Controversies in childhood osteosarcoma.

Osteosarcoma, the most frequent bone cancer of children and adolescents, will almost always result in death due to pulmonary metastatic disease unless treated by surgery and effective multidrug chemotherapy. Imaging of the primary tumor is by X-ray and magnetic resonance imaging. Imaging of the chest is by computed tomography, but many questions regarding the interpretation of small, nonspecific findings and how to deal with them remain. The diagnosis must be confirmed by a well-placed biopsy. Chemotherapy is usually initiated prior to definitive surgery. Treatment generally includes high-dose methotrexate, doxorubicin, and cisplatin, with some regimens also incorporating ifosfamide. While limb-saving resections have become standard after completion of skeletal growth, reconstruction in the growing child poses much greater challenges. The use of modern, expandable endoprostheses, but also rotation-plasties and even amputation may all be valid options in selected cases. Histologic response of the primary to preoperative chemotherapy has been identified as an important prognostic factor. Various imaging methods can help to predict tumor response to preoperative chemotherapy, yet all have their limitations. Results of a randomized trial assessing if modifying postoperative treatment based on the extent of response will improve results, EURAMOS-1, are pending. The debate about whether biologic agents or targeted therapies added to chemotherapy might improve outcomes is ongoing. Follow-up to detect late-effects of treatment and recurrences of osteosarcoma must be continued for several decades.

Osteosarcoma over the age of forty.

The European Musculo Skeletal Oncology Society (EMSOS) has carried out a retrospective review of patients over the age of 40 years with osteosarcoma. 481 patients from 12 centres or multicentric groups were included. 42 patients had osteosarcoma arising in Paget's disease, median survival was 9 months. Patients with axial or metastatic tumours also did badly whilst 41 patients with radiation-induced osteosarcoma had a prognosis paralleling conventional osteosarcoma matched for patient age and site of the tumour. 238 patients had high grade non-metastatic osteosarcoma and had a survival of 46% at 5 years. Older patients had less chemotherapy and fared worse. Osteosarcoma in the elderly is a curable condition and warrants intensive treatment with chemotherapy and surgical resection.

High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma.

In this report, we describe our experience with high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) in 15 children with relapsed osteosarcoma who were treated by members of the Cooperative Osteosarcoma Study Group. Eight patients received HDC after the first relapse, six patients after the second relapse and one after the sixth relapse. Thirteen patients underwent HDC and ASCT in complete remission and two patients had macroscopic tumor residues. Seven patients received HDC based on melphalan and etoposide. Four of these patients were treated with additional carboplatinum. Two patients received carboplatinum, etoposide, and thiotepa or cyclophosphamide. In six patients double HDC was performed. In all six of these, the first HDC consisted of thiotepa/ cyclophosphamide. The second regimens included melphalan/etposide (two patients), melphalan/etposide/ carboplatinum (one patient), and melphalan/busulfan (one patient). Three of the 15 patients died of toxic complications. Eight patients developed further relapses, two patients showed persistent disease, and two patients are presently in continuous complete remission. The probability of relapse-free survival was 0.20 +/- 0.12 within a median follow-up (MFU) of 8 months and the probability of overall survival was 0.29 +/- 0.12 after a MFU of 16 months. In conclusion, utilization of HDC and ASCT in this patient group did not significantly improve the treatment outcome compared to conventional relapse therapy.

SV40 sequences in human osteosarcoma of German origin.

Simian virus 40 (SV40) is a dsDNA polyomavirus that induces osteosarcomas and mesotheliomas in hamsters and transforms many types of cells in tissue culture, including human cells. Osteosarcoma is a bone malignancy with multiple molecular lesions underlining progression from normal bone to osteosarcoma. Recent investigations have identified SV40 DNA sequences in osteosarcomas, suggesting that SV40 may contribute to tumor development. However, these studies also demonstrated that geographical differences exist between SV40 and tumor association. Our study analyzed 46 frozen German tumor specimens (42 osteosarcomas and 4 sarcomas initially suspected to be osteosarcomas) for the presence of SV40 DNA sequences by using PCR. Two different primer sets amplifying a 573 bp region of SV40 Tag gene with the complete intron sequence (SV.for 2/SV.rev) and a 172 bp region with no intron sequence (SV.5/SV.6) were used. DNA sequencing analysis verified the results. No SV40 sequences could be detected using the primer set SV.for 2/SV.rev, while 2 out of 42 osteosarcoma specimens and 1 out of 4 poorly-differentiated tumor specimens contained SV40 sequences, using the primer set SV.5/SV.6. From one of these two positive osteosarcomas, multiple tumor biopsies taken at different times during the dissection, including metastasis, tested positive for SV40. These results indicated that in Germany, only rare osteosarcomas can be linked to SV40. These results support previous findings involving geographical differences in the presence of SV40. Finally, the specific detection of SV40 sequences with multiple specimens from one of the two patients and the absence of SV40 sequences in all other samples underscores the specificity and reproducibility of this investigation and ruled out PCR contamination.

