Human Reproduction Update, Vol.7, No.4 pp. 370±377, 2001

Sperm banking and assisted reproduction treatment for couples following cancer treatment of the male partner

Amir Lass1, Fidelis Akagbosu and Peter Brinsden

Bourn Hall Clinic, Bourn, Cambridge CB3 7TR, UK

1To whom correspondence should be addressed at: Serono Pharmaceuticals Ltd., Bedfont Cross, Stanwell Road, Feltham, Middlesex TW14 8NX, UK. E-mail: [email protected]

In recent years, the survival of young males suffering from cancer has been improved. Development of new techniques such as IVF and intracytoplasmic sperm injection enables even low quality spermatozoa to be used successfully. It is possible therefore to preserve fertility potential of cancer patients before embarking on adjuvant and radiotherapy. Recognizing the importance of protecting the fertility potential of these young males, we present our recommendations for sperm based on the 11 year experience of Bourn Hall and the British Joint Council for Clinical Oncology consultation report. This paper discusses the options available for patients who recover from cancer to become fathers. In many cases patients are concerned about possible abnormalities and teratogenic risks to their future children who have been conceived naturally or by fertility treatment. The data available in the literature may reassure the medical community that there is no such increased risk. However, due to the relatively small number of children born after such treatment, a long-term follow-up is required. There is an ongoing debate regarding the justi®cation for the programme due to the small number of patients who make use of their banked spermatozoa. The authors believe in the importance of protecting the fertility potential of cancer patients, enabling them to father their genetic children in the future while ®ghting their illness.

Key words: assisted reproductive techniques/cancer/chemotherapy/semen cryopreservation

TABLE OF CONTENTS 1995). Further deterioration has been observed due to the damaging effect of chemotoxic agents on spermatogenesis, which Introduction may be temporary or permanent (Buchanan et al., 1975; Drasga Recommendation for sperm cryopreservation et al., 1983; Fossa et al., 1985; Johnson et al., 1985; Hansen et al., Semen cryopreservation Other considerations before treatment for cancer patients 1990; Presti et al., 1993; Pont and Albrecht., 1997). The sperm Fertility following cancer treatment quality following cancer treatment depends on many factors: the Assisted reproduction treatment after cancer treatment using banked initial sperm characteristics, the type of cancer (Lass et al., spermatozoa 1999a), the chemotherapy and/or radiotherapy agents in use, i.e. Special situations the dose and number of cycles (Meirow and Schenker, 1995; Pont Monitoring of children born after fertility treatment and Albrecht, 1997). It is impossible to predict who will have Should sperm cryopreservation be offered routinely to cancer normal spermatogenesis and who will become azoospermic. patients? Many of these patients are young men who have not started or References completed their families. This factor, combined with the developments in the treatment of male fertility treatment, especially intracytoplasmic injection (ICSI), motivates patients and clinicians to preserve fertility potential of cancer patients Introduction before embarking on adjuvant therapy. Recognizing the importance of fertility potential for young Survival rates of young men suffering from various types of male and female cancer patients, the British Joint Council for cancer have improved dramatically in recent years, due to Clinical Oncology convened a sub-committee comprising medical advanced diagnostic techniques and better treatment modalities. and clinical oncologists and fertility specialists that produced a In many cancer subjects sperm quality is already reduced before consultation report (Working Party of the Joint Council for receiving any treatment (Fossa et al., 1989; Meirow and Schenker, Clinical Oncology, 1998). The following recommendations are

