The Interaction of COVID-19 and Lung Cancer Treatment: History
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Contributor:
Maristella Bungaro

SARS-CoV-2 infection has dramatically impacted the real-world management of cancer patients. Given the higher risk of a longer and more severe course of COVID-19 disease in lung cancer patients, oncological services have been profoundly reorganized. The world’s leading professional organizations provided new recommendations for the diagnosis, treatment, and follow-up of lung cancer patients during the pandemic. Telemedicine was preferred for non-urgent visits, and screening programs were temporarily suspended, leading to possible diagnostic delays and an estimated increase of cause-specific mortality. The vaccination campaign has definitively inverted this negative trend, with the administration of the booster dose prioritized in frail immune-depressed patients. The efficacy and duration of a humoral immune response in cancer patients still represents an opened question, requiring further investigation in dedicated studies.

  • COVID-19
  • lung cancer
  • lung cancer therapies
  • treatment delays
  • diagnosis delays

1. Effect of COVID-19 on Lung Cancer Diagnosis and Treatment Delays

Quantifying the impact of COVID-19 on cancer diagnosis and treatment delays remains an appealing and challenging topic. Elliss-Brookes et al. showed that cancer diagnostic delays of 2 weeks are associated with a later stage of disease at presentation [1]. Furthermore, diagnosis after an initial admission to an emergency department appears to be associated with worse survival outcomes than all other routes [1]. A recent national population-based modeling study estimated the number of cancer deaths attributable to delays in cancer diagnosis as a result of COVID-19 blockade in the United Kingdom (UK) [2]. The estimated increase in cancer deaths up to 5 years after diagnosis, ranges from 4–8% for lung cancer to 16% for colorectal cancer [2]. A retrospective single-center study conducted at the National Hospital Organization Kyoto Medical Center reported a lung cancer treatment delay rate of 9.1% during the COVID-19 pandemic [3]. Most patients were treated with immunotherapy and delayed administration at their own request. No TKIs-treated patients experienced treatment delays [3]. A recent Italian study presented at the World Conference on Lung Cancer (WCLC) 2021, reported a 4.4% delay in diagnostic, therapeutic, and palliative oncological procedures [4]. A total of 135 procedures were performed in 125 lung cancer patients, most including lung biopsies with diagnostic intent. A nasopharyngeal swab for SARS-CoV-2 screening was performed before each procedure to avoid the spread of the virus within the hospital environments. Six procedures were postponed due to COVID-19 positivity and were performed at recovery with a median delay of 36 days (range 14–55) [4]. The COVID-19 pandemic also required an unprecedented disruption to cancer screening programs. An expert panel of 24 members, including pulmonologists, thoracic radiologists, and thoracic surgeons was formed to provide consensus statements on lung cancer screening and lung nodule evaluation during the pandemic (CHEST Expert Panel Report) [5]. The consensus on delaying the evaluation of lung nodules with indolent features incidentally detected by screening was unanimous. The consensus was less uniform as regards the management of nodules with a mean diameter > 8 mm: if the probability of malignancy is greater than 85%, such nodules should not undergo further diagnostic tests and the treatment approach should be discussed directly within a multidisciplinary setting [5]. The University of Cincinnati oncology group reported the results of their low-dose computed tomography (CT) screening program, comparing a pre-COVID19 baseline period with the pandemic period [6]. Screening was suspended between March and June 2020. There was a total decrease in terms of monthly consultations as well as in the number of new patients screened during the COVID-19 period. The proportion of patients with suspected malignant pulmonary nodules (Lung-RADS 4) was significantly increased after resumption of screening (29% vs. 8%), and a decrease in visit compliance was also observed after reopening the program [6].

