Matthias Kevric

Osteosarcoma of the Pelvis: Experience of the Cooperative Osteosarcoma Study Group

PURPOSE To define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed. PATIENTS AND METHODS Sixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy. RESULTS Local failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P =.0137), primary metastases (P =.0001), and no or intralesional surgery (P <.0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P =.0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P =.0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P <.0001), and no radiotherapy (RR = 4.196; P =.0059) were independent poor prognostic factors. CONCLUSION An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.

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

PURPOSE To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma. PATIENTS AND METHODS Two hundred forty-nine consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes. RESULTS Five-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions. CONCLUSION To our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.

Osteosarcoma: The COSS Experience

COSS, the interdisciplinary Cooperative German-Austrian-Swiss Osteosarcoma Study Group, was founded in 1977 and has since registered some 3,500 bone sarcoma patients from over 200 institutions. For the purpose of the Pediatric and Adolescent Osteosarcoma Conference in Houston, March 2008, the outcomes of 2,464 consecutive patients with high-grade central osteosarcoma, who had been diagnosed between 1980 and 2005 and had been treated on neoadjuvant COSS protocols, were reviewed. Intended treatment had included surgery and multidrug chemotherapy, with high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide being used in most protocols. After a median follow-up of 7.31 years for 1,654 survivors, 5- and 10-year survival estimates were 0.748/0.695 for 2,017 patients with localized extremity tumors and 0.369/0.317 for 444 patients with axial tumors or/and primary metastases, respectively. Tumor response to preoperative chemotherapy was of independent prognostic significance. Over the years, there was a major shift from amputation towards limb-salvage. This development was least evident for patients below the age of 10. While survival expectancies improved from the first to the second half of the recruitment period, no further improvement was evident within the latter period. In the manuscript, the results described above are discussed based on the findings of the previous analyses of our group.

Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas.

Osteosarcomas are the most frequent bone sarcomas. The molecular chromosomal aberrations in osteosarcomas were analyzed by comparative genomic hybridization (CGH). We studied 47 frozen tumors (41 primary samples, 6 relapses) in osteosarcoma patients registered in the Cooperative Osteosarcoma Study (COSS) protocol. Genomic imbalances were detected in 40 of 41 primary tumors and 6 of 6 relapsed tumors. Gains were more frequent than losses (ratio of 1.3:1). The median number of changes was 16 and 12 in primary and relapsed osteosarcomas, respectively. The median number of aberrations in primary high‐grade osteosarcomas (17.0) was significantly higher than in low‐ or intermediate‐grade osteosarcoma subtypes (3.0) (p = 0.038). The most frequent gains included 8q, 1p21‐p31 and 1q21‐q24, and the most frequent losses were 10q, 5q and 13q. High‐level gains were observed on 8q23‐q24, 17p13 and 1q21‐q24. A gain of 19p (p < 0.001) or loss of 9p (p = 0.027) was more frequent in poor responders than in good responders. Univariate analysis revealed that patients with primary metastases (p = 0.002), poor histologic responses (p = 0.005), high‐level gains of 19p (p = 0.012) or losses of 13q14 (p = 0.042) had significantly lower event‐free survival (EFS), whereas patients with a loss of 5q (p = 0.007) or a loss of 10q21‐22 (p = 0.017) had significantly higher EFS than patients without these aberrations. Multivariate analysis demonstrated that primary metastasis, loss of 13q14 and loss of 5q were independent prognostic factors. The findings of our study seem to be useful for evaluating the prognosis of patients and may finally lead to treatment strategies based on genetic background of osteosarcoma.

Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials

The prognostic relevance of dose intensity in the treatment of osteosarcoma is still under discussion. The aim of this study was to investigate whether higher dose intensities of chemotherapy correlated with better outcomes.

