Document 63446

Carboplatin/Ifosfamide Window Therapy for Osteosarcoma:
Results of the St Jude Children’s Research Hospital
OS-91 Trial
By William H. Meyer, Charles B. Pratt, Catherine A. Poquette, Bhaskar N. Rao, David M. Parham, Neyssa M. Marina,
Alberto S. Pappo, Hazem H. Mahmoud, Jesse J. Jenkins, James Harper, Michael Neel, and Barry D. Fletcher
Purpose: To determine the activity of carboplatin/ifosfamide in patients with previously untreated osteosarcoma and to estimate patient outcomes after a multiagent
chemotherapy protocol that eliminated cisplatin.
Patients and Methods: Sixty-nine patients with newly
diagnosed, previously untreated osteosarcoma received
three cycles of carboplatin (560 mg/m2 ⴛ 1) and ifosfamide
(2.65 g/m2/d ⴛ 3). Assessment of response was evaluated
after two (week 6) and three (week 9) chemotherapy cycles. At week 9, histologic response was assessed. Adjuvant
therapy comprised two additional carboplatin/ifosfamide
cycles, doxorubicin, and high-dose methotrexate. Patients
were stratified at enrollment: stratum A, resectable primary
tumor without metastases; stratum B, unresectable primary
tumor; and stratum C, metastatic disease at diagnosis.
Week 6 response was compared with that of a historic
group that received only ifosfamide during the initial window evaluation.
Results: The clinical and radiographic response rate
to three cycles of carboplatin/ifosfamide was 67.7%
(95% confidence interval, 55.0% to 78.8%). Compared
with the historic population who received only ifosfamide, the combination of carboplatin and ifosfamide
reduced the progressive disease rate at week 6 (31.9%
v 9%, P ⴝ .003). For patients in stratum A, the 3-year
event-free survival and survival were 72.3% ⴞ 6.7%
and 76.4% ⴞ 6.4%, respectively. Patients who received
carboplatin-based therapy had less long-term renal
toxicity and ototoxicity.
Conclusion: This pilot trial suggests that carboplatin/ifosfamide combination chemotherapy has substantial antitumor activity. In the context of a multiagent chemotherapy protocol comprising high-dose
methotrexate and doxorubicin, we found that the addition of carboplatin/ifosfamide resulted in patient outcomes comparable to trials using cisplatin-based therapy with less long-term toxicity.
J Clin Oncol 19:171-182. © 2001 by American
Society of Clinical Oncology.
STEOSARCOMA IS the most common primary malignant bone tumor in children and adolescents. At
least two thirds of patients with resectable primary tumors
and without metastatic disease at diagnosis will be cured
with resection of the primary tumor and effective multiagent
chemotherapy.1-5 Patients with unresectable primary tumors
and those with metastatic disease present at diagnosis have
a much less favorable outcome.6,7
The improved cure rate for osteosarcoma is primarily a
result of effective use of multiagent chemotherapy.1
In single-agent trials, the greatest proportion of antitumor
responses has been noted with the use of doxorubicin,8,9
cisplatin,10-12 high-dose methotrexate,13,14 and ifosfamide.15-17 Although none of these agents has consistently
caused tumor regressions in more than approximately 30%
of patients with measurable tumors, when used in adjuvant
combination therapy trials, cure rates of 60% to 70% are
routinely reported. Toxicity for these multiagent trials is
substantial, and for some patients, such toxicity is permanent. In particular, cisplatin causes irreversible renal impairment18 and ototoxicity.19-21 These side effects occur in a
substantial proportion of survivors of osteosarcoma.22,23 In
addition, even with the use of newer, more effective
antiemetic agents, cisplatin continues to be one of the most
emetogenic chemotherapy agents.
Carboplatin was synthesized in hopes of identifying an
effective platin analog with less short- and long-term
toxicity than cisplatin. Carboplatin causes more early bone
marrow suppression than cisplatin but much less permanent
renal toxicity and ototoxicity.24,25 The relative efficacy of
these platin analogs seems to be tumor-specific. In some
clinical settings, carboplatin is as effective as cisplatin.
Randomized trials that compare cisplatin and carboplatin in
From the Departments of Hematology/Oncology, Biostatistics and
Epidemiology, Surgery, and Pathology and Laboratory Medicine, St
Jude Children’s Research Hospital, and University of Tennessee
Memphis, Memphis, TN; Department of Pathology, University of
Arkansas for Medical Sciences, Little Rock, AR; and University of
Nebraska Medical Center, Omaha, NE.
Submitted June 14, 1999; accepted July 28, 2000.
Supported by grant no. PO1 CA-23099 and Cancer Center Core
Grant CA-21765 from the National Cancer Institute, National Institutes of Health, Bethesda, MD, and by the American Lebanese Syrian
Associated Charities, Memphis, TN.
Address reprint requests to William H. Meyer, MD, Hematology/
Oncology Section, Department of Pediatrics, University of Oklahoma
Health Sciences Center, PO Box 26901, Oklahoma City, OK; email
[email protected]
© 2001 by American Society of Clinical Oncology.