370 Ó European Society of Human Reproduction and Embryology Assisted reproduction for male cancer patients based on this report and our experience at , before they have had any chemotherapy or radiotherapy (Lass which has had a successful sperm cryopreservation programme et al., 1998). for cancer patients for the last 11 years. In our clinic we do not actively follow up the patients after completion of their chemotherapy, therefore we do not have data Recommendation for sperm cryopreservation on their survival or whether they have been able to conceive spontaneously. Patients are advised to give semen samples ~6±12 Awareness of the need to refer cancer patients for sperm months post chemotherapy to assess restoration of fertility cryopreservation capacity, but very few have chosen to do so. Men diagnosed with cancer should be referred as soon as possible to a licensed sperm banking unit to give a sample or samples for Semen cryopreservation freezing. We found in a large retrospective study that the median time from diagnosis of cancer to the ®rst semen assessment at Following the detailed consultation, patients obtain sperm Bourn Hall was 3 weeks (range 1 day to 16 weeks). Although the samples by masturbation into two dry pots and the pre-freeze time lag from diagnosis to referral was relatively short in patients semen sample is analysed according to published guidelines with testicular cancer or haematological malignancy, in other (World Health Organization, 1992). Post-thaw analysis is not malignancies there was a delay of a few weeks to referral for done routinely because in many cases the sperm concentration is semen cryopreservation (Lass et al., 1998). The causes of the so low that performing this test would jeopardize the amount delay were: a lower level of awareness of the need for semen available for freezing. Any sample with motile spermatozoa, even banking by the medical team due to a lack of data about the if it is below the required minimum for standard IVF (in our unit a effectiveness of this option, and a longer investigation period to total of 23106 motile spermatozoa/ml), should be frozen. achieve accurate diagnosis and staging of the primary disease in Introduction of intracytoplasmic sperm injection (ICSI) technique solid tumours. Although there was no correlation between the can bypass even the most severe sperm concentration and motility time lag and sperm parameters, it is vital to send these patients for problems (Working Party of the Joint Council for Clinical semen cryopreservation immediately after diagnosis, to enable Oncology, 1998; P®fer and Coutifaris, 1999). Cryopreserv- them to store suf®cient semen samples before starting chemother- ation is performed on any semen sample containing motile apy. spermatozoa by our routine protocol (Richardson, 1979). Semen Our impression, after 11 years experience of sperm cryopre- is diluted with cryoprotectant and 0.7 ml aliquots are transferred servation for these men, is that only a minority of eligible patients to 1.5 ml screw-top plastic vials to enable future use without the is offered sperm cryopreservation. Even men who have previously need to thaw the whole sample. Samples are cooled by suspension been treated with chemotherapy or radiotherapy and who have in vapour phase nitrogen at a rate of approximately ±10°C/min, suffered a relapse of their disease should be referred for for 30 min, and then transferred to liquid nitrogen. Patients are cryopreservation, because two-thirds of them have spermatozoa asked to give a sample every 2±3 days until they have had 12 suitable for freezing. It should be a top priority to increase the ampoules frozen. However, many of them have had to start awareness of general practitioners, oncologists, haematologists chemotherapy treatment immediately and had time to supply only and patients themselves to the new opportunities opened to them one or two samples. Reassuringly, it has been demonstrated that, in recent years (Kliesch et al., 1996; Agarwal et al., 1999; Lass in cancer patients, semen after abstinence of 24±48 h has a post- et al., 1999b). Regrettably, in the UK, sperm cryopreservation is thaw quality similar to semen obtained after longer abstinence not widely available as a National Health Service (NHS)-funded period (Agarwal et al., 1995). Therefore, the period from service (Working Party of the Joint Council for Clinical diagnosis to starting chemotherapy treatment can be shortened Oncology, 1998). without jeorpadizing the frozen sperm quality. The quality of frozen spermatozoa following thawing is The sperm cryopreservation programme for cancer patients at dependent on its initial quality before freezing (Shekarriz et al., Bourn Hall Clinic 1995; Padron et al., 1997; Hallak et al., 1999a). The cryopreser- Patients are referred to our unit by Oncology and/or Haematology vation process itself affects cancer patients' spermatozoa in a Specialists in East Anglia, for semen cryopreservation before manner similar to its effect on donors' spermatozoa (Hallak et al., proceeding with chemotherapy. Their ages range from 14 to 55 1999b). years. They are seen by a specially assigned nurse for the programme, and receive an information lea¯et. This is followed Other considerations before treatment for cancer by consultation with one of the clinic's medical team, when the patients logic of semen cryopreservation and the options for future use are discussed. Blood samples are taken for HIV and hepatitis B and C Gonadal shielding screening. In the UK, spermatozoa can be stored only after A special, and sometimes ignored, issue is the protection of testes patients sign a form [HFEA 96 (6)] which provides consent and during abdominal radiotherapy. Hansen et al. analysed semen instructions for storage and use of the spermatozoa during life and quality in men who received external-beam irradiation for after death. Appropriate, con®dential and free-of-charge counsel- testicular cancer without gonadal shielding, and found that whilst ling is an inseparable part of the programme and is always offered 51% of patients had low sperm counts before therapy, all of them to patients. Patients should be made aware of the possibility that had low sperm counts 2 years after treatment and 82% of them up to 15% of men will already be azoospermic at that stage, had persistently low counts at a mean of 8 years after therapy

