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Journal of Clinical Oncology, Vol 20, Issue 3 (February), 2002: 776-790
© 2002 American Society for Clinical Oncology

Prognostic Factors in High-Grade Osteosarcoma of the Extremities or Trunk: An Analysis of 1,702 Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols

By Stefan S. Bielack, Beate Kempf-Bielack, Günter Delling, G. Ulrich Exner, Silke Flege, Knut Helmke, Rainer Kotz, Mechthild Salzer-Kuntschik, Matthias Werner, Winfried Winkelmann, Andreas Zoubek, Heribert Jürgens, Kurt Winkler for the Cooperative German-Austrian-Swiss Osteosarcoma Study Group

From the Klinik und Poliklinik für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, and Klinik und Poliklinik für Allgemeine Orthopädie, Universitätsklinikum, Münster; Abteilung für Osteopathologie, Abteilung fur Pädiatrische Radiologie, and Abteilung für Pädiatrische Hämatologie und Onkologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany; Universitätsklinik für Orthopädie, Wiener Knochengeschwulstregister, and St Anna Kinderspital, Vienna, Austria; and Orthopädische Universitätsklinik Balgrist, Zurich, Switzerland.

Address reprint requests to Stefan Bielack, MD, Cooperative Osteosarkomstudiengruppe, Universitätsklinikum Münster, Klinik und Poliklinik für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, Albert-Schweitzer-Str 33, D-48149 Münster, Germany; email: coss@ uni-muenster.de.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease.

PATIENTS AND METHODS: A total of 1,702 consecutive newly diagnosed patients with high-grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic, tumor-related, and treatment-related variables, response, and survival. The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions.

RESULTS: Axial tumor site, male sex, and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis. Actuarial 10-year overall and event-free survival rates were 59.8% and 48.9%. Among the variables assessable at diagnosis, patient age (actuarial 10-year survival >= 40, 41.6%; < 40, 60.2%; P = .012), tumor site (axial, 29.2%; limb, 61.7%; P < .0001), and primary metastases (yes, 26.7%; no, 64.4%; P < .0001), and for extremity osteosarcomas, also size (>= one third, 52.5%; < one third, 66.7%; P < .0001) and location within the limb (proximal, 49.3%; other, 63.9%; P < .0001), had significant influence on outcome. Two additional important prognostic factors were treatment related: response to chemotherapy (poor, 47.2%; good, 73.4%; P < .0001) and the extent of surgery (incomplete, 14.6%; macroscopically complete, 64.8%; P < .0001). All factors except age maintained their significance in multivariate testing, with surgical remission and histologic response emerging as the key prognostic factors.

CONCLUSION: Tumor site and size, primary metastases, response to chemotherapy, and surgical remission are of independent prognostic value in osteosarcoma.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OSTEOSARCOMA, the most frequent, yet still rare, primary malignant bone tumor, most often originates in the metaphyses of long bones of adolescents. Because of a high rate of systemic spread, cure is rare after surgical treatment alone.1 The inclusion of aggressive polychemotherapy into an interdisciplinary treatment concept has led to dramatic prognostic improvements in young patients with seemingly localized extremity disease, with relapse-free survival rates of approximately 50% to 80% reported by specialized centers or multicentric groups.1-16 However, a substantial subgroup of all osteosarcoma patients historically has been excluded from all studies. Frequent reasons for exclusion were age older than adolescence, axial tumor site, primary metastases, osteosarcoma presenting as a secondary malignancy, and a variety of other reasons that were felt to justify the exclusion of a particular patient. Although treatment concept, prognostic factors, and outcome for the typical young patient with localized extremity osteosarcomas have been outlined accurately, the amount of evidence based information about the fate of all other patients suffering from variants of the same disease remains limited. Consequently, considerable uncertainty about the true success rate of osteosarcoma treatment in the era of polychemotherapy remains.

For two decades, most osteosarcoma patients from Germany, Austria, and Switzerland have been treated on protocols of the Cooperative Osteosarcoma Study Group (COSS). A uniform treatment concept of preoperative and postoperative chemotherapy in combination with aggressive surgery has formed the basis of all consecutive neoadjuvant study protocols since 1980.16 Registration was never limited to the typical young patients with localized limb tumors; rather, all patients with osteosarcoma were eligible for study entry. According to German Pediatric Cancer Registry data, the recruitment of pediatric osteosarcoma patients into the COSS studies has been more or less complete for many years.17 In addition to the pediatric population, many affected adults were also registered. Owing to the group’s long-standing international and interdisciplinary cooperation, the COSS database is now sufficiently large and mature enough to draw conclusions about the long-term outcome of a wide spectrum of patients with high-grade osteosarcoma in the era of polychemotherapy and about the relative importance that various possible prognostic indicators might have.


    PATIENTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recruitment
From the start of the first neoadjuvant COSS study (COSS-80) in 1980 until June of 1998, 1,905 consecutive patients with histologically proven osteosarcoma were enrolled onto a neoadjuvant COSS study. The main target was patients younger than 40 years of age with de novo, localized high-grade central extremity osteosarcoma, but all other osteosarcoma patients were also registered and followed prospectively. All patients with high-grade tumors were to be treated according to the same guidelines as the young patients with localized extremity tumors. All studies were accepted by the local ethics committee, the Protocol Review Committee of the German Ministry for Science and Technology, or the Protocol Review Committee of the German Cancer Society. Informed consent was required from all patients or their legal guardians, depending on the patient’s age.

Seventy-one patients with parosteal or periosteal osteosarcoma, 10 with low-grade central, 10 with extraosseous, and 34 with craniofacial osteosarcoma were not included in this analysis, and neither were 42 patients who had only been entered on relapse and 46 who had been subjected to radiotherapy or chemotherapy before entry. This study covers the remaining 1,702 patients with nonpretreated high-grade osteosarcoma of bone (1,696 high-grade central and 6 high-grade surface) of an extremity or the axial skeleton and is based on data submitted until November 1999.

Diagnostic Staging and Treatment
Procedures used to define the extension of the primary tumor included conventional radiography in all studies, whereas other methods (computed tomography scan and magnetic resonance imaging) varied with time and, hence, availability. The minimum requirements for exclusion of primary metastases were a negative chest x-ray and a negative 99Tc-methylene diphosphonate bone scan. As of 1991, computed tomography scan 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.

Preoperative and postoperative chemotherapy was to be given to all patients according to the COSS protocol active at time of enrollment. All protocols included high-dose methotrexate at 12 g/m2 per course with leucovorin rescue. In addition, doxorubicin 60 to 90 mg/m2 per course, cisplatin 90 to 150 mg/m2 per course, ifosfamide 6 to 10 g/m2 per course, and bleomycin, cyclophosphamide, and dactinomycin were used in varying combinations. The scheduled duration of chemotherapy ranged from 24 to 38 weeks. Definitive surgery was scheduled to take place between weeks 9 and 18 in study COSS-80 and between weeks 9 and 11 in all other protocols.16 The type of surgery was not specified, but complete removal of the tumor with wide or radical surgical margins should have been attempted. All primary metastases were also to be removed surgically, whenever feasible.

Assessment of Patient, Tumor, and Treatment-Related Variables
The following variables, all collected prospectively, were evaluated for their distribution in the patient cohort and for possible correlations with outcome.

Patient age. Studies by our group and others have generally focused on children and young adults.1-16 As was the case in the COSS studies analyzed, an age limit of 40 years was used to divide between older and younger patients in univariate and mutivariate analyses.

Patient sex. This variable is self-explanatory.

Tumor site. Osteosarcomas of the limbs were compared with those of the trunk, with clavicles and scapulae included among the axial sites. In case of multifocal bone involvement, the clinically leading lesion was considered the primary lesion. Osteosarcomas of the proximal femur or proximal humerus were jointly compared with all other limb tumors.

Tumor size. 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.

Primary metastases. Primary dissemination was assumed whenever metastases other than skip lesions were detected on initial staging, except when the suspicion was later excluded by surgery with negative histology. Patients with a radiologic diagnosis of primary metastases who never underwent surgery for the suspected metastases were included among those with primary dissemination.

Primary or secondary osteosarcomas. Patients were assessed as to whether their osteosarcoma represented the first or a subsequent malignancy.

Duration of symptoms. Most COSS protocols, except for those active between 1985 and 1990, included an assessment of symptom duration. Both the onset of pain and of tumor-associated swelling were documented. The median interval between first symptom and biopsy was used to divide the cohort into two groups.

Delay of treatment. The lag-time from diagnostic biopsy to the first day of tumor-specific therapy (primary chemotherapy or primary surgery) was assessed in univariate and multivariate analyses. As in the reported COSS studies,4,7,15,16 a treatment delay was defined by an interval of longer than 3 weeks.

Type of local treatment. Patients were evaluated as to whether their local therapy consisted of surgery, radiotherapy, or no local treatment. Among surgical procedures, amputation, disarticulation, and rotation-plasty were grouped as ablative procedures and compared with (limb-saving) resections. The first attempt to remove the tumor formed the basis for all analyses, regardless of possible subsequent operations.

Timing of surgery. Primary surgery was assumed whenever an attempt to remove the primary lesion had been performed before the initiation of chemotherapy, whether this had been done with or without knowledge of the correct diagnosis, whereas primary chemotherapy was assumed if the start of chemotherapy had preceded surgery. Tumors that were never operated on were not included in this particular analysis.

