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Journal of Clinical Oncology, Vol 26, No 4 (February 1), 2008: pp. 633-638
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2008.14.0095

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Osteosarcoma: The Addition of Muramyl Tripeptide to Chemotherapy Improves Overall Survival—A Report From the Children's Oncology Group

Paul A. Meyers, Cindy L. Schwartz, Mark D. Krailo, John H. Healey, Mark L. Bernstein, Donna Betcher, William S. Ferguson, Mark C. Gebhardt, Allen M. Goorin, Michael Harris, Eugenie Kleinerman, Michael P. Link, Helen Nadel, Michael Nieder, Gene P. Siegal, Michael A. Weiner, Robert J. Wells, Richard B. Womer, Holcombe E. Grier

From the Children's Oncology Group, Arcadia, CA

Corresponding author: Paul A. Meyers, MD, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: meyersp{at}mskcc.org


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Purpose To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma.

Patients and Methods Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 x 2 factorial design. The primary end points for analysis were EFS and overall survival.

Results In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96).

Conclusion The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
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. Approximately 20% of patients present with clinically detectable metastatic disease.

The value of adjuvant chemotherapy for treatment of OS is well established.2,3 Agents that have shown activity against OS include doxorubicin, cisplatin, and high-dose methotrexate with leucovorin rescue (HDMTX).4 Some investigators reported objective responses with ifosfamide in patients with OS whose disease relapsed after treatment with these agents.5-7

Muramyl tripeptide phosphatidyl-ethanolamine (MTP-PE) is a synthetic lipophilic analog of muramyl dipeptide, which is a component of the cell wall of Bacille Calmette-Guerin. MTP-PE has been encapsulated in liposomes, which help to deliver the agent selectively to monocytes and macrophages. These cells become activated and tumoricidal, as has been shown in rodent xenograft models and in spontaneous canine osteosarcoma.8,9 In preclinical studies, chemotherapy did not interfere with liposomal MTP-PE stimulation of macrophage cytotoxicity.10 We have shown that simultaneous administration of ifosfamide and liposomal MTP-PE did not increase toxicity of either agent and did not interfere with liposomal MTP-PE stimulation of cytokines.11

From November 1993 through November 1997, the Children's Cancer Group (CCG) and the Pediatric Oncology Group carried out Intergroup Study 0133 (CCG-7921, POG-9351). This was a prospective, randomized, phase III trial of treatment of newly diagnosed osteosarcoma in patients age 30 years or younger. The study posed two questions in a 2 x 2 factorial design (Appendix Fig A1, online only). The first factor was a comparison of the three-drug chemotherapy regimen of doxorubicin, cisplatin, and HDMTX with a four-drug regimen using these agents with ifosfamide for event-free survival (EFS) or overall survival. The second factor was whether addition of liposomal MTP to chemotherapy would improve EFS or overall survival. We have previously reported the preliminary results of this trial.12 With additional follow-up and review our conclusions about the study have changed, and we report an update of the results of this trial.


    PATIENTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Patient Selection
Study patients were required to have histologically confirmed high-grade intramedullary OS. Detailed eligibility requirements have previously been described.12

Treatment
Treatment details have been previously described.12 Approval from the institutional review board (IRB) was required at every institution before enrollment. Informed consent was obtained from all patients or their guardians, and the appropriate IRB-approved written informed consent was signed.

Statistical Methods
The study was conducted as a factorial design. At enrollment a patient was assigned to one of the following treatment plans: (1) chemotherapy A without MTP-PE, (2) chemotherapy A with MTP-PE, (3) chemotherapy B without MTP-PE, or (4) chemotherapy B with MTP-PE.

The primary goals of the study were to be addressed in patients without detectable metastases at diagnosis. The prospectively defined analytic strategy called for exclusion of patients whose primary tumor was assessed to be unresectable at study entry by the enrolling investigator. These patients were included in the previously published analysis but are excluded from consideration from this report.12 We planned to assess relative risks associated with two different chemotherapies and biologic intervention as marginal analyses within the factorial design. Marginal analyses are valid only if there is no evidence of interaction. 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 effects of MTP-PE.

