TREATMENT
BETSY M. BICKERT
OF COMMON CHILDHOOD MALIGNANCIES
Treatment of Common
Childhood Malignancies
Betsy M. Bickert, PharmD
Malignancy is the fourth leading cause of death in persons
aged 1 to 19 years. The success of the pediatric oncology co-
operative group clinical trials has allowed a systematic ap-
proach to the treatment of relatively rare malignancies. Each
trial builds on previous results in terms of both survival and
KEY WORDS: pediatric, oncology, cancer, chemotherapy.
M ALIGNANCY IS THE FOURTH leading cause of
death in persons aged 1 to 19 years. In 1998,
12,400 persons younger than 20 years of age were diag-
nosed with a malignancy, and it was the cause of death
for an estimated 2500 children. Newborn males have a
1 in 300 chance of developing a malignancy by the age
of 20, and the number is slightly higher for females.1
The incidence of the most common malignancies of
childhood is presented in Figure 1.
In a 1992 survey of protocol participation, 62% of
pediatric oncology patients treated at pediatric centers
were enrolled onto a treatment protocol, whereas only
2% of adults were enrolled on such protocols.2 This has
allowed a systematic approach to the treatment of rela-
tively rare diseases by accruing large numbers of pa-
tients to consecutive protocols within a cooperative
group to compare therapeutic regimens. These re-
search protocols allow the discovery of therapeutic
successes and failures as well as characterizing treat-
ment-related toxicity. This article will discuss the cur-
rent treatment regimens and their long-term complica-
tions for common pediatric malignancies developed
through this process. Results are presented as averages
Address correspondence to: Betsy M. Bickert, PharmD, Oncology
and Bone Marrow Transplant Clinical Specialist, Department of
Pharmacy Services, The Children’s Hospital of Philadelphia, 34th
St and Civic Center Blvd, Philadelphia, PA 19104. E-mail: bickert@
email.chop.edu
JOURNAL OF PHARMACY PRACTICE, 15:1 42–51
© 2002 Sage Publications
DOI: 10.1106/JYT9-MA70-6CP3-XGCT
toxicity. This article will discuss the current treatment regi-
mens for several of the more common pediatric malignancies
and their long-term complications developed through this
process.
of all stages or grades of each tumor type unless other-
wise specified.
HEMATOLOGIC MALIGNANCIES
Leukemias are identified based on the cell of origin:
lymphoid or myeloid. The leukemias are the most com-
mon malignancies in childhood and are the primary
cause of cancer-related mortality in the United States.1
Acute lymphoblastic leukemia (ALL) composes 75%
of childhood leukemia, and acute myelogenous leuke-
mia composes approximately 19%.1 Infant leukemia is
a separate entity that has been reviewed elsewhere.3,4
Acute Lymphoblastic Leukemia
Approximately 2400 persons younger than 20 years
of age are diagnosed with ALL annually in the United
States.1 The peak incidence is between 2 and 5 years of
age. ALL is 30% more common in males than in fe-
males, and white children are twice as likely to develop
ALL as black children. Children with Down syndrome,
neurofibromatosis, Schwachmann syndrome, Bloom
syndrome, ataxia telangiectasia, Langerhans cell
histiocytosis, and Klinefelter syndrome are at higher
risk of developing ALL.
In the 1960s, a remission could be achieved in more
than 90% of children treated with prednisone and
vincristine, but resistance would develop within
months of continued therapy. At that time, 50% of chil-
dren with ALL developed central nervous system
(CNS) involvement of the disease.5 The method of treat-
 TREATMENT OF COMMON CHILDHOOD MALIGNANCIES

Other (20%)
Leukemia (25%)

Kidney (4%)

Sympathetic (5%)

Bone (6%)
Brain tumors (17%)

Soft Tissue (7%)