Tumor response. Response to preoperative chemotherapy was assessed histologically according to the six-grade scale of Salzer-Kuntschik et al,18 where grade 1 denotes no viable tumor; grade 2, solitary viable cells or one islet of less than .5 cm; grade 3, less than 10%; grade 4, 10% to 50%; grade 5, more than 50% viable tumor; and grade 6, no effect of chemotherapy.18 A good response was defined as less than 10% viable tumor (response grades 1 through 3). In addition to evaluating response as a prognostic factor, response was also the end point of a multivariate analysis, where those factors that would be assessable at the start of treatment were evaluated for possible correlations with response.

Surgical remission. A complete surgical remission was assumed only when all detectable tumor foci were removed during first-line therapy and if this removal was macroscopically complete.

Statistical Analyses
All 1,702 patients were evaluated on an intent-to-treat basis. All cofactors were first investigated by univariate techniques. {chi}2 analysis or Student’s t test were used to compare unrelated samples when appropriate. Survival was calculated using the Kaplan-Meier method19 together with standard errors. Overall survival was calculated from the date of the diagnostic biopsy until death from any cause or 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.20 The multivariate analysis of overall survival was carried out using Cox proportional hazards regression model.21 Only variables that had presented with a significant prognostic value in univariate analysis were included into the multivariate models of survival. Multivariate analysis of response was performed by logistic regression,22 with all variables assessable on the first day of tumor directed therapy being entered into the model.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Distribution of Demographic and Tumor-Related Variables
Recruitment varied from 69 to 125 eligible patients per year, with the higher numbers in the latter years. Of a total of 133 participating institutions, only six centers contributed more than 50 patients each. The median age at diagnosis was 15 years (range, 2 to 68 years; mean, 16.7 ± 8.5 years). There were 1,007 male patients (59.2%; median age, 16 years; range, 2 to 68 years) and 695 female patients (40.2%; median age, 14 years; range, 3 to 64 years). Osteosarcomas in toddlers were exceedingly rare, with only 13 (0.8%) presenting in the first 5 years of life. Two hundred one osteosarcomas (11.8%) were detected in the first, 1,161 (68.2%) in the second, 223 (13.1%) in the third, and 63 (3.7%) in the fourth decade of life, and only 54 (3.2%) were detected later. Compared with their younger counterparts, patients 40 years of age or older were more likely to present with axial tumors (P < .001, {chi}2), secondary osteosarcomas (P < .001, {chi}2), or a prolonged history of symptoms (P = .012, {chi}2). They were also more likely to experience a delayed start of treatment (P < .001, {chi}2).

A total of 1,595 primary tumors (93.7%) were located in an extremity and 107 (6.3%) in the trunk (Fig 1). Of 1,595 extremity tumors, 1,399 (87.7%) were situated in a leg and 196 (12.3%) in an arm. The primary tumors involved the knee (distal femur, proximal tibia, or proximal fibula) in 1,208 patients (75.7% of limb tumors and 71% of all osteosarcomas). Compared with extremity lesions, osteosarcomas of the axial skeleton were associated with higher age (P < .001, t test), prolonged symptom duration (P < .001, {chi}2), and increased likelihood of primary metastases (P = .008, {chi}2) as well as a higher proportion of secondary osteosarcomas (P < .001, {chi}2). Information on tumor size was available for 1,560 of the 1,595 extremity osteosarcomas, of which 1,037 (66.5%) were considered small because they measured less than one third of the involved bone. The proportion of large tumors decreased with increasing distance from the trunk. The proportion was highest in the proximal femur or proximal humerus (122 of 236; 51.7%), followed by the more distal part of these bones (280 of 758; 36.9%) (P < .01, {chi}2) and was lowest for tumors of the tibia, fibula, or forearm (118 of 560; 21.1%) (P < .01, {chi}2). Osteosarcomas of the arm (102 of 194; 53.1%) were more likely to be large than those of the leg (327 of 1,268; 25.7%) (P < .01, {chi}2). Compared with patients with smaller tumors, patients with larger lesions were younger (P < .001, t test) and had primary metastases more often (P < .001, {chi}2).



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Fig 1. Skeletal distribution of 1,702 osteosarcomas.

 
Of 1,702 patients, 1,491 (87.6%) presented with seemingly localized disease. This group included 18 patients in whom a thoracotomy for suspected pulmonary metastases revealed no tumor and 31 patients with histologically proven or radiologically suspected skip metastases without other signs of dissemination. Two hundred eleven patients (12.4%) presented with distant metastases, which were histologically verified in 128 and proven by progression in 54 patients. The diagnosis of primary metastases relied solely on the results of diagnostic imaging in 29 patients. Primary metastases involved the lungs in 183 patients, distant bones in 45, and other sites in 19 (lymph nodes, 15; skin, one; brain, one; liver, one; and other soft tissues, three) (Fig 2). Compared with patients with localized disease, patients with primary metastatic osteosarcoma were more likely to present with axial tumors (P = .008, {chi}2), have large tumors (P < .001, {chi}2), and have a long history of symptoms (P < .001, {chi}2).



