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Osteosarcoma Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS)

From the Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie; Universitätsklinikum Münster, Medizinische Klinik und Poliklinik A; Universitätsklinikum Münster, Klinik und Poliklinik für Thorax-, Herz- und Gefäßchirurgie, Münster; Krankenhaus Großhansdorf, Zentrum für Pneumologie und Thoraxchirurgie, Großhansdorf; Universitätsklinikum Düsseldorf, Klinik für Kinder-Onkologie, -Hämatologie und -Immunologie, Düsseldorf; Universitätsklinikum Hamburg-Eppendorf, Universitätsklinik und Poliklinik für Kinder- und Jugendmedizin, Abteilung für Pädiatrische Radiologie; Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Pädiatrische Hämatologie und Onkologie; Radiologische Privat-Praxis Raboisen; Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Radiologie, Abteilung für Strahlentherapie und Radioonkologie, Hamburg; Zentrum für Kinderheilkunde und Jugendmedizin des Klinikums der Johann Wolfgang Goethe-Universität, Klinik für Kinderheilkunde III, Pädiatrische Onkologie, Hämatologie und Hämostaseologie, Frankfurt; Olgahospital Stuttgart, Pädiatrie 5 (Onkologie, Hämatologie und Immunologie), Stuttgart, Germany; Orthopädische Universitätsklinik Balgrist, Zürich; Kantonsspital Basel, Institut für Pathologie, Basel, Switzerland; Universitätsklinik für Orthopädie, Allgemeines Krankenhaus Wien, Vienna; St Anna Kinderspital, Vienna, Austria

Address reprint requests to Beate Kempf-Bielack, Cooperative Osteosarkomstudiengruppe (COSS), Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie, Albert-Schweitzer-Str 33, D-48149 Münster, Germany; e-mail: coss{at}uni-muenster.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors’ Disclosures of... REFERENCES

 
PURPOSE: To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma.

PATIENTS AND METHODS: Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients).

RESULTS: After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy.

CONCLUSION: Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.

	INTRODUCTION

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Many osteosarcomas are cured by multiagent chemotherapy and surgery, but a significant number will still relapse. Recurrences usually occur as pulmonary metastases or, less frequently, metastases to distant bones or local recurrences.¹ Despite various attempts at using second-line chemotherapy and improved surgical techniques, most reports—including an early paper from our group² on 38 patients with metachronous lung metastases and a later report from one of our institutions³ on 28 relapses of any site—have concluded that few affected patients will become disease-free survivors.^4-12 The number of patients, however, was limited in most series, selection criteria were variable, and follow-up was often short. Consequently, there is no consensus as to which patient and tumor-related factors correlate with outcome. Among treatment-related variables, only complete surgery has been reliably linked to improved survival. The role of chemotherapy in improving rates of survival is being debated and radiotherapy has not been addressed.^2-22

In 2002, our group presented data on 1,702 consecutive patients with high-grade osteosarcoma.²³ We now evaluate all recurrences developing in this cohort, a large, unselected group of osteosarcomas that are relapsing despite intensive chemotherapy and complete surgery. The aims of this study were to describe the presentation of recurrent osteosarcoma and the probability of long-term survival in heavily pretreated patients, to identify prognostic factors for postrelapse survival, and to evaluate therapeutic measures and their possible impact on outcome.

	PATIENTS AND METHODS

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Patients
This report includes all the patients with recurrences from a previously published cohort²³ of 1,702 consecutive, newly diagnosed patients with localized or primary metastatic high-grade osteosarcoma of the trunk or limbs registered onto the neoadjuvant studies of the Cooperative Osteosarcoma Study Group (COSS) between the end of 1979 and July 1998. Intended first-line treatment included pre- and postoperative chemotherapy according to the COSS protocol active at time of enrollment, as well as surgery of all operable lesions. All protocols prescribed high-dose methotrexate. In addition, they included doxorubicin, cisplatin, ifosfamide, and/or bleomycin/cyclophosphamide/dactinomycin in varying combinations.^23-27 All studies were accepted by the appropriate ethics and/or protocol review committee.^23-27 Informed consent was required from all patients and/or their legal guardians, depending on the patient’s age.

