-
Heikki Joensuu,
Mikael Eriksson, Kirsten Sundby Hall,
Jörg T Hartmann,
Daniel Pink,
Jochen Schütte,
Giuliano Ramadori,
Peter Hohenberger,
Justus Duyster,
Salah-Eddin Al-Batran, [......],
Maarit Sarlomo-Rikala,
Bengt Nilsson,
Harri Sihto,
Odd R Monge,
Petri Bono,
Raija Kallio,
Aki Vehtari,
Mika Leinonen,
Thor Alvegård,
Peter Reichardt
[show abstract]
[hide abstract]
ABSTRACT: Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo.
To investigate the role of imatinib administration duration as adjuvant treatment of patients who have a high estimated risk for GIST recurrence after surgery.
Patients with KIT-positive GIST removed at surgery were entered between February 2004 and September 2008 to this randomized, open-label phase 3 study conducted in 24 hospitals in Finland, Germany, Norway, and Sweden. The risk of GIST recurrence was estimated using the modified National Institutes of Health Consensus Criteria.
Imatinib, 400 mg per day, orally for either 12 months or 36 months, started within 12 weeks of surgery.
The primary end point was RFS; the secondary end points included overall survival and treatment safety.
Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio [HR], 0.46; 95% CI, 0.32-0.65; P < .001; 5-year RFS, 65.6% vs 47.9%, respectively) and longer overall survival (HR, 0.45; 95% CI, 0.22-0.89; P = .02; 5-year survival, 92.0% vs 81.7%). Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence.
Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence.
clinicaltrials.gov Identifier: NCT00116935.
JAMA The Journal of the American Medical Association 03/2012; 307(12):1265-72. · 30.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate the relationships between pretreatment folate concentrations, MTX pharmacokinetics and acute toxicities following high dose methotrexate (HD MTX) therapy.
MTX and its major extracellular metabolite 7-OH-MTX were measured in eight serum samples per HD MTX cycle in 65 consecutive osteosarcoma patients (288 cycles) and AUC (area under the blood concentration-time curve) was calculated. Pretreatment concentrations of folate in serum (S) and erythrocytes (ER) were determined. Hepatic, renal and haematological toxicities, assessed by routine laboratory parameters, as well as mucositis were graded according to National Cancer Institute Common Terminology Criteria for adverse events (CTCAE v.3.0). Dermatitis and pleuritis were reported as occurred or not.
S- and ER-folate pretreatment concentrations increased significantly with increasing number of HD MTX cycles (P < 0.001). ER-folate pretreatment concentrations were higher among males (median 610 nmol l⁻¹, 95% CI 550, 680) compared with females (median 465 nmol l⁻¹, 95% CI 430, 520, P < 0.001), but showed no correlation with MTX or 7-OH-MTX pharmacokinetics. We found correlations between alanine aminotransferase peak concentration (ALAT(max) ) and clearance of MTX (P < 0.001), gender (P < 0.001), age (P < 0.001) and 7-OH-MTX concentrations (P < 0.001), the latter being the main factor influencing ALAT(max) .
Our results suggest that 7-OH-MTX is involved in the development of HD MTX hepatic toxicity and that young female patients are most affected.
British Journal of Clinical Pharmacology 06/2011; 73(1):106-14. · 2.96 Impact Factor
-
Sigbjørn Smeland,
Oyvind S Bruland,
Lars Hjorth,
Otte Brosjö,
Bodil Bjerkehagen,
Gustaf Osterlundh,
Ake Jakobson, Kirsten Sundby Hall,
Odd R Monge,
Olle Björk,
Thor A Alvegaard
[show abstract]
[hide abstract]
ABSTRACT: The Scandinavian Sarcoma Group (SSG) XIV protocol is based on experience from previous SSG trials and other osteosarcoma intergroup trials, and has been considered the best standard of care for patients with extremity localized, non-metastatic osteosarcoma. We analyzed the outcome in 63 consecutive patients. Patients and methods From 2001 through 2005, 63 patients recruited from centers in Sweden, Norway, and Finland were included. They received preoperative chemotherapy consisting of 2 cycles of paired methotrexate (12 g/m²), cisplatin (90 mg/m²), and doxorubicin (75 mg/m²). 3 cycles were administered postoperatively, and poor histological responders were given 3 additional cycles of ifosfamide (10-12 g/m²) as a salvage strategy.
