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Tumor Necrosis in Pediatric Osteosarcoma:
Impact of Modern Therapies
Eleanor Hendershot, MN, RN, ACNP
Alberto Pappo, MD
David Malkin, MD
Lillian Sung, MD
Tumor necrosis following preoperative chemotherapy in patients with osteosarcoma is a predictor of overall survival. With modern therapies, 45% of patients are
expected to achieve more than 90% tumor necrosis.
Investigators at the authors’ center, however, increasingly noted that patients were experiencing inferior
necrosis responses. A retrospective study of treated
patients at the center was undertaken to examine this.
The purpose of this study was to determine (1) whether
the number of patients with favorable histological
responses had changed over time and (2) whether the
percentage of patients with favorable responses was
similar to published outcomes. Chart reviews were performed on patients treated from 1993 to 2003 according
to the Pediatric Oncology Group 9351, regimen A protocol. Twenty-one patients met all eligibility requirements; 52% of patients had more than 90% necrosis. No
correlation existed between degree of necrosis and year
of treatment (r = 0.06; P = .8). Patients with osteosarcoma treated at the authors’ institution have comparable tumor necrosis responses to published outcomes,
and no change occurred over time. This study stresses
the importance of rigorous retrospective reviews before
implementing treatment changes.
Key words: osteosarcoma, tumor necrosis, prognostic
factors, chemotherapy, survival
© 2006 by Association of Pediatric Oncology Nurses
DOI: 10.1177/1043454206289786
176
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. It arises
from mesenchymal bone-forming cells and most commonly affects the metaphyseal growth plate of long
bones. It affects 5.6 per million children younger than
15 years annually, with a peak incidence occurring
in the second decade of life (Hartford et al., 2006).
Osteosarcoma occurs more often in African Americans
compared with whites and in males compared with
females (Link, Gebhardt, & Meyers, 2002).
The cause of osteosarcoma is unknown; however, several risk factors have been identified
including ionizing radiation and periods of rapid
bone growth. Prior diagnosis of retinoblastoma, bone
dysplasias, Li-Fraumeni syndrome, Paget’s disease,
Eleanor Hendershot, MN, RN, ACNP, works in the outpatient hematology/
oncology clinic at the Hospital for Sick Children in Toronto, Ontario,
Canada, as the nurse practitioner in the Solid Tumor Program. She is a lecturer in the Faculty of Nursing at the University of Toronto. Alberto Pappo,
MD, is a staff oncologist in the Division of Hematology/Oncology at the
Hospital for Sick Children. He is the head of the Solid Tumor Section and
a professor of pediatrics at the University of Toronto. David Malkin, MD,
is a staff oncologist and clinician-scientist in the Division of Hematology/
Oncology at the Hospital for Sick Children. He is a professor of pediatrics
and medical biophysics, University of Toronto. Lillian Sung, MD, PhD, is
a clinician-scientist in the Division of Hematology/Oncology at the
Hospital for Sick Children in Toronto, Ontario. She is an assistant professor in the Department of Pediatrics and the Department of Health
Policy Management and Evaluation at the University of Toronto. Address
for correspondence: Eleanor Hendershot, MN, RN, ACNP, Division of
Hematology/Oncology, Hospital for Sick Children, 555 University
Avenue, Toronto, Ontario, Canada M5G 1X8; e-mail: eleanor.hendershot@
sickkids.ca.
Journal of Pediatric Oncology Nursing, Vol 23, No 4 (July-August), 2006: pp 176-181
Tumor Necrosis in Pediatric Osteosarcoma
and Rothmund-Thompson syndrome have also been
associated with an increased risk for developing
osteosarcoma (Link et al., 2002).