This study is based on data submitted until December 2002. As of then, a first complete remission (CR), defined as macroscopically complete surgery, had been documented for 1,512 of 1,702 patients (185 macroscopic residue, 5 no data); 897 of 1,512 were in first CR, 39 patients had died of other (36 patients) or unknown (3 patients) causes. The remaining 576 consecutive, unselected patients suffered a relapse (local or metastatic). They form the basis of this study.

Detection of Relapse
Routine follow-up included serial clinical evaluations and x-rays of the chest and primary tumor site at specified intervals. Routine computed tomography scans or bone scans were not mandatory. On suspicion of relapse, appropriate imaging of the chest, the primary tumor site, and a bone scan were required. Relapse diagnosis was based on the treating institution’s assessment.

Treatment Strategy for Relapsed Osteosarcoma
Relapse therapy was not standardized; however, most protocols included general recommendations. In addition, the COSS study center was available for guidance. Surgical removal of all detectable tumor foci was recommended whenever feasible. The decision to use second-line chemotherapy and the choice of drugs were left to the discretion of the treating physician. COSS suggested chemotherapy for all but late, solitary pulmonary metastases, and from approximately 1990, to include carboplatin and etoposide if chemotherapy was considered. The protocols did not include recommendations regarding radiotherapy.

Data Collection and Definition of Variables
Data concerning patient demographics, tumor characteristics at initial diagnosis, and first-line therapy was collected prospectively and coded as described previously by Bielack et al.²³ First-line chemotherapy was reviewed, with particular attention to doxorubicin, methotrexate, cisplatin, and ifosfamide. Follow-up information collected prospectively included the date and site of first relapse, the date the patient was last known to be alive, and for deceased patients, the date and cause of death. Further details of relapse presentation, treatment, and outcome were collected retrospectively from status report forms, radiology, pathology, and surgery reports, progress letters, and telephone notes available at the data center. The relevant information from the COSS database and the study charts of all 576 patients were reviewed twice by two of the authors (B.K.-B., S.S.B.), and the following variables were coded: time to relapse—interval from diagnostic biopsy until relapse; number of lesions—solitary = single lesion, multiple = two lesions, based on the largest number reported, regardless of the method used for detection; site of relapse—local, metastatic, or combined; metastases—lung, distant bone, or other; lung metastases—unilateral or bilateral; pleural disruption—lung metastases extending by contiguous growth into the pleural cavity, chest wall, diaphragm, or mediastinum, or causing a malignant pleural effusion; treatment of relapse: surgery—attempt to remove tumor, regardless of its success; second CR—macroscopically complete surgical removal of all tumor (based on the treating institution’s assessment and, if present, surgery and pathology reports); chemotherapy for first relapse—cytostatic therapy administered between diagnosis of first relapse and second relapse or last follow-up in remission (for patients with second CR), or until last follow-up or death (for patients without second CR). Drugs used were recorded and categorized. The use of radiotherapy was also recorded.

Statistics
All patients were evaluated retrospectively on an intention-to-treat basis. All parameters were first investigated by univariate techniques. ² analysis was used to compare unrelated samples. Follow-up periods were calculated from the date relapse was diagnosed to the date of last documented information. Overall survival was calculated to the date of patient death from any cause, and event-free survival until second relapse or death, whichever occurred first. Patients without a second CR were assumed to have suffered an event on day 1. Survival analyses were performed using the Kaplan-Meier method.²⁸ The log-rank test was used to compare survival curves.²⁹ Multivariate analyses of survival were completed using the Cox proportional hazards model.³⁰ Only variables that presented with a significant prognostic value in univariate analysis and relapse therapy (surgery, chemotherapy, or radiotherapy) were included in the multivariate models. All P values were two-sided and a P value of less than .05 was significant.

