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Primary Metastatic Osteosarcoma: Presentation and Outcome
of Patients Treated on Neoadjuvant Cooperative Osteosarcoma
Study Group Protocols
By Leo Kager, Andreas Zoubek, Ulrike Po
¨ tschger, Ulrike Kastner, Silke Flege, Beate Kempf-Bielack, Detlev Branscheid, Rainer Kotz,
Mechthild Salzer-Kuntschik, Winfried Winkelmann, Gernot Jundt, Hartmut Kabisch, Peter Reichardt, Heribert Ju¨rgens,
Helmut Gadner, and Stefan S. Bielack, for the Cooperative German-Austrian-Swiss Osteosarcoma Study Group
29% (SE ⴝ 3%) and 24% (SE ⴝ 4%), respectively. In univariate analysis, survival was significantly correlated with
patient age, site of the primary tumor, number and location
of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox
regression analysis, only multiple metastases at diagnosis
(relative hazard rate [RHR] ⴝ 2.3) and macroscopically
incomplete surgical resection (RHR ⴝ 2.4) remained significantly associated with inferior outcomes.
Conclusion: The number of metastases at diagnosis and
the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in
patients with proven primary metastatic osteosarcoma.
J Clin Oncol 21:2011-2018. © 2003 by American
Society of Clinical Oncology.
LINICALLY DETECTABLE metastatic disease at initial
diagnosis occurs in less than 20% of patients with high-grade
osteosarcoma (OS) and predicts a poor outcome, with long-term
survival rates between 10% and 40%.1-8 However, patients with
primary metastatic osteosarcoma (MOS) are a heterogeneous group;
a 5-year event-free survival rate of up to 75% is reported for patients
presenting with unilateral lung metastases,5 whereas multifocal
bone spread of OS seems to herald a catastrophic outcome.9 In
addition, skip lesions are described as a poor prognostic factor.10
Therefore, increased emphasis must be placed on more precise risk
assessment, not only for counseling of patients but also for definition of treatment regimes based on reliable stratification criteria. To
date, neither prognostic factors nor optimal management are well
established in patients with MOS, and the series published encompasses numbers of patients between three and 73, respectively.1-17
During the last two decades, most patients with OS from
Germany, Switzerland, and Austria were enrolled onto the
consecutive studies of the Cooperative Osteosarcoma Study
Group (COSS). These patients were treated according to a
uniform concept of preoperative and postoperative chemotherapy in combination with aggressive surgery, and the results of
prognostic factor analyses from 1,702 patients registered between 1980 and June 1998 have been published recently.18
We report on 202 patients with proven MOS at initial
presentation from the COSS database, evaluating statistically
relevant prognostic factors.
PATIENTS AND METHODS
C
Recruitment
From the start of the first neoadjuvant COSS study (COSS-80) at the end
of 1979 until December 1998, 1,765 patients with a first diagnosis of a
histologically proven high-grade OS of the extremities or trunk (excluding
craniofacial sites) were enrolled onto the consecutive neoadjuvant COSS
studies. Details of the recruitment and the protocols have been reviewed
recently.18,19 All studies were accepted by the local ethics committee or the
protocol review committees of the German Ministry for Science and
Technology or the German Cancer Society, respectively. Informed consent
was obtained from all patients or their legal guardians, depending on the
patient’s age.
From the St Anna Children’s Hospital and Departments of Orthopaedics
and Pathology, University Hospital of Vienna, Vienna, Austria; Centre for
Pneumonology and Thoracic Surgery, Grosshansdorf; Department of Pediatrics, University Hospital of Hamburg, Hamburg; Charite, Campus BerlinBuch, Robert Roessle Klinik, Berlin; Department of Orthopaedics, University Hospital of Muenster, and Department of Pediatric Hematology and
Oncology, University Children’s Hospital Muenster, Germany; and Institute
for Pathology, Kantonsspital Basel, Basel, Switzerland.
Submitted August 20, 2002; accepted March 7, 2003.
Address reprint requests to Leo Kager, MD, Cooperative GermanAustrian-Swiss Osteosarcoma Study Center, Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, AlbertSchweitzer Str 33, 48129 Muenster, Germany; email: coss@uni-muenster.de.