371 A.Lass, F.Akagbosu and P.Brinsden

(Hansen et al., 1990). With pelvic irradiation of 5000 cGy, a factors affect the recovery of fertility: the pre-treatment sperm shield should provide a 99% block. For testicular cancer, standard quality, the type of malignancy, with testicular cancer having the irradiation doses range from 2500 to 3500 cGy; therefore, shields worst recovery rates (Naysmith et al., 1998); the treatment should allow <2% penetration. It is critical that gonadal shielding modality, i.e. alkylating agents have worst effect, the total be used for all men receiving infra-diaphragmatic radiation therapeutic dose and number of treatment cycles (Meirow and treatment directed to pelvic lymph nodes in the case of testicular Schenker, 1995; Pont and Albrecht, 1997). Because of the long cancer or for any other cancer. recovery time for spermatogenesis to resume, patients are advised to give a sperm sample for testing after a year in full remission; Hormonal manipulation to protect the testis before cancer thereafter, men who regain their spermatogenesis are encouraged treatment to impregnate their partners naturally. Those who fail to do so Glode et al. put forth the theory that the process of spermatogen- have to make the choice of using either the partner's frozen esis might be slowed or suspended, and therefore protected from spermatozoa or donor spermatozoa, and, if they choose the the devastating effects of chemotherapy on rapidly dividing former, the type of fertility treatment they would need (Figure 1). tissues, by giving hormones that suppress the hypothalamic± pituitary±gonadal axis (Glode et al., 1981). Researchers have Assisted reproduction after cancer treatment using since used a variety of hormonal manipulations in animal models banked spermatozoa with variable results. In the few studies with human subjects, the results have been largely disappointing (Johnson et al., 1985; Where adequate amounts of spermatozoa have been banked and Waxman et al., 1987). As experiments are re®ned, however, it is allows, arti®cial insemination by husband (AIH) of conceivable that hormonal manipulation may emerge as a testis the female partner using the thawed spermatozoa could be protective therapy of considerable utility (Turek et al., 1998). considered. Some centres may then offer gamete intra-Fallopian transfer (GIFT). IVF techniques are generally recommended Testicular tissue banking where the quantity of spermatozoa available is small, suboptimal In certain situations, especially in azoospermic males, testicular for intrauterine insemination (IUI) or if female pelvic pathology tissue banking would be appropriate at orchidectomy. One study dictates. The decision to offer ICSI is based on the semen quality (Yavetz et al., 1997) reported a pregnancy resulting from frozen± pre-freeze and post-thaw. Table I summarizes outcomes of thawed embryos achieved by intracytoplasmic injection of assisted reproduction treatments for cancer patients in published cryopreserved sperm cells extracted from an orchidectomized, studies which speci®ed using cryobanked spermatozoa. seminoma-bearing testis, causing obstructive azoospermia. AIH Preservation of testicular tissue before cancer treatment Sanger et al. reported 115 births after AIH using husband's or A study has described how spermatogenesis could be reinstated in partner's semen, banked before cancer treatment (Sanger et al., mice sterilized with busulphan by injecting their seminiferous 1992). There were nine miscarriages and seven sets of twins tubules with a suspension of testicular cells derived from an included in the data resulting in 117 pregnancies and 115 allogeneic donor (Brinster and Zimmerman, 1994). These livebirths. The reported cumulative pregnancy rates after AIH remarkable results suggested that human testicular cells might with cryopreserved spermatozoa ranged from 20 to 45% (Sanger be harvested and cryopreserved before the start of chemotherapy et al., 1992). In general, the number of births reported is an and reintroduced into the testis on its completion. A clinical trial underestimate as semen banking facilities do not receive all data testing this hypothesis is underway (Radford et al., 1999). regarding births.

IVF and ICSI Fertility following cancer treatment Since 1984, few authors have reported individual cases in which Only 20±50% of cancer patients resume spermatogenesis 2±3 healthy babies were born following IVF treatment using frozen years after completion of treatment (Kreuser et al., 1986; Nijman spermatozoa to patients diagnosed with cancer (Table I). Levron et al., 1987; Naysmith et al., 1998; Hartmann et al., 1999). A few et al. reported the ®rst pregnancy established after the subzonal

Figure 1. Options for achieving a pregnancy in couples following cancer treatment of the male partner.

372 Assisted reproduction for male cancer patients

Table I. Summary of published studies on outcome of gamete intra-Fallopian transfer (GIFT), subzonal insemination (SUZI), IVF and intracytoplasmic sperm injection (ICSI) treatments in cancer patients using pre- therapy cryobanked semen

Study Diagnosis Method No. of No. of No. of (®rst author) patients pregnancies deliveries

Schill (1984) Testicular cancer IVF 1 1 1 Rowland (1985) Testicular cancer IVF 2 2 2a Naz (1985) Other cancer IVF 1 1 1 Milligan (1989) NS GIFT 2 2 2 Davis (1990) Hodgkin's IVF 2 1 1 Tournaye (1991) Hodgkin's IVF 5 6 7b Levron (1992) Seminoma SUZI 2 1 1 Khalifa (1992) Various cancer IVF and/or ICSI 10 6 2 Hakim (1995) Testicular cancer ICSI 2 2 4a Hultling (1995)c Testicular cancer ICSI 6 5 4 Chen (1996) Testicular cancer ICSI 1 1 1 Yavetz (1997) Testicular cancer ICSI 1 1 1 Rosenlund (1998)c Testicular cancer IVF and/or ICSI 15 12 11 Hallak (1998) Various cancer IVF and/or ICSI 10 5 3 Agarwal (1999) Various cancer IVF and/or ICSI 19 14 4 Audrins (1999) Various cancer IVF and/or ICSI 18 6 4 Ramsewak (1999) Neuroglioma ICSI 1 1 1 Lass (2000) Various cancer IVF and/or ICSI 11 7 6b Total 109 74 56