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Fig 2. Sites of primary metastatic involvement in 211 affected patients

 
Osteosarcoma arose as a secondary malignancy in 32 patients. The first cancers had been retinoblastoma in seven, sarcoma in 10 (Ewing sarcoma, four; rhabdomyosarcoma, four; fibrosarcoma, one; and chondrosarcoma, one), carcinoma in eight (uterus or cervix, four; breast, four; and stomach, two), testicular cancer in two, and medulloblastoma in one patient; hematologic neoplasms (Hodgkin’s disease, two; acute lymphatic leukemia, one; and non-Hodgkin’s lymphoma, one) comprised the other four malignancies. One patient had already suffered from gastric as well as lung carcinoma, and one from rhabdomyosarcoma and melanoma before the osteosarcoma. Patients with secondary osteosarcoma were older than those with primary disease (P < .001, t test) and were more likely to have axial involvement (P < .001, {chi}2).

Information regarding the duration of symptoms before the diagnostic biopsy was available for 1,136 patients, the median being 69 days (range, 1 day to 5 years 8 months). The history of symptoms exceeded 6 months in 118 patients (10.4%). A total of 1,089 patients reported tumor-related pain a median of 68 days before biopsy, whereas tumor-related swelling occurred a median of 40 days before biopsy in 843 patients. In the 796 patients for whom both pain and swelling were reported, pain preceded swelling in 373 (46.9%), swelling preceded pain in 32 (4.0%), and both were noted simultaneously in 391 (49.1%) patients. Axial primaries (P < .001, {chi}2), primary metastases (P = .007, {chi}2), and increasing age (P < .001, t test) were associated with a prolonged history.

Osteosarcoma Treatment
Before the diagnosis of osteosarcoma, 19 patients had had inadequate surgical treatment for pathologic fractures, and another 12 for arthroscopic knee surgery. Multiple biopsies were reported for an additional 41 patients. Tumor-directed therapy (surgery or preoperative chemotherapy) commenced after a median of 7 days (range, 0 to 252 days) from the diagnostic procedure. Of 1,702 patients, 1,700 (99.9%) went on to receive chemotherapy. Information about local treatment was available for 1,692 osteosarcomas. Of these, 1,608 (95.0%) were operated on, 881 (54.8%) by tumor resection and 720 (44.8%) by ablative procedures (322 amputations, 138 disarticulations, and 260 rotation plasties); the type of surgery was not recorded in seven patients. The use of ablative surgery decreased from 60.1% (455 of 757) in the 1980s to 31.4% (265 of 844) in the 1990s (P < .001, {chi}2) (Fig 3). Compared with those treated by ablative surgery, patients whose tumors were removed by resections were older (P < .001, t test), more likely to have small tumors and a good response to chemotherapy (both P < .001, {chi}2), and less likely to achieve a complete remission (P = .032, {chi}2). Only a minority of all axial lesions (13 of 107) was removed by ablative surgery. The first attempt to remove the primary tumor was performed before the initiation of chemotherapy in 157 patients, in 85 cases without knowing the correct diagnosis of osteosarcoma. The use of primary surgery was associated with older patient age (P < .001, t test), axial tumor site (P < .001, {chi}2), small tumor size (P = .026, {chi}2), nonablative surgery (P = .017, {chi}2), and failure to achieve a complete remission (P = .002, {chi}2). Of 1,545 osteosarcomas treated with upfront chemotherapy, 1,451 went on to definitive surgery (93.9%) and 84 (5.4%) did not (10 without sufficient data). The duration of preoperative chemotherapy, available for 1,443 of the 1,451 patients, varied between 1 and 335 days (median, 85). Of the 84 osteosarcomas that were not operated on, 26 were irradiated (13 electively and 13 because of local or systemic inoperability) and 58 received no local therapy. Eight patients died during the neoadjuvant phase of chemotherapy (seven of complications and one of osteosarcoma), and 41 were considered inoperable. Five patients refused any form of local treatment and four were lost to follow-up before surgery.



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Fig 3. Changing pattern of surgery with time (by year of diagnosis). Dark shading represents amputation/disarticulation; grey, rotation plasty; and white, (limb-saving) resection.

 
Histologic Response to Preoperative Chemotherapy
Information on response was available for 1,320 of 1,451 tumors operated on after primary chemotherapy, of which 734 (55.6%) achieved a good response (< 10% viable tumor). Male sex, axial tumor site, long history of symptoms, and long treatment delay after biopsy were associated with a higher likelihood of poor response in univariate {chi}2 analyses. Patients whose tumors responded poorly were also less likely to receive limb-salvage surgery and to achieve a complete surgical remission (Table 1).


