British Columbia Medical Journal, December 2010 issue Please download or visit this entire issue online at http://bcmj.org/issue/december-2010

1. Lauren MacDonald, BScH, MSc, Chris Fryer, FRCPC, Mary L. McBride, MSc,
Paul C. Rogers, FRCPC, Sheila Pritchard, FRCPC
The need for long-term
follow-up of childhood cancer
survivors in British Columbia
Initiating a prospective surveillance system and follow-up registry
would contribute to the health and well-being of British Columbians
who have received cancer treatment as children or adolescents.
n British Columbia there are ap- existence in 2006 for long-term fol-
I
ABSTRACT: Many survivors of child-
hood cancer have incomplete knowl- proximately 3000 patients aged 17 low-up for pediatric cancer.10 Unfor-
edge of their past treatment and are years or older who are survivors of tunately, only one such program was
unaware of the risks they may face, childhood cancer (diagnosed before identified in Canada, the Provincial
including long-term negative health the age of 17 years). Each year an Pediatric Oncology AfterCare Program
consequences such as second can- additional 120 or more patients “grad- through the Pediatric Oncology Group
cers, cardiovascular disease, and uate” to become adult survivors of of Ontario.
infertility. These late effects are pre- childhood cancer. There is increasing
dominantly the result of radiation, evidence that although children, ado- Late effects
anthracycline therapy, and alkylator lescents, and young adults diagnosed Long-term sequelae in survivors of
therapy. Currently there is no formal with cancer have an improved sur- childhood cancer are predominantly
program for long-term care of British vival rate, many survivors face long- secondary to radiation, anthracycline
Columbians who have survived can- term negative health, educational, and therapy, and alkylator therapy. Late
cer in childhood or adolescence. A social consequences of their cancer effects of cancer treatment are not
program is needed to provide life- experience.1-5 Many of these survivors unique to survivors of childhood can-
long health surveillance, counseling, are unaware of the specific cancer cer, but they are usually more severe
and a registry for this population. therapy they received earlier in life than those experienced by survivors
Such a program would also provide and do not know that they may face of adult cancer, as the cancer treat-
GPs with current and relevant rec- significant long-term risks to their ment is received during periods of
ommendations for follow-up care health and well-being.2,6-8 These “late growth and development. Knowledge
and support the shared goals of the effects” may not become apparent of health risks has resulted in changes
federally funded Canadian Partner- until many years after treatment. The in therapy to obviate untoward effects.
ship Against Cancer and the BC Can- most serious health risks are late
cer Agency. recurrence of disease, as well as sec- Ms MacDonald is a research scientist in
ond cancers, cardiovascular disease, the Cancer Control Research Program at
and endocrinological and neuropsy- the BC Cancer Agency in Vancouver, British
chological abnormalities. In 2003 the Columbia. Dr Fryer is a consultant pediatric
American Institute of Medicine iden- and radiation oncologist at BC Children’s
tified the need for a systems approach Hospital (BCCH) in Vancouver. Ms McBride
to the health care needs of survivors of is a research scientist in the Cancer Control
childhood cancer and made specific Research Program at the BC Cancer
recommendations. 9 The National Agency. Dr Rogers is a consultant pediatric
Cancer Institute’s Office of Cancer oncologist at BCCH. Dr Pritchard is a con-
This article has been peer reviewed. Survivorship identified programs in sultant pediatric oncologist at BCCH.
504 BC MEDICAL JOURNAL VOL. 52 NO. 10, DECEMBER 2010 www.bcmj.org

2. The need for long-term follow-up of childhood cancer survivors in British Columbia
For example, radiation therapy is mendations for follow-up care and obstetrical problems, and posttraum-
now rarely used in the treatment of new knowledge about late effects of atic stress disorder.
