Originally published as JCO Early Release 10.1200/JCO.2008.16.2305 on December 15 2008

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Second and Subsequent Recurrences of Osteosarcoma: Presentation, Treatment, and Outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group Patients

From the Klinikum Stuttgart, Olgahospital, Klinik für Kinder und Jugendmedizin, Pädiatrie 5 (Onkologie, Hämatologie, Immunologie) and Pädiatrie 1 (Allgemeine Pädiatrie, Rheumatologie, Neurologie, Allergologie/Pulmologie, Gastroenterologie), Stuttgart; Universitätsklinikum Münster, Klinik und Poliklinik für Kinder und Jugendmedizin, Pädiatrische Hämatologie und Onkologie, Münster; Krankenhaus Groβhansdorf, Zentrum für Pneumologie und Thoraxchirurgie, Groβhansdorf; Klinik Schillerhöhe, Zentrum für Pneumologie und Thoraxchirurgie, Gerlingen; Universitätsklinikum Hamburg-Eppendorf, Universitätsklinik und Poliklinik für Kinder und Jugendmedizin, Abteilung für Pädiatrische Radiologie; Radiologische Privat-Praxis Raboisen; Universitätsklinikum Hamburg-Eppendorf, Ambulanzzentrum GmbH des UKE, Bereich Strahlentherapie, Hamburg, Germany; Universitätsspital beider Basel, Institut für Pathologie; Universitätskinderspital beider Basel, Onkologie/Hämatologie, Basel, Switzerland; and St. Anna Kinderspital, Vienna, Austria.

Corresponding author: Stefan S. Bielack, MD, Cooperative Osteosarkomstudiengruppe, Klinikum Stuttgart – Olgahospital, Pädiatrie 5 (Onkologie, Hämatologie, Immunologie), Bismarckstr 8, D-70176 Stuttgart, Germany; e-mail: coss{at}olgahospital-stuttgart.de.

	ABSTRACT

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Purpose To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma.

Patients and Methods Two hundred forty-nine consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes.

Results Five-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions.

Conclusion To our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.

	INTRODUCTION

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Prognosis after osteosarcoma recurrence is poor, with a less than 20% long-term survival rate. Nevertheless, some patients survive multiple bouts of disease.^1–22 So far, however, there have been no large-scale analyses of unselected patients with osteosarcoma rerecurrences, and prognostic estimates are largely based on personal experiences and small series.

The Cooperative Osteosarcoma Study Group (COSS) has previously presented data on 1,702 consecutive patients with osteosarcoma,²³ 576 of whom had a first recurrence.²⁰ Prognosis after first recurrence was better for patients with longer recurrence-free intervals and those with solitary lesions. Complete surgery was basically required for cure. In comparison, the use of second-line chemotherapy correlated with much more limited survival gains.²⁰ Three hundred thirty-nine of the 576 patients achieved a second complete surgical remission.²⁰ Here, we evaluate all of these patients who suffered further recurrences. The aims of this study were to describe the presentation of second and subsequent osteosarcoma recurrences, assess the probabilities of surviving such events, identify prognostic factors, and evaluate therapeutic measures for their possible impact on outcomes.

	PATIENTS AND METHODS

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Patients
This report includes all patients with second recurrences originating from a published cohort of 1,702 unselected, consecutive patients with newly diagnosed high-grade osteosarcoma.²³ Intended first-line treatment included pre- and postoperative chemotherapy as well as surgery. All studies were accepted by the appropriate ethics and/or protocol review committee.²³ Informed consent was required from all patients and/or their legal guardians, depending on the patient's age.

Of the 1,702 patients, 576 had experienced a first recurrence.²⁰ Two hundred thirty-seven of these patients did not achieve a second (macroscopically) complete surgical remission. Of the other 339 patients, 90 remained in second surgical remission, and 249 developed second recurrences; the 249 patients who experienced second recurrences form the basis of all further analyses.

Detection of Relapse
Routine follow-up included serial clinical evaluations and x-rays of the chest and primary site. On suspicion of relapse, appropriate imaging of the chest and the primary site and a bone scan were required. The diagnosis of relapse was based on the treating institutions' assessment.

Treatment Strategy for Second and Subsequent Osteosarcoma Recurrences
The COSS protocols did not provide treatment guidelines for rerecurrences; therefore, therapy was not standardized. The COSS center was available for guidance, and surgical removal of detectable tumor was generally recommended whenever feasible. The use of chemotherapy and the choice of drugs were left to the discretion of the treating physicians. The protocols did not include recommendations regarding radiotherapy.