© 2003 by American Society of Clinical Oncology.
0732-183X/03/2110-2011/$20.00
Journal of Clinical Oncology, Vol 21, No 10 (May 15), 2003: pp 2011-2018
DOI: 10.1200/JCO.2003.08.132
2011
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Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
Purpose: To determine demographic data and define
prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation.
Patients and Methods: Of 1,765 patients with newly
diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative
Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and
therefore were enrolled onto an analysis of demographic-,
tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and
postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions.
Results: With a median follow-up of 1.9 years (5.5 years
for survivors), 60 patients were alive, 37 of whom were in
continuously complete surgical remission. Actuarial overall
survival rates at 5 and 10 (same value for 15) years were
2012
whichever occurred first. Patients who never achieved a complete surgical
remission were assumed to have suffered an event on day 1. The log-rank test
was used to compare survival curves.27 A method developed by Simon and
Makuch28 was used to compare overall survival distributions according to
the quality of surgery (complete v incomplete); this method accounts for
patients transferring from one group to another. The multivariate analysis of
overall survival was carried out using the Cox proportional hazards regression model.29 Complete surgical remission was included as a time-dependent
covariate in the Cox model. Only variables with a significant prognostic
value in univariate analysis were included in the multivariate models of
survival. Because of the lack of data, histologic response was not included in
the Cox model. SAS (version 8.01; SAS Institute, Inc, Cary, NC) was used
for statistical analysis.
RESULTS
Diagnostic Staging
Procedures used to define the extension of primary tumor and metastases
included conventional radiography in all studies, whereas other methods
(computed tomography, magnetic resonance imaging) varied with time and,
hence, availability. The minimum work-up for primary metastases included
a chest x-ray in several planes and a technetium-99 methylene diphosphonate
bone scan. As of 1991, computed tomography of the chest was also
mandatory. During follow-up, radiograms of the chest and the primary tumor
were to be repeated at regular intervals specified in the respective treatment
protocols. Tumor size could only be evaluated for extremity tumors, because
prospective measurements had only been collected for this subgroup of
patients. Tumors measuring at least one third of the length of the involved
bone or more were defined as being large, and all others as small.
Treatment
Chemotherapy was given to all 202 patients according to the COSS
protocols active at the time of enrollment. Details of these protocols,
including chemotherapy administration and modification, have been reviewed previously.19,22-24 Surgery of the primary tumor was scheduled to
take place between weeks 9 and 18 in study COSS-80 and between weeks 9
and 11 in all other protocols.18 The objective of surgery was complete
resection of the primary tumor with wide margins and resection of all
metastases, whenever feasible. In patients in whom complete surgery of all
tumor sites was deemed feasible on the basis of results of diagnostic imaging,
the sequence of surgery varied, but resection of the primary tumor mostly
preceded resection of metastases. Nonscheduled treatment modalities, generally chosen at the discretion of the participating institutions, were used in
inoperable OS, including conventional radiotherapy, targeted internal radiotherapy with samarium-153 ethylene diamine tetramethylene phosphonate
(EDTMP), locoregional hyperthermia, and in palliative situations, administration of alternative chemotherapeutic agents such as melphalan, mitoxantrone, or epirubicin.
Statistical Methods
All 202 eligible patients were evaluated on an intent-to-treat basis. We
examined the following factors for prognostic significance: age, sex, site and
size of primary tumor, site and extent of metastatic disease at diagnosis,
status and time point of surgical remission (complete surgical remission was
assumed only when all detectable tumor foci were removed macroscopically
completely during first-line therapy), and response to preoperative chemotherapy according to the six-grade scale of Salzer-Kuntschik et al.25 A good
response was defined as less than 10% viable tumor (grade 1 to 3 according
to the scale of Salzer-Kuntschik et al). The extent of primary metastatic
disease was determined in all patients according to the number of metastases
and involved organ systems. According to their localization, metastases were
integrated into one of three groups: lung, bone, and other organs (outside
lung and bone; eg, lymph node or CNS), and patients with isolated and
combined organ system involvement were compared.