Combined modality treatment for osteosarcoma occurring as a second malignant disease. Cooperative German-Austrian-Swiss Osteosarcoma Study Group.

PURPOSE: The prognosis of osteosarcoma occurring as a second malignant disease (OS-SMD) is thought to be poor. We attempted to evaluate whether this holds true when OS-SMD is treated with combined modality therapy as developed for primary osteosarcoma and if factors that influence survival might be identified. PATIENTS AND METHODS: All patients with OS-SMD registered at the Cooperative German-Austrian-Swiss Osteosarcoma Study Group (COSS) study center between 1980 and June 1996 were evaluated for patient- and treatment-related factors, local and systemic outcome, and survival. Therapy was to be given according to contemporary COSS protocols for primary extremity osteosarcoma, including surgery and multiagent chemotherapy. RESULTS: Thirty patients with OS-SMD were registered (median latency period, 9 years 2 months). The first malignancies had been retinoblastoma (10 patients), sarcoma (10 patients), lymphoma (five patients), carcinoma (four patients), and medulloblastoma (one patient). Treatment for these malignancies had included radiotherapy in 24 patients, surgery in 20, and chemotherapy in 14. Twelve osteosarcomas were located axially and 18 were located in an extremity; 17 were radiation-related. Twenty-seven patients presented with localized disease; three presented with primary metastases (two skip, one lung). All 30 patients received chemotherapy, 29 with multiple drugs. Twenty-eight patients underwent operation. At 7 years, actuarial overall survival, survival free from osteosarcoma progression, and survival free from progression of any cancer were 50%, 34%, and 30%, respectively. In 24 patients with local tumor control, the corresponding values were 63%, 46%, and 38%. All seven local failures occurred in patients with axial osteosarcomas who did not undergo operation with wide surgical margins. CONCLUSION: Provided that local tumor control is achieved, OS-SMD treated with combined modality therapy may have a prognosis that approaches that of otherwise comparable primary osteosarcoma.

[Neoadjuvant therapy for localized osteosarcoma of extremities. Results from the Cooperative osteosarcoma study group COSS of 925 patients]. / Neoadjuvante Therapie des lokalisierten Osteosarkoms der Extremitäten. Erfahrungen der Cooperativen Osteosarkomstudiengruppe COSS an 925 Patienten.

BACKGROUND: Owing to twenty years of multicentric interdisciplinary cooperation, the COSS group has been able to collect data on a large group of osteosarcoma patients treated by neoadjuvant therapy. This paper reviews results achieved in patients with localized extremity tumors. INCLUSION CRITERIA: Registration into a completed neoadjuvant COSS-Study. Histologically confirmed, primary, localized, high-grade, central osteosarcoma of an extremity; age < 40 years; no pretreatment; interval diagnosis to chemotherapy < or = 3 weeks; no severe comorbidity. Chemotherapy: HD-methotrexate +/- doxorubicin +/- cisplatin +/- ifosfamide +/- BCD. Scheduled local therapy: Surgery. RESULTS: 925 evaluable patients from 101 institutions. Median age 15 years, m:f 1.4:1. Primary site: femur 510, tibia 251, humerus 100, fibula 51, other 13. Tumor-size < 1/3 of the involved bone 616, > or = 1/3 304. Definitive surgery in 903/925 cases, 443 limb salvage procedures. Good response (> 90% necrosis) in 469/806 (58.2%) evaluated tumors. Median follow-up for surviving patients: 5.42 years. Actuarial survival after 5 and 10 years: 72.5% (95%-CI 69.3-75.7) and 66.3% (62.5-70.0), relapse-free 62.1% (58.7-65.4) and 59.4% (55.8-63.0). 683/925 alive (601 first remission), 242 deceased (212 tumor progression, 30 other causes). 66.2% (97.3%) of all relapses within 2 (5) years. Prognosis correlates with tumor-size (< vs. > or = 1/3: 69.9% vs. 58.3% at 10 years) and -site (tibia: 74.2%, humerus: 54.5%) and -response (good vs. poor: 78.2% vs. 52.5%) (all p < 0.01). Actuarial 10-year survival by response grading I-VI according to Salzer-Kuntschik 80.9%, 82.8%, 71.1%, 60.7%, 47.7%, 27.3%. COSS-studies with preoperative 4-drug therapy more efficacious than less aggressive protocols. No impact of doxorubicin scheduling (sequential: rapid vs. 48 h-continuous infusion) or cisplatin scheduling (randomized: 5 h vs. 72 h-infusion) on prognosis detected. CONCLUSIONS: Intensive multiagent chemotherapy and delayed surgery for localized extremity osteosarcoma led to excellent oncologic results in the COSS-studies. Tumor-size, -site, and -response as well as the intensity of upfront chemotherapy correlated with outcome. Giving doxorubicin and cisplatin by continuous infusions did not result in discernible prognostic disadvantages.