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Primary Metastatic Osteosarcoma: Presentation and Outcome of Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols

From the St Anna Children’s Hospital and Departments of Orthopaedics and Pathology, University Hospital of Vienna, Vienna, Austria; Centre for Pneumonology and Thoracic Surgery, Grosshansdorf; Department of Pediatrics, University Hospital of Hamburg, Hamburg; Charite, Campus Berlin-Buch, Robert Roessle Klinik, Berlin; Department of Orthopaedics, University Hospital of Muenster, and Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Germany; and Institute for Pathology, Kantonsspital Basel, Basel, Switzerland.

Address reprint requests to Leo Kager, MD, Cooperative German-Austrian-Swiss Osteosarcoma Study Center, Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Albert-Schweitzer Str 33, 48129 Muenster, Germany; email: coss{at}uni-muenster.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation.

Patients and Methods: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions.

Results: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes.

Conclusion: The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CLINICALLY DETECTABLE metastatic disease at initial diagnosis occurs in less than 20% of patients with high-grade osteosarcoma (OS) and predicts a poor outcome, with long-term survival rates between 10% and 40%.^1–8 However, patients with primary metastatic osteosarcoma (MOS) are a heterogeneous group; a 5-year event-free survival rate of up to 75% is reported for patients presenting with unilateral lung metastases,⁵ whereas multifocal bone spread of OS seems to herald a catastrophic outcome.⁹ In addition, skip lesions are described as a poor prognostic factor.¹⁰ Therefore, increased emphasis must be placed on more precise risk assessment, not only for counseling of patients but also for definition of treatment regimes based on reliable stratification criteria. To date, neither prognostic factors nor optimal management are well established in patients with MOS, and the series published encompasses numbers of patients between three and 73, respectively.^1–17

During the last two decades, most patients with OS from Germany, Switzerland, and Austria were enrolled onto the consecutive studies of the Cooperative Osteosarcoma Study Group (COSS). These patients were treated according to a uniform concept of preoperative and postoperative chemotherapy in combination with aggressive surgery, and the results of prognostic factor analyses from 1,702 patients registered between 1980 and June 1998 have been published recently.¹⁸

We report on 202 patients with proven MOS at initial presentation from the COSS database, evaluating statistically relevant prognostic factors.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Recruitment
From the start of the first neoadjuvant COSS study (COSS-80) at the end of 1979 until December 1998, 1,765 patients with a first diagnosis of a histologically proven high-grade OS of the extremities or trunk (excluding craniofacial sites) were enrolled onto the consecutive neoadjuvant COSS studies. Details of the recruitment and the protocols have been reviewed recently.^18,19 All studies were accepted by the local ethics committee or the protocol review committees of the German Ministry for Science and Technology or the German Cancer Society, respectively. Informed consent was obtained from all patients or their legal guardians, depending on the patient’s age.

From the 1,765 patients (1,759 patients with high-grade central OS and six patients with high-grade surface OS), 272 patients (15.4%) were reported to have presented with clinically detectable metastatic disease. This analysis was restricted to those patients in whom the presence of primary metastases was unequivocally confirmed either by surgery or by progression; that is, to 202 (11.4%) of the 1,765 patients. The other 70 patients were not considered: In 20 patients, the radiologic evidence of primary metastases could be excluded by surgery; in the remaining 50 patients, the evidence for primary spread was limited to diagnostic imaging, but unequivocal surgical or clinical proof for the assumed metastases was lacking. Skip lesions (defined as a second, smaller focus of OS occurring in the same bone or a second lesion of OS on the opposing side of a joint)^20,21 were considered as metastases and consequently were included in our analysis.

Diagnostic Staging
Procedures used to define the extension of primary tumor and metastases included conventional radiography in all studies, whereas other methods (computed tomography, magnetic resonance imaging) varied with time and, hence, availability. The minimum work-up for primary metastases included a chest x-ray in several planes and a technetium-99 methylene diphosphonate bone scan. As of 1991, computed tomography of the chest was also mandatory. During follow-up, radiograms of the chest and the primary tumor were to be repeated at regular intervals specified in the respective treatment protocols. Tumor size could only be evaluated for extremity tumors, because prospective measurements had only been collected for this subgroup of patients. Tumors measuring at least one third of the length of the involved bone or more were defined as being large, and all others as small.

