Professional Documents
Culture Documents
23
NUMBER
MARCH
20
2005
O R I G I N A L
R E P O R T
Purpose
To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could
improve the probability for event-free survival (EFS) in newly diagnosed patients with
osteosarcoma (OS).
Patients and Methods
Six hundred seventy-seven patients with OS without clinically detectable metastatic disease
were treated with one of four prospectively randomized treatments. All patients received
identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive
surgical resection of the primary tumor. Patients were randomly assigned to receive or not
to receive ifosfamide and/or MTP in a 2 2 factorial design. The primary end point for
analysis was EFS.
Results
Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not
analyze the results by factorial design because we observed an interaction between the
addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy
achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a
3-year EFS rate of 78%.
Conclusion
The addition of ifosfamide in this dose schedule to standard chemotherapy did not
enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional
clinical and laboratory investigation will be necessary to explain the interaction between
ifosfamide and MTP.
J Clin Oncol 23:2004-2011. 2005 by American Society of Clinical Oncology
INTRODUCTION
Osteosarcoma (OS) is a pleomorphic malignant tumor of bone in which the proliferating spindle cells produce osteoid or
immature bone.1 It can arise in any bone
but is most common in the metaphyses
of long bones. Roughly 20% of patients
2004
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Fig 1. Protocol road map. DOXO, doxorubicin; CDDP, cisplatin; HDMTX, high-dose
methotrexate; L-MTP-PE, liposomal muramyl tripeptide phosphatidylethanolamine;
IFOS, ifosfamide.
2005
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Meyers et al
fourth and subsequent doses to prevent fevers or chills. Corticosteroids were not permitted during MTP administration because
the presumptive mechanism of MTP activity was recruitment of
effector cells, which could be inhibited by corticosteroids. MTP
was administered twice weekly for 12 weeks beginning at week 12
and then weekly for an additional 24 weeks beginning at week 24.
MTP was not interrupted for delays in chemotherapy.
MTP was administered through a 3-m filter to decrease risk
of infusion of large aggregates of liposomes into patients. Filters
were supplied by the sponsor and distributed by the National
Cancer Institute. In June 1995, the filter manufacturer was unable
to provide filters. The study committee instructed investigators to
continue to administer MTP to patients who had already begun
this agent. Patients who were due to begin receiving this agent had
initiation delayed until filters were available in January 1996. Patients who entered during that period and were assigned to receive
MTP-PE were at risk of not receiving the assigned treatment. We
designated all patients during this period as a noncompliance
cohort and increased planned accrual to compensate for them.
Accrual continued until the number of patients accrued reached
the number designed in the a priori power calculations, even
allowing for exclusion of the noncompliance cohort.
Definitive surgery was performed at week 10. Procedure
choice was left to the institutional orthopedic surgeon. Limb preservation was encouraged strongly whenever possible. After primary tumor removal, global assessment of necrosis was made by
the institutional pathologist. Necrosis was classified using the
scoring system designed by Huvos, as modified by CCG to subdivide grade 2.3,12
Statistical Methods
The study was conducted as a factorial design. At enrollment,
a patient was assigned one of the following treatment plans:
(1) chemotherapy A without MTP-PE; (2) chemotherapy A with
MTP-PE; (3) chemotherapy B without MTP-PE; and (4) chemotherapy B with MTP-PE. Assignment randomization was blocked
in groups of eight within each of 12 possible strata, which were
defined by presence versus absence of metastatic disease, lactate
dehydrogenase above versus below the institutional upper limit of
normal, and initial tumor resection versus biopsy; patients without evidence of metastases also were stratified by tumor location
(proximal v distal to knee or elbow).
The primary goals of the study were to be addressed in
patients without detectable metastases at diagnosis. We planned to
assess relative risks associated with two different chemotherapies
and biologic intervention with a factorial approach. Patients assigned to regimen A would be compared with patients assigned to
regimen B after stratification for MTP-PE assignment to assess
effects of the regimens. A similar approach was to be used for
assessing the effects of MTP-PE.
Using the factorial analysis approach, we determined that we
needed a sample of 585 patients enrolled over 4 years and observed
for another 2 years to detect reduction in risk for therapy-related
events of 0.64 with 80% power, using a two-sided test of 0.05. The
analytic procedure included a test of assumption of equal relative
risks for one intervention compared across strata defined for
the second intervention. Assumption of absence of interaction
between regimens was crucial to the validity of the factorial
analysis approach.