Figure 1. Cancer incidence
<20 years of age from 1975 to
Lymphoma (16%) 1995.1

ment and prevention of CNS relapse was cranial or Dexamethasone decreased the CNS relapse rate and in-
craniospinal irradiation. creased 3-year event-free survival by 5% over
In an effort to maintain remission, St. Jude prednisone in standard risk patients.13 Dexamethasone
Children’s Research Hospital developed the concept of was also associated with an increased incidence of
total therapy to include induction, consolidation, and hyperglycemia. The current standard risk protocol in-
maintenance. Induction is the initial therapy given to cludes dexamethasone in all phases of treatment.
induce a remission; consolidation targets leukemia As survival improved with new treatments, certain
cells in the CNS; and maintenance utilizes low-dose prognostic factors became apparent. Children with a
therapy to ensure clearance of residual leukemia cells white blood cell count greater than 100,000/mm3,
over a longer period of time. This approach achieved a bulky extramedullary disease, and age younger than 1
9-year, event-free survival rate of 51% in the 1970s.6 year and greater than 10 years had worse outcomes. At
In 1976, the Berlin/Frankfurt/Munster (BFM) group the same time, technological advances determined that
added a pulse of delayed intensification to enhance having ≥50 chromosomes is favorable and having <45
therapy against residual leukemia with novel agents is unfavorable. Nonrandom chromosomal transloca-
that achieved a 70% long-term survival rate.7 Delayed tions were also identified. Translocation (4;11) and the
intensification (DI) increased 5-year event-free survival Philadelphia chromosome t (9;22) are unfavorable and
from 61% to 73% in patients with intermediate risk place patients in the high-risk group. The translocation
ALL and increased 7-year event-free survival from 40% involving the MLL gene on chromosome 11 band q23 is
associated with infant ALL and a 5-year event-free sur-
to 63% for high-risk patients in the United States.8,9 The
vival of only 37%.1 Risk factors identified through the
addition of a second delayed intensification (double
delayed intensification [DDI]) has improved event-free
survival at 6 years from 87% with a single DI to 91% Table 1
with DDI in patients with intermediate risk ALL.10 The 1997 National Cancer Institute Acute
14
current standard risk protocol randomizes patients to Lymphoblastic Leukemia Risk Stratification
either one or two delayed intensification phases. White Blood
In 1983, a randomized trial showed that 3 years of Risk Age Cells
therapy was equivalent to 5 years of therapy.11 Miller
3
Group (years) (cells/mm ) Karyotype
and colleagues12 showed that for girls, 2 years of ther- Standard 1 to <10 <50,000 No t(9;22) or t(4;11)
apy was equivalent to 3 years of therapy, but that for High 1 to <10 ≥50,000
boys 3 years of therapy was better than 2 years, which <1 or ≥10 Any
Any Any t(9;22) or t(4;11)
remains the current standard length of treatment.12