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Table 1.  Univariate Analysis of Tumor Response
 
The logistic models for response to chemotherapy are listed in Tables 2 and 3. According to the model built for all tumor locations, axial site, male sex, and a long history of symptoms were independently associated with poor response (Table 2). In the model for extremity osteosarcomas, only male sex and long history, but not tumor size or tumor location, were associated with poor response (Table 3).


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Table 2.  Logistic Models for Poor Response to Chemotherapy for All Sites
 

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Table 3.  Logistic Models for Poor Response to Chemotherapy for Extremity Osteosarcoma
 
Surgical Remission
One hundred thirteen patients (6.6%) retained macroscopic residual tumor at the site of their primary tumor, and 180 (10.6%) were left with tumor at any site. Among the 113 patients with gross local residual tumor, 84 had not been operated on and 29 were left with tumor after definitive surgery. In univariate analysis, failure to achieve a surgical remission was associated with increasing age (P = .003, t test), axial site (P < .001, {chi}2), large tumor size (P < .001, {chi}2), primary metastases (P < .001, {chi}2), long history (P = .001, {chi}2), delayed start of therapy (P = .002, {chi}2), primary surgery (P = .002, {chi}2), nonablative surgery (P = .032, {chi}2), and poor response to chemotherapy (P = .001, {chi}2). In addition to the 113 patients who never achieved a local surgical remission, 84 developed a local recurrence at some time of their disease course, so that permanent local surgical control was not achieved in 11.6% of all cases.

Overall and Event-Free Survival
Median follow-up was 3.8 years (range, 9 days to 19 years) for all 1,702 patients and 5.5 years (same range) for 1,160 survivors. Actuarial survival rates at 5, 10, and 15 years were 65.3%, 59.8%, and 57.3%, respectively (Table 4 and Fig 4). Of 542 deceased patients, 477 died from osteosarcoma. Fifty-nine patients died from other causes, 36 in first complete remission. Acute side effects of first- or second-line chemotherapy (34 patients), mostly consequences of myelosuppression, anthracycline-induced cardiomyopathy (eight), secondary malignancy (eight), and perioperative complications (five), were the most frequent causes of death apart from osteosarcoma. No information concerning the cause of death was available for six patients.


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Table 4.  Univariate Analysis of Overall and Event-Free Survival
 


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Fig 4. Overall and event-free survival probabilities of all 1,702 patients. Numbers represent patients at risk.

 
At last follow-up, 939 patients survived in first complete surgical remission, for 5-, 10-, and 15-year probabilities of event-free survival of 52.8%, 49.4%, and 48.3%, respectively (Table 4 and Fig 4). Events as defined occurred in 763 patients; 180 failed to achieve a complete surgical remission, 36 died in first complete remission, and 547 developed a relapse. In the latter, the median time from diagnosis to relapse was 1.5 years (range, 49 days to 14.3 years). Two thirds of all recurrences (n = 361) manifested within 2 years and 95.6% (n = 523) within 5 years from diagnosis. Only two of 204 patients followed for longer than 10 years went on to develop a first recurrence. One patient developed pulmonary and mediastinal metastases at 10.3 years, and one patient developed a distant bone lesion at 14.3 years.

Univariate Analysis of Prognostic Factors
There was no correlation between patient sex and survival or event-free survival. Also, no correlation between the duration of prediagnostic symptoms, history of previous malignancy, or interval from biopsy to tumor-directed therapy and prognosis could be detected (Table 4). An age of 40 years or older, axial tumor site, and the presence of primary metastases were associated with inferior overall and event-free survival probabilities in univariate analysis (Table 4 and Fig 5). Among the 211 patients with suspected or proven primary metastases, the 155 in whom only the lung was involved had a better prognosis than the 56 in whom other sites were affected alone or in combination with pulmonary metastases (Table 4). In the latter group of 56 patients, complete surgery of all affected sites was performed in only eight. After a median follow-up of 1.3 years, only 15 of 56 patients survived and only four in first complete remission. In contrast, 85 (54.8%) of 155 patients with primary metastases restricted to the lungs reached a complete surgical remission. With a median follow-up of 2.5 years for all 155 patients and 4.4 years for survivors, 65 patients were still alive, 30 in first remission. If the 29 patients with abnormal diagnostic imaging as the only suggestion of metastases had not been included among those with primary metastases, the 10-year survival probability of the remaining 182 would have dropped to 20.8% (SE 4%). Among the 182 patients, the 93 in whom the primary tumor as well as all detectable metastases could be removed had a 10-year survival probability of 40.3% (SE 7%).



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Fig 5. Kaplan-Meier curves of overall survival for variables with prognostic significance in univariate and multivariate analyses. See text for definitions and Table 3 for P values. Response graded according to Salzer-Kuntschik et al.18 See Patients and Methods for details.

 
In extremity tumors, size correlated with outcome (this measurement was not available for axial tumors) (Table 4 and Fig 5). Among extremity osteosarcomas, those of the tibia had the best prognosis and those of the humerus had the worst (Table 5). Osteosarcomas of the proximal humerus or proximal femur had an inferior prognosis to other extremity osteosarcomas (Table 4 and Fig 5).


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Table 5.  Response, Local Control, and Survival in Relation to the Location of the Primary Tumor
 
When patients who received primary surgery were compared with those who received primary chemotherapy followed by delayed surgery, no advantage of one over the other approach became apparent. Also, there was no correlation between the type of surgery (ablative v limb-salvage) and survival (Table 4). As detailed above, there was a significant imbalance in the distribution of other cofactors for both timing and types of surgery.

Response to preoperative chemotherapy emerged as a highly significant predictor of outcome (Tables 4, 6, and 7). When response was not only divided between good and poor but also according to the six regression grades defined by Salzer-Kuntschik et al,19 a more gradual impact became apparent, with stepwise improvement of survival from grade 6 to grade 1 (Table 4 and Fig 5).

Long-term survival without complete surgical removal of both the primary tumor and, if present, primary metastases was the rare exception (Table 4 and Fig 5). Altogether, only 14 of 180 patients seemingly left with macroscopic tumor survived for longer than 5 years. Seven of these had unproven primary metastases as the only site of incomplete surgery, and the other seven retained tumor at the site of the primary tumor. One of these patients was alive without progression 5.2 years after an intralesional resection of a vertebral and another 13.3 years after intralesional resection of a thoracic osteosarcoma. The remaining five long-term survivors had received local irradiation instead of surgery during first-line treatment. Only two of the five patients were still alive without disease progression.

Multivariate Analysis of Prognostic Factors
In the multivariate Cox model evaluating the five factors that had shown a correlation with survival in univariate analysis, all except age retained their significance (Table 6). The Cox model for extremity osteosarcomas is presented in Table 7. Because failure to achieve a surgical remission had been defined as an event, calculations including this variable had to be restricted to the analysis of overall survival.


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Table 6.  Multivariate Cox Models of Overall and Event-Free Survival for All Sites
 

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Table 7.  Multivariate Cox Models of Overall and Event-Free Survival for Extremity Osteosarcomas
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This analysis of prospectively collected data provides reliable evidence that more than half of all patients presenting with a previously untreated high-grade osteosarcoma of the extremity or trunk can become long-term survivors with appropriate therapy. The analysis of 1,702 such patients, to our knowledge the largest cohort reported from the polychemotherapy era, allowed the identification of several independent prognostic factors. Among variables assessable at diagnosis are tumor site and size as well as primary metastatic disease. A definitive statement about an individual patient’s prognosis, however, can only be made later in the course of the disease, when the quality of surgical remission and tumor response to upfront chemotherapy can be evaluated.

The analysis focused on high-grade osteosarcoma of bone. Low-grade variants and craniofacial osteosarcomas, both associated with a lower likelihood of metastases,23 were not included. High-grade surface osteosarcomas, albeit rare, with only six cases, were included, because they behave like high-grade central tumors.24 Overall, the distribution of demographic and tumor-related variables was similar to that of other large published series23,25 and typical for this disease. Elderly patients were underrepresented, but this situation is by no means unique to the COSS trials and is typical for cancer trials in general.26

All COSS studies were based on intensive preoperative and postoperative chemotherapy in addition to surgery of all identified tumor lesions, an aggressive treatment approach that can be considered appropriate according to today’s standards. Approximately 90% of all deceased patients died from progressive osteosarcoma. Many of the remaining deaths must be considered treatment related. Death during therapy was mostly attributable to complications of pancytopenia; late deaths in remission were mainly caused by anthracycline cardiomyopathy or second malignant neoplasms. Here, more problems must be feared with increasing follow-up.

Many previous studies have shown tumor response to preoperative chemotherapy to represent the most important prognostic factor for patients with localized, operable extremity osteosarcoma.25,27 Other variables with possible prognostic impact include tumor size,28 patient sex,29 older29 or younger age,8,30 proximal tumor site,6,13 high alkaline phosphatase,10,31 and high lactate dehydrogenase values.10,32 More recently, prognostic significance was claimed for multidrug resistance status,33 loss of heterozygosity of the RB gene,34 and HER2/erbB-2 expression,35,36 but these claims have yet to be substantiated by large-scale prospective studies.