2. Effect of Anticancer Treatment on COVID-19 Cancer Patients

Some studies suggested that COVID-19-positive patients receiving systemic anticancer therapy were at higher risk of reporting severe clinical outcomes than patients not receiving any anticancer treatment [7], while other studies did not support this hypothesis [8][9]. Two recent meta-analyses were conducted to clarify whether and which anticancer treatments may produce a detrimental effect on clinical outcomes in COVID-19-positive cancer patients.
Liu et al. analyzed data from 29 studies involving more than 5000 patients undergoing different anticancer treatments [10]. The most common type of treatment among cancer patients with COVID-19 was chemotherapy (30% pooled rate), followed by targeted therapy, radiotherapy, endocrine therapy, surgery, and immunotherapy. There were no significant differences in terms of mortality between patients who received or did not receive anticancer treatment. No effect of anticancer treatment on either intensive care unit admission rate or respiratory support rate was reported. Chemotherapy, however, resulted in a higher mortality rate of patients affected by hematological malignancies who received chemotherapy within 3 months prior to COVID-19 diagnosis [10].
In line with the previous data, Yekedüz and colleagues’ meta-analysis included 16 studies showing that the administration of immunotherapy, targeted therapy, radiotherapy, and cancer surgery in the last 30 days before the diagnosis of COVID-19 did not increase the risk of severe disease and death in cancer patients [11]. Conversely, although there was no increased risk of severe disease, the risk of death from COVID-19 was higher in the chemotherapy group at the multivariate analysis [11].
A major concern for cancer patients is the potential impact of immune checkpoint inhibition on the clinical course of COVID-19 disease [12]. Immunotherapeutic agents such as programmed death-1 (PD-1) inhibitors, programmed death ligand-1 (PD-L1) inhibitors, or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors act by enhancing T-cell functions against tumor cells or viruses. The adaptive immune cells involved in this process, particularly CD8+ and CD4+ T cells, are crucial for regulating immunity against viruses, thus immune checkpoint inhibitors (ICI) may improve the immunological control of viral infections, potentially offering a protection against the development of severe COVID-19 disease.
Growing evidence demonstrated upregulation of immune checkpoint receptors in severe cases of COVID-19 disease characterized by lymphopenia [13]. Indeed, following SARS-CoV-2 infection, cytokine storms induce T-cell hyperactivation and culminate in T-cell depletion, resulting in lymphopenia [14]. T-cell depletion associated with severe COVID-19 can lead to acute respiratory distress syndrome (ARDS). As ICI increases both the number and function of cytotoxic T cells, the clinical features of COVID-19 could make ICI a considerable option for treating COVID-19 disease.
Immunotherapies (convalescent plasma therapy, human monoclonal antibodies, and interferon) have been shown to be safe and effective treatment options for COVID-19-positive patients [15]. Immune checkpoint receptors studied as therapeutic targets for anti-COVID therapies include PD-1 as well as novel receptors like NKG2A and C5aR. Preclinical studies have shown that the inhibition of these immune checkpoint receptors enhances T-cell expansion and antitumor immunity [16]. Particularly, the inhibition of NKG2A increases the anti-tumor activity of T-cells and NK cells [17].
Despite these evidences, some concerns remain on the application of ICI for the treatment of COVID-19. T-cells reactivated by immunotherapy may increase cytokine secretion as well as the risk of a cytokine storm, worsening the course of COVID-19 disease and leading to unfavorable organ injury. The use of the IL-6R inhibitor tocilizumab has been shown to reduce cytokine release, allowing patients to continue receiving immunotherapy [18].
Rogiers and colleagues conducted a multicenter, retrospective cohort study of 110 patients with SARS-CoV-2, contracted during treatment with ICI, with the aim of identifying risk factors for hospitalization and mortality [19]. Thirty-two percent of patients were admitted to hospital. Factors associated with an increased risk of hospitalization were ECOG ≥ 2, combined ICI treatment, and the presence of symptomatic COVID-19 disease. Seventy-three percent of patients either discontinued or stopped ICI due to SARS-CoV-2 infection. The mortality rate was 16% and was related to COVID-19 in almost half of the cases (7%). All patients who died had advanced disease and only four had been admitted to the intensive care unit. COVID-19-related mortality in the ICI-treated population was higher than that reported in the general COVID-19 positive population (1.4–2.3%) but was on the lower side of the range reported for cancer patients (7.6–33%) [19].
Another challenge for lung cancer patients receiving ICI-based therapy during the COVID-19 pandemic is the differential diagnosis between ICI-induced pneumonia and COVID-19-related pneumonia. Indeed, there is a wide range of radiological features and clinical symptoms that overlap, sometimes, complicating the clinical management of these patients.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10040776