Hodgkin disease in children, and the cancer therapy as it becomes avail-
recommended maximum total dose of able. In order to ensure quality life- Second tumors
anthracylines has been significantly long care, it is also essential to obtain Studies show that survivors of child-
reduced. However, it is not yet known feedback and maintain a database re- hood malignancy have a three to ten
how increasing the intensity of thera- garding late health problems as they times increased risk of developing a
py currently used and new or innova- develop in order to assess longer-term second malignancy compared with
tive cancer treatments may affect the risks and new problems as they arise the general population.12,13 Radiation
observed late effects. This lack of among the survivor population. A exposure increases the risk for brain
knowledge of future long-term side
effects provides further rationale for
lifelong surveillance of survivors at
risk. It is important to emphasize that
not all childhood cancer survivors are
at risk for late effects and therefore Survivors of childhood cancer face a
surveillance recommendations should
be risk-based. Surveillance also pro-
number of health risks, including a second
vides an opportunity to undertake re- malignancy, recurrence of their original
search into host factors such as genet-
ic polymorphisms that may make an
disease, fertility and obstetrical problems,
individual more susceptible to late and posttraumatic stress disorder.
sequelae.11
Surveillance
practice in BC
In BC most adult survivors of child-
hood cancer have been discharged systematic follow-up program is tumors, breast cancer, thyroid cancer,
from cancer care programs and are not needed to link pediatricians, oncolo- bone tumors, and soft tissue sarcoma.
followed by physicians knowledge- gists, and GPs through surveillance Exposure to alkylating agents and the
able about their health risks. They are clinics to ensure successful transition topoisomerase II inhibitors increases
no longer being cared for by a pedia- of childhood cancer survivors from the risk for myeloid malignancy and
trician and the majority do not require treatment and recovery to survivor myelodysplastic syndromes.14
the specialist care of an oncologist. care.10 Currently in BC there is no sep- Basu and colleagues reported the
While pediatric and radiation oncolo- arate funding available to support cumulative incidence of breast cancer
gists are the most knowledgeable such a program, nor is there appropri- among female survivors of Hodgkin
health care providers concerning the ate reimbursement for GPs to under- disease who received radiation to the
late sequelae of cancer therapy in chil- take surveillance and prevention. This chest region in their teenage years was
dren, it is inappropriate for them to considerable deficiency must be ad- 19% by 25 years after diagnosis, ris-
provide life-long surveillance. dressed given that the unique needs ing to 24% by 30 years and to 35% by
In our health care system, the gen- of childhood cancer survivors in BC 40 years after diagnosis.15 The expect-
eral practitioner is in the best position require an effective province-wide ed cumulative incidence of breast can-
to carry out surveillance of late health survivor follow-up program and post- cer in the matched general population
problems and comorbid conditions, cancer care from GPs. is 10%. This gives a risk of treatment-
promote follow-up care, and counsel related breast cancer developing in one
patients on lifestyle issues. Given the Health risks in four female survivors of Hodgkin
complexity of diagnosis and treat- Survivors of childhood cancer face disease treated with chest irradiation
ment-specific late effects, GPs need to a number of health risks, including within 40 years of initial diagnosis.
be provided with current and relevant a second malignancy, recurrence of Goshen and colleagues reported that
information on the risks and recom- their original disease, fertility and survivors of childhood leukemia who
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3. The need for long-term follow-up of childhood cancer survivors in British Columbia
received low-dose cranial irradiation years. The most common second ma- lator exposure in the prepubertal child
have a 15% risk of developing benign lignancies were breast cancers (18%), may result in primary ovarian failure,
meningiomas within 20 years of ini- thyroid cancers (18%), and central while lower doses may result in nor-
tial diagnosis, while Strojan and col- nervous system tumors (15%). This is mal development of puberty and men-
leagues reported an 8% cumulative consistent with the experience from struation but premature menopause,
incidence at 25 years following high- other countries.12,13 which can occur at any age from mid-
dose cranial irradiation.16,17 These tu- teens onwards.28,29 Methods for preser-
mors are often asymptomatic—a con- Premature death vation of female fertility are limited
cern because surgical cure can only be Survivors of childhood cancer have a but include ovarian shielding or trans-
achieved with early diagnosis. reduced life expectancy when com- posing (repositioning the ovaries out
pared with the general population.20 of the radiation field) during radia-
CAYACS data reveal that the stan- tion; ovarian suppression with GnRH
dardized mortality rate is nine times analogs during chemotherapy (this is
that observed for age- and sex-matched experimental and not currently accept-
controls in the general BC popula- ed practice);30 oocyte cryopreserva-
Total anthracycline tion.21 However, 77% of the observed tion for postpubertal females only
dose tolerated by deaths (139/181) were due to recur- (requires ovarian stimulation over at
rence of the subjects’ original disease, least 2 weeks prior to starting chemo-
adults can be 8% were related to second malignan- therapy or radiation, so it is not usual-
associated with cies, and only 12% were not cancer ly possible for acute malignancies in
related, with cardiovascular causes adolescents); cryopreservation of ovar-
cardiac failure when being the most common. The cause of ian tissue (this is experimental and so
given to children. death was unknown in 3% of cases.21 far unsuccessful); and embryo cryo-
The CAYACS data confirm what other preservation (requires ovarian stimu-
childhood cancer survivor study data lation and a partner and has both moral
show—that, after cancer, cardiovas- and ethical implications).
