Denosumab in patients with giant-cell tumor of bone in Norway: results from a nationwide cohort.

BACKGROUND: Denosumab is a relatively new treatment option for patients with giant-cell tumor of bone (GCTB). The purpose of this study was to report the results for patients treated in Norway. MATERIALS AND METHODS: Patients treated with denosumab for GCTB were identified from the clinical databases at the Norwegian sarcoma reference centers. Data were retrieved from the clinical databases and supplemented by retrospective review of patient records. Denosumab was given as a subcutaneous injection every 4 weeks with loading doses on day 8 and 15 in cycle 1. RESULTS: Eighteen patients treated with denosumab for GCTB were identified. Denosumab was given for recurrent disease in seven cases and as first-line treatment in 11 patients, of which 6 received therapy as part of a neoadjuvant/adjuvant strategy and 5 for surgically unsalvageable primary tumor. Ten of 12 patients with unresectable disease are still on denosumab without progression with median treatment duration of 41 months (range 18-60). Two patients discontinued treatment due to osteonecrosis of the jaw and reduced compliance, respectively. In the adjuvant group, four patients experienced disease recurrence after stopping denosumab. In three of six patients, the extent of surgery was reduced due to neoadjuvant therapy. Seventeen of 18 patients underwent response evaluation with 18F-FDG PET/CT at median 4.7 weeks from starting denosumab. Median baseline SUVmax was 11.0 and median SUVmax at evaluation was 4.9 (p < 0.001). CONCLUSIONS: In a nationwide GCTB patient cohort, denosumab was an effective agent and durable responses were observed. Our results do not support the use of adjuvant therapy in routine clinical practice. 18F-FDG PET/CT could be a valuable tool for early response evaluation.

Targeting a novel bone degradation pathway in primary bone cancer by inactivation of the collagen receptor uPARAP/Endo180.

In osteosarcoma, a primary mesenchymal bone cancer occurring predominantly in younger patients, invasive tumour growth leads to extensive bone destruction. This process is insufficiently understood, cannot be efficiently counteracted and calls for novel means of treatment. The endocytic collagen receptor, uPARAP/Endo180, is expressed on various mesenchymal cell types and is involved in bone matrix turnover during normal bone growth. Human osteosarcoma specimens showed strong expression of this receptor on tumour cells, along with the collagenolytic metalloprotease, MT1-MMP. In advanced tumours with ongoing bone degeneration, sarcoma cells positive for these proteins formed a contiguous layer aligned with the degradation zones. Remarkably, osteoclasts were scarce or absent from these regions and quantitative analysis revealed that this scarcity marked a strong contrast between osteosarcoma and bone metastases of carcinoma origin. This opened the possibility that sarcoma cells might directly mediate bone degeneration. To examine this question, we utilized a syngeneic, osteolytic bone tumour model with transplanted NCTC-2472 sarcoma cells in mice. When analysed in vitro, these cells were capable of degrading the protein component of surface-labelled bone slices in a process dependent on MMP activity and uPARAP/Endo180. Systemic treatment of the sarcoma-inoculated mice with a mouse monoclonal antibody that blocks murine uPARAP/Endo180 led to a strong reduction of bone destruction. Our findings identify sarcoma cell-resident uPARAP/Endo180 as a central player in the bone degeneration of advanced tumours, possibly following an osteoclast-mediated attack on bone in the early tumour stage. This points to uPARAP/Endo180 as a promising therapeutic target in osteosarcoma, with particular prospects for improved neoadjuvant therapy.

Referral patterns, treatment and outcome of high-grade malignant bone sarcoma in Scandinavia--SSG Central Register 25 years' experience.

AIMS: The objectives of this study were to present changes in referral patterns, treatment and survival in patients with high-grade malignant bone sarcoma in Sweden and Norway based on data in the Scandinavian Sarcoma Group (SSG) Central Register. METHOD: Data on 1,437 patients with diagnosis 1986-2010 was analyzed. RESULTS: Osteosarcoma was the most frequentl diagnosis (45%), followed by Ewing sarcoma (21%) and chondrosarcoma (17%). Thirty-one percent of Swedish and 41% of Norwegian patients had tumors in the axial skeleton. Eighty-six percent of extremity tumors and 66% of axial tumors were referred to a sarcoma center prior to unplanned surgery or biopsy. During the past decade, limb salvage surgery has risen from under 50% to over 80%. Five-year overall survival in non-metastatic osteosarcoma was 70% for extremity tumors, and 35% for axial tumors. No improvement in osteosarcoma survival was observed during the last decade. Five-year survival in Ewing sarcoma improved from 50% to 69%. CONCLUSION: Referral patterns in bone sarcomas have improved. However, greater efforts should be dedicated to improving referral of patients with possible tumors in the axial skeleton to multidisciplinary teams (MDTs). Overall survival of patients with high-grade malignant bone sarcomas in Sweden and Norway is in line with other reports.

Prognostic factors and follow-up strategy for superficial soft-tissue sarcomas: Analysis of 622 surgically treated patients from the scandinavian sarcoma group register.