aOne miscarriage and one twin term pregnancy. bOne set of twins. cFresh spermatozoa used, following chemotherapy for testicular carcinoma. NS = not speci®ed. insertion of frozen±thawed spermatozoa obtained from a patient conception treatment using the frozen semen. Two had successful with seminoma and severe oligoasthenozoospermia (Levron et al. IUI cycles, each resulting in the delivery of a healthy girl; one 1992). Chen et al. reported a live birth following ICSI using couple had conceived in their ®rst IVF attempt, followed by cryopreserved semen from a man with testicular cancer (Chen delivery of healthy twins. Two women conceived after ICSI et al., 1996). Retrospective case series and case reports con®rm treatment and the sixth woman achieved only a biochemical that even poor quality (either pre-freeze or post-thaw) cryopre- pregnancy after numerous IVF and frozen embryo replacement served spermatozoa from cancer patients, irrespective of the cycles. length of storage, may provide successful results with techniques The fertilizing capacity of cryopreserved spermatozoa from such as ICSI (Khalifa et al., 1992; Chen et al., 1996; Hallak et al., patients with cancer was investigated in 10 patients (Hallak et al., 1998; Lass et al., 1998) 1998). Of these patients, ®ve had Hodgkin's disease, two Khalifa et al. reported on the outcome of IVF treatment in 10 testicular cancer, one leukaemia and two prostate cancer. The men with malignant disease who had cryopreserved spermatozoa length of specimen storage ranged from 14 to 135 months before initiation of cancer therapy (Khalifa et al., 1992). (median 49, interquartile range 24±82). A total of 18 assisted Fertilization was achieved when the swim-up technique of sperm reproduction cycles were performed among 10 couples with an preparation recovered a mean of 1.8 6 0.53106 spermatozoa/ml overall pregnancy rate of 50% per couple, with two deliveries, and when insemination was performed with at least a calculated one ongoing pregnancy and two miscarriages. The pregnancy rate motile sperm concentration of 13105/oocyte. The fertilization per cycle of IVF and ICSI was 36.4% with an implantation rate of rate was 60%. Four patients achieved a pregnancy: two of them 13%. delivered a single healthy baby, one delivered triplet healthy Audrins et al. reported their experience with semen storage for babies and one had a preclinical abortion. In two patients (three special purposes at Monash IVF from 1977 to 1997 (Audrins cycles), no motile spermatozoa were recovered after thawing, and et al., 1999). Eighteen of the 258 men who underwent micromanipulation of oocytes for assisted fertilization was chemotherapy and/or radiation therapy returned for treatment, performed; although fertilized oocytes were transferred, those and six pregnancies were achieved. Twelve couples attempted a couples did not achieve a pregnancy. total of 53 cycles of AIH with two conceptions, one resulting in a Lass et al. reported on 8 years experience of semen cryopre- live birth and the other in a miscarriage. Of the 11 couples who servation in men with malignant disease referred to the unit for did not conceive by AIH, ®ve attempted IVF procedures and three semen cryopreservation (Lass et al., 1998). Following chemother- had live births. Of the three couples who had spermatozoa of apy, six out of the 191 men who had suf®cient suitable insuf®cient quality for AIH, two conceived using IVF (one couple spermatozoa for freezing attended the clinic for assisted conceived twice). The couple who conceived twice achieved their

373 A.Lass, F.Akagbosu and P.Brinsden second pregnancy from the transfer of frozen±thawed embryos; Hultling et al. treated 10 anejaculatory men after testis cancer the conception resulted in twins. The three couples with co- treatment with rectal probe ejaculation (Hultling et al., 1995). existing female factors underwent a total of eight cycles of IVF, Successful recovery of spermatozoa was possible in nine out of 10 but no pregnancy resulted. patients. Six couples used electroejaculation in combination with Rosenlund et al. reported on IVF and ICSI in the treatment of IVF, and ®ve conceived. after testicular cancer (TC). Fifteen out of 17 couples Chung et al. reported the use of ICSI with electroejaculates evaluated for infertility after TC underwent a total of 21 treatment from anejaculatory men (Chung et al., 1998). The aetiologies of cycles, resulting in 18 embryo transfers (Rosenlund et al., 1998). anejaculation included a history of retroperitoneal lymph node Spermatozoa were obtained by transrectal electroejaculation (TE) dissection for testicular cancers, spinal cord injury and psycho- in 16 cycles, by masturbation in three cycles and by testicular genic causes. Electroejaculates typically have normal sperm sperm extraction (TESE) in one. Fertilization and cleavage was numbers but poor motility, morphology, and functional de®cien- achieved by IVF in seven cycles and ICSI in 11 cycles; average cies. In all, 13 couples underwent a total of 18 ICSI cycles with fertilization rates of 57 and 55% respectively were observed. clinical pregnancy rate of 55.6% per retrieval and implantation Twelve clinical pregnancies occurred, of which 11 had been rate of 33.3% similar to the rates obtained in standard IVF for delivered or were ongoing. The ongoing pregnancy rate was 57% non-male factor infertility or ICSI for male factor infertility. per cycle. Pre-pubertal boys with malignant disease Agarwal et al. reported on fertilization and pregnancy outcome of cryopreserved sperm patients with cancer (Agarwal et al., Spermatozoa can be obtained by masturbation from about the age 1999). The 19 men were divided into three groups according to of 14 years (Kliesch et al., 1996). The only possible option for the type of cancers: group I, testicular cancer (n = 5); group II, younger boys is to donate a testicular biopsy for sperm maturation Hodgkin's disease (n = 9); and group III, patients with prostate in vitro at a later stage. This technique, not yet tested clinically, cancer (n = 2), leukaemia (n = 1), metastatic neuroendocrine raises many ethical, ef®cacy and safety dilemmas (Bahadur et al., cancer (n = 1) and thyroid cancer (n = 1). IUI was performed in 2000). ®ve patients, IVF in four and ICSI in 10 patients. The fertilization rate, pregnancy rate, and the live birth rate showed no differences Monitoring of children born after fertility treatment between the three cancer groups. They concluded that cryopre- From our experience, patients are mostly concerned with the served spermatozoa from cancer patients, irrespective of the type following dilemmas: of tumour, are able to fertilize and initiate pregnancy with assisted · What are the chances of natural conception following cancer reproductive techniques. treatment? · What are the risks for the future children from using frozen spermatozoa obtained while having malignant disease? Special situations A recent survey of 283 survivors of cancer from the Cleveland Post-mortem sperm retrieval and posthumous use of banked Clinic Foundation tumour registry (men and women) examined spermatozoa their attitudes, emotions, and choices with regard to having children (Schover et al., 1999). Nineteen per cent had signi®cant Post-mortem sperm retrieval with subsequent arti®cial insemina- anxiety that their cancer treatment could affect negatively their tion has been employed for posthumous conception. Ahuja et al. children's future health, and only 57% received information from reported pregnancy following ICSI treatment with dead husband's their health care providers about infertility after cancer. Other spermatozoa (Ahuja et al., 1997). A variety of legal questions reproductive concerns were discussed less often. exist involving the rights and relationships of the deceased, his Patients with cancer may have chromosomal abnormalities in family and his issue (Kahan et al., 1999). the malignant cell of origin (Testoni et al., 1996), and an In the event of a patient dying whose spermatozoa are banked, increased frequency of human sperm chromosomal abnormalities it is important to realize that subsequent insemination or assisted after radiotherapy has been reported (Martin et al., 1986). reproduction treatment in the wife/partner can only take place if However, reassuringly, a few studies have shown that children the patient provided explicit consent whilst in sound frame of born after completion of cancer treatment have no increased risk mind prior to death. In the UK, there is no obligation on the for chromosomal abnormalities or birth defects before or after Human Fertilisation and Embryology Authority (HFEA)-ap- treatment (Senturia et al., 1985; Hansen et al., 1991; Nygaard proved clinic to perform an insemination. However, registered et al., 1991; Chatarjee and Goldstone, 1996; Hartman et al., clinics can pass on the samples in appropriate condition to another 1999). licensed centre which has agreed to perform such an insemination. Nicholson and Byrne examined fertility and pregnancy of survivors after treatment for cancer during childhood and Retrograde ejaculation and anejaculation following adulthood (Nicholson and Byrne, 1993). They summarized their retroperitoneal lymph node dissection for testicular cancers comprehensive literature review with the conclusions that Treatment options for men who do not antegrade ejaculate after offspring of survivors appear to have no increased risk of retroperitoneal lymph node dissection for testis cancer include a childhood cancer or birth defects. trial of sympathomimetic medication, to which ~30% of men Sankila et al. examined the risk of cancer among 5847 offspring respond with some antegrade ejaculation, or rectal probe of 14 652 survivors of cancer in childhood or adolescence ejaculation. diagnosed since the 1940s and 1950s in Scandinavia for a total

