New Normal for Lung Cancer Clinical Trials Under Coronavirus Disease 2019

Abstract

The pandemic of coronavirus disease 2019 (COVID-19) has continued to be raging throughout the world, putting huge burden on all walks of life. So far, 435,411,937 people in total has been confirmed with having COVID-19 and 5,949,716 died of it globally (provided by the Johns Hopkins Center for Systems Science and Engineering).1Dong E. Du H. Gardner L. An interactive web-based dashboard to track COVID-19 in real time.Lancet Infect Dis. 2020; 20: 533-534Abstract Full Text Full Text PDF PubMed Scopus (4553) Google Scholar Among all, Europe, North America, and South America have relatively higher incidence rate whereas Eastern Europe and South America suffered notably higher case-fatality rate (Fig. 1A). Although several vaccinations have been developed and proved to be efficient and safe,2Sandmann F.G. Davies N.G. Vassall A. Edmunds W.J. Jit M. Centre for the Mathematical Modelling of Infectious Diseases COVID-19 working group. The potential health and economic value of SARS-CoV-2 vaccination alongside physical distancing in the UK: a transmission model-based future scenario analysis and economic evaluation.Lancet Infect Dis. 2021; 21: 962-974Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 3Madhi S.A. Baillie V. Cutland C.L. et al.Efficacy of the ChAdOx1 nCoV-19 COVID-19 vaccine against the B.1.351 variant.N Engl J Med. 2021; 384: 1885-1898Crossref PubMed Scopus (583) Google Scholar, 4Shinde V. Bhikha S. Hoosain Z. et al.Efficacy of NVX-CoV2373 COVID-19 vaccine against the B.1.351 variant.N Engl J Med. 2021; 384: 1899-1909Crossref PubMed Scopus (237) Google Scholar virus variants cause insensitivity to corresponding vaccinations along with high infectivity, probably making it last for a long period of time.5Wang P. Nair M.S. Liu L. et al.Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.Nature. 2021; 593: 130-135Crossref PubMed Scopus (920) Google Scholar,6Torjesen I. COVID-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear.BMJ. 2021; 375: n2943Crossref PubMed Scopus (88) Google Scholar As frequently encountered disease, patients with cancer suffered from both life-threatening disease and indispensable hospitalization. Specifically, lung cancer remains one of the leading causes of cancer death worldwide.7Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (12814) Google Scholar Despite the fact that increasing advances of novel therapeutic drugs in lung cancer leads to decreased mortality annually since 2008,8Howlader N. Forjaz G. Mooradian M.J. et al.The effect of advances in lung-cancer treatment on population mortality.N Engl J Med. 2020; 383: 640-649Crossref PubMed Scopus (340) Google Scholar lung cancer is still one of the major public health issues remaining to be solved. Symptoms caused by lung cancer are likely to result in functional damage of respiratory system in varying degrees. Any accompanied respiratory disease including COVID-19 may inevitably deteriorate and impact patients’ subsequent treatment and prognosis. Several previous studies9Rogado J. Pangua C. Serrano-Montero G. et al.COVID-19 and lung cancer: a greater fatality rate?.Lung Cancer. 2020; 146: 19-22Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 10Luo J. Rizvi H. Preeshagul I.R. et al.COVID-19 in patients with lung cancer.Ann Oncol. 2020; 31: 1386-1396Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 11Provencio M. Mazarico Gallego J.M. Calles A. et al.Lung cancer patients with COVID-19 in Spain: GRAVID study.Lung Cancer. 2021; 157: 109-115Abstract Full Text Full Text PDF Scopus (14) Google Scholar, 12Bhalla S. Bakouny Z. Schmidt A.L. et al.Care disruptions among patients with lung cancer: a COVID-19 and cancer outcomes study.Lung Cancer. 2021; 160: 78-83Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 13Nie L. Dai K. Wu J. et al.Clinical characteristics and risk factors for in-hospital mortality of lung cancer patients with COVID-19: a multicenter, retrospective, cohort study.Thorac Cancer. 2021; 12: 57-65Crossref Scopus (10) Google Scholar, 14Liang W. Guan W. Chen R. et al.Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.Lancet Oncol. 2020; 21: 335-337Abstract Full Text Full Text PDF PubMed Scopus (2600) Google Scholar, 15Zhang H. Wang L. Chen Y. et al.Outcomes of novel coronavirus disease 2019 (COVID-19) infection in 107 patients with cancer from Wuhan, China.Cancer. 2020; 126: 4023-4031Crossref PubMed Scopus (64) Google Scholar, 16Calles A. Aparicio M.I. Alva M. et al.Outcomes of COVID-19 in patients with lung cancer treated in a tertiary hospital in Madrid.Front Oncol. 