Data Collection and Definition of Variables
Patient demographics, tumor characteristics at initial diagnosis, and first-line therapy were collected prospectively and coded as described.^20,23 Follow-up information collected prospectively included dates and sites of all recurrences, the date last known to be alive, and, for deceased patients, date and cause of death. Additional details of relapse presentation, treatment, and outcome were collected retrospectively from status forms; radiology, pathology, and surgery reports; progress letters; and telephone notes and were coded as described.²⁰ The relevant information from the COSS database and the study charts of all 249 patients were reviewed twice by two of the authors (B.K.-B. and S.S.B.).

Statistics
All patients were evaluated on an intent-to-treat basis. ² analysis was used to compare unrelated samples. Wilcoxon signed rank test and Pfanzagl trend test²⁴ were used to evaluate trends from first to fifth recurrence. Follow-up periods were calculated from the date a specific relapse was diagnosed until the date of the last documented information. Overall survival was calculated until death from any cause, and event-free survival was calculated until subsequent recurrence or death, whichever occurred first. Patients who did not achieve a surgical remission were assumed to have suffered an event on day 1.

Survival analyses were performed using the Kaplan-Meier method.²⁵ The log-rank test was used to compare survival curves.²⁶ Multivariate analyses of survival including the variables that had correlated with prognosis at first recurrence (ie, interval to recurrence, number of lesions, use of chemotherapy, and surgical remission status²⁰) were carried out using the Cox proportional hazards model.²⁷ SPSS version 14.0 (SPSS Inc, Chicago, IL) was used for statistical calculations. All P values are two-sided, and significant implies P < .05.

	RESULTS

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Patient and Tumor Characteristics
Among 249 patients with second recurrences, 93 suffered a third, 38 a fourth, 14 a fifth, five a sixth, three a seventh, two an eighth, and one each a ninth through 13th recurrence, for a total of 409 episodes of recurrent osteosarcoma (Figs 1 and 2; Tables 1 and 2). Information regarding first-line chemotherapy was available for 235 patients, of whom 208 (88.5%) had received at least three of the following four drugs: doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide. Eighty-five (40.1%) of 212 patients with osteosarcoma assessable for response had been good responders to first-line chemotherapy (< 10% viable tumor). First recurrences had been metastatic in 217 patients, local in 21 patients, and combined in 11 patients. Details on treatment at first recurrence were available for 246 patients, of whom 165 (67.1%) had again received chemotherapy.

View larger version (30K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Outcome of 249 patients with multiple osteosarcoma recurrences. MFU, median follow-up; RFI, median relapse-free interval (years) since diagnosis of a particular recurrence (numbers in parentheses represent ranges); CR, complete surgical remission. (*) Two patients died of causes other than osteosarcoma in CR3.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival according to number of osteosarcoma recurrences (first, n = 576; second, n = 249; third, n = 93; fourth, n = 38; fifth, n = 14). The curve for first recurrences is from Kempf-Bielack et al.20

Number of Lesions and Sites of Involvement
The number of lesions was reported for 379 of 409 rerecurrences; 145 (38.3%) were solitary, and 234 (61.7%) involved multiple lesions, with no increase of multiple lesions with increasing number of recurrences (P = .32 for trend; Table 2). Intervals between recurrences shorter than median correlated with multiple lesions (P = .002).

Among 249 second recurrences, 238 were metastatic, six were local, and five were combined. Only three of 11 patients with local or combined second recurrences had not had involvement of the former primary site at first recurrence. One each of 93 third and 38 fourth recurrences were combined local and metastatic events, both after previous local and/or combined recurrences, whereas all other 158 third and subsequent recurrences were purely metastatic.

Among patients with pulmonary metastases, the proportion of patients with bilateral involvement decreased with increasing numbers of recurrence (P = .021 for trend). There were 203 episodes of unilateral lung recurrences with known laterality of involvement that were later followed by subsequent rerecurrences. At rerecurrence, the lungs were again involved in 179 of 203 recurrences, and laterality of pulmonary reinvolvement was reported for 159 of these 179 recurrences. Among these 159 recurrences, the originally affected side was again involved in 121 patients (76.1%; 86 ipsilateral only, 35 bilateral), whereas isolated contralateral involvement was limited to 38 instances (23.9%).

The proportion of patients with bone metastases remained relatively stable throughout recurrences. The proportion of patients with metastases outside of lungs or bones increased (P = .0001 for trend), mainly as a result of increasing chest wall involvement (Table 1). Occasional metastases involved CNS, liver, or extrathoracic soft tissues. Metastases to other parenchymatous organs were exceedingly rare. None of seven second recurrences involving the CNS but three of four third recurrences and the single fourth recurrence with brain involvement occurred after previous brain metastases. Five bouts of hepatic metastases occurred in distinct patients.