Journal of Clinical Oncology, Vol 19, No 1 (January 1), 2001: pp 171-182
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ovarian cancer and lung cancer have shown similar response
rates and survival outcomes.26 However, cisplatin has superior efficacy in other adult tumors, including germ cell
tumors,27,28 bladder cancer,29 and head and neck cancers30
(reviewed in26).
Carboplatin has not been as adequately tested in many
childhood and adolescent malignancies, including osteosarcoma. In preclinical osteosarcoma models, carboplatin has
antitumor activity. In human osteosarcoma cell lines, colony
formation was completely abolished by both carboplatin
and cisplatin, with 10-fold greater exposures for carboplatin, which is consistent with much greater dosing clinically
for this agent.31 Dogs that received adjuvant therapy with
carboplatin after amputation for osteosarcoma have prolongation of survival, similar to a cohort that received adjuvant
cisplatin.32 In a human osteosarcoma xenograft model,
carboplatin, 20 mg/kg intraperitoneally, reduces tumor
growth.33 A phase I trial of carboplatin that included 10
patients with recurrent osteosarcoma reported one complete
response.34 The sole single-agent relapse phase II trial of
carboplatin conducted in children failed to show antitumor
activity in patients with recurrent osteosarcoma.35 Of the 12
assessable patients in this study, 11 had received prior
cisplatin therapy; tumors in these patients possibly had
developed acquired resistance to platinating agents. Such
acquired cross-resistance after exposure to cisplatin has
been reported in an osteosarcoma cell line.36 More recently,
Petrilli et al37 evaluated responses to intra-arterial carboplatin therapy in 33 consecutive patients with osteosarcoma,
reporting clinical and radiologic responses in 81% and 73%
of patients, respectively.
In several tumors that commonly occur in children and
adolescents, including neuroblastoma, rhabdomyosarcoma,
and osteosarcoma, agents that unequivocally are active
against tumors previously not exposed to anticancer agents
will show less activity in classic phase II trials. For this
reason, pediatric investigators have used an investigative
up-front window approach,38-42 testing the new agent or
combination of agents before exposure to known effective
drugs. In osteosarcoma, this strategy has been useful in
demonstrating antitumor activity for single-agent ifosfamide43 and the combination of ifosfamide/etoposide.44 In a
previous St Jude trial of osteosarcoma, single-agent ifosfamide window therapy showed clinical and radiographic
responses in 30% of patients.45 However, the tumors of
approximately 30% of patients in this trial showed disease
progression during the 6-week single-agent ifosfamide window. Patients who failed to respond to ifosfamide did not
have a worse ultimate outcome. Subsequently, in the present
trial (OS-91), we combined carboplatin with ifosfamide to
determine the activity of this combination in patients with
previously untreated osteosarcoma and to estimate the
outcome for patients treated with a multiagent chemotherapy protocol that eliminated cisplatin.
Patients with previously untreated osteosarcoma, malignant fibrous
histiocytoma of bone, fibrosarcoma, or multipotential sarcoma of bone
and with good performance status (Eastern Cooperative Oncology
Group scores 0 to 2) and normal renal, cardiac, and hepatic function
were eligible for enrollment. At the time of enrollment, patients were
placed into one of three strata on the basis of resectability of the
primary tumor and the presence of metastatic disease at the time of
diagnosis: stratum A, resectable primary tumor without evidence of
metastases; stratum B, unresectable primary tumor, without evidence of
metastases; and stratum C, metastatic disease at diagnosis regardless of
resectability of the primary tumor.
Biopsy of the primary tumor was required for diagnosis; typically, open
incisional biopsies were performed. Biopsy of metastatic lesions was not
required at time of diagnosis; however, patients with metastatic pulmonary
lesions underwent delayed thoracotomy unless the pulmonary lesions were
judged unresectable. The initial staging workup included plain radiographs, computed tomography (CT) scan, and magnetic resonance (MR)
imaging (including dynamic contrast MR imaging [DEMRI]46,47) of the
primary tumor, 99TcDMP bone scanning, 210thallium scan of tumor area,
plain chest radiograph and noncontrast CT scan of lungs, comprehensive
chemistry panel, echocardiogram, and pure-tone audiometry. After the first
cohort of patients enrolled showed no evidence of hearing loss on serial
studies, routine close follow-up by serial audiometry was discontinued.
Response evaluation after two and three cycles of presurgery carboplatin/
ifosfamide chemotherapy (at weeks 6 and 9, respectively) comprised plain
radiographs, CT and MR imaging, and 210thallium scanning of tumor area.
Known metastatic tumor sites were also evaluated for response. Complete
re-evaluation of tumor status was performed at completion of therapy.
Follow-up evaluation for tumor recurrence comprised plain chest radiographs every 6 weeks, CT scans of lungs every 3 months, and bone
scanning every 6 months for the first 2 years. After this point, patients were
evaluated only by clinical assessment and plain chest radiographs unless
clinical symptoms suggested tumor recurrence.
