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Osteosarcoma: The Same Old Drugs or More?

Klinikum Stuttgart, Olgahospital, Pädiatrie 5 (Onkologie, Hämatologie, Immunologie), Stuttgart; and Universitätsklinikum Münster, Pädiatrische Hämatologie und Onkologie, Münster, Germany

Neyssa Marina

Division of Hematology-Oncology, Stanford University Medical Center & Lucile Packard Children's Hospital, Palo Alto, CA

Stefano Ferrari

Sezione di Chemioterapia, Istituto Ortopedico Rizzoli, Bologna, Italy

Lee J. Helman

Center for Cancer Research, National Institutes of Health, Bethesda, MD

Sigbjørn Smeland

Division of Cancer Medicine and Radiotherapy, The Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway

Jeremy S. Whelan

Department of Oncology, University College Hospital, London, United Kingdom

Gregory H. Reaman

Division of Oncology, Children's National Medical Center, George Washington University, Washington, DC

To the Editor:

Evaluation of treatment strategies in osteosarcoma has historically been a controversial subject. In the early 1980s, many outstanding investigators argued both for and against the utility of adjuvant chemotherapy.^1-4 This issue was eventually settled when prospective randomized trials demonstrated superior outcome for patients receiving adjuvant treatment. We are now faced with a similar controversy regarding the role of an adjunct to conventional chemotherapy. Meyers et al⁵ and the Children's Oncology Group are to be congratulated on the largest ever completed randomized trial in osteosarcoma. After more than 20 years of stagnation with conventional chemotherapy, their report seems to suggest that liposomal muramyl tripeptide ethanolamine (MTP), an immune modulator, improves the overall survival for patients with this disease. In this trial, INT0133, 662 young patients with localized, resectable osteosarcoma were randomly assigned to high-dose methotrexate, cisplatin, and doxorubicin plus ifosfamide in a 2 x 2 factorial design which also included a randomized evaluation of MTP.^5,6

Several osteosarcoma groups have obtained their best results using ifosfamide-containing regimens.⁷ In the schedule used by the authors, however, the addition of ifosfamide neither enhanced event-free survival (EFS) nor overall survival.^5,6 Before abandoning ifosfamide from osteosarcoma chemotherapy, however, it should be noted that cisplatin was omitted from preoperative chemotherapy in the ifosfamide-containing arm of INT0133, so that evaluation of the role of ifosfamide was hampered due to the lack of clarity as to its contribution as a substitute or adjunct.

As for MTP, the first analysis reported by the authors concluded that there was a significant interaction with ifosfamide, and no significant impact on EFS.⁶ In the current analysis, however, the authors report a trend for better EFS (P =.08) and improved overall survival (P =.03) for the MTP arm. The previously observed interaction was no longer apparent.⁵ Does this mean that MTP, provided it becomes commercially available, should now be considered an integral part of systemic first-line therapy for osteosarcoma? Must it be considered standard-of-care as an adjunct to any conventional chemotherapy for localized osteosarcoma?

Like all other clinicians dedicated to the care of bone tumor patients, we would welcome additional effective agents as weapons in our armamentarium, but we believe that some words of caution are appropriate before universally adopting MTP as standard-of-care. First, even in rare diseases such as osteosarcoma, decisions with such wide-ranging implications should never be based on a single trial. Second, it is not evident that MTP improves EFS in osteosarcoma. INT0133 leaves ample room for discussion and speculation about the reasons behind any observed survival differences. Taking a closer look at the life-tables in the article, for instance, one cannot fail to observe that, despite the lack of a statistically proven interaction, the EFS for the three-drug arm was absolutely identical regardless of whether MTP was added or not. Such an observation argues against any substantial efficacy of MTP, at least in this combination.

Furthermore, EFS and overall survival are extremely closely linked in osteosarcoma.⁷ The reasons why this should not be the case when MTP is used as part of treatment are obscure. The authors try to convince us that the differences in postrecurrence treatment were in no way responsible. Their claim, however, that there is no suggestion that the use of chemotherapy at the time of recurrence has an impact on subsequent survival is not substantiated by all of the references they use to support it—quite to the contrary: the use of chemotherapy in recurrent osteosarcoma correlates with prolonged survival in unresectable disease^8,9 and has been found to correlate with improved EFS in resectable recurrences in the largest reported series.⁹

What happens after recurrence that would make prior treatment with MTP seem advantageous? Might different rates of surgical remissions or different approaches to second-line chemotherapy have influenced the results, rather than MTP? Could other factors have been responsible? Is MTP only beneficial when given in conjunction with ifosfamide? Is it or the combination truly efficacious in prolonging survival without any difference in intervening recurrences?

In summary, the updated results of INT0133 strongly suggest that MTP is an agent that warrants additional investigation given the substantial uncertainties that remain regarding its true role in the treatment of osteosarcoma. The data reported here mandate a randomized comparative evaluation to substantiate its utility. Undoubtedly, confirmatory trials would be required before the agent can be considered for routine use.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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: Stefan S. Bielack, IDM Pharma (C); Neyssa Marina, IDM Pharma (C); Stefano Ferrari, IDM Pharma (U); Sigbjørn Smeland, IDM Pharma (U); Jeremy S. Whelan, IDM Pharma (U) Stock Ownership: None Honoraria: Stefan S. Bielack, IDM Pharma; Neyssa Marina, IDM Pharma Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Lange B, Levine AS: Is it ethical not to conduct a prospectively controlled trial of adjuvant chemotherapy in osteosarcoma? Cancer Treat Rep 66:1699-1704, 1982[Medline]

2. Jaffe N, van Eys J, Gehan E: Response to "Is it ethical not to conduct a prospectively controlled trial of adjuvant chemotherapy in osteosarcoma?" Cancer Treat Rep 67:1743-1745, 1983

3. Carter SK: Adjuvant chemotherapy in osteosarcoma: The triumph that isn't? J Clin Oncol 2:147-148, 1984[Medline]

4. Holland JF: Adjuvant chemotherapy of osteosarcoma: No runs, no hits, two men left on base. J Clin Oncol 5:4-6, 1987[Medline]

5. 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]

6. Meyers PA, Schwartz CL, Krailo MD, et al: Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival—A report from the Children's Oncology Group. J Clin Oncol 26:633-638, 2008[Abstract/Free Full Text]

7. Bielack SS, Machatschek JN, Flege S, et al: Delaying surgery with chemotherapy for osteosarcoma of the extremities. Expert Opin Pharmacother 5:1243-1256, 2004[CrossRef][Medline]

8. Ferrari S, Briccoli A, Mercuri M, et al: Postrelapse survival in osteosarcoma of the extremities: Prognostic factors for long-term survival. J Clin Oncol 21:710-715, 2003[Abstract/Free Full Text]

9. Kempf-Bielack B, Bielack SS, Jürgens 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]

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