Survival was calculated using the Kaplan-Meier method together with
SEs.26 Overall survival was calculated from the date of diagnostic biopsy
until death from any cause and event-free survival until relapse or death,
Patient Characteristics
All 202 patients had high-grade central OS, and the diagnosis
of metastases was confirmed by surgery in 145 patients (71.8%)
and radiographically by progression of disease in 57 patients
(28.2%). There was a slight predominance of males without any
correlation between sex and survival (Table 1). The median age
at diagnosis was 15 years (range, 2 to 66 years). Twenty-eight
cases of MOS (13.9%) were detected in the first decade of life,
129 cases (63.8%) were detected in the second decade, 29 cases
(14.3%) were detected in the third, eight cases (4%) were
detected in the fourth decade, and only eight (4%) were detected
later. We divided the patients arbitrarily into three groups:
younger than 20 years, 20 to 39 years of age, and 40 years of age
or older. Survival was correlated with age in univariate analysis
and was significantly better for patients younger than 20 years of
age (Table 1). In five of the 202 patients, the OS arose as a
second malignancy. The inclusion of such patients into our
analysis might be controversial. We therefore additionally analyzed all data excluding these five patients. The results were not
affected by inclusion or exclusion of these patients.
Overall and Event-Free Survival
Median follow-up was 1.9 years (range, 22 days to 19 years)
for all 202 patients and 5.5 years (same range) for 60 survivors,
of whom 37 were in continuous complete surgical remission.
Actuarial survival rates at 5 and 10 (same value for 15) years
were 29% (SE ⫽ 3%) and 24% (SE ⫽ 4%), respectively (Fig 1).
Of 142 patients who died, 138 (97%) died from OS at a
median of 1.4 years (range, 55 days to 7.4 years) after diagnosis.
Two (3%) of the remaining four died in complete surgical
remission, one at 9.7 years as a result of a secondary malignancy
(hepatocellular carcinoma arising after chronic hepatitis C) and
one at 1.4 years as a result of a thromboembolic complication.
The other two died with active disease, one from suicide and one
from acute side effects of chemotherapy (septic death in aplasia).
Event-free survival rates at 5 and 10 (same value for 15) years
were 18% (SE ⫽ 3%) and 16% (SE ⫽ 3%), respectively (Fig 1).
Events as defined occurred in 165 patients (81.7%); 97 failed to
achieve a complete surgical remission, two died in first complete
remission, and 66 developed a relapse at a median of 1.2 years
after initial diagnosis. Fifty-one patients with relapse died at a
median of 10 months (range, 6 days to 3.8 years) after diagnosis
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From the 1,765 patients (1,759 patients with high-grade central OS and six
patients with high-grade surface OS), 272 patients (15.4%) were reported to
have presented with clinically detectable metastatic disease. This analysis
was restricted to those patients in whom the presence of primary metastases
was unequivocally confirmed either by surgery or by progression; that is, to
202 (11.4%) of the 1,765 patients. The other 70 patients were not considered:
In 20 patients, the radiologic evidence of primary metastases could be
excluded by surgery; in the remaining 50 patients, the evidence for primary
spread was limited to diagnostic imaging, but unequivocal surgical or clinical
proof for the assumed metastases was lacking. Skip lesions (defined as a
second, smaller focus of OS occurring in the same bone or a second lesion
of OS on the opposing side of a joint)20,21 were considered as metastases and
consequently were included in our analysis.
KAGER ET AL
2013
PRIMARY METASTATIC OSTEOSARCOMA
Table 1.
