The influence of "bad news" and "neutral/good news" on patients' perception of physician empathy during oncology consultations.

OBJECTIVES: Being met with empathy increases information sharing, treatment coherence, and helps patients to recover faster. However, we do not know how the content of the conversation about disease progression, new treatments, or other issues concerning serious illness affects patients' perceptions of the physician's empathy, and thus, the quality of the conversation. This study aimed to test the hypothesis that patients will rate their physician lower following a "bad news" consultation using the consultation and relational empathy (CARE) measure. METHODS: A total of 186 outpatients from the Department of Oncology were recruited for this study. After meeting with a patient, the physician filled out a form, placing the patient in either the "bad news" group, or the "neutral/good news" group along with information about the patient and the consultation. The patient was given the CARE measure after the visit. RESULTS: The patients who had received bad news rated their physicians a significantly lower score on the CARE measure, even though the effect size was small, than those who had neutral/good news. On average, bad news consultations were 11 min longer. CONCLUSIONS: Physicians need to be aware of the patients' need to be known and understood, in addition to having skills to attend to emotional cues and concerns, since the current study's finding could be a sign either of the content being projected onto the physician or that the physician is focused on the message rather than on the patient.

Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008-2019.

BACKGROUND: Proton radiotherapy (RT) is an attractive tool to deliver local therapy with minimal dose to uninvolved tissue, however, not suitable for all patients. The aim was to explore complications, especially severe late complications (grades 3-4), following proton RT delivered to a complete Swedish cohort of paediatric patients aged <18 years treated 2008-2019. MATERIAL AND METHODS: Data was downloaded from a national registry. Complications with a possible causation with RT are reported. Proton treatments until July 2015 was performed with a fixed horizontal 172 MeV beam (The Svedberg Laboratory (TSL), Uppsala) in a sitting position and thereafter with gantry-based pencil-beam scanning technique (Skandion Clinic, Uppsala) in a supine position. RESULTS: 219 courses of proton RT (77 at TSL and 142 at Skandion) were delivered to 212 patients (mean age 9.2 years) with various tumour types (CNS tumours 58%, sarcomas 26%, germ cell tumours 7%). Twenty-five patients had severe acute complications (skin, mucous membrane, pharynx/oesophagus, larynx, upper gastrointestinal canal, lower gastrointestinal canal, eyes, ears). Fifteen patients had severe late complications; with increased proportion over time: 4% at 1-year follow-up (FU), 5% at 3-year, 11% at 5-year. Organs affected were skin (1 patient), subcutaneous tissue (4), salivary glands (1), upper GI (1), bone (7), joints (2), CNS (2), PNS (1), eyes (1) and ears (5). Twenty-one of the 28 patients with 10-year FU had at least one late complication grades 1-4 and fourteen of them had more than one (2-5 each). CONCLUSION: The most important result of our study is the relatively low proportion of severe late complications, comparable with other proton studies on various tumours. Furthermore, the numbers of late complications are lower than our own data set on a mixed population of photon and proton treated paediatric patients, assuring the safety of using proton therapy also in the clinical practice.

Patterns of Communication About Serious Illness in the Years, Months, and Days before Death.

Background: Communication with patients and families about serious illness impacts quality of life and helps facilitate decision-making. Objective: To elucidate the pattern of communication about serious illness for patients who have died in an inpatient setting. Design: Three hundred patients from the Swedish Registry of Palliative Care 2015-2017 were randomly selected for manual chart review. Setting: Patients who died in a palliative care, oncology, or internal medicine unit in Sweden were selected. Measurements: We report on the frequency of conversations at three time points, 6 months or longer before death ("Years"), 15 days-6 months before death ("Months"), and 0-14 days before death ("Days"). We also report the timing of the conversation about dying. Results: A total of 249 patients were included after exclusions; they had an average of 2.1 conversations (range 1-6). The first conversation took place a median of 53 days before death and the last conversation took place a median of 9 days before death. Separate conversations with the next of kin took place a median of two days before death. We could verify a conversation about dying in only 156/249 (63%) medical records. Conclusions: Communication about serious illness between clinicians, patients, and families occurs iteratively over a period before death. Measuring the quality of communication about serious illness using a years, months, and days framework may help ensure that patients and families have sufficient information for medical and personal decision making.

