ECCO Essential Requirements for Quality Cancer Care : Soft Tissue Sarcoma in Adults and Bone Sarcoma. A critical review

Background: ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Sarcoma: essential requirements for quality care Sarcomas - which can be classified into soft tissue and bone sarcomas - are rare, but all rare cancers make up more than 20% of cancers in Europe, and there are substantial inequalities in access to high-quality care. Sarcomas, of which there are many subtypes, comprise a particularly complex and demanding challenge for healthcare systems and providers. This paper presents essential requirements for quality cancer care of soft tissue sarcomas in adults and bone sarcomas. High-quality care must only be carried out in specialised sarcoma centres (including paediatric cancer centres) which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis and follow-up, to treatment, to improve survival and quality of life for patients. Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for soft tissue sarcomas in adults and bone sarcomas. The ECCO expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams is guaranteed to all patients with sarcoma. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.Peer reviewe

Towards patient-tailored care for soft tissue sarcoma

Over the past few decades, there has been a paradigm shift in cancer research from focusing on the homogeneity within a patient population to emphasizing the diversity or heterogeneity in presentation and clinical outcomes among patients. This concept has been commonly referred to as personalised medicine. The foundation of personalised medicine lies in delivering effective care tailored to each individual patient. In this thesis, we aimed to contribute to a more personalised and patient-tailored approach in the management of patients with soft tissue sarcoma (STS), a rare type of cancer. We achieved this goal by developing and validating different prediction tools and assessing how prediction tools could play a role in the clinical decision making process for STS. The following three main questions were addressed in this thesis:1. PART I: Given the current practice,what is the variation in clinical presentation and oncological outcome of patients with STS? which factors influence this variation in oncological outcome?2. PART II: How to better identify patients at risk and predict oncological outcome in patients with STS?3. PART III: How could prognostic tools play a role in the clinical decision making and management of STS?<br/

Advanced radiotherapy techniques: Improving outcomes in sarcoma

Radiotherapy is an important modality in the management of the primary tumour in bone and soft tissue sarcomas. Traditionally radiotherapy for sarcomas has been delivered with a three-dimensional conformal technique (3DCRT). In extremity soft tissue sarcomas this frequently leads to high doses of radiation being given to normal soft tissues outside the target. In Ewing sarcoma arising in specific sites such as the pelvis, it is difficult to avoid significant dose from 3DCRT to sensitive normal tissue structures adjacent to the target (small bowel, rectum, bladder and reproductive organs), potentially limiting the dose that can safely be given to the target. This body of work explores the burden of late effects of 3DCRT in patients with bone and soft tissue sarcoma and how advanced radiotherapy techniques including intensity modulated radiotherapy (IMRT) and proton beam therapy (PBT), that produce more conformal dose distributions around the target, might be used to reduce the risk of late side effects while optimising target coverage. The experimental work comprises three studies examining different aspects of the research topic, culminating in the development of a prospective phase II clinical trial. The first study is a survey of late effects and functional outcomes in patients with extremity bone and soft tissue sarcoma treated with 3DCRT. Risk factors for late toxicity in this cohort are identified. The second study is a comparative planning study of 3DCRT versus volumetric modulated arc therapy (VMAT), a rotational IMRT technique, in upper and lower extremity sarcomas. The third study is a comparative double planning study of VMAT and PBT in patients with pelvic Ewing sarcoma. How this work has directly fed into the development and opening of IMRiS, a currently recruiting prospective national phase II clinical trial of IMRT in bone and soft tissue sarcoma, is discussed

ECCO Essential Requirements for Quality Cancer Care: Soft Tissue Sarcoma in Adults and Bone Sarcoma. A critical review

ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Sarcoma: essential requirements for quality care • Sarcomas – which can be classified into soft tissue and bone sarcomas – are rare, but all rare cancers make up more than 20% of cancers in Europe, and there are substantial inequalities in access to high-quality care. Sarcomas, of which there are many subtypes, comprise a particularly complex and demanding challenge for healthcare systems and providers. This paper presents essential requirements for quality cancer care of soft tissue sarcomas in adults and bone sarcomas. • High-quality care must only be carried out in specialised sarcoma centres (including paediatric cancer centres) which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. • It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis and follow-up, to treatment, to improve survival and quality of life for patients. Conclusion Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for soft tissue sarcomas in adults and bone sarcomas. The ECCO expert group is aware that it is not possible to propose a ‘one size fits all’ system for all countries, but urges that access to multidisciplinary teams is guaranteed to all patients with sarcoma

EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen.