Osteosarcoma of the Hand and Forearm: Experience of the Cooperative Osteosarcoma Study Group

BackgroundOsteosarcoma is extremely rare in the hand and forearm. Therefore, only limited data are available for planning treatment or predicting the outcome and prognosis of osteosarcoma in the peripheral upper extremity.MethodsEpidemiological, clinical, and histopathologic data were analyzed in 39 patients with osteosarcoma of the forearm or hand who were enrolled in studies of the Cooperative German-Austrian-Swiss Osteosarcoma Study Group from 1977 to December 2000. In patients with high-grade osteosarcoma, the treatment entailed surgical resection in combination with chemotherapy, whereas patients with low-grade osteosarcoma underwent only surgery.ResultsThe 5-year overall survival rate among the 33 patients with high-grade central osteosarcoma of the distal upper extremity was 86.2% ± 6.4%. The 5-year event-free survival rate was 65.4% ± 9.6%. Five of the eight patients with secondary metastases were in remission at the time of analysis. Four patients died of their disease, and two patients died of chemotherapy-related complications. The mean overall survival rate was 88.0% ± 6.5% in patients treated by wide or radical tumor resection and was 75.0% ± 21.7% in patients with nonwide margins of resection. Whether amputation or local resection was performed had no significant influence on the prognosis. All six patients whose osteosarcoma was not classified as high-grade central osteosarcoma were in remission at the time of analysis.ConclusionsThe results demonstrate a remarkably high survival rate for patients with high-grade osteosarcoma of the hand and forearm and confirm that multiagent chemotherapy in combination with wide excision is a highly effective treatment for this malignant tumor.

Epidermal Growth Factor Receptor Expression in High-Grade Osteosarcomas Is Associated with a Good Clinical Outcome

Purpose: The expression of the epidermal growth factor receptor (EGFR) in osteosarcomas has repeatedly been described. With the introduction of anti-EGFR–targeted therapies in clinical practice, these findings regain increased attention. Experience with anti-EGFR–targeted therapies in other cancers has made clear that besides the expression status of EGFR, a detailed knowledge about gene mutations is of major predictive power. We therefore aimed to explore the EGFR expression and gene mutation status in high-grade osteosarcomas. Experimental Design: We investigated tumor samples of osteosarcoma patients of all age groups by means of immunohistochemistry (n = 111) and egfr fluorescence in situ hybridization (n = 39). Sixty-three patients were treated according to the Cooperative Osteosarcoma Study Group protocols and complete clinical follow-up was available in these cases. Results: Ninety-one of 111 (81%) of osteosarcomas revealed an expression of EGFR. EGFR expression showed a dose-response relation with improved event-free and overall survival. This was independent of the degree of tumor regression due to neoadjuvant chemotherapy. Nine of 39 (23%) osteosarcomas showed egfr amplifications by means of fluorescence in situ hybridization. All these cases expressed EGFR. When comparing EGFR expression between primary biopsy and resection specimen (n = 19), viable residual tumor cells in resection specimens revealed a lower EGFR expression and a tendency toward membranous staining compared with the initial biopsy. Conclusions: In conclusion, expression and amplification of EGFR are frequently observed in high-grade osteosarcomas and are associated with improved prognosis in a dose-responsive way. This implies that low EGFR expression possibly predicts lack of response to conventional treatment in high-grade osteosarcomas and may warrant a more intensive therapeutic approach, although not based on EGFR targeting.

Solitary skeletal osteosarcoma recurrence. Findings from the Cooperative Osteosarcoma Study Group

Solitary skeletal osteosarcoma (OS) manifestations distant from the site of the primary tumor rarely arise as only sign of disease recurrence.

More on osteosarcoma and phylloides tumor.