The results of our analysis provide evidence for the importance of several independent prognostic factors, which apply not only to localized extremity osteosarcomas but to a much wider spectrum of the disease. Age per se does not seem to be one of them. The impression that older patients do worse is rather attributable to the increased proportion of unfavorable axial lesions with increasing age. In accordance with recent data from the Rizzoli Institute, where 29 patients aged 40 to 60 years with extremity osteosarcoma had a survival rate of 62%,37 40 patients aged 40 years or older with limb osteosarcoma from our series had a 10-year survival probability of 56.4%, almost identical to that of younger patients. These results should encourage the use of multimodal therapy for osteosarcoma at least in the fifth and sixth decades of life. Too few older patients were enrolled to draw any conclusions beyond 60 years of age.

The Scandinavian Sarcoma Group found sex to correlate with outcome, female patients having fewer relapses and better survival than their male counterparts.29 We found female sex to be associated with a higher likelihood of good response in univariate and even in multivariate analysis. Other than might be expected, this did not translate into a survival advantage for females, despite the strong overall correlation between response and survival.

In the COSS series, more than 90% of all primary tumors were situated in a limb, with the well-known preponderance for the knee. As with other studies,10,38,39 we found the tibia to be a prognostically favorable site. In contrast to observations suggesting that the earlier growth spurt of the humerus was associated with an earlier development of osteosarcoma at this site,40 we saw no such age effect. Although the humerus was a favorable site in the Memorial Sloan-Kettering Cancer Center’s series,10 the opposite was true in our cohort.

Overall, the proportion of large tumors increased with increasing proximity to the trunk. However, the prognostic differences between different extremity locations cannot be reduced to a mere effect of tumor size, because proximal site remained an independent adverse factor even in multivariate analyses. Similar observations have been reported by the Children’s Cancer Group,13 the Dana-Farber Cancer Institute/the Children’s Hospital-study III,6 and the European Osteosarcoma Intergroup.41 Variations in chemosensitivity cannot explain the poor prognosis associated with proximal location, because there was absolutely no correlation between various extremity sites and response. The reason proximal site represents an independent risk factor remains to be determined.

The percentage of only 6.3% axial tumors in our cohort is lower than that reported by other studies,23,25 probably because of an underrepresentation of elderly patients. Still, the 107 patients with axial osteosarcomas form one of the largest cohorts of such individuals reported to date. Despite aggressive chemotherapy, the outcome for patients with axial osteosarcoma was far from being satisfactory. This experience is by no means unique, as exemplified by 5-year survival rates for pelvic osteosarcoma of only 18% (41% with chemotherapy) and 34% reported from the Royal Orthopaedic Hospital in Birmingham42 and the Memorial Sloan-Kettering Cancer Center,43 respectively. Failure to achieve and maintain local control was the main contributor to the low overall success rate in all series. In addition, axial osteosarcomas were more likely to present with primary metastases, which could well be related to the observed prolonged latency period before making the correct diagnosis, and less likely to respond to preoperative chemotherapy. However, a curative approach including both aggressive systemic therapy and aggressive local treatment measures can be successful.

The prognostic importance of tumor size, which could only be evaluated for extremity sites, could once again be confirmed. Interestingly, there was no correlation between tumor size and response. The higher relapse risk of patients with large primary tumors must then be attributable to an increase in metastatic burden parallel to tumor size, best exemplified by the increasing likelihood of primary metastases but obviously extending to micrometastatic load as well.

Clinically detectable primary metastases were an independent adverse prognostic factor in all univariate and multivariate analyses. Results similar to ours have been reported from the Memorial Sloan-Kettering Cancer Center, where only 11% of 62 patients with clinically detectable metastasis at initial presentation survived,44 and the Rizzoli Institute, where the chance for 44 patients with primary lung metastases to be alive after 5 years was only 14%.45 Other than Bacci et al,46 who recently reported primary spread to be associated with shorter prediagnostic symptom duration and hypothesized about a more aggressive biologic behavior, we found primary metastases to be associated with prolonged symptoms before diagnosis and large size of the primary tumor, which is another indicator of advanced disease. Identical age and sex distributions again argue against basic biologic differences between primary metastatic and seemingly localized osteosarcomas. The same holds true for tumor response to preoperative chemotherapy, which was independent of whether primary metastases were present or not, again contradicting observations by Bacci et al.47

It has been suggested that patients with primary metastases have such a poor outcome with standard treatment that experimental therapies should be used upfront.44 Our results disagree with this proposal. Patients with primary metastases obviously benefit from a good response to chemotherapy. It seems more reasonable to use intensive upfront systemic treatment with the drugs most likely to induce such a good response and to combine this with maximally aggressive surgery of the primary tumor and all metastatic foci rather than to rely on experimental therapies of questionable efficacy. After all, the main reason for the low success rate in primary metastatic disease is not that chemotherapy is less effective than in localized disease but that complete surgery is so difficult to accomplish. We found a 10-year survival probability of 40.3% for patients with primary metastases who had a complete surgical remission, which is far from being dismal.