374 Assisted reproduction for male cancer patients of 86 780 person-years (Sankila et al., 1998). They did not ®nd Table II. Outcome of assisted conception treatment cycles using frozen any evidence of signi®cantly increased risk of non-hereditary spermatozoa for patients with cancer cancer among these offspring. Thus, survivors of cancer should not be discouraged from having children and can expect a good Case Diagnosis Treatment Outcome outcome of pregnancy. no. Only scarce data exist on the possible risks for children born 1 Hodgkin's lymphoma IVF33 NP after fertility treatment. To the best of our knowledge, only 56 FER34 babies have been born so far to couples undergoing assisted 2 Hodgkin's lymphoma IVF Healthy twin girls reproduction treatment (nine IVF or ICSI) after recovery from 3 Multiple myeloma IVF32 NP cancer. No birth defects or any abnormalities have been described FER32 NP in the literature, but the number is obviously too small for de®nite IVF Healthy boy IVF32 NP conclusion. It is vital therefore to keep records of patients having 4 Hairy cell leukaemia IUI Healthy girl post-cancer infertility treatment and to monitor the children born 5 Gastric cancer IUI NP as a consequence of these treatments. 6 Non Hodgkin's lymphoma IUI Healthy girl 7 Hodgkin's lymphoma IUI35 NP IVF33 Should sperm cryopreservation be offered routinely to FER31 cancer patients? 8 Testicular cancer IVF Failed to fertilize ICSI Healthy boy In recent years some authors have raised doubts about the 9 Hodgkin's lymphoma ICSI32 NP justi®cation and necessity of providing the facilities for banking ICSI Healthy girl spermatozoa before chemotherapy because of the relatively small 10 Acute lymphocytic leukaemia IUI33 NP number of men making use of it following completion of IVF31 NP treatment and therefore the small number of children born as a ICSI Missed abortion result of using cryopreserved spermatozoa (Milligan et al., 1989; ICSI Healthy girl Radford et al., 1999). 11 Non-Hodgkin's lymphoma IUI Healthy girl Indeed, we and others found that only a relatively small minority of patients (<10%) return for fertility treatment (Fossa NP = non-pregnant; FER = frozen embryo replacement; ICSI = intracyto- et al., 1989; Sanger et al., 1992; Audrins et al., 1999; Schover plasmic sperm injection; IUI = intrauterine insemination. et al., 1999; Lass et al., 2000). During 11 years of running the programme at Bourn Hall Clinic, only 11 (3.6%) of the 306 strongest predictor of emotional well-being. Patients' knowledge patients who have banked their spermatozoa before chemotherapy that their fertility potential is secured would help in the emotional or radiotherapy have returned for assisted reproduction treatment battle against the cancer. Many, however, are left with signi®cant (Table II). These ®ndings are explicable for several reasons: anxieties and insuf®cient information about reproductive issues. recovery or waiting for possible recovery of gonadal function, The improvement in cancer treatment and life expectancy, short period from original illness, anxiety regarding potential risks combined with greater awareness for the fertility options and for the children and uncertainty about their long-term health and careful reassurance of the survivors regarding the safety of their therefore their suitability to be parents. A large group comprised children, will undoubtedly increase the number of patients young men who have not yet established family life, and requesting sperm freezing and using it following recovery. unfortunately, patients who succumbed to their malignant disease. Sperm cryopreservation should therefore be offered routinely to Hallak et al. surveyed 56 patients in their programme who all cancer patients less than 55 years old (the maximum age for requested to discontinue storing of spermatozoa (out of the total freezing spermatozoa by the HFEA regulation) (Working Party of 342 men who banked their spermatozoa) (Hallak et al., 1998). the Joint Council for Clinical Oncology, 1998), and especially to Reasons for disposal of spermatozoa were patient death (n = 21); young men who have not yet completed their family. Local fertility, but no plans for more children (n = 23); good sperm protocols should exist to ensure that health professionals are quality (n = 8); and no plans to have children (n = 4). They aware of the value of semen cryostorage in these circumstances, concluded that most patients decided to discontinue sperm so that they deal with the situation quickly and effectively banking because either they regained fertility or had improved (Working Party of the Joint Council for Clinical Oncology, 1998). semen quality. The authors concluded that sperm banking should The authors strongly believe that the freezing process and use of be strongly recommended for all patients with malignant diseases the spermatozoa in the future fertility treatment, regardless of the who may wish to have children, even if they eventually decide method, should be funded by the State as part of ®ghting that the specimens are not needed. We support this conclusion and malignancy and its consequences. believe that the medical community should not be deterred from New options for preserving male fertility of cancer patients offering the sperm-freezing service to patients. might become available in the future. Radford et al. recently The Cleveland survey revealed that, of those currently child- described an unpublished study in which human testicular cells less, 76% wanted children in the future. Moreover, ~80% of the are harvested before chemotherapy and reintroduced into the sample viewed themselves positively as actual or potential testes on its completion (Radford et al., 1999). There are no parents. The great majority of younger cancer survivors see their results yet on semen analysis following this procedure. This cancer experience as potentially making them better parents. technique would enable inde®nite sperm production, natural Feeling healthy enough to be a good parent after cancer was the conception and would be applicable to pre-pubertal boys.

