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Background: Knowledge on periprosthetic infection and mortality rate following total knee arthroplasty (TKA) is essential for justifying this treatment in patients with cancer; however, relevant data from population-based studies are lacking. Therefore, we examined 1-year periprosthetic infection, mortality, and 5-year relative survival rates in cancer patients who underwent TKA. Methods: This is a population-based cohort study based on analysis of the Taiwan National Health Insurance Research Database. We enrolled a total of 2294 cancer patients and 131,849 patients without cancer (control group) who underwent TKA between January 1, 1997, and December 31, 2011. All patients were followed until death, infection, withdrawal from the National Health Insurance, or December 31, 2012. Results: The periprosthetic knee joint infection rate in cancer patients (1.73%) was not significantly higher than that in the control group (1.87%). However, the 1-year mortality rate was significantly higher (p <0.05) in the cancer group (4.10%) than in the control group (1.66%). The overall 5-year survival rate was 93.10% as compared with those without cancers. Conclusion: Low periprosthetic knee joint infection rates and high 5-year relative survival rates indicate the feasibility of TKA in cancer patients. However, the surgeon should take into account a higher mortality rate in the first year following TKA. Keywords: Total knee arthroplasty, Cancer survivors, Survival rate, revision rate Background treatment as well as in cancer prevention and screening The prevalence of cancer continues to increase because . There were more than 10 million cancer survivors in of the aging population, sedentary lifestyles, increased the United States in 2007 . obesity, and improved survival amongst cancer patients. The majority of the cancer survivors are elderly In 2011, the Health Promotion Administration Ministry people, who are generally affected by osteoarthritis (OA) of Health and Welfare in Taiwan reported that there , one of the most common disorders affecting the mus- were approximately 100,000 new cancer patients every culoskeletal system of this population, resulting in phys- year in this country, translating to an annual incidence ical deficiencies and poor quality of life [3, 4]. In severe of about 0.41% . The median age of patients diag- cases of OA [5, 6], total knee arthroplasty (TKA) is an nosed with cancer was 62 years . The survival rates effective treatment option for relieving knee pain and for some cancers have increased because of advances in restoring joint function. However, the operation of TKA in the elderly may lead to adverse effects that include longer hospital stay, higher incidences of surgical * Correspondence: firstname.lastname@example.org complications, and higher mortality rates [7–15]. School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan Hence, elderly cancer patients may find it difficult to Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kao et al. BMC Cancer (2018) 18:628 Page 2 of 9 Fig. 1 Study flow chart decide whether to undergo TKA and might be appre- approved by the institutional Review Board of E-Da hensive about spending the rest of their lives with a Hospital, Taiwan (EMRP-103-011; EMRP-103-012) and TKA prosthesis. the Taiwan NHRI (NHIRD-103-116). In this 10-year population-based retrospective study, we used the Taiwan National Health Insurance Research Definition of study groups and outcomes Database (NHIRD) to examine the one-year postopera- Patients diagnosed with cancer before receiving TKA be- tive surgical infection rate and survival rate in cancer pa- tween January 1, 1997, and December 31, 2011, were tients who underwent TKA. In addition, we used the identified from the NHIRD and included in the TKA demographic and medical data of these patients to group. Patients with musculoskeletal cancers were not evaluate the risk factors for mortality after TKA. enrolled. We also excluded those whose cancer was di- agnosed more than 5 years before undergoing TKA, be- Methods cause the cancer status might be considered as having Data source been cured in some of these patients. Their inclusion Through the National Health Insurance (NHI) program, would be inappropriate given that our analysis aimed to established in 1995, the Taiwan Department of Health inform the decision making on TKA surgery in cancer covers the health care of 22.9 million residents of patients, instead of those who had cured a