New Normal for Lung Cancer Clinical Trials Under Coronavirus Disease 2019.

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). 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. 1 A). Although several vaccinations have been developed and proved to be efficient and safe,2, 3, 4 virus variants cause insensitivity to corresponding vaccinations along with high infectivity, probably making it last for a long period of time. ,

Figure 1

Epidemic of COVID-19 and influence of COVID-19 for lung cancer trials. (A) Global map of latest incidence rate and case-fatality ratio of COVID-19 adapted from Johns Hopkins Coronavirus Resource Center Website. (B) Change of Num. of interventional trials for lung cancer from 2019 to 2021. (C) Change of Num. of interventional trials for lung cancer on different regions. Apr, April; COVID-19. Coronavirus disease 2019; Dec, December; Jan, January; Jul, July; Jun, June; Mar, March; Num., number; Sep, September; Oct, October.

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. Despite the fact that increasing advances of novel therapeutic drugs in lung cancer leads to decreased mortality annually since 2008, 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 studies9, 10, 11, 12, 13, 14, 15, 16, 17 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 1

Narrative Review of Impact of COVID-19 in Patients With LC

Study	Regions	Duration	Patients With COVID-19 Diagnosed With LC	Severe COVID-19 in Patients With LC	Mortality of LC With COVID-19
Rogado et al. (2020)9	Spain	March 5, 2020–April 7, 2020	17/1878 (0.9%)	Not applicable	9/17 (52.9%)
Luo et al. (2020)10	USA	March 12, 2020–May 11, 2020	102	34/101 (33.7%)	25/102 (24.5%)
Mariano et al. (2021)11	Spain	April 24, 2020–July 3, 2020	447	281/447 (62.9%)	146/447 (32.7%)
Sheena et al. (2021)12	USA	March 2, 2020–March 6, 2020	13/313 (4.2%)	Not applicable	Not applicable
Lei et al. (2020)13	People’s Republic of China	January 3, 2020–May 6, 2020	50/11,660 (0.4%)	12/45 (26.7%)	11/45 (24.4%)
Liang et al. (2020)14	People’s Republic of China	January 31, 2020	5/1590	1/5 (20.0%)	Not applicable
Zhang et al. (2020)15	People’s Republic of China	January 5, 2020–March 18, 2020	21	11/21 (52.4%)	5/21 (23.8%)
Calles et al. (2020)16	Spain	March 4, 2022–May 12, 2020	23	9/23 (39.1%)	8/23 (34.8%)
Dai et al. (2020)17	People’s Republic of China	January 1, 2020–February 24, 2020	22	6/22 (27.3%)	4/22 (18.2%)

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. 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. 1 B). Specifically, Europe has suffered from remarkably decreased lung cancer trials whereas there is inapparent influence for Asia and North America (Fig. 1 C). 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. 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.

CRediT Authorship Contribution Statement

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.