JOURNAL OF PHARMACY PRACTICE 2002(15.1) • 43

 BETSY M. BICKERT
Table 2
Standard Acute Lymphoblastic Leukemia Therapy
Phase (duration) Standard-risk Therapy
Induction (1 month) Intrathecal therapy, vincristine, steroid,
asparaginase
Consolidation Mercaptopurine, vincristine, intrathecal
(4 weeks/5 weeks) methotrexate
Interim maintenance Methotrexate, mercaptopurine, vincristine,
(2 months) steroid, intrathecal methotrexate
Delayed intensification Vincristine, dexamethasone, pegaspargase,
(8 weeks/7 weeks) doxorubicin, cyclophosphamide, thioguanine,
cytarabine, intrathecal methotrexate
Maintenance Methotrexate, mercaptopurine, vincristine,
(12-week cycles) dexamethasone, intrathecal methotrexate
Oral methotrexate, mercaptopurine, and thioguanine are most effective if given at bedtime on an empty stomach.
cooperative group trials resulted in the 1997 Na-
tional Cancer Institute ALL Risk Stratification as seen
in Table 1.14 These criteria are now used to determine
treatment for children presenting with newly diag-
nosed ALL.
Most chemotherapy agents do not readily cross the
blood-brain barrier. This allows leukemic cells to use
the CNS as a sanctuary site from treatment. Intrathecal
chemotherapy, cranial irradiation, and high-dose intra-
venous methotrexate or cytarabine are all effective
methods to prevent spread of the disease into the CNS.
Intrathecal therapy consists of cytarabine alone,
methotrexate alone, or methotrexate, hydrocortisone,
and cytarabine in combination. Tubergan and
colleagues9 found intrathecal methotrexate is equiva-
lent to cranial irradiation for CNS prophylaxis in chil-
dren younger than 10 years of age. Italian investigators
have also found that cranial irradiation can be replaced
with 4 doses of intravenous methotrexate in consolida-
tion and with additional intrathecal methotrexate in
maintenance therapy with a less than 1% incidence of
CNS relapse at 6 years.15 Prophylactic cranial irradia-
tion has been eliminated for patients without CNS dis-
ease at diagnosis in the United States due to the long-
term sequelae of radiation. Long-term sequelae of cra-
nial radiation include short stature, delayed learning
deficits, thyroid dysfunction, obesity, and brain
tumors.16-18
The current model of therapy for standard risk ALL
includes induction, consolidation, 1 or 2 interim main-
tenance cycles, 1 or 2 delayed intensification cycles, and
maintenance (Table 2). Standard 3-drug induction with
vincristine, prednisone, or dexamethasone, and
asparaginase achieves remission in 97% to 99% of chil-
dren. Patients also receive intrathecal chemotherapy.
Consolidation allows intensive treatment of the CNS to
prevent relapse. Delayed intensification is designed to
44 • JOURNAL OF PHARMACY PRACTICE 2002(15.1)
High-risk Therapy
Intrathecal therapy, vincristine, steroid,
daunorubicin
Mercaptopurine intrathecal methotrexate,
cyclophosphamide, cytarabine, prednisone
Methotrexate, mercaptopurine, intrathecal
methotrexate
Vincristine, dexamethasone, asparaginase,
doxorubicin, cyclophosphamide, thioguanine,
cytarabine, intrathecal methotrexate
Methotrexate, mercaptopurine, vincristine,
prednisone, intrathecal methotrexate
kill residual leukemic cells while limiting develop-
ment of drug resistance by administering agents with
different mechanisms of action. Interim maintenance is
given in between intense cycles to maintain remission
but to avoid toxicity from continuously intense ther-
apy. Low-dose pulses of chemotherapy are given dur-
ing maintenance to further ensure the clearance of re-
sidual leukemic clones. Patients with unfavorable
cytogenetics or with slow early response after induc-
tion receive augmented therapy with higher doses of
some agents, such as steroids, and the addition of other
agents to increase the probability of a remission.
Children with high-risk ALL receive more intense
chemotherapy (Table 2). On Day 7 of treatment, the
bone marrow is assessed for residual leukemic blasts.
Patients with greater than 25% blasts are considered
slow early responders and receive even more intense
therapy. This stratification increased 5-year event-free
survival from 55% to 75%.19
Modifications based on study results have improved
survival rates by building on existing treatment regi-
mens rather than relying on development of new
agents. Current therapy yields an 80% to 85% long-
term survival.1 For patients with high-risk disease who
receive more intense therapy, the survival is only 50%
to 78%.1,19 The 5-year survival for black children is only
64%.1
If a patient relapses after first-line therapy, a second
remission may be induced in 82% to 95% of patients
treated with an anthracycline, steroid, vincristine, and
asparaginase/pegaspargase; however, the long-term
prognosis is worse the second time around.20-21
Matched sibling bone marrow transplantation (BMT) is
the treatment of choice for ALL in second remission.
Five-year event-free survival after a matched sibling
BMT in second remission is 40%, versus 17% with
chemotherapy alone.22 Patients who relapse more than