Univariate Analysis of Overall and Event-Free Survival
No. of Patients
107
95
31 ⫾ 5
28 ⫾ 5
157
37
8
33 ⫾ 5
19 ⫾ 7
13 ⫾ 12
181
21
5-Year EFS ⫾ SE (%)
P
P
.667
16 ⫾ 4
21 ⫾ 4
.793
.005
21 ⫾ 3
8⫾4
0
.012
54 ⫾ 4
14 ⫾ 8
⬍ .001
20 ⫾ 3
5⫾5
⬍ .001
86
87
35 ⫾ 5
28 ⫾ 5
.192
24 ⫾ 5
16 ⫾ 4
.148
160
42
32 ⫾ 4
19 ⫾ 6
.007
21 ⫾ 3
10 ⫾ 5
.006
124
9
15
21
33
33 ⫾ 4
56 ⫾ 17
53 ⫾ 13
13 ⫾ 8
8⫾5
46
70
24
41
57
57 ⫾ 7
20 ⫾ 5
75 ⫾ 9
26 ⫾ 7
23 ⫾ 6
38
69
91
67 ⫾ 8
24 ⫾ 5
19 ⫾ 4
19 ⫾ 4
33 ⫾ 16
47 ⫾ 13
10 ⫾ 6
0
⬍ .001
⬍ .001
45 ⫾ 7
4⫾2
58 ⫾ 10
23 ⫾ 7
3⫾3
⬍ .001
55 ⫾ 8
19 ⫾ 5
2⫾2
⬍ .001
⬍ .001
⬍ .001
⬍ .001
⬍ .001
Abbreviations: OS, overall survival; EFS, event-free survival.
*Seventeen patients with isolated distant bone involvement and four patients with isolated lymph node involvement.
†All combinations except lung combined with skip.
‡Isolated lungs (n ⫽ 124): in eight patients, the localization within the lungs was unknown.
of relapse; the remaining 15 patients were alive at a median of
3.9 years (range, 3 months to 15 years) after diagnosis of relapse.
Primary Tumor Site and Size
A total of 181 (89.6%) primary tumors were located in an
extremity, whereas 21 (10.4%) occurred in the axial skeleton
(Table 2). In univariate analysis, the location of the primary
tumor was significantly correlated with survival (Table 1; Fig 2).
From the 21 patients with axial tumor site, only one achieved a
complete surgical remission and was alive 4.6 years after
diagnosis. Another patient with unresectable disease received
multimodal therapy, including targeted internal radiotherapy
with samarium-153 EDTMP, and was alive 3.7 years after
Table 2.
Fig 1. Overall and event-free survival curves for all 202 patients from the time
of osteosarcoma diagnosis.
Site of Primary Tumors
Localization
No. of Patients
Extremity
Femur
Tibia
Humerus
Fibula
Foot
Radius
Ulna
Axial
Pelvis
Thorax or spine
Scapula
181 (89.6%)
107
34
25
11
2
1
1
21 (10.4%)
17
3
1
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Sex
Male
Female
Age
⬍ 20 years
20 to ⬍ 40 years
ⱖ 40 years
Site of primary tumor
Extremities
Trunk
Size of primary tumor, extremities
Small, ⬍ one third
Large, ⬎ one third
No. of meta-organ systems
One organ system
Multiple organ systems
Site of metastases
Isolated lung
Lung combined with skip
Isolated skip
Isolated, other ⫹ distant bone*
Combined metastases†
Isolated lungs‡
Unilateral
Bilateral
Solitary
2-5
⬎5
No. of metastases
1
2-5
⬎5
5-Year OS ⫾ SE (%)
2014
KAGER ET AL
diagnosis; all others died at a median of 1.3 years (range, 102
days to 3 years) after diagnosis.
Information on tumor size was available for 173 primary
tumors, of which 86 were considered to be small because they
measured less than one third of the involved bone. The size of
the primary tumor was not significantly correlated with
survival (Table 1).
Site of Metastases
The sites of primary metastatic involvement in the 202 eligible
patients are depicted in Fig 3. The most frequent metastatic site
was the lung (164 patients; 81.2%). Survival at 5 years was 33%
(SE ⫽ 4%) in 124 patients with metastases confined to the lung
and 20% (SE ⫽ 7%) in 40 patients with lung metastases
combined with other sites (P ⫽ .0129). In the former group,
those who presented with unilateral lung involvement had a
significantly better 5-year survival than those with bilateral
involvement (Table 1; Fig 2). Of the 40 patients with combined
lung metastases, the distribution of pulmonary nodules was
known in 39 patients. Thirty-two patients presented with bilateral deposits (5-year survival rate, 16%; SE ⫽ 7%), and seven
patients presented with unilateral deposits (5-year survival rate,
42%; SE ⫽ 19%).
Metastases to the bones were detected in 69 patients (34.2%).
Of these, 24 (11.9%) had skip lesions (15 isolated, nine combined with lung), and 45 (22.3%) had metastases to distant bones
(17 isolated, 28 combined with either lung or other sites).