Protocol Drug Administration
Patients received two cycles of carboplatin (560 mg/m2 on day 1) and
ifosfamide (2.65 g/m2/d for 3 days with mesna uroprotection), followed by
response assessment at week 6. Unless there was evidence of tumor
progression, a third cycle of carboplatin/ifosfamide was administered.
After complete clinical and radiographic assessment, patients in stratum A
and those in stratum C with resectable primary tumors underwent ablative
surgery of the primary tumor. Limb-salvage surgery was attempted when
deemed feasible by the surgeon. All joint reconstructions used metallic
custom endoprosthetic devices. For those few reconstructions that did not
involve a joint, allograft bone with intramedullary rod fixation was used.
Patients with unresectable primary tumors typically were removed from
protocol to receive individualized local therapy, usually with local irradiation of the primary tumor.
After resection of the primary tumor, patients received doxorubicin
(five treatments at 75 mg/m2/dose as 72-hour continuous infusion,
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Fig 1. Chemotherapy Outline. The “S” box indicates scheduled surgery.
For the OS-91 protocol, alternate chemotherapy for progressive disease is in
hatched area. Abbreviations and dosages: i, ifosfamide 1.6 g/m2/d ⴛ 5; ic,
ifosfamide 2.65 g/m2/d ⴛ 3, carboplatin 560 mg/m2/dose; m, methotrexate 12 g/m2/dose; a, doxorubicin 75 mg/m2 72-hour continuous infusion;
a*, doxorubicin 90 mg/m2/cycle (OS-86); ap, doxorubicin 75 mg/m2/dose
and cisplatin 100 mg/m2/dose; Rx, treatment; PD, progressive disease.
usually administered in the ambulatory setting) and high-dose methotrexate (nine treatments at 12 g/m2/dose with leucovorin rescue).
Patients whose tumors demonstrated clinical and radiographic progression during the 9-week presurgical phase of the protocol received
cisplatin (100 mg/m2/dose) in substitution for carboplatin/ifosfamide
cycles. All other patients received two additional cycles of carboplatin/
ifosfamide. The outlines of chemotherapy for OS-91 and for the
historic comparison trial, OS-86, are shown in Fig 1.
Response Evaluation
Clinical and radiographic responses were recorded at weeks 6 and 9
of the protocol. Patients who became pain-free without analgesics and
had increased peripheral rimming calcification (healing mineralization)48 or had decrease in tumor size were coded as having clinical
responses. Patients with no significant radiographic change in tumor
were coded as having stable disease. Patients with tumors who had
measurable tumor growth were defined as having disease progression.
Histologic assessment at week 9 used the four-grade system described
by Huvos et al.49,50
Statistical Methods
The study was designed with two primary end points: (1) estimating
the response rate to presurgical chemotherapy using carboplatin/
ifosfamide, and (2) determining whether combination therapy with
these two agents would significantly decrease the rate of disease
progression compared with presurgical ifosfamide alone, administered
in the prior St Jude OS-86 protocol (30% disease progression rate at
week 6). This was the most appropriate end point for comparison with
the historical control group enrolled onto OS-86 for several reasons.
First, clinical and radiologic assessment of response in osteosarcoma
may be difficult and somewhat subjective; therefore, comparison of the
proportions responding was not feasible. However, the assessment of
tumor progression, with increased tumor bulk and usually continued
tumor pain during the 6-week evaluation, was not difficult to discern.
Second, by study design, patients enrolled onto OS-86 had surgical
ablation of the primary tumor at week 13, after exposure to high-dose
methotrexate and doxorubicin. Comparison of histologic grading in this
group with that of the OS-91 patients who received only carboplatin/
ifosfamide was meaningless. Evaluation of at least 40 patients was
required to detect a decrease in the progressive disease rate to 10%,
with a type I error rate of 5% and power of 80% (one-tailed test). When
preliminary analysis showed that the estimated progressive disease rate
was less than 10%, accrual to the study was continued to allow a better
estimate of the outcomes of patients with resectable tumors.
Fisher’s exact test was used to compare progressive disease rates
during the window treatment (at week 6) for OS-86 and OS-91.
Response rates were calculated as binomial proportions, and exact 95%
confidence intervals were computed. The association between histologic and clinical response was investigated using the exact Jonckheere-Terpstra test,51 which considers both rows and columns as
ordinal variables. Survival was defined as the interval from diagnosis to
death from any cause or to last follow-up. Event-free survival was
defined as the interval from diagnosis to relapse or progressive disease,
second malignancy, or death from any cause. We also calculated
event-free survival by excluding progressive disease in the window as
an event for patients in stratum A. The rationale for this exclusion was
that the protocol allowed patients in stratum A to have progressive
disease in the window and to continue on the protocol with substitution
of cisplatin for carboplatin/ifosfamide. Survival and event-free survival
were estimated using the method of Kaplan and Meier52; associated
SEs were calculated using the method of Peto et al.53 Differences in
survival distributions were tested using the Mantel-Haenszel test.54
Exact log-rank tests were used when groups were small. A test
developed by Mantel and Byar55 was used to compare event-free
survival distributions by type of surgery (limb-salvage v amputation);
this method accounts for patients transferring from one group to
another. StatXact3 (CYTEL Software Corporation, Cambridge, MA)
and SAS (Version 6.12, SAS Institute, Inc, Cary, NC) were used for
statistical analysis.