cancer. Tak- Taiwan, which is > 99% of the total population. The ing into account that data in the NHIRD could not as- medical claims from 1997 to 2012 of these insurants are certain whether a cancer was cured, we restricted the encrypted and released for research by the Taiwan eligibility to emphasize our study population. The con- National Health Research Institutes as the NHIRD. trol group comprised patients without cancer who The Department of Health and the NHI Administra- underwent TKA. One-year postoperative infection rates tion Bureau of Taiwan ensure the completeness and and mortality rates in the two groups were evaluated accuracy of the NHIRD. and compared (Fig. 1). The one-year postoperative The study data were obtained from the NHIRD. All mortality rates was calculated from the analysis of patients included in the analysis were followed for out- survival rate of patients (with/without cancer) who come identification by using the International Classifica- underwent TKA. Periprosthetic joint infection was tion of Disease, Ninth Revision, Clinical Modification, defined as the occurrence of surgically treated codes until the end of 2012. Because the NHIRD con- osteomyelitis or septic arthritis in the vicinity of the tains encrypted and deidentified data, this study was joint implants. Surgical interventions included debride- exempted from a full ethics review. This study was ment, prosthesis removal, or resection arthroplasty Kao et al. BMC Cancer (2018) 18:628 Page 3 of 9 Table 1 Characteristics of the Study Subjects Non-cancer Cancer p- value N = 8784 N = 2196 Age 71.09 ± 7.19 71.4 ± 7.09 0.0739 Age Group 0.9160 20–39 9 (0.10) 2 (0.09) 40–59 593 (6.75) 140 (6.38) 60–79 7339 (83.55) 1847 (84.11) > =80 843 (9.60) 207 (9.43) Gender 1.0000 Female 6100 (69.44) 1525 (69.44) Male 2684 (30.56) 671 (30.56) CCI 0.8847 0 1457 (16.59) 355 (16.17) 1 2158 (24.57) 556 (25.32) 2 2105 (23.96) 520 (23.68) 2+ 3064 (34.88) 765 (34.84) Comorbidities Myocardial infarct 198 (2.25) 59 (2.69) 0.2304 congestive heart failure 980 (11.16) 254 (11.57) 0.5865 peripheral vascular 294 (3.35) 73 (3.32) 0.9577 cerebrovascular disease 1796 (20.45) 458 (20.86) 0.6706 dementia 231 (2.63) 63 (2.87) 0.5348 chronic lung disease 3497 (39.81) 869 (39.57) 0.8378 connective tissue disease 658 (7.49) 149 (6.79) 0.2569 Ulcer 4583 (52.17) 1134 (51.64) 0.6535 chronic liver disease 1407 (16.02) 339 (15.44) 0.5058 Diabetes 2455 (27.95) 617 (28.1) 0.8901 diabetes with end organ damage 367 (4.18) 102 (4.64) 0.3333 Hemiplegia 92 (1.05) 22 (1) 0.8506 moderate or severe kidney disease 642 (7.31) 178 (8.11) 0.2039 Moderate or severe liver disease –– AIDS –– Infection 164 (1.87) 38 (1.73) 0.6700 1-year Mortality 146 (1.66) 90 (4.10) <.0001 Chemotherapy 0 (0.00) 708 (32.24) Metastasis 0 (0.00) 7 (0.32) (Appendix). Conditions existing prior to TKA were Subcohorts were defined to evaluate the overall 5-year classified as comorbidities according to Charlson’s survival rate of cancer patients who underwent TKA. In score . Among the cancer patients, the number addition, the 1- and 5-year relative survival rates were with and without metastasis and those who had re- calculated [17, 18]. ceived chemotherapy at the time of TKA were also calculated (Appendix). All patients were followed until Statistical analysis death, withdrawal from the NHI program, or the end Pearson’s chi-square test and Fisher Yates continuity cor- of the study period (December 31, 2012). Figure 1 il- rection were used to compare categorical variables. Stu- lustrates the study flow chart. dent’s t test was used for continuous ones. Traditional Kao et al. BMC Cancer (2018) 18:628 Page 4 of 9 Fig. 2 Distribution of different types of cancer and periprosthetic knee joint infectio survival analysis only considers one event at a time (e.g., analysis using the Fine and Gray regression model to death or infection). Thus, certain events may be over- calculate subdistribution hazards, and p-values were deter- looked, and the resulting risk values may be overesti- mined using Gray’stest. P < 0.05 was considered signifi- mated. Therefore, these results should not be directly cant. All statistical tests and subdistribution hazard ratio interpreted and applied in clinical settings. Our study (sHR) calculations were performed using Statistical Ana- considered mortality and the competing risk survival lysis Software, Version 9.4 (SAS Institute, Cary, NC, USA). Table 2 Prediction for infection Crude Adjusted a a sHR (95%C.I.) p-value sHR (95%C.I.) p-value Cancer