key: cord-273725-0i0xg7gv authors: Gao, Y.; Liu, M.; Shi, S.; Chen, Y.; Sun, Y.; Chen, J.; Tian, J. title: Cancer is associated with the severity and mortality of patients with COVID-19: a systematic review and meta-analysis date: 2020-05-06 journal: nan DOI: 10.1101/2020.05.01.20087031 sha: doc_id: 273725 cord_uid: 0i0xg7gv Background: Cancer patients are considered a highly vulnerable population in the COVID-19 epidemic, but the relationship between cancer and the severity and mortality of patients with COVID-19 remains unclear. This study aimed to explore the prevalence of cancer in patients with COVID-19 and to examine whether cancer patients with COVID-19 may be at an increased risk of severe illness and mortality. Methods: A comprehensive electronic search in seven databases was performed, to identified studies reporting the prevalence of cancer in COVID-19 patients, or providing data of cancer between patients with severe or non-severe illness or between non-survivors and survivors. Meta-analyses were performed to estimate the pooled prevalence and odds risk (OR) using the inverse variance method with the random-effects model. Results: Thirty-four studies with 8080 patients were included. The pooled prevalence of cancer in patients with COVID-19 was 2.0% (95% CI: 2.0% to 3.0%). The prevalence in Italy (5.0%), France (6.0%), and Korea (4.0%) were higher than that in China (2.0%). Cancer was associated with a 2.84-fold significantly increased risk of severe illness (OR = 2.84, 95%CI: 1.75 to 4.62, P < 0.001) and a 2.60-fold increased risk of death (OR = 2.60, 95%CI: 1.28 to 5.26, P = 0.008) in patients with COVID-19. Sensitivity analyses showed that the results were stable after excluding studies with a sample size of less than 100. Conclusions: Cancer patients have an increased risk of COVID-19 and cancer was associated with a significantly increased risk of severity and mortality of patients with COVID-19. Coronavirus disease 2019 (COVID- 19) , acute pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, first appeared in December 2019 and rapidly spread to a large number of countries and has become a pandemic [1] [2] [3] . As of April 22, 2020, a total of 2,471,136 laboratory-confirmed cases were reported worldwide, with a mortality rate of 6.8% [4] . Previous studies have shown that comorbidities in patients with COVID-19 are associated with poor prognosis, including hypertension, diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular disease, and cerebrovascular disease [5] [6] [7] . Cancer patients are in a state of systemic immunosuppression and are considered a highly vulnerable population in the COVID-19 epidemic [8, 9] . Previous original studies revealed that cancer patients infected with COVID-19 had a higher risk of serious clinical events and death than those without cancer [9, 10] . A previous meta-analysis also evaluated the relationship between cancer and patients with COVID-19 and suggested cancer did not increase the risk of disease progression. Another two meta-analyses investigated the prevalence of cancer among patients with . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint 4 COVID-19, but their results were inconsistent. Furthermore, these meta-analyses were limited by the small sample size and the conclusions were inconclusive. Therefore, a comprehensive meta-analysis is urgently needed to answer clinical questions. The primary objective of this study was to investigate the prevalence of cancer in patients with COVID-19. The secondary objectives were to examine whether cancer patients with COVID-19 may be at an increased risk of severe illness and whether cancer is associated with mortality in patients with COVID-19. We reported this systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [11] . The study protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42020181622). Studies that met the following criteria were included: (1) patients have a laboratory-confirmed diagnosis of COVID-19; (2) described the prevalence of cancer in infected patients, or provided data of cancer between patients with severe or non-severe illness or between non-survivors and survivors; (3) published in Chinese and English. We excluded following studies: (1) studies with a sample size of fewer than 20 patients; (2) studies focused on only suspected cases or suspected cases and confirmed cases; (3) studies did report data related to cancer patients; (4) review articles, protocols, guidelines, consensus, comments, abstracts, letters, and editorials. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. (CNKI), and Wanfang Database up to April 12, 2020. Search terms included the following words: "COVID-19", "coronavirus disease-19", "new coronavirus", "2019-nCoV", "novel corona virus", "novel coronavirus", "nCoV-2019", "novel coronavirus pneumonia", "2019 novel coronavirus", "coronavirus disease 2019", "SARS-CoV-2", "severe acute respiratory syndrome coronavirus 2", "neoplasms", "neoplasia", "tumor", "tumour", "cancer", "malignancy", "clinical characteristic" "clinical feature", "risk factor", and "comorbidities". The search strategy of PubMed is presented in Appendix Word 1. Reference lists of eligible studies and relevant systematic reviews were manually searched for potentially eligible studies. The retrieved records were imported into EndNote X8 (Thomson Reuters (Scientific) LLC Philadelphia, PA, US) software for management. Two authors independently (YG and ML) screened the titles and abstracts of the records to determine if they met the inclusion criteria. Then, the same two authors retrieved the full text of all potentially eligible studies and assessed the eligibility of each study according to the inclusion criteria. Regarding multiple studies from the same teams or studies with samples from the same settings, we evaluated the time frame and detailed . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. 13] . We used the Newcastle-Ottawa quality assessment scale (NOS) to assess the quality of included studies [14] . Studies that obtained more than 7 stars were considered as high quality, 5-7 stars were considered as moderate quality, and lower than 5 stars were considered as low quality [15] . The data extraction and quality assessment were performed by one reviewer (YG, ML, SZS, or YMC) and checked by a second reviewer (YS and JC). Discrepancies were resolved by consensus or by the discussion with a third reviewer (JHT). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. We conducted a rate meta-analysis to estimate the pooled prevalence and its 95% confidence interval (CI) for cancer among patients with COVID-19. Pairwise meta-analyses were conducted to compute the odds ratio (OR) and 95% CI of cancer prevalence in COVID-19 patients with or without severe illness, and non-survivors or survivors. The meta-analyses were performed using the inverse variance method with the random-effects model. The statistical heterogeneity was assessed with the I 2 statistic, and value of < 25%, 26-50%, and > 50% was considered as low, moderate, and high level of heterogeneity, respectively [16] . We planned to conduct subgroup analyses of the outcomes between different countries. Sensitivity analyses were conducted by excluding studies with a sample size of less than 100. We also performed univariate meta-regression analyses to assess if either the outcomes or the heterogeneity was associated with the publication languages and number of centers of the study conducted. The funnel plot and Egger's test were adopted to detect the publication bias. All analyses were conducted using Stata (13.0; Stata Corporation, College Station, Texas, USA Stata) and the statistical level of significance was set at P < 0.05. We identified 1592 records through the literature search, among which 838 were from English databases, 751 were from Chinese databases, and 3 were from other . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint 8 sources. After removing duplicates and reviewing the titles and abstracts, 1466 records were excluded. Through full-text evaluation of the remaining 126 records, 92 records were further excluded. Finally, 34 studies were included for our meta-analyses. The flowchart of the screening process is presented in Figure 1 . All included studies were published in 2020, enrolled patients between Korea. 23 studies published in English and 11 studies [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] published in Chinese. The sample size per study ranged from 28 to 1,591 and the total sample size was 8,080 (4,867 males, 3,213 females). Seven studies [18, 20, 21, 23, 29, 33, 44] were rated as high quality and 27 studies [17, 19, 22, 24-28, 30-32, 34-43, 45-50] were rated as moderate quality according to the NOS scale. The detailed characteristics and quality of the included studies are summarized in Table 1 . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. All included studies reported the number cancer patients among the COVID-19 patients. The meta-analysis showed that the pooled prevalence of cancer in patients with COVID-19 was 2.0% (95% CI: 2.0% to 3.0%), with significant heterogeneity among the studies (I 2 = 68.8%, Figure 2 (Figure 2 ). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. Sensitivity analyses showed that the prevalence did not change after excluding studies with a sample size of less than 100 (Appendix Figure 1 ). Thirteen studies [20, 23, 24, 29, 32, 37, 40, 43-45, 47, 49, 50] 2.21 to 6.63) between cancer and COVID-19 severity (Appendix Figure 2 ). Six studies [18, 19, 23, 27, 36, 38] , totaling 2,671 samples, reported cancer data between dead and surviving COVID-19 patients. Cancer was observed to be associated with a significantly enhanced risk of death (OR = 2.60, 95%CI: 1.28 to 5.26, P = 0.008; I 2 = 6.2%), Figure 4 . Sensitivity analysis by excluding studies with a sample size of less than 100 showed similar results (OR = 2.63, 95%CI: 1.14 to 6.06) (Appendix Figure 3 ). Univariate meta-regression analyses revealed that publication languages and the number of centers of studies conducted were not the sources of heterogeneity or the factors affecting the cancer prevalence (Appendix Figure 4-5) , the association . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint 11 between cancer and COVID-19 severity (Appendix Figure 6-7) , and the association between cancer and the mortality of COVID-19 (Appendix Figure 8 ). We found that there was a possibility of publication bias for cancer prevalence (P = 0.001) (Appendix Figure 9 ). Egger's tests indicated there was no statistically significant publication bias for the association between cancer and COVID-19 severity (P = 0.865) (Appendix Figure 10) , and the association between cancer and COVID-19 mortality (P = 0.439) (Appendix Figure 11 ). This study included 34 studies from China, Italy, France, and Korea, identified from a comprehensive search of seven electronic databases. We systematically evaluated the prevalence of cancer among COVID-19 patients and the association between cancer and the severity and mortality of patients with COVID-19. Our meta-analyses indicated that the pooled prevalence of cancer in patients with COVID-19 was 2.0% and the prevalence in Italy, France, and Korea were higher than that in China. Cancer was associated with a 2.84-fold significantly enhanced risk of severe COVID-19 disease and a 2.60-fold significantly enhanced risk of death in patients with COVID-19. Sensitivity analyses showed that the results did not change substantially after excluding studies with a sample size of less than 100. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. A previous meta-analysis revealed that the pooled prevalence of malignancy among hospitalized COVID-19 patients was estimated to be 0.92% (95% CI: 0.56% to 1.34%) [51] . Another meta-analysis showed that the overall prevalence of cancer in patients with COVID-19 was 2.0% (95% CI: 2.0% to 3.0%), and the prevalence in studies with a sample size < 100 was slightly higher than that in studies with a sample size > 100 [52] . In the current study, we found the prevalence of cancer in COVID-19 patients was 2.0% (95% CI: 2.0% to 3.0%) and the prevalence did not change after excluding studies with a sample size of less than 100. Compared to these two studies, our study has several advantages that make it more conclusive. First, the present meta-analysis included 34 studies involving a total of 8,080 COVID-19 patients compared to no more than 3,561 patients in previous meta-analyses. Thus, our study had enlarged sample sizes and added statistical power of nearly 4500 cases. Second, studies included in previous meta-analyses were all from China, so the results may not apply to other countries and data selection bias may exist. However, our meta-analysis included studies from four countries, although only three studies from Italy, France, and Korea. Third, in addition to conducting subgroup analyses to evaluate the difference of prevalence between different countries, we also performed sensitivity analyses and meta-regression analyses and these analyses indicated that the results of our study were stable. A previous meta-analysis found that there was no correlation between cancer and the severity of patients with COVID-19 [7] . However, our meta-analysis indicated . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint 13 that cancer was significantly associated with an increased risk of severe COVID-19 disease, which was inconsistent with the previous meta-analysis [7] . The previous reviewers conducted a meta-analysis based on only four studies with a sample of 1,356 patients [7] . We performed a meta-analysis of 3,450 cases from thirteen studies and sensitivity analysis by excluding studies with a sample size of less than 100 showed a stronger association. Therefore, the result of our study is more convincing. According to the current meta-analysis, the pooled prevalence of cancer in patients with COVID-19 was 2.0%. Combined with previously published results [9, 51, 52] , we can conclude that patients with cancer have an increased risk of COVID-19. The development of cancer is usually related to a blunted immune status [53, 54] , and anti-cancer treatments (such as chemotherapy and surgery) can also put cancer patients in an immunosuppressive state [8] . Therefore, immunodeficiency may be the main reason for cancer patients susceptible to COVID-19. Our subgroup analyses found that the prevalence of cancer among COVID-19 patients in Italy, France, and Korea were higher than that in China, although the result was limited by the sample size. These results suggest that cancer patients should be provided with special precautions and advised to use stronger personal protection. Our meta-analysis found that cancer was associated with a 2.84-fold significantly increased risk of severe illness in patients with COVID-19, as well as with a 2.60-fold increased risk of death. Although our data are potentially limited by the sources of studies, these findings highlight the need for oncology professionals to be vigilant to . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. should avoid treatments causing immunosuppression [10] . However, there is currently no recommendation regarding the treatment strategies of immunotherapy, radiotherapy, chemotherapy, or delaying adjuvant therapy for cancer patients with COVID-19 [52] . The results of our meta-analysis also provide the latest references for the development of new guidelines. High-quality evidence-based guidelines clarify protection measures for cancer patients, and care and treatment strategies for cancer patients with COVID-19 are urgently needed. To the best of our knowledge, this is the first meta-analysis systematically evaluated the prevalence of cancer among COVID-19 patients, and the association between cancer and the severity and mortality of patients with COVID-19. Besides, we also conducted sensitivity analyses and meta-regression analyses to evaluate factors that may affect the results. However, our study also has some limitations. First, most of the studies included were from China, so the current findings may not fully reflect the global situation and should be interpreted with caution. Second, although this meta-analysis included 34 studies, there are few data available for subgroup analysis. Third, we performed sensitivity and meta-regression analyses to explore heterogeneity, but some factors were not evaluated due to limited data. Fourth, the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint patient overlap is still possible between a few studies, although we have ruled out many studies with overlap samples during the study selection and data extraction processes. Finally, we did not evaluate which types of cancer patients are more susceptible to COVID-19 or more associated with severe illness and mortality. As data from more countries become available, it is necessary to update this study and performed more comprehensive analyses to answer questions to guide clinical practice. Our meta-analyses indicated that cancer patients have an increased risk of COVID-19, and cancer is associated with a 2.84-fold increased risk of severe illness and a 2.60-fold increased risk of death in patients with COVID-19. However, due to the limitations of this study, more high-quality studies from different countries are needed to provide robust evidence to support clinical practice. Newcastle-Ottawa quality assessment scale; OR: odds ratio; CI: confidence interval. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. Not applicable. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of China: retrospective case series WHO Director-General's opening remarks at the media briefing on COVID-19: 11 World Health Organization. Coronavirus disease (COVID-2019) situation reports Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome Prevalence and severity of corona virus disease 2019 (COVID-19): A systematic review and meta-analysis Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis Clinical Characteristics of COVID-19 After Gynecologic Oncology Surgery in Three Women: A Retrospective Review of Medical Records. The oncologist Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Annals of oncology : official journal of the European Society for Medical Oncology Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement Hypertension and its severity or mortality in Coronavirus Disease 2019 (COVID-19): a pooled analysis The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses Arterial hypertension and risk of death in patients with COVID-19 infection: systematic review and meta-analysis Measuring inconsistency in meta-analyses Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chinese medical journal. 2020. on COVID-19 Coronavirus Disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up. The Journal of infection Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America COVID-19 in a Designated Infectious Diseases Hospital Outside Hubei Province Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. The Lancet Infectious diseases Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Clinical Characteristics of Imported Cases of COVID-19 in Jiangsu Province: A Multicenter Descriptive Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory medicine Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Initial clinical features of suspected coronavirus disease 2019 in two emergency departments outside of Hubei Comparative Study for Clinical Features between COVID-19 Patients with Conventional Type and Heavy/Critical Type A study of laboratory confirmed cases between laboratory indexesand clinical classification of 342 cases with Corona Virus Disease Analysis on Chinese medical clinical characteristics of 64 patients with common type COVID-19 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity Digestive system manifestations and analysis of disease severity in 54 patients with corona virus disease Clinical characteristics, treatment, and prognosis in 89 cases of COVID Prevalence of Underlying Diseases in Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis. Archives of academic emergency medicine COVID-19 and Cancer: Lessons From a Pooled Meta-Analysis Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion Risk of COVID-19 for patients with cancer International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity The authors thank all investigators and supporters involved in this study. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Not applicable.. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint The authors declare that they have no competing interests.. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 6, 2020. . https://doi.org/10.1101/2020.05.01.20087031 doi: medRxiv preprint