As part of a program project grant, the trial was approved by the
Clinical Therapy and Evaluation Program of the National Cancer
Institute and by the local institutional review boards. The trial was
monitored annually by the local institutional review boards and the St
Jude Children’s Research Hospital Clinical Protocol Scientific Review
and Monitoring Committee. Informed consent of the patient and/or
parent or legal guardian was obtained before enrollment.
Patient Characteristics
Patient characteristics for the 69 OS-91 patients are listed
in Table 1. Patients were enrolled onto three strata: the
majority of patients (n ⫽ 47; 68%) had potentially resectable primary lesions (stratum A), five patients had unresectable primary lesions (stratum B), and the remaining 17
patients had metastatic disease at diagnosis (stratum C). The
median age at diagnosis of the 69 patients was 14.1 years
(range, 1.2 to 24.1 years). Thirty-five patients (51%) were
male; 47 (68%) were white. The most common sites of the
primary tumor were the femur (n ⫽ 36) and the tibia (n ⫽
11), which accounted for 68% of the cases. Fifty-six
patients had extremity primaries, and two had multifocal
primary sites. The most common histologies at initial
biopsy were osteosarcoma (not otherwise specified) (n ⫽
41; 59%) and osteoblastic osteosarcoma (n ⫽ 12; 17%). Of
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Table 1.
Patient Characteristics
A (resectable primary lesion)
B (unresectable primary lesion)
C (metastatic disease at diagnosis)
Primary site
Other extremity
Flat bones
Site of metastases at diagnosis (n ⫽ 17)
Lung only
Bone only
Lung and bone
No. of
the 17 patients with metastatic disease at diagnosis, 12 had
lung metastases only, two had bone metastases only, two
had both lung and bone metastases, and one had a drop
metastatic lesion at the costophrenic angle. Thirty-nine
patients (57%) were alive with a median follow-up of 4.8
years (range, 2.6 to 8.2 years).
The characteristics of these 69 patients were compared with
those of the 51 patients enrolled onto OS-86. The median age
at diagnosis for OS-86 patients was 14.9 years (range, 4.8 to
23.6 years). Thirty-seven patients (73%) were placed in stratum A, two (4%) in stratum B, and 12 (24%) in stratum C. The
median follow-up for the 30 survivors enrolled onto OS-86
was 11.2 years (range, 4.7 to 13.1 years); 93% of survivors had
their most recent follow-up within 1 year. There was no
evidence that age at diagnosis or distribution of patients by
stratum differed significantly between OS-86 and OS-91 (P ⫽
.73 and P ⫽ .77, respectively).
Comparison of Disease Progression Rates (week 6)
One primary objective of OS-91 was to determine
whether combination therapy with carboplatin/ifosfamide
significantly decreased the rate of disease progression compared with ifosfamide alone (OS-86). The disease progression rates for these two protocols were compared at week 6.
Forty-seven of 51 OS-86 patients and 67 of 69 OS-91
patients were assessable for this comparison of response. Of
the four nonassessable patients enrolled onto OS-86, one
was ineligible (wrong diagnosis) and three had resection of
tumor before week 6. Two OS-91 patients were not assessable at week 6: one had surgery before the evaluation
(pathologic fracture) and one refused all therapy after one
carboplatin/ifosfamide cycle. Fifteen of 47 assessable
OS-86 patients (31.9%) had progressive disease at week 6,
whereas only six of 67 assessable OS-91 patients (9.0%)
had progressive disease at week 6 (P ⫽ .003). Among
patients in stratum A assessable at week 6, two (4.4%)
of 45 OS-91 patients had progressive disease, whereas
eight (24.2%) of 33 OS-86 patients had progressive
disease (P ⫽ .015).
Clinical/Radiologic Responses
The other primary objective of OS-91 was to estimate the
response rate to the carboplatin/ifosfamide window. Responses were coded at both weeks 6 and 9. Nine patients
overall had disease progression during the window at either
week 6 or week 9. Six patients had progressive disease at
week 6. Three additional patients had no radiographic or
clinical changes in tumor at week 6, received a third cycle
of carboplatin/ifosfamide, and had tumor progression at the
week-9 evaluation. One patient who had early amputation
for pathologic fracture and another who refused all therapy
after one carboplatin/ifosfamide cycle (noted above) were
not assessable for response at weeks 6 and 9. Two other
patients with unresectable tumors were treated with local
irradiation after the week-6 evaluation and were not assessable for the week-9 response. All patients enrolled were
included in the survival analyses discussed below, except
where specifically noted. Of the remaining 56 patients with
induction responses coded, 12 had stable disease throughout
the window and 44 had tumors that showed clinical/
radiographic response. Twenty-two patients had tumors that
showed responses at both week 6 and week 9; 13 had
responding tumors at week 6 with no further change in
radiographic appearance at week 9. Of the 24 patients with
stable disease at week 6, nine became responders by week
9, 12 remained stable, and three experienced progression of
their disease. The response rate to three cycles of carboplatin/ifosfamide window for assessable patients was 67.7%
(44 of 65; 95% confidence interval, 55.0% to 78.8%).
