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Rare cancers are defined by an incidence of less than six per 100 000 people per year. They represent roughly 20% of all human cancers and are associated with worse survival than are so-called frequent tumours, because of delays to accurate diagnosis, inadequate treatments, and fewer opportunities to participate in clinical trials (because of a paucity of dedicated trials from both academic and industrial sponsors). In this Series paper, we discuss how these challenges can be addressed by research consortia and suggest the integration of these consortia with reference networks, which gather multidisciplinary expert centres, for management of rare tumours.

Background: Missing covariates are common in observational research and can lead to bias and loss of statistical power. Limited data regarding prognostic factors of survival outcomes of sarcomas in irradiated fields (SIF) are available. Because of the long lag time between irradiation of first cancer and scarcity of SIF, missing data are a critical issue when analyzing long-term outcomes. We assessed prognostic factors of overall (OS), progression-free (PFS), and metastatic-progression-free (MPFS) survivals in SIF using three methods to account for missing covariates. Methods: We relied on the NETSARC French Sarcoma Group database, Cox (OS/PFS), and competitive hazards (MPFS) survival models. Covariates investigated were age, sex, histological subtype, tumor size, depth and grade, metastasis, surgery, surgical resection, surgeon’s expertise, imaging, and neo-adjuvant treatment. We first applied multiple imputation (MI): observed data were used to estimate the missing covariate. With the missing-data modality approach, a category missing was created for qualitative variables. With the complete-case (CC) approach, analysis was restricted to patients without missing covariates. Results: CC subjects (N = 167; 33%) presented more often with soft-tissue sarcoma (versus visceral sarcoma) and grade I–II tumors as compared to the 504 eligible cases. With MI (N = 504), factors associated with the worst outcome included metastasis (p = 0.04) and R1/R2 resection (p < 0.001) for OS; higher grade/non-gradable tumors (p = 0.002) and R1/R2 resection (p < 0.001) for PFS; and metastasis (p = 0.01) for M-PFS. The ‘missing-data modality’ approach (N = 504) led to different associations, including significance reached due to variables with the modality ‘missing’. The CC analysis led to different results and reduced precision. Conclusion: The CC population was not representative of the eligible population, introducing bias, in addition to worst precision. The ‘missing-data modality method’ results in biased estimates in non-randomized studies, as outcomes may be related to variables with missing values. Appropriate statistical methods for missing covariates, for example, MI, should therefore be considered.

ObjectivesWhile some metals have been reported as carcinogens or potential carcinogens, only few modern-standard datasets including a large number of elements are available. The present analysis established a first trace elements spectrum by relating the concentration of metals and trace elements in the serum of sarcoma patients with survival data.MethodsPatients with sarcoma and controls were retrospectively selected from the International Sarcoma Kindred Study database (ISKS). As part of the ISKS study, blood samples were prospectively collected at the Leon Bérard Cancer Center from February 2012 to July 2019. Stable specimens and copper isotopes (65Cu/63Cu) were analyzed using Triple Quadrupole Inductively Coupled Plasma Mass Spectrometer (ICP-MS) and the Multicollector MC-ICP-MS Nu Plasma HR 500. Wilcoxon rank sum test, log-rank test, and multivariate Cox regression models were used for statistics.ResultsIn total, 151 patients and 59 healthy controls were included. At the time of blood sample collection, 62% of patients had locally advanced or metastatic disease. Copper (Cu), copper/zinc (Cu/Zn) and potassium/rubidium (K/Rb) ratio were significantly higher in patients compared to controls and were also significantly higher in patients with advanced compared to early-stage sarcoma. Whereas S and Se were significantly correlated in patients, no correlation was observed in controls. Importantly, levels of K, Rb, Se, Fe, P, Si, S, δ65Cu, Cu, S/Se and Cu/Zn ratio were independently associated with overall survival.ConclusionsThese results depict the metallomic spectrum in sarcoma and highlight substantial variation associated with survival, enhancing our understanding of sarcoma’s biology.