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children.

BACKGROUND AND PURPOSE: Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. MATERIAL AND METHODS: The European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. RESULTS: Myeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3-4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III-IV evidence. Preferential TBI dose in children is 12-14.4 Gy in 1.6-2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. CONCLUSIONS: These ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.

Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin.

Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA+DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.

Longitudinal in vivo biodistribution of nano and micro sized hydroxyapatite particles implanted in a bone defect.

Hydroxyapatite (HA) has been widely used as a bone substitute and more recently as a carrier for local delivery of bone targeted drugs. Majority of the approved HA based biomaterials and drug carriers comprise of micrometer sized particulate HA (mHA) or granules and can therefore only be used for extracellular drug release. This shortcoming could be overcome with the use of cell penetrating HA nanoparticles (nHA) but a major concern with the clinical use of nHA is the lack of data on its in vivo biodistribution after implantation. In this study, we aimed to study the in vivo biodistribution of locally implanted nHA in a clinically relevant tibial void in rats and compare it with mHA or a combination of mHA and nHA. To enable in vivo tracking, HA particles were first labelled with 14C-zoledronic acid (14C-ZA), known to have a high binding affinity to HA. The labelled particles were then implanted in the animals and the radioactivity in the proximal tibia and vital organs was detected at various time points (Day 1, 7 and 28) post-implantation using scintillation counting. The local distribution of the particles in the bone was studied with micro-CT. We found that majority (>99.9%) of the implanted HA particles, irrespective of the size, stayed locally at the implantation site even after 28 days and the findings were confirmed using micro-CT. Less than 0.1% radioactivity was observed in the kidney and the spleen at later time points of day 7 and 28. No pathological changes in any of the vital organs could be observed histologically. This is the first longitudinal in vivo HA biodistribution study showing that the local implantation of nHA particles in bone is safe and that nHA could potentially be used for localized drug delivery.

Sustained and controlled delivery of doxorubicin from an in-situ setting biphasic hydroxyapatite carrier for local treatment of a highly proliferative human osteosarcoma.

Doxorubicin (DOX) is a cornerstone drug in the treatment of osteosarcoma. However, achieving sufficient concentration in the tumor tissue after systemic administration with few side effects has been a challenge. Even with the most advanced nanotechnology approaches, less than 5% of the total administered drug gets delivered to the target site. Alternatives to increase the local concentration of DOX within the tumor using improved drug delivery methods are needed. In this study, we evaluate a clinically approved calcium sulfate/hydroxyapatite (CaS/HA) carrier, both in-vitro and in-vivo, for local, sustained and controlled delivery of DOX to improve osteosarcoma treatment. In-vitro drug release studies indicated that nearly 28% and 36% of the loaded drug was released over a period of 4-weeks at physiological pH (7.4) and acidic pH (5), respectively. About 63% of the drug had been released after 4-weeks in-vivo. The efficacy of the released drug from the CaS/HA material was verified on two human osteosarcoma cell lines MG-63 and 143B. It was demonstrated that the released drug fractions functioned the same way as the free drug without impacting its efficacy. Finally, the carrier system with DOX was assessed using two clinically relevant human osteosarcoma xenograft models. Compared to no treatment or the clinical standard of care with systemic DOX administration, the delivery of DOX using a CaS/HA biomaterial could significantly hinder tumor progression by inhibiting angiogenesis and cell proliferation. Our results indicate that a clinically approved CaS/HA biomaterial containing cytostatics could potentially be used for the local treatment of osteosarcoma. STATEMENT OF SIGNIFICANCE: The triad of doxorubicin (DOX), methotrexate and cisplatin has routinely been used for the treatment of osteosarcoma. These drugs dramatically improved the prognosis, but 45-55% of the patients respond poorly to the treatment with low 5-year survival. In the present study, we repurpose the cornerstone drug DOX by embedding it in a calcium sulfate/hydroxyapatite (CaS/HA) biomaterial, ensuring a spatio-temporal drug release and a hypothetically higher and longer lasting intra-tumoral concentration of DOX. This delivery system could dramatically hinder the progression of a highly aggressive osteosarcoma compared to systemic administration, by inhibiting angiogenesis and cell proliferation. Our data show an efficient method for supplementary osteosarcoma treatment with possible rapid translational potential due to clinically approved constituents.

Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation.

OBJECTIVES: Total body irradiation (TBI) is commonly used prior to hematopoietic stem cell transplantation (HSCT) in myeloablative conditioning regimens. However, TBI may be replaced by total marrow irradiation (TMI) at centres with access to Helical TomoTherapy, a modality that has the advantage of delivering intensity-modulated radiotherapy to long targets such as the entire bone marrow compartment. Toxicity after organ sparing TMI prior to HSCT has not previously been reported compared to TBI or with regard to engraftment data. METHODS: We conducted a prospective observational study on 37 patients that received organ sparing TMI prior to HSCT and compared this cohort to retrospective data on 33 patients that received TBI prior to HSCT. RESULTS: The 1-year graft-versus-host disease-free, relapse-free survival (GRFS) was 67.5% for all patients treated with TMI and 80.5% for patients with matched unrelated donor and treated with TMI, which was a significant difference from historical data on TBI patients with a hazard ratio of 0.45 (P = .03) and 0.24 (P < .01). Engraftment with a platelet count over 20 [K/µL] and 50 [K/µL] was significantly shorter for the TMI group, and neutrophil recovery was satisfactory in both treatment cohorts. There was generally a low occurrence of other treatment-related toxicities. CONCLUSIONS: Despite small cohorts, some significant differences were found; TMI as part of the myeloablative conditioning yields a high 1-year GRFS, fast and robust engraftment, and low occurrence of acute toxicity.

Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.

BACKGROUND AND PURPOSE: To reduce relapse risk, Total Body Irradiation (TBI) is part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric acute leukemia. The study purpose was to evaluate clinical practices regarding TBI, such as fractionation, organ shielding and delivery techniques, among SIOPE affiliated radiotherapy centers. METHODS: An electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously. RESULTS: From over 25 countries, 82 responses were collected. For TBI-performing centers, 40/48 irradiated ≤10 pediatric patients annually (range: 1-2 to >25). Most indications concerned acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Four different fractionation schedules were used, of which 12 Gy in 6 fractions was applied in 91% for ALL and 86% for AML. Dose reduction to the lungs, mostly to a mean dose of 8-10 Gy, was applied by 28/33 centers for ALL and 19/21 centers for AML, in contrast to much less applied dose reduction to the kidneys (7/33 ALL and 7/21 AML), thyroid (2/33 ALL and 2/21 AML), liver (4/33 ALL and 3/21 AML) and lenses (4/33 ALL and 4/21 AML). Conventional TBI techniques were used by 24/29 responding centers, while 5/29 used advanced optimized planning techniques. CONCLUSION: Across SIOPE, there is a high level of uniformity in fractionation and use of lung shielding. Practices vary regarding other organs-at-risk shielding and implementation of advanced techniques. A SIOPE radiotherapy working group will be established to define international guidelines for pediatric TBI.

High Recurrence Rate of Myxofibrosarcoma: The Effect of Radiotherapy Is Not Clear.

BACKGROUND: Myxofibrosarcoma (MFS) is one of the more common types of soft-tissue sarcoma (STS) in patients over 60 years of age. Local recurrence (LR) rates have been reported to be higher compared to other STS types. PATIENTS AND METHODS: Using a population-based series from the southern Sweden health care region, 56 consecutive patients with MFS and localized disease at diagnosis were analyzed with respect to LR and distant metastases after surgery ± adjuvant treatment. RESULTS: The overall local recurrence (n = 15) and metastasis (n = 13) rates were 27% and 21%, respectively; 6 patients had both. Surgical margin was the only statistically significant prognostic factor for LR. Patients operated with a marginal margin had an HR of 4.5 (CI 1.3-15.1, p=0.02) and those operated with an intralesional margin 9.4 (CI 2.0-43.5, p=0.004) compared to those operated with a wide surgical margin. There was no difference in the LR rate depending on radiotherapy or not, although the latter group had smaller and more superficial tumors. 23 patients received radiotherapy, 9 of whom developed LR, all within the irradiated field. A tumor size >5 cm and intralesional surgical margin were shown to be risk factors for distant metastases. CONCLUSIONS: The rate of LR for patients with myxofibrosarcoma was high. The impact of RT on local tumor control was unclear. The surgical margin was important for both local and distant tumor control. Large tumor size was a risk factor for distant metastasis.