Treatment of Recurrence
Surgery was reported for 256 of 409 rerecurrences (no surgery, n = 136; no data, n = 17), resulting in complete surgical remission in 199 patients (77.7% of 256 patients who underwent surgery; 48.7% of all 409 rerecurrences; Table 3). Patients with solitary lesions (75.9%) and recurrence-free intervals at or greater than the median for a particular recurrence (59.4%) were more likely to achieve complete remissions than patients with multiple lesions (34.6%) or intervals less than the median (37.1%), respectively (², both P < .0001). Data on radiotherapy were available for 383 of 409 rerecurrences; it was used in 60 recurrences (15.7%) and was more frequently administered to patients who did not achieve surgical remission compared with patients who did achieve surgical remission (42 of 210 v 18 or 199 patients, respectively; P = .001).

Postrecurrence Survival
Follow-up information was available for 247 of 249 second, 92 of 93 third, and all 67 subsequent recurrences (Table 3). Median survival time was 1.02 years after the second recurrence, 1.02 years after the third recurrence, 0.98 years after the fourth recurrence, and 0.94 years after the fifth recurrence. Overall, 197 of 249 patients died; 189 died of osteosarcoma, four died of unreported causes (all with active disease at last previous follow-up), and four died of other causes (sepsis, n = 2; cardiomyopathy, n = 1; perioperative complications, n = 1). Thirty-seven patients remained alive in complete surgical remission (Fig 1; median, 2.92 years after last recurrence; range, 0.02 to 15.52 years; > 5 years, n = 10; > 10 years, n = 3).

Intervals between the current and the previous recurrence greater than median generally correlated with better outcomes, as did a history of having had a longer first recurrence-free interval. Patients with solitary lesions did better than those with multiple lesions, and patients with lung metastases did better if the metastases were unilateral (Table 3).

Considering all 409 rerecurrences combined, 210 patients did not achieve a complete surgical remission, and only 15 of these patients were still alive at end of study (eight with a follow-up time of < 1 month). Median follow-up time for the remaining seven patients was 0.90 years (range, 0.22 to 7.76 years) from last recurrence. Among these patients, the patient with the longest survival was reported to have evidence of recurrent bilateral lung metastases on imaging as a third recurrence and was treated with carboplatin and etoposide, after which the presumed metastases were no longer detectable; surgical exploration was not performed. Another patient was still alive 4.67 years after a second recurrence in the cervical spine, which was operated intralesionally, followed by treatment with radiotherapy (45 Gy), ifosfamide, carboplatin, and etoposide. The longest follow-up for any of the other patients alive without complete surgery was 1.06 years. Median survival times for patients achieving versus not achieving a renewed complete surgical remission were 1.94 v 0.49 years at second, 1.75 v 0.55 years at third, 2.16 v 0.48 years at fourth, and 5.46 v 0.63 years at fifth recurrence.

The use of chemotherapy consistently correlated with longer overall survival in patients who did not achieve surgical remissions. At second recurrence, there was also a correlation between the use of chemotherapy and improved event-free survival in patients who achieved a surgical remission; however, there was no such correlation with overall survival (Table 3). Results of multivariate testing are listed in Table 4.

	DISCUSSION

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Even when considering first osteosarcoma recurrences, only a few series have included more than 100 patients.^14,15,^19,20 Therefore, it is not surprising that most of the current knowledge about subsequent recurrences stems from case reports, small cohorts, or, more often, subgroups from first recurrence series.^{1–13,15,16,20–22} To our knowledge, the largest numbers of patients with osteosarcoma rerecurrences stem from two reports from the Rizzoli Institute^18,19 (Bologna, Italy) that included overlapping cohorts with slightly varying eligibility criteria. Briccoli et al,¹⁸ from the surgical unit, analyzed 107 patients with rerecurrences after thoracotomy. Bacci et al,¹⁹ from the oncology unit, in a report on 235 first recurrences, also provided some information about 120 second and 56 subsequent recurrences.