Of the 47 patients in stratum A, 31 had tumors that
responded to the carboplatin/ifosfamide window, 10 had
stable disease, two had disease progression at week 6, and
one had progressive disease at week 9. The response rate for
all patients in stratum A was 66% (31 of 47). By protocol
design, the three patients with progressive disease during
window carboplatin/ifosfamide received subsequent cisplatin therapy.
There were only five patients in stratum B: one had
progressive disease at week 6, one had a tumor that showed
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Table 2.
Histologic and Clinical Responses
Clinical and Radiographic Assessment
Histologic Response
All assessable patients
Assessable patients in stratum A
response at week 6 but was not assessable at week 9 because
the patient was removed from the protocol to receive local
irradiation, one had tumor that responded at both weeks 6
and 9, one had a response at week 6 and stable disease at
week 9, and one had stable disease at both weeks 6 and 9.
Three of the 17 patients with metastatic disease at
diagnosis had disease progression at week 6. Two additional
patients developed disease progression by week 9. Eleven
patients had clinical response to induction; one had stable
disease. The response rate for patients in stratum C was
64.7% (11 of 17).
Histologic Grading
Histologic grades were evaluated in 56 of 69 patients
enrolled onto the study. Twelve patients did not have
histologic grade because they did not undergo surgical
resection of the primary tumor; one additional patient who
underwent surgical resection of an ethmoid primary was not
assigned a histologic grade. Grades I and II histologic
necrosis were combined (⬍ 90% tumor necrosis), as were
grades III and IV (ⱖ 90% tumor necrosis). Of the samples
available for histologic grade, 31 were grade III or IV
histologic necrosis and 25 were grade I or II. The tumors of
55 patients had coded both histologic grade and clinical
responses to induction at week 9. We investigated whether
there was an association between clinical/radiographic response (after three cycles of carboplatin/ifosfamide) and
histologic grade among these patients. There was evidence
that the distributions of week-9 responses (progressive
disease, stable disease, and partial response) were significantly different by histologic grade (I/II v III/IV; P ⬍ .001).
Tumors in 94% of patients with good histologic necrosis (III
or IV) showed clinical response to induction, whereas only
50% of tumors with grade I or II showed clinical response
(Table 2).
Findings were similar for the subset of patients in stratum
A (Table 2). Forty-three of 47 tumors in patients in stratum
A had both histologic and clinical responses coded. Ninety-
two percent of tumors (22 of 24) with good histologic grade
(grade III or IV) at week 9, but only 42% (8 of 19) of tumors
with poor histologic necrosis (grade I or II), showed clinical
response (P ⬍ .001).
Fifty-seven of 69 patients had tumor resections; twelve
did not. These twelve patients included two patients in
stratum A who refused therapy, including surgical resection
of tumor (after one and three cycles of carboplatin/ifosfamide chemotherapy). One patient who underwent resection
of her primary ethmoid tumor was not assigned a histologic
response grade.
Of the 57 patients who had surgery (all strata), 41 had
limb-salvage procedures (five later converted to amputation), 14 had primary amputations, and two had other
operations (resection of primary ethmoid tumor and resection of a rib). Among the 55 patients with definitive surgery,
all received their next course of chemotherapy within 26
days of their first definitive surgery (median time, 14 days).
For a comparison of survival and event-free survival between limb-salvage and amputation surgery groups, we
used only patients in stratum A with extremity tumors. Of
these 44 patients, two had no surgery, seven had primary
amputations, and 35 had limb salvage operations, including
the five patients who later had amputations. Of these five
patients, none had progressive or recurrent local disease that
required subsequent amputation. One had microscopic residual tumor at the bone margin of resection of limb-salvage
and was converted to amputation 1.4 months after limbsalvage. The other four patients had postoperative complications (wound infections, abscesses, or chronic osteomyelitis) that required amputation after limb salvage. The
median time from limb salvage to amputation for these five
patients was 5.3 months (range, 1.4 to 11.2 months). No
difference was noted in event-free survival by type of
surgery (3-year estimates: 80 ⫾ 9 for limb salvage v 75 ⫾
12 for amputation; P ⫽ .96)
The following analyses were performed on all patients
enrolled (except where specifically noted), including those
who refused therapy or definitive surgery. The 3-year
estimate of survival for all patients enrolled onto OS-91 was
62.1% ⫾ 6.1%. The estimated 3-year survival for patients in
stratum A was 76.4% ⫾ 6.4% (Fig 2). Event-free survival
by stratum is shown in Fig 3; 3-year estimates of event-free
survival were 72.3% ⫾ 6.7% for patients in stratum A,
60.0% ⫾ 21.9% for those in stratum B, and 5.9% ⫾ 4.0%
for those with metastatic disease. Excluding progression of
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Fig 2. Kaplan-Meier estimated survival for patients in
stratum A enrolled onto the
OS-86 and OS-91 trials.
disease during the window as an event, the 3-year event-free
survival for patients in stratum A was 74.5% ⫾ 6.6%.