375 A.Lass, F.Akagbosu and P.Brinsden

However, until these methods become established, and more treatment of anejaculatory infertility after testicular cancer. Hum. Reprod., importantly, until their safety is ensured without risk of 10, 847±850. Johnson, D.H., Linde, R., Hainsworth, J.D. et al. (1985) Effect of a luteinising transmitting the cancer back to patients, sperm cryopreservation hormone releasing hormone agonist given during combination is strongly advised. chemotherapy on post therapy fertility in male patients with lymphoma: preliminary observations. Blood, 65, 831. Kahan, S.E., Seftel, A.D. and Resnick, M.I. (1999) Postmortem sperm References procurement: a legal perspective. J. Urol., 161, 1840±1843. Khalifa, E., Oehninger, S., Acosta, A.A. et al. (1992) Successful fertilization Agarwal, A., Sidhu, R.K., Shekarriz, M. and Thomas, A.J. (1995) Optimum and pregnancy outcome in in-vitro fertilization using cryopreserved/ abstinence time for cryopreservation of semen in cancer patients. J. Urol., thawed spermatozoa from patients with malignant diseases. Hum. 154, 86±88. Reprod., 7, 105±108. Agarwal, A., Pasqualotto, F.F., Kobayashi, H. et al. (1999) Fertilisation and Kliesch, S., Behre, H.M., Jurgens, H. and Nieschlag, E. (1996) pregnancy of cryopreserved spermatozoa from patients with cancer. P- Cryopreservation of semen from adolescent patients with malignancies. 268, American Society for Reproductive Medicine and Canadian Fertility Med. Pediatr. Oncol., 26, 20±27. and Andrology Society, Conjoint Annual Meeting, September 25±30, Kreuser, E.D., Harsch, U., Hetzel, D. and Schreml, W. (1986) Chronic gonadal Toronto, Canada, S175. toxicity in patients with testicular cancer after chemotherapy. Eur. J. Ahuja, K.K., Mamiso, J., Emmerson, G. et al. (1997) Pregnancy following Cancer Clin. Oncol., 232, 289±294. intracytoplasmic sperm injection treatment with dead husband's Lass, A., Akagbosu, F., Abusheikha, N. et al. (1998) A program of semen spermatozoa: ethical and policy considerations. Hum. Reprod., 12, cryopreservation for patients with malignant disease: lessons from eight 1360±1363. years experience. Hum. Reprod., 11, 3256±3261. Audrins, P., Holden, C.A. McLachlan, R.I. and Kovacs, G.T. (1999) Semen Lass, A., Akagbosu, F., Abusheikha, N. et al. (1999a) Correlation between storage for special purposes at Monash IVF from 1977 to 1997. Fertil. sperm quality of patient suffering from cancer and the aetiology of their Steril., 72, 179±181. malignancy. Annual meeting of the American Society for Reproductive Brinster, R.L. and Zimmerman, J.W. (1994) Spermatogenesis following male Medicine/CFAS September 25±30, p-267, S175. germ-cell transplantation. Proc. Natl Acad. Sci. USA, 91, 11298±11302. Lass, A., Abusheikha, N., Akagbosu, F. and Brinsden, P. (1999b) Cancer Bahadur, G., Chatterjee, R. and Ralph, D. (2000) Testicular tissue patients should be offered semen cryopreservation. Br. Med. J., 318, 1556. cryopreservation in boys. Ethical and legal issues: case report. Hum. Lass, A., Burnley, A. and Brinsden, P. (2000) Sperm cryopreservation for Reprod., 15, 1416±1420. cancer patients. Fertil. Steril., 72, 418. Buchanan, J.D., Fairely, K.F. and Barrie, J.U. (1975) Return of Levron, J., Lightman, A., Stein, D.W. et al. (1992) Pregnancy after subzonal spermatogenesis after stopping cyclophosphamid therapy. Lancet, ii, insertion of cryopreserved spermatozoa from a patient with testicular 156±157. seminoma. Fertil. Steril., 58, 839±840. Chatarjee, R. and Goldstone, A.H. (1996) Gonadal damage and effects on Martin, R.H., Hildebrand, K., Yamamoto, J. et al. (1986) An increase fertility in adult patients with hematological malignancy undergoing stem frequency of human sperm chromosomal abnormalities after cell transplantation. Bone Marrow Transplant, 17, 5±11. radiotherapy. Mutat. Res., 174, 219±225. Chen, S., Ho, N., Chen, H. et al. (1996) Pregnancy achieved by Meirow, D. and Schenker, J.G. (1995) Cancer and . Hum. intracytoplasmic sperm injection using cryopreserved semen from a Reprod., 10, 2017±2022. man with testicular cancer. Hum. Reprod., 11, 2645±2647. Milligan, D.W., Hughes, R. and Lindsay, K.S. (1989) Semen cryopreservation Chung, P.H., Palermo, G., Schlegel, P.N. et al. (1998) The use of intracytoplasmic sperm injection with electroejaculates from in men undergoing cancer chemotherapy Ð a UK survey. Br. J. Cancer, anejaculatory men. Hum. Reprod., 13, 1854±1858. 