Continued implications of the COVID-19 pandemic environment on non-small cell lung cancer characteristics and treatment in the United States

Introduction

Coronavirus disease 2019 (COVID-19) was a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The initial outbreak of COVID-19 in the United States was characterized by a surge of new cases in March to April 2020 with relative plateau until October 2020, when another significant wave occurred through December 2020 (1). During the first year of the pandemic, national public health initiatives to curb viral transmission included stay at home orders, government issued lockdowns, and recommendations to the general public to avoid large gatherings and public places, to socially distance, and to wear protective personal equipment (2). Despite these recommendations, and the availability, and wide reception, of a vaccine and booster series (3), another two surges of COVID-19 cases occurred between August to September 2021 and November to December 2021, associated with significant disruption of routine life throughout 2021.

COVID-19 disrupted many facets of the healthcare industry throughout the pandemic and may have permanently altered modern healthcare delivery. Postponed, avoided, or cancelled patient appointments and screening exams are likely responsible for the observed decrease in new cancer diagnoses, on the order of 50%, that were documented across many cancers compared to pre-pandemic years (4). We have previously analyzed the impact of the first year of the COVID-19 pandemic on non-small cell lung cancer (NSCLC) characteristics and treatment and found that the first year of the COVID-19 pandemic significantly impacted both the stage of presentation and the subsequent treatment therapies for patients who were diagnosed with NSCLC (5). However, the continued affects of the COVID-19 pandemic on NSCLC after the first year of the pandemic remain unstudied.

Given two major waves of COVID-19 throughout 2021, the purpose of this study was to determine the ongoing effects of the COVID-19 pandemic on initial patient oncologic presentation and subsequent treatment strategies for NSCLC throughout the second year of the pandemic (2021, termed “pandemic-year-two”), in comparison to both the pre-pandemic year [2019] and pandemic-year-one [2020]. We hypothesized that there would continue to be delays to diagnosis due to ongoing disruption resulting in increased stage of presentation, as well as delays to treatment and altered recommendations. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1334/rc).

Methods

Ethical oversight

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This research utilized deidentified, publicly available data through the NCDB and thus was exempt from review by the Colorado Multi-Institutional Review Board.

Study design and patient selection

This was a retrospective cohort study using the prospectively collected NCDB Participant Use File. The NCDB is maintained by the American College of Surgeons Commission on Cancer and collects clinical oncology metrics from hospital registry data sourced from over 1,500 CoC-accredited institutions (6).

For the purposes of our study, patients in the NSCLC cohort diagnosed between 2019 to 2021 were targeted for inclusion. Data prior to 2018 was not considered to limit potential confounders, including changes in oncology recommendations or standards of care over time, advancements in oncologic therapies, or use of new therapies. Data beyond 2021 was not included as it was not yet available due to the delay in reporting by the NCDB. We defined patients diagnosed in 2019 as the pre-pandemic cohort, patients diagnosed in 2020 as the pandemic-year-one cohort, and patients diagnosed in 2021 as the pandemic-year-two cohort. Patients with missing pertinent data were excluded.

The primary outcome of this study was initial presenting American Joint Committee on Cancer (AJCC) clinical TNM stage. Secondary outcomes included tumor grade, AJCC clinical T stage, N stage, and M stage, histology, and treatment strategy variables. Treatment variables of interest included those related to surgery including extent of resection and approach, those related to radiation including surgery/radiation sequencing, those related to systemic therapy including surgery/systemic therapy sequencing, and those related to palliative care measures. Additionally, time variables were explored with reference to diagnosis, including time to first treatment, time to surgery, time to radiotherapy, and time to systemic therapy.

Statistical analysis

We first performed a comparative analyses of patient demographic characteristics, oncologic variables, and treatment therapies between the pre-pandemic, pandemic-year-one, and pandemic-year-two cohorts using the Chi-squared test for categorical variables and one-way analysis of variance (ANOVA) for continuous variables. We then performed multivariate logistic regression controlling for patient demographic information to assess risk-adjusted differences in patient oncologic variables. For AJCC clinical staging outcomes and clinical grade we utilized a cumulative logit model. Finally, we performed multivariate logistic regression controlling for demographic and oncologic variables to determine risk-adjusted differences in patient treatment variables. For outcomes of interest involving temporal variables, we used a model assuming a negative binomial distribution for the outcome. P values <0.05 were considered statistically significant. All analyses were completed using SAS version 9.4 (SAS Inc., Carey, NC, USA).