Prognosis did not differ between isolated (5-year survival rate,
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Fig 2. Kaplan-Meier curves of overall survival for variables with prognostic significance in univariate analysis. A, site of primary tumor; B, site of metastases; C,
number of lung metastases; D, distribution of lung metastases; E, number of metastases; F, histologic response. Years from diagnosis, except otherwise indicated. See
text for details.
2015
PRIMARY METASTATIC OSTEOSARCOMA
Metastatic sites in 202 patients with primary metastatic osteosarcoma.
53%; SE ⫽ 13%) or combined skip lesions (5-year survival rate,
56%; SE ⫽ 17%). The 17 patients with isolated distant bone
metastases had the same poor survival rate (5-year survival rate,
13%; SE ⫽ 8%) as the 28 patients who presented with combined
distant bone involvement (5-year survival rate, 10%; SE ⫽ 6%;
P ⫽ .771). Of 45 patients with distant bone lesions, seven (15%)
were alive at a median of 3.3 years (range, 59 days to 12 years);
all others died at a median of 1.1 years (range, 55 days to 3.7
years) after diagnosis. Only four of 45 patients survived longer
than 3 years.
The 18 patients (8.9%) presenting with metastases to other
sites had a poor prognosis, with a survival rate of 8% (SE ⫽ 7%)
at 5 years. Four patients (2%) had isolated lymph node involvement (one is alive at 6.7 years after diagnosis; three died of
disease); the remaining 14 (6.9%) had combined metastases with
either two (seven patients) or more (seven patients) organ systems
involved. All patients with metastases to parenchymal organs (three
CNS, one liver, and one adrenal gland) and soft tissues (two muscle,
one skin) presented with widespread disease and died a median of
1.2 years (range, 1 to 1.5 years) after diagnosis. From the 11 patients
with combined lymph node involvement, only one was alive with
disease at 4.1 years; all others died after a median of 1.1 years
(range, 110 days to 1.6 years).
In univariate analysis, patients with deposits in one organ
system had a better outcome than those with more systems
involved (Table 1).
Number of Metastases
The number of metastases was available for 198 of 202
patients and was significantly correlated with survival (Table 1;
Fig 2). In 38 patients with solitary metastases, 24 occurred in the
lung, three occurred in lymph nodes, two occurred in distant
bones, and nine presented as skip lesions. Sixty-nine patients had
two to five metastases (41 lung, four skip, 11 distant bone, one
lymph node, and 12 combined sites), whereas 91 had more than
five metastases (57 lung, four distant bone, 30 combined sites).
OS Treatment
Chemotherapy was given to all 202 patients and was initiated
a median of 7 days after diagnostic biopsy (range, 0 to 209 days).
In 30 patients (14.9%), no surgical treatment was performed.
Attempts to remove the primary tumors and metastases were
performed in 162 (80.2%) and 145 (71.8%) patients, respectively. Information about the sequence of chemotherapy and
surgery was available for 161 of 162 patients who underwent
surgery for their primary tumors. Eight patients (4%) had
complete resection of the primary tumor before chemotherapy,
and 153 (75.7%) underwent resection of the primary tumor a
median of 85 days (range, 12 to 536 days) after start of
chemotherapy. For different reasons (eg, unresectable primary or
metastatic tumors), the primaries were not operated on in 40
patients (19.8%).
One hundred forty-five patients (71.8%) underwent resection
of metastases. Of these, 16 (7.9%) had concomitant surgery with
the primary tumor, 11 (5.5%) had resection of the metastases
before, and 92 (45.5%) had resection of metastases after surgery
of the primary tumor (median, 110 days; range, 8 to 788 days).
For the remaining 26 patients (12.9%), the time points of surgery
were not available. In 57 patients (28.2%), no attempt to remove
the metastases had been performed because they had either
residual or unresectable tumor at the primary or metastatic site,
they had progressive disease during preoperative chemotherapy,
or they refused surgery.
Fourteen patients (6.9%) received radiotherapy (10 patients
for tumor control of unresectable primaries, and four for pain
control in metastatic sites). Of these, two are alive 3.7 and 4.7
years after diagnosis, and all others died a median of 1 year
(range, 0.5 to 1.5 years) after diagnosis.