Implementing safe and robust Total Marrow Irradiation using Helical Tomotherapy - A practical guide.

Total Marrow Irradiation (TMI) with Helical Tomotherapy is a radiotherapy treatment technique that targets bone marrow and sanctuary sites prior to stem cell or bone marrow transplantation (SCT/BMT). TMI is a complex procedure that involves several critical steps that all need to be carefully addressed for a successful implementation, such as dose homogeneity in field junctions, choice of target margins, integrity of treatment and back-up planning. In this work we present our solution for a robust and reproducible workflow throughout the treatment chain and data for twenty-three patients treated to date. MATERIAL & METHODS: Patients were immobilized in a whole body vacuum cushion and thermoplastic mask. CT-scanning and treatment were performed in two parts with field matching at the upper thigh. Target consisted of marrow containing bone and sanctuary sites. Lungs, kidneys, bowel, heart and liver were defined as organs at risk (OAR). A fast surface scanning system was used to position parts of the body not covered by the imaging system (MVCT) as well as to reduce treatment time. RESULTS: All patients completed their treatment and could proceed with SCT/BMT. Doses to OARs were significantly reduced and target dose homogeneity was improved compared to TBI. Robustness tests performed on field matching and patient positioning support that the field junction technique is adequate. Replacing MVCT with optical surface scanning reduced the treatment time by 25 min per fraction. CONCLUSION: The methodology presented here has shown to provide a safe, robust and reproducible treatment for Total Marrow Irradiation using Tomotherapy.

Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone.

BACKGROUND: Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies. METHODS: The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only). RESULTS: Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment. CONCLUSION: Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab. TRIAL REGISTRATION: ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

Solitary juvenile xanthogranuloma in the spine pretreated with neoadjuvant denosumab therapy followed by surgical resection in a 5-year-old child: case report and literature review.

PURPOSE: We present a case report that describes neoadjuvant denosumab therapy initiated in a child with a solitary giant cell-rich juvenile xanthogranuloma tumor involving the spine, and review the current literature. METHODS: A giant cell-rich histiocytic lesion involving the 11th thoracic vertebral body was identified in a healthy 5-year-old girl with persistent back and pelvic pain for several months. Imaging examinations and an open biopsy were performed to obtain a definite pathologic diagnosis. As the tumor appeared to be aggressive in nature, we administered adjuvant therapy with denosumab preoperatively and then performed a total spondylectomy. RESULTS: Histopathology confirmed that the tumor was juvenile xanthogranuloma. No tumor metastases or recurrence were detected at the 3-year follow-up, and the patient was asymptomatic. CONCLUSIONS: In giant cell-rich tumors, denosumab is occasionally used as neoadjuvant or adjuvant therapy, especially for tumors in difficult locations or with substantial soft tissue extensions. Rare adverse events in children include skin infections and disruption of calcium homeostasis. Surgical treatment is aimed at removing the tumor and relieving the symptomatic spinal cord compression. Use of denosumab as neoadjuvant therapy for juvenile xanthogranuloma involving the spine has not been reported previously.

Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors-A Scandinavian Sarcoma Group study (SSG XX).

