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Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 2004-2011 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.06.031 Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose MethotrexateFrom the Children's Oncology Group, Arcadia, CA Address reprint requests to 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
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 x 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.
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 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 (MTP) phosphatidylethanolamine (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 to deliver the agent selectively to monocytes and macrophages to activate them to become tumoricidal and was active in rodent xenograft models and in spontaneous canine OS.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 (POG) carried out Intergroup Study 0133 (CCG-7921 and POG-9351). This was a prospective, randomized phase III trial of treatment of newly diagnosed OS in patients who were 30 years old or younger. The study posed two questions in a 2 x 2 factorial design (Fig 1). The first question was whether addition of ifosfamide to doxorubicin, cisplatin, and HDMTX would improve event-free survival (EFS). The second question was whether addition of liposomal MTP to chemotherapy would improve EFS. We report the results of this trial for patients who presented without clinically detectable metastatic disease.
Patient Selection Study patients had to have histologically confirmed, high-grade, intramedullary OS. Initial surgery was specified as biopsy only, but patients who had primary ablative surgery, typically amputation, were eligible. Patients who received any prior chemotherapy or radiation were ineligible. Patients with clinically detectable metastatic disease were eligible at CCG institutions but ineligible at POG institutions. Patients had to have adequate renal function, as defined by serum creatinine  1.5 x normal or creatinine clearance more than 40 mL/min/m2 or more than 70 mL/min/1.73 m2; adequate hepatic function, as defined by bilirubin 1.5 x normal and AST or ALT 2.5 x normal; and adequate cardiac function, as defined by fractional shortening on echocardiogram  29% or ejection fraction by radionuclide angiography 50%. 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.
Treatment Both regimens called for an initial period of chemotherapy, which was designated as induction, that lasted 10 weeks, followed by definitive resection of primary tumor. Maintenance was scheduled to begin at week 12 but did not begin until the surgeon determined that wound healing was adequate. Maintenance continued until week 31 in regimen A and week 38 in regimen B. Regimen A consisted of four courses of cisplatin 120 mg/m2 over 4 hours combined with doxorubicin 75 mg/m2 administered as a 72-hour continuous infusion administered twice during induction at weeks 0 and 5 and twice during maintenance at weeks 12 and 17. An additional two courses of doxorubicin without cisplatin were administered at weeks 22 and 27. HDMTX 12 g/m2 with a maximum dose of 20 g was administered as a 4-hour infusion followed by leucovorin administration at 10 mg (not adjusted to body-surface area) beginning 24 hours from initiation of methotrexate infusion and continuing until the serum methotrexate level was less than 1 x 10–7 mol/L (100 nmol/L). Serum methotrexate levels and renal function were monitored daily, and hydration, alkalinization, and leucovorin doses were specified in the event of delayed methotrexate excretion. HDMTX was administered 12 times, four times during induction at weeks 3, 4, 8, and 9 and eight times during maintenance at weeks 15, 16, 20, 21, 25, 26, 30, and 31. To maintain dose-intensity of doxorubicin, the protocol specified that, if there was a delay greater than 1 week between the first and second of each pair of HDMTX administrations, the second was omitted. Regimen B included ifosfamide 1.8 g/m2/d with mesna uroprotection for 5 days; a total dose of 9 g/m2 was administered five times, twice during induction at weeks 0 and 5 and three times during maintenance at weeks 