	RESULTS

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Patient and Tumor Characteristics at Initial Diagnosis and at Relapse
Among the 576 eligible patients, there were 350 males (60.8%) and 226 females (39.2%; Table 1). At initial diagnosis, the median age of all eligible patients was 15.5 years (range, 2.2 to 68.2 years). Five hundred fifty-four osteosarcomas (94.6%) were situated in an extremity and 31 osteosarcomas (5.4%) were in the axial skeleton. Sixty-six patients (11.6%) had primary metastases. The osteosarcoma was a secondary malignancy in 14 patients (2.4%). Information regarding first-line chemotherapy was available for 548 of 576 patients. Five hundred forty-five patients (99.5%) received methotrexate, 536 patients (97.8%) received doxorubicin, 493 patients (90.0%) received cisplatin, and 389 patients (71.0%) received ifosfamide; 493 patients (90%) received at least three of these four chemotherapy agents, and 384 patients (70.3%) received all four agents. Information on histologic response to first-line chemotherapy was available for 481 osteosarcomas, of which 201 (41.8%) had responded well (< 10% viable tumor), and 280 (58.2%) responded poorly.

Altogether, there were 501 metastatic relapses (87.0%), 44 local relapses (7.6%), and 31 combined relapses (5.4%). Lung metastases were part of 469 relapses (81.4%); lung metastases were the only site of recurrence in 373 patients (64.8%), they were unilateral in 227 patients (52.1% of patients with pulmonary involvement), and bilateral in 209 patients (47.9%; laterality was unknown in 33 patients). Lung metastases were reported to have disrupted the pleura in 66 patients. Distant bones were involved in 90 (15.6%) of 576 relapses; they were the only site of recurrence in 45 patients (7.8%). "Other" metastases were reported in 54 patients (9.4%), and as the only site of recurrence in only 12 patients (2.1%). Sites involved by extrapulmonary/extraosseous metastases were (multiple mentions possible): regional (five patients) and distant (25 patients; 22 intrathoracical, three abdominal, one cervical) lymph nodes, CNS (eight patients), soft tissues (eight patients), pleura (five patients), liver (four patients), kidney (one patient), pericardium (one patient), stomach (one patient), retina (one patient), and regional node or soft tissue (one patient).

Treatment of Relapse
Tumor-directed therapy was reported for 511 of 576 relapses (51 none, 14 insufficient information). Four hundred twenty-two patients had surgery, and 339 of these patients achieved a second CR. Both surgery and a second CR were more likely to have been reported in patients with late or solitary relapses than in others (P < .001). Chemotherapy was reported for 381 of 576 relapses (173 none, 22 no data). Information about drugs administered was available for 376 of 381 patients. Of these, 43 patients (11.4%) were treated with a single agent and 333 patients (88.6%) with two or more. In addition to the agents detailed in Table 3, chemotherapy included actinomycin in 27 patients (7.2%), bleomycin in 21 patients (5.6%), vinca alkaloids in 18 patients (4.8%), dacarbazine in two patients, and fludarabine, paclitaxel, and mitomycin in one patient each. The use of second-line chemotherapy correlated with good response to first-line chemotherapy (P = .022), multiple lesions at relapse (P = .001), and bilateral pulmonary involvement (P = .001), but not time to relapse (P = .953).

Postrelapse Survival
Follow-up information was available for 575 of 576 patients. After a median of 1.2 years (range, 2 days to 18.4 years) for all patients and 4.2 years for 148 survivors (range, 5 days to 18.4 years), actuarial overall survival at 5 and 10 years was 0.23 (SE, 0.02) and 0.18 (SE, 0.02), respectively (Fig 1). A second relapse developed in 249 of 339 patients that were surgically disease free. The median time from first to second relapse was 0.8 years (range, 3 weeks to 9.8 years), shorter than the first relapse-free interval in 205 patients (82.3%) and longer in 44 patients (17.6%). Among the 148 survivors, 82 were in continuous second CR, with event-free survival rates of 0.13 (SE, 0.01) and 0.11 (SE, 0.02) at 5 and 10 years, respectively (Fig 1). Thirty-seven patients were alive in later CR (third CR, 24; fourth CR, seven; fifth CR, four; seventh CR, one; eighth CR, one) and 29 patients were alive with disease (without second CR, 14 patients; in second CR, eight patients; in third CR, six patients; in fourth relapse, one patient). Four hundred twenty-seven of 576 patients died (median, 0.9 years after first relapse; range, 2 days to 13.0 years); 397 patients of osteosarcoma and 19 of other causes, seven of these patients were in second CR and two in third CR. Nine of 19 patients died of sepsis and/or multiorgan failure; two each as a result of perioperative complications, thromboembolic events, or cardiomyopathy; one each as a result of acute myelogenous leukemia, pulmonary fibrosis, and anorexia nervosa. The cause of death was not reported for 11 patients (10 with uncontrolled osteosarcoma, one in CR at previous follow-up).