EFS was the primary outcome measure used to compare
efficacy of regimens. It was defined as the time from entry until an
adverse event or last patient contact, whichever came first. EFS
JOURNAL OF CLINICAL ONCOLOGY
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after definitive surgery was defined as the time from start of first
course of maintenance therapy until an adverse event or last patient contact, whichever came first. Adverse events included disease progression, diagnosis of second malignant neoplasm, or
death before disease progression or second malignant neoplasm.
Patients without adverse events were censored at date of last contact. Data current to April 2003 were used for this analysis.
One hundred eighteen patients comprised the noncompliance cohort. Of these patients, 101 did not have metastases at
diagnosis. Outcomes and relative risks of comparisons examined
in this report were virtually the same in the compliance and
noncompliance cohorts, so data from all eligible patients were
used in the analysis.
EFS was estimated with the Kaplan-Meier method.13 Risk of
adverse events was compared across groups defined by treatment
or prognostic factors using the log-rank statistic.13 Patient assignments were used in all comparisons that involved regimens. Prognostic significance and associated relative risk of various
patient characteristics measured at entry were assessed with a
proportional hazards regression model with the characteristic
of interest as the only component.13 CIs for relative risks were
derived from the proportional hazards regression model. Interim monitoring was conducted three times during the period
of accrual. The method of Lan and DeMets13 was used with the
spending function t2.
RESULTS
Patient Characteristics
Among 793 patients enrolled onto Intergroup Study
0133, 16 were considered ineligible. Ten patients were not
treated within 30 days of diagnostic biopsy, as required by
the protocol. Three patients were determined subsequently
to not have OS; one patient had low-grade OS and two had
chondrosarcoma. One patient did not have normal cardiac
function at enrollment. Two patients were declared ineligible because the IRBs at their institutions had not completed
protocol review before entry.
Of the remaining 777 patients, 100 had clinically
detectable metastases. The 677 patients without metastases are the subjects of this report. Among them, 373
(55%) were male, and 304 (45%) were female (Table 1).
Patient ages ranged from 1 to 30 years, with a median age
at entry of 13 years.
Surgery
Twelve patients had amputations before entry, and 19
of the remaining 665 patients had axial tumors. Among the
other 646 patients, 14 had adverse events before definitive
surgery, and data were not available to classify operations of
91 patients. Four hundred fifteen patients had limb-sparing
surgery, and 126 had amputations.
Toxicity of Therapy
Toxicity was reported for all patients on study, including the noncompliance cohort. There were five treatmentrelated deaths; four deaths were from infections during
Sex
Male
Female
Age at enrollment (years)
0-11 years
12-14 years
15-30 years
Race
White
Hispanic
Black
Asian
Other
Primary tumor site
Femur
Below knee
Humerus
Below elbow
Leg NOS
Arm NOS
Pelvis
Other axial
Not reported
Alkaline phosphatase
ULN
ULN
Not reported
Lactate dehydrogenase
ULN
ULN
No. of
Patients
373
304
55
45
224
204
249
33
30
37
453
84
93
14
33
67
12
14
2
5
374
185
73
12
2
1
12
10
8
55
27
11
2
1
1
2
2
392
268
17
58
40
438
239
65
35
The ULN for this analysis was the ULN in the institution where the patient
was treated.
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Meyers et al
withdraw from therapy before completion of all protocolspecified therapy on these arms.
Outcome
As of April 2003, 230 of 677 patients had adverse
events. Seven patients (1%) died without evidence of disease progression, 11 patients (1.6%) developed second malignant neoplasms, and 212 patients (31%) experienced
disease recurrence. Of the seven patients who experienced
death as a first event, three were treated on regimen A
without MTP, two were treated on regimen B with MTP,
and two were treated on regimen B without MTP. Four
patients died of infectious complications, one patient died
of an operative complication after definitive surgery, one
patient died from an overdose of a self-administered illegal
No. of
Patients
Relative
Risk
95% CI
373
304
1.0
1.1
0.81 to 1.4
.68
224
204
249
1.0
0.84
1.0
0.60 to 1.2
0.75 to 1.4
.44
453
84
93
47
1.0
1.3
0.87
0.94
0.87 to 1.8
0.58 to 1.3
0.54 to 1.6
.53
197
447
22
11
1.0
1.5
2.4
1.1 to 2.0
1.2 to 4.5
.0095
260
338
79
1.0
1.5
1.1 to 2.0
.0044
128
132
158
180
79
1.0
1.0
1.4
1.6
0.63 to 1.6
0.90 to 2.1
1.1 to 2.4
.0041
438
239
1.0
1.7
1.3 to 2.2
.00016
Prognostic Factors
Age, sex, and race did not correlate with EFS (Table 2).