vs. Non-cancer 0.92 (0.64–1.32) 0.6374 0.91 (0.63–1.31) 0.6089 Comorbidities Myocardial infarct 1.58 (0.74–3.36) 0.2355 1.47 (0.68–3.18) 0.3334 congestive heart failure 1.18 (0.77–1.79) 0.4473 1.07 (0.70–1.64) 0.7466 peripheral vascular 1.42 (0.73–2.78) 0.3036 1.33 (0.68–2.63) 0.4084 cerebrovascular disease 1.22 (0.87–1.69) 0.2500 1.08 (0.76–1.53) 0.6857 dementia 1.79 (0.92–3.51) 0.0874 1.63 (0.82–3.24) 0.1631 chronic lung disease 1.17 (0.88–1.55) 0.2827 1.11 (0.82–1.50) 0.4975 connective tissue disease 1.06 (0.63–1.80) 0.8218 1.05 (0.62–1.78) 0.8579 Ulcer 1.10 (0.83–1.46) 0.5153 1.03 (0.77–1.38) 0.8437 chronic liver disease 1.09 (0.75–1.59) 0.6491 1.07 (0.73–1.57) 0.7438 Diabetes 1.14 (0.84–1.54) 0.4175 0.99 (0.71–1.40) 0.9698 diabetes with end organ damage 1.77 (1.03–3.06) 0.0401 1.67 (0.91–3.06) 0.1007 Hemiplegia 1.52 (0.48–4.80) 0.4733 1.28 (0.40–4.12) 0.6779 moderate or severe kidney disease 1.12 (0.67–1.87) 0.6631 1.07 (0.64–1.79) 0.7902 Moderate or severe liver disease –– AIDS .- – Chemotherapy 0.96 (0.54–1.72) 0.8913 0.99 (0.47–2.09) 0.9815 Metastasis 8.66 (1.24–60.50) 0.0296 10.13 (1.19–86.34) 0.0343 sHR : subdistribution hazard ratio Kao et al. BMC Cancer (2018) 18:628 Page 5 of 9 Results Table 3 Prediction for infection(only patients with Cancer) Baseline characteristics of the patients Adjusted A total of 2294 cancer patients who underwent TKA sHR (95%C.I.) p-value were identified and included in the TKA group, whereas Comorbidities the control group comprised 131,849 patients. Score Myocardial infarct – matching for gender and Charlson’s comorbidity index congestive heart failure 1.21 (0.45–3.26) 0.7122 yielded 2196 patients in the TKA group and 8784 in the peripheral vascular 1.58 (0.36–7.02) 0.5493 control group. Among these 10,980 patients, 3355 (30. cerebrovascular disease 1.65 (0.78–3.48) 0.1866 56%) were male and 7625 (69.44%) female, and 10,236 (93.22%) patients were older than 60 years. The baseline dementia 2.81 (0.80–9.85) 0.1060 characteristics and comorbidities of all patients are listed chronic lung disease 0.76 (0.37–1.56) 0.4507 in Table 1. Among the cancer patients, 7 (0.32%) cases connective tissue disease 1.80 (0.63–5.20) 0.2757 had metastatic diseases and 708 (32.34%) of them ever Ulcer 1.59 (0.81–3.12) 0.1759 received chemotherapy when TKA was performed. The chronic liver disease 1.12 (0.46–2.72) 0.7990 most common cancers were breast, colon, prostate, cer- Diabetes 0.78 (0.33–1.81) 0.5613 vical, and rectal cancers (Fig. 2). The subcohort groups comprised 1100 and 4400 patients with and without diabetes with end organ damage 1.87 (0.47–7.52) 0.3770 cancer, respectively. Hemiplegia 1.92 (0.24–15.21) 0.5363 moderate or severe kidney disease 0.94 (0.28–3.14) 0.9147 One-year infection rate of prosthetic joints Moderate or severe liver disease The number of patients with infected prosthetic joints AIDS 1 year after TKA were 38 (1.73%) and 164 (1.87%) in the Chemotherapy 1.02 (0.49–2.14) 0.9608 cancer and control groups, respectively (Table 1). A multivariate-adjusted model revealed no association be- Metastasis 11.10 (1.22–101.30) 0.0328 tween infection and cancer (Table 2). In the unadjusted sHR : subdistribution hazard ratio analysis, diabetes with end organ damage was associated with prosthetic joint infection (sHR, 1.77; 95% CI, 1. 03–3.06); however, this association was nonsignificant Table 4 Prediction for mortality in theFineand Gray regression model(Table 2). The Adjusted status of metastatic disease but not the use of chemo- sHR (95%C.I.) p-value therapy was associated with prosthetic joint infection Cancer vs. Non-cancer 2.46 (1.71–3.52) <.0001 (Table 2 and Table 3). Comorbidities Mortality rates in cancer patients after TKA Myocardial infarct 1.98 (0.98–3.99) 0.0557 The 1-year mortality rate after TKA was significantly congestive heart failure 1.56 (0.98–2.49) 0.0632 higher (p < 0.001) in the cancer group (90 patients; 4. peripheral vascular 0.53 (0.17–1.64) 0.2717 10%), (1-year cumulative incidence of 1.73%; 95% confi- cerebrovascular disease 0.83 (0.57–1.20) 0.3263 dence interval [CI], 1.26–2.37%) than in the control dementia 0.97 (0.40–2.34) 0.9477 group (146 patients; 1.66%), (1-year cumulative inci- dence of 1.71%; 95% CI, 1.46–2.0%) (Tables 1, 4 and chronic lung disease 1.26 (0.74–2.17) 0.3943 Fig. 3). The 1-year relative survival rate was 97.52%. connective tissue disease 1.23 (0.65–2.32) 0.5240 The Fine and Gray regression model did not show a Ulcer 1.31 (0.67–2.56) 0.4305 significant association between metastasis and postop- chronic