Osteosarcoma most commonly occurs in the distal
femur, proximal tibia, and proximal humerus and most
often metastasizes to lung and bone. Gross metastatic
disease is evident at diagnosis in less than 20% of
patients (Kager et al., 2003). However, micrometastatic
disease is likely almost always present at the time of
diagnosis. Patients with osteosarcoma often present
with signs and symptoms that may have been present
for weeks to months. The most common presenting
symptom is a visible or palpable mass in the affected
area. Pain is usually a presenting complaint that is often
aggravated by physical activity. A history of trauma is
not uncommon, although its clinical relevance is
unclear. Constitutional symptoms such as fever, weight
loss, or night sweats are rare.
Radiographs of the affected area will confirm the
presence of a destructive bony lesion that can be lytic,
sclerotic, or mixed. The presence of a Codman’s triangle is characteristic on plain films and represents a
periosteal reaction (Ragland, Bell, Lopez, & Siegal,
2002). A “sunburst” pattern is also occasionally seen
on plain radiographs and represents ossification in the
soft tissues (Marina, Gebhardt, Teot, & Gorlick, 2004)
(Figure 1). Once a tumor is identified, magnetic resonance imaging of the entire affected bone and adjacent
soft tissues area should be performed to evaluate the
extent of tumor, vascular supply, its proximity to joints
and the neurovascular bundle, and “skip” lesions representing proximal or distal regional metastatic bony
disease (Figure 2). The metastatic workup involves
imaging of the chest with computed tomography scan
to identify any pulmonary nodules. A whole-body bone
scan is performed to determine if there are bone metastases. There are no specific blood tests diagnostic of
osteosarcoma; however, lactic acid dehydrogenase and
alkaline phosphatase levels are elevated in 30% and
50% of patients, respectively (Link et al., 2002). These
enzymes reflect osteoclast and osteoblast activity
within the bone and may suggest a high tumor burden.
A biopsy is performed to confirm the diagnosis of
osteosarcoma. Osteosarcoma cells are spindle shaped
and are characterized by the production of malignant
osteoid (Jurgens, Winkler, & Gobel, 1997). There are
various histological subtypes of osteosarcoma, the
most common of which is osteoblastic, which is seen
in 78% of patients (Pinkerton, 1999). Other histologies
Journal of Pediatric Oncology Nursing 23(4); 2006
Figure 1. Plain Radiograph: Osteosarcoma of Tibia With
Visible Sunburst Periosteal Reaction
Figure 2. Magnetic Resonance Imaging Showing Osteosarcoma of the Proximal Tibia
include chondroblastic and fibroblastic and then, with
decreasing frequency, malignant fibrous histiocytomalike, giant cell-rich, telangiectatic, low-grade intraosseous, small cell, and juxtacortical.
Tumor staging evaluated using the Enneking staging system is based on the presence of intracompartmental and extracompartmental extension of the tumor
as well as tumor grade and the presence of metastases.
177
Hendershot et al.
Tumors are divided into low and high grade depending
on the aggressive nature of the tumor and its potential
to metastasize (Davis, Bell, & Goodwin, 1994).
Osteosarcoma is treated with combined modality
therapy that includes surgery and chemotherapy. Both
are vital for long-term survival. Osteosarcoma originally
treated with surgery alone yielded survival rates of only
15% to 20%, providing compelling evidence that even
in the absence of overt metastases at diagnosis, micrometastases are likely present and cause disease recurrence (Marina et al., 2004). Local control must always
be in the form of surgical resection because osteosarcoma is not generally a radiosensitive tumor.
The use of adjuvant chemotherapy over the past 20
years has dramatically improved the outcome of these
patients. The concept of preoperative chemotherapy was
pioneered at Memorial-Sloan Kettering Cancer Center
(Rosen et al., 1979). The goals of preoperative chemotherapy are 3-fold: the immediate treatment of micrometastatic disease, limb preservation, and assessment of
response to chemotherapy. The most commonly used
chemotherapeutic agents include doxorubicin, cisplatin,
and high-dose methotrexate (Zalupski et al., 2004).
Some investigators have also advocated the use of
etoposide and ifosfamide, especially in the presence of
metastatic disease. Several cycles of chemotherapy are
given, followed by surgical resection of the tumor. This
is then followed by maintenance chemotherapy using
the same agents.