60, 966±967. Davis, O.K., Bedford, J.M., Berlerley, A.S. et al. (1990) Pregnancy achieved Naysmith, T.E., Blake, D.A., Harvey, V.J. and Johnson, N.P. (1998) Do men through in vitro fertilization with cryopreserved semen from a man with undergoing sterilizing cancer treatments have a fertile future? Hum. Hodgkin's lymphoma. Fertil. Steril., 53, 377±378. Reprod., 13, 3250±3255 Drasga, R.E. Einborn, L.H., Williams, S.D. et al. (1983) Fertility after Naz, R.K., Littman, B.A. and Stiilman, R.J. (1985) Successful human chemotherapy for testicular cancer. J. Clin. Oncol., 1, 179±183. pregnancy following in vitro fertilization using frozen semen. J. In Vitro Fossa, S.D., Aass, N. and Molne, K. (1989) Is routine pre-treatment Fertil. , 2, 143±145. cryopreservation of semen worthwhile in the management of patients Nicholson, H.S. and Byrne, J. (1993) Fertility and pregnancy after treatment with testicular cancer? Br. J. Urol., 64, 524±529. for cancer during childhood or adolescence. Cancer, 71, 3392±3399. Glode, L.M., Robinson, J. and Gould, S.F. (1981) Protection from Nijman, J.M., Schraffordt koops, H., Kremer, J. and Sleijfer, D.T. (1987) cyclophosphamide induced testicular damage with an analog of Gonadal function after surgery and chemotherapy in men with stage II and gonadotrophin-releasing hormone. Lancet, i, 1132. III non-seminomatous testicular tumors. J. Clin. Oncol., 5, 651±656. Hakim, L.S., Lobel, S.M. and Oates, R.D. (1995) The achievement of Nygaard, R., Clausen, N.M., Siimes, M.A. et al. (1991) Reproduction pregnancies using assisted reproductive technologies for male factor following treatment for childhood leukemia: a population based infertility after retroperitoneal lymph node dissection for testicular prospective cohort study of fertility and offsprings. Med. Pediatr. carcinoma. Fertil. Steril., 64, 1141±1146. Oncol., 19, 459±466. Hallak, J., Sharma, R.K., Thomas, A.J. Jr and Agarwal, A. (1998) Why cancer Padron, O.F., Sharma, R.K., Thomas, A.J. and Agarwal, A. (1997) Effects of patients request disposal of cryopreserved semen specimens posttherapy: a cancer on spermatozoa quality after cryopreservation: a 12-year retrospective study. Fertil. Steril., 69, 889±893. experience. Fertil. Steril., 67, 326±331. Hallak, J., Kolettis, P.N., Sekhon, V.S. et al. (1999a) Cryopreservation of P®fer, S.M. and Coutifaris, C. (1999) Reproductive technologies 1998: options sperm from patients with leukemia. Cancer, 85, 1973±1978. available for the cancer patients. Med. Pediatr. Oncol., 33, 34±40. Hallak, J., Kolettis, P.N., Sekhon, V.S. et al. (1999b) Sperm cryopreservation Pont, J. and Albrecht, W. (1997) Fertility after chemotherapy for testicular in patients with testicular cancer. Urology, 54, 894±899. cancer. Fertil. Steril., 68, 1±5. Hansen, S.W., Berthelsen, J.G. and van der Maase, H. (1990) Long-term Presti, J.C., Herr, H.W. and Carroll, P.R. (1993) Fertility and testis cancer. fertility and Leydig cell function in patients treated for germ cell cancer Urol. Clin. N. Am., 20, 173±179. with cisplatin, vinblastin, and bleomycin versus surveillance. J. Clin. Radford, J.A., Shalet, S.M. and Liberman, B.A. (1999) Fertility after treatment Oncol., 8, 1695±1698. for cancer. Questions remain over ways of preserving ovarian and Hansen, P.V., Glavind, K., Panduro, J. and Pedersen, M. (1991) Paternity in testicular tissue. Br. Med. J., 319, 935±936. patients with testicular germ cell cancer: pretreatment and post-treatment Ramsewak, S., Naraynsingh, A., Kuruvilla, A. and Duffy, S. (1999) Successful ®ndings. Eur. J. Cancer, 27, 1385±1389. pregnancy by intracytoplasmic sperm injection after radiotherapy-induced Hartmann, J.T., Albrecht, C., Schmoll, H.J. et al. (1999) Long-term effects on azoospermia. West Ind. Med. J., 48, 240±241. sexual function and fertility after treatment of testicular cancer. Br. J. Richardson, D.W. (1979) Techniques in sperm storage. In Arti®cial Cancer, 80, 801±807. Insemination. Royal College of Obstetricians and Gynaecologists, Hultling, C., Rosenlund, B., Tornblom, M. et al. (1995) Transrectal London, pp. 97±125. electroejaculation in combination with in-vitro fertilization: an effective Rosenlund, B., Sjoblom, P., Tornblom, M. et al. (1998) In-vitro fertilization

