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Skip Metastases in Osteosarcoma: Experience of the Cooperative Osteosarcoma Study Group

Leo Kager, Andreas Zoubek, Ulrike Kastner, Beate Kempf-Bielack, Jenny Potratz, Rainer Kotz, G. Ulrich Exner, Christiane Franzius, Susanna Lang, Rainer Maas, Heribert Jürgens, Helmut Gadner, Stefan Bielack

From the St Anna Children's Hospital; Departments of Pathology and Orthopedics, University Hospital Vienna, Vienna, Austria; Department of Orthopedics, University Hospital Zürich, Zürich, Switzerland; Diagnostic Radiology, Hamburg; Department of Nuclear Medicine, University Hospital Muenster; Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster; and Olgahospital, Pediatrics 5–Oncology, Hematology, Immunology, Stuttgart, Germany

Address reprint requests to Stefan Bielack, MD, Olgahospital, Pediatrics 5, Bismarckstr 8, D-70176 Stuttgart, Germany; e-mail: coss{at}olgahospital-stuttgart.de

	ABSTRACT

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PURPOSE: The outlook for patients with osteosarcoma who present with synchronous regional bone metastases (skip metastases), either in the primary bone site or transarticular, is considered to be extremely poor. This study was conducted to further investigate the prognostic implication of skip metastases in osteosarcoma.

PATIENTS AND METHODS: The authors retrospectively analyzed the collected data of 1,765 consecutive patients with newly diagnosed high-grade osteosarcoma of bone who were registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies and identified 24 patients (1.4%) with unequivocally proven skip metastases. All 24 patients were treated by an aggressive surgical approach coupled with polychemotherapy. Demographic, diagnostic, tumor, and treatment-related variables and response and survival data were analyzed.

RESULTS: Skip metastases were identified preoperatively in 11 of 24 patients by bone scan, eight of 22 patients by plain x-ray, 15 of 18 patients by magnetic resonance imaging, and five of 10 patients by computed tomography. A complete surgical remission (CSR) of all clinically detectable tumor sites was achieved in 22 of 24 patients during front-line therapy. With a median follow-up time of 4.4 years (8 years for survivors) from diagnosis, 12 patients were alive, all of whom were in continuous CSR. Survival did correlate with location of skip metastases and histologic response to neoadjuvant chemotherapy.

CONCLUSION: Synchronous regional bone metastases are rare in osteosarcoma, and preoperative detection relies on appropriate diagnostic imaging. Aggressive multimodal therapy holds the promise to achieve prolonged survival, especially in patients in whom these metastases occur within the same bone as the primary lesion and whose tumors respond well to chemotherapy.

	INTRODUCTION

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Clinically detectable metastatic disease at initial diagnosis is the most consistent adverse prognostic factor in osteosarcoma.^1,2 It is well established that patients with osteosarcoma and synchronous lung metastases benefit from contemporary treatment approaches, which include multiagent chemotherapy coupled with aggressive surgical resection of all clinically detectable tumors.^3-6 However, patients who present with extrapulmonary metastatic disease, such as bone metastases, are often considered to have a dismal outlook.⁷ The poor prognosis in patients with synchronous bone metastases has been reported to be independent of the localization of these metastases relative to the primary tumor (ie, synchronous regional or skip metastases^8-12 and synchronous distant bone metastases^4,7,13-15).

Skip metastases are defined according to Enneking and Kagan^8,9 as synchronous smaller foci of tumor occurring in the same bone anatomically separated from the primary lesion or as synchronous smaller foci of tumor on the opposing side of a joint. The classic studies on skip metastases in osteosarcoma, which focused on patients who were treated with surgery only^8,9 or included a considerable number of patients from the prechemotherapy era,¹⁰ reported high rates of local recurrence and distant metastases during course, resulting in poor outcomes. Subsequently, these dismal outcomes seemed to be confirmed in two cohorts treated with surgery and chemotherapy.^11,12 However, the statement of a fatal course has recently been challenged by anecdotal reports that described survival in osteosarcoma patients presenting with skips who had been treated with wide surgical resection and polychemotherapy.^16,17 These preliminary findings were corroborated in a larger series of patients with osteosarcoma enrolled onto trials of the Cooperative Osteosarcoma Study Group (COSS).⁶ Here, we present detailed information about this cohort of patients with skip metastases.

