Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma.

PURPOSE: The primary objective of this phase I trial was to define the maximum-tolerated dose of external-beam radiation with concurrent fixed-dose continuous-infusion doxorubicin followed by surgical resection and electron-beam intraoperative radiation therapy (EB-IORT) for patients with localized, potentially resectable retroperitoneal sarcomas (RPS). PATIENTS AND METHODS: Thirty-five patients with radiographically resectable primary or recurrent intermediate- or high-grade RPS were treated. Doxorubicin was administered each week for 4 or 5 weeks as an initial bolus (4 mg/m2) followed by a 4-day continuous infusion (4 mg/m2/d). Concurrent radiation therapy was administered in escalating doses of 18.0, 30.6, 36.0, 41.4, 46.8, or 50.4 Gy in 1.8-Gy fractions. Radiographic restaging was performed 4 to 8 weeks after chemoradiation, and patients with localized disease underwent surgical resection with EB-IORT (15 Gy). RESULTS: Chemoradiation was completed as outpatient therapy in 31 patients (89%); four patients required hospital admission during chemoradiation or in the postchemoradiation preoperative period. At the highest radiation dose of 50.4 Gy, two (18%) of 11 patients had grade 3 or 4 nausea. Twenty-nine patients (83%) underwent laparotomy; six patients had interval disease progression and did not undergo surgery. Grossly complete resection (R0 or R1) was performed in 26 (90%) of 29 patients who had surgery. EB-IORT was feasible and successfully administered to 22 patients who had R0 or R1 resections. CONCLUSION: Preoperative chemoradiation, surgical resection, and EB-IORT are feasible for patients with RPS. Preoperative external-beam radiation can be administered to a total dose of 50.4 Gy with continuous-infusion doxorubicin.

Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.

PURPOSE: Prostate cancer specifically metastasizes to bone where it leads to bone formation. We previously reported that coculturing MDA PCa 2b prostate cancer cells with primary mouse osteoblasts (PMOs) induced PMO proliferation and differentiation. An osteoblastic reaction was also observed in vivo after injection of MDA PCa 2b cells into the bones of severe combined immunodeficient disease mice. The aim of this study was to identify the sequence of events that leads to these osteoblastic lesions in vivo and, using this in vitro model, to define the contributions of various genes and cellular pathways in the pathophysiology of osteoblastic bone metastases of prostate cancer. EXPERIMENTAL DESIGN AND RESULTS: We show histological evidence of de novo bone formation as early as 2 weeks after injection of MDA PCa 2b cells in the bone of severe combined immunodeficient disease mice. In vitro, we show that PMOs induce MDA PCa 2b proliferation, suggesting a synergistic paracrine loop between these cells and PMOs. Endothelin (ET)-1, which is a mitogen for several cell types, is produced by all prostate cancer cell lines tested, and Atrasentan, an antagonist of ET-1 receptor A, partially reversed PMO proliferation induced by MDA PCa 2b cells. ET-1 is known to be comitogenic with a number of growth factors, including insulin-like growth factor (IGF)-I. In this study, we report that IGF-binding protein (IGFBP)-3 transcripts (that regulate levels of free IGF) are down-regulated in prostate cancer cells cocultured with PMO, whereas prostate-specific antigen (a protease known to cleave IGFBP-3) is detected in the 150-400 ng/ml range. Accordingly, IGFBP-3 has antiproliferative effects in PMOs, which were attenuated in our in vitro system. Taken together, our studies also implicate the IGF axis to play a role in this model of bone metastases. Secondly, the transcript level of mouse double minute 2 (a protein that regulate p53) was increased in prostate cancer cells grown with PMOs. The p53-dependent and -independent oncogenic activities of mouse double minute 2 suggest that osteoblasts induce a survival advantage in prostate cancer cells. Lastly, we show that expression of osteoprotegerin is decreased and of receptor activator of nuclear factor-kappaB ligand is increased in PMOs cultured in the presence of MDA PCa 2b cells, two events associated with osteoclast activation and bone resorption. CONCLUSIONS: Our results provide evidence that multiple and distinct molecular events affecting both bone formation and bone resorption concur to the increase bone mass in prostate cancer bone metastases. These data also provide a rationale for developing therapeutic strategies designed to target these molecular changes.

Recommendations for the reporting of bone tumors. Association of Directors of Anatomic and Surgical Pathology.

The diagnosis of a bone tumor is often an arduous task, even for the most experienced orthopedic pathologist. As a starting point, the classification of bone tumors is based on a histogenetic perspective encompassing the type of matrix produced (or not produced) by the tumor. In general, the surgical pathology report should include data pertinent to the treatment and prognostication of an individual patient, and the report should be delivered to the clinician in a clear, concise fashion. Reporting of most bone tumors is similar and includes such information as the type of surgery done, anatomic site, histological type and grade of the tumor (if applicable), and the adequacy of surgical margins. Special emphasis is needed for those tumors with distinct and well-established prognostic and therapeutic features such as osteosarcoma and Ewing's sarcoma/peripheral neuroectodermal tumor. Our recommendation emphasizes a standardized protocol for these sarcomas, especially in light of evidence that postchemotherapeutic tumor necrosis is of prognostic significance. It is also important to note that radiographic imaging plays a very important, often critical, role in allowing the pathologist the opportunity to reach the best final diagnosis. This is especially true when a malignant interpretation is contemplated and in subtyping lesions. We recommend close collaboration between musculoskeletal radiologists, clinicians, and pathologists when dealing with complicated neoplasms of bone.

Management and outcome of 239 adolescent and adult rhabdomyosarcoma patients.

Adult rhabdomyosarcoma (RMS) is a rare tumor that has inferior outcome compared to younger patient population. The present work aims to study the age-related differences in management of adolescents and adults with RMS. Under an institutional review board-approved protocol, we retrospectively analyzed 239 patients, 10 years of age and greater, diagnosed with RMS at MD Anderson Cancer Center from 1957 through 2003. Of the 239 patients, 163 patients were nonmetastatic with a median overall survival (OS) of 3.8 years (95% CI 2.8-7.6). In the multivariate analysis, age >50 was significantly associated with shorter OS and recurrence-free survival (RFS) for primary patients. Metastases were present in 76 patients, the median OS was 1.4 years. Approximately 13% of metastatic patients <50 years old had a long-term survival exceeding 15 years. Multimodality therapy, including surgery, radiotherapy, and chemotherapy was significantly associated with longer OS in primary and metastatic patients. Use of bi- and triple modality treatment decreased in metastatic patients over 50 years of age compared to younger patients. RMS in adolescents and adults has a poor outcome compared with younger individuals. Increased use of multidisciplinary therapy may improve older patient clinical outcome.