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.

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.

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.

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).

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.

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.

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.

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.

Technical recommendations for implementation of Volumetric Modulated Arc Therapy and Helical Tomotherapy Total Body Irradiation.

As a component of myeloablative conditioning before allogeneic hematopoietic stem cell transplantation (HSCT), Total Body Irradiation (TBI) is employed in radiotherapy centers all over the world. In recent and coming years, many centers are changing their technical setup from a conventional TBI technique to multi-isocenter conformal arc therapy techniques such as Volumetric Modulated Arc Therapy (VMAT) or Helical Tomotherapy (HT). These techniques allow better homogeneity and control of the target prescription dose, and provide more freedom for individualized organ-at-risk sparing. The technical design of multi-isocenter/multi-plan conformal TBI is complex and should be developed carefully. A group of early adopters with conformal TBI experience using different treatment machines and treatment planning systems came together to develop technical recommendations and share experiences, in order to assist departments wishing to implement conformal TBI, and to provide ideas for standardization of practices.

Clinical practice in European centres treating paediatric posterior fossa tumours with pencil beam scanning proton therapy.

BACKGROUND AND PURPOSE: As no guidelines for pencil beam scanning (PBS) proton therapy (PT) of paediatric posterior fossa (PF) tumours exist to date, this study investigated planning techniques across European PT centres, with special considerations for brainstem and spinal cord sparing. MATERIALS AND METHODS: A survey and a treatment planning comparison were initiated across nineteen European PBS-PT centres treating paediatric patients. The survey assessed all aspects of the treatment chain, including but not limited to delineations, dose constraints and treatment planning. Each centre planned two PF tumour cases for focal irradiation, according to their own clinical practice but based on common delineations. The prescription dose was 54 Gy(RBE) for Case 1 and 59.4 Gy(RBE) for Case 2. For both cases, planning strategies and relevant dose metrics were compared. RESULTS: Seventeen (89 %) centres answered the survey, and sixteen (80 %) participated in the treatment planning comparison. In the survey, thirteen (68 %) centres reported using the European Particle Therapy Network definition for brainstem delineation. In the treatment planning study, while most centres used three beam directions, their configurations varied widely across centres. Large variations were also seen in brainstem doses, with a brainstem near maximum dose (D2%) ranging from 52.7 Gy(RBE) to 55.7 Gy(RBE) (Case 1), and from 56.8 Gy(RBE) to 60.9 Gy(RBE) (Case 2). CONCLUSION: This study assessed the European PBS-PT planning of paediatric PF tumours. Agreement was achieved in e.g. delineation-practice, while wider variations were observed in planning approach and consequently dose to organs at risk. Collaboration between centres is still ongoing, striving towards common guidelines.

Treatment plan comparison using grading analysis based on clinical judgment.

PURPOSE: In this work we explore a method named clinical grading analysis (CGA) which is based on clinical assessments performed by radiation oncologists (ROs). The purpose is to investigate how useful the method is for treatment plan comparisons, and how the CGA results correlate with dosimetric evaluation parameters, traditionally used for treatment plan comparisons. MATERIAL AND METHODS: Helical tomotherapy (HTT) and seven-beam step-and-shoot intensity modulated radiation therapy (SS-IMRT) plans were compared and assessed by 10 experienced ROs for 23 patient cases. A CGA was performed where the plans were graded based on how the ROs thought they compared to each other. The resulting grades from the CGA were analyzed and compared to dose-volume statistics and equivalent uniform dose (EUD) data. RESULTS: For eight of the 23 cases the CGA revealed a significant difference between the HTT and the SS-IMRT plans, five cases were in favor of HTT, and three in favor of SS-IMRT. Comparing the dose-volume statistics and EUD-data with the result from the CGA showed that CGA results correlated well with dose-volume statistics for cases regarding difference in target coverage or doses to organs at risk. The CGA results also correlated well with EUD-data for cases with difference in clinical target volume (CTV) coverage but the correlation for cases with difference in planning target volume (PTV) coverage was not as clear. CONCLUSIONS: This study presents CGA as a useful method of comparing radiotherapy treatment plans. The proposed method offers a formalized way of introducing and evaluating the implementation of new radiotherapy techniques in a clinical setting. The CGA identify patients that have a clinical benefit of one or the other of the advanced treatment techniques available to them, i.e. in this study HTT and SS-IMRT, which facilitates a more optimal use of a clinics' advanced treatment resources.

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.

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.

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.

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.

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.

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.

Changing clinical presentation of angiosarcomas after breast cancer: from late tumors in edematous arms to earlier tumors on the thoracic wall.

Angiosarcoma is a rare complication of breast cancer treatment. In order to define predictors, clinical presentation, and outcome, we characterized a population-based 50-year cohort of angiosarcomas after breast cancer. Clinical data were collected from all females with previous breast cancer who developed angiosarcomas/lymphangiosarcomas on the thoracic wall/upper extremity between 1958 and 2008 in the Southern Swedish health care region. In total, 31 angiosarcomas developed at a median age of 71 years. The patients formed two distinct groups; 14 females treated for breast cancer with radical mastectomy and radiotherapy 1949-1988 developed angiosarcomas in edematous arms (Stewart-Treves syndrome) after median 11 years, and 17 females treated by segmental resection, anti-hormonal treatment and radiotherapy 1980-2005 developed angiosarcomas in the irradiated field on the thoracic wall after median 7.3 years. The clinical presentations were heterogeneous and included hematoma-like lesions, multiple bluish-reddish nodules, and asymptomatic lumps. The overall 5-year survival was 16%. In this population-based cohort, the early angiosarcomas developed in edematous arms after radical mastectomies, whereas more recent cases occurred after a shorter time period in the irradiated fields following breast conserving surgery. We conclude that the clinical presentation of angiosarcomas has changed, parallel with altered treatment principles for breast cancer.

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.