	PATIENTS AND METHODS

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Patients
We conducted a retrospective study on a cohort of 1,765 patients with a first diagnosis of high-grade osteosarcoma of the extremities or trunk who were enrolled onto consecutive neoadjuvant COSS studies between 1979 and 1998. Details of the treatment protocols have been reviewed recently.¹ All studies were accepted by the appropriate ethics and/or protocol review committee. Informed consent was required from all patients, parents, or legal guardians before enrollment, as appropriate.

Diagnostic Staging
Diagnostic work-up and follow-up investigations for primary tumor and metastases varied over time and were performed as previously described.^1,6 Plain x-rays of the region of the primary tumor and the chest and technetium-99–labeled diphosphonate bone scans were performed in all studies, whereas the use of computed tomography (CT) investigations and magnetic resonance imaging (MRI) was restricted to more recent trials. Size of the primary tumor was estimated as follows: tumors measuring less than one third of the length of the involved bone were defined as being small, and all other tumors were defined as large.

Data Collection and Definition of Skip Metastases
Data on patient demographics, tumor characteristics, front-line therapy, and follow-up information were collected prospectively and coded as previously described.¹ All patients who had been reported to have evidence for primary metastases were reviewed twice by two of the authors (L.K. and U.K.). Skip metastases were defined according to Enneking and Kagan.^8,9 Further details on patients who had been reported to have evidence for skip metastases, including 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. Patients in whom skips presented concomitantly with lung metastases were included in this analysis, as were patients with secondary osteosarcoma and skip metastases. Patients in whom regional bone metastases arose as part of a more generalized skeletal or otherwise extrapulmonary spread were not considered.

Treatment
All patients received polychemotherapy according to the COSS protocols active at the time of enrollment.^18-21 Timing of surgery was scheduled as described previously.⁶ The type of surgery was not specified, but complete removal of the tumor(s) with wide or radical surgical margins should have been attempted. The COSS study center was available for guidance. The surgical margins of the primary tumor were assessed after surgery and classified as radical, wide, marginal, or intralesional. Metastases were classified as being completely or incompletely resected. Additional treatment (eg, radiotherapy) was administered to selected patients and chosen at the discretion of the participating institutions.

Statistical Methods
All patients were evaluated on an intent-to-treat basis. The following factors were analyzed for prognostic significance: age, sex, size of primary tumor, number and localization of skips, extent of metastatic disease, surgical options, time point of completion of front-line surgery, and response to preoperative chemotherapy according to the classification of Salzer-Kuntschik et al.²²

Survival was calculated using the Kaplan-Meier method together with SEs.²³ Overall survival was calculated from date of diagnosis until death from any cause, and event-free survival was calculated from date of diagnosis until relapse or death, whichever occurred first. Differences between survival curves were evaluated using the log-rank test.²⁴ Patients who never achieved a complete surgical remission (CSR) were assumed to have suffered an event on day 1. All statistical analyses were performed in R version 2.1.1 software (http://www.r-project.org).

	RESULTS

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Patient Characteristics and Diagnosis of Skip Metastases
All eligible 1,765 patients had a biopsy-proven first diagnosis of high-grade osteosarcoma. A total of 35 patients were reported to have evidence of skip metastases. However, this analysis focused on the 24 (1.4%) of 1,765 patients in whom the presence of skips was unequivocally confirmed by either surgery (n = 23) or by documented progression in imaging (n = 1, patient 9; Table 1). The remaining 11 patients for whom skip metastases were reported were not considered for this study because skips had occurred concomitantly either with metastases to distant bones (n = 4) or with multiple metastases to distant organs (n = 1). In six patients, MRI revealed evidence for a solitary skip in the same bone as the primary (n = 5) or transarticulary (n = 1). However, histology of the suspicious region was negative for osteosarcoma in all six patients. Thirteen patients were male, and 11 were female. The median age at diagnosis was 14.6 years (range, 8.5 to 52 years). In two patients, osteosarcoma had occurred as a second malignancy.

Primary Tumors and Skip and Lung Metastases
Details on the distribution and size of the primary tumors, distribution and number of skips, and lung metastases are listed in Table 1. Twenty-one primary tumors were localized within the lower extremities, whereas only three primary tumors were localized within the upper extremities. Ten of the 24 primary tumors were considered to be small because they measured less than one third of the involved bone. Fifteen patients had a solitary skip metastasis, and nine presented with multiple skips. Transarticular skips were found in one of three patients; the remaining patients had discontinuous tumors in the primary bone site. Skips were localized proximal (n = 12), distal (n = 10), or on both sides to the primary tumor. A total of nine patients had skips and additional lung metastases.