cular disease, most likely related to Males. Testicular function is also
radiation or chemotherapy, is the prin- extremely sensitive to radiation and
The Childhood, Adolescent, Young cipal cause of death in survivors of high-dose alkylating agents. Radia-
Adult Cancer Survivorship Research childhood cancer.22 Total anthracy- tion doses greater than 600 cGy in
Program (CAYACS) is a population- cline dose tolerated by adults can be boys can cause permanent azosper-
based study utilizing BC Cancer Agen- associated with cardiac failure when mia.28 The doses of alkylating agents
cy and BC Children’s Hospital data given to children.23-25 Furthermore, often used for Hodgkin disease may
linked to provincial databases for the there is accumulating evidence that also permanently impair spermatoge-
examination of long-term outcomes progressive cardiac dysfunction may nesis. Methods for fertility preserva-
of cancer survivors diagnosed before manifest itself up to 22 years after tion in males include shielding of the
age 25.18 CAYACS reported 55 second treatment.26 Radiation to the heart and testes during radiation, which is done
malignant neoplasms among a popu- great vessels can also result in prema- whenever possible; sperm banking for
lation-based cohort of 2322 5-year ture coronary disease or vascular dam- patients with Tanner stage 4 or higher;
survivors diagnosed in BC before 20 age, increasing the risk of cerebrovas- surgical sperm retrieval if patient is
years of age; 15 of these neoplasms cular accidents.27 Tanner stage 4 but unable to produce
were found in males and 40 in fe- a semen sample; and testicular tissue
males.19 The mean age at diagnosis Gonadal and fertility effects preservation for prepubertal boys (this
of a second malignant neoplasm was Male and female fertility can be im- is experimental and so far unsuccess-
27 years and the mean time from the paired by exposure to radiation and ful).
original diagnosis was 15 years. The high doses of chemotherapy, particu-
increased cumulative prevalence of larly alkylating agents.28 Other late effects
second malignant neoplasms over the Females. The ovaries may be dam- Every organ system can be affected by
normal population was 1.3% at 15 aged if in or adjacent to the radiation radiation and chemotherapy, especial-
years, 2.5% at 20 years, and 4% at 25 field. High doses of radiation or alky- ly during early developmental years.
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4. The need for long-term follow-up of childhood cancer survivors in British Columbia
The endocrine system is suscepti- problems.8 This fact, together with the associated with therapy at the time of
ble to a number of late effects. Adreno- extensive evidence for late effects of diagnosis, but also the risks revealed
corticotropic hormone deficiency sec- childhood cancer, and the observed as new information becomes available.
ondary to pituitary lesions or cranial excess health services utilization, in-
radiation may occur and can result in dicates an increased need for a com- Surveillance monitoring
death from a simple upper respiratory prehensive follow-up care strategy. All adult survivors of childhood can-
infection.31 Irradiation to the thyroid It is important to impart knowledge cer in BC, together with their primary
gland results in a very high incidence to primary health care providers and health care providers, should be given
of hypothyroidism.32 Cranial radiation autonomy to cancer survivors by using a medical summary including details
and chemotherapy have been linked BC-specific data to develop risk-based of their diagnosis and therapy. They
to an increased incidence of obesity in follow-up guidelines that address the should also be counseled regarding
survivors of childhood leukemia.33 special needs of these patients. anticipated health risks by nurse prac-
An increased incidence of miscar- Initiation of a prospective surveil- titioners or physicians knowledgeable
riages, complications during delivery, lance system and follow-up registry about late sequelae.9 Survivors should
and low birth weight infants are relat- would contribute to the health and be asked to consent to annual contact
ed to pelvic radiation.34,35 well-being of adult survivors by pre- (directly, via their primary health care
Late deafness, poor educational venting or ameliorating late effects. provider, or both) for follow-up of
outcomes, psychological effects such The recommendations for surveillance their health. Risk-based guidelines
as posttraumatic stress disorder, and monitoring of cancer survivors varies should be made available to patients
impaired quality of life have all been slightly with country and resources, and health care professionals. In the
reported.36-38 making it important to generate a set interim, the following general recom-
of uniform, evidence-based guide- mendations are provided to address
Health care utilization lines appropriate to the situation in the most important potential late seque-
Not surprisingly, CAYACS data show BC. This will not only provide stan- lae in survivors of childhood cancer:
these late morbidities result in increas- dards of follow-up care, but enable • All survivors should receive educa-
ed health care utilization with respect ongoing evaluation of the guidelines tion on healthy lifestyle to minimize
to physician visits, hospitalizations, and effectiveness of any intervention- the added effects of obesity on car-
and outpatient procedures.39,40 Among al health action. This will also assist in diovascular disease and the risk of
survivors, 24% had at least one subse- identifying late-onset health issues malignancy associated with obesity.