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Management of soft tissue sarcomas in extremities: variation in treatment recommendations and surveillance according to specialty and continent

Background This study aimed to provide an insight into clinical decision-making and surveillance strategy of sarcoma specialists for patients with primary soft tissue sarcoma of the extremities (eSTS). The secondary aim was to quantify the role of patient- and tumor-specific factors in the perioperative management. Methods Members of sarcoma societies were sent a Web-based 21-item survey about eSTS management. The survey concerned only primary resectable high-grade eSTS in adults. Results The study enrolled 396 respondents. The majority of the surgical specialists thought the evidence for perioperative chemotherapy (CTX) for high-grade eSTS was insufficient. Radiotherapy (RTX) was less frequently offered in Asia than in North America and Europe. The specialties and continents also differed regarding the importance of patient and tumor characteristics influencing RTX and CTX recommendation. For surveillance after initial treatment outpatient visits, chest computed tomography (CT) scans, and magnetic resonance images of the extremity were the methods primarily used. The specialists in North America preferred chest CT scan over chest x-ray, whereas those in Asia and Europe had no clear preference. Discussion Specialty and continent are important factors contributing to the variation in clinical practice, treatment recommendations, and surveillance of patients with primary resectable high-grade eSTS.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective multicenter study

[Background] Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm arising from the synovium of joints, bursae, and tendon sheaths affecting small and large joints. It represents a wide spectrum ranging from minimally symptomatic to massively debilitating. Most findings to date are mainly from small, retrospective case series, and thus the morbidity and actual impact of this rare disease remain to be elucidated. This study prospectively explores the management of TGCT in tertiary sarcoma centers.[Methods] The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study involving 12 tertiary sarcoma centers in 7 European countries, and 2 US sites. This study enrolled for 2 years all consecutive ≥ 18 years old patients, with histologically diagnosed primary or recurrent cases of diffuse-type TGCT. Patient demographic and clinical characteristics were collected at baseline and every 6 months for 24 months. Quality of life questionnaires (PROMIS-PF and EQ-5D) were also administered at the same time-points. Here we report baseline patient characteristics.[Results] 166 patients were enrolled between November 2016 and March 2019. Baseline characteristics were: mean age 44 years (mean age at disease onset: 39 years), 139/166 (83.7%) had prior treatment, 71/166 patients (42.8%) had ≥ 1 recurrence after treatment of their primary tumor, 76/136 (55.9%) visited a medical specialist ≥ 5 times, 66/116 (56.9%) missed work in the 24 months prior to baseline, and 17/166 (11.6%) changed employment status or retired prematurely due to disease burden. Prior treatment consisted of surgery (i.e., arthroscopic, open synovectomy) (128/166; 77.1%) and systemic treatments (52/166; 31.3%) with imatinib (19/52; 36.5%) or pexidartinib (27/52; 51.9%). Treatment strategies at baseline visits consisted mainly of watchful waiting (81/166; 48.8%), surgery (41/166; 24.7%), or targeted systemic therapy (37/166; 22.3%). Patients indicated for treatment reported more impairment compared to patients indicated for watchful waiting: worst stiffness NRS 5.16/3.44, worst pain NRS 6.13/5.03, PROMIS-PF 39.48/43.85, and EQ-5D VAS 66.54/71.85.[Conclusion] This study confirms that diffuse-type TGCT can highly impact quality of life. A prospective observational registry in rare disease is feasible and can be a tool to collect curated-population reflective data in orphan diseases.[Name of registry] Tenosynovial Giant Cell Tumors (TGCT) Observational Platform Project (TOPP).[Trial registration number] NCT02948088.[Date of registration] 10 October 2016.[URL of Trial registry record] https://clinicaltrials.gov/ct2/show/NCT02948088?term=NCT02948088&draw=2.Sponsored by Daiichi Sankyo, Co., Ltd; ClinicalTrials.gov Number NCT02948088. The Department of Orthopaedics of the Leiden University Medical Center receives research funding from Daiichi Sankyo. All research funding for Memorial Sloan Kettering is supported in part by a grant from the National Institutes of Health/National Cancer Institute (#P30 CA008748).Peer reviewe