Front-Line Treatment
All patients received polychemotherapy according to the COSS protocols active at the time of enrollment.^18-21 Chemotherapy was initiated a median of 5 days after diagnostic biopsy (range, 0 to 29 days). Upfront surgery was performed in one patient; all other patients received neoadjuvant chemotherapy. A macroscopically complete surgical resection of the primary tumor was achieved in all patients a median of 12 weeks (range, 3 days to 18 weeks) from diagnostic biopsy. Surgical options included amputation (n = 11), rotationplasty (n = 5), and limb salvage surgery either with endoprosthetic replacement (n = 6) or autograft reconstruction (n = 2). The rate of amputations was higher in the patient group with skips compared with osteosarcoma patients without skips (46% v 28%, respectively; data not shown). Skips were removed completely in 22 of 24 patients a median of 12 weeks (range, 3 days to 22 weeks) from diagnosis. Pulmonary deposits were removed completely in all nine patients who presented with lung metastases a median of 27 weeks (range, 18 to 61 weeks) after diagnosis. A complete resection of all clinically detectable tumors was achieved in 22 of 24 patients a median of 15 weeks (range, 3 days to 61 weeks) from diagnostic biopsy. Details are listed in Table 2.

Overall and Event-Free Survival
The median follow-up time was 4.4 years (range, 0.6 to 21 years) for all 24 patients and 8 years (range, 3.9 to 21 years) for the 12 survivors. All survivors were in CSR (first remission, n = 10; third remission, n = 2) at the time of this analysis. Actuarial survival rate at 5 years was 50% (SE, 10%; Fig 1). All 12 deceased patients died from osteosarcoma at a median of 2.1 years (range, 7 months to 4.8 years) after diagnosis.

View larger version (8K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve of overall survival for 24 patients with high-grade osteosarcoma and skip metastases.

There was no correlation between patient age or sex, size of the primary tumor, number of skips, and survival. In addition, patients who presented with skips and lung metastases had similar outcomes compared with patients who presented with isolated skips (Table 3). Outlook was significantly better in patients who had skip metastases within the same bone as the primary compared with patients who presented with transarticular skips (P = .023; Fig 2). The 10 patients whose primary tumors showed a good response to neoadjuvant chemotherapy (< 10% viable tumor) had a better 5-year survival rate of 70% (SE, 14%) than the 12 patients with a poor response (5-year survival rate, 25%; SE, 13%; P = .022; Fig 3). There was no difference in outcome among patients who underwent amputations, rotationplasties, or limb salvage surgery (Table 3). However, only three of 11 patients who had skips and underwent amputations remained in remission more than 6 years from diagnosis compared with five of eight patients who underwent limb salvage surgery. The 5-year overall survival probability for the 15 patients who had presented with extremity osteosarcoma and skip metastases as the only site of dissemination was 53% compared with 73% for the 1,402 of 1,765 patients who had presented with localized extremity osteosarcoma without skip metastases (P = .09).

View larger version (9K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves of overall survival for patients with skips that occurred in the same bone as the primary tumor versus patients with transarticular skips (P = .023, log-rank test).

View larger version (8K): [in this window] [in a new window]   Fig 3. Kaplan-Meier curves of overall survival for patients with good versus poor response of the primary tumor to neoadjuvant chemotherapy (P = .022, log-rank test).

	DISCUSSION

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It is well established that diagnostic imaging procedures, including MRI, technetium-99–methylene diphosphonate bone scan, plain x-rays, and CT, are not reliable enough to detect all skip metastases preoperatively,^10-12,17 and our results confirm these earlier findings. In agreement with other reports, appropriate MRI (ie, analysis of the whole bone segment) was found to be the most accurate modality to detect skips.^26-29

As previously reported,^10,12 we found that age at diagnosis, sex ratio, and distribution of primary tumor sites did not differ significantly between patients who had and who did not have skip metastases. However, patients who presented with skips had large primary tumors more often (58%) compared with osteosarcoma patients without skip metastases (33%).¹ The distribution pattern of skips relative to the primary tumors was similar in our patients compared with patients described earlier.¹⁰