Treatment
Chemotherapy was given to all 202 patients according to the COSS protocols active at the time of enrollment. Details of these protocols, including chemotherapy administration and modification, have been reviewed previously.^19,22–24 Surgery of the primary tumor was scheduled to take place between weeks 9 and 18 in study COSS-80 and between weeks 9 and 11 in all other protocols.¹⁸ The objective of surgery was complete resection of the primary tumor with wide margins and resection of all metastases, whenever feasible. In patients in whom complete surgery of all tumor sites was deemed feasible on the basis of results of diagnostic imaging, the sequence of surgery varied, but resection of the primary tumor mostly preceded resection of metastases. Nonscheduled treatment modalities, generally chosen at the discretion of the participating institutions, were used in inoperable OS, including conventional radiotherapy, targeted internal radiotherapy with samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP), locoregional hyperthermia, and in palliative situations, administration of alternative chemotherapeutic agents such as melphalan, mitoxantrone, or epirubicin.

Statistical Methods
All 202 eligible patients were evaluated on an intent-to-treat basis. We examined the following factors for prognostic significance: age, sex, site and size of primary tumor, site and extent of metastatic disease at diagnosis, status and time point of surgical remission (complete surgical remission was assumed only when all detectable tumor foci were removed macroscopically completely during first-line therapy), and response to preoperative chemotherapy according to the six-grade scale of Salzer-Kuntschik et al.²⁵ A good response was defined as less than 10% viable tumor (grade 1 to 3 according to the scale of Salzer-Kuntschik et al). The extent of primary metastatic disease was determined in all patients according to the number of metastases and involved organ systems. According to their localization, metastases were integrated into one of three groups: lung, bone, and other organs (outside lung and bone; eg, lymph node or CNS), and patients with isolated and combined organ system involvement were compared.

Survival was calculated using the Kaplan-Meier method together with SEs.²⁶ Overall survival was calculated from the date of diagnostic biopsy until death from any cause and event-free survival until relapse or death, whichever occurred first. Patients who never achieved a complete surgical remission were assumed to have suffered an event on day 1. The log-rank test was used to compare survival curves.²⁷ A method developed by Simon and Makuch²⁸ was used to compare overall survival distributions according to the quality of surgery (complete v incomplete); this method accounts for patients transferring from one group to another. The multivariate analysis of overall survival was carried out using the Cox proportional hazards regression model.²⁹ Complete surgical remission was included as a time-dependent covariate in the Cox model. Only variables with a significant prognostic value in univariate analysis were included in the multivariate models of survival. Because of the lack of data, histologic response was not included in the Cox model. SAS (version 8.01; SAS Institute, Inc, Cary, NC) was used for statistical analysis.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
All 202 patients had high-grade central OS, and the diagnosis of metastases was confirmed by surgery in 145 patients (71.8%) and radiographically by progression of disease in 57 patients (28.2%). There was a slight predominance of males without any correlation between sex and survival (Table 1). The median age at diagnosis was 15 years (range, 2 to 66 years). Twenty-eight cases of MOS (13.9%) were detected in the first decade of life, 129 cases (63.8%) were detected in the second decade, 29 cases (14.3%) were detected in the third, eight cases (4%) were detected in the fourth decade, and only eight (4%) were detected later. We divided the patients arbitrarily into three groups: younger than 20 years, 20 to 39 years of age, and 40 years of age or older. Survival was correlated with age in univariate analysis and was significantly better for patients younger than 20 years of age (Table 1). In five of the 202 patients, the OS arose as a second malignancy. The inclusion of such patients into our analysis might be controversial. We therefore additionally analyzed all data excluding these five patients. The results were not affected by inclusion or exclusion of these patients.

View larger version (17K): [in this window] [in a new window]   Fig 1. Overall and event-free survival curves for all 202 patients from the time of osteosarcoma diagnosis.

Primary Tumor Site and Size
A total of 181 (89.6%) primary tumors were located in an extremity, whereas 21 (10.4%) occurred in the axial skeleton (Table 2). In univariate analysis, the location of the primary tumor was significantly correlated with survival (Table 1; Fig 2). From the 21 patients with axial tumor site, only one achieved a complete surgical remission and was alive 4.6 years after diagnosis. Another patient with unresectable disease received multimodal therapy, including targeted internal radiotherapy with samarium-153 EDTMP, and was alive 3.7 years after diagnosis; all others died at a median of 1.3 years (range, 102 days to 3 years) after diagnosis.