References

  1. Elliss-Brookes, L.; McPhail, S.; Ives, A.; Greenslade, M.; Shelton, J.; Hiom, S.; Richards, M. Routes to diagnosis for cancer—Determining the patient journey using multiple routine data sets. Br. J. Cancer 2012, 107, 1220–1226.
  2. Maringe, C.; Spicer, J.; Morris, M.; Purushotham, A.; Nolte, E.; Sullivan, R.; Rachet, B.; Aggarwal, A. The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: A national, population-based, modelling study. Lancet Oncol. 2020, 21, 1023–1034, Erratum in Lancet Oncol. 2021, 22, e5.
  3. Fujita, K.; Ito, T.; Saito, Z.; Kanai, O.; Nakatani, K.; Mio, T. Impact of COVID-19 pandemic on lung cancer treatment scheduling. Thorac. Cancer 2020, 11, 2983–2986.
  4. Bungaro, M.; Bertaglia, V.; Audisio, M.; Parlagreco, E.; Pisano, C.; Cetoretta, V.; Persano, I.; Jacobs, F.; Baratelli, C.; Consito, L.; et al. Oncological Procedures and Risk Assessment of COVID-19 in Thoracic Cancer Patients: A Picture From an Italian Cancer Center. J. Thorac. Oncol. 2021, 16, S923–S924.
  5. Mazzone, P.J.; Gould, M.K.; Arenberg, D.A.; Chen, A.C.; Choi, H.K.; Detterbeck, F.C.; Farjah, F.; Fong, K.M.; Iaccarino, J.M.; Janes, S.M.; et al. Management of Lung Nodules and Lung Cancer Screening During the COVID-19 Pandemic: CHEST Expert Panel Report. Chest 2020, 158, 406–415.
  6. Van Haren, R.M.; Delman, A.M.; Turner, K.M.; Waits, B.; Hemingway, M.; Shah, S.A.; Starnes, S.L. Impact of the COVID-19 Pandemic on Lung Cancer Screening Program and Subsequent Lung Cancer. J. Am. Coll. Surg. 2021, 232, 600–605.
  7. Crolley, V.E.; Hanna, D.; Joharatnam-Hogan, N.; Chopra, N.; Bamac, E.; Desai, M.; Lam, Y.C.; Dipro, S.; Kanani, R.; Benson, J.; et al. COVID-19 in cancer patients on systemic anti-cancer therapies: Outcomes from the CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London) cohort study. Ther. Adv. Med. Oncol. 2020, 12, 1758835920971147.
  8. Nowara, E.; Działach, E.; Grajek, M.; Kolosza, Z.; Huszno, J. Outcome of COVID-19 infection in cancer patients during active systemic anticancer treatment. Single-institution experience. A retrospective analysis. Contemp. Oncol. 2021, 25, 147–152.
  9. van Marcke, C.; Honoré, N.; van der Elst, A.; Beyaert, S.; Derouane, F.; Dumont, C.; Aboubakar Nana, F.; Baurain, J.F.; Borbath, I.; Collard, P.; et al. Safety of systemic anti-cancer treatment in oncology patients with non-severe COVID-19: A cohort study. BMC Cancer 2021, 21, 578.
  10. Liu, H.; Yang, D.; Chen, X.; Sun, Z.; Zou, Y.; Chen, C.; Sun, S. The effect of anticancer treatment on cancer patients with COVID-19: A systematic review and meta-analysis. Cancer Med. 2021, 10, 1043–1056.
  11. Yekedüz, E.; Utkan, G.; Ürün, Y. A systematic review and meta-analysis: The effect of active cancer treatment on severity of COVID-19. Eur. J. Cancer 2020, 141, 92–104.
  12. Luo, J.; Rizvi, H.; Egger, J.V.; Preeshagul, I.R.; Wolchok, J.D.; Hellmann, M.D. Impact of PD-1 Blockade on Severity of COVID-19 in Patients with Lung Cancers. Cancer Discov. 2020, 10, 1121–1128, Published Correction Appears in Cancer Discov. 2021, 11, 520.
  13. Pezeshki, P.S.; Rezaei, N. Immune checkpoint inhibition in COVID-19: Risks and benefits. Expert Opin. Biol. Ther. 2021, 21, 1173–1179.
  14. Zheng, M.; Gao, Y.; Wang, G.; Song, G.; Liu, S.; Sun, D.; Xu, Y.; Tian, Z. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell. Mol. Immunol. 2020, 17, 533–535.
  15. Mansourabadi, A.H.; Sadeghalvad, M.; Mohammadi-Motlagh, H.R.; Rezaei, N. The immune system as a target for therapy of SARS-CoV-2: A systematic review of the current immunotherapies for COVID-19. Life Sci. 2020, 258, 118185.
  16. Wang, Y.; Zhang, H.; He, Y.W. The Complement Receptors C3aR and C5aR Are a New Class of Immune Checkpoint Receptor in Cancer Immunotherapy. Front. Immunol. 2019, 10, 1574.
  17. André, P.; Denis, C.; Soulas, C.; Bourbon-Caillet, C.; Lopez, J.; Arnoux, T.; Bléry, M.; Bonnafous, C.; Gauthier, L.; Morel, A.; et al. Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell 2018, 175, 1731–1743.e13.
  18. Stroud, C.R.; Hegde, A.; Cherry, C.; Naqash, A.R.; Sharma, N.; Addepalli, S.; Cherukuri, S.; Parent, T.; Hardin, J.; Walker, P. Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J. Oncol. Pharm. Pract. 2019, 25, 551–557.
  19. Rogiers, A.; Pires da Silva, I.; Tentori, C.; Tondini, C.A.; Grimes, J.M.; Trager, M.H.; Nahm, S.; Zubiri, L.; Manos, M.; Bowling, P.; et al. Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition. J. Immunother. Cancer 2021, 9, e001931, Erratum in J. Immunother. Cancer 2021, 9.
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