Results

Patient cohort

A total of 376,193 NSCLC cases were included; 135,649 (36.1%) were diagnosed in the pre-pandemic year [2019], 119,338 (31.7%) were diagnosed in pandemic-year-one [2020], and 121,206 (32.2%) were diagnosed in pandemic-year-two [2021]. The rate of COVID-19 testing was significantly different across the three cohorts, with 1.4% of patients being tested in the pre-pandemic cohort, 47.3% in the pandemic-year-one cohort and 66.5% in the pandemic-year-two cohort (P<0.001). Additionally, rates of COVID-19 positivity differed with 0.1% positive in the pre-pandemic cohort, 3.0% positive in the pandemic-year-one cohort and 6.0% positive in the pandemic-year-two cohort (Figure 1). Unadjusted comparisons of patient characteristics are summarized in Table 1.

Figure 1 Rates of COVID-19 testing (left axis) and positivity (right axis) across the three cohorts. COVID-19, coronavirus disease 2019.

Table S1 summarizes the unadjusted oncologic characteristics across the three groups. There were significant differences in the distribution of primary tumor site (P<0.001), laterality (P=0.01), histology (P<0.001), clinical tumor grade (P<0.001), clinical T-stage (P<0.001), clinical N-stage (P<0.001), clinical M-stage (P<0.001), overall clinical stage (P<0.001), pathologic T stage (P<0.001), and overall pathologic stage (P<0.001).

Table S2 summarizes the unadjusted treatment characteristics across groups. There were significant differences in the distribution of all treatment variables, including differences in overall treatment status (P<0.001), reception of a diagnostic staging procedure (P<0.001), primary site surgery (P<0.001), surgical approach (P<0.001), radiation/surgery sequencing (P<0.001), systematic therapy/surgery sequencing (P<0.001), and palliative care measures (P<0.001). Additionally, there were significant differences across all time points, including differences in time to staging (P<0.001), to first treatment (P<0.001), to surgery (P<0.001), to radiation (P<0.001), and to systemic therapy (P<0.001).

Pandemic-year-two vs. pre-pandemic cohort

Table 2 summarizes the risk-adjusted comparison of oncologic characteristics between the pre-pandemic and pandemic-year-two cohorts. When compared to the pre-pandemic cohort, patients in pandemic-year-two had significantly increased odds of an overlapping lesion site [odds ratio (OR) =1.126; 95% confidence interval (CI): 1.051–1.207] or main bronchial lesion (OR =1.279; 95% CI: 1.222–1.339) compared to a reference of upper lobe lesion and also had higher odds of epithelial neoplasms (OR =1.089; 95% CI: 1.053–1.136) compared to a reference of squamous cell histology. Compared to the pre-pandemic year, pandemic-year-two patients had higher odds of an increased clinical T-stage (OR =1.017; 95% CI: 1.003–1.031), clinical N-stage (OR =1.048; 95% CI: 1.033–1.063), clinical M-stage (OR =1.044; 95% CI: 1.028–1.060), and overall clinical stage (OR =1.038; 95% CI: 1.023–1.052).

Table 3 summarizes the risk-adjusted comparison of treatment characteristics between the pre-pandemic and pandemic-year-two cohorts. Overall, when compared to the pre-pandemic cohort, those patients diagnosed in pandemic-year-two had increased time from diagnosis to first treatment (OR =1.143; 95% CI: 1.133–1.154) and had significantly higher odds of receiving no treatment (OR =1.039; 95% CI: 1.014–1.065). Regarding surgical treatment, when compared to pre-pandemic patients, pandemic-year-two patients had increased days from diagnosis to surgery (OR =1.117; 95% CI: 1.093–1.141) and had higher odds of undergoing sub lobar resection with reference to lobectomy (OR =1.061; 95% CI: 1.025–1.098), and lower odds of pneumonectomy (OR =0.797; 95% CI: 0.707–0.899). Pandemic-year-two patients were less likely to undergo an open operation (OR =0.896; 95% CI: 0.862–0.932), and more likely to undergo a robotic operation (OR =1.110; 95% CI: 1.071–1.150) compared to a video-assisted thoracoscopic (VATS) approach. While pandemic-year-two patients had decreased time from diagnosis to radiotherapy (OR =0.0982; 95% CI: 0.973–0.991), there were no differences in radiotherapy reception or sequencing. Pandemic-year-two patients had increased time from diagnosis to systemic therapy (OR =1.021; 95% CI: 1.924–1.039); however, again there were no differences in systemic therapy reception or sequencing. When compared to pre-pandemic patients, pandemic-year-two patients had higher odds of palliative surgery (OR =1.022; 95% CI: 1.020–1.024), palliative systemic therapy (OR =1.146; 95% CI: 1.145–1.147), palliative pain management (OR =1.010; 95% CI: 1.099–1.011), and combination palliative therapy (OR =1.025; 95% CI: 1.024–1.026), all with reference to no palliative therapy. They did, however, have decreased odds of receiving palliative radiotherapy (OR =0.989; 95% CI: 0.988–0.990).

