Encyclopedia
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Maristella Bungaro.
Lung cancer patients have been associated with an increased risk of COVID-19 infection, pulmonary complications, and worse survival outcomes compared to the general population. Cancer patients have been associated with an increased risk of COVID-19 infection compared to the general population, due to the systemic immunosuppression caused by both the tumor itself and the anti-cancer treatments. Specifically, lung cancer patients may have an increased risk of pulmonary complications from COVID-19 (such as admission to the intensive care unit for invasive ventilation) with worse survival outcomes.
- SARS-CoV-2
- COVID-19
- lung cancer
1. Epidemiology, Transmission and Clinical Features of SARS-CoV-2 Infection
In December 2019, a pneumonia cluster of unknown etiology appeared in the city of Wuhan (China’s Hubei). Virus isolation and molecular analysis allowed a novel coronavirus (CoV) to be identified, named SARS-CoV-2, by the International Committee on Virus Taxonomy, representing the seventh member of the Coronaviridae family to infect humans. Initial investigations suggested that it could be originally transmitted by bats, as SARS CoV-2 had a nucleotide identity that was a 96% match with bat coronavirus, although the real origin of the infection is still debated [1].
The main clinical features of SARS CoV-2 disease (COVID-19) are fever, cough, muscle pain, and dyspnea, while atypical symptoms include diarrhea and vomiting. The clinical severity of COVID-19 was graded as follows: