High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study.

BACKGROUND: Patients with metastatic osteosarcoma at diagnosis or axial primary tumors have a poor prognosis. The aim of the study was to evaluate the feasibility and efficacy of intensified treatment with high-dose chemotherapy (HDCT) and stem cell rescue in this group. METHODS: From May 1996 to August 2004, 71 patients were included in a Scandinavian-Italian single arm phase II study. Preoperative chemotherapy included methotrexate, doxorubicin, cisplatin and ifosfamide, and postoperative treatment consisted of two cycles of doxorubicin, one cycle of cyclophosphamide and etoposide and two courses of high-dose etoposide and carboplatin with stem cell rescue. RESULTS: Twenty-nine patients (43%) received two courses and 10 patients (15%) received one course of HDCT. HDCT was associated with significant toxicity, but no treatment-related deaths were recorded. Fourteen patients (20%) had disease progression before completion of the study protocol, and only 29/71 patients (41%) received the full planned treatment. Median event-free survival (EFS) was 18 months, and estimated 5-year EFS was 27%. Median overall survival (OS) was 34 months, and estimated 5-year OS was 31%. When patients who did not receive HDCT due to disease progression were excluded, there was no difference in EFS (P = 0.72) or OS (P = 0.49) between patients who did or did not receive HDCT. CONCLUSIONS: The administration of high-dose chemotherapy with stem cell rescue was feasible, but associated with significant toxicity. Patient outcome seemed comparable to previous studies using conventional chemotherapy. We conclude that HDCT with carboplatin and etoposide should not be further explored as a treatment strategy in high-risk osteosarcoma.

Radiotherapy for spinal metastases from breast cancer with emphasis on local disease control and pain response using repeated MRI.

AIMS: To evaluate metastatic lesions within the radiation field using repeated magnetic resonance imaging (MRI) and to compare the imaging findings with pain response following radiotherapy (RT) in patients with spinal metastases (SM) from breast cancer. MATERIAL AND METHODS: 32 Patients with SM from breast cancer admitted for fractionated RT were included in this study. MRI examinations of the spine were scored for the extent of bone metastases, epidural disease and the presence and severity of vertebral fractures. Clinical response was defined according to the updated international consensus on palliative RT endpoints. RESULTS: At 2 and 6 months after RT, 38% and 44% of the patients were classified as responders. None of the patients developed motor deficits. Importantly, a decrease in the intraspinal tumor volume after RT was reported in all patients. Only 6% of the patients showed bone metastases progression within the RT field, whereas 60% of the patients showed disease progression outside the RT portals. 5 Patients developed new fractures after RT, and fracture progression was observed in 21 of the 38 lesions (55%). The pain response to RT did not correlate with the presence of vertebral body fracture before RT, fracture progression or other recorded MRI features of metastatic lesions. CONCLUSION: RT provided excellent local tumor control in patients with SM. Most patients benefit from RT even in cases of progressive vertebral fracture. Pain response was not associated with imaging findings and MRI cannot be used to select patients at risk of not responding to RT.

Incidence and mortality of second sarcomas - a population-based study.

BACKGROUND: Studies on second sarcoma in unselected populations of cancer survivors have not previously been published. METHODS: Second sarcoma was defined as a sarcoma following a previous invasive cancer. Patients with this malignancy were retrieved from the Cancer Registry in Norway for the period 1960-2007 among a total of 728874 cancer patients including 11 612 with a sarcoma. Changes in incidence and average annual percent change (AAPC) were studied with join-point analyses. Overall and sarcoma-related mortalities were assessed using the Kaplan-Meier and competing risk methods, respectively. RESULTS: A total of 900 second sarcomas were identified comprising 7.5% of all sarcomas. The AAPC of second sarcoma incidence was 6.2 (95% CI=5.7-6.7) as compared to 2.5 (95% CI=2.1-2.8) for all sarcomas and 2.5 (95% CI=2.4-2.6) for cancer in general. The annual incidence of second sarcomas doubled during the last decade of the study period. The distribution of histological subtypes was significantly different between second and sporadic sarcomas. The overall mortality was significantly higher and sarcoma-related mortality was significantly lower for patients with a second sarcoma compared to sporadic sarcoma. CONCLUSIONS: There is an increasing incidence of second sarcomas among cancer survivors, and one may speculate a relation to the intensified use of cytotoxic treatment of the preceding malignancy. Sarcoma-related mortality after second sarcomas is significantly below that of sporadic sarcoma.

Reliability of Margin Assessment after Surgery for Extremity Soft Tissue Sarcoma: The SSG Experience.

Surgery remains the mainstay of soft tissue sarcoma (STS) treatment and has been the primary treatment for the majority of patients in Scandinavia during the last 30 years although the use of adjuvant radiotherapy has increased. Patient and treatment characteristics have been recorded in the Scandinavian Sarcoma Group (SSG) Register since 1987. When the effect of new radiotherapy guidelines from 1998 was evaluated, the reliability of surgical margin assessments among different Scandinavian institutions was investigated. Margins were reevaluated by a panel of sarcoma surgeons, studying pathology and surgical reports from 117 patients, randomly selected among 470 recorded patients treated between 1998-2003. In 80% of cases, the panel agreed with the original classification. Disagreement was most frequent when addressing the distinction between marginal and wide margins. Considered the element of judgment inherent in all margin assessment, we find this reliability acceptable for using the Register for studies of local control of STS.