PURPOSE: To investigate the outcome following adjuvant doxorubicin and ifosfamide in a prospective non-randomised study based on a soft tissue sarcoma (STS) patient subgroup defined by specific morphological characteristics previously shown to be at a high-risk of metastatic relapse. The expected 5-year cumulative incidence of metastases in patients with this risk profile has previously been reported to be about 50% without adjuvant chemotherapy. METHODS: High-risk STS was defined as high-grade morphology (according to the Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade II-III) and either vascular invasion or at least two of the following criteria: tumour size ≥8.0 cm, infiltrative growth and necrosis. Six cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2) were given. Postoperative accelerated radiotherapy was applied and scheduled between cycles 3 and 4. RESULTS: For the 150 eligible patients, median follow-up time for metastases-free survival was 3.9 years (range 0.2-8.7). Five-year metastases-free survival (MFS) was 70.4% (95% confidence interval [CI]: 63.1-78.4) with a local recurrence rate of 14.0% (95% CI: 7.8-20.2). For overall survival (OS), the median follow-up time was 4.4 years (range: 0.2-8.7). The five-year OS was 76.1% (95% CI: 68.8-84.2). Tumour size, deep location and reduced dose intensity (<80%) had a negative impact on survival. Toxicity was moderate with no treatment-related death. CONCLUSIONS: A benefit of adjuvant chemotherapy, compared to similar historical control groups, was demonstrated in STS patients with defined poor prognostic factors. Vascular invasion, tumour size, growth pattern and necrosis may identify patients in need of adjuvant chemotherapy.

Population-based study of giant cell tumor of bone in Sweden (1983-2011).

INTRODUCTION: Giant-cell tumor of bone (GCTB) is a locally aggressive histologically benign neoplasm with a less common malignant counterpart. Longitudinal data sources on GCTB are sparse, limited to single institution case series or surgical outcomes studies. The Swedish Cancer Registry is one of the few national population-based databases recording GCTB, representing a unique source to study GCTB epidemiology. We estimated incidence rate (IR) and overall mortality rates based on registry data. MATERIALS AND METHODS: We identified patients with a GCTB diagnosis in the Swedish Cancer Registry from 1983 to 2011: benign (ICD-7 196.0-196.9; PAD 741) and malignant (PAD 746). Results were stratified by age at diagnosis, gender, and anatomical lesion location. RESULTS: The cohort included 337 GCTB cases (IR of 1.3 per million persons per year). The majority (n=310) had primary benign GCTB (IR of 1.2 per million per year). Median age at diagnosis was 34 years (range 10-88) with 54% (n=183) females. Malignant to benign ratio for women was 0.095 (16/167) and for men 0.077 (11/143). Incidence was highest in the 20-39 years age group (IR of 2.1 per million per year). The most common lesion sites were distal femur and proximal tibia. Mortality at 20 years from diagnosis was 14% (n=48) and was slightly higher for axial (17%; n=6) and pelvic (17%; n=4) lesions. Recurrence occurred in 39% of primary benign cases and 75% of primary malignant cases. CONCLUSIONS: In our modern population-based series primary malignant cases were uncommon (8%), peak incidence 20-39 years with slight predominance in women. Recurrence rates remain significant with overall 39% occurring in benign GCTB, and 75% in malignant form. The linkage between databases allowed the first population based estimates of the proportion of patients who received surgery at initial GCTB diagnosis, and those who also received subsequent surgeries.

Incidence Trends in the Diagnosis of Giant Cell Tumor of Bone in Sweden Since 1958.

BACKGROUND: The Swedish Cancer Registry (founded in 1958) constitutes a unique resource for epidemiological studies of giant cell tumor of bone with potential for use for population-based studies of incidence over time. The aim of this study was to provide what we believe is the first modern population-based assessment of the incidence trends of giant cell tumor, a unique osteoclastogenic lytic stromal tumor with both benign and malignant histological forms, and to compare the findings with data from the same registry on osteosarcoma, a tumor that may display similar histological characteristics. METHODS: Cases were identified with use of codes for pathological bone tumor (International Classification of Diseases [ICD]-7 196). Specific morphological coding distinguishes benign (PAD 741) from malignant giant cell tumor (PAD 746) and osteosarcoma (PAD 766). RESULTS: During the period of 1958 to 2011, 4625 bone tumors were reported, including 505 giant cell tumors (383 benign and 122 malignant) and 1152 osteosarcomas. From 1958 to 1982 the ratio of malignant to benign giant cell tumors was 1.3, whereas from 1983 to 2011 the ratio inverted to 0.09, suggesting a change in the reporting or diagnosis of malignant or benign cases. Cases of giant cell tumor diagnosed from 1983 to 2011 displayed an age and sex distribution (median age at diagnosis, 34.0 years; 54% female) that were consistent with those in large published case series but differed from those in 1958 to 1982 (median age at diagnosis, 31.5 years; 48% female). The most current data (1983 to 2011) showed the giant cell tumor incidence in Sweden to be 1.3 per million per year, while the osteosarcoma incidence was 2.3 per million per year. CONCLUSIONS: Early Swedish Cancer Registry data (1958 to 1982) revealed a higher proportion of malignant giant cell tumors than seen in large sequential case series and a distinct age and sex profile compared with more recent data (1983 to 2011). This likely represents changes in the diagnostic workup and introduction of multidisciplinary review of giant-cell-containing tumors around 1982. Recent data may reflect the impact of expert centralized biopsy and multidisciplinary case review and more comprehensive reporting of benign giant cell tumors.

