effectiveness of sperm banking in adolescents and young adults with cancer : a regional experience
TRANSCRIPT
Effectiveness of Sperm Banking in Adolescentsand Young Adults With CancerA Regional Experience
Michael S. Neal, MSc, PhD1
Kim Nagel, RN, BHSc (N), CCRA2
JoAnn Duckworth, RN2
Haimant Bissessar, BSc1
Marc A. Fischer, MD1
Carol Portwine, MD, PhD2
Richard Tozer, MD, PhD3
Ronald D. Barr, MB, ChB, MD2
1 Center for Reproductive Care, Hamilton, Ontario,Canada.
2 McMaster Children’s Hospital, Hamilton, Ontario,Canada.
3 Juravinski Cancer Center, Hamilton HealthSciences, Hamilton, Ontario, Canada.
BACKGROUND. Improving success in the treatment of cancer has resulted in an
increasing number of survivors. An important quality of life issue among younger
survivors is the ability to have a family. Current gonadotoxic treatments for can-
cer pose a challenge to future fertility. Preservation of fertility after gonadotoxic
therapy is an important consideration for these patients. In a regional center, the
authors evaluated efficacy and utilization of sperm banking for preservation of
male fertility in adolescents and young adults (AYA) with cancer.
METHODS. A retrospective chart review was conducted to obtain data on clinical
features, andrology, and fertility from patients (ages < 30 years) who cryopre-
served samples of semen from 1995–2005.
RESULTS. Of 821 newly diagnosed male AYA cancer patients, aged 14–30 years,
only 146 (17.8%) used sperm cryopreservation technology. Patients who used
their cryopreserved semen for attempted conception had a 36.4% success rate
with intrauterine insemination (IUI) and a 50.0% clinical pregnancy rate with in
vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).
CONCLUSIONS. Sperm cryopreservation by AYA males with cancer is an effica-
cious method for preserving future fertility. Awareness and employment of
assisted reproductive technologies needs to be implemented by an interdisciplin-
ary team of experts caring for these patients and can result in successful pater-
nity in males after treatment for cancer. Cancer 2007;110:1125–8. � 2007
American Cancer Society.
KEYWORDS: sperm preservation, adolescent, neoplasm, fertility.
C ancer in adolescents and young adults (AYA) is a unique distri-
bution of diseases with increasing incidence during the past
quarter century.1 AYA in the age group 15–29 years have a higher
risk than children (<15 years of age) of developing cancer, with the
risk directly proportional to age.1 Although cancer in these young
people is still life threatening, 5-year overall survival rates exceed
70% for both children and AYA.2 However, altered testicular function
and subsequent compromised fertility may occur with current can-
cer treatment regimens. This has contributed to a heightened
awareness of quality-of-life issues in survivors of cancer that
occurred early in life.
In AYA male cancer patients, surgery, radiation, and chemotherapy
can precipitate transient or permanent infertility by affecting either
ejaculatory or erectile function or by impairing spermatogenesis.3 Can-
cer that occurs between the ages of 15 and 30 years is 2.7 times more
common than cancer that occurs in the first 15 years of life.4 In this age
group, the incidence has increased steadily during the last 25 years.4
Address for reprints: Michael S. Neal, MSc, PhD,Centre for Reproductive Care, West End Clinic,Hamilton Health Sciences, 690 Main Street West,Hamilton, Ontario, Canada L8S 1A4; Fax: (905)521-2609; E-mail: [email protected]
Received March 5, 2007; revision received May9, 2007; accepted May 9, 2007.
ª 2007 American Cancer SocietyDOI 10.1002/cncr.22889Published online 23 July 2007 in Wiley InterScience (www.interscience.wiley.com).
1125
For these young men, an important question, beyond
conquering their disease, is how the malignancy or its
treatment will affect future fertility. One approach to
this challenge is to bank sample(s) of semen before
treatment. It is well established that the duration of sto-
rage of cryopreserved sperm does not impact fertility
outcome.5,6 Depending on the number and quality of
cryopreserved sperm, conception can be attempted by
thawing the sample and using it for intrauterine insem-
ination (IUI). Alternatively, patients with compromised
seminal quality, due to systemic effects of disease or
treatment, may opt for more advanced techniques such
as in vitro fertilization (IVF) with or without intracyto-
plasmic sperm injection (ICSI).
The utilization patterns of cryopreserved sperm,
and pregnancy outcomes when these sperm are
employed with IUI and IVF, are uncertain. The cur-
rent study evaluated the use of sperm banking over a
10-year period (1995–2005) in a single regional center
in Canada.