Evaluation of strategies for reducing the burden of COPD in the UK using Bayesian methods

Chronic obstructive pulmonary disease (COPD) is responsible for 5.3% of all deaths and 1.7% of all hospital admissions in the UK. This thesis focuses on strategies to reduce COPD burden by targeting three aspects across the public healthcare system: prevention, emergency treatment, and long-term management. Analyses were performed in a Bayesian framework to exploit its flexibility in modelling uncertainty and the incorporation of prior knowledge. First, I assessed whether communication of personalised disease risk in primary care is an effective smoking cessation intervention, using cost-effectiveness and value of information analyses based on various data sources across the literature. The odds ratio for the effectiveness of communication of personalised disease risk was 1.48 (95%CrI:0.91-2.26). While I found a probability of cost-effectiveness of about 90%, further research up to a maximum of £27 million is justified to reduce the uncertainty around this estimate. Secondly, I assessed whether case ascertainment affects the detection of poorly performing hospital trusts in the treatment of acute exacerbation of COPD (AECOPD) in secondary care, using data from the National Asthma and COPD Audit Programme. Case ascertainment was associated with 30-day mortality (OR:1.74; 1.25-2.41) and adjusting for it impacted the findings, with 5 trusts becoming outliers and 2 trusts no longer classified as outliers. Finally, using general practice data from Clinical Practice Research Datalink, I assessed whether new guidelines suggesting triple therapy (long-acting beta-2 agonists, LABA + long-acting muscarinic antagonists, LAMA + inhaled corticosteroids, ICS) for the treatment of those with poorly-controlled COPD on LABA+LAMA dual therapy improves disease outcomes. Triple therapy was not associated with severe AECOPD (IRR:1.00; 0.93-1.07) or mortality (IRR:0.95; 0.86-1.06), but was associated with increased risk of pneumonia (IRR:1.19; 1.05-1.35). This thesis applied sophisticated Bayesian methods to increase understanding of how COPD burden could be reduced in different areas of the public healthcare system.Open Acces

Incorporating the patient voice in sarcoma research: How can we assess health-related quality of life in this heterogeneous group of patients? a study protocol

Sarcomas comprise 1% of adult tumors and are very heterogeneous. Long-lasting and cumulative treatment side-effects detract from the (progression-free) survival benefit of treatment. Therefore, it is important to assess treatment effectiveness in terms of patient-reported outcomes (PROs), including health-related quality of life (HRQoL) as well. However, questionnaires capturing the unique issues of sarcoma patients are currently lacking. Given the heterogeneity of the disease, the development of such an instrument may be challenging. The study aims to (1) develop an exhaustive list of all HRQoL issues relevant to sarcoma patients and determine content validity; (2) determine a strategy for HRQoL measurement in sarcoma patients. We will conduct an international, multicenter, mixed-methods study (registered at clinicaltrials.gov: NCT04071704) among bone or soft tissue sarcoma patients ≥18 years, using EORTC Quality of Life Group questionnaire development guidelines. First, an exhaustive list of HRQoL issues will be generated, derived from literature and patient (n = 154) and healthcare professional (HCP) interviews (n = 30). Subsequently, another group of sarcoma patients (n = 475) and HCPs (n = 30) will be asked to rate and prioritize the issues. Responses will be analyzed by priority, prevalence and range of responses for each item. The outcome will be a framework for tailored HRQoL measurement in sarcoma patients, taking into account sociodemographic and clinical variables