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Osteonecrosis as a Complication of Treating Acute Lymphoblastic Leukemia in Children: A

Report From the Children's Cancer Group
Clin Pediatr (Phila) 2002; 41; 63
DOI: 10.1177/000992280204100114

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 Literature Reviews:
Pediatric Hematology!Oncology
Section Editor: John B. Lampe, MD, Cleveland Clinic Foundation
Guest Editor: Michael G. Levien, MD, Cleveland Clinic Foundation
Osteonecrosis as a Complication of Treating Acute Lymphoblastic
Leukemia in Children: A Report From the Children's Cancer Group
Mattano L, Sather H, et al. J Clin Oncol. 2000;18:3262-32 72.
Summary: Osteonecrosis is a well-recognized compli-
cation of corticosteroid use. Morbidity is caused by
progressive joint damage, articular collapse, and
arthritis. Weight-bearing joints are commonly af-
fected, and total joint replacement is often necessary
to restore function. Corticosteroids are integral for
the optimal management of childhood acute lym-
phoblastic leukemia. The authors in conjunction
with pediatric oncologists from 111 pediatric oncol-
ogy centers undertook an extensive retrospective
study of a treatment protocol of high-risk leukemia
patients (CCG 1882). Between May 1989 and June
1995, a total of 1541 patients were registered on this
protocol; 1409 of these patients were included in this
analysis. Eligibility of patient participation in this
protocol included patients 1 to 9 years old with a
white blood cell (WBC) count greater than
50,000/cm3, and children older than 10 years irre-
spective of the WBC count. Patients with lymphoma-
tous features and Burkitts leukemia were excluded. A
detailed osteonecrosis data questionnaire was ob-
tained for each patient. This included symptoms,
joint involvement, diagnostic evaluations, modifica-
tions of acute lymphoblastic leukemia (ALL) ther-
apy, and orthopedic interventions. Additional infor-
mation was obtained from the Children's Cancer
Group data bank.
In the entire study population, 111 of 1409 pa-
tients had osteonecrosis, with a 3-year life-table esti-
mated incidence of 9.3%. There was only one occur-
rence of osteonecrosis (ON) 3 years after diagnosis of
ALL. ON also varied by sex and age at diagnosis of
ALL. There was a very low rate in the group less than
10 years old (4/516 patients) compared with the 10-
to 15-year-old group (85/736 patients) and the 16- to
22-year-old group (22/157 patients). ON occurred
significantly more often in females than males with a
3-year incidence of 12.2% and 7.7%, respectively. The
relative incidence in the white population was five
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times greater than that in the black population.The
diagnosis of ON resulted in the discontinuation of
further corticosteroid therapy in 60 patients and dose
modifications in six patients. Therapy was not altered
in 40 patients still on treatment. Three had com-
pleted treatment at diagnosis of ON. Thirty-five pa-
tients (32%) were diagnosed with ON during year 1
of therapy, 60 (54%) were diagnosed with ON in year
2, 15 (13%) in year 3, and 1 patient was diagnosed in
year 5. Based on the results of this investigation, cur-
rent Children's Oncology Group ALL protocols de-
crease by 40% the amount of dexamethasone admin-
istered to older children and adolescents receiving
repeated courses of corticosteroids.
Commentary: Osteonecrosis is a rare diagnosis in
children. Idiopathic osteonecrosis or avascular necro-
sis can occur in the immature, growing child. Legg-
Calve-Perthes disease or osteonecrosis of the capital
femoral epiphysis is a good example. Patients with
protein C and protein S deficiencies, thrombophilia,
and hypofibrinolysis are at increased risk for these
events. Patients with sickle cell disease (particularly
SC disease) and those with chronic, long-term corti-
costeroid use are at definite risk of developing os-
teonecrosis. Before the use of dexamethasone in the
high-risk ALL protocols, osteonecrosis was consid-
ered a rare complication of ALL therapy. According
to the Children's Cancer Group (CCG) data, of the
4000 children who received prednisone-based treat-
ment on the CCG ALL protocols in the 1980s, not a
single patient with osteonecrosis was reported.