 TREATMENT OF COMMON CHILDHOOD MALIGNANCIES
36 months after completion of initial therapy may
benefit from chemotherapy alone, although allogeneic
transplantation is the best option, if available. Trans-
plantation during first remission is controversial. The
exception is Philadelphia chromosome–positive pa-
tients (3% to 5% of childhood ALL) who have a poor
prognosis and in whom benefit from matched related
donor BMT in first remission has been demonstrated.23
Secondary acute myeloid leukemia occurs in about
5% of children following ALL treatment with high
doses and intensive schedules of etoposide or
teniposide;24 therefore, these agents are no longer in-
cluded in the cooperative group trials. Corticosteroid
use has been associated with osteopenia, avascular ne-
crosis, and hyperglycemia.25 Native E coli asparaginase
causes hypersensitivity reactions in approximately
50% of ALL patients.26
In addition, anthracyclines used in high-risk or re-
lapsed patients can cause cardiomyopathy.
Doxorubicin may result in decreased left ventricular
mass with subsequent increase in left ventricular
afterload and decreased contractility. Congestive heart
failure has been reported during or within 1 year of
therapy. Late cardiotoxic effects have been found 2 to
15 years following therapy, with an incidence of 65%
in survivors of childhood ALL.27 Risk factors include
female sex, young age at diagnosis, rapid infusion rate,
mantle irradiation, and cumulative dose greater than
400 mg/m2.27
Acute Myelogenous Leukemia
There is an increased incidence of Acute Myeloge-
nous Leukemia (AML) in Hispanic children, patients
who have received epidopophyllotoxins or alkylating
agents, and patients with trisomy 21, neuro-
fibromatosis Type I, or Kostmann syndrome.1,28
Children with Down syndrome have the best outcomes
and now receive lower doses of chemotherapy agents
secondary to excessive toxicity.29-31 Monosomy 7 or 7q
deletions are associated with poor outcomes in both
children and adults.32 Clinical trials have improved 5-
year survival through incremental intensification of
therapy from 17% in 1976 to 42% in 1996 for patients
younger than 20 years of age.33 Children with Down
syndrome have a 70% event-free survival at 5 years.30
Unfortunately, treatment-induced morbidity limits fur-
ther intensification of current therapy, and relapse rates
remain unacceptable.
AML therapy consists of induction, consolidation,
and intensification. Maintenance therapy is no longer
used in the United States. The goals of induction ther-
apy are to restore normal hematopoiesis, reduce leuke-
mic blast cells in the bone marrow to less than 5%, and
eliminate extramedullary disease.28 Current induction
regimens consist of two 4-day cycles of high-dose ther-
apy separated by 1 week that allows recruitment and
synchronization of blasts into S phase at the time of the
second pulse.34 These regimens consist of idarubicin or
daunorubicin, etoposide, cytarabine, thioguanine, and
dexamethasone. This requires a minimum of 1 month
in the hospital.
Following remission, it is recommended to proceed
with a matched related BMT if a suitable donor is avail-
able. The 8-year survival with an allogeneic BMT is
60% and only 53% with chemotherapy alone.35 If there
is no donor, then the patient proceeds with consolida-
tion and intensification chemotherapy. Consolidation
with high-dose cytarabine has replaced maintenance
therapy and increased survival at 5 years from 41%
to 58%.36 Patients receiving autologous BMT do not
suffer from graft versus host disease; however, they
cannot benefit from the graft versus leukemia effect.
Multiple studies have shown no benefit to autologous
BMT.34,35,37,38
A role for monoclonal antibodies is currently being
sought for childhood AML. Gemtuzumab ozogamicin
was recently marketed for the treatment of adult AML.
Gemtuzumab consists of a humanized anti-CD33 anti-
body linked to calicheamicin, a toxin. The antibody is
internalized after binding to CD33, which is expressed
on greater than 90% of childhood AML cells, and the
toxin is released intracellularly. The pediatric dose-
finding clinical trials are not yet completed, but there
are plans to include gemtuzumab ozogamicin in the
next randomized phase-3 pediatric AML clinical trial.
With induction therapy, mortality risk is 10% to
20%.28 The prolonged bone marrow suppression pre-
disposes patients to bacterial and fungal complications
that are the leading cause of morbidity and mortality.
Viridans streptococcal infections are common in pa-
tients receiving high-dose cytarabine.39 Prophylactic
penicillin and fluconazole have only short-lived suc-
cess due to the development of resistance. Empiric
amphotericin is started after only 3 days of persistent
fever for these patients instead of the common 5 to 7
days. Many patients surviving childhood AML for
more than 10 years developed growth abnormalities
(51%), endocrine dysfunction (16%), infertility (25%),
neurocognitive impairment (30%), cataracts (12%),