Pandemic-year-two vs. pandemic-year-one

Table 2 summarizes the risk-adjusted comparison of oncologic characteristics between pandemic-year-one and pandemic-year-two cohorts. When compared to the pandemic-year-one, patients in pandemic-year-two had significantly increased odds of worsening clinical grade (OR =1.028; 95% CI: 1.009–1.048), increased clinical N-stage (OR =1.039; 95% CI: 1.023–1.054), clinical M-stage (OR =1.073; 95% CI: 1.057–1.090) and overall clinical stage (OR =1.055; 95% CI: 1.040–1.071).

Table 3 summarizes the risk-adjusted comparison of treatment characteristics between pandemic-year-one and pandemic-year-two cohorts. When compared to pandemic-year-one patients, pandemic-year-two patients experienced increased time from diagnosis to first treatment (OR =1.162; 95% CI: 1.151–1.173) and had higher odds of not receiving treatment (OR =1.043; 95% CI: 1.018–1.069). Regarding surgical care, pandemic-year-two patients had increased time to surgery (OR =1.120; 95% CI: 1.096–1.145) and were more likely to undergo sublobar resection (OR =1.045; 95% CI: 1.009–1.082) and less likely to undergo pneumonectomy (OR =0.800; 95% CI: 0.708–0.905) with reference to lobectomy. Additionally, compared to pandemic-year-one patients, they had higher odds of undergoing a robotic approach (OR =1.119; 95% CI: 1.078–1.161) and decreased odds of an open approach (OR =0.906; 95% CI: 0.869–0.944), both with reference to the VATS approach. Compared to pandemic-year-one, patients diagnosed in pandemic-year-two had longer time to radiation (OR =1.017; 95% CI: 1.008–1.027), but no differences in reception or sequencing of it. They also had longer time to systemic therapy (OR =1.047; 95% CI: 1.039-1.054) and increased odds of receiving systemic therapy both before and after surgery (OR =1.342; 95% CI: 1.136–1.587). Compared to pandemic-year-one, there were increased odds of utilization of palliative pain management (OR =1.106; 95% CI: 1.021–1.198) and combination palliative therapy (OR =1.087; 95% CI: 1.034–1.143) but no differences in utilization of palliative surgery, radiotherapy or systemic therapy.

Discussion

In this study, we demonstrate that the diagnosis and treatment landscape for patients with NSCLC in the United States remains impacted in the years following the COVID-19 pandemic, with several noteworthy findings. First, patients in pandemic-year-two presented at more advanced clinical stages compared to both pre-pandemic and pandemic-year-one patients. This finding is likely secondary to widespread interruptions in cancer care observed during the COVID-19 pandemic. Previous work has demonstrated a decrease in lung and other cancer screenings, biopsies, diagnoses, and encounters coinciding with the height of the COVID-19 pandemic in the United States (7,8). The authors of these studies predicted that these interruptions would lead to patients presenting with cancer at more advanced stages. Interestingly, the present study not only supports this hypothesis, but also illustrates that the trend continues two years into the pandemic despite widespread dissemination of COVID-19 vaccination and attempts to return to normal healthcare operations. While hospital-level factors likely play a role, it is also important to consider patient-level factors such as fear of contracting COVID-19 that may continue to influence this trend (9). Projects such as the “Return-to-Screening” joint initiative from the American College of Surgeons and the American Cancer Society aim to ameliorate the COVID-induced screening gap with the hopes of identifying lung and other cancers at earlier stages when they are more easily treated (10,11).

Even when controlling for stage of presentation and other oncologic factors, patients in pandemic-year-two experienced universal and surgical treatment delays and were less likely to receive treatment compared to both pre-pandemic and pandemic-year-one patients. Given the non-emergent nature of most cancer care, it is possible that some of the delays and lack of treatment seen in the early pandemic waves was due to prioritization of emergent health services over routine, elective healthcare. However, the persistence of the trend into the second year of the pandemic suggests other factors may be contributing. With respect to surgical delays specifically, there certainly was a “backlog” of cases created by the COVID-19 pandemic; some estimates have suggested it would take up to two years for physicians to work through this backlog, but only if they could operate 10–20% above historical levels (12). Undoubtedly, this would be a challenging task given that hospitals have struggled to return to their former baseline levels of operation following COVID-19. In an analysis of surgical cases at a single quaternary care institution from 2019 to 2021, investigators found that surgical volume declined to 45% at the peak of the pandemic and recovered to just 86%, with inconsistent recovery across surgical subspecialties (13). Thoracic surgery was one of the few specialties that neither recovered procedural volumes in the post-COVID-19 peak period nor returned to pre-COVID-19 volumes in the post-vaccine period (13).