View larger version (30K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves of overall survival for variables with prognostic significance in univariate analysis. A, site of primary tumor; B, site of metastases; C, number of lung metastases; D, distribution of lung metastases; E, number of metastases; F, histologic response. Years from diagnosis, except otherwise indicated. See text for details.

Site of Metastases
The sites of primary metastatic involvement in the 202 eligible patients are depicted in Fig 3. The most frequent metastatic site was the lung (164 patients; 81.2%). Survival at 5 years was 33% (SE = 4%) in 124 patients with metastases confined to the lung and 20% (SE = 7%) in 40 patients with lung metastases combined with other sites (P = .0129). In the former group, those who presented with unilateral lung involvement had a significantly better 5-year survival than those with bilateral involvement (Table 1; Fig 2). Of the 40 patients with combined lung metastases, the distribution of pulmonary nodules was known in 39 patients. Thirty-two patients presented with bilateral deposits (5-year survival rate, 16%; SE = 7%), and seven patients presented with unilateral deposits (5-year survival rate, 42%; SE = 19%).

View larger version (31K): [in this window] [in a new window]   Fig 3. Metastatic sites in 202 patients with primary metastatic osteosarcoma.

The 18 patients (8.9%) presenting with metastases to other sites had a poor prognosis, with a survival rate of 8% (SE = 7%) at 5 years. Four patients (2%) had isolated lymph node involvement (one is alive at 6.7 years after diagnosis; three died of disease); the remaining 14 (6.9%) had combined metastases with either two (seven patients) or more (seven patients) organ systems involved. All patients with metastases to parenchymal organs (three CNS, one liver, and one adrenal gland) and soft tissues (two muscle, one skin) presented with widespread disease and died a median of 1.2 years (range, 1 to 1.5 years) after diagnosis. From the 11 patients with combined lymph node involvement, only one was alive with disease at 4.1 years; all others died after a median of 1.1 years (range, 110 days to 1.6 years).

In univariate analysis, patients with deposits in one organ system had a better outcome than those with more systems involved (Table 1).

Number of Metastases
The number of metastases was available for 198 of 202 patients and was significantly correlated with survival (Table 1; Fig 2). In 38 patients with solitary metastases, 24 occurred in the lung, three occurred in lymph nodes, two occurred in distant bones, and nine presented as skip lesions. Sixty-nine patients had two to five metastases (41 lung, four skip, 11 distant bone, one lymph node, and 12 combined sites), whereas 91 had more than five metastases (57 lung, four distant bone, 30 combined sites).

The number of pulmonary metastases was available for 122 of 124 patients with isolated lung involvement. The highest number of pulmonary nodules surgically removed was 250. In univariate analysis, the number of metastases was significantly correlated with survival (Table 1; Fig 2). Of 57 patients with more than five metastases confined to the lung, 10 (17.5%) were alive at a median 6.4 years (range, 2.7 to 15.5 years) after diagnosis. In one patient, 20 nodules had been removed successfully.

In contrast to other metastatic sites, skip lesions were seen more often solitarily (solitarily, n = 9; multiple, n = 13; unknown, n = 2). However, there was no difference in outcome between solitary (5-year overall survival rate, 56%; SE = 17%) and nonsolitary (5-year overall survival rate, 54%; SE = 13%; P = .955) skip lesions.

From the 17 patients with metastases confined to distant bones, two had solitary lesions and were alive at 73 days and 12.1 years, whereas only one with multiple bone metastases was alive at 3.7 years. All others died a median of 1.2 years (range, 157 days to 3.7 years) after diagnosis.

Forty-two patients presented with combined metastases (10 patients with two to five metastases, and 32 with > five) and had a 5-year survival rate of 19% (SE = 6%).

OS Treatment
Chemotherapy was given to all 202 patients and was initiated a median of 7 days after diagnostic biopsy (range, 0 to 209 days). In 30 patients (14.9%), no surgical treatment was performed. Attempts to remove the primary tumors and metastases were performed in 162 (80.2%) and 145 (71.8%) patients, respectively. Information about the sequence of chemotherapy and surgery was available for 161 of 162 patients who underwent surgery for their primary tumors. Eight patients (4%) had complete resection of the primary tumor before chemotherapy, and 153 (75.7%) underwent resection of the primary tumor a median of 85 days (range, 12 to 536 days) after start of chemotherapy. For different reasons (eg, unresectable primary or metastatic tumors), the primaries were not operated on in 40 patients (19.8%).