2020; 10: 1777Crossref PubMed Scopus (16) Google Scholar, 17Dai M. Liu D. Liu M. et al.Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak.Cancer Discov. 2020; 10: 783-791Crossref PubMed Scopus (822) Google Scholar investigated the impact of COVID-19 in patients with lung cancer, revealing that lung cancer may worsen the degree of COVID-19, leading to higher incidence of severe COVID-19. Meanwhile, patients with lung cancer accompanied by COVID-19 may suffer from higher mortality rate in a relatively short period of time, suggesting the underlying damaging interaction between lung cancer and COVID-19 (Table 1).Table 1Narrative Review of Impact of COVID-19 in Patients With LCStudyRegionsDurationPatients With COVID-19 Diagnosed With LCSevere COVID-19 in Patients With LCMortality of LC With COVID-19Rogado et al. (2020)9Rogado J. Pangua C. Serrano-Montero G. et al.COVID-19 and lung cancer: a greater fatality rate?.Lung Cancer. 2020; 146: 19-22Abstract Full Text Full Text PDF PubMed Scopus (53) Google ScholarSpainMarch 5, 2020–April 7, 202017/1878 (0.9%)Not applicable9/17 (52.9%)Luo et al. (2020)10Luo J. Rizvi H. Preeshagul I.R. et al.COVID-19 in patients with lung cancer.Ann Oncol. 2020; 31: 1386-1396Abstract Full Text Full Text PDF PubMed Scopus (104) Google ScholarUSAMarch 12, 2020–May 11, 202010234/101 (33.7%)25/102 (24.5%)Mariano et al. (2021)11Provencio M. Mazarico Gallego J.M. Calles A. et al.Lung cancer patients with COVID-19 in Spain: GRAVID study.Lung Cancer. 2021; 157: 109-115Abstract Full Text Full Text PDF Scopus (14) Google ScholarSpainApril 24, 2020–July 3, 2020447281/447 (62.9%)146/447 (32.7%)Sheena et al. (2021)12Bhalla S. Bakouny Z. Schmidt A.L. et al.Care disruptions among patients with lung cancer: a COVID-19 and cancer outcomes study.Lung Cancer. 2021; 160: 78-83Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarUSAMarch 2, 2020–March 6, 202013/313 (4.2%)Not applicableNot applicableLei et al. (2020)13Nie L. Dai K. Wu J. et al.Clinical characteristics and risk factors for in-hospital mortality of lung cancer patients with COVID-19: a multicenter, retrospective, cohort study.Thorac Cancer. 2021; 12: 57-65Crossref Scopus (10) Google ScholarPeople’s Republic of ChinaJanuary 3, 2020–May 6, 202050/11,660 (0.4%)12/45 (26.7%)11/45 (24.4%)Liang et al. (2020)14Liang W. Guan W. Chen R. et al.Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.Lancet Oncol. 2020; 21: 335-337Abstract Full Text Full Text PDF PubMed Scopus (2600) Google ScholarPeople’s Republic of ChinaJanuary 31, 20205/15901/5 (20.0%)Not applicableZhang et al. (2020)15Zhang H. Wang L. Chen Y. et al.Outcomes of novel coronavirus disease 2019 (COVID-19) infection in 107 patients with cancer from Wuhan, China.Cancer. 2020; 126: 4023-4031Crossref PubMed Scopus (64) Google ScholarPeople’s Republic of ChinaJanuary 5, 2020–March 18, 20202111/21 (52.4%)5/21 (23.8%)Calles et al. (2020)16Calles A. Aparicio M.I. Alva M. et al.Outcomes of COVID-19 in patients with lung cancer treated in a tertiary hospital in Madrid.Front Oncol. 2020; 10: 1777Crossref PubMed Scopus (16) Google ScholarSpainMarch 4, 2022–May 12, 2020239/23 (39.1%)8/23 (34.8%)Dai et al. (2020)17Dai M. Liu D. Liu M. et al.Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak.Cancer Discov. 2020; 10: 783-791Crossref PubMed Scopus (822) Google ScholarPeople’s Republic of ChinaJanuary 1, 2020–February 24, 2020226/22 (27.3%)4/22 (18.2%)COVID-19, coronavirus disease 2019; LC, lung cancer; USA, United States of America. Open table in a new tab COVID-19, coronavirus disease 2019; LC, lung cancer; USA, United States of America. Clinical trial of lung cancer is definitely the crucial approach to test and verify the clinical feasibility and safety of novel treatments, providing highly potent drugs for patients with lung cancer. Nevertheless, whether COVID-19 pandemic might affect the process of lung cancer trials remains poorly explored. In this issue, Smeltzer et al.18Smeltzer M.P. Scagliotti G.V. Wakelee H.A. et al.International Association for the Study of Lung Cancer study of the impact of Coronavirus Disease 2019 on international lung cancer clinical trials.J Thorac Oncol. 