We analyzed EFS, which was defined as the time from study entry until adverse event or last patient contact, whichever came first. Adverse events included disease progression, diagnosis of second malignant neoplasm, or death before disease progression. Overall survival was defined as the time from entry until death or last patient contact. Patients without events were censored at date of last contact. Cooperative group trials require adverse events to be reported as soon as they are detected. To avoid potential bias introduced by earlier reporting of adverse events, we used only data up to August 31, 2005, for this analysis.

EFS and overall survival were estimated with the Kaplan-Meier method.13 Statistical significance of the comparisons of risk for adverse event was assessed by means of the log-rank test. For outcomes measured from the time of enrollment and involving the randomized regimens, the stratified log-rank test was used. The stratification as determined at study enrollment was used in the adjustment. Confidence intervals (CIs) for relative risks were derived from the proportional hazards regression model. Interim monitoring for EFS was conducted three times during the period of accrual. We did not perform interim monitoring for survival. The method of DeMets and Lan14 was used with the spending function {alpha}t2.

Interaction between assigned chemotherapy and assigned biologic agent was assessed using the proportional hazards regression model. The hazard of an event was modeled as:

Formula

Briefly, the following terms were included in the regression model: c, chemotherapy, coded as 1 if the patient was assigned regimen B and 0 otherwise; m, biologic agent, coded as 1 if the patient was assigned to receive MTP-PE and 0 otherwise; and interaction, coded as the product of c and m, that is, 1 if the patient received both regimen B and MTP-PE and 0 otherwise. A P value associated with the test of hypothesis (β12 = 0) of .10 or less was considered evidence of a significant interaction.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Patient Characteristics
Among 793 patients enrolled onto INT-0133, 16 patients were considered ineligible. Ten patients were not treated within 30 days of diagnostic biopsy, as required by the protocol. Three patients were determined subsequently not to have osteosarcoma. One patient did not have normal cardiac function at enrollment. Two patients were declared ineligible because the appropriate IRB had not completed protocol review before entry.

Of the remaining 777 patients, 91 had clinically detectable metastases, and 24 patients were recorded as having an unresectable primary tumor by institutional investigators at study entry. The 662 patients without metastases and resectable primary tumors are the subjects of this report. Among them, 361 patients were male and 301 patients were female (Appendix Table A1, online only). Patient age at enrollment ranged from 1 to 30 years, with median age at entry of 13 years.

Outcome
As of August 2005, 240 of 662 patients had adverse events. Ten patients (1.5%) died without evidence of disease progression, 13 patients (2%) developed second malignant neoplasms, and 217 patients (33%) experienced disease recurrence. The 10 patients who experienced death as a first event were equally distributed among the four treatment arms. Four patients died as a result of infectious complications, one patient died as a result of an operative complication after definitive surgery, two patients died as a result of car accidents, one patient died as a result of a gunshot wound, one patient died as a result of an overdose of a self-administered illegal drug, and the cause of death for one patient could not be determined. The 13 patients who developed second malignant neoplasms were equally distributed among the treatment arms. The median follow-up for patients with no adverse events at analysis was 7.7 years.

Necrosis After Induction Chemotherapy
Patients who underwent definitive resection after induction had evaluation of necrosis by institutional pathologist. Necrosis was graded according to the method of Huvos, as modified by CCG.12,15 Ninety-four patients could not be evaluated for survival from definitive surgery: 73 patients were eliminated because detailed necrosis grading was not available, 29 patients were eliminated because the start date for the first maintenance course was not reported, and six patients were eliminated because they underwent amputation before study enrollment. Overall, 264 (47.1%) of 559 assessable patients exhibited grade 3 or 4 necrosis. There was no statistically significant difference between treatment arms in the probability of favorable grade 3 or 4 necrosis (Appendix Table A2, online only). Necrosis assessment preceded the introduction of MTP. None of the apparent differences in necrosis between treatment arms can be ascribed to MTP.