With a median follow-up of 77 months for survivors, the estimated metastasis-free and sarcoma-related survival at 5 years was 70% and 76%, respectively. 53 patients were treated with limb salvage surgery or rotationplasty and 2 patients experienced a local recurrence. 3 toxic deaths were recorded, all related to acute toxicity from chemotherapy. The 5-year metastasis-free survival of poor histological responders receiving add-on treatment with ifosfamide was 47%, as compared to 89% for good histological responders.
Outcome from the SSG XIV protocol compares favorably with the results of previous SSG trials and other published osteosarcoma trials. However, salvage therapy given to poor responders did not improve outcome to a similar degree as for good responders. In a multi-institutional setting, more than four-fifths of the patients were operated with limb salvage surgery or rotationplasty, with few local recurrences.
Acta Orthopaedica 03/2011; 82(2):211-6. · 2.17 Impact Factor
-
Acta oncologica (Stockholm, Sweden) 01/2011; 50(1):148-50. · 2.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To evaluate adjuvant chemotherapy and interpolated accelerated radiotherapy (RT) for adult patients with high-risk soft tissue sarcoma in the extremities or trunk wall.
High-risk soft tissue sarcoma was defined as high-grade malignancy and at least two of the following criteria: size≥8 cm, vascular invasion, or necrosis. Six cycles of doxorubicin and ifosfamide were prescribed for all patients. RT to a total dose of 36 Gy (1.8 Gy twice daily) was inserted between two chemotherapy cycles after marginal margin resection regardless of tumor depth or after wide-margin resection for deep-seated tumors. RT was boosted to 45 Gy in a split-course design in the case of intralesional margin resection.
A total of 119 patients were eligible, with a median follow-up of 5 years. The 5-year estimate of the local recurrence, metastasis-free survival, and overall survival rate was 12%, 59%, and 68%, respectively. The group receiving RT to 36 Gy had a local recurrence rate of 10%. In contrast, the local recurrence rate was 29% in the group treated with RT to 45 Gy. The presence of vascular invasion and low chemotherapy dose intensity had a negative effect on metastasis-free and overall survival. Toxicity was moderate after both the chemotherapy and the RT.
Accelerated RT interposed between chemotherapy cycles in a selected population of patients with high-risk soft tissue sarcoma resulted in good local and distant disease control, with acceptable treatment-related morbidity. The greater radiation dose administered after intralesional surgery was not sufficient to compensate for the poorer surgical margin. Vascular invasion was the most important prognostic factor for metastasis-free and overall survival.
International journal of radiation oncology, biology, physics 10/2010; 81(5):1359-66. · 4.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hematogenous spread of tumor cells is an early event in osteosarcoma and present in the majority of patients at primary diagnosis. Eradication of such micrometastases by adjuvant combination chemotherapy is crucial for survival. However, a survival plateau of 60-70% was reached over two decades ago, above which it seems difficult to further advance with the currently available therapies. In this study we have, by an immunomagnetic isolation procedure, examined the presence and prognostic impact of disseminated tumor cells in bone marrow aspirates taken at primary diagnosis in a cohort of 41 non-metastatic patients with extremity localized, high-grade osteosarcoma.
Cancer treatment and research 01/2010; 152:509-15.
-
Acta orthopaedica. Supplementum 01/2009; 80(334):1-104.
-
[show abstract]
[hide abstract]
ABSTRACT: Adjuvant radiotherapy has during the past decades become increasingly used in the treatment of localized soft tissue sarcoma. We evaluated the effect of radiotherapy (RT) on local recurrence rates (LRRs) in Scandinavia between 1986 and 2005.
A total of 1,093 adult patients with extremity or trunk wall soft tissue sarcoma treated at four Scandinavian sarcoma centers were stratified according to the treatment period (1986-1991, 1992-1997, and 1998-2005). The use of adjuvant RT, quality of the surgical margin, interval between surgery and RT, and LRR were analyzed. The median follow-up was 5 years.