and secondary malignant neoplasms (14%).40
Hodgkin’s Disease
In children younger than 15 years of age, Hodgkin’s
disease (HD) is more common in males; it is more com-
JOURNAL OF PHARMACY PRACTICE 2002(15.1) • 45
 BETSY M. BICKERT
mon in females after the age of 15 years. There is a bi-
modal age distribution, with peak incidence occurring
in the second and fifth decades of life in industrialized
countries.41 Clinical trials have improved 5-year sur-
vival for patients younger than 20 years of age with HD
from 85% in 1976 to 93% in 1996.33 Since the survival
rate is so high, the focus of most trials is to maintain ef-
ficacy while decreasing long-term sequelae, such as in-
fertility and secondary malignancy.
Most pediatric protocols for HD utilize multiagent
chemotherapy regimens with or without low-dose,
involved-field radiation. The addition of radiation in
patients with bulky disease or B symptoms (that is,
high temperature for 3 days, drenching night sweats,
and ≥10% unexplained weight loss over 6 months) at
diagnosis may reduce the risk of relapse and may allow
for fewer cycles of intensive chemotherapy. Adoles-
cents may receive high-dose radiation therapy for lo-
calized disease. For low stage (I, II, IIIA) and favorable
disease, patients receive 4 to 6 courses of COPP (cyclo-
phosphamide, vincristine, procarbazine, prednisone)/
ABV (doxorubicin, bleomycin, vinblastine) hybrid
therapy and low-dose, involved field radiation.42
Certain clinical risk factors predict a worse outcome.
These risk factors define unfavorable disease and in-
clude large mediastinal mass, massive splenic involve-
ment, extranodal involvement, elevated erythrocyte
sedimentation rate, 3 involved lymph node areas, and
anemia.42 Advanced-stage and unfavorable disease
have received MOPP-ABV (M = mechlorethamine) hy-
brid therapy with radiation.41 Currently, the BEACOPP
(bleomycin, etoposide, doxorubicin, cyclophos-
phamide, vincristine, prednisone, procarbazine) regi-
men shown to be effective in adults is being investi-
gated in children.42 High-dose chemotherapy alone is
usually avoided to prevent potential morbidity from
myelosuppression, gonadal injury, and secondary ma-
lignant neoplasms. Children treated with radiation ±
chemotherapy from 1935 until 1994 had an increased
risk of secondary malignancy 10 to 30 years following
diagnosis.43 Attempts at decreasing the alkylating agent
doses in order to decrease toxicity have resulted in in-
ferior survival rates.41 Cardiopulmonary toxicity has
decreased secondary to careful monitoring and limita-
tion of cumulative doses of bleomycin and doxorubicin
in combination with radiation.
Non-Hodgkin’s Lymphoma
The incidence of non-Hodgkin’s lymphoma (NHL)
begins to increase after 10 years of age, with a peak inci-
dence at 15 to 19 years.1 Seventy percent of cases occur
46 • JOURNAL OF PHARMACY PRACTICE 2002(15.1)
in males.1 Thirty-four percent of NHL cases are Bur-
kitt’s, 29% are lymphoblastic, and 27% are large cell.44
Two thirds of children have widespread disease at di-
agnosis secondary to the rapid growth of NHL. Newer
regimens have improved 5-year survival for NHL pa-
tients younger than 20 years of age from 43% in 1976 to
74% in 1996; however, children with less extensive
disease (that is, Stage I or II disease) have an 85% to
95% long-term survival.33,44
Chemotherapy is the main modality for treatment of
NHL. Surgery is only used for diagnostic purposes un-
less there is an isolated gut mass. Radiation of the pri-
mary site is restricted to emergency situations.
Intrathecal therapy is an integral part of therapy to pre-
vent or treat CNS disease for all types of childhood
NHL. Choice of chemotherapy differs by the cell of ori-
gin, as discussed below. Large cell lymphoma has been
treated with both strategies but only achieves long-term
event-free survival in 50% to 70% of patients.44
B-cell lymphomas usually receive intensive, repeti-
tive therapy with alkylating agents and antimetabolites
for 9 weeks to 8 months. Low-stage disease is treated
with COP (cyclophosphamide, vincristine, and predni-
sone). Higher stage disease (that is, Stage III or IV) re-
ceives COP plus doxorubicin and high-dose
methotrexate ± etoposide, ifosfamide, cytarabine, or
cisplatin.44 Current therapy aims to decrease duration
of therapy, leading to decreased anthracycline-induced
cardiomyopathy and alkylating agent-induced
sterility.
T-cell lymphoblastic lymphomas are treated much
like ALL for 12 to 32 months. Patients receive multiple
agents in 3 phases: induction, consolidation, and main-
tenance. Therapy in the United States is tailored after
the work of the BFM group. The NHL-BFM–90 regimen
treated patients with an 8 drug induction for 9 weeks,
consolidation with high-dose methotrexate for 8
weeks, and maintenance with oral methotrexate/
mercaptopurine to complete 24 months. High-risk pa-
tients also received 8 weeks of intensification prior to
maintenance that included cranial radiation. The 5-
year event-free survival was 90%.45 No patients died of