One hundred forty-five patients (71.8%) underwent resection of metastases. Of these, 16 (7.9%) had concomitant surgery with the primary tumor, 11 (5.5%) had resection of the metastases before, and 92 (45.5%) had resection of metastases after surgery of the primary tumor (median, 110 days; range, 8 to 788 days). For the remaining 26 patients (12.9%), the time points of surgery were not available. In 57 patients (28.2%), no attempt to remove the metastases had been performed because they had either residual or unresectable tumor at the primary or metastatic site, they had progressive disease during preoperative chemotherapy, or they refused surgery.

Fourteen patients (6.9%) received radiotherapy (10 patients for tumor control of unresectable primaries, and four for pain control in metastatic sites). Of these, two are alive 3.7 and 4.7 years after diagnosis, and all others died a median of 1 year (range, 0.5 to 1.5 years) after diagnosis.

Surgical Remission
A total of 11 patients died during the first 6 months after diagnosis, and two had an observation period of less than 6 months. Consequently, these 13 patients have been excluded from that analysis. Among the eligible 189 patients, completeness and the time point of surgical remission had a significant impact on survival rates (Figs 4 and 5). A macroscopically complete surgical resection of all tumor sites had been achieved in 103 patients at a median of 6 months after diagnosis (range, 3 days to 1.7 years). Of the 86 patients in whom no complete surgical remission had been achieved, 79 died at a median of 1.3 years (range, 7 months to 3.7 years) after diagnosis; the remaining seven patients were alive a median of 3.4 years after diagnosis (range, 1.4 to 4 years). Patients with unresectable macroscopic tumor burden had a five-fold higher risk of dying (relative hazard rate = 4.9; 95% confidence interval, 3.3 to 7.3; P < .001) than patients in whom a complete surgical resection of all tumor deposits had been performed. A complete surgical resection of all tumor sites during front-line therapy had been achieved in 22 (92%) of 24 patients with skip lesions at diagnosis.

View larger version (20K): [in this window] [in a new window]   Fig 4. Overall survival (OS) curves for eligible patients according to the time point of complete surgical remission. Within 3 months after diagnosis, 5-year OS, 67% (SE = 8%); within 3 to 6 months, 5-year OS, 50% (SE = 9%), later or never, 5-year OS, 19% (SE = 4%). P < .001.

View larger version (18K): [in this window] [in a new window]   Fig 5. Overall survival curves as a function of surgical remission. Method according to Simon and Makuch.28 Landmark time, half year. See text for details.

Multivariate Analysis of Prognostic Factors
In a multivariate Cox regression model, multiple metastases at diagnosis (relative hazard rate = 2.3) compared with solitary deposits and, more powerfully, macroscopically incomplete surgical resection (relative hazard rate = 2.4) were significantly associated with inferior outcome (Table 3).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Long-term survival for the 202 patients was 24% (SE = 4%). Although still unacceptably poor, survival in our contemporary series was higher than the 11% 2-year overall survival rate reported for patients from the Memorial Sloan-Kettering Cancer Center.¹ Smaller series of prospectively collected patients reported 5-year survival rates between 16% (European Osteosarcoma Intergroup; 45 patients) and 53% (Pediatric Oncology Group [POG]; 30 patients).^5,8 The better prognosis in the latter group might be explained by a priori exclusion of patients whose primary tumors seemed to be unresectable, the overrepresentation of patients with isolated lung involvement (87%, compared with 61% in our data), and the different chemotherapy schedule used in the POG series.⁵ The 3-year survival estimate of 24% in the prospective OS-91 trial (n = 17 patients) was comparable to our findings.³ A better prognosis (3-year survival rate of 50%) was described for 12 patients enrolled in the OS-86 trial.³ Taken together, these results indicate that approximately one third of patients with MOS at diagnosis can become long-term survivors, if they are treated with an aggressive surgical approach yielding the removal of all tumor deposits coupled with polychemotherapy.

