Gunnar Follerås

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

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 Pagets 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.

Cement is recommended in intralesional surgery of giant cell tumors : A Scandinavian Sarcoma Group study of 294 patients followed for a median time of 5 years

Backgroundu2003Giant cell tumors of bone rarely metasta-size but often recur locally after surgery. There is limited knowledge about the risk of recurrence related to different types of treatment. Patients and methodsu2003We analyzed factors affecting the local recurrence rate in 294 patients with giant cell tumors of the extremities using prospectively collected material from 13 centers. The median follow-up time was 5 (0.2–18) years. Resultsu2003A local recurrence was diagnosed in 57 of 294 patients (19%). The overall 5-year local recurrence rate was 0.22. Univariate analysis identified young age and intralesional surgery to be associated with a higher risk of recurrence. Based on multivariate analysis, the relative risk was 2.4-fold for intralesional surgery compared to more extensive operative methods. There was no correlation between tumor size, tumor extension, sex of the patient, tumor location, or fracture at diagnosis and outcome. In the subgroup of 200 patients treated with intralesional surgery, the method of filling (cement or bone) was known for 194 patients and was statistically highly significant in favor of the use of cement. Interpretationu2003Intralesional surgery should be the first choice in most giant cell tumors, even in the presence of a pathological fracture. After thorough evacuation, the cavity should be filled with cement.

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII

Abstract From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume 4.5 μM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in >70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

Clinical course of nonvisceral soft tissue leiomyosarcoma in 225 patients from the Scandinavian Sarcoma Group.

Leiomyosarcoma of nonvisceral soft tissues is an uncommon malignant tumor; thus, only small numbers of cases have been reported. This study was based on a large series of patients from the Scandinavian Sarcoma Group Register acquired during a 15‐year period (from 1986 to 2001). Follow‐up information was available for all patients.

Treatment of local recurrences of giant cell tumour in long bones after curettage and cementing: A SCANDINAVIAN SARCOMA GROUP STUDY.

We retrospectively studied local recurrence of giant cell tumour in long bones following treatment with curettage and cementing in 137 patients. The median follow-up time was 60 months (3 to 166). A total of 19 patients (14%) had at least one local recurrence, the first was diagnosed at a median of 17 months (3 to 29) after treatment of the primary tumour. There were 13 patients with a total of 15 local recurrences who were successfully treated by further curettage and cementing. Two patients with a second local recurrence were consequently treated twice. At the last follow-up, at a median of 53 months (3 to 128) after the most recent operation, all patients were free from disease and had good function. We concluded that local recurrence of giant cell tumour after curettage and cementing in long bones can generally be successfully treated with further curettage and cementing, with only a minor risk of increased morbidity. This suggests that more extensive surgery for the primary tumour in an attempt to obtain wide margins is not the method of choice, since it leaves the patient with higher morbidity with no significant gain with respect to cure of the disease.

Cytogenetic analysis of 101 giant cell tumors of bone: Nonrandom patterns of telomeric associations and other structural aberrations

Giant cell tumor of bone (GCTB) is a benign but locally aggressive tumor with metastatic potential. We performed cytogenetic analysis on 101 GCTB from 92 patients. Karyotypes were obtained from 95 tumors, 47 of which had clonal aberrations. The majority of the cytogenetically abnormal GCTB had multiple, up to 28 per tumor, clones. Clonal telomeric associations (tas) and other structural and numerical changes were found in about 70, 60, and 30%, respectively, of clonally abnormal tumors. Forty‐seven aberrations were recurrent, of which 35 are novel. The vast majority of the recurrent aberrations were tas, confirming the important role of telomeric fusions in the development of GCTB. The frequency of tas in GCTB cultures increased with passaging, suggesting a selective advantage of tas‐positive cells in vitro. The termini most frequently involved in tas were 22p, 13p, 15p, 21p, 14p, 19q, 1q, 12p, 11p, and 20q. The frequency of tas (irrespective of their clonality) was significantly higher in tumors carrying clonal changes, indicating that tas are precursors of other types of aberrations. In line with this assumption, the chromosomes preferentially involved in tas in a given tumor were also the ones most often affected by other rearrangements. We did not find the previously reported amplicon in 20q11.1, assessed by fluorescence in situ hybridization in 10 tumors. Nor did we find any association between cytogenetic features and adverse clinical outcome. Thus, local recurrences probably depend more on the adequacy of surgical treatment than on the intrinsic biology of the tumors.

Real time MRI-guided excision and cryo-treatment of osteoid osteoma in os ischii--a case report.

A 36-year-old electrician had not been able towork during the last 8 months due to intense painin his left buttock. Plain radiographs were normal,but scintigraphy, MRI and CT indicated an osteoidosteoma in the left tuber os ischii. The patient wasgiven spinal anesthesia, and placed in a 0.5T GESigna SP/i open MRI (General Electric, Milwau-kee, USA) (Figure 1). With the patient in decubi-tus position, a surface coil was attached and thenidus located. A biopsy needle was placed in thecenter of the lesion, using an optical tracking sys-tem integrated in the magnet gantry, for placementof the needle. A 4 mm cylinder was cored out andfixed in formaldehyde for histologic examinationwhich confirmed the diagnosis osteoid osteoma.Then a 3 mm cryo probe (Galil Medical, Haifa,Israel) was placed centrally in the lesion (Figure2). 4 cycles (1/2–2 min) with cooling to –180€°Cinterrupted by passive thawing were used. ControlMRI showed the defect after the biopsy. The pa-tient was pain-free one day after the operation,soon resumed full-time work, and had no symp-toms 1 year later.