treatment-related toxicity, but one patient developed a
secondary malignant neoplasm.
Patients with recurrent NHL and HD may respond to
DECAL (dexamethasone, etoposide, cisplatin,
cytarabine, and asparaginase). Sixty-five percent of HD
patients and 42% of NHL patients had an initial re-
sponse, but the 5-year survival is only 26% and 23%,
respectively.46 Late effects of NHL therapy include in-
fertility from alkylating agents, secondary malignant
neoplasms from alkylating agents and radiation,
 TREATMENT OF COMMON CHILDHOOD MALIGNANCIES
Table 3
Survival and Treatment of Common Pediatric Brain Tumors
Tumor Type 5-Year PFS
Standard risk PNET 60%
High-risk PNET 30%
Low-grade astrocytoma 70%
High-grade astrocytoma 20%
Brainstem glioma 5%
Ependymoma 30%
PFS = progression-free survival; PNET = primitive neuroectodermal tumor = medulloblastoma; XRT = radiation therapy
cardiomyopathy from doxorubicin, and radiation-
induced growth abnormalities, renal dysfunction, or
pulmonary toxicity.
SOLID TUMORS
Brain Tumors
Central nervous system tumors are the second most
common malignancy of childhood. The incidence of
invasive tumors is 18% higher in white than black chil-
dren and more common in males than females.1 Brain
tumor incidence appears to have increased in the last
20 years, but this may be the result of improved diag-
nostic imaging and not a true increase. Clinical trials
have improved 5-year survival for patients younger
than 20 years of age from 56% in 1976 to 66% in 1996.33
Treatment regimens depend on tumor pathology, tu-
mor location, and patient age. Certain tumors, such as
cerebellar pilocytic astrocytoma, may be cured by sur-
gical resection alone, whereas hypothalamic gliomas
require repeated resections. Others, such as germ cell
tumors, may respond to radiation therapy alone. Pa-
tient age limits the amount of radiation a patient can re-
ceive because younger patients are more susceptible to
the cognitive and developmental effects of
craniospinal irradiation. However, some remain inef-
fectively treated using surgical resection, radiation,
and chemotherapy. Table 3 presents the most common
brain tumors of childhood, their survival rate, and the
regimen used most frequently following surgical resec-
tion. The primary cause of treatment failure is the in-
ability to achieve local control often due to surgical in-
accessibility. Strategies to improve medical therapy
include agents to disrupt the blood-brain barrier to in-
crease the penetration of chemotherapy, antiangi-
ogenesis agents, and gene therapy.
Each treatment modality has associated short- and
long-term side effects. Most neurosurgical deficits are
47,55-57
Treatment Regimen
Craniospinal XRT ± cisplatin/lomustine/vincristine
Triple peripheral blood stem cell transplant
XRT ± carboplatin/vincristine to delay XRT if <2 years
Total resection is best; XRT + lomustine + vincristine
54-55 Gy XRT ± radiosensitizer such as topotecan
Total resection is best therapy; cisplatin or cyclophosphamide
+ etoposide + vincristine + XRT
short-lived depending on the areas resected, but pa-
tients may experience permanent behavioral changes
or motor deficits. Radiation-induced injury is progres-
sive over time and correlates with the amount received,
location of tumor, and age at time of treatment. There is
an inverse relationship between age and the severity of
injury; thus, current treatment strategies include using
chemotherapy to delay radiation until the patient is
older if possible.47 Brain irradiation is associated with
hormonal deficits, cognitive deficits, hearing loss, and
secondary malignant neoplasms. Spinal irradiation is
associated with primary hypothyroidism, cardiac dam-
age, restrictive pulmonary disease, and impaired verte-
bral growth. Some patients may benefit from
methylphenidate 0.6 mg/kg/dose (maximum 20 mg) to
improve attention span.48 Less is known about long-
term sequelae of the chemotherapy, but reports include
hearing loss from platinum agents, pulmonary fibrosis
from lomustine, and motor deficits from vincristine.
Ewing’s Sarcoma
The Ewing family of tumors may arise from either
bone or soft tissue of extremities or the central axis
(45%).1 Ewing’s sarcoma (ES) is 9 times more common
in white than black children.1 Twenty percent to 25%
of patients have metastases at diagnosis, most com-
monly in the lung (50%), bone (25%), and bone mar-
row (25%).49 Clinical trials have improved 5-year sur-
vival for patients younger than 20 years of age with ES
from 42% in 1975 to 58% in 1994.1
Surgical excision of the primary tumor is desirable
when in a feasible location. Radiation therapy is
avoided in young children if possible due to its effects
on growth and a 10% to 20% incidence of secondary
malignant neoplasms.49 However, local radiation is
highly effective. Typical management consists of in-
duction chemotherapy followed by local control (sur-
gery and/or radiation) and then additional chemother-
JOURNAL OF PHARMACY PRACTICE 2002(15.1) • 47
 BETSY M. BICKERT
apy. Standard chemotherapy consists of alternating