Only 19 patients had grade 1 necrosis. For grade 2 to 4 necrosis after induction, increasing necrosis was correlated with improved prognosis (Appendix Fig A2, online only).

EFS
In this cohort of patients, EFS was 66% at 4 years and 64% at 6 years from entry (Fig 1; Table 1).


Figure 1
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Fig 1. Event-free survival (EFS) and overall survival for patients newly diagnosed with osteosarcoma without clinically detectable metastatic disease.

 

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Table 1. EFS According to Treatment Regimen

 
Overall Survival
In this cohort of patients, overall survival was 81% at four years and 74% at six years from study entry (Fig 1; Table 1).

Outcome by Treatment Study Arm
EFS results for the four arms are shown in Figure 2A and Table 1. Regimen A without MTP was associated with a 66% and 64% probability of EFS at 4 and 6 years, respectively. The addition of MTP to regimen A resulted in 65% and 63% probability of EFS at 4 and 6 years, respectively. The use of four chemotherapy drugs including ifosfamide (regimen B without MTP) resulted in 60% and 58% probability of EFS at 4 and 6 years, respectively. Treatment with four chemotherapy drugs including ifosfamide and the addition of MTP (regimen B with MTP) resulted in 74% and 71% probability of EFS at 4 and 6 years, respectively (Fig 2A; Table 1). To analyze the study in accordance with the initial factorial design, there had to be no interaction between the two study questions. The proportional hazards regression analysis P value associated with the test of the hypothesis of no interaction between the chemotherapy intervention and the MTP intervention was .102, which does not meet the conventional level of significance of less than .1 (Table 2). EFS for all patients treated with cisplatin, doxorubicin, and HDMTX was 65% and 63% at 4 and 6 years, respectively. EFS for patients who received these three drugs with the addition of ifosfamide was 66% and 64% at 4 and 6 years, respectively. There was no difference between the two chemotherapy regimens (P = .91; Fig 2B). EFS rates for the patients treated with chemotherapy alone were 63% and 61% at 4 and 6 years, respectively. EFS for the patients treated with MTP and chemotherapy was 69% and 67% at 4 and 6 years, respectively (Fig 2C; Table 1). The hazard ratio for EFS for patients who received MTP was 0.80 (95% CI, 0.62 to 1.0; Table 2). This apparent improvement does not meet a conventional P < .05 level of significance (P = .08).


Figure 2
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Fig 2. (A) Event-free survival (EFS) for patients according to treatment arm. Regimen A included cisplatin, doxorubicin, and high-dose methotrexate. Regimen B included the same agents with the addition of ifosfamide. Regimens A+ and B+ also included the investigational agent muramyl tripeptide (MTP). (B) EFS for all patients assigned to treatment with regimen A versus regimen B, independent of assignment to receive or not receive MTP (P = .91). (C) EFS for all patients assigned to receive or not receive MTP, independent of assignment to chemotherapy regimen (P = .08).

 

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Table 2. Analysis of Interaction of MTP

 
Survival for the four treatment arms is shown in Figure 3A and Table 1. Regimen A without MTP was associated with a probability of survival of 78% and 71% at 4 and 6 years, respectively. The addition of MTP achieved a probability of survival of 82% and 75% at 4 and 6 years, respectively. Regimen B without MTP was associated with a probability of survival of 77% and 70% at 4 and 6 years, respectively. Treatment with four chemotherapy drugs including ifosfamide and the addition of MTP (regimen B with MTP) resulted in a probability of survival of 86% and 81% at 4 and 6 years, respectively. For overall survival, the proportional hazards regression analysis P value associated with the test of the hypothesis of no interaction between the chemotherapy intervention and the MTP intervention was .60, which does not meet a conventional level of significance (Table 2). We performed the stratified analysis as prospectively defined. There is no evidence of an interaction. The two chemotherapy regimens seem to convey the same risk of death (P = .83; Fig 3B). The relative risk of death for patients randomly assigned to receive MTP is 0.71 (95% CI, 0.52 to 0.96; P = .03; Fig 3C; Table 2).