To the Editor: Jaing et al1 report 3 female osteosarcoma patients who developed phyllodes tumors (PT) of the breast several years after multimodal treatment for osteosarcoma. The Cooperative Osteosarcoma Study Group database of over 4000 osteosarcoma patients adds 5 additional females for whom the occurrence of both tumors was reported. As in Jaing and colleague’s series, all patients were treated by surgery and multiagent chemotherapy for osteosarcoma (1 only following PT), 1 also received radiotherapy to the chest before developing PT. It is noteworthy that one of the 3 patients in Jaing and colleague’s series and 3 of ours suffered additional malignancies from the Li-Fraumeni spectrum (Table 1). Germline TP53 mutations have been found strongly associated with osteosacoma and even more so PT.2 Notably, the only one of our patients investigated (no. 2) carried such a mutation, as did one of Jaing’s. Also, both suffered from further malignancies. Although the cooccurrence of osteosarcoma and PT has been reported in case reports,3,4 most large series of secondary malignant neoplasms (SMN) after osteosarcoma do not mention PT at all. The CCSS series of SMN after childhood cancer in general reported only 3 PT among 14,358 patients, 1382 of whom suffered at least 1 SMN.5 Even though the not always fully malignant nature of PT may lead to some underreporting, the available evidence suggests that the risk of developing both osteosarcoma and PT is considerably lower than the 3/86 described by Jaing and colleagues. Nevertheless, we support their recommendation that long-term follow-up of female osteosarcoma patients should include life-long breast examinations. Patients who develop both osteosarcoma and PT should be offered TP53 genetic testing and should be informed about the risk of subsequent malignancies.

High BMI at diagnosis is not associated with inferior survival in patients with osteosarcoma. A report from the Cooperative Osteosarcoma Study Group.

To the editor:We read with interest the report by Altaf et al. from the Children’s Oncology Group, who observed being overweight or obese at diagnosis of osteosarcoma to be associated with inferior survival [1]. We set out to validate their finding in an independent data set. We evaluated a previously characterized cohort of patients with high-grade central osteosarcoma from the Cooperative German-Austrian-Swiss Osteosarcoma Study Group COSS [2]. In order to mirror the selection criteria chosen by Altaf et al. as closely as possible, we selected 1,611 patients who had presented with localized extremity osteosarcoma between their 2nd and 20th birthdays. Among these, information on both height and weight at diagnosis was available for 1,405. For reasons of comparability, we started out using the same age and gender specific body-mass index percentiles from the United States (US-BMI) asAltaf et al. to distinguish three groups of patients. According to their definitions, US-BMI was classified as low (<5th US-percentile) in 264 (18.8%), normal in 1,109 (78.9%), and high (>85th US-percentile) in only 32 (2.3%) of COSS patients. After a median follow-up of 9.0 years (range: 0.02–31.0) for all 1,405 and 11.0 years (same range) for 994 survivors, 5-year event-free and overall survival rates were 75.7%/64.5% with low, 75.6%/64.4% with normal, and 86.7%/81.3% with high US-BMI, respectively (all log-rank P-values for intergroup comparisons >0.1). Given that so few of our European patients fulfilled the criteria for high US-BMI, we repeated the analysis using German age and gender specific BMI percentiles (GER-BMI) [3], but set the borders for normal between the third and 75th percentiles, as values for 5th and 85th percentiles were not available. According to this revised definition, GER-BMI was classified as low in 141 (10.0%), normal in 995 (70.8%), and high in 269 (19.1%). Five-year event-free/ overall survival expectancies were 77.1%/63.0% with low, 75.1%/ 65.2% with normal, and 78.0%/64.7% with high GER-BMI, respectively (all log-rank P-values again >0.1). We could also not detect any association of high BMI with inferior survival when setting the border at the 90th GER-BMI percentile or when adjusting for sex, tumor site, and treatment period using Cox proportional hazards models. The presence or lack of an association between high BMI and poor survival from osteosarcoma may vary substantially between different social environments and healthcare scenarios. It might therefore not have been high BMI per sewhich was responsible for the adverse outcomes observed by Altaf et al. Being overweight or obese might merely have flagged other problems which disadvantaged their affected patients. We conclude that young patients with osteosarcoma from theGerman speaking regions of Central Europe are much less likely to present overweight or obese according to US criteria than their American peers and that a high BMI at diagnosis of osteosarcoma is not associated with inferior survival in all regions of the world.