cycles of VAdriaC (vincristine, doxorubicin, cyclo-
phosphamide) ± (dactinomycin and ifosfamide/
etoposide). Womer and colleagues50 found that dose in-
tensification could be achieved by compressing the in-
terval between cycles of induction chemotherapy us-
ing filgrastim from 21 days to an average of 16 days
during induction chemotherapy. This achieved a 73%
event-free survival at 30 months. Long-term survival
for patients with metastatic disease remains a dismal
19% to 30%.49 Late effects include cardiomyopathy
from doxorubicin ± chest irradiation, infertility, or de-
layed puberty secondary to cyclophosphamide/
ifosfamide, secondary malignant neoplasms, renal dys-
function from ifosfamide, and growth abnormalities or
functional defects at the primary site of disease.
Osteosarcoma
Peak incidence for osteosarcoma (OS) is 15 years of
age and corresponds to a time of rapid bone growth. OS
is more common in black than white children.1 Primary
sites are usually long bones, with 78% in the lower
limbs.1 Almost all patients have subclinical micro-
scopic metastases at diagnosis, and 20% to 25% have
detectable metastases (90% in the lung).49 Only 15% of
patients with surgical resection alone will not have a
recurrence.49 Clinical trials have improved 5-year sur-
vival for patients younger than 20 years of age with OS
from 20% in 1971 to 63% in 1994.1,51
Surgical excision of the primary tumor and meta-
static lesions is crucial in OS due to the relative resis-
tance to radiation. Amputation is often avoided in OS
in lieu of limb-salvage procedures with cadaveric bone
grafts, vascularized grafts, or prostheses following ef-
fective chemotherapy. Preoperative chemotherapy al-
lows an assessment of early response from surgical
specimens. Chemotherapy continues after surgery and
consists of alternating regimens containing combina-
tions of doxorubicin, high-dose methotrexate, ifos-
famide, and cisplatin. The use of high-dose
methotrexate remains controversial.51 New agents,
such as MTP-PE, are targeting micrometastases.51 Late
effects of therapy include cardiomyopathy from
doxorubicin, secondary malignant neoplasms from
ifosfamide or radiation, and hearing loss, renal dys-
function, and electrolyte wasting from cisplatin.
Rhabdomyosarcoma
Rhabdomyosarcoma (RMS) accounts for more than
50% of soft-tissue sarcomas in children.49 The 2 pri-
48 • JOURNAL OF PHARMACY PRACTICE 2002(15.1)
mary histological subtypes are embryonal (75%) and
alveolar (worse prognosis). Twenty-nine percent of em-
bryonal RMS occurs in the head and neck region, 11%
in the orbital, and 28% in the genital-urinary tract re-
gion.1 Thirty-nine percent of alveolar RMS occurs in
the extremities.1 Approximately 50% of patients have
readily resectable disease at diagnosis, and 15% have
metastatic disease.49 Clinical trials have improved 5-
year survival for patients younger than 20 years old
with RMS from 25% in the 1960s to 75% in 1990.49
Primary tumor excision for RMS is desirable either
before or after chemotherapy. Radiation therapy is
highly effective for local control and administered to
virtually all patients once the tumor burden is de-
creased. If surgical resection is not possible due to tu-
mor location, radiation may be administered prior to
chemotherapy. Chemotherapy is based on prognostic
factors such as tumor location, extent of disease, and
histology from the 4 International Rhabdomyosarcoma
Study Group trials from 1972 to 1998. Treatment lasts 8
to 12 months. Low-risk patients receive vincristine and
dactinomycin. Intermediate-risk patients receive VAC
(vincristine, dactinomycin, cyclophosphamide). High-
risk patients have a 20% chance of long-term survival
following VAC with possible new agents or high-dose
chemotherapy and hematopoietic stem cell transplan-
tation. Late effects include infertility or delayed pu-
berty secondary to cyclophosphamide, secondary ma-
lignant neoplasms from cyclophosphamide or
radiation, cataracts from radiation to the head, and
growth abnormalities or functional defects at the pri-
mary site of disease.
Wilms Tumor
Wilms tumor composes 95% of renal malignancies
in persons younger than 15 years of age.1 Approxi-
mately 500 cases are diagnosed annually in the United
States, with the highest incidence in children younger
than 5 years of age. Wilms tumor primarily occurs in
only one kidney. Seven percent of patients have in-
volvement of both kidneys, and 12% of patients have
disease outside of the kidney, primarily in the lung.1
Survival and treatment depend on the stage and histol-
ogy of the tumor. Clinical trials have improved 5-year
survival for patients younger than 20 years of age with
Wilms tumor from 74% in 1976 to 93% in 1996.33
A summary of the results of the 4 completed Na-
tional Wilms Tumor Study (NWTS) Group trials is pre-
sented in Table 4. These trials defined a successful regi-
men for low-stage disease and then refined the regimen
to maintain efficacy and decrease toxicity. Each trial
 TREATMENT OF COMMON CHILDHOOD MALIGNANCIES