Disease progression during window. We compared survival for patients with and without progressive disease at
week 6. Patients who were not assessable for response were
excluded from this analysis. Six patients had progressive
disease at week 6: of these, five died (three were patients in
stratum C). There was a significant difference in the survival
distributions among patients with progressive disease at
week 6 and those with other assessable responses (stable
disease or partial response; P ⫽ .050). Among patients in
stratum A, only two had progression at week 6 (one died).
Similarly, we compared survival among patients with
progressive disease at any time during the window (week 6
or week 9) with survival among those with other assessable
responses. The results were similar to the those of the
previous analysis. There was a significant difference in
survival among patients with and without progressive disease in the window (P ⫽ .001). Adjusted by stratum, the
difference remained significant (P ⫽ .022). For the entire
Fig 3. Kaplan-Meier estimated event-free survival by
stratum for patients enrolled onto
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Fig 4. Kaplan-Meier estimated event-free survival for
patients in stratum A enrolled
onto the OS-91 protocol by histologic grade. This figure excludes progressive disease at
week 6 or 9 as an event as
discussed in Patients and
cohort entered onto OS-91, nine patients had progressive
disease during the window and eight died. Three-year
survival estimates were 22.2% ⫾ 11.3% for patients with
progressive disease during the window and 71.2% ⫾ 6.4%
for patients with other assessable responses. Only three
patients in stratum A had progressive disease during the
carboplatin/ifosfamide window; two of these died of disease
progression. Three-year survival estimates for patients in
stratum A were 33.3% ⫾ 19.2% for patients with progressive disease in the window and 82.6% ⫾ 6.1% for those
with other assessable responses.
Histologic necrosis grade. Survival distributions were
compared for patients with good (grade III or IV) and poor
(grade I or II) histologic necrosis. For all patients, 3-year
survival estimates were 68.0% ⫾ 9.3% (grade I/II) and
70.2% ⫾ 8.6% (grade III/IV). There was no significant
difference in survival by histologic necrosis grade (P ⫽
.81). Results were similar for patients in stratum A, with no
evidence of a difference in survival distributions (P ⫽ .69).
Three-year survival estimates were 80.0% ⫾ 8.9% (grades
I/II) and 78.5% ⫾ 8.6% (grades III/IV). There was also no
evidence of a difference in event-free survival by histologic
grade among patients in stratum A (P ⫽ .90; Fig 4). This
trial was designed to detect a difference in week-6 response
rates compared with the historical population treated with
ifosfamide only (OS-86) and not designed to establish
differences in outcome by histologic necrosis grade. Hence,
power to detect differences among survival distributions
was limited. As discussed above, histologic necrosis was
correlated with the induction response. However, although
progressive disease during the window correlated with
survival, histologic grade did not.
Comparison With OS-86
We compared survival distributions of patients enrolled
onto OS-86 and OS-91. The median follow-up periods for
OS-86 and OS-91 were 11.2 years (range, 4.7 to 13.1 years)
and 4.8 years (range, 2.6 to 8.2 years), respectively. Threeyear survival estimates were 74.5% ⫾ 6.0% for OS-86 and
62.1% ⫾ 6.1% for OS-91 (all strata). Four-year estimates
were 66.7% ⫾ 6.5% for OS-86 and 60.4% ⫾ 6.8% for
OS-91. There was no significant difference in survival
distributions between the two protocols (P ⫽ .35). For
patients in stratum A, 3-year survival estimates were 83.8%
⫾ 6.0% (OS-86) and 76.4% ⫾ 6.4% (OS-91) (P ⫽ .96).
Patients with metastatic disease at diagnosis enrolled onto
OS-91 had a worse outcome when compared with those in
the OS-86 study, with 3-year survival estimates of 23.5% ⫾
10.3% (OS-91) and 50.0% ⫾ 13.4% (OS-86; P ⫽ .062).
Although disease progression rate during the first 6-week
window of OS-86 was much higher than that in the OS-91
trial, there was no significant difference in survival for
patients enrolled onto OS-86 with or without progressive
disease at week 6 (P ⫽ .61).
Toxicity was moderate and manageable for most patients.
Patients received doxorubicin infusions primarily in the
ambulatory setting, carrying infusion pumps for the 72-hour
infusions. All patients had external venous access devices
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Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
(Hickman and Broviac catheters), which eliminated concerns regarding extravasation of continuous infusion doxorubicin. The acute renal toxicities of carboplatin/ifosfamide
for the initial cohort enrolled onto this trial have been
reported recently.56 Fifteen percent of this cohort developed
significant acute electrolyte problems during the first three
cycles of carboplatin/ifosfamide. Grade 3 or 4 renal toxicity
developed in only two (5%) of the 42 patients alive and
assessable 1 year after completion of therapy with carboplatin and ifosfamide (OS-91) but in six (21%) of 29
patients after therapy with cisplatin and ifosfamide (OS-86).