Figure 3
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Fig 3. (A) Overall survival for patients according to treatment arm. Regimens are the same as in Figure 2. (B) Overall survival for all patients assigned to treatment with regimen A versus regimen B, independent of assignment to receive or not receive muramyl tripeptide (MTP) (P = .83). (C) Overall survival for all patients assigned to receive or not receive MTP, independent of assignment to chemotherapy regimen (P = .03).

 
We examined the treatment patients received after disease recurrence. We have data available for 207 (86%) of 240 patients who experienced disease recurrence as a first event. The missing data are evenly distributed across study arms (Appendix Table A3, online only).

We examined the site of the first recurrence after protocol therapy. We compared the number of patients whose first recurrence was limited to the lungs with the number of patients whose first recurrence occurred at all other sites. Patients with metastasis to the lung and another site were included with the patients whose first site of recurrence was outside the lungs. There was no difference among the study arms (Appendix Table A4, online only).

We compared the number of patients who were reported to have surgery performed after relapse. There is no difference between arms in the likelihood that patients underwent surgery after recurrence (Appendix Table A5, online only).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
EFS for all 662 patients was 66% and 64% at 4 and 6 years from diagnosis, respectively. Most outcome reports of OS have focused on EFS of patients 21 years or younger with tumors limited to the appendicular skeleton. In the current series, we treated 623 patients who met these criteria, and their 4- and 6-year EFS rates were 66% and 64%, respectively.

MTP-PE demonstrated the ability to decrease the risk of OS recurrence in dogs and in phase I human trials, and we wished to evaluate the ability of the addition of MTP-PE to chemotherapy to improve the outcome of the treatment of human OS.9-11

We used a factorial design, and the power calculations were based on the assumption that we would conduct a marginal analysis within the 2 x 2 factorial design. To ensure the validity of the marginal analysis, there should be no evidence of interaction. Before this study, we performed a small pilot study of simultaneous chemotherapy and MTP.11 We did not observe any interaction. We chose to introduce MTP after definitive surgery. We did not wish to introduce it before surgery because we believed that the biologic agent would have its best opportunity to influence survival after tumor bulk was minimized. We considered delaying MTP introduction until after completion of chemotherapy to avoid the risk of interaction completely. We rejected this option because clinical progression of OS is observed weeks to months after tumor cells develop resistance to chemotherapy and begin to proliferate. The timing of relapse after treatment for OS suggested that most patients whose treatments fail develop resistant tumor clones while still receiving chemotherapy. If we had delayed the introduction of MTP until after chemotherapy, we might have lost the opportunity to see an effect on tumor control.

In an earlier report of the results of this trial, we concluded that the existence of an interaction invalidated the prospective factorial design for the analysis of the impact of MTP on EFS.12 We did not previously analyze overall survival, nor did we examine any impact of interaction between the interventions on overall survival. Using the same prospectively defined test for interaction that we used in the current analysis, the previous analysis of EFS provided significant evidence of an interaction between the chemotherapy regimen and treatment with MTP (P = .049). With additional follow-up and with further examination of the data, we now believe that the a priori defined marginal analysis strategy remains valid to analyze the impact of the addition of MTP. Our analysis of the outcome for both EFS and overall survival does not identify an interaction between the two interventions, and our prospectively defined stratified analysis remains appropriate. When MTP was added to chemotherapy, EFS improved, but the difference does not meet a conventional definition of significance. For all patients who were not assigned to receive MTP, 6-year EFS was 61%; 6-year EFS for patients assigned to receive MTP was 67% (P = .08). The inclusion of five cycles of ifosfamide at a dose of 9 g/m2/cycle had no impact on EFS. Although the interaction test does not meet the statistical test, the value was close to the conventional level of significance used to define an interaction. Inspection of the EFS outcome suggests that the impact of MTP on EFS was different for patients who received ifosfamide and for those who did not (Fig 2A), although there is no suggestion that the interaction is qualitative. There is no suggestion of any interaction between chemotherapy and MTP in the impact on overall survival.

