown before (Sieniawski et al., 2008; van der Kaaij et al., 2009). Treatment planned also appears to be a factor in the decision-making process: men who were to be treated with chemotherapy (systemic treatment, as opposed to radiotherapy usually not leading to significant exposure of the testicles) were four times more likely to cryopreserve their semen. In our study, 78 of 363 (21%) Hodgkin survivors used their cryopreserved semen. This appears higher than the 5–10% estimates (Agarwal et al., 2004; Chung et al., 2004; van Casteren et al., 2008; Sheth et al., 2012; Behringer et al., 2013; Botchan et al., 2013) obtained until now, and might be due to the long period of follow-up of our study: most data published come from fertility centres covering a period of only 2–4 years after inclusion. The only other study on cryopreserved semen use in cancer patients with long follow-up gives a 29% actuarial 10-year use rate, comparable to our study (Blackhall et al., 2002). We observed no influencing factors on the use rate other than lower use in patients treated more recently and the obvious negative effects of alkylating and more aggressive treatment regimens on fertility. We found a success rate amongst those using cryopreserved semen of 62%, and several men were still in the process of fertility treatment at the time of the survey. Estimated crude success rates published up to date are at least 54% (Hourvitz et al., 2008; van Casteren et al., 2008). Success rate differs widely between publications, ranging from 20 to van der Kaaij et al.
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