METHODSThe Research Ethics Board of McMaster University
and Hamilton Health Sciences provided approval to
conduct this study. Patients’ records were reviewed
for data on clinical features, andrology, and fertility.
All males �30 years old with cancers who had
banked their sperm between 1995 and 2005 were
included in the study. Patients were separated into 2
groups, based on age (Group A, �18 and Group B
between 18 and 30 years of age at the time of sperm
banking) for comparison. Clinical data retrieved from
the archived chart included age at diagnosis, type of
cancer, modalities of therapy, and outcome. A rou-
tine analysis of semen, based on World Health Orga-
nization (WHO) guidelines,7 was performed on each
sample before cryopreservation. Briefly, the seminal
analysis included volume, pH, viscosity, sperm con-
centration, motility, viability, and morphology. The
sample was considered normal if it met or exceeded
the 3 standard benchmark values for concentration,
motility, and strict morphology.7 After obtaining
informed consent, we froze samples according to a
standard sperm cryopreservation protocol and stored
them in liquid nitrogen. Any sample containing
sperm in the ejaculate was banked after informed
consent was obtained, because only a few sperm are
required for IVF with ICSI.
A subgroup of patients who used their samples
for assisted conception was analyzed for IUI or IVF
outcomes including number of oocytes retrieved, fer-
tilization success, embryo development and quality,
number of embryos transferred and frozen, and
implantation and pregnancy rates. The number of
normally fertilized oocytes (based on the presence of
2 pronulcei, 16–18 hours after the ICSI procedure) di-
vided by the number of oocytes injected determined
the fertilization rate. Embryo quality was quantified
by a cumulative embryo score (CES). CES was calcu-
lated as the product of blastomere number and
embryo grade. The grade assigned is based on the
degree of cellular fragmentation (descending scale of
5 to 1) observed at the 48-hour and 72-hour time-
periods of assessment. Higher CES indicates a better
morphological appearance of the embryo.8 Implanta-
tion rate was calculated by the number of fetal sacs
present at ultrasound divided by the number of
embryos transferred. Patients were considered preg-
nant when they had a positive bhCG result 17 days
after IUI or 14 days after embryo transfer, and clini-
cal pregnancy was determined by ultrasound at 6–
7 weeks of gestation.
RESULTSFrom 1995 to 2005, there were 821 newly diagnosed
male AYA patients with cancer, aged 14–30 years. Of
these, 146 (17.8%) banked semen at our facility.
Thirty-four (23.3%) of these patients were pediatric
(�18 years of age, Group A), and 112 (76.7%) were
between 18 and 30 years of age (Group B) at the
time of banking. The most common cancer diagnosis
was Hodgkin lymphoma (37.5%) for Group A and
testicular cancer (43.9%) for Group B (Fig. 1). Overall,
21.1% of patients presented with a normal semen
analysis at the time of banking. Of the pediatric
group, only 9.4% had a normal semen analysis com-
pared with 25.6% of the adult population. Volume
and concentration were not affected by the cancer
diagnosis, but reduced motility and strict morphol-
ogy appear to be the main reasons for abnormal
semen analysis (Table 1). One-third of the non-
Hodgkin lymphoma patients in Group A and half of
Hodgkin lymphoma patients in Group B had a nor-
mal seminal analysis at the time of banking (Fig. 2).
Although the sample size is small, none of the
patients diagnosed with a brain tumor had a normal
seminal analysis in either age category; the same
being true for those with a diagnosis of leukemia or
testicular cancer in Group A (Fig. 2). Despite this,
banking was undertaken, as there was adequate
sperm for a future IVF attempt with ICSI.
The majority (103, 70.5%) of sperm samples are
still being maintained in storage for future use, and
22 (15.1%) samples have been purged (10 due to
death, 12 voluntarily). There have been 21 (14.4%)
patients who have used their banked samples to
1126 CANCER September 1, 2007 / Volume 110 / Number 5
attempt conception by assisted reproductive technol-
ogies. Eleven of these patients used their samples for
IUI (range, 1 to 8 cycles per patient). Four (36.4%)
patients achieved a successful pregnancy with their
partners.
The samples from the remaining 10 patients
were used for IVF with ICSI, and the stimulation and
IVF outcome measures are summarized in Table 2.
These outcome performance measures are equal to
or better than those of other couples without cancer,
cycling during the same time period in our clinic,
and for those reported in literature.9 Two couples did
not have embryos available for transfer on Day 3.