The addition of MTP to chemotherapy resulted in enhanced overall survival. The addition of MTP to chemotherapy resulted in improvement in 6-year overall survival from 70% to 78% (P = .03; relative risk = 0.71). This is an almost one third reduction in the risk of death. We think the improved survival can appropriately be ascribed to the prospectively randomized addition of MTP. In some diseases, therapy after relapse can have a marked impact on postrelapse survival. Several analyses of survival after relapse of OS have been carried out.16-18 All of them reach similar conclusions. The factors that predict survival after OS relapse include the interval from completion of initial therapy to the detection of relapse, the number and sites of relapse, and adequacy of surgical resection of all sites of clinically detected metastatic disease. None of the studies has suggested that the use of chemotherapy or the use of any specific chemotherapy agents at the time of recurrence has an impact on subsequent survival. We analyzed the patients who experienced relapse after initial therapy on this trial. We compared patients who did or did not receive MTP as part of that initial therapy. For patients who had recurrence of disease as a first event, we compared the time from study enrollment across randomized regimens. There was no significant difference in median time to disease recurrence. There was no difference between the groups in number and sites of relapse or extent of surgical resection of metastases. This leads us to conclude that the significant improvement in overall survival with median follow-up of 7.7 years can be ascribed to the addition of MTP to initial chemotherapy treatment.

We were unable to detect an improvement in the treatment of OS from the addition of ifosfamide in this dose schedule to cisplatin, doxorubicin, and high-dose methotrexate. The EFS we documented using that three-drug combination was similar to that reported by other groups using multiagent regimens and was superior to the simpler combination of cisplatin and doxorubicin alone.19 We observed improvement in both EFS and overall survival for patients who received MTP.

MTP-PE is currently an investigational agent and is not available for administration to patients except through participation in a clinical trial. The results of this study will require thoughtful consideration of the appropriate role for inclusion of MTP-PE in the treatment of patients with OS in the future.


    AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Gene P. Siegal, National Institutes of Health Expert Testimony: Paul A. Meyers, IDM (U) Other Remuneration: Paul A. Meyers, IDM


    AUTHOR CONTRIBUTIONS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Conception and design: Paul A. Meyers, Cindy L. Schwartz, Mark D. Krailo, Mark L. Bernstein, Donna Betcher, Mark C. Gebhardt, Eugenie Kleinerman, Michael P. Link, Helen Nadel, Michael A. Weiner, Robert J. Wells, Richard B. Womer, Holcombe E. Grier

Administrative support: Paul A. Meyers, Cindy L. Schwartz

Provision of study materials or patients: Paul A. Meyers, Cindy L. Schwartz, John H. Healey, Mark L. Bernstein, William S. Ferguson, Allen M. Goorin, Michael Nieder, Michael A. Weiner, Robert J. Wells, Holcombe E. Grier

Collection and assembly of data: Paul A. Meyers, Cindy L. Schwartz, Mark D. Krailo, John H. Healey, Donna Betcher, William S. Ferguson, Mark C. Gebhardt, Allen M. Goorin, Michael Nieder, Gene P. Siegal, Robert J. Wells

Data analysis and interpretation: Paul A. Meyers, Cindy L. Schwartz, Mark D. Krailo, John H. Healey, Donna Betcher, William S. Ferguson, Michael P. Link, Michael Nieder, Gene P. Siegal, Robert J. Wells, Richard B. Womer, Holcombe E. Grier

Manuscript writing: Paul A. Meyers, Cindy L. Schwartz, Mark D. Krailo, John H. Healey, Donna Betcher, William S. Ferguson, Allen M. Goorin, Michael P. Link, Michael Nieder, Gene P. Siegal, Michael A. Weiner, Robert J. Wells, Richard B. Womer, Holcombe E. Grier

Final approval of manuscript: Paul A. Meyers, Cindy L. Schwartz, Mark D. Krailo, John H. Healey, Mark L. Bernstein, Donna Betcher, William S. Ferguson, Mark C. Gebhardt, Michael B. Harris, Eugenie Kleinerman, Michael P. Link, Michael Nieder, Gene P. Siegal, Michael A. Weiner, Robert J. Wells, Holcombe E. Grier


    Appendix
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
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Figure 4
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Fig A1. Protocol road map. DOXO, doxorubicin; CDDP, cisplatin; HDMTX, high-dose methotrexate; IFOS, ifosfamide; L-MTP-PE, muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes.