The use of RT (77% treated postoperatively) increased from 28% to 53%, and the 5-year LRR decreased from 27% to 15%. The rate of wide surgical margins did not increase. The risk factors for local recurrence were histologic high-grade malignancy (hazard ratio [HR], 5), an intralesional (HR, 6) or marginal (HR, 3) surgical margin, and no RT (HR, 3). The effect of RT on the LRR was also significant after a wide margin resection and in low-grade malignant tumors. The LRR was the same after preoperative and postoperative RT. The median interval from surgery to the start of RT was 7 weeks, and 98% started RT within 4 months. The LRR was the same in patients who started treatment before and after 7 weeks.
The results of our study have shown that adjuvant RT effectively prevents local recurrence in soft tissue sarcoma, irrespective of the tumor depth, malignancy grade, and surgical margin status. The effect was most pronounced in deep-seated, high-grade tumors, even when removed with a wide surgical margin.
International Journal of Radiation OncologyBiologyPhysics 08/2008; 71(4):1196-203. · 4.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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).
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.
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.
Radiation-induced sarcoma is rare and harbours an aggressive clinical behaviour. Complete surgical resection is mandatory for cure.
Acta oncologica (Stockholm, Sweden) 05/2008; 47(8):1475-82. · 2.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of the study was to compare the quality of life (QoL), fatigue and mental distress in survivors of malignant extremity bone tumours (EBT survivors) with age and gender-matched survivors of Hodgkin's disease (HD survivors) and testicular cancer (TC survivors) as well as normative samples from the general population.
Five years or more after end of treatment, 75 EBT survivors were mailed a questionnaire containing Short Form-36 (SF-36), the Hospital Anxiety and Depression Scale, the Fatigue Questionnaire and questions about demography. Fifty-eight EBT survivors responded. TC survivors, HD survivors and normative samples (NORMs) had earlier on filled in the same questionnaire. For EBT survivors, gender and age-matched controls were randomly selected among TC survivors, HD survivors and NORMs.
No significant differences in the fatigue or mental distress scores were observed between the survivor groups. The EBT survivors had significantly higher fatigue scores and lower depression scores than NORMs and significantly lower scores on all physical dimensions of QoL than TC survivors, HD survivors and NORMs. In multivariate analysis, a low level of education and lack of employment were significantly associated with caseness of mental distress. Older age at survey, female gender, being an EBT survivor and lack of employment were associated with caseness on the SF-36 Physical Component Summary Scale.
At long-term follow-up, EBT survivors did not show impaired mental health or fatigue at the group level, although their post-treatment status was characterised by reduced QoL dimensions on physical function compared to TC survivors, HD survivors and NORMs.
Supportive Care Cancer 10/2007; 15(9):1087-96. · 2.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
The authors analyzed the clinical features of 225 patients with cutaneous, subcutaneous, or deep-seated leiomyosarcoma of the extremities, trunk wall, and superficial parts of the head and neck region to determine the natural course of the disease. Only patients who received their treatment at a specialist sarcoma center were included. Re-evaluation of histopathology was performed.
The age of the patients (121 women and 104 men) ranged from 20 years to 98 years (median, 70 years), and the tumors ranged in size from 0.6 cm to 35 cm (median, 4.0 cm). Eighty-two percent of the tumors were classified as high grade. The median follow-up for survivors was 5.5 years. The local treatment was adequate in 154 of 206 patients (75%) who were without metastasis at presentation. At 10 years, 84% of the 206 patients with localized disease at presentation were free from local recurrence, 66% remained metastasis free, and 49% were alive. Multivariate analysis showed that higher malignancy grade (P = .006), larger tumor size (P = .003), and deeper tumor location (P = .002) were correlated significantly with decreased metastasis-free survival, inadequate local treatment was correlated with local recurrence (P = .007), and high malignancy grade was correlated with decreased overall survival (P = .007).
The long-term prognosis for patients with subcutaneous and deep-seated soft tissue leiomyosarcoma remains poor despite the ability to achieve adequate local control through nonmutilating surgery with or without radiotherapy.