The consequences of treatment delays should not be overlooked. A recent meta-analysis examining mortality due to delays in cancer treatment demonstrated a significant increase in mortality with just a 4-week increase in delayed surgical treatment for breast, colon, bladder, and head and neck cancer and in delayed adjuvant treatment for breast, colon, and head and neck cancer (14). Although it did not achieve statistical significance, a similar trend was seen for four-week delays in surgical and adjuvant treatment of NSCLC (14). In light of the impact of COVID-19 on surgical cancer care, some have proposed a new guiding system for prioritizing care for these patients during COVID-19 and other pandemics that emphasizes better risk/benefit modeling, quality objectives, treatment flexibility, information transparency, and logistical surgical capacities (15).

Despite the negative consequences of the COVID-19 pandemic on the treatment landscape for NSCLC, there are some encouraging findings from this study. First, there were few alterations in the utilization of radiotherapy and systemic therapy observed in pandemic-year-two compared to both pre-pandemic and pandemic-year-one. Perhaps this finding suggests that appropriate multidisciplinary treatment decisions were being made amongst healthcare team members and that patients ultimately were receiving guideline-concordant care, within the limitations of the pandemic. Second, trends in surgical treatment illustrated increased utilization of sublobar resections versus lobectomy and of the robotic approach, in line with current trends and recommendations (16,17).

Outside of these observations, the COVID-19 pandemic provided valuable lessons about healthcare delivery that can inform and improve preparedness for future pandemics. One key takeaway is the importance of early and adaptive planning. The ability to rapidly mobilize resources and develop contingency strategies is critical to managing surges in demand for healthcare services. Supply chain resilience emerged as an are vital area for improvement (18). Stockpiling essential resources, diversifying suppliers, and fostering international collaboration can help prevent similar shortages in future crises. Additionally, policies to ensure efficient resource allocation and distribution will be essential for mitigating the impact of resource constraints. The pandemic also underscored the importance of addressing health equity. Disparities in access to care and outcomes were particularly pronounced among vulnerable populations, such as those with low socioeconomic status, limited transportation access, or preexisting health disparities (19). Efforts to address social determinants of health, such as providing transportation, improving housing stability, and supporting employment, must be integrated into pandemic preparedness to ensure that all populations receive equitable care. Finally, the pandemic also highlighted the immense value of technology, particularly telemedicine, in maintaining healthcare access during periods of physical distancing. Telehealth services allowed patients to consult with providers, manage chronic conditions, and receive mental health support while minimizing the risk of exposure to COVID-19 (20). Moving forward, healthcare systems can build on this progress by expanding telemedicine infrastructure and addressing barriers such as limited access to technology and digital literacy, ensuring equitable access to remote care.

There are some important limitations to consider when interpreting the results of this study. Many of the findings are statistically significant, though small differences in the odds reported may not have clinical relevance. The database from which these data are derived is limited by selection bias and lack of some clinically relevant endpoints, including complications and disease-free survival. While the NCDB contains 30- and 90-day mortality as an endpoint, the reporting of these outcomes is significantly delayed and as such were not available for analysis or comparison. Additionally, NCDB does not contain information on discrete cause of death data to know if death was COVID related, versus oncologic, versus otherwise. Thus, the conclusions of this study may not be broadly generalizable, and future work should investigate the impact of the aforementioned findings on clinical endpoints such as cancer recurrence and survival.

Conclusions

The COVID-19 global pandemic significantly altered the healthcare landscape, and the United States experience with diagnosing and treating NSCLC has not returned to the pre-pandemic baseline. Specifically, when compared to the pre-pandemic year, patients diagnosed with NSCLC in the US during pandemic-year-two continue to present at later clinical stage and experience delays to treatment including delays to staging, first course therapy, surgery and systemic therapy.

Acknowledgments

This work was presented at the European Society of Thoracic Surgeons Annual Meeting, May 26–28, 2024 in Barcelona, Spain.

Funding: This work was supported by an internal grant from the Department of Surgery, University of Colorado School of Medicine. The funding organization 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. C.M.S. and R.A.M. had full data access to all of the data in the study and take full responsibility for its integrity and the accuracy of analysis.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1334/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1334/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1334/coif). J.D.M. reports that he performs consulting for Intuitive Surgical, Inc. R.A.M. reports that he consults for Medtronic, Inc. C.M.S. receives salary support, in part, by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32CA17468. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).This research utilized deidentified patient data and thus was deemed exempt from review by the Colorado Multi-Institutional Review Board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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