2022; 17: 651-660Abstract Full Text Full Text PDF Scopus (1) Google Scholar reported the results of how COVID-19 affect the international lung cancer clinical trials on behalf of the International Association for the Study of Lung Cancer. By comparing clinical trial enrollment during the same period of time before and after COVID-19, a 14% decline of clinical trial enrollment globally was found right after the burst of COVID-19 especially in April to June but with no considerable difference in October to December when most countries have taken action on it for a period of time. Given that high infectivity of COVID-19, contact isolation, and tremendous workload in hospitals have undoubtedly put huge influence to clinical trial enrollment during the early phase of COVID-19, this survey revealed that the primary barriers to trial recruitment are reduction in eligible patients, poor compliance, and suspension of trials. In addition, active COVID-19 infection (24%) or quarantine (40%) considerably hinder the recruitment process. Nevertheless, implementation of mitigation strategies including modified monitoring requirements, telehealth visits, and modified required visits to adjust COVID-19 pandemic has apparently revealed its desired effect, whereas similar clinical trial enrollment is found in relative late phase of COVID-19. On the basis of the current situation of COVID-19 globally and its high variability, the pandemic would definitely last for 1 or 2 years, and such flexibility in time and place would necessarily be the new normal for clinical trial enrollment and monitoring. Another intriguing supplement to this issue is the impact of COVID-19 in initiated lung cancer clinical trials which this survey has not discussed. By integrating registered interventional trials of lung cancer from ClinicaTrials.gov in 2019, 2020, and 2021, an apparent decrease of lung cancer clinical trials during initiation of the pandemic is found; however, a striking increase is observed a couple of months after the initiation of the global pandemic which sustained for a long period of time (Fig. 1B). Specifically, Europe has suffered from remarkably decreased lung cancer trials whereas there is inapparent influence for Asia and North America (Fig. 1C). Indeed, it goes without saying that the pandemic of COVID-19 has accelerated initiation of lung cancer clinical trials in disguised form which might be the consequences of mitigation strategies for trial management. Similar to what the authors stated in this global survey, though the pandemic worsened, trial enrollment improved with more flexible approaches to access clinical trials even beyond the pandemic. With the development of COVID-19 vaccines and extensive vaccine administration, the pandemic seems to reach the plateau at present, though multiple resistant variants are identified. Most importantly, the mortality rate is gradually decreased and the newly confirmed cases are similar (data from Johns Hopkins Coronavirus Resource Center Website), indicating reduced harmfulness of COVID-19, and as a matter of fact, more patients are diagnosed with having mild COVID-19 without any symptoms. A previous large retrospective study involving 72,314 COVID-19 cases revealed that 889 patients (1.2%) were asymptomatic.19The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China.Zhonghua Liu Xing Bing Xue Za Zhi Zhonghua Liuxingbingxue Zazhi. 2020; 41: 145-151PubMed Google Scholar As the disease might be as universal as flu with long-term persistence, it might not be that necessary to provide full-scale virus screening and monitoring but live with it probably. In general, this is, so far, the largest multicenter survey of exploring the impact of COVID-19 on lung cancer clinical trials globally and discussed the mitigation strategies to overcome the barriers to trial recruitment. Although the COVID-19 has put devastating influence toward all human beings, causing uncountable economic loss and serious public health issue, physicians have put their heart and soul to overcome this global crisis by not only developing vaccine but also generating more flexible approaches to adjust the post-pandemic circumstances. Results of this global survey have revealed, from one aspect, that COVID-19 has not heavily inflicted lung cancer trials but improved trial enrollment owing to potential mitigation strategies. Such flexible trial monitoring modalities could be extended and generalized to other cancer types. Together, these may facilitate the process of cancer trials and guarantee that more effective antineoplasmic agents could be successfully provided to patients with cancer under the persistent COVID-19 pandemic. Chao Zhang: Conceptualization, Data curation, Formal analysis, Writing - original draft, Writing - review & editing. Wen-Zhao Zhong: Conceptualization, Supervision, Writing - review & editing. Yi-Long Wu: Conceptualization, Writing - review & editing.