Osteosarcomas are among the most frequent secondary malignancies, particularly after childhood cancer.48-50 As described by others,51 we found the trunk to be overrepresented and age to be higher in secondary than in primary osteosarcoma. From the results reported here and in a previous publication by our group52 on secondary osteosarcomas that included craniofacial tumors, it seems that the poor prognosis often ascribed to secondary osteosarcomas is related more to their predilection for unfavorable sites than to their secondary nature.

Information on the duration of symptoms must necessarily be collected retrospectively, casting considerable doubt on its reliability. Still, the results obtained are plausible. The median history of approximately 2 months is similar to the 56 days reported for 350 children with osteosarcoma from Pediatric Oncology Group trials.53 Despite the association of prolonged symptom duration with indicators of advanced disease, such as large tumor size and primary metastases, it was, somewhat surprisingly, not associated with an inferior outcome. An earlier Danish study54 of 184 osteosarcomas, which included many patients treated without effective chemotherapy, even found a superior outcome for patients with a longer history. In the era of effective systemic therapy, such a simple correlation between symptom duration and outcome no longer exists. On the one hand, the group with prolonged symptom duration includes patients with neglected or misdiagnosed and far advanced disease; on the other hand, it may contain osteosarcomas that are characterized by a less aggressive biology.

COSS has so far used an arbitrary cutoff of 3 weeks from biopsy to start of treatment for eligibility.4,7,15,16 In the present study, we could not substantiate an impact of this lag time on outcome. When taking into account published data on the impact of dose intensity in osteosarcoma,55 it may be more important to keep up the intensity of chemotherapy once treatment has commenced than to start therapy a few days earlier.

Even though neoadjuvant chemotherapy is now used almost universally, the question of whether it conveys a survival benefit has not been convincingly answered. A small randomized study by the Pediatric Oncology Group found no advantage of one over the other approach in localized extremity disease.56 Large, prospective trials are missing. In our series, any possible impact of surgical timing could well have been obscured by its association with other important risk factors, exemplified for instance by a preponderance of small tumors among those treated by primary surgery. If surgery is performed upfront, the chance to evaluate response to chemotherapy is lost, so that one of the most reliable prognostic indicators remains obscure. Also, it has been well documented that the local recurrence rate will decline with increasing preoperative tumor cell destruction.57,58 It therefore seems prudent to continue the use of preoperative chemotherapy and to restrict the use of primary surgery to selected cases.

Whereas less than one third of all primary tumors were removed by limb-salvage procedures in the early studies of our group, this proportion rose to over two thirds in the latter years. Only half of the remaining patients had limbs amputated. The others received rotation plasties, procedures which may result in equal or even slightly superior function compared with endoprosthetic surgery.59 Small tumors and those responding well to chemotherapy were overrepresented in the limb-salvage group. The dramatic shift of surgical preferences with time and the unequal distribution of risk factors must be kept in mind when trying to detect any possible correlation between various surgical procedures and prognosis. Still, these results show that many osteosarcoma patients can safely retain their limbs as long as certain measures of caution are not neglected.

Tumor response to preoperative chemotherapy has emerged as probably the most important prognostic factor in primary, localized extremity osteosarcoma.27 In the present study, its outstanding importance became evident for a much broader spectrum of the disease. Response, however, is not an all or nothing, and it must not be assumed that the arbitrary 10% viability cutoff line drawn by many investigators represents an absolute border beyond which chemotherapy is no longer effective. Male sex, long history, and, most notably, axial location confer a higher risk of poor response. Still, it is presently not possible to predict with reasonable certainty at diagnosis how an osteosarcoma is going to respond.

Although most patients with localized extremity osteosarcomas go into complete surgical remission, this goal is more often than not missed in individuals with axial primaries or metastatic dissemination. The prognostic importance carried by complete surgery cannot be overstressed. In our series, failure to achieve a complete remission emerged as the strongest negative prognostic factor. Apart from few irradiated patients, those who became long-term survivors without removal of all visible tumor usually had radiologically suspected yet histologically unproven primary metastases as the only remaining focus. Survival estimates would have approximated zero if the definition of nonremission had been restricted to proven sites of osteosarcoma. The dire need for alternative local treatment options in inoperable osteosarcoma, regardless of site, is self-evident. Radiotherapy, possibly in conjunction with targeted radionuclide application,60,61 may offer an option in selected situations.

In conclusion, the analysis of a large cohort of osteosarcoma patients has allowed the definition of several independent prognostic factors. Although some of these, such as tumor site and size and primary metastases, are assessable at diagnosis, a reliable prediction of prognosis can only be made later in the course of the disease, when information on tumor response and the quality of surgical remission become available.


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

We thank all 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.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
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Submitted December 14, 2000; accepted June 14, 2001.


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