Renal tubular toxicity developed in four additional patients
in the OS-86 group more than 1 year after completion of
therapy. Of the 33 patients with serial audiograms enrolled
onto OS-91 who did not receive cisplatin, none had hearing
loss detectable by serial pure-tone audiometric assessment.
Because no hearing toxicity was detected in the initial
cohort enrolled onto OS-91, routine serial audiometric
assessment was stopped. Of the patients whose disease
progressed during the carboplatin/ifosfamide window and
who subsequently received cisplatin, four of five with serial
audiograms had changes in hearing thresholds detected by
serial audiometry.
Improvements in the cure rate for osteosarcoma depend
on the identification of new active agents. Such agents have
been identified traditionally through phase II studies in
patients with recurrent disease. Several such phase II studies
demonstrated that ifosfamide was active in recurrent osteosarcoma.16,17,57,58 However, estimates of response varied; a
more accurate assessment of responsiveness of osteosarcoma awaited up-front window trials conducted in previously untreated patients.
Harris et al42,43 conducted a phase II window trial of
single-agent ifosfamide in previously untreated patients
with metastatic osteosarcoma. This study demonstrated a
higher response rate than that seen in a similar phase II trial
of ifosfamide conducted in previously treated patients. The
OS-86 trial, conducted during the same period, showed a
response rate in previously untreated patients similar to that
reported by Harris et al. Of significant concern, more than
30% of patients enrolled onto the OS-86 trial developed
disease progression during the 6-week window therapy, a
progressive disease rate also equivalent to that reported by
Harris et al. Although the overall outcomes of patients
enrolled onto the OS-86 trial with or without progressive
disease during the ifosfamide window were similar, such
progressive disease rates are not acceptable. Consequently,
we elected to combine ifosfamide with carboplatin in the
next window trial. This permitted direct historic compari-
son. Although assessment of response in osteosarcoma is
problematic, progression of disease is a more straightforward end point. We thus selected this end point for
comparison with the OS-86 trial.
With the use of the combination of carboplatin and
ifosfamide, the rate of disease progression at week 6 was
statistically significantly lower than that observed with
ifosfamide alone, which demonstrates the antitumor activity
of this combination. Single-agent carboplatin has been
reported to cause regression of osteosarcoma.59 However,
the only single-agent phase II trial conducted in patients
with recurrent tumors failed to demonstrate activity against
osteosarcoma.60 The Pediatric Oncology Group conducted a
single-agent trial of carboplatin in previously untreated
patients with metastatic and/or unresectable osteosarcoma.61
Although antitumor responses were observed in at least one
tumor site in 22% of patients, only one of the 37 patients
enrolled onto this trial had an overall partial response defined
by traditional criteria (more than 50% regression of tumor at all
sites). Our data may suggest clinical synergy for the combination of carboplatin/ifosfamide.
The hypothesis that platin analogs and oxazaphosphorines are synergistic is supported by preclinical data and
similar clinical experiences with other drug combinations
used in pediatric sarcomas. The combination of cisplatin
and cyclophosphamide showed therapeutic synergism
against advanced Ridgway osteogenic sarcoma and P388
leukemia.62 Therapeutic synergism was reported for the
combination of ifosfamide and cisplatin in L1210 leukemia,
with greater than four-fold increase in life span compared
with ifosfamide or cisplatin used as single agents.63 The
more recent clinical experience with topotecan in childhood
sarcomas provides a clinical example of possible synergism.
In a classic phase II trial, Nitschke et al64 reported that
single-agent topotecan induced no responses in children
with recurrent rhabdomyosarcoma. However, the combination of topotecan and moderate-dose cyclophosphamide is
active in recurrent rhabdomyosarcoma, with responses seen
in the initial phase I65 and phase II (H. Grier, personal
communication, November 1998) Pediatric Oncology
Group trials. The probable clinical synergism for topotecan
and cyclophosphamide also is predicted from preclinical
data for this combination.66,67 Finally, single-agent etoposide has minimal activity in osteosarcoma; however, when
combined with ifosfamide, the drug pair has shown more
activity in osteosarcoma than other agents tested by the
Pediatric Oncology Group in window trials.44
Of significance, the design of our trial permitted assessment of the long-term outcome for patients with osteosarcoma who received adjuvant therapy without cisplatin. For
the entire patient population enrolled onto OS-91, including
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Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
patients with metastatic and unresectable tumors, the 3- and
4-year survival estimates were 62.1% and 60.4%, respectively. Most adjuvant trials for osteosarcoma enroll and
report results only for those patients with nonmetastatic
tumors that are located in an extremity or are resectable, the
type of patients we enrolled onto stratum A. For this
stratum, the 3-year event-free survival was 72.3%, similar to
that of other contemporary clinical trials for this disease.
This event-free survival estimate includes two patients who
refused therapy before surgical resection of the primary
tumor, experienced disease progression, and ultimately died
of tumor.