Background Although the management of sarcoma is improving, non adherence to clinical practice guidelines (CPGs) remains high, mainly because of the low incidence of the disease and the variety of histological subtypes. Since little is known about the health economics of sarcoma, we undertook a cost-effectiveness analysis (within the CONnective TIssue CAncer NETwork, CONTICANET) comparing costs and outcomes when clinicians adhered to CPGs and when they did not. Methods Patients studied had a histological diagnosis of sarcoma, were older than 15 years, and had been treated in the Rhône-Alpes region of France (in 2005/2006) or in the Veneto region of Italy (in 2007). Data collected retrospectively for the three years after diagnosis were used to determine relapse free survival and health costs (adopting the hospital's perspective and a microcosting approach). All costs were expressed in euros (€) at their 2009 value. A 4% annual discount rate was applied to both costs and effects. The incremental cost-effectiveness ratio (ICER) was expressed as cost per relapse-free year gained when management was compliant with CPGs compared with when it was not. To capture uncertainty surrounding ICER, a probabilistic sensitivity analysis was performed based on a non-parametric bootstrap method. Results A total of 219 patients were included in the study. Compliance with CPGs was observed for 118 patients (54%). Average total costs reached 23,571 euros when treatment was in accordance with CPGs and 27,313 euros when it was not. In relation to relapse-free survival, compliance with CPGs strictly dominates non compliance, i.e. it is both less costly and more effective. Taking uncertainty into account, the probability that compliance with CPGs still strictly dominates was 75%. Conclusions Our findings should encourage physicians to increase their compliance with CPGs and healthcare administrators to invest in the implementation of CPGs in the management of sarcoma.

Rare cancer patients face lower survival and experience delays in diagnosis and therapeutic mismanagement. Considering the specificities of rare cancers, referral networks have been implemented in France to improve the management and survival of patients. The IGéAS research program aims to assess the networks’ ability to reduce inequalities. Data analysis of the IGéAS cohort (n = 20,590, sarcoma diagnosed between 2011 and 2014) by gathering medical data and geographical index will identify risk factors associated with the belated access to expertise or with no access to expertise. Intermediate results show that referral networks give sarcoma patients access to sarcoma expertise despite the remoteness of some of them. Regional expert centers mostly receive requests from within their area while national referral centers receive requests from the whole country. Delays in the access to expertise may be reduced by making outside practitioners more sensitive to the issues of rare cancers. The perception and involvement of outside practitioners in this device will be assessed using a qualitative survey. All the results are discussed and will contribute to design guidelines to improve early access to expertise and reduce inequalities. Results of the IGéAS research program may contribute to the assessment of referral sarcoma networks and provide some useful lessons to improve cancer care management.

Background Spatial inequalities in health result from different exposures to health risk factors according to the features of geographical contexts, in terms of physical environment, social deprivation, and health care accessibility. Using a common geographical referential, which combines indices measuring these contextual features, could improve the comparability of studies and the understanding of the spatial dimension of health inequalities. Methods We developed the Geographical Classification for Health studies (GeoClasH) to distinguish French municipalities according to their ability to influence health outcomes. Ten contextual scores measuring physical and social environment as well as spatial accessibility of health care have been computed and combined to classify French municipalities through a K-means clustering. Age-standardized mortality rates according to the clusters of this classification have been calculated to assess its effectiveness. Results Significant lower mortality rates compared to the mainland France population were found in the Wealthy Metropolitan Areas (SMR = 0.868, 95% CI 0.863–0.873) and in the Residential Outskirts (SMR = 0.971, 95% CI 0.964–0.978), while significant excess mortality were found for Precarious Population Districts (SMR = 1.037, 95% CI 1.035–1.039), Agricultural and Industrial Plains (SMR = 1.066, 95% CI 1.063–1.070) and Rural Margins (SMR = 1.042, 95% CI 1.037–1.047). Conclusions Our results evidence the comprehensive contribution of the geographical context in the constitution of health inequalities. To our knowledge, GeoClasH is the first nationwide classification that combines social, environmental and health care access scores at the municipality scale. It can therefore be used as a proxy to assess the geographical context of the individuals in public health studies.