Patients with alkaline phosphatase levels above their institutions upper limit of normal had worse prognoses. Patients with lactate dehydrogenase levels above institutional
upper limit of normal also had worse prognoses. Patients
with primary tumors of the distal appendicular skeleton
had the best prognosis, followed by those with tumors of the
proximal appendicular skeleton. Patients with axial primary tumors had the worst prognosis. There was no difference in outcome between patients who had primary
ablation of their tumor and patients who had definitive
surgery after induction.
Necrosis After Induction Chemotherapy
Patients who underwent definitive resection after induction underwent evaluation of necrosis by an institutional
pathologist. Necrosis was graded according to the method of
Huvos, as modified by CCG.3,12 Because MTP was not introduced until after surgery, patients were classified only by regimen assignment (A or B; Table 3). Besides the 12 patients who
had amputations before chemotherapy, 22 had adverse events
before definitive resection after induction. Necrosis grading
was not available for an additional 59 patients. Overall, 265
(45%) of 584 patients exhibited grade 3 or 4 necrosis. There
was no difference in frequency of favorable necrosis between
chemotherapy arms.
Necrosis after induction correlated with prognosis
monotonically (Fig 2). Necrosis is not a true prognostic
factor because it cannot be evaluated before therapy and,
therefore, cannot be used for patient stratification at entry.
EFS
For patients without metastases, EFS was 70% at 3 years
and 63% at 5 years from entry (Fig 3). One hundred one
1.0
1.8
1.4 to 2.4
.00001
12
665
1.0
1.2
0.46 to 3.4
.66
2008
Necrosis Grade
1
2A
2B
Chemotherapy
Regimen
No.
No.
No.
No.
No.
A
B
11
7
4
2
44
33
15
11
112
112
38
38
84
95
29
33
41
45
14
15
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Fig 2. Necrosis observed in the primary tumor at the time of definitive surgical
resection after induction chemotherapy correlates with event-free survival.
patients entered onto the study while filter availability compromised MTP administration. Our analysis that excluded the
noncompliance cohort did not alter study conclusions.
We used a 2 2 factorial design. To analyze the study
in accordance with the initial factorial design, there had to
be no interaction between the two study questions. We
observed an interaction between the study interventions
(Fig 4). The usual factorial analytic strategy estimates a
treatment effect by an analysis stratifying the population by
the other treatment factor. The presence of an interaction
invalidates this procedure because there is no single treatment effect of interest; the effect differs across groups
formed by stratifying according to the other intervention.
We considered regimen A (cisplatin, doxorubicin, and
Fig 3. Event-free survival (EFS) and overall survival for patients newly
diagnosed with osteosarcoma without clinically detectable metastatic disease.
Randomized
Regimen
No. of
Patients
Relative
Risk
95% CI
A
A
A
B
A
B
172
168
172
167
172
170
1.0
1.0
1.0
1.3
1.0
0.78
0.71 to 1.5
0.93 to 1.9
0.54 to 1.2
.88
.12
.22
2009
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drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: Michael Link,
Onyx Pharmaceutical, Yamaguchi Pharmaceutical. Research Funding: Michael Link, Bristol-Meyers Squibb. For a
detailed description of these categories, or for more information about ASCOs conflict of interest policy, please refer
to the Author Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section of Information for
Contributors found in the front of every issue.
6. Miser JS, Kinsella TJ, Triche TJ, et al: Ifosfamide with mesna uroprotection and etoposide:
An effective regimen in the treatment of recurrent
sarcomas and other tumors of children and young
adults. J Clin Oncol 5:1191-1198, 1987
7. Kung FH, Pratt CB, Vega RA, et al: Ifosfamide/etoposide combination in the treatment
of recurrent malignant solid tumors of childhood:
A Pediatric Oncology Group phase II study. Cancer 71:1898-1903, 1993
8. Fidler IJ, Sone S, Fogler WE, et al: Eradication of spontaneous metastases and activation
of alveolar macrophages by intravenous injection
of liposomes containing muramyl dipeptide. Proc
Natl Acad Sci U S A 78:1680-1684, 1981
9. MacEwen EG, Kurzman ID, Rosenthal RC,
et al: Therapy of osteosarcoma in dogs with
intravenous injection of liposome encapsulated
muramyl tripeptide. J Natl Cancer Inst 81:935936, 1989
10. Kleinerman ES, Snyder JS, Jaffe N: Influence of chemotherapy administration on monocyte activation by liposomal muramyl tripeptide
phosphatidylethanolamine in children with osteosarcoma. J Clin Oncol 9:259-267, 1991
2011
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