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      Risk of second primary malignancies among patients with prostate cancer: A population-based cohort study

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          Abstract

          Purpose

          The rising incidence and life expectancy associated with prostate cancer (PCa) has led to increasing interest in predicting the risk of second primary malignancies (SPMs) among PCa survivors, although data regarding SPMs after PCa are controversial.

          Methods

          We identified 30,964 patients from the National Health Insurance Research Database in Taiwan who had newly diagnosed PCa between 2000 and 2010. Each patient was randomly frequency-matched with an individual without PCa, based on age, comorbidity, and index year. Competing-risks regression models were used to estimate subhazard ratios (SHRs) of SPMs development associated with PCa. The Bonferroni adjustment was used in multiple comparisons.

          Results

          Men with PCa had a trend of lower risk of developing overall SPMs compared to those without PCa (adjusted SHR = 0.94, 99.72% confidence interval [CI] = 0.89–1.00, p = 0.06). The risks of lung and liver cancer were significantly lower. In contrast, these patients had a significantly higher risk of thyroid cancer. There is a trend for a higher risk of developing SPMs in the urinary bladder and rectum/anus. Further analyses indicated that PCa patients who received radiation therapy (RT) had an increased risk of overall SPMs, hematologic malignancies, esophageal cancer, liver cancer, lung cancer, and urinary bladder cancer compared with those who did not receive RT.

          Conclusion

          Men with PCa tended to have a lower risk of SPMs, but a significantly higher risk of subsequent thyroid cancer. Continued cancer surveillance is required among PCa survivors, especially in specific sites and in individuals who received RT.

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          Most cited references24

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          Changing demography of prostate cancer in Asia.

          There has been a recent trend in Asia towards increasing incidence of prostate cancer, with some low-risk regions, such as Japan and Singapore, reporting a more rapid increase than high-risk countries. In this study, age-specific and age-standardised (world) incidence rates and mortality rates for prostate cancer in Asian countries for 1978-1997 were retrieved and compared. The results confirm that the incidence of prostate cancer has risen by 5-118% in the indexed Asian countries. Incidence at centres in Japan rose as much as 102% (Miyagi 6.3-12.7 per 100,000 person-years) whilst the incidence in Singaporean Chinese increased 118% from 6.6 to 14.4 per 100,000 person-years. The lowest incidence rate recorded was in Shanghai, China and the highest rates were in Rizal Province in the Philippines, although still much lower than those in the United States of America (USA) and many European countries. Whilst the absolute value of the increase is not comparable to North American and European populations, the incidence ratio in many Asian centres is similar to that of the high-risk countries. The mortality data for prostate cancer showed a similar rising trend. The increases in age-adjusted mortality rates per 100,000 person-years, adjusted to the world standard, ranged from 50% in Thailand to 260% in Korea. The difference may be partly due to genetic polymorphism in the androgen receptor and androgen metabolism pathway enzymes as well as to dietary or environmental factors. In particular, phytochemicals, such as isoflavonoids and tea polyphenols, which are common in Asian diets showed promising anti-mitotic activity in animal and clinical studies. In conclusion, with gradual Westernisation, many Asian countries may be losing their cultural protective factors and acquiring high-risk ones. A better understanding of how these factors interact to cause prostate cancer through further studies with a multi-ethnic perspective will facilitate appropriate public health strategies to minimise high-risk factors and maintain protective factors and keep prostate cancer at bay.
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            Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis

