Nina L. Jebsen

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.

Young survivors of malignant bone tumours in the extremities : a comparative study of quality of life, fatigue and mental distress

PurposeThe 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.Patients and methodsFive 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.ResultsNo 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.ConclusionAt 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.

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.

Health Status at Long-Term Follow-Up in Patients Treated for Extremity Localized Ewing Sarcoma or Osteosarcoma: A Scandinavian Sarcoma Group Study

The purpose of this study was to evaluate late effects and symptom complaints in long‐term survivors (>5 years) of Extremity Bone Sarcoma (EBS survivors). The results were compared with findings in age‐ and gender‐matched individuals from the general population (NORMs).

Adjuvant radiotherapy in retroperitoneal sarcomas. A Scandinavian Sarcoma Group study of 97 patients

Abstract Background. Currently there is no consensus on the use of adjuvant radiotherapy (RT) in retroperitoneal sarcoma (RPS). We have analysed clinical outcomes in patients with localised RPS treated at two Scandinavian Sarcoma Group (SSG) centres: Haukeland University Hospital (HUH), Bergen, Norway and Skåne University Hospital (SUH), Lund, Sweden to clarify the effects of adjuvant RT on local control and overall survival (OS). Material and methods. Local databases and registers at HUH and SUH as well as the SSG central register were used to identify RPS patients. Patients with localised RPS who underwent surgery in Bergen between 1988 and 2009 and in Lund from 1998 to 2009 were included. Medical records were examined for clinical data, tumour characteristics, treatment factors and follow-up status. Archived tumour sections and tumour tissue were reviewed, and when necessary, restained and reclassified. Cox regression was used to analyse the association of potential prognostic factors with local recurrence-free survival (LRFS), metastasis-free survival (MFS) and OS. Results. The study included 97 patients: 52 from Norway and 45 from Sweden. The proportion of high-grade tumours was 73%. The five-year LRFS, MFS and OS were 55%, 59% and 60%, respectively. RT was significantly associated with improved local control resulting in a five-year LRFS of 77% compared with 39% without (p < 0.001). Furthermore, five-year OS was 71% in the RT group in contrast to 52% with surgery alone (p = 0.019). In the adjusted analysis RT proved to be a significant factor also for MFS (HR = 0.42, 95% CI 0.20–0.88, p = 0.021). In addition, high-grade malignancy, large tumour and positive surgical margin were risk factors for local recurrence. High malignancy grade was the only significant adverse prognostic factor for metastasis. High age and high-grade malignancy were negative prognostic factors for OS. Conclusion. Adjuvant RT was significantly associated with an improved five-year LRFS and OS.

Can dose-response models predict reliable normal tissue complication probabilities in radical radiotherapy of urinary bladder cancer? The impact of alternative radiation tolerance models and parameters.

PURPOSE To analyze the consequences of selecting alternative normal tissue complication probability (NTCP) models and parameters for evaluation of radiotherapy of urinary bladder cancer. METHODS AND MATERIALS Treatment plans of 24 bladder cancer patients referred to radical 4-field conformal radiotherapy were analyzed. Small intestinal and rectal NTCPs were determined using both the probit and relative seriality models with several sets of published radiation tolerance parameters. Various combinations of NTCP models and parameters were applied to find the prescription dose in individual patients as well as to estimate the benefit of the conformal radiotherapy setup. RESULTS Different risk estimates were predicted from the two NTCP models, even when the same clinical radiation tolerance doses were fitted into the two models. The demonstrated variability translated into significant deviations (7-10 Gy) in the recommended prescription doses. Even if it was possible to discriminate between a 2-field plan and the 4-field conformal setup using a given complication model and set of tolerance parameters, the estimated benefit of the conformal treatment in terms of permitted dose escalation varied with as much as 10-12 Gy between the different NTCP models/parameters used. CONCLUSION Different NTCP models and tolerance parameters might propose different answers to important clinical questions in radiotherapy treatment of bladder cancer, such as dose prescription and scoring of rival treatment plans. We therefore recommend that the variability caused by tolerance parameter uncertainty and model selection should be taken into account in dose-response modeling of radiotherapy treatment.

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.

The Scandinavian Sarcoma Group Central Register : 6,000 patients after 25 years of monitoring of referral and treatment of extremity and trunk wall soft-tissue sarcoma

Purpose — We wanted to examine the potential of the Scandinavian Sarcoma Group (SSG) Central Register, and evaluate referral and treatment practice for soft-tissue sarcomas in the extremities and trunk wall (STS) in the Nordic countries. Background — Based on incidence rates from the literature, 8,150 (7,000–9,300) cases of STS of the extremity and trunk wall should have been diagnosed in Norway, Finland, Iceland, and Sweden from 1987 through 2011. The SSG Register has 6,027 cases registered from this period, with 5,837 having complete registration of key variables. 10 centers have been reporting to the Register. The 5 centers that consistently report treat approximately 90% of the cases in their respective regions. The remaining centers have reported all the patients who were treated during certain time periods, but not for the entire 25-year period. Results — 59% of patients were referred to a sarcoma center untouched, i.e. before any attempt at open biopsy. There was an improvement from 52% during the first 5 years to 70% during the last 5 years. 50% had wide or better margins at surgery. Wide margins are now achieved less often than 20 years ago, in parallel with an increase in the use of radiotherapy. For the centers that consistently report, 97% of surviving patients are followed for more than 4 years. Metastasis-free survival (MFS) increased from 67% to 73% during the 25-year period. Interpretation — The Register is considered to be representative of extremity and trunk wall sarcoma disease in the population of Scandinavia, treated at the reporting centers. There were no clinically significant differences in treatment results at these centers.

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

Abstract 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.

Improved Prognosis for Patients with Ewing Sarcoma in the Sacrum Compared with the Innominate Bones: The Scandinavian Sarcoma Group Experience.

BACKGROUND Treatment of Ewing sarcoma of the pelvic bones remains one of the most difficult tasks in the treatment of bone sarcomas. Whether surgery or radiation therapy is the best local treatment is still a matter of debate. The aim of the present study was to compare sacral and nonsacral sites with regard to the treatment and outcome of pelvic Ewing sarcomas. METHODS Patients with Ewing sarcoma of the osseous pelvis diagnosed between 1986 and 2011 were identified through the Scandinavian Sarcoma Group registry. Data regarding tumor size, local treatment (surgery or radiation therapy), metastatic disease, surgical margins, local recurrence, and overall survival were analyzed. RESULTS Of the 117 patients examined, eighty-eight had tumors in the innominate bones and twenty-nine, in the sacrum. Radiation therapy was the sole local treatment for 40% of the innominate bone tumors in contrast to 79% of the sacral tumors. The five-year disease-free survival rate in the latter group (66%) was greater than that in the group with tumors in the innominate bones (40%) (p = 0.02 adjusted for size). CONCLUSIONS Disease-free survival among patients with Ewing sarcoma was improved when the tumor was localized in the sacrum compared with the innominate bones, where these tumors are generally larger. Local radiation therapy alone appears to result in good local tumor control and may be the treatment of choice for sacral tumors.