The 3-year disease-free survival in localized osteosarcoma is in the range of 60% to 70% (Bacci et al.,
2002). Those who respond well to preoperative
chemotherapy, as evidenced by a high degree of tumor
necrosis, have 5-year overall survival (OS) rates of
75% to 80%; those who respond poorly to preoperative chemotherapy have 5-year OS rates of 45% to
55% (Bielack et al., 2002). Those who present with
metastatic disease have long-term OS rates in the
range of 10% to 40% (Goorin et al., 2002).
Background
Histological response to preoperative chemotherapy is strongly associated with survival in pediatric
osteosarcoma. At the time of local control, this response
is estimated by measuring the percentage of tumor
necrosis in the resected specimen. The percentage of
tumor necrosis correlates with chemosensitivity and
178
clinical outcome (Eilber et al., 2001). The point at which
degree of necrosis is determined to be significant has
been somewhat controversial. Most groups now define a
“good” histological response as having less than 10%
viable tumor at the time of surgery. A “poor” response is
defined as the presence of more than 10% viable tumor
cells (Link et al., 2002; Marina et al., 2004).
Results of the Pediatric Oncology Group (POG) protocol for localized osteosarcoma, termed POG 9351, or
Children’s Cancer Group (CCG) 7921, found that 45%
of patients had favorable responses (>90% necrosis) following preoperative chemotherapy (Meyers et al.,
2005). At our center, however, some clinicians questioned the tumor necrosis results in our patients. The
POG 9351/CCG 7921 regimen A protocol is currently
the protocol used at our center as the standard of care for
patients with localized high-grade osteosarcoma in the
absence of an open clinical trial. The primary objective
of this study was to determine whether there had been an
overall change in tumor necrosis over the past 10 years
in patients treated for localized osteosarcoma of the
extremity on the POG 9351/CCG 7921 protocol.
Secondary objectives were (1) to qualitatively describe
the proportion of patients with a good response to preoperative chemotherapy (>90% necrosis) to examine
whether our institutional outcomes were similar to those
reported in the literature and (2) to evaluate the relationship between tumor necrosis with clinical outcome.
Patients and Methods
A retrospective chart review was performed, after
having obtained institutional research ethics board
approval. Patients with localized osteosarcoma of the
extremity were identified from 1993, the year in which
the POG 9351/CCG 7921 protocol was opened,
through 2003, the year this study closed. A list of
patients was generated through the hospital’s database
of oncology diagnoses. All patients with localized,
high-grade osteosarcoma of the extremity were identified, and those treated on or as per the POG 9351/CCG
7921 regimen A were included in the study. Preoperative chemotherapy included 2 full cycles of chemotherapy. Each cycle included 1 course of cisplatin and
doxorubicin and 2 courses of high-dose methotrexate
(Table 1). Patients with secondary osteosarcomas were
excluded from the study because of their prior exposure to chemotherapy agents.
Journal of Pediatric Oncology Nursing 23(4); 2006
Tumor Necrosis in Pediatric Osteosarcoma
12
Drug
10
Dose
Day
Cisplatin
Doxorubicin
120 mg/m2
25 mg/m2
Methotrexate
Methotrexate
12 g/m2
12 g/m2
1
1-3 (72-hour
continuous infusion)
21
28
Information regarding age, date of diagnosis, date
of surgery, tumor location, and type of surgery was
collected.
Number of Patients
Table 1. Chemotherapy Agents and Doses Used Before
Local Control (2 Cycles)
8
6
4
2
0
>90%
70-79%
50-59%
30-39%
10-19%
Degree of Tumor Necrosis (%)
Statistical Analysis
Figure 3. Patients With Various Degrees of Histological
Response Following Preoperative Chemotherapy
For the primary objective, we examined whether there
was an association between percentage tumor necrosis
and year of diagnosis using Spearman’s correlation coefficient. To examine whether the percentage of tumor
necrosis was associated with patient outcomes including
OS, the Cox proportional hazards model was used.