In the COSS trials, the median interval from initial diagnosis until first recurrence was 1.6 years.²⁰ In this study, we found the median interval from first to second recurrence to be only 9 months, which is similar to the interval of 8 months described by Briccoli et al,¹⁸ and the median interval between subsequent recurrences to remain quite constant at approximately 6 months. The strong correlation between the first recurrence-free interval and the intervals between subsequent recurrences emphasizes that individual osteosarcomas may vary in their growth potential. Interestingly, some patients enjoyed long intervals between recurrences. Some of the presumed late rerecurrences, such as a third recurrence arising in a radiation field after an interval of more than 10 years, may indeed have represented second primary osteosarcomas rather than true recurrences. However, this does not obviate the need for long-term, tumor-directed surveillance.

There was no increase in the proportions of multiple lesions or bilateral pulmonary involvement with increasing numbers of rerecurrences; in fact, the proportion of bilateral lung metastases even declined. Recurrence at the former primary site was rare and mostly limited to patients who had experienced local failure previously. An increase in the proportion of patients with metastases outside the lungs or skeleton was mainly a result of chest wall involvement. In primary osteosarcoma, surgery that does not result in wide, uncontaminated margins carries a high risk of local failure.²⁸ It seems reasonable to assume that many of the reported chest wall metastases were seeded during previous intralesional attempts to remove lung metastases and that cure rates might improve if intralesional surgery was reduced to a minimum. The fact that patients with unilateral pulmonary metastases tended to develop ipsilateral rerecurrences argues in the same direction because at least some of the recurrent ipsilateral metastases probably represented local recurrences of incompletely removed lung metastases from previous recurrences rather than new metastases.

Long-term survival has been described for some patients who underwent reoperation for multiple recurrences.^{2,5,6,8,11–13,16–19} For example, Briccoli et al,¹⁸ who analyzed 107 patients with recurrences after a previous thoracotomy, reported that 26 of these patients survived in third remission and six survived in fourth through sixth remission. They calculated 3- and 5-year event-free survival probabilities of 33% and 32%, respectively, for a selected subgroup of 94 patients who went on to have a second metastasectomy. However, as exemplified by their eligibility criteria (ie, no metastases beyond the lung, no local recurrence, possibility of achieving complete resection without causing respiratory insufficiency, acceptable operative risk), series from the surgical literature generally suffer from selection bias—only patients who reach the surgical department are included, and therefore, the most difficult patients are notoriously underrepresented.

As for more unselected series, 10 of 36 children and young adults from the Mayo Clinic (Rochester, MN) and Children's Hospital and Regional Medical Center (Seattle, WA) with second osteosarcoma recurrences were reported to be alive in third to sixth remission. Unfortunately, length of follow-up information was not provided, making it impossible to draw clear-cut prognostic conclusions.¹⁶ At University of California, San Francisco, only one of 25 patients with second osteosarcoma recurrences was alive in third remission, whereas an additional three patients survived after subsequent recurrences.²²

In our unselected cohort series of 249 patients with second osteosarcoma recurrences of any site, we found 5-year actuarial overall and event-free survival rates of 16% and 9%, respectively. As for first osteosarcoma recurrences,²⁰ longer disease-free intervals and solitary lesions at recurrence correlated with better outcomes. Among the 119 patients who achieved a third surgical remission, 5-year actuarial overall and event-free survival rates increased to 32% and 18%, respectively. Even after subsequent rerecurrences, the 5-year survival estimate for patients who again achieved surgical remissions was approximately 25%. In contrast, as seen by others,¹⁹ there was almost no long-term survival without surgical clearance, re-enforcing the paramount importance of surgery in the curative therapy of recurrent osteosarcoma. Although the available data did not allow us to adequately assess the role of radiotherapy, the fact that radiotherapy to an incompletely resected bone metastasis was used in one of only two patients who became long-term survivors without surgical clearance supports suggestions^29,30 that radiotherapy might be efficacious against selected inoperable osteosarcoma lesions.

The role of chemotherapy remains controversial even for first osteosarcoma recurrences. Of the two largest series that reported correlations between the use of second-line chemotherapy and improved outcomes, the series from the Rizzoli Institute did so only for patients who did not achieve a second remission;¹⁵ our group's findings also suggested an adjuvant effect, albeit moderate, for patients in second remission. Data on the potential efficacy of chemotherapy for subsequent recurrences are almost nonexistent. Prospective data are completely lacking, and small retrospective analyses are inherently difficult to interpret. Briccoli et al¹⁸ reported no evidence for a role of chemotherapy in 94 patients who underwent a second thoracotomy. In contrast, our results, both those of univariate and multivariate testing, argue for a limited role of chemotherapy even in heavily pretreated patients with multiple rerecurrences. A correlation between the use of chemotherapy and somewhat prolonged survival for patients who did not achieve renewed surgical remissions is quite obvious and fits well with published data on first recurrences.^15,20 Our observations are also compatible with the suggestion of at least some adjuvant effect of chemotherapy. Of course, prospective trials would be needed to prove such an allegation, but because of the rarity of the condition, these are not likely to ever happen. Our group is currently collaborating with the Italian and Scandinavian Sarcoma Groups to establish a large prospective database for patients with recurrent osteosarcoma (EURELOS),³¹ which might help to reduce some of the diagnostic and therapeutic uncertainties.