Background Sarcomas are rare malignant tumors. Accurate initial histological diagnosis is essential for adequate management. We prospectively assessed the medical management of all patients diagnosed with sarcoma in a European region over a one-year period to identify the quantity of first diagnosis compared to central expert review (CER). Methods Histological data of all patients diagnosed with sarcoma in Rhone-Alpes between March 2005 and Feb 2006 were collected. Primary diagnoses were systematically compared with second opinion from regional and national experts. Results Of 448 patients included, 366 (82%) matched the inclusion criteria and were analyzed. Of these, 199 (54%) had full concordance between primary diagnosis and second opinion (the first pathologist and the expert reached identical conclusions), 97 (27%) had partial concordance (identical diagnosis of conjonctive tumor but different grade or subtype), and 70 (19%) had complete discordance (different histological type or invalidation of the diagnosis of sarcoma). The major discrepancies were related to histological grade (n = 68, 19%), histological type (n = 39, 11%), subtype (n = 17, 5%), and grade plus subtype or grade plus histological type (n = 43, 12%). Conclusions Over 45% of first histological diagnoses were modified at second reading, possibly resulting in different treatment decisions. Systematic second expert opinion improves the quality of diagnosis and possibly the management of patients.

Background: The coronavirus disease 2019 (COVID-19) pandemic was an unprecedented shock to the healthcare systems, and its consequences on managing rare cancers are unknown. We investigated COVID-19’s impact on the activity of sarcoma-labeled networks by comparing key indicators in 2019–2020 (before and during the pandemic, respectively). Methods: We compared the incidence of limb and trunk soft tissue sarcomas, surgery rate, surgery center, surgery quality, and surgery delays nationally and in various regions, focusing on the three most severely affected regions. Findings: In this study, sarcoma incidence did not decrease, and the tumor and patient characteristics were similar in both years. The number of patients who underwent surgery in the labeled centers increased significantly (63% versus 57%, p = 0.015), the rate of R0 resection increased (55% versus 47%, p = 0.004), and the rate of re-excision decreased (12% versus 21%, p < 0.0001). In the univariate analysis, the time to surgery was similar in both years. Cox regression analysis revealed that the factors associated with a longer time to surgery were age > 70 years (p = 0.003), retroperitoneal location (p > 0.001), tumor size (p < 0.001), deep tumors (p < 0.001), and regions (p < 0.001). However, we have observed an increase in the time before surgery in the regions most stroked by the COVID-19 pandemic. Interpretation: The model of the labeled center network for managing rare tumors was resilient. Paradoxically, the quality indicators improved during the pandemic due to the direct referral of patients with sarcomas to the labeled centers. Summary: This study shows that a nationwide network organization has made it possible to maintain care for these rare tumors during the pandemic.

The exact overall incidence of sarcoma and sarcoma subtypes is not known. The objective of the present population-based study was to determine this incidence in a European region (Rhone-Alpes) of six million inhabitants, based on a central pathological review of the cases. From March 2005 to February 2007, pathology reports and tumor blocks were prospectively collected from the 158 pathologists of the Rhone-Alpes region. All diagnosed or suspected cases of sarcoma were collected, reviewed centrally, examined for molecular alterations and classified according to the 2002 World Health Organization classification. Of the 1287 patients screened during the study period, 748 met the criteria for inclusion in the study. The overall crude and world age-standardized incidence rates were respectively 6.2 and 4.8 per 100,000/year. Incidence rates for soft tissue, visceral and bone sarcomas were respectively 3.6, 2.0 and 0.6 per 100,000. The most frequent histological subtypes were gastrointestinal stromal tumor (18%; 1.1/100,000), unclassified sarcoma (16%; 1/100,000), liposarcoma (15%; 0.9/100,000) and leiomyosarcoma (11%; 0.7/100,000). The observed incidence of sarcomas was higher than expected. This study is the first detailed investigation of the crude incidence of histological and molecular subtypes of sarcomas.

Digital Epidemiology and E-Health Research Hub, Department of Population Health, Luxembourg Institute of Health, Strassen, Luxembourg Guy Fagherazzi 7. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Beyond the map: evidencing the spatial dimension of health inequalities [RAW_REF_TEXT] Yohan Fayet ORCID: orcid.org/0000-0002-5664-46361,2 , Delphine Praud3,4 , Béatrice Fervers3,4 , Isabelle Ray-Coquard1,2 , Jean-Yves Blay5 , Françoise Ducimetiere1 , Guy Fagherazzi6,7 & Elodie Faure7,8 [/RAW_REF_TEXT] International Journal of Health Geographics volume 20, Article number: 1 (2021) Cite this article [RAW_REF_TEXT] 137 Accesses Metrics details The original article was published in International Journal of Health Geographics 2020 19:46