liver disease 1.43 (0.32–6.48) 0.6403 erative mortality (Table 4). Diabetes 1.04 (0.67–1.63) 0.8608 In the 5-year follow-up, a significantly lower overall sur- diabetes with end organ damage 1.24 (0.55–2.79) 0.5993 vival rate was observed in cancer patients as compared with the controls (Fig. 4). The overall 5-year survival rate Hemiplegia 1.80 (0.52–6.24) 0.3566 was 89.36% in the cancer cohort and was relatively 93.10% moderate or severe kidney disease 1.84 (0.64–5.32) 0.2614 as compared with the non-cancer controls. Moderate or severe liver disease – AIDS – Discussion Metastasis 1.17 (0.68–2.01) 0.5754 Infection is common in patients with cancer , be- cause several risk factors—such as neutropenia , cellular immune dysfunctions (e.g., defects in T- sHR : subdistribution hazard ratio Kao et al. BMC Cancer (2018) 18:628 Page 6 of 9 Fig. 3 1-year mortality rate after total knee arthroplasties lymphocytes and mononuclear phagocytes), humoral im- the 1-year periprosthetic infection rate of 1.73% in can- mune dysfunction, bone marrow and stem cell trans- cer patients is not significantly higher than that (1.87%) plantation, local factors (e.g., tumor metastasis and in non-cancer patients. The result showed that the use operative procedures), use of central venous catheters, of chemotherapy did not increase the risk of infection. splenectomy, and use of chemotherapeutic agents , Although this study does not provide information on lower their resistance to infections . Gram-positive prophylactic strategies for periprosthetic knee joint in- organisms cause approximately 50%–55% of all infec- fections, our results suggest that the currently used tious diseases in cancer patients with neutropenia, and prophylactic methods are effective for cancer patients Staphylococci are the most common organisms isolated who have undergone TKA. Nevertheless, orthopedicians from neutropenic and nonneutropenic cancer patients must pay attention to the immunocompromised condi- . Although no studies have reported periprosthetic tions especially in neutropenic status caused by chemo- infection rates in cancer patients after TKA, some stud- therapy in cancer patients receiving TKA in order to ies have reported an increase in deep infection rates of prevent periprosthetic knee joint infections. up to 9.1% after TKA in immunocompromised patients A decrease in the long-term survival rate of patients such as patients with AIDS . receiving TKA most likely reflects the natural process of Under these detrimental defence circumstances, one aging . However, a higher mortality rate than usual is can reasonably suspect higher infection rates in cancer expected when cancer patients receive TKA, possibly be- patients after TKA. However, this study revealed that cause of a trend similar to that in the United States, Kao et al. BMC Cancer (2018) 18:628 Page 7 of 9 Fig. 4 5-years overall survival rate of cancer patients after total knee arthroplasties where cancer is the leading cause of death in people small in our study. We are unable to investigate the real aged less than 85 years . The post-TKA 1-year mor- effect of metastatic diseases on the mortality rate. Never- tality rate (4.10%) was significantly higher in cancer pa- theless, rather than create a spurious association, such a tients in the present study. But metastasis diseases are stringent inclusion criteria would bias the results toward not associated with mortality in our study. We think that a null association. Finally, the effect of unaccounted con- this phenomenon is caused by lower desire of received founders cannot be ruled out; for example, we could not TKA in cancer patients with metastatic disease. Never- examine the potential influence of body weight, cigarette theless, because of advances in the control, prevention, smoking, alcohol drinking, and dietary habits because early detection, and treatment of cancer since 1990 this information is unavailable in the NHIRD. More- [27, 28], cancer-related death rates have decreased. over, because the data is deidentified, we could not Cancer mortality rates have declined by approximately collect this information from the patients directly. 