 
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Figure 5
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Fig A2. Necrosis observed in the primary tumor at the time of definitive surgical resection after induction chemotherapy is correlated with event-free survival.

 
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Table A1. Patient Characteristics

 
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Table A2. Necrosis in the Primary Tumor After Induction Chemotherapy

 
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Table A3. Data for Postrelapse Therapy by Study Arm

 
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Table A4. Site of Relapse by Study Arm

 
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Table A5. Surgery After Relapse by Study Arm

 


    ACKNOWLEDGMENTS
 
Ernest Conrad, MD, and Judith Sato, MD, contributed to the conception and design, provision of study material or patients, collection and assembly of data, and data analysis and interpretation of this study.


    NOTES
 
Supported by Children's Oncology Group Grant No. CA98543. A complete listing of grant support for research conducted by Children's Cancer Group and Pediatric Oncology Group before initiation of the Children's Oncology Group grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.


    REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
1. Meyers PA, Gorlick R: Osteosarcoma. Pediatr Clin North Am 44:973-989, 1997[CrossRef][Medline]

2. Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314:1600-1606, 1986[Medline]

3. Meyers PA, Heller G, Healey J, et al: Chemotherapy for nonmetastatic osteogenic sarcoma: The Memorial Sloan-Kettering experience. J Clin Oncol 10:5-15, 1992[Medline]

4. Link M, Meyers PA, Gebhardt M: Osteosarcoma, in Pizzo P, Poplack DG (eds): Principles and Practice of Pediatric Oncology. Philadelphia, PA, Lippincott Williams & Wilkins, 2006, pp 1074-1115

5. Harris MB, Cantor AB, Goorin AM, et al: Treatment of osteosarcoma with ifosfamide: Comparison of response in pediatric patients with recurrent disease versus patients previously untreated—A Pediatric Oncology Group study. Med Pediatr Oncol 24:87-92, 1995[Medline]

6. 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[CrossRef][Medline]

7. 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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

9. MacEwen EG, Kurzman ID, Rosenthal RC, et al: Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst 81:935-938, 1989[Abstract/Free Full Text]

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[Abstract]

11. Kleinerman ES, Meyers PA, Raymond AK, et al: Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: Tolerability, toxicity, and immune stimulation. J Immunother Emphasis Tumor Immunol 17:181-193, 1995[Medline]

12. Meyers PA, Schwartz CL, Krailo M, et al: Osteosarcoma: A randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 23:2004-2011, 2005[Abstract/Free Full Text]

13. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

14. DeMets DL, Lan KK: Interim analysis: The alpha spending function approach. Stat Med 13:1341-1352, 1994[Medline]

15. Rosen G, Marcove RC, Caparros B, et al: Primary osteogenic sarcoma: The rationale for preoperative chemotherapy and delayed surgery. Cancer 43:2163-2177, 1979[CrossRef][Medline]

16. Chou AJ, Merola PR, Wexler LH, et al: Treatment of osteosarcoma at first recurrence after contemporary therapy: The Memorial Sloan-Kettering Cancer Center experience. Cancer 104:2214-2221, 2005[CrossRef][Medline]

17. Hawkins DS, Arndt CA: Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer 98:2447-2456, 2003[CrossRef][Medline]

18. Kempf-Bielack B, Bielack SS, Jurgens H, et al: Osteosarcoma relapse after combined modality therapy: An analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 23:559-568, 2005[Abstract/Free Full Text]

19. Souhami RL, Craft AW, Van der Eijken JW, et al: Randomised trial of two regimens of chemotherapy in operable osteosarcoma: A study of the European Osteosarcoma Intergroup. Lancet 350:911-917, 1997[CrossRef][Medline]

Submitted September 10, 2007; accepted October 23, 2007.


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