Seventy percent of the 202 patients in our series died, and there was only one patient whose death must be considered treatment-related. Higher rates of treatment-related complications and even deaths were observed with more toxic experimental therapy.⁷ We agree that experimental treatment is justified for patients for whom no chance of cure can be expected by the application of standard treatment schedules. However, the results of our study provide reliable evidence that a subgroup of patients with MOS can be cured when treated with standard neoadjuvant treatment regimens and calls previous recommendations to enroll all patients with MOS at diagnosis into experimental treatment trials into question.^1,3

The number and distribution of nodules within the lung have been reported to predict prognosis, with better outcomes for patients with unilateral deposits and a low number of metastases, and our results confirm these findings.^1–3,5,13 The best prognostic subgroup in our series was the patient group with solitary lung metastases (n = 24), with a 5-year survival estimate of 75%. However, we arbitrarily assigned patients according to the number of metastases into one of three groups: one, two to five, and more than five metastases. The cutoff point concerning the number of metastases, discriminating reliably between better- and poor-risk patients, has to be estimated. Our study confirms the significantly better survival for patients with unilateral lung deposits.

Skip lesions were observed in only 1.4% of patients with OS. The poor prognosis ascribed to patients with skip lesions by Wuisman et al, ¹⁰ with a high rate of local recurrence (30%) and a high rate of distant metastases (95%) during the course, might be explained by the fact that approximately half of their patients were from the prechemotherapy era. Our results indicate that these patients seem to have a better prognosis than previously assumed.

Metastases to distant bones were detected in 22% of patients in our series. Two thirds had additional deposits in other sites, indicating widespread disease. The prognosis was poor, and 85% of these patients died at a median of only 1 year after diagnosis. Summarizing the data from the literature of the chemotherapy era and our results, of 117 patients with distant bone metastases at diagnosis (isolated and combined with lung), only eight (6.8%) survived more than 3 years after diagnosis.^{1,5,6,9,14,16,17,31} A complete surgical resection of all tumor sites had been achieved in four of these eight patients.^6,16 The reported 2-year survival rate of 58% (SE = 14%) in 12 patients with primary metastases to bones (± lung) enrolled onto a phase II/III POG group study examining high-dose ifosfamide and etoposide is encouraging.⁷ However, to recommend in general such an approach with considerable toxicity, these results must be confirmed in a higher number of patients with longer observation periods.

In our series, 7% of patients with primary metastases had lymph node involvement; of these, only two were alive more than 4 years after diagnosis. Taking together the few data from the literature (a total of four cases, all of whom died)^1,5 and our results, we conclude that lymph node involvement in patients with OS predicts an extremely poor prognosis. Primary OS metastases to parenchymal organs and soft tissues are extremely rare. All eight affected patients in our cohort had multiorgan involvement and rapid progressive disease and died within 1.5 years from diagnosis.

The intended treatment of the 202 patients in our study included aggressive surgery combined with multiagent chemotherapy. The risk-benefit ratio of an aggressive surgical approach may be questionable for the reasons of delay in chemotherapy administration, higher morbidity, and operative mortality. However, our results and those of others strongly indciate that resectable metastases should be resected regardless of their number and localization.³² It cannot be overstressed that patients with a clinically detectable tumor burden had a five-fold greater risk of dying than patients in whom a complete surgical resection of all detectable tumors had been achieved. In addition, no patient with such tumor burden was alive beyond 5 years from diagnosis. However, it is important to note that our data set was restricted to patients with proven metastases and does not allow statements about patients with solely radiologically suspected metastases and whether some of these might be cured without the benefit of surgical resection.

A good histologic response in the primary tumor assessed after preoperative chemotherapy has been reported to predict a better probability of survival,¹ and our results confirm these findings. It is noteworthy that patients whose resected primaries showed a good response to chemotherapy were more likely to achieve a complete surgical remission during front-line therapy. However, polychemotherapy scheduled according to neoadjuvant COSS protocols was unable to cure patients without concomitant surgical resection of all clinical detectable tumor sites. The use of radiotherapy in conjunction with targeted radionuclide application may offer a therapeutic option in selected cases.³³

We have identified the number of metastases and the completeness of surgical remission as independent prognostic factors that could serve as criteria for the stratification of patients with MOS in future international cooperative trials. The use of novel therapies for the group with unresectable tumor burden is justified, and innovative therapy regimens should be a major effort of future regimen studies in this group of patients who continue to have a catastrophic outcome.

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Submitted August 20, 2002; accepted March 7, 2003.

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