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      Post-radiation sarcoma: A study by the Eastern Asian Musculoskeletal Oncology Group

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          Abstract

          The oncologic risk of ionizing radiation is widely known. Sarcomas developing after radiotherapy have been reported, and they are a growing problem because rapid advancements in cancer management and screening have increased the number of long-term survivors. Although many patients have undergone radiation treatment in Asian countries, scarce reports on post-radiation sarcomas (PRSs) have been published. We investigated the feature and prognostic factors of PRSs in an Asian population. The Eastern Asian Musculoskeletal Oncology Group participated in this project. Cases obtained from 10 centers were retrospectively reviewed. Patients with genetic malignancy predisposition syndrome, or who had more than one type of malignancy before the development of secondary sarcoma were excluded. Forty-two high-grade sarcomas among a total of 43 PRSs were analyzed. There were 29 females and 13 males, with a median age of 58.5 years; 23 patients had bone tumors and 19 had soft tissue tumors. The most common primary lesion was breast cancer. The median latency period was 192 months. There were no differences in radiation dose, latency time, and survival rates between bone and soft tissue PRSs. The most common site and diagnosis were the pelvic area and osteosarcoma and malignant fibrous histiocytoma for bone and soft tissue PRSs. The median follow-up period was 25.5 months. Five-year metastasis-free and overall survival rates were 14.5% and 16.6%, and 39.1% and 49.6% for bone and soft tissue PRSs. Survival differences depending on initial metastasis and surgery were significant in soft tissue sarcomas. Although this study failed to find ethnic differences, it is the largest review on PRS in an Asian population. As early recognition through long-term surveillance is a key to optimal management, clinicians should take efforts to understand the real status of PRS.

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          Can we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review.

          Second primary malignancies (SPMs) occurring after oncological treatment have become a major concern during the past decade. Their incidence has long been underestimated because most patients had a short life expectancy after treatment or their follow-up was shorter than 15 years. With major improvement of long-term survival, longer follow-up, cancer registries and end-result programs, it was found that the cumulative incidence of SPM could be as high as 20% of patients treated by radiotherapy. This cumulative proportion varies with several factors, which ought to be studied more accurately. The delay between irradiation and solid tumor emergence is seldom shorter than 10 years and can be as long as half a century. Thus, inclusion in a cohort of patients with a short follow-up leads to an underestimation of the proportion of SPM caused by treatment, unless actuarial cumulative incidence is computed. The incidence varies with the tissue and organs, the age of the patient at treatment, hereditary factors, but also, and probably mainly, with dose distribution, size of the irradiated volume, dose, and dose-rate. An effort toward a reduction in their incidence is mandatory. Preliminary data suggest that SPMs are mainly observed in tissues having absorbed doses above 2 Gy (fractionated irradiation) and that their incidence increases with the dose. However, in children thyroid and breast cancers are observed following doses as low as 100 mGy, and in adults lung cancers have been reported for doses of 500 mGy, possibly due to interaction with tobacco. The dose distribution and the dose per fraction have a major impact. However, the preliminary data regarding these factors need confirmation. Dose-rates appear to be another important factor. Some data suggest that certain patients, who could be identified, have a high susceptibility to radiocancer induction. Efforts should be made to base SPM reduction on solid data and not on speculation or models built on debatable hypotheses regarding the dose-carcinogenic effect relationship. In parallel, radiation therapy philosophy must evolve, and the aim of treatment should be to deliver the minimal effective radiation therapy rather than the maximal tolerable dose.
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            Cancer risks after radiation exposure in middle age.

            Epidemiological data show that radiation exposure during childhood is associated with larger cancer risks compared with exposure at older ages. For exposures in adulthood, however, the relative risks of radiation-induced cancer in Japanese atomic bomb survivors generally do not decrease monotonically with increasing age of adult exposure. These observations are inconsistent with most standard models of radiation-induced cancer, which predict that relative risks decrease monotonically with increasing age at exposure, at all ages. We analyzed observed cancer risk patterns as a function of age at exposure in Japanese atomic bomb survivors by using a biologically based quantitative model of radiation carcinogenesis that incorporates both radiation induction of premalignant cells (initiation) and radiation-induced promotion of premalignant damage. This approach emphasizes the kinetics of radiation-induced initiation and promotion, and tracks the yields of premalignant cells before, during, shortly after, and long after radiation exposure. Radiation risks after exposure in younger individuals are dominated by initiation processes, whereas radiation risks after exposure at later ages are more influenced by promotion of preexisting premalignant cells. Thus, the cancer site-dependent balance between initiation and promotion determines the dependence of cancer risk on age at radiation exposure. For example, in terms of radiation induction of premalignant cells, a quantitative measure of the relative contribution of initiation vs promotion is 10-fold larger for breast cancer than for lung cancer. Reflecting this difference, radiation-induced breast cancer risks decrease with age at exposure at all ages, whereas radiation-induced lung cancer risks do not. For radiation exposure in middle age, most radiation-induced cancer risks do not, as often assumed, decrease with increasing age at exposure. This observation suggests that promotional processes in radiation carcinogenesis become increasingly important as the age at exposure increases. Radiation-induced cancer risks after exposure in middle age may be up to twice as high as previously estimated, which could have implications for occupational exposure and radiological imaging.
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              Long-term results with resection of radiation-induced soft tissue sarcomas.