1% annually and by more than 25% in the last The merits of this study are that the NHIRD is repre- 25 years . The 5-year relative survival rate was 93. sentative of all residents of Taiwan and that there was 10% in the present study; the majority of the patients no loss to follow-up. had ample time to experience the benefits of TKA, including functional improvement of the knee, knee Conclusion joint pain relief, and improved quality of life. In conclusion, after TKA, similar 1-year periprosthetic Our study has some limitations that should be ad- infection rates but differing 1-year mortality rates were dressed. First, the severity of the comorbidities could not observed in patients with and without cancer. The high be determined from the NHIRD. Second, data on cancer 5-year relative survival rates in cancer patients who staging was unavailable, which might induce a healthy underwent TKA indicate that TKA is a feasible treat- patient bias. The numbers of metastatic diseases were ment option for cancer patients with severe OA. Kao et al. BMC Cancer (2018) 18:628 Page 8 of 9 Appendix interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, the Department of Health, or the NHRI. Table 5 ICD-9-CM codes and the corresponding diseases or The authors are grateful to Ms. Tzu-Shan Chen for her efficient assistance. procedures Funding Disease or procedures Corresponding ICD-9-CM codes This study was supported by the Center for Database Research, E-DA Healthcare all cancer 140.XX-208.XX Group, E-DA hospital, Kaohsiung, Taiwan(EDAHP-103048). The funding body had no role in the design of the study and collection, analysis, and interpretation of Exclusion: musculoskeletal cancers data and in writing the manuscript. 170.0–170.9 Metastasis 164.8; 165.8 Availability of data and materials The data that support the findings of this study are available from NHIRD 196.0~ 196.9 but restrictions apply to the availability of these data, which were used 197.0~ 197.8 under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with 198.0~ 198.7 permission of NHIRD. 198.81; 198.82; 198.89 Authors’ contributions Chemotherapy management 05221A; 37005B; 37025B FCK: wrote the manuscript; conceived and designed this study; contributed with critical reviews of data analyses, interpretation of findings and critical 37031B~37041B edit of manuscript YCH: conceived and designed this study; contributed with Total knee replacement 64164B critical reviews of data analyses, interpretation of findings and critical edit of manuscript; reviewed the manuscript; supervised the study PYL: contributed Periprosthetic Infection of Knee with critical reviews of data analyses, interpretation of findings and critical joint edit of manuscript; reviewed the manuscript; CBW: performed the infection due to internal device 996.66; 996.67; 996.69 experiments, collected and analyzed the data; reviewed the manuscript; YKT: conceived and designed this study; WKC: performed the experiments, surgical wound infection 998.5; 998.51; 998.59 collected and analyzed the data. All authors have read and approved the osteomyelitis 730.01~ 730.04; 730.07 final manuscript. 730.11~ 730.14; 730.17 Ethics approval and consent to participate 730.21~ 730.24; 730.27 This study was approved by the institutional Review Board of E-Da Hospital, Taiwan (EMRP-103-011; EMRP-103-012) and the Taiwan NHRI (NHIRD-103-116). 730.31~ 730.34; 730.37 Competing interests 730.7; 730.70~ 730.79 The authors declare that they have no competing interests. 730.81~ 730.84; 730.87 730.91~ 730.94; 730.97 Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in Septic arthritis 711.01~ 711.04; 711.07 published maps and institutional affiliations. 711.1; 711.10~ 711.19 Author details 711.2; 711.20~ 711.29 1 2 Department of Orthopaedics, E-Da Hospital, Kaohsiung, Taiwan. School of 711.31~ 711.34; 711.37 Medicine, I-Shou University, Kaohsiung, Taiwan. School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan. Department of Internal Medicine, 711.41~ 711.44; 711.47 E-Da Hospital, Kaohsiung, Taiwan. Graduate Institute of Clinical Medical 711.51~ 711.54; 711.57 Science, China Medical University, Taichung, Taiwan. Department of Oncology, E-Da Hospital, Kaohsiung, Taiwan. Graduate Institute of Public 711.61~ 711.64; 711.67 Health, China Medical University, Taichung, Taiwan. Department of Statistics, 711.7; 711.70~ 711.79 National Taipei University, Taipei, Taiwan. Department of Applied Cosmetology, National Tainan Junior College of Nursing, Tainan, Taiwan. 711.8; 711.81~ 711.89 Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan. 711.91~ 711.94; 711.97 Surgical intervention for 64004C, 64005B, 64053B, Received: 7 July 2016 Accepted: 3 April 2018 periprosthetic infection of knee 64055B,64198B, 48004C, 48005C, joint 48006C; Exclusion: 64003C, 64056B, 64057B, 64200B, 64199B References 1. 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