Table 4
58-59
Results of the National Wilms Tumor Study Group Trials

Study Results

NWTS 1 XRT not necessary for Group I <2 years; VCR + DAC > VCR = DAC. Preoperative chemotherapy had no effect on
(1969-1973) overall survival.
NWTS 2 6 months = 15 months chemo in Stage I; no postoperative XRT needed for FH Stage I/II; VCR + DAC + DOX > VCR
(1974-1978) + DAC for Stage II/III/IV FH disease.
NWTS 3 10 weeks = 24 weeks VCR + DAC in Stage I FH; DOX had no benefit on Stage II FH survival; no XRT = 20 Gy in
(1979-1986) Stage II FH; 10.8 Gy XRT = 20 Gy XRT in Stage III FH; DOX ↑ survival for Stage III FH; CPM did not ↑ survival
for Stage IV FH; CPM + VCR + DAC + DOX > VCR + DAC + DOX in Stages II-IV UH.
NWTS 4 6 months = 15 months chemo in Stage II/III/IV FH; pulse-intensive chemotherapy is equivalent to divided doses.
(1986-1994)
CPM = cyclophosphamide; DAC = dactinomycin; DOX = doxorubicin; FH = favorable histology; NWTS = National Wilms Tumor Study; UH = unfavorable histology;
VCR = vincristine; XRT = radiation.

Table 5
59
National Wilms Tumor Study Group 5 Treatment Regimens

Stage of Disease Chemotherapy Duration Radiation

Stage I/II FH, Stage I Anaplastic DAC + VCR, pulse-intensive 18 weeks None
Stage III/IV FH, Stage II-IV focal anaplasia DAC + VCR + DOX, pulse-intensive 24 weeks Abdominal; IV = abdomen + lungs
Stage II-IV diffuse anaplasia DAC + VCR + DOX + CPM + ETOP 24 weeks Tumor bed
CPM = cyclophosphamide; DAC = dactinomycin; DOX = doxorubicin; ETOP = etoposide; FH = favorable histology; VCR = vincristine. Prognosis: FH > focal
anaplasia > diffuse anaplasia.

has also improved success for patients with high-risk CONCLUSION

disease by intensifying therapy. Pulse-intensive therapy
(maximum tolerated doses at more frequent intervals)
yielded equal efficacy, increased dose intensity, de-
creased hematologic toxicity, fewer clinic visits, fewer
days hospitalized than standard administration, and
consequently decreased cost.52 Following surgical re-
section, children currently receive the treatment regi-
mens utilized in NWTS 5 as presented in Table 5.
Overall, the therapy is quite effective with minimal
late effects of treatment. Mantle radiation and
doxorubicin are both associated with cardiomyopathy.
Twenty years after diagnosis, the cumulative incidence
of congestive heart failure for patients treated with
doxorubicin on NWTS 1 through 4 is 4.4%; however, it
is 17.4% among those treated with doxorubicin for
their first or subsequent relapse.53 Whole-lung radia-
tion may decrease total lung capacity. Vincristine and
dactinomycin cause hepatotoxicity in 3% of recipients
of the combination.54 The combination of neph-
rectomy, local irradiation, and chemotherapy may
cause decreased renal function and hypertension. Pa-
tients receiving megavoltage radiation therapy and
nephrectomy are at risk for spinal deformity. Ovarian
and testicular function are damaged by abdominal ra-
diation, and shielding should be used if possible. There
is a 1.6% cumulative risk of developing a secondary
malignant neoplasm within 15 years of diagnosis.54
Extensive progress has been made in the treatment
of pediatric oncology patients. Pharmacists have a key
role in ensuring patients receive the therapy outlined
in the protocol. Having a basic understanding of the
common treatment strategies can facilitate this process.
Pharmacists can also play an integral role in the sup-
portive care used to treat and prevent adverse effects.
Assisting the oncology team in making rational, cost-
effective choices and monitoring patients for adverse
effects over time can improve the care of these complex
patients.
Acknowledgments
I thank Dave Henry, MS, for his critical review of this
manuscript.
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