In conclusion, our analysis of 249 unselected patients with 409 second and subsequent osteosarcoma recurrences confirms the overwhelming importance of surgery. Prognostic indicators resemble those already known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant setting, remains to be defined.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: Stefan S. Bielack, IDM Pharma Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Stefan S. Bielack

Administrative support: Stefan S. Bielack, Dorothe Carrle, Matthias Kevric

Provision of study materials or patients: Stefan S. Bielack, Detlev Branscheid, Godehard Friedel, Gernot Jundt, Thomas Kühne, Rainer Maas, Rudolf Schwarz, Andreas Zoubek, Heribert Jürgens

Collection and assembly of data: Stefan S. Bielack, Beate Kempf-Bielack, Knut Helmke, Matthias Kevric, Gernot Jundt, Rainer Maas

Data analysis and interpretation: Stefan S. Bielack, Beate Kempf-Bielack, Matthias Kevric, Rudolf Schwarz

Manuscript writing: Stefan S. Bielack, Andreas Zoubek

Final approval of manuscript: Stefan S. Bielack, Beate Kempf-Bielack, Detlev Branscheid, Dorothe Carrle, Godehard Friedel, Knut Helmke, Matthias Kevric, Gernot Jundt, Thomas Kühne, Rainer Maas, Rudolf Schwarz, Heribert Jürgens

	Appendix

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Participating institutions: The patients included in this analysis were registered by the Pediatric Hematology/Oncology Units of the University Hospitals Aachen, Berlin, Bonn, Cologne, Düsseldorf, Essen, Erlangen, Frankfurt/Main, Freiburg, Giessen, Göttingen, Hamburg, Hannover, Heidelberg, Homburg/Saar, Jena, Kiel, Lübeck, Magdeburg, Munich (Kinderklinik & Poliklinik TU), Münster, Rostock, Tübingen, Ulm, Würzburg, Germany; Graz, Innsbruck, Austria; and Basel, Switzerland; by the Medical Hematology/Oncology Units of the University Hospitals Berlin-Buch, Berlin, Hamburg, Hannover, Heidelberg (first medical department), Lübeck, Mainz, Munich, TU, Münster, Nuremberg, Ulm, Würzburg, Germany; Graz, Austria; and Lausanne, Switzerland; by the Orthopedic University Hospitals Innsbruck, Vienna, Austria; and Zürich Balgrist, Switzerland; by the Pediatric Oncology Units of the Kinderklinik Stenglinstr. Augsburg, Prof Hess Kinderklinik Bremen, Städtisches Kinderkrankenhaus Cologne, Städtische Kliniken Dortmund, Städtisches Klinikum Karlsruhe, Kinderklinik Mannheim, Städt. Krankenhaus Munich, Johanniter Kinderklinik St. Augustin, Olgahospital Stuttgart, Germany; St. Anna Kinderspital Vienna, Austria; and Ostschweizer Kinderspital St. Gallen, Switzerland; by the Pediatric Surgery Department of the University Hospital Leipzig, Germany; and by the Medical Oncology Units of the Zentralklinikum Augsburg, Städtisches Krankenhaus Hildesheim, Städtisches Klinikum Karlsruhe, Städtische Kliniken Kassel, Städtisches Krankenhaus Lübeck-Süd, Stadtspital Triemli Zürich, Switzerland; and the Radiooncology Department, Saarbrücker Winterberg-Kliniken, Germany.

	Acknowledgment

 
We thank all patients who contributed to the COSS studies and acknowledge the physicians, nurses, data managers, and support staff of the collaborating centers. We would like to thank Silke Flege and Christoph IntVeen for their contributions to data management and evaluation.

	NOTES

 
Supported by Deutsche Krebshilfe, Bundesministerium für Forschung und Technologie, and Fördergemeinschaft Kinderkrebszentrum Hamburg.

Presented in part at the 18th Annual Meeting of the European Musculo-Skeletal Oncology Society, May 25-27, 2005, Trieste, Italy, and the Sarcoma Meeting Stuttgart 2005, June 15-17, 2005, Stuttgart, Germany.

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

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Submitted January 14, 2008; accepted July 24, 2008.

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