Exploration of potential risk factors for COVID-19 severity in patients participating in oncology clinical trials

Abstract

Coronavirus disease 2019 (COVID-19) has created the greatest threat to global health worldwide [[1]Khan G. Sheek-Hussein M. Al Suwaidi A.R. Idris K. Abu-Zidan F.M. Novel coronavirus pandemic: a global health threat.Turk J Emerg Med. 2020; 20: 55-62Crossref PubMed Scopus (20) Google Scholar]. Several studies have claimed that cancer patients are highly susceptible to COVID-19 [2Liu C. Zhao Y. Okwan-Duodu D. Basho R. Cui X. COVID-19 in cancer patients: risk, clinical features, and management.Cancer Biol Med. 2020; 17: 519-527Crossref PubMed Scopus (75) Google Scholar, 3Dai M. Liu D. Liu M. Zhou F. Li G. Chen Z. Zhang Z. You H. Wu M. Zheng Q. Xiong Y. Xiong H. Wang C. Chen C. Xiong F. Zhang Y. Peng Y. Ge S. Zhen B. Yu T. Wang L. Wang H. Liu Y. Chen Y. Mei J. Gao X. Li Z. Gan L. He C. Li Z. Shi Y. Qi Y. Yang J. Tenen D.G. Chai L. Mucci L.A. Santillana M. Cai H. Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak.Canc. 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Additionally, factors associated with the severity of COVID-19 could hamper the results of clinical trials. Therefore, our goal was to investigate potential risk factors for COVID-19 severity in patients participating in clinical cancer trials. Senescent cells secrete a set of pro-inflammatory factors collectively called the senescence-associated secretory phenotype (SASP) [[7]Zlotorynski E. Defective mitochondria ignite the SASP.Nat. Rev. Mol. Cell Biol. 2020; 21: 179Crossref PubMed Scopus (7) Google Scholar]. The SASP includes several pro-inflammatory molecules, including TNF-α, IL-1α/β, IL-6, IL-8, and chemokines (Ccl2, Cxcl10 and Ccl17) [[8]Coperchini F. Chiovato L. Croce L. Magri F. Rotondi M. The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system.Cytokine Growth Factor Rev. 2020; 53: 25-32Crossref PubMed Scopus (757) Google Scholar,[9]Colombo M. Mirandola L. Chiriva-Internati M. Basile A. Locati M. Lesma E. Chiaramonte R. 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Due to the development of chemoresistance, cancer cells can still evade chemotherapy, which is a major barrier to cancer treatment [[16]Bukowski K. Kciuk M. Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy.Int. J. Mol. Sci. 2020; 21Crossref Scopus (382) Google Scholar]. Additionally, chemoresistance can increase metastasis, which makes it challenging to improve the clinical outcomes of cancer patients [[17]Zheng H.C. The molecular mechanisms of chemoresistance in cancers.Oncotarget. 2017; 8: 59950-59964Crossref PubMed Scopus (368) Google Scholar]. Preliminary studies have reported that chemoresistance is associated with the severity of COVID-19 in cancer patients [[18]Gupta K. Gandhi S. Mebane 3rd, A. Singh A. Vishnuvardhan N. Patel E. Cancer patients and COVID-19: mortality, serious complications, biomarkers, and ways forward.Cancer Treat Res Commun. 2021; 26: 100285Crossref PubMed Scopus (13) Google Scholar,[19]Moujaess E. Kourie H.R. Ghosn M. Cancer patients and research during COVID-19 pandemic: a systematic review of current evidence.Crit. Rev. Oncol. Hematol. 2020; 150: 102972Crossref PubMed Scopus (133) Google Scholar]. Therefore, the chemoresistance status of cancer patients participating in clinical trials should be assessed during the COVID-19 pandemic. COVID-19 targets the lungs; thus, patients with COVID-19 can develop various lung diseases, including chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, moderate to severe asthma, and lung cancer [[20]Martin Gimenez V.M. Inserra F. Tajer C.D. Mariani J. Ferder L. Reiter R.J. Manucha W. Lungs as target of COVID-19 infection: protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment.Life Sci. 2020; 254: 117808Crossref PubMed Scopus (74) Google Scholar]. On the other hand, several studies have stated that many types of heart disease, including coronary artery disease, cardiomyopathy, pulmonary hypertension, and congenital heart disease, are associated with the severity of COVID-19 in cancer patients [21Bansal M. Cardiovascular disease and COVID-19.Diabetes Metab Syndr. 