The women were 38 and 42 years of age. Advanced
maternal age may be an important factor that contri-
butes to poor embryo development and outcome.
Seventy percent (7 of 10) of couples were successful
at initiating a pregnancy (based on a positive bhCG14 days after embryo transfer) after IVF with ICSI by
using their frozen-thawed sperm samples. One of
these conceptions was a biochemical pregnancy;
another resulted in a miscarriage at 6 weeks of preg-
nancy; and the 5 remaining are ongoing or delivered,
for a clinical pregnancy rate of 50% (5 of 10).
DISCUSSIONWhen adolescents and young adults (AYA) are diag-
nosed with cancer, every aspect of their lives is influ-
enced. This includes their physical, emotional,
economic, spiritual, interpersonal, psychosocial, and
sexual well-being.10,11 In clinical practice and qual-
ity-of-life research, sexual, interpersonal, and repro-
ductive late effects of treatment may not be
addressed adequately.10 Although cancer in AYA
remains relatively rare, it has been suggested that
better services for these young people are needed. To
afford them the opportunity to have a family (in the
FIGURE 1. Proportion of sperm samples banked by type of cancer includ-ing brain tumors (n 5 5, 4.4%); Hodgkin lymphoma (n 5 30, 26.3%); leuke-
mias (n 5 11, 9.7%); testicular cancer (n 5 40, 35.1%); Ewing sarcoma
and other solid tumors (n 5 8, 7.0%); non-Hodgkin lymphoma (n 5 11,
9.7%) and other cancer diagnosis (n 5 9, 7.9%). Gray bar represents Group
A (<18 years of age, n 5 34), and white bar represents Group B (>18
years of age, n 5 112).
TABLE 1Semen Analysis Parameters for Each Cancer Diagnosis Category
Cancer
Diagnosis
Volume,
mL
Concentration,*
million/mL
Motility,*
%
Strict
Morphology,* %
Brain tumors 3.6 � 1.0 223.4 � 162.0 41.0 � 10.0 2.0 � 1.0
Hodgkin lymphoma 2.2 � 0.3 79.5 � 15.5 48.0 � 4.0 3.0 � 1.0
Leukemias 1.4 � 0.3 46.0 � 28.3 44.0 � 7.0 3.0 � 1.0
Testicular cancers 3.0 � 0.3 38.4 � 5.1 60.0 � 3.0 4.0 � 0.0
Ewing sarcoma/
Other solid tumors 2.9 � 1.0 141.1 � 49.2 53.0 � 7.0 12.0 � 8.0
Non-Hodgkin
lymphoma 2.6 � 0.3 61.2 � 30.1 50.0 � 7.0 5.0 � 1.0
Other 2.5 � 0.9 39.5 � 28.4 32.0 � 7.0 1.0 � 0.0
Values are expressed as mean � standard error of the mean.
* Normal ranges based on WHO criteria are: > 20 million sperm/mL for concentration; > 50% motil-
ity; and > 4.0% strict morphology.7
FIGURE 2. Proportion of patients with a normal semen analysis by type ofcancer including brain tumors (n 5 0, 0.0%); Hodgkin lymphoma (n 5 10,
33.3%); leukemias (n 5 1, 9.1%); testicular cancer (n 5 9, 22.5%); Ewing
sarcoma and other solid tumors (n 5 2, 25.0%); non-Hodgkin lymphoma
(n 5 2, 18.2%) and other cancer diagnoses (n 5 0, 0.0%). Gray bar repre-
sents Group A (<18 years of age; n 5 34), and white bar represents Group
B (>18 years of age; n 5 112).
Sperm Banking for AYA Cancer Patients/Neal et al. 1127
future), after overcoming the challenge of a life-
threatening disease, would be one such service.
Because this study was a retrospective chart review,
we were unable to determine the reason behind the
low proportion of patients who banked sperm sam-
ples. However, it is evident that better education is
required for both patients and professional health
staff. Educational material should be developed spe-
cifically for AYA patients to encourage appropriate
discussion with their healthcare providers before
treatment in an effort to improve referral to a local
fertility program.