            Objective To determine the association between exposure to radiotherapy for the treatment of prostate cancer and subsequent second malignancies (second primary cancers). Design Systematic review and meta-analysis of observational studies. Data sources Medline and Embase up to 6 April 2015 with no restrictions on year or language. Study selection Comparative studies assessing the risk of second malignancies in patients exposed or unexposed to radiotherapy in the course of treatment for prostate cancer were selected by two reviewers independently with any disagreement resolved by consensus. Data extraction and synthesis Two reviewers independently extracted study characteristics and outcomes. Risk of bias was assessed with the Newcastle-Ottawa scale. Outcomes were synthesized with random effects models and Mantel-Haenszel weighting. Unadjusted odds ratios and multivariable adjusted hazard ratios, when available, were pooled. Main outcome measures Second cancers of the bladder, colorectal tract, rectum, lung, and hematologic system. Results Of 3056 references retrieved, 21 studies were selected for analysis. Most included studies were large multi-institutional reports but had moderate risk of bias. The most common type of radiotherapy was external beam; 13 studies used patients treated with surgery as controls and eight used patients who did not undergo radiotherapy as controls. The length of follow-up among studies varied. There was increased risk of cancers of the bladder (four studies; adjusted hazard ratio 1.67, 95% confidence interval 1.55 to 1.80), colorectum (three studies; 1.79, 1.34 to 2.38), and rectum (three studies; 1.79, 1.34 to 2.38), but not cancers of the hematologic system (one study; 1.64, 0.90 to 2.99) or lung (two studies; 1.45, 0.70 to 3.01), after radiotherapy compared with the risk in those unexposed to radiotherapy. The odds of a second cancer varied depending on type of radiotherapy: treatment with external beam radiotherapy was consistently associated with increased odds while brachytherapy was not. Among the patients who underwent radiotherapy, from individual studies, the highest absolute rates reported for bladder, colorectal, and rectal cancers were 3.8%, 4.2%, and 1.2%, respectively, while the lowest reported rates were 0.1%, 0.3%, and 0.3%. Conclusion Radiotherapy for prostate cancer was associated with higher risks of developing second malignancies of the bladder, colon, and rectum compared with patients unexposed to radiotherapy, but the reported absolute rates were low. Further studies with longer follow-up are required to confirm these findings.
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              Risk of second primary tumors in men diagnosed with prostate cancer: a population-based cohort study.

              The survival of men diagnosed with prostate cancer has improved over time, and the current 10-year relative survival rate is 99.7%. The long survival of patients with this common cancer raises questions about the risk of a second primary cancer and the need for continued surveillance.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 April 2017
                2017
                : 12
                : 4
                : e0175217
                Affiliations
                [1 ]Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
                [2 ]Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
                [3 ]College of Medicine, China Medical University, Taichung, Taiwan
                [4 ]Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
                [5 ]Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
                [6 ]Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
                Thomas Jefferson University, UNITED STATES
                Author notes

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

                • Conceptualization: C-YF C-HK.

                • Data curation: C-YF W-YH C-SL Y-FS C-HL C-CT M-YL C-LL C-HK.

                • Formal analysis: C-YF W-YH C-SL Y-FS C-HL C-CT M-YL C-LL C-HK.

                • Funding acquisition: C-HK.

                • Investigation: C-YF C-HK.

                • Methodology: C-LL C-HK.

                • Project administration: C-HK.

                • Resources: C-YF C-HK.

                • Software: C-LL C-HK.

                • Supervision: C-HK.

                • Validation: C-YF W-YH C-SL Y-FS C-HL C-CT M-YL C-LL C-HK.

                • Visualization: C-YF W-YH C-SL Y-FS C-HL C-CT M-YL C-LL C-HK.

                • Writing – original draft: C-YF W-YH C-SL Y-FS C-HL C-CT M-YL C-LL C-HK.

                • Writing – review & editing: C-YF W-YH C-SL Y-FS C-HL C-CT M-YL C-LL C-HK.

                Author information
                http://orcid.org/0000-0002-6368-3676
                Article
                PONE-D-16-38745
                10.1371/journal.pone.0175217
                5383246
                28384363
                d3639904-2697-4cd1-b703-30ed7bb6c63b
                © 2017 Fan 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
                : 6 October 2016
                : 16 March 2017
                Page count
                Figures: 0, Tables: 4, Pages: 11
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100008903, Ministry of Health and Welfare;
                Award ID: MOHW106-TDU-B-212-113004
                Award Recipient :
                This study is supported in part by study project of Tri-service General Hospital (TSGH-C106-038); Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-133019); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM10501010037); NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039 -005); Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and Health, and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW104-TDU-B-212-124-002, Taiwan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
                Categories
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                Oncology
                Cancers and Neoplasms
                Genitourinary Tract Tumors
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