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

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.

Effects of denosumab on pain and analgesic use in giant cell tumor of bone: interim results from a phase II study.

BACKGROUND: Giant cell tumor of bone (GCTB) is an aggressive primary osteolytic tumor. GCTB often involves the epiphysis, usually causing substantial pain and functional disability. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κΒ ligand (RANKL), is an effective treatment option for patients with advanced GCTB. This analysis of data from an ongoing, open-label study describes denosumab's effects on pain and analgesic use in patients with GCTB. MATERIAL AND METHODS: Patients with unresectable disease (e.g. sacral or spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into Cohort 1 (N = 170), and patients with resectable disease whose planned surgery was associated with severe morbidity (e.g. joint resection, limb amputation, or hemipelvectomy) were enrolled into Cohort 2 (N = 101). Patients received denosumab (120 mg) subcutaneously every four weeks, with additional doses on study days 8 and 15. Patients assessed worst pain severity with the Brief Pain Inventory - Short Form (BPI-SF) at baseline, at each visit for the first six months, and every three months thereafter. RESULTS: Clinically relevant pain improvement was reported by 29% of patients in Cohort 1 and 35% in Cohort 2 during week 1 and by ≥ 50% of patients in each cohort at each study visit from months 2-30. Median time to clinically relevant improvement was 30 (95% CI 16, 57) days in Cohort 1 and 15 (95% CI 15, 29) days in Cohort 2. Results in patients with moderate/severe pain at baseline were similar. Fewer than 30% of patients in Cohort 1 and 10% in Cohort 2 experienced clinically relevant pain worsening at any visit through 27 months. Most patients had no/low analgesic use during the study. CONCLUSION: Most patients treated with denosumab experienced clinically relevant decreases in pain within two months.

Assessment of volume segmentation in radiotherapy of adolescents; a treatment planning study by the Swedish Workgroup for Paediatric Radiotherapy.

BACKGROUND AND PURPOSE: The variability in target delineation for similar cases between centres treating paediatric and adolescent patients, and the apparent differences in interpretation of radiotherapy guidelines in the treatment protocols encouraged us to perform a dummy-run study as a part of our quality assurance work. The aim was to identify and quantify differences in the segmentation of target volumes and organs at risk (OARs) and to analyse the treatment plans and dose distributions. MATERIALS AND METHODS: Four patient cases were selected: Wilm's tumour, Hodgkin's disease, rhabdomyosarcoma of the prostate and chordoma of the skull base. The five participating centres received the same patient-related material. They introduced the cases in their treatment planning system, delineated target volumes and OARs and created treatment plans. Dose-volume histograms were retrieved for relevant structures and volumes and dose metrics were derived and compared, e.g. target volumes and their concordance, dose homogeneity index (HI), treated and irradiated volumes, remaining volume at risk and relevant Vx and Dx values. RESULTS: We found significant differences in target segmentation in the majority of the cases. The planning target volumes (PTVs) varied two- to four-fold and conformity indices were in the range of 0.3-0.6. This resulted in large variations in dose distributions to OARs as well as in treated and irradiated volumes even though the treatment plans showed good conformity to the PTVs. Potential reasons for the differences in target delineation were analysed. CONCLUSION: Considerations of the growing child and difficulties in interpretation of the radiotherapy information in the treatment protocols were identified as reasons for the variation. As a result, clarified translated detailed radiotherapy guidelines for paediatric/adolescent patients have been recognised as a way to reduce this variation.