Cryopreservation of semen is an acceptable
method for fertility preservation in postpubertal males
who are about to undergo cancer therapy.12 The high
frequency of abnormal samples of sperm in this study
is unexplained, although such findings are well
described in young men with Hodgkin lymphoma
and testicular tumors before therapy.13 Newer techni-
ques for harvesting mature sperm cells for assisted
reproductive technology, such as microsurgical epi-
didymal sperm aspirations (MESA), testicular sperm
extraction (TESE), and microscopic testicular sperm
extraction (mTESE), have been implemented in cases
of obstructive and nonobstructive azoospermia,
respectively.14 Fertility-sparing measures in prepuber-
tal boys, however, still require much more research,
and the ability to preserve or restore natural fertility
in older adult cancer patients is also desirable.15
Approximately 15% to 30% of male cancer survi-
vors of reproductive age are permanently sterile after
treatment.16 Among patients in whom spermatogen-
esis recovers after treatment, the integrity of the
sperm DNA may impair future fertility. The introduc-
tion of semen cryopreservation has changed repro-
ductive prospects for AYA men who are treated for
cancer.16 Furthermore, advanced assisted reproduc-
tive technologies, such as IVF with ICSI, allow crea-
tion of in vitro embryos with only a few normal
sperm. However, because IVF and ICSI procedures
bypass natural biological control mechanisms asso-
ciated with fertilization and have been used clinically
for little more than a decade, the long-term health
implications for these offspring are unknown, espe-
cially when sperm is collected after chemotherapy
and radiotherapy. Whereas animal studies focus on
acute gonadotoxicity,17 few studies address the ques-
tion of human sperm DNA integrity in relation to
anticancer therapy.18 A recent case-control study by
Thomson et al. showed no difference in sperm DNA
integrity between sperm samples from men who
were childhood cancer survivors and age-matched
controls.19 However, because this study had a small
sample size, further investigation into the DNA frag-
mentation of sperm after potentially gonadotoxic
chemotherapy treatment is necessary. This under-
lines the importance of banking samples of semen
before fertility-damaging treatment. Moreover, the
results of this study clearly demonstrate that sperm
banking provides an excellent opportunity for
patients to father children of their own with the help
of assisted reproductive technologies.
Young adult males may be more able to accept
the idea of sperm banking, as it may preserve their
reproductive capacity in the future, whereas adoles-
cents may be more intimidated and embarrassed by
this concept.20 In a 1996 study by Kleish et al., it was
found that adolescent males, ranging in age from 14
to 17 years, were eligible for sperm banking.21 More-
over, the study by Kleish et al., found that sperm
concentration, motility, and morphology were similar
in adolescent and adult patients, thus supporting the
position that cryopreservation of semen is an option
for young male patients with cancer. In addition to
this, the American Society of Clinical Oncology
recently published recommendations on fertility
preservation in cancer patients that highlighted the
finding that more education is required to encourage
increased use of fertility preservation methods in
young cancer patients.22 Our study confirms that
sperm banking is an efficacious, but underused,
option for young men who are about to undergo
gonadotoxic treatment for malignant disease. The
use of fertility-preserving options, as part of the
treatment protocol for AYA males with cancer,
TABLE 2Information on Women Using Their Partners’ Banked Sperm for IVF
Description Mean (SEM) Range
Women’s age, y 32.6 (1.4) 28–42
*E2 at hCG, pmol/L 8614.9 (790.1) 4275.0–11122.0
No. oocytes retrieved 12.0 (2.0) 4–20
Fertilization rate, % 72.5 (7.0) 20.0–88.9yCES at 48 h 11.6 (1.5) 2.0–16.4yCES at 72 h 24.9 (3.7) 26.5–40.0yCES at embryo transfer 28.1 (5.6) 32.0–48.0
No. of embryos transferred 1.8 (0.3) 0–3.0
No. embryos frozen 3.1 (1.0) 0–10.0
Implantation rate, % 60.4 (16.0) 0–100.0{Pregnancy rate 1bhCG, % 70.0 NA§Clinical pregnancy rate, % 50.0 NA
IVF indicates in vitro fertilization; SEM, standard error of the mean; NA, not available.
* E2, estradiol measured at the time of hCG is a measure of the ovarian response to controlled ovar-
ian hyperstimulation.y CES, cumulative embryo score.{ a bhCG value greater than 10 IU/L indicated a positive pregnancy test.§ Clinical pregnancy rate was based on the presence of a fetal heart beat at the time of ultrasound
at 6.5 weeks of gestation.
1128 CANCER September 1, 2007 / Volume 110 / Number 5
requires expertise and cooperation among a multidis-
ciplinary team of experts that includes oncologists,
nurses, urologists, andrologists, and those specializing
in reproductive medicine.
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