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Fig 3.
The number of pulmonary metastases was available for 122 of
124 patients with isolated lung involvement. The highest number
of pulmonary nodules surgically removed was 250. In univariate
analysis, the number of metastases was significantly correlated
with survival (Table 1; Fig 2). Of 57 patients with more than five
metastases confined to the lung, 10 (17.5%) were alive at a
median 6.4 years (range, 2.7 to 15.5 years) after diagnosis. In one
patient, 20 nodules had been removed successfully.
In contrast to other metastatic sites, skip lesions were seen
more often solitarily (solitarily, n ⫽ 9; multiple, n ⫽ 13;
unknown, n ⫽ 2). However, there was no difference in outcome
between solitary (5-year overall survival rate, 56%; SE ⫽ 17%)
and nonsolitary (5-year overall survival rate, 54%; SE ⫽ 13%;
P ⫽ .955) skip lesions.
From the 17 patients with metastases confined to distant
bones, two had solitary lesions and were alive at 73 days and
12.1 years, whereas only one with multiple bone metastases was
alive at 3.7 years. All others died a median of 1.2 years (range,
157 days to 3.7 years) after diagnosis.
Forty-two patients presented with combined metastases (10
patients with two to five metastases, and 32 with ⬎ five) and had
a 5-year survival rate of 19% (SE ⫽ 6%).
2016
KAGER ET AL
Table 3.
Multivariate Cox Regression Model on Prognostic Factors
Variable
RHR
95% CI
P
Age, ⬎ 20 v ⬍ 20 years
Trunk v extremities
Multiple organ system v one
Other v lung/skip
Multiple v solitary
Incomplete surgical remission
1.0
1.5
0.9
1.5
2.3
2.4
0.66 to 1.6
0.87 to 2.7
0.53 to 1.4
0.93 to 2.4
1.2 to 4.3
1.4 to 4.3
.840
.136
.581
.096
.012
.003
Abbreviations: RHR, relative hazard rate; CI, confidence interval.
Fig 4. Overall survival (OS) curves for eligible patients according to the time
point of complete surgical remission. Within 3 months after diagnosis, 5-year OS,
67% (SE ⴝ 8%); within 3 to 6 months, 5-year OS, 50% (SE ⴝ 9%), later or never,
5-year OS, 19% (SE ⴝ 4%). P < .001.
Surgical Remission
A total of 11 patients died during the first 6 months after
diagnosis, and two had an observation period of less than 6
months. Consequently, these 13 patients have been excluded
from that analysis. Among the eligible 189 patients, completeness and the time point of surgical remission had a significant
impact on survival rates (Figs 4 and 5). A macroscopically
complete surgical resection of all tumor sites had been achieved
in 103 patients at a median of 6 months after diagnosis (range, 3
days to 1.7 years). Of the 86 patients in whom no complete
surgical remission had been achieved, 79 died at a median of 1.3
years (range, 7 months to 3.7 years) after diagnosis; the remaining seven patients were alive a median of 3.4 years after
diagnosis (range, 1.4 to 4 years). Patients with unresectable
macroscopic tumor burden had a five-fold higher risk of dying
(relative hazard rate ⫽ 4.9; 95% confidence interval, 3.3 to 7.3;
P ⬍ .001) than patients in whom a complete surgical resection of
all tumor deposits had been performed. A complete surgical
resection of all tumor sites during front-line therapy had been
achieved in 22 (92%) of 24 patients with skip lesions at diagnosis.
Information on response to chemotherapy in the resected
specimens of the primary tumors was available for 87 patients in
whom a complete surgical remission had been achieved. The 50
patients whose tumors showed a good response (⬍ 10% viable
tumor) had a 5-year survival rate of 63% (SE ⫽ 7%) compared
with 37% (SE ⫽ 9%) in the 37 patients with a poor response
(P ⬍ .059). Data on response to preoperative chemotherapy were
available for only 44 patients who did not achieve a complete
surgical remission. There was a better survival probability for the
patients with a good chemotherapy response (n ⫽ 17 patients;
3-year overall survival rate, 24%; SE ⫽ 10%) compared with
those with a poor response (n ⫽ 27; 3-year overall survival rate,
4%; SE ⫽ 4%; P ⫽ .047). Taking together all patients in whom the
chemotherapy response was available, those with a good response
(n ⫽ 67; 5-year overall survival rate, 51%; SE ⫽ 6%) had a
significantly better outcome than those with a poor response (n ⫽
64; 5-year overall survival rate, 24%; SE ⫽ 6%; P ⬍ .001; Fig 2).