View larger version (27K): [in this window] [in a new window]   Fig 1. Estimates of overall and event-free postrelapse survival for all patients. n, number of patients.

View larger version (15K): [in this window] [in a new window]   Fig 2. Estimates of postrelapse overall survival in relation to surgical remission status. Log-rank P < .0001. 2nd CR, second complete remission.

View larger version (14K): [in this window] [in a new window]   Fig 3. Estimates of postrelapse overall survival in relation to use of second-line multidrug chemotherapy. Log-rank P = .012.

	DISCUSSION

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Presentation and distribution data of recurrent osteosarcoma were the same as that reported by others. The median time from diagnosis to first relapse—1.6 years—was almost identical to that described in other current reports,^11,12,32 but approximately half a year shorter than the median time of 23 months from first CR to first relapse reported in a study of 162 patients by the Rizzoli Institute.¹⁰ In the latter series and ours, some very late relapses developed after more than 10 years, implying that tumor-directed follow-up should be extended well into the second decade.

Our series included both local and systemic recurrences. The lung, involved in more than 80% of all patients, and as the only site in nearly two thirds of all patients, was by far the most frequently involved site. Similar rates have been reported by others.^{3,4,6,8,10-12,17,32} Of note, only 20% of patients with lung metastases had additional disease, in contrast to half of those with bone metastases, and most of those with other metastases. As was observed in other reports,⁸ early relapses were particularly likely to be multifocal in our study, and in the case of lung metastases, bilateral, or to disrupt the pleura.

While various chemotherapy protocols had been used for first-line chemotherapy in other studies, all had included intensive multidrug regimens.^23-27 Accordingly, 90% of the osteosarcomas from our series had already been exposed to at least three of the agents considered most active against the disease, namely high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide. Nevertheless, treatment for recurrence was once again rather intensive. Three quarters of all patients had surgery and two thirds received second-line chemotherapy, mostly with multiple agents. Despite such comprehensive treatment, the long-term postrelapse survival rate was disappointingly low, with 5- and 10-year survival estimates of only 0.23 and 0.18, respectively. Comparison of these survival estimates with others is hampered by the fact that basically all other series have used narrower selection criteria. Reports from the surgical literature, for instance, tend to be restricted to patients with lung metastases advancing to thoracotomy,^{5,22,31,33-37} thereby excluding poor-risk patients with extensive disease. Still, our results fit well into the overall picture, with only approximately one quarter of patients surviving for 5 years or longer.^3-12,16,18 Even these low survival estimates should by no means be confused with cure, as late tumor-related deaths do occur.

Several independent risk factors are associated with the probability to develop osteosarcoma recurrences. In the COSS trials, these factors included axial site and large size of the primary tumor, and primary metastases.²³ Interestingly, none of these factors predicted for outcome after relapse. Poor response to first-line chemotherapy is another robust predictive factor for relapse.^2,23 While good responders had better postrelapse survival, response to first-line chemotherapy was not of independent prognostic value for outcome after recurrence. Rather, the benefit for relapsing good responders seemed to have been mediated by longer times to recurrence.

Others have reported conflicting results regarding time to relapse, with some^{3,9-11,15,33,38} demonstrating and others^{5,7,8,17,19,31} failing to detect an association with postrelapse survival. Our results clearly confirm that patients with late relapses fare better, but their survival curve does not reach a plateau and the ultimate course of disease tends to be relentless in most cases.