              Radiation therapy is increasingly used as adjuvant treatment of many childhood and adult malignancies. Radiation-induced sarcoma is a well recognized if uncommon event. The objective of this study is to determine the prevalence and long-term outcome for patients who develop radiation-induced sarcomas. From July 1982 to December 2001, 4884 adult patients with sarcoma were admitted and treated at our institution and recorded in a prospective database. There were 123 (2.5%) patients who had radiation-induced soft tissue sarcomas. Survival was determined by Kaplan-Meier analysis. Patient, tumor, and treatment characteristics were tested for their prognostic significance by log rank and the Cox proportional hazards model. The median interval between radiation and development of sarcoma was 103 (6 to 534) months. In 114 patients with radiation-induced sarcoma who underwent curative resection, the 5-year actuarial survival was 41%, with a median survival of 48 months at a median follow-up of 36 months for survivors. The most common malignancy for which radiation was used was breast cancer (29%), followed by lymphoma (16%) and prostate cancer (15%). Malignant fibrous histiocytoma (23%) was the most common histologic diagnosis, followed by fibrosarcoma (15%) and angiosarcoma (15%). High-grade tumors (n = 85; 79%), age > 60 years (n = 61; 50%), and gross positive resection margin (n = 36; 32%) were predictive of poor sarcoma-specific survival on univariate and multivariate analysis. The increasing utilization of adjuvant radiation therapy, especially for early-stage breast cancer mandates long-term follow-up to detect radiation-induced sarcoma. Surgical resection remains the primary therapy, but 5-year survival remains approximately 40%.
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                Author and article information

                Contributors
                Role: Data curationRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: ConceptualizationRole: InvestigationRole: Project administration
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 October 2018
                2018
                : 13
                : 10
                : e0204927
                Affiliations
                [1 ] Department of Orthopaedic Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Banpo 4-dong, Seocho-gu, Seoul, Republic of Korea
                [2 ] Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan
                [3 ] Orthopaedic Oncology Service, National Cancer Center, Goyang, Republic of Korea
                [4 ] Daegu Top Hospital, Daegu, Republic of Korea
                [5 ] Department of Orthopedic Oncology Surgery, Beijing Ji Shui Tan Hospital, Beijing, Xicheng District, China
                [6 ] Department of Musculoskeletal Oncology, HCG Bangalore Institute of Oncology, Bangalore, India
                [7 ] Department of Orthopaedic Surgery, Seoul National University Hospital, aehak-ro, Jongno-gu, Seoul, Republic of Korea
                [8 ] Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro, Gangnam-Gu, Seoul, Republic of Korea
                [9 ] Department of Orthopaedic Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Republic of Korea
                Kanazawa University, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-2024-514X
                http://orcid.org/0000-0001-8153-8205
                Article
                PONE-D-18-03746
                10.1371/journal.pone.0204927
                6192585
                30332455
                625329af-4863-44ce-95dc-8b0eda811f4c
                © 2018 Joo et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 February 2018
                : 17 September 2018
                Page count
                Figures: 3, Tables: 3, Pages: 14
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Sarcomas
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Radiation Therapy
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Oncology
                Radiation Therapy
                Medicine and Health Sciences
                Oncology
                Clinical Oncology
                Radiation Therapy
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Soft Tissues
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Soft Tissues
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Lesions
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Lesions
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Surgical Oncology
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Oncology
                Surgical Oncology
                Medicine and Health Sciences
                Oncology
                Clinical Oncology
                Surgical Oncology
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Medicine and Health Sciences
                Diagnostic Medicine
                Cancer Detection and Diagnosis
                Medicine and Health Sciences
                Oncology
                Cancer Detection and Diagnosis
                Medicine and Health Sciences
                Oncology
                Metastasis
                Medicine and Health Sciences
                Oncology
                Basic Cancer Research
                Metastasis
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                All relevant data are within the paper and its Supporting Information files.

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