In addition, in 75% of patients with a good response to chemotherapy, a complete surgical remission had been achieved, compared
with only 58% of patients with a poor response (P ⫽ .042).
Multivariate Analysis of Prognostic Factors
In a multivariate Cox regression model, multiple metastases at
diagnosis (relative hazard rate ⫽ 2.3) compared with solitary
deposits and, more powerfully, macroscopically incomplete
surgical resection (relative hazard rate ⫽ 2.4) were significantly
associated with inferior outcome (Table 3).
DISCUSSION
Fig 5. Overall survival curves as a function of surgical remission. Method
28
according to Simon and Makuch. Landmark time, half year. See text for details.
We recently reported on prognostic factors of 1,702 patients
with high-grade OS of the extremities and trunk who had been
treated on neoadjuvant COSS protocols between 1980 and July
1998 and found the presence of metastatic disease at diagnosis as
one independent poor prognostic factor.18 In that analysis, 211
patients were considered as having primary metastatic disease,
and their 5-year survival rate was calculated to be 31.6% (SE ⫽
4%). However, as in other published series on MOS, patients
with proven and suspected primary metastases were enrolled.
According to a recent study on the reliability of diagnostic
imaging in MOS, quite a few patients with radiologically
suspected metastases (especially those with solitary pulmonary
lesions) will actually have no metastases.30 The inclusion of
patients with radiology-only metastases into analyses of primary
MOS will necessarily bias all findings by including an errone-
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Histologic Response to Preoperative Chemotherapy
PRIMARY METASTATIC OSTEOSARCOMA
Skip lesions were observed in only 1.4% of patients with OS.
The poor prognosis ascribed to patients with skip lesions by
Wuisman et al, 10 with a high rate of local recurrence (30%)
and a high rate of distant metastases (95%) during the course,
might be explained by the fact that approximately half of their
patients were from the prechemotherapy era. Our results
indicate that these patients seem to have a better prognosis
than previously assumed.
Metastases to distant bones were detected in 22% of patients
in our series. Two thirds had additional deposits in other sites,
indicating widespread disease. The prognosis was poor, and 85%
of these patients died at a median of only 1 year after diagnosis.
Summarizing the data from the literature of the chemotherapy
era and our results, of 117 patients with distant bone metastases
at diagnosis (isolated and combined with lung), only eight
(6.8%) survived more than 3 years after diagnosis.1,5,6,9,14,16,17,31
A complete surgical resection of all tumor sites had been achieved
in four of these eight patients.6,16 The reported 2-year survival rate
of 58% (SE ⫽ 14%) in 12 patients with primary metastases to bones
(⫾ lung) enrolled onto a phase II/III POG group study examining
high-dose ifosfamide and etoposide is encouraging.7 However, to
recommend in general such an approach with considerable toxicity,
these results must be confirmed in a higher number of patients with
longer observation periods.
In our series, 7% of patients with primary metastases had
lymph node involvement; of these, only two were alive more
than 4 years after diagnosis. Taking together the few data from
the literature (a total of four cases, all of whom died)1,5 and our
results, we conclude that lymph node involvement in patients
with OS predicts an extremely poor prognosis. Primary OS
metastases to parenchymal organs and soft tissues are extremely
rare. All eight affected patients in our cohort had multiorgan
involvement and rapid progressive disease and died within 1.5
years from diagnosis.