quent hospitalization compared with related to newer therapies. Such a sur- • Survivors who received anthracy-
13% of age- and gender-matched con- veillance system should be lifelong clines should have echocardiograms
trols. Overall, demand for physician and based on the latest evidence avail- to measure ejection fraction and
visits, hospitalizations, and outpatient able. This type of program will pro- fractional shortening, and ECG mon-
services were greatest among sur- vide a positive reinforcement mecha- itoring every 5 years, and be advised
vivors of a brain tumor, female sur- nism through annual contact, and regarding the latest “healthy heart”
vivors, and older survivors. empower the patient to make any rec- recommendations.25,41
ommended changes in lifestyle. • Females who received radiation to
Recommendations Lifelong surveillance should be the chest region should have mam-
A program providing lifelong health supported by an ongoing registry for mography or MRI breast screening
surveillance, counseling, and an on- adult survivors of childhood cancer to starting at age 25.42-45
going registry for adult survivors of provide vital facts regarding diagno- • Survivors who received radiation to
childhood and adolescent cancer is sis, treatment, and risk category for the brain should be screened for
greatly needed in BC in accordance late effects, while providing the means benign meningiomas by MRI start-
with the Institute of Medicine recom- for quantifying the extent and severity ing at 10 years posttreatment.
mendations.9 Currently there is no of any subsequent health problems in a • Survivors who received radiation to
formal program for long-term care of longitudinal population-based fashion. the brain or thyroid should be screen-
this population. Many adult survivors Health care providers and institu- ed for thyroid nodules with ultra-
have incomplete knowledge regard- tions have professional, ethical, and sounds of the neck starting at 5 years
ing their past diagnoses, treatment, legal responsibilities to inform pa- posttreatment, and monitored for
and risks for significant future health tients, not only of the known risks thyroid function with T4 and TSH.
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5. The need for long-term follow-up of childhood cancer survivors in British Columbia
Fertility counseling and BC Cancer Agency: to reduce the inci- and treatment: Childhood Cancer Sur-
obstetric monitoring dence of cancer and the number of vivor Study. JAMA 2002;287:1832-1899.
Female survivors should be counseled cancer-related deaths, and to improve 9. Hewitt M, Greenfield S, Stovall E (eds).
regarding their risk for infertility and the quality of life for those living with From cancer patient to cancer survivor:
premature menopause. Monitoring for cancer. Lost in transition. Washington, DC:
ovarian reserve to predict early meno- National Academies Press; 2005.
pause is important but is not easy. Acknowledgments 10. Aziz NM, Oeffinger KC, Brooks S, et al.
Although changes in menstrual histo- Grants for this project were provided by Comprehensive long-term follow-up pro-
ry and an increase in follicle-stimulat- the Canadian Institute for Health Research, grams for pediatric cancer survivors. Can-
ing hormone are easily monitored, the the Canadian Cancer Society Research cer 2006;107:841-848.
abnormalities indicating impending Institute, and the Canadian Cancer Society 11. Ross CJ, Katzov-Eckert H, Dubé MP, et
ovarian failure occur late. Serial antral BC and Yukon Division. al. Genetic variants in TPMT and COMT
follicle count by ultrasound is more are associated with hearing loss in chil-
accurate but time-consuming and not Competing interests dren receiving cisplatin chemotherapy.
readily available. Measurement of anti- None declared. Nat Genet 2009;41:1345-1349.
müllerian hormone (AMH) reflects 12. Olsen JH, Moller T, Anderson H, et al.
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