2020; 14: 247-250Crossref PubMed Scopus (486) Google Scholar, 22Kochi A.N. Tagliari A.P. Forleo G.B. Fassini G.M. Tondo C. Cardiac and arrhythmic complications in patients with COVID-19.J. Cardiovasc. Electrophysiol. 2020; 31: 1003-1008Crossref PubMed Scopus (347) Google Scholar, 23Long B. Brady W.J. Koyfman A. Gottlieb M. Cardiovascular complications in COVID-19.Am. J. Emerg. Med. 2020; 38: 1504-1507Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar]. Additionally, many studies have claimed that type 1 or type 2 diabetes could increase the complications of COVID-19 [24Bornstein S.R. Rubino F. Khunti K. Mingrone G. Hopkins D. Birkenfeld A.L. Boehm B. 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In addition, the type of clinical studies (screening/prevention, phases of trials) and kinds of treatment (cytotoxic chemotherapy, targeted therapy, immunotherapy, surgery, radiation) should be considered for clinical evaluation [[27]Arruebo M. Vilaboa N. Saez-Gutierrez B. Lambea J. Tres A. Valladares M. Gonzalez-Fernandez A. Assessment of the evolution of cancer treatment therapies.Cancers. 2011; 3: 3279-3330Crossref PubMed Scopus (444) Google Scholar]. Taken together, the factors mentioned above should be evaluated for patients participating in oncology clinical trials during the COVID-19 pandemic. Cytokines are a group of polypeptide signaling molecules that are essential for many biological processes [[28]Costela-Ruiz V.J. Illescas-Montes R. Puerta-Puerta J.M. Ruiz C. Melguizo-Rodriguez L. SARS-CoV-2 infection: the role of cytokines in COVID-19 disease.Cytokine Growth Factor Rev. 2020; 54: 62-75Crossref PubMed Scopus (552) Google Scholar]. However, several studies have claimed that elevated levels of cytokines and chemokines, such as IL-6, IL-2, IL-8, IL-4, IFN-γ, CSF, VEGF, HGF, IP-10, MCP-1, and MIP 1-α are associated with complications of COVID-19 [28Costela-Ruiz V.J. Illescas-Montes R. Puerta-Puerta J.M. Ruiz C. Melguizo-Rodriguez L. SARS-CoV-2 infection: the role of cytokines in COVID-19 disease.Cytokine Growth Factor Rev. 2020; 54: 62-75Crossref PubMed Scopus (552) Google Scholar, 29Chi Y. Ge Y. Wu B. Zhang W. Wu T. Wen T. Liu J. Guo X. Huang C. Jiao Y. Zhu F. Zhu B. Cui L. Serum cytokine and chemokine profile in relation to the severity of coronavirus disease 2019 in China.J. Infect. Dis. 2020; 222: 746-754Crossref PubMed Scopus (173) Google Scholar, 30Xu Z.S. Shu T. Kang L. Wu D. Zhou X. Liao B.W. Sun X.L. Zhou X. Wang Y.Y. Temporal profiling of plasma cytokines, chemokines and growth factors from mild, severe and fatal COVID-19 patients.Signal Transduct Target Ther. 2020; 5: 100Crossref PubMed Scopus (69) Google Scholar]. Elevated cytokines could be related to unsuitable inflammatory responses, triggering weak and inappropriate immune responses that need to be studied further for full clarification [[31]Zhang J.M. An J. Cytokines, inflammation, and pain.Int. Anesthesiol. Clin. 2007; 45: 27-37Crossref PubMed Scopus (1478) Google Scholar]. Therefore, to explain the potential impact of elevated cytokine levels in clinical trials during the COVID-19 pandemic, cytokine levels need to be effectively measured and characterized for patients participating in oncology clinical trials. Rather than using an experimental agent, it is necessary to consider an approved COVID-19 vaccine for cancer patients participating in clinical studies. In addition, the dates of the first and second dose and possible side effects should be recorded. These data may help to evaluate the efficacy and safety of the COVID-19 vaccine and the potential impact of the vaccine in oncology clinical trials. In conclusion, COVID-19 has placed a burden on health systems around the world. Unfortunately, there are still no promising guidelines for conducting clinical trials involving cancer patients during the COVID-19 pandemic. Furthermore, many unknown factors could hamper the results of clinical trials, which need to be studied. Due to the COVID-19 pandemic, few preclinical and clinical data are available, but there will be greater efforts to establish a promising guideline for conducting oncology clinical trials during the COVID-19 pandemic. Therefore, we anticipate that the factors associated with the severity of COVID-19 that we explored in the present study could help establish proper guidance for oncology clinical trials.