The second presenting factor which strongly correlated with outcome in our series was the number of lesions, confirming previous observations made using various cut-off points.^{5,8-12,15,31,38} Again in agreement with others,^5,10-12,33 and pointing out that more disease implies inferior outcome, bilateral pulmonary metastases were associated with a worse prognosis than unilateral disease. Extrapulmonary recurrence is often believed to carry a particularly grave prognosis. Our results imply that it is not the extrapulmonary site as such, but rather the high likelihood that extrapulmonary metastases are part of a disseminated disease process that leads to this impression. Other recent reports have also demonstrated that metachronous osteosarcoma limited to distant bone is not associated with a bleak prognosis.^39-41

The location and number of lesions cannot be viewed independently from resectability. As observed in many smaller series,^4-22 we found long-term survivors exclusively among patients who achieved a second surgical remission. This closely parallels the situation known from first-line treatment²³ and underscores the dire need for effective alternate therapies in inoperable osteosarcoma. Owing to the nature of the data on which this report is based, the definition of second CR, macroscopic removal of all known tumor sites as reported by the treating institution, was not strict. Goorin et al⁴ have used much more stringent criteria, namely removal of macroscopic disease, no microscopic disease at resection margins, and no histologic evidence of pleural disruption by tumor. The use of such rigid criteria would narrow down considerably the number of patients assumed to have achieved a second CR, possibly allowing a better definition of the subgroup from which survivors will originate.

The role of second-line chemotherapy for relapsed, intensively pretreated osteosarcoma is not as obvious as that of surgery. The few previous reports that suggested better outcomes with chemotherapy did so only for subgroups of patients or retrospectively defined regimens. Norwegian investigators⁸ reported that "adequate salvage chemotherapy" had independent predictive value for improved overall survival in 60 patients with distant metastases. In the Rizzoli series,¹⁰ better overall survival with chemotherapy was limited to the subgroup of patients unable to achieve a second remission. However, because most patients treated without chemotherapy for a first relapse will doubtlessly receive chemotherapy for subsequent recurrences, analyses of overall survival unwittingly compare immediate with delayed chemotherapy rather than chemotherapy with observation. This bias does not apply to analyses of event-free survival, which stop at the second recurrence. By performing such analyses, we were indeed able to expand previous observations of a positive correlation between second-line chemotherapy and outcome to patients achieving a second surgical remission, suggesting an adjuvant effect, albeit limited, even in these heavily pretreated patients. The adjuvant effect is much less obvious than that of first-line treatment, and may easily be missed when analyzing small cohorts. Owing to the retrospective nature of our analysis, we cannot exclude that some of the benefit attributed to chemotherapy was due to selection bias. However, we might even have underestimated the efficacy of chemotherapy, as the patients that received chemotherapy were more likely to have presented with more extensive recurrences. Our data does not allow conclusions about the relative efficacy of individual agents, but suggests that treatment with more than one drug might be preferable.

We are not aware of previous systematic analyses of radiotherapy for relapsed osteosarcoma. In the COSS series, radiotherapy was almost exclusively administered to patients failing to achieve a second CR. In this subgroup, similar to our group’s experience with unresectable pelvic or vertebral osteosarcoma,^42,43 radiotherapy was associated with a limited prolongation of survival. Again, the retrospective nature of the analysis did not allow us to conclude whether this was an effect of radiotherapy or whether other factors, such as patient selection, were responsible.

In conclusion, our results, derived from a large, unselected cohort of intensively pretreated patients with long-term follow-up, confirm the poor prognosis of recurrent osteosarcoma. A short time to relapse, recurrences involving more than one lesion, and, in the case of lung metastases, bilateral disease and pleural disruption, are negative prognostic factors. Complete surgery can be a prerequisite for cure. Second-line chemotherapy, especially chemotherapy with more than one agent, seems to contribute to limited improvements of outcome. Patients with unresectable disease may benefit from radiotherapy. Collaborative, prospective efforts are warranted to further elucidate the role of specific interventions for osteosarcomas that relapse despite adequate first-line treatment, and to evaluate innovative approaches.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors’ Disclosures of... REFERENCES