BACKGROUND AND OBJECTIVES: Our study aimed to describe the clinical outcome of patients with superficial soft-tissue sarcomas (SSTS), define prognostic factors and provide evidence for a rational surveillance scheme. METHODS: Data for 622 consecutive, surgically treated SSTS patients were retrieved from the Scandinavian Sarcoma Group Register. We assessed the rates of local recurrence (LR) and metastasis (M), as well as overall survival (OS), local recurrence free-survival (LRFS) and metastasis-free survival (MFS) of the cohort. RESULTS: The incidence of LR and M was 9% and 12%, respectively. OS at 5 years was 79%, LRFS was 74% and MFS 76%. Factors that affected OS, LRFS, and MFS were tumor size and patient age. Additionally, tumor grade was an independent prognostic factor for LRFS. The majority of LR and M events were observed the first 2 years of follow-up. Clear surgical margins were correlated to lower risk for LR. Selected patients benefited from adjuvant radiotherapy. CONCLUSIONS: SSTS have a favourable prognosis, which is mainly determined by tumour-associated factors. Adequate surgical margins are important for local control, whereas radiotherapy has a secondary role. The data support current surveillance schemes, with a closer follow-up the first 2 years after surgery.

Patterns of local recurrence and dose fractionation of adjuvant radiation therapy in 462 patients with soft tissue sarcoma of extremity and trunk wall.

PURPOSE: To study the impact of dose fractionation of adjuvant radiation therapy (RT) on local recurrence (LR) and the relation of LR to radiation fields. METHODS AND MATERIALS: LR rates were analyzed in 462 adult patients with soft tissue sarcoma who underwent surgical excision and adjuvant RT at five Scandinavian sarcoma centers from 1998 to 2009. Medical records were reviewed for dose fractionation parameters and to determine the location of the LR relative to the radiation portals. RESULTS: Fifty-five of 462 patients developed a LR (11.9%). Negative prognostic factors included intralesional surgical margin (hazard ratio [HR]: 7.83, 95% confidence interval [CI]: 3.08-20.0), high malignancy grade (HR: 5.82, 95% CI: 1.31-25.8), age at diagnosis (HR per 10 years: 1.27, 95% CI: 1.03-1.56), and malignant peripheral nerve sheath tumor histological subtype (HR: 6.66, 95% CI: 2.56-17.3). RT dose was tailored to margin status. No correlation between RT dose and LR rate was found in multiple Cox regression analysis. The majority (65%) of LRs occurred within the primary RT volume. CONCLUSIONS: No significant dose-response effect of adjuvant RT was demonstrated. Interestingly, patients given 45-Gy accelerated RT (1.8 Gy twice daily/2.5 weeks) had the best local outcome. A total dose of 50 Gy in 25 fractions seemed adequate following wide margin surgery. The risk of LR was associated with histopathologic subtype, which should be included in the treatment algorithm of adjuvant RT in soft tissue sarcoma.

External validation of the Bayesian Estimated Tools for Survival (BETS) models in patients with surgically treated skeletal metastases.

BACKGROUND: We recently developed two Bayesian networks, referred to as the Bayesian-Estimated Tools for Survival (BETS) models, capable of estimating the likelihood of survival at 3 and 12 months following surgery for patients with operable skeletal metastases (BETS-3 and BETS-12, respectively). In this study, we attempted to externally validate the BETS-3 and BETS-12 models using an independent, international dataset. METHODS: Data were collected from the Scandinavian Skeletal Metastasis Registry for patients with extremity skeletal metastases surgically treated at eight major Scandinavian referral centers between 1999 and 2009. These data were applied to the BETS-3 and BETS-12 models, which generated a probability of survival at 3 and 12 months for each patient. Model robustness was assessed using the area under the receiver-operating characteristic curve (AUC). An analysis of incorrect estimations was also performed. RESULTS: Our dataset contained 815 records with adequate follow-up information to establish survival at 12 months. All records were missing data including the surgeon's estimate of survival, which was previously shown to be a first-degree associate of survival in both models. The AUCs for the BETS-3 and BETS-12 models were 0.79 and 0.76, respectively. Incorrect estimations by both models were more commonly optimistic than pessimistic. CONCLUSIONS: The BETS-3 and BETS-12 models were successfully validated using an independent dataset containing missing data. These models are the first validated tools for accurately estimating postoperative survival in patients with operable skeletal metastases of the extremities and can provide the surgeon with valuable information to support clinical decisions in this patient population.

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.

Five-year results from a Scandinavian sarcoma group study (SSG XIII) of adjuvant chemotherapy combined with accelerated radiotherapy in high-risk soft tissue sarcoma of extremities and trunk wall.

PURPOSE: To evaluate adjuvant chemotherapy and interpolated accelerated radiotherapy (RT) for adult patients with high-risk soft tissue sarcoma in the extremities or trunk wall. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

Radiotherapy to improve local control regardless of surgical margin and malignancy grade in extremity and trunk wall soft tissue sarcoma: a Scandinavian sarcoma group study.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSION: 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.