This analysis represents the largest study of symp-
tomatic osteonecrosis in patients with ALL. Increas-
ing numbers of high-risk ALL patients have been re-
ceiving increased doses and courses of
dexamethasome. The use of dexamethsone over
prednisone has increased the long-term survival of
children with ALL. This may be due to the increased
CLINICAL PEDIATRICS
CLINICAL PEDIATRICS
6363
 Literature Reviews
sensitivity of lymphoblasts to dexamethasone and in-
creased penetration into the central nervous system
when compared to prednisone use. Other factors that
may contribute to the development of osteonecrosis
in this patient population include the use of other
agents such as methotrexate, which can cause os-
teoporosis, and the fact that about 2% of patients
with ALL will present with osteopenia and patho-
logic fractures, particularly of the vertebrae. The lat-
ter is probably related to bone-resorbing effects of
lymphoblasts.
Late Mortality Experience in Five-Year Survivors of Childhood and
Adolescent Cancer: The Childhood Cancer Survivor Study
Mertens A, Yasui Y. et al.J Clin Oncol. 2001;19:3163-3172
Summary: Approximately 12,400 cases of cancer in
children and adolescents less than 20 years of age
are diagnosed yearly in the United States. The in-
troduction of new therapeutic strategies (new
chemotherapy agents and regimens; improved sur-
gical and radiation therapy techniques) over the
past 30 years has dramatically improved the survival
rates of many diagnostic groups of cancer. The over-
all 5-year survival rate of children and adolescents
with cancer diagnosed before the age of 20 in 1998
was 80%. Despite this remarkable statistic, cancer re-
mains the leading medical cause of death in chil-
dren between 1 and 20 years.
The Childhood Cancer Survivor Study (CCSS)
was designed to study late effects of childhood cancer
survivors. This retrospective cohort study was initi-
ated in 1994 and included 5-year survivors who were
diagnosed with cancer before the age of 21 between
1970 and 1986. Underlying causes of death were ob-
tained from death certificates and other sources and
categorized as recurrent disease, sequelae of cancer
treatment, or non-cancer related. Age, sex, and stan-
dardized mortality rates (SMRs) were calculated us-
ing United States population mortality data. Among
the cohort of 20,227 5-year survivors, 2030 patients
(10.0%) died before Dec. 31,1996. Overall deaths oc-
curred in this population about 11 times more than
expected (SMR=10.8). Increased standard mortality
rates were seen in both males and females (SMR of
8.5 and 18, respectively). Overall, cumulative mortal-
ity was 6.4% at 10 years from diagnosis, 9.3% at 15
years, 11.4% at 20 years, and 14% at 25 years. All in-
dividuals remained at excessive risk of death through-
out this period.
64
64 PEDIATRICS
CLINICAL PEDIATR[CS
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The remarkable increased long-term survival rate
of children with ALL (>80%) is a tribute to the highly
organized treatment protocols of the Children's On-
cology Group. This intensive analysis is another ex-
ample of the dedication of the physician scientists in
this international study group. The goal and result of
this study were to increase physician awareness of the
diagnosis of this complication of antileukemic ther-
apy and to make treatment safer by modifying corti-
costeroid doses in specific patient populations with-
out compromising efficacy. -MGL
Patients with the original diagnosis of kidney can-
cer and neuroblastoma had the best overall survival
with a mortality rate of 5% at 20 years. Patients with
central nervous system tumors had the poorest over-
all survival with a mortality rate of 16.8% at 20 years.
Recurrent disease was the leading cause of death with
1,246 patient deaths (67.4%) attributed to the recur-
rence of the original childhood cancer. Death was at-
tributed to treatment-related consequences in 394
patients (21.3%), including 235 (12.7%) with sec-
ondary or subsequent cancer, 83 (4.5%) with cardiac
toxicity (anthracycline exposure, mediastinal radia-
tion), 33 (1.8%) with pulmonary complications
(chemotherapy and pulmonary radiation), and 13
(0.7%) with infections. The cumulative cause specific
mortality was greatest for recurrent disease, 7% at 25
years after diagnosis.
The goal of this study was to examine the patterns
of death in 5-year survivors to gain a better under-
standing of late relapse and late effects of therapy. By
studying mortality rates within specific therapeutic
modalities as well as in clinical and demographic sub-
groups, one gains insights into the therapeutic
modalities that are associated with greatest mortality,
identification of patients who require closer follow-
up, and development of strategies and interventions
to modify treatment to decrease mortality without
sacrificing survival.
Commentary: The dramatic increase in survival of pe-
diatric oncology patients over the past 30 years is one
of the major success stories in pediatrics. In this study,
90% of patients were alive at the time of analysis, 5 to
35 years after diagnosis. Although this is a remarkable
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