 
Participating institutions. The patients included in this analysis were registered by the Pediatric Hematology/Oncology Units of the University Hospitals in Aachen, Berlin, Bonn, Cologne, Dresden, Düsseldorf, Essen, Erlangen, Frankfurt/Main, Freiburg, Giessen, Göttingen, Hamburg, Hannover, Heidelberg, Homburg/Saar, Jena, Kiel, Lübeck, Magdeburg, and Munich (Kinderklinik & Poliklinik TU), Munich, Poliklinik Pettenkoferstr LMU, Munich, Dr von Haunersches Kinderspital LMU, Münster, Rostock, Tübingen, Ulm, Würzburg, Germany; Graz, Innsbruck, Vienna, Austria; Basel, Geneva, and Zurich, Eleonoren-Stiftung, Switzerland; by the Medical Hematology/Oncology Units of the University Hospitals Berlin-Buch, Berlin, Charité Campus Virchow, Bochum, Düsseldorf, Frankfurt/Main, Freiburg, Giessen, Halle/Saale, Hamburg, Hannover, Heidelberg (first med dept), Heidelberg (fifth med dept), Homburg/Saar, Lübeck, Magdeburg, Mainz, Munich, TU, Munich, LMU, Münster, Nuremberg, Regensburg, Tübingen, Ulm, Würzburg, Germany; Graz, Austria; Basel (Kantonsspital), and Lausanne, Switzerland; by the Orthopedic University Hospitals Innsbruck, Vienna, Austria; and Zurique Balgrist, Switzerland, by the Pediatric Oncology Units of the Kinderklinik Stenglinstr Augsburg, Kinderklinik Bayreuth, Helios Klinikum Berlin-Buch; Prof Hess Kinderklinik Bremen, Kinderklinik Klinikum Chemnitz, Städtisches Kinderkrankenhaus Cologne, Städtische Kliniken Dortmund, Kinderklinik St Elisabeth Hamm, Städtische Kliniken Kassel, Städtisches Klinikum Karlsruhe, Kinderklinik Mannheim, Städt Krankenhaus Munich, Cnopf’sche Kinderklinik Nuremberg, Klinikum Saarbrücken-Winterberg, Kinderklinik Klinikum Schwerin, Johanniter Kinderklinik St Augustin, Olgahospital Stuttgart, Germany; and St Anna Kinderspital Vienna, Austria; by the Pediatric Surgery Department of the Krankenhaus St Elisabeth/St Barbara, Halle/Saale and University Hospital Leipzig, Germany; by the Medical Oncology Units of the Zentralklinikum Augsburg, Zentralkrankenhaus St Jürgenstr Bremen, Städtische Kliniken Dortmund, Johannishospital Duisburg, Hospital zum Heiligen Geist Frankfurt/Main, Städtisches Krankenhaus Gütersloh, Krankenhaus Siloah Hannover, Städtisches Krankenhaus Hildesheim, Städtisches Klinikum Karlsruhe, Städtische Kliniken Kassel, Städtisches Krankenhaus Kiel, Städtisches Krankenhaus Lübeck-Süd, Klinikum Mannheim, Städtische Klinik Oldenburg, Krankenhaus Barmherzige Brüder Regensburg, Germany; Kantonspital Liestal, Allgemeines Öffentliches Krankenhaus Linz, Austria; and Stadtspital Triemli Zurich, Switzerland; by the Orthopedic Hospital Vienna-Gersthof, Austria; and the Radiooncology Dept, Saarbrücker Winterberg-Klniken, Germany.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors’ Disclosures of... REFERENCES

 
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. Received more than $2,000 a year from a company for either of the last two years: Wolfgang E. Berdel, Merck KgaA.

	Acknowledgment

 
We thank all of the patients who contributed to the COSS studies and acknowledge the physicians, nurses, data managers, and support staff of the collaborating centers for their active participation. We also thank Silke Flege and Merle Eselgrim for their contributions to data management and evaluation.

	NOTES

 
Supported in part by Deutsche Krebshilfe.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003, and at the 36th Congress of the International Society of Paediatric Oncology, Oslo, Norway, September 16-19, 2004.

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

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Submitted April 8, 2004; accepted October 7, 2004.

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