17, 27, and 35. The first four courses of ifosfamide were to be administered with doxorubicin. Cisplatin 120 mg/m2 was administered four times, all during maintenance, at weeks 12, 22, 32, and 38. The first two courses of cisplatin were scheduled to be administered with doxorubicin. Doxorubicin and methotrexate were administered at the same doses and in the same weeks as regimen A. Total doses of cisplatin, doxorubicin, and HDMTX were the same in the two arms (cisplatin 480 mg/m2, doxorubicin 450 mg/m2, and HDMTX 144 g/m2). Timing of doxorubicin and HDMTX was the same in both arms. Patients assigned to regimen B received ifosfamide during induction to maximize its effect on tumor response. Thus, from the perspective of evaluating tumor necrosis, regimen B could be considered a substitution of ifosfamide for cisplatin. The overall strategy was that regimen B differed from regimen A by the addition of ifosfamide to the combination of cisplatin, doxorubicin, and HDMTX. Half the patients were assigned randomly at entry to receive liposomal MTP beginning at week 12. It was administered at a dose of 2 mg/m2. Patients initially were not permitted to have premedications and were monitored for signs of biologic activity, which was defined as fever, chills, or increase in the C-reactive protein. If a patient had no sign of biologic activity, the next dose of MTP was 2 mg/m2, with an additional 1 mg. If a patient had no sign of biologic activity after the first dose escalation, a second dose escalation of 2 mg/m2, with an additional 2 mg, was used for the third dose of MTP. No further escalation was allowed. Each subsequent dose of MTP was either the dose that provoked signs of biologic activity or the maximum dose. Premedication limited to acetaminophen and diphenhydramine was permitted with the 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-µm 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 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 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
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 Administration of MTP was associated with fever and chills. The protocol called for dose escalation of MTP until these effects were observed to assure biologic activity. Most patients did not need dose escalation. Reactions to MTP decreased with time for most patients, but fever and chills continued for some patients with each administration of MTP, despite premedication. Administration was scheduled to continue beyond completion of chemotherapy in both arms that called for MTP. Patients were more likely to withdraw from therapy before completion of all protocol-specified therapy on these arms.
Outcome
Prognostic Factors
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 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 x 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 HDMTX without MTP) the standard arm of this trial. The easiest way to recognize the interaction was to observe the effect of MTP addition to the patients assigned to receive ifosfamide compared with the standard arm. Patients treated with regimen A– had a 64% probability of EFS at 5 years. Patients who received cisplatin, doxorubicin, HDMTX, and ifosfamide (regimen B–) had a 53% probability of EFS at 5 years. Patients who received cisplatin, doxorubicin, HDMTX, ifosfamide, and MTP (regimen B+) had a 72% probability of EFS at 5 years. Addition of ifosfamide to standard treatment seemed to decrease EFS, whereas the addition of ifosfamide and MTP seemed to increase EFS (Table 4).
Because the study could not be analyzed according to its original factorial design, we provided estimates of EFS according to treatment assignments. The results of the four arms are shown in Figure 4. Regimen A– was associated with a 71% and 64% probability of EFS at 3 and 5 years, respectively. The addition of MTP (regimen A+) resulted in a 68% and 63% probability of EFS at 3 and 5 years, respectively. The addition of ifosfamide (regimen B–) resulted in a 61% and 56% probability of EFS at 3 and 5 years, respectively. The addition of ifosfamide and MTP resulted in a 78% and 72% probability of EFS at 3 and 5 years, respectively (Fig 4).