376 Assisted reproduction for male cancer patients

and intracytoplasmic sperm injection in the treatment of infertility after lymphocytic leukemia after autologous bone marrow transplantation. testicular cancer. Hum. Reprod., 13, 414±418. Bone Marrow Transplant, 18, 1141±1145. Rowland, G.F., Cohen, J., Steptoe, P.C. and Hewitt, J. (1985) Pregnancy Tournaye, H., Camus, M., Bollen, N. et al. (1991) In vitro fertilization following in vitro fertilization using cryopreserved semen from a man techniques with frozen-thawed sperm: a method for preserving the with testicular teratoma. Urology, 26, 33±36. progenitive potential of Hodgkin patients. Fertil. Steril., 55, 443±445. Sanger, W.G., Olson, G.H. and Sherman, J.K. (1992) Semen cryobanking for Turek, P.J., Lowther, D.N. and Carroll, P.R. (1998) Fertility issues and their men with cancer Ð criteria change. Fertil. Steril., 58, 1024±1027. management in men with testis cancer. Urol. Clin. North Am., 25, Sankila, R., Jorgen, H.O., Anderson, A. et al. (1998) Risk of cancer among 517±531. offspring of childhood-cancer survivors. New Engl. J. Med., 338, Waxman, J.H., Ahmed, R., Smith, D. et al. (1987) Failure to preserve fertility 1339±1344. in patients with Hodgkin's disease. Cancer Chemother. Pharmacol., 19, Schill, W.B. and Trotnow, S. (1984) Verwendung von Kryospermia fur die In- 159. vitro-Fertilisation (IVF). Hatarzt, 35, 313±5. Working Party of the Joint Council for Clinical Oncology (1998) Management Schover L.R., Rybicki, L.A., Martin, B.A. and Bringelsen, K.A. (1999) of Gonadal Toxicity Resulting from Treatment of Adult Cancer. London. Having children after cancer. A pilot survey of survivors' attitudes and World Health Organization (1992) WHO Laboratory Manual for the experiences. Cancer, 86, 697±709. Examination of Human Semen and Sperm±Cervical Mucus Interaction, Senturia, Y.D., Peckham, C.S. and Peckham, M.J. (1985) Children fathered by 3rd edn. Cambridge University Press, Cambridge, pp. 44±45. men treated for testicular cancer. Lancet, ii, 766±769. Yavetz, H., Hauser, R., Botchan, A. et al. (1997) Pregnancy resulting from frozen±thawed embryos achieved by intracytoplasmic injection of Shekarriz, M., Tolentino, M.V., Ayzman, I. et al. (1995) Cryopreservation and cryopreserved sperm cells extracted from an orchidectomized, sperm quality in patients with Hodgkin's disease. Andrology, 75, seminoma-bearing testis, causing obstructive azoospermia. Hum. 2732±2736. Reprod., 12, 2836±2838. Testoni, N., Martinelli, G., Zaccaria, A. et al. (1996) Detection of occasional and clonal chromosome aberrations in patients with acute non- Received on 6 March 2000; accepted on 27 March 2001

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