Results
From January 1993 to November 2003, 24 patients
were treated according to the POG 9351/CCG/7921
regimen A protocol at our institution. Two had secondary osteosarcomas and 1 had a complete resection
before receiving chemotherapy and were excluded,
leaving 21 patients who were included in our study.
The median age at diagnosis was 13.1 years (range,
6.6-17.4 years). The median degree of tumor necrosis
was 90% (range, 10%-99%). The 3-year OS was 71%
± 11%. Fifty-two percent (11) of children showed a
good histological response, defined as more than 90%
necrosis (Figure 3). There was no relationship between
necrosis and year of surgery (r = –0.06, P = .8) (Figure
4). There was no relationship between percentage
necrosis and OS (hazard ratio 0.98, P = .2). There was
almost no power to look at this though because there
were only 5 deaths out of the 21 patients.
Discussion
We found that despite our clinical suspicion, there was
no change in the percentage necrosis over the 10-year
Journal of Pediatric Oncology Nursing 23(4); 2006
Figure 4. No Correlation Between Percentage Necrosis and
Year of Treatment
period of our study, and the proportion of patients at
our institution with a good response to preoperative
chemotherapy was similar to that reported in the
literature.
One limitation of our study is that we only included
those patients receiving 1 particular chemotherapy regimen. Nonetheless, because it was patients following
this regimen who contributed to the recent observations of inferior necrosis rates who prompted this
review, examination of just those patients following
the POG 9351/CCG 7921 regimen A protocol was
justifiable.
179
Hendershot et al.
The results of this review were reassuring in that
they reinforced for us that tumor necrosis responses
to preoperative chemotherapy at our institution are
similar to rates reported by Meyers and colleagues
(2005) for the entire study group. Our initial concern
was raised because we had 3 consecutive patients in
8 months who experienced inferior necrosis rates in
2003, prompting this review (Figure 4).
The phenomenon of regression to the mean is a
possible explanation for our recent results with poor
tumor necrosis at our institution. This statistical phenomenon can make normal variations in repetitive
data look like an actual change or trend (Barnett, van
der Pols, & Dobson, 2005). When extreme observations are observed, on average, the next observation
will be closer to the mean value. Regression to the
mean can make effects attributable to chance look
like real change (Morton & Torgerson, 2003). This
type of situation can have serious implications in
health care. If action is taken based on 1 abnormal
result and a treatment is prescribed, then the intervention may look as though it was successful because
the successive measurement is closer to the mean.
Regression to the mean, however, would predict that
the repeated measurements without the intervention
would likely have been closer to the mean regardless.
We had hypothesized that delays in chemotherapy
administration, medication administration methods,
medication timing, and drug resistance as well as
changing tumor biology could potentially account for
changes in response to preoperative chemotherapy in
patients with osteosarcoma at our institution. However,
the results that we obtained were important to alleviate
concerns that institutional practices were contributing
to our patients having perceived worse outcomes than
those reported in the literature.
Conclusions
There was no change in histological response to
preoperative chemotherapy in patients with highgrade osteosarcoma of the extremity over the past 10
years treated at our institution on the POG 9351/CCG
7921 regimen A protocol. Our results were congruent
with those reported in the literature. These results and
this study do, however, highlight 2 very important
points. The first is the importance of recognizing limitations and dangers of basing medical decisions and
practice on anecdotal evidence and case reports. The
180
second point stresses the value of rigorous analyses
using retrospective reviews. Natural variation in data
may appear significant when in fact successive measurements will likely show that they are closer to the
mean. These findings highlight the importance of performing rigorous data analyses using retrospective
reviews before implementing treatment changes.
Acknowledgments
We thank Carol Winter, RN, data manager at the
Hospital for Sick Children, for her assistance in obtaining a list of patients from the hematology/oncology
database.
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