We sought to obtain prospective information about several factors at diagnosis that were reported to correlate with EFS. We confirmed that serum alkaline phosphatase and lactate dehydrogenase elevations above institutional normal values correlated with lower probability for EFS. We confirmed that proximal tumors and tumors of the axial skeleton, especially pelvic primary tumors, have lower probability for EFS. Tumor size correlated with outcome. Unlike some reports that used retrospective analysis, we did not identify age, sex, or ethnicity as predictive of outcome. Eligibility was limited to patients 30 years of age or younger, so we cannot comment on the effect on prognosis of age beyond 30 years. EFS for all 677 patients was 70% and 63% at 3 and 5 years from diagnosis, respectively. Most outcome reports of OS have focused on EFS of patients 21years old or younger with tumors limited to the appendicular skeleton. In the current series, we treated 622 patients who met these criteria, and their 3- and 5-year EFS rates were 70% and 63%, respectively. We used a factorial design, and a priori power calculations were based on the assumption that we would collapse study arms to aggregate all patients for each question. Factorial analysis relies on no interaction between the interventions tested. 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. Unfortunately, we did observe an interaction between addition of ifosfamide and addition of MTP. Factorial analysis does not require that the magnitude of the effect of an intervention be the same, but the direction of that effect must be the same. The easiest way to observe the interaction between the two interventions is to compare treatment regimen B– and regimen B+ to the standard arm (regimen A–) of the protocol. When ifosfamide was added to cisplatin, doxorubicin, and HDMTX (regimen B–), EFS decreased. When ifosfamide was added to the same three agents with MTP (regimen B+), EFS increased. The interaction made it impossible to perform the factorial analysis as planned, so we had to examine study outcome as a four-arm trial. The study was not designed to analyze four arms with adequate power. We consider regimen A– to be the standard arm of this trial. None of the other three arms of this study was significantly different from regimen A– (Table 4). Rates of favorable necrosis for the two induction arms were identical. We concluded that ifosfamide and cisplatin are equivalent in their ability to contribute to favorable necrosis. The addition of ifosfamide to cisplatin, doxorubicin, and HDMTX did not enhance EFS. The four-drug B– regimen actually seemed to have the worst outcome. Addition of MTP to the standard chemotherapy treatment (regimen A+) had no impact on EFS. Addition of MTP to the four-drug chemotherapy regimen (regimen B+) resulted in the most favorable EFS of the four arms.
How can we understand these confusing results? One possible explanation is that the apparent differences among the arms were the result of chance. Because of failure of the factorial design, our study did not have the power to exclude that possibility with complete confidence. The A possible biologic explanation for the observed outcome involves the interaction between fas and fas ligand. Lafleur et al14 showed that 4-hydroperoxy-cyclophosphamide, an active metabolite of oxazaphosphorine chemotherapy, enhances fas ligand expression in an OS cell line. This upregulation was not observed with doxorubicin, cisplatin, or methotrexate. They found that MTP stimulates multiple cytokines, including interleukin (IL) -12, and that IL-12 upregulates expression of fas in an OS cell line selected for high probability to metastasize.15 Administration of ifosfamide and MTP could activate the fas/fas-ligand pathway that initiates apoptosis. This hypothesis suggests that we should investigate other agents with the potential to affect IL-12 and the fas/fas-ligand pathway. 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 HDMTX. The EFS we documented using that three-drug combination was similar to that reported by other groups using multiagent regimens and superior to the simpler combination of cisplatin and doxorubicin alone.15 We observed a potential interaction between the alkylating agent ifosfamide and MTP. This interaction will need further laboratory and clinical investigation to evaluate potential mechanisms and confirm any clinical value.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for 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 ASCO‘s 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.
A complete listing of grant support for research conducted by the Children's Cancer Group and the 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 are found at the end of this article.
1. Meyers PA: Malignant bone tumors in childhood: Osteosarcoma. Hematol Oncol Clin North Am 1:655-665, 1987[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[Abstract] 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 4. Link MP, Meyers PA, Gebhardt M: Osteosarcoma, in Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology (ed 4). Philadelphia: Lippincott Williams & Wilkins, 2001, pp 1051-1089 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. 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[CrossRef][Medline]
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 81:935-936, 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[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. Provisor AJ, Ettinger LJ, Nachman JB, et al: Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: A report from the Children's Cancer Group. J Clin Oncol 15:76-84, 1997 13. Kalbfleisch J, Prentice R: The Statistical Analysis of Failure Time Data. New York, NY: John Wiley and Sons, 1980
14. Lafleur EA, Jia S-F, Worth LL, et al: Interleukin (IL)-12 and IL-12 gene transfer up-regulate fas expression in human osteosarcoma and breast cancer cells. Cancer Res 61:4066-4071, 2001 15. 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 June 3, 2004; accepted December 1, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
t2. 
2 analysis for homogeneity suggested that the probability of the outcome we observed is only 4%, but a major contribution to the inhomogeneity is the unexpectedly inferior outcome of regimen B–. 