Cancer 02/2007; 109(2):282-91. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: All cases of high-grade osteosarcoma (OS) (n = 196) and Ewing's sarcoma of bone (ES) (n = 56) treated at the Norwegian Radium Hospital in the period 1980-1999 were analyzed retrospectively. They were allocated to consecutive ten-year periods by their time of diagnosis. Patient and tumour characteristics have been relatively stable. Eighty percent of all patients received surgical treatment and the amputation rate decreased from 64% to 23%. The percentage of patients receiving chemotherapy has remained around 80%. The use of radiotherapy in primary treatment decreased gradually from 33% to 18%. Sarcoma specific survival (SSS) at five years for all patients increased significantly from 39% to 53%. Similar trends for improvement were seen for both OS and ES. In multivariate analysis, independent prognostic factors for improved SSS were non-metastatic disease at diagnosis, age under 40, extremity tumours, small tumours and treatment from 1995 onwards. No major new treatment options have emerged over these 20 years. The improved outcome appears partly to be due to refinements in the use of existing modalities and improved quality and integration of multidisciplinary approaches. Improved formalized organisation of the sarcoma group and annual audited reports of its patient and research activity may also have contributed to improved focus and performance.
Acta Oncologica 02/2006; 45(1):38-46. · 3.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Prognostic factors for metastasis in soft tissue sarcoma govern decisions regarding adjuvant treatment. However, the significance of initial tumor-related prognostic factors over time is largely unknown.
The current study included 338 patients with malignant fibrous histiocytoma (MFH) of the extremities or the trunk wall whose tumors were reviewed by the Scandinavian Sarcoma Pathology Review Group. Of these 338 patients, 329 (97%) had high-grade tumors. The median follow-up period was 7 years. Metastases occurred in 110 of 338 of patients after a median follow-up period of 14 months, with roughly one-third (32 of 110) occurring after 2 years. The authors investigated the prognostic significance of tumor size, tumor depth, histologic grade, microscopic tumor necrosis, vascular invasion, mitotic rate, and local tumor recurrence at various time intervals using metastases as an endpoint.
On univariate analysis, all investigated factors were found to be correlated with metastases for the entire follow-up period and also for the first 2 years of follow-up; beyond this time point, only size, tumor depth, and local recurrence were significant. On multivariate analysis, necrosis and local tumor recurrence were significant for the entire follow-up duration and also for the first 2 years of follow-up, whereas only tumor depth and local recurrence were significant beyond 2 years of follow-up. For all initial factors, the annual metastasis risks in the high-risk and low-risk groups converged to < 0.1 after 2 years and to near 0 after 5 years.
Prognostic factors for metastasis in MFH were time dependent. The predictive value of the initial prognostic factors was limited to the first 2 years of follow-up. The lack of observed prognostic value beyond 2 years of follow-up probably was attributable to heterogeneity within risk categories as a result of measurement errors and unknown biologic variations.
Cancer 06/2004; 100(10):2233-9. · 4.77 Impact Factor
-
Gunnar Saeter, Kirsten Sundby Hall,
Øyvind S Bruland,
Øyvin P Solheim,
Johan Høie,
Gunnar Follerås,
Per Helgerud,
Anna E Stenwig,
Bodil Bjerkehagen,
Kristian Talle,
Ingeborg Taksdal,
Mette Winderen
[show abstract]
[hide abstract]
ABSTRACT: The Norwegian Radium Hospital's sarcoma group is a multidisciplinary group with a leading role in the diagnosis and treatment of bone and soft tissue sarcomas in Norway.
From 1980 through 1999, 1,355 patients with soft tissue sarcoma and 458 patients with bone sarcoma were treated. In a retrospective analysis of trends over time, patients were allocated to consecutive five-year periods.
Patient characteristics were relatively stable, but there was an increasing proportion of soft tissue sarcomas being referred without prior surgery. Treatment principles have remained unchanged, with surgery with or without radiotherapy dominating in soft tissue sarcoma and surgery with or without chemotherapy in bone sarcoma. The amputation rate for bone sarcoma has fallen from 78% to 17%, and survival has increased significantly for both soft tissue and bone sarcoma patients.
The results indicate significant improvements in the quality of treatment of soft tissue and bone sarcoma. More resources for treatment and organizational development of a multidisciplinary group may contribute to improved quality of care.
Tidsskrift for Den norske legeforening 10/2002; 122(21):2089-94.
-
[show abstract]
[hide abstract]
ABSTRACT: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field The article offers information on the Scandinavian Sarcoma Group (SSG) whose aim is to uphold and improve the quality of diagnostics, treatment and care of sarcoma patients by sharing information and education and stimulate and coordinate basic and clinical research. SSG is composed of oncologists, surgeons and radiologists. Since 1979, SSG is conducting the following studies which include soft tissue sarcoma, osteosarcoma and Ewing's sarcoma.