The intended treatment of the 202 patients in our study
included aggressive surgery combined with multiagent chemotherapy. The risk-benefit ratio of an aggressive surgical
approach may be questionable for the reasons of delay in
chemotherapy administration, higher morbidity, and operative
mortality. However, our results and those of others strongly
indciate that resectable metastases should be resected regardless of their number and localization.32 It cannot be overstressed that patients with a clinically detectable tumor
burden had a five-fold greater risk of dying than patients in
whom a complete surgical resection of all detectable tumors
had been achieved. In addition, no patient with such tumor
burden was alive beyond 5 years from diagnosis. However, it
is important to note that our data set was restricted to patients
with proven metastases and does not allow statements about
patients with solely radiologically suspected metastases and
whether some of these might be cured without the benefit of
surgical resection.
A good histologic response in the primary tumor assessed
after preoperative chemotherapy has been reported to predict a
better probability of survival,1 and our results confirm these
findings. It is noteworthy that patients whose resected primaries
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Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
ously classified subgroup of patients who, in fact, had localized
disease, suggesting better outcomes than true MOS might have
had. The recruitment period of our study encompasses almost 20
years, during which the quality of diagnostic imaging varied
considerably, so the problem of misclassification by radiology
would have been particularly serious. We therefore decided to
focus exclusively on patients with unequivocally proven metastatic disease. This selection procedure may explain the lower
percentage of patients with MOS at diagnosis (11.4%), compared with 17% described in another large cohort.1
Long-term survival for the 202 patients was 24% (SE ⫽ 4%).
Although still unacceptably poor, survival in our contemporary
series was higher than the 11% 2-year overall survival rate
reported for patients from the Memorial Sloan-Kettering Cancer
Center.1 Smaller series of prospectively collected patients reported 5-year survival rates between 16% (European Osteosarcoma Intergroup; 45 patients) and 53% (Pediatric Oncology
Group [POG]; 30 patients).5,8 The better prognosis in the latter
group might be explained by a priori exclusion of patients whose
primary tumors seemed to be unresectable, the overrepresentation of patients with isolated lung involvement (87%, compared
with 61% in our data), and the different chemotherapy schedule
used in the POG series.5 The 3-year survival estimate of 24% in
the prospective OS-91 trial (n ⫽ 17 patients) was comparable to
our findings.3 A better prognosis (3-year survival rate of 50%)
was described for 12 patients enrolled in the OS-86 trial.3 Taken
together, these results indicate that approximately one third of
patients with MOS at diagnosis can become long-term survivors,
if they are treated with an aggressive surgical approach yielding the
removal of all tumor deposits coupled with polychemotherapy.
Seventy percent of the 202 patients in our series died, and
there was only one patient whose death must be considered
treatment-related. Higher rates of treatment-related complications and even deaths were observed with more toxic experimental therapy.7 We agree that experimental treatment is justified for patients for whom no chance of cure can be expected by
the application of standard treatment schedules. However, the
results of our study provide reliable evidence that a subgroup of
patients with MOS can be cured when treated with standard
neoadjuvant treatment regimens and calls previous recommendations to enroll all patients with MOS at diagnosis into
experimental treatment trials into question.1,3
The number and distribution of nodules within the lung have
been reported to predict prognosis, with better outcomes for
patients with unilateral deposits and a low number of metastases,
and our results confirm these findings.1-3,5,13 The best prognostic
subgroup in our series was the patient group with solitary lung
metastases (n ⫽ 24), with a 5-year survival estimate of 75%.
However, we arbitrarily assigned patients according to the
number of metastases into one of three groups: one, two to
five, and more than five metastases. The cutoff point concerning the number of metastases, discriminating reliably between
better- and poor-risk patients, has to be estimated. Our study
confirms the significantly better survival for patients with
unilateral lung deposits.
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KAGER ET AL
showed a good response to chemotherapy were more likely to
achieve a complete surgical remission during front-line therapy.
However, polychemotherapy scheduled according to neoadjuvant COSS protocols was unable to cure patients without
concomitant surgical resection of all clinical detectable tumor
sites. The use of radiotherapy in conjunction with targeted
radionuclide application may offer a therapeutic option in
selected cases.33
We have identified the number of metastases and the completeness of surgical remission as independent prognostic factors
that could serve as criteria for the stratification of patients with
MOS in future international cooperative trials. The use of novel
therapies for the group with unresectable tumor burden is
justified, and innovative therapy regimens should be a major
effort of future regimen studies in this group of patients who
continue to have a catastrophic outcome.
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Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
REFERENCES