The 5-year survival probability in our series of patients with osteosarcoma and skip metastases was 50% (SE, 10%), which stands in stark contrast to most previous studies that usually reported fatal outcomes.^8-12 In the original analysis from the W. Thaxton Springfield Center for Orthopedic Study and Research, only one of 23 patients with skip metastases survived more than 12 years after tumor surgery.¹⁰ However, half of the patients were from the prechemotherapy era, where prognosis was poor even for patients without skips. In two subsequent studies from other groups, all 13 patients with skip metastases and osteosarcoma died within 75 months from diagnosis.^11,12 Five of these patients had concomitant metastases to other sites at presentation. Conversely, Leavey et al¹⁶ reported on two patients with isolated skips; both were alive and free of disease 6 years and 3 years from diagnosis. In addition, preliminary data from the M.D. Anderson Cancer Center suggest that the outlook for patients with skip metastases treated with conventional therapy does not necessarily have to be dismal.¹⁷

In 92% of our patients with skip metastases, a CSR of all clinically detectable tumors had been achieved initially, but a total of 50% of patients subsequently died from disease. This parallels the results obtained in our larger series of patients with primary metastatic osteosarcoma in whom survival probability was approximately 50% when a CSR had been achieved during front-line therapy.⁶ Moreover, outcome was surprisingly good in the nine patients who presented with skips and lung metastases, and this might largely be the result of successful surgery in this small cohort. In our series, the rate of amputations was higher in patients with skips compared with osteosarcoma patients without skips. Although the number of patients is small, our results provide evidence that limb salvage surgery can be feasible in selected osteosarcoma patients with skips and that amputations do not necessarily result in better outcomes.

Besides CSR, a good histologic response of the primary tumor assessed after preoperative chemotherapy has been reported to be a key prognostic factor in osteosarcoma,¹ which is herein confirmed for the subgroup of patients with skips. We observed identical responses in primaries and skips in 90% of analyzed patients, which suggests a similar drug-resistance phenotype in primaries and skips. The reason for better responses in skip metastases compared with primary tumors in the remaining two patients is unknown.

In this study, we document that a subset of osteosarcoma patients who present with skip metastases and who are aggressively treated with chemotherapy and surgery can achieve long-term, disease-free survival. In addition, we provide evidence that patients with skips who have transarticular lesions and/or whose tumors respond poorly to neoadjuvant chemotherapy have a significantly lower survival probability than other patients. In contrast to the Enneking and Kagan classification system for skip metastases, the American Joint Committee on Cancer consortium defines skips as "discontinuous tumors in the primary bone site" (stage III disease), thereby excluding transarticular lesions.³⁰ Our results strongly support the American Joint Committee on Cancer classification system, and patients presenting with transarticular lesions should rather be classified as having synchronous distant bone metastases (stage IV disease) because, in our experience, they have the same poor outlook as patients with distant metastases. For this subset of osteosarcoma patients and for patients whose tumors do not respond sufficiently to conventional chemotherapy, new treatment strategies are urgently needed.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Stefan Bielack Administrative support: Jenny Potratz, Stefan Bielack Provision of study materials or patients: Andreas Zoubek, Rainer Kotz, G. Ulrich Exner, Christiane Franzius, Susanna Lang, Rainer Maas, Heribert Jürgens, Helmut Gadner, Stefan Bielack Collection and assembly of data: Leo Kager, Ulrike Kastner, Beate Kempf-Bielack, Jenny Potratz, G. Ulrich Exner, Susanna Lang, Heribert Jürgens, Helmut Gadner, Stefan Bielack Data analysis and interpretation: Leo Kager, Beate Kempf-Bielack, Christiane Franzius, Stefan Bielack Manuscript writing: Leo Kager, Stefan Bielack Final approval of manuscript: Leo Kager, Andreas Zoubek, Ulrike Kastner, Beate Kempf-Bielack, Jenny Potratz, Rainer Kotz, G. Ulrich Exner, Christiane Franzius, Susanna Lang, Rainer Maas, Heribert Jürgens, Helmut Gadner, Stefan Bielack

 

	Acknowledgment

 
We thank all patients who contributed to the Cooperative Osteosarcoma Study Group studies and acknowledge the physicians, nurses, data managers, and support staff of the collaborating centers for their active participation. The outstanding support of Matthias Kevric for data monitoring and Meyling Cheok for computer expertise is appreciated.

	NOTES

 
Supported by Deutsche Krebshilfe and Forschungsinstitut fuer krebskranke Kinder, St Anna Kinderspital (Vienna, Austria).

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 Sarcoma Meeting Stuttgart, Stuttgart, Germany, June 15-17, 2005.

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

	REFERENCES

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Submitted September 20, 2005; accepted January 31, 2006.

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