Extremity and non-extremity high-grade osteosarcoma -- the Norwegian Radium Hospital experience during the modern chemotherapy era.

Of 103 patients with high-grade osteosarcoma, 27% had tumours localized outside the extremities. Non-extremity patients were significantly older at diagnosis than patients with extremity tumours (median 38 vs. 17 years). More than 90% of patients with extremity tumours received adequate treatment (aggressive chemotherapy plus at least marginal surgery), compared with only 25% of patients with non-extremity tumours. Failure of adequate treatment was due to inoperable tumour, intralesional surgery and age preventing aggressive chemotherapy. There was a highly significant difference in both local tumour control and overall survival, both favouring patients with extremity tumours. Within the extremity tumour group, patients who were treated in prospective multicentre trials had a significantly better outcome than non-trial patients. Our results show that the fraction of patients with high-grade tumours that fall outside trials designed for classical osteosarcoma may be larger than is usually acknowledged, and that the results reported for the classical group are by no means representative of the whole patient population. Improved and new treatment approaches are needed for patients with non-extremity tumours, particularly in the older age groups.

Giant cell tumor of bone The Scandinavian Sarcoma Group experience

Background Few authors have investigated function and pain after surgical treatment of patients with bone metastases. In 1999 the Scandinavian Sarcoma Group (SSG) initiated the Skeletal Metastasis Registry as a multi-centric, prospective study to provide a scientific basis for recommendations of treatment. Patients and methods We have analyzed function and pain in 530 patients (mean age 65 yr) operated on (599 operations) for non-spinal skeletal metastases at 9 SSG centres. 7% were operated for more than 1 metastasis. Carcinoma of the breast, prostate, kidney, and lung were the dominating sites for primary tumors. Results 25% of the patients died within 6 weeks after operation. 11% of the patients had complications. 6% had reoperation. In patients surviving more than 1 year the reoperation rate was 12%. 92% of the patients had no, light or moderate pain from metastasis at 6 weeks (first control) and 6 months follow-up. Patients using opioids were reduced from 40% preoperative to 30% at 6 months after surgery. In patients with metastases in pelvis or lower extremity 79% were walking with or without crutches, 6 weeks and 88%, 6 months after surgery. More patients with metastases; in proximal femur were mobile at 6 weeks and 6 months when treated with prosthetic replacement compared to internal fixation. Interpretation Palliative surgery for bone metastases improves function and reduce pain. Mobility is improved by surgery in patients with metastases in the pelvis or lower extremity. Prosthetic replacement seems to do better than internal fixation for metastases in the proximal femur. We need to analyze function and pain earlier than 6 weeks postoperative to investigate the benefit of surgery in patients with short time survival.Background and purpose The Scandinavian Sarcoma Group (SSG) XIV protocol was based upon the organisations experience from 3 previous osteosarcoma trials and was considered best standard of care for patients with extremity localised, non-metastatic osteosarcoma. We report the outcome of this protocol. Patients and methods From March 2001 to April 2005, 63 patients recruited from 10 centres in Finland, Sweden and Norway were included in this analysis. Patients received pre-operative chemotherapy consisting of 2 cycles of paired methotrexate (12 g/m(2)), cisplatin (90 mg/m(2)) and doxorubicin (75 mg/m(2)). Good histological responders continued with 3 cycles postoperatively whilst poor responders were salvaged with the addition of 3 cycles of ifusfamide (10-12 g/m(2)). Outcome data was compared to previous SSG osteosarcoma trials. Results With a median follow-up of 64 months for survivors, the projected metastasis-free and sarcoma-related survivals at 5 years were 69% and 77%, respectively. 84% of the patients were treated with limb salvage surgery (49 patients) or rotationplasty (4 patients). 3 toxic deaths (5%) were recorded, all related to acute chemotherapy toxicity. The 5-year metastasis-free survival of patients receiving salvage therapy was 47% compared to 89% for good histological responders that only received the 3 drug combination postoperatively. Interpretation Outcome in the SSG XIV protocol compares favourably to previous SSG osteosarcoma trials and other published trials. The addition of ifosfamide to poor responders as an add on treatment did not improve outcome for poor responders to a similar level as for good responders. In a multi-institutional setting limb salvage surgery can safely be used in more than 80% of the patients. (Less)Gastrointestinal stromal tumors (GISTs) have a malignant potential varying from virtually no risk of recurrence (microscopic GISTs) to a high risk. Acquired secondary mutations that interfere with imatinib binding have been identified as a common mechanism for drug resistance and tumor progression in advanced GIST. Patients with advanced GIST but with a small tumor mass have the longest time to disease progression suggesting that the rate of secondary mutations that confer drug resistance may be low when the number of cancer cells is small. Thus, early administration of imatinib in the adjuvant setting might result in a low rate of secondary mutations and might improve survival. The results of the ACOSOG Z9001 trial demonstrated a significantly longer recurrence-free survival among patients treated with adjuvant imatinib as compared to placebo. Although data on influence of adjuvant imatinib on overall survival is lacking, its administration may be warranted to patients who have a high risk of recurrence and death from GIST that likely exceeds the risks related to adjuvant administration of imatinib. Many aspects of adjuvant treatment remain unknown including the overall benefits and harms of adjuvant treatment, optimal selection of patients for treatment, and the duration of adjuvant treatment, which is currently being investigated in the ongoing Scandinavian Sarcoma Group/AIO trial (SSG/AIO XVIII).