We were unable to demonstrate any difference in outcome, based on histologic response. Our study was not
designed to test this end point, and power to detect differences was low. However, the outcomes for good and poor
histologic necrosis were similar. This finding is not consistent with those of many other neoadjuvant chemotherapy
trials in osteosarcoma; this may be a direct reflection of the
study design. Patients received carboplatin/ifosfamide without other known effective agents before surgical resection
of the primary tumor. The postsurgical therapy comprised
primarily doxorubicin and high-dose methotrexate cycles,
with only two additional cycles of carboplatin/ifosfamide.
Consequently, lack of response to the experimental drug
pair would not necessarily predict a poor outcome when the
remainder of the therapy was predominantly with agents of
known efficacy in the treatment of osteosarcoma.
Two important toxicities associated with curative therapy
for osteosarcoma were less prominent in patients enrolled
onto the OS-91 trial. Cisplatin-based therapy for this tumor
routinely results in irreversible hearing loss in some patients. We have previously reported that one half of patients
treated for osteosarcoma on the OS-86 trial, using both
ifosfamide and cisplatin, had hearing loss of sufficient
magnitude to require amplification.68 In the OS-91 study,
hearing loss developed only in the small number of patients
who had tumor progression in the window and subsequently
received cisplatin. No other patients had measurable
changes in hearing thresholds. Similarly, late renal toxicity
occurred less frequently. Although some patients who
received carboplatin/ifosfamide had renal tubular toxicity
during therapy, at 1 year after the end of treatment, few
patients who were enrolled onto OS-91 had permanent
sequelae; several patients similarly treated on the OS-86
trial required long-term electrolyte supplementation, and
one had irreversible renal failure.69
Is window therapy a safe approach for patients with
osteosarcoma? In both the OS-86 and OS-91 trials, the
survival and disease-free survival for patients with nonmetastatic, resectable disease was similar to those obtained
in other modern multiagent trials. Patients with disease
progression during the single-agent ifosfamide window did
not have inferior outcomes. However, the disease progression rate with single-agent ifosfamide was unacceptable for
a group of patients with good long-term outcome and for
whom limb salvage was a potential surgical option. This, in
part, was the rationale for combining carboplatin with
ifosfamide in the OS-91 study. With the addition of a
second agent, the progressive disease rate dropped significantly. However, the predicted outcome for patients enrolled onto our stratum A is clearly higher than that judged
acceptable by the recent National Cancer Institute Consensus Panel for pediatric window therapy trials in previously
untreated patients. We believe that in appropriate circumstances and with appropriate patient safeguards and early
stopping rules, continued window trials are an acceptable
and efficient way to test new agents in pediatric oncology.
However, they should include only those patients with
osteosarcoma who have been determined to be at higher risk
of treatment failure, specifically patients with unresectable
primary tumors and patients with metastatic disease present
at diagnosis.
Additional challenges remain with window trials in
osteosarcoma. Assessment of tumor response using standard clinical and radiologic techniques in patients with
osteosarcoma is difficult. These tumors often do not change
in size, even with effective multiagent chemotherapy; therefore, standard definitions for partial and complete response
based on change in tumor size are not useful.70 Although
newer radiologic techniques, such as DEMRI functional
imaging46,47,71 and thallium scanning,72 are promising, they
are not routinely used in multi-institutional trials. In particular, DEMRI imaging requires technical expertise and is not
widely available. However, although assessing response is
problematic, determining that a tumor is progressing during
initial therapy is typically unequivocal.
Histologic assessment of response remains the gold
standard. However, this assessment also has problems:
investigators have reported substantial variations in grading
response50,73-75; typically, only one cross-section of tumor
is assessed; assessment is available for one point in time;
degree of response may be dependent on length of presurgical therapy2 and agents used; and this assessment is not
applicable for tumors that cannot be resected. Assessment of
response of pulmonary metastatic lesions is also imperfect.
Not all pulmonary lesions seen on CT imaging are tumor.
As with the primary tumor, chemotherapy may cause
complete tumor necrosis without change in the size of the
pulmonary lesions. Not all patients with pulmonary metastatic disease are candidates for thoracotomy and metastasectomy. Finally, survival estimates for patients with met-
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Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
astatic disease are more variable than outcomes reported for
patients with nonmetastatic resectable tumors.6,43 Investigators who design and conduct such trials must carefully
define response criteria and encourage histologic response
assessment in as many patients as feasible.
This trial demonstrates that the combination of carboplatin and ifosfamide has substantial antitumor activity in
osteosarcoma and, in the context of multiagent therapy,
produces outcomes comparable to regimens that include
cisplatin with less long-term toxicity. Whether this combination will have substantial benefit, as judged by improve-
ment in outcome or similar outcome with significantly less
long-term toxicity than cisplatin-based treatment, requires
assessment by a prospective randomized comparative study.
We are indebted to the patients and families who participated in this
trial and to the staff members at St Jude Children’s Research Hospital
and the University of Nebraska Medical Center who assisted in their
care. We thank Mickey Cain and Loraine Avery for expert data
management support. This work is dedicated to Matt and his family.
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