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Osteosarcoma is the most common malignant bone tumor in children. Osteosarcoma patients who respond poorly to chemotherapy are at a higher risk of relapse and adverse outcome. Therefore, it was the aim of this study to identify prognostic factors at the time of diagnosis to characterize the genes predictive of poor survival outcome and to identify potential novel therapeutic targets. Expression profiling of 30 osteosarcoma diagnostic biopsy samples, 15 with inferior necrosis following induction chemotherapy (Huvos I/II) and 15 with superior necrosis following induction chemotherapy (Huvos III/IV), was conducted using Affymetrix U95Av2 oligonucleotide microarrays. One hundred and four genes were found to be statistically significant and highly differentially expressed between Huvos I/II and III/IV patients. Statistically significant genes were validated on a small independent cohort comprised of osteosarcoma xenograft tumor samples. Markers of Huvos I/II response predominantly were gene products involved in extracellular matrix (ECM) microenvironment remodeling and osteoclast differentiation. A striking finding was the significant decrease in osteoprotegerin, an osteoclastogenesis inhibitory factor. Additional genes involved in osteoclastogenesis and bone resorption, which were statistically different, include annexin 2, SMAD, PLA2G2A, and TGFbeta1. ECM remodeling genes include desmoplakin, SPARCL1, biglycan, and PECAM. Gene expression of select genes involved in tumor progression, ECM remodeling, and osteoclastogenesis were validated via quantitative reverse transcription-PCR in an independent cohort. We propose that osteosarcoma tumor-driven changes in the bone microenvironment contribute to the chemotherapy-resistant phenotype and offer testable hypotheses to potentially enhance therapeutic response.

Background: With the introduction of intensive high-dose chemotherapy for the treatment of osteosarcoma, changes in the pattern of metastases observed at relapse have been reported. To further investigate this hypothesis, the relapse patterns among groups receiving chemotherapy regimens of variable intensity at Memorial Sloan-Kettering Cancer Center were analyzed., Procedure: All patients treated with the protocols T4, T5, T7, T10, and T12 were included. Patients were divided into two groups, one including those patients treated with less intense therapy (T4, T5, and T7) and the other, those treated with current regimens (T10 and T12)., Results: Of the 25 patients who relapsed on the earlier protocols, 76% relapsed to the lungs, 8% had local recurrences, and 16% distant metastases to the bone. The median time to first relapse was 12 months. Of the 69 patients who relapsed on the T10 and T12 protocols, 75% relapsed in the lungs, 9% had local recurrences, and 16% distant bone metastases. The median time to first relapse was 17 months. There was no statistically significant difference in the timing of relapse between the two groups studied, although a longer median time to relapse was observed for patients treated on the later protocols. The range of time to relapse was also wider in the later protocols., Conclusions: These data do not support the hypothesis that patterns of relapse are changing with alterations in osteosarcoma treatment. This limited single institutional experience can be explored further in the context of a multi-institutional effort., (Copyright 2003 Wiley-Liss, Inc.)

Purpose: To improve the long-term event-free survival of patients with Ewing's family of tumors (EFTs) using high-dose, short-term chemotherapy., Patients and Methods: P6 was a prospective study of previously untreated patients with newly diagnosed EFTs. Patients received seven cycles of chemotherapy. Cycles 1, 2, 3, and 6 consisted of cyclophosphamide 2,100 mg/m2/d on days 1 and 2, and a 72-hour continuous infusion of doxorubicin 75 mg/m2 and vincristine 2 mg/m2 starting day 1. Cycles 4, 5, and 7 consisted of 5 consecutive days of ifosfamide 1,800 mg/m2/d and etoposide 100 mg/m2/d., Results: Sixty-eight patients were enrolled from 1991 to 2001 (median age, 18.7 years; range, 3.7 to 39.9 years). At diagnosis, 44 patients had local-regional disease, and 24 had distant metastases. The 4-year event-free survival (EFS) rate for patients with local-regional disease is 82%; overall survival (OS) is 89%. The 4-year EFS rate for patients with distant metastases is 12%; the OS rate is 17.8%. All events occurred within 51 months of diagnosis. Four patients with distant metastases had progressive disease during therapy, and no patient with local-regional disease experienced disease progression during therapy., Conclusion: Sustained EFS and OS can be achieved with intensive chemotherapy in children and young adults with local-regional EFTs. This therapy is relatively ineffective in the treatment of metastatic EFTs.

Background: The authors investigated the incidence and relative risk of secondary malignant neoplasms in long-term survivors of osteosarcoma., Methods: A comprehensive list of 509 patients with primary osteosarcoma treated at our institution between February 1973 and March 2000 was identified. All study patients received chemotherapy and/or surgery on one of six different protocols (T4, 5, 7, 10, 12, and CCG-7921/POG-9351). Chemotherapy was scheduled for up to 40 weeks with some variations in the actual treatment period and consisted of various combinations of the following agents: high-dose methotrexate, doxorubicin, bleomycin, cyclophosphamide, dactinomycin, vincristine, cisplatin, and ifosfamide., Results: Secondary malignant neoplasms (SMN) occurred in 14 of 509 patients. Only one had pulmonary metastasis at diagnosis and subsequent multiple recurrences that required thoracotomies and further modification of the chemotherapy regimen. The median age at diagnosis for osteosarcoma was 16.6 years (range, 3.1-74.4 years). The median follow-up was 5.2 years (range, 0.1-25.0 years). The time interval from diagnosis of the primary osteosarcoma to the development of SMN was 1.3-13.1 years (median, 5.5; 95% confidence interval [CI], 3.6-9.6). The most common SMN occurred in the central nervous system (n = 4): anaplastic glioma, meningioma, high-grade glioma, and maxillary astrocytoma. There were two cases of acute myeloid leukemia and one case each of myelodysplastic syndrome, non-Hodgkin lymphoma, high-grade pleomorphic sarcoma, leiomyosarcoma, fibrosarcoma, breast carcinoma, and mucoepidermoid carcinoma. The overall 5 and 10-year cumulative incidences of SMNs were 1.4% +/- 1.1% and 3.1% +/- 1.8%. The standardized incidence ratio was 4.6 (95% CI, 2.53-7.78, P = 0.00001) for the cohort and 3.64 (95% CI, 1.82-6.52, P = 0.0007) when patients with a history of retinoblastoma or Rothmund-Thomson syndrome were excluded., Conclusions: The overall incidence of secondary malignancies in long-term survivors of osteosarcoma was significantly higher than the expected incidence of cancer in the general population. However, the standardized incidence ratios were much lower than those reported for Hodgkin disease and retinoblastoma. Although additional follow-up is warranted, the successes of current treatment regimens consisting of intensive, high-dose chemotherapy in combination with topoisomerase II inhibitors outweigh the risks., (Copyright 2002 American Cancer Society.)