Radiotherapy or surgery for spine metastases?

BACKGROUND AND PURPOSE: Radiotherapy (RT) remains the cornerstone of management of spine metastases (SM), even though surgery is a well-established treatment for selected patients. We compared the use of RT and surgery in a population-based cohort of patients with SM, investigated pre-treatment factors that were associated with use of these treatment modalities, and examined survival. PATIENTS AND METHODS: 903 patients in the south-eastern Norway who were admitted for RT or surgery for SM for the first time during an 18-month period in 2007-2008 were identified and their medical records were reviewed. RESULTS: The primary treatment was surgery in 58 patients and RT in 845 patients, including 704 multiple-fraction (MF) and 141 single-fraction (SF) RT schedules. 11 of 607 patients without motor impairment (2%) and 47 of 274 patients with motor impairment (17%) underwent primary operations. 11 of 58 operated patients and 244 of 845 irradiated patients died within 2 months after the start of treatment. 26% of those who received multiple-fraction RT or surgery died within 2 months. INTERPRETATION: Motor impairment was the main indication for surgery. Better identification of patients with short survival is needed to avoid time-consuming treatment (major surgery and long-term RT).

Synchronous and metachronous skeletal osteosarcomas: the Norwegian Radium Hospital experience.

Background. The purpose of this work was to study clinical and histopathological tumor characteristics of patients treated for synchronous or metachronous skeletal osteosarcoma at The Norwegian Radium Hospital from January 1, 1980 to January 1, 2008. Patients and methods. The hospital sarcoma database and patient records were reviewed to identify cases with synchronous or metachronous skeletal osteosarcoma. Patients with more than one skeletal lesion in the absence of pulmonary or other soft tissue tumor manifestations were included in the study, and histopathological slides from these tumors were reviewed. Results. Among a total of 297 registered osteosarcoma patients, six with synchronous (2.0%) and 10 with metachronous (3.4%) skeletal osteosarcomas were identified. All tumors were of high-grade malignancy. Treatment at the time of the first osteosarcoma diagnosis was in most cases wide resections and multi-agent chemotherapy according to international protocols, whereas the treatment for metachronous tumors was individualized and in general much less intensive. One patient was diagnosed with Li-Fraumeni syndrome, two other individuals may be suspected to have the same syndrome, and yet another patient had previously been treated for a bilateral retinoblastoma. Thirteen patients are dead, 11 from metastatic osteosarcoma, one from myelodysplastic syndrome, and one from wound infection and methotrexate-related nephrotoxicity; whereas three patients are still alive with no evidence of osteosarcoma. Conclusions. The prognosis for patients with synchronous and metachronous skeletal osteosarcoma is poor. However, because long-term survival is seen, aggressive treatment to selected cases, e.g., patients with an osteosarcoma predisposing syndrome and/or late occurring metachronous tumours, is justified. Revealing a possible clonal relationship between these tumors, e.g., by karyotyping, may be of interest for estimating prognosis and guide therapy intensiveness.

Radiation-induced sarcoma: 25-year experience from the Norwegian Radium Hospital.

BACKGROUND: The aim of this study was to determine the prevalence and outcome of radiation-induced sarcomas (RISs) among sarcoma patients referred to the Norwegian Radium Hospital (NRH). MATERIAL AND METHODS: Ninety patients were identified from the institutional sarcoma data base. Medical records and histological and cytological material from both primary and secondary tumours were reviewed. RESULTS: RIS represented 3.0 % of the sarcomas in the data base. The median latency time from radiotherapy of the primary tumour to the diagnosis of RIS was 13.6 years (range 2.5-57.8 years). Gynaecological, breast and testicular cancers were the most common primary diagnoses. For the RISs 13 different histological types were identified including 25 malignant fibrous histiocytomas (28% of all) and 22 osteosarcomas (24%). The sarcoma-related 5-year crude survival was 33% (95 % CI 23-43 %). Unfavourable prognostic factors were metastases at presentation, incomplete surgery and presence of tumour necrosis. CONCLUSION: Radiation-induced sarcoma is rare and harbours an aggressive clinical behaviour. Complete surgical resection is mandatory for cure.

Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1-PBX1 fusion gene in a myoepithelioma.

Chromosome banding as well as molecular cytogenetic methods are of great help in the diagnosis of mesenchymal tumors. Myoepithelial neoplasms of soft tissue including myoepitheliomas, mixed tumors, and parachordomas are diagnoses that have been increasingly recognized the last few years. It is still debated which neoplasms should be included in these morphologically heterogeneous entities, and the boundaries between them are not clear-cut. The pathogenetic mechanisms behind myoepithelial tumors are unknown. Only five parachordomas and one mixed tumor have previously been karyotyped, and nothing is known about their molecular genetic characteristics. We present a mesenchymal tumor classified as a myoepithelioma that had a balanced translocation t(1;22)(q23;q12) as the sole karyotypic change. A novel EWSR1-PBX1 fusion gene consisting of exons 1-8 of the 5'-end of EWSR1 and exons 5-9 of the 3'-end of PBX1 was shown to result from the translocation. Both genes are known to be targeted also by other neoplasia-specific translocations, PBX1 in acute lymphoblastic leukemia and EWSR1 in several solid tumors, most of which are malignant. Based on the structure of the novel fusion gene detected, its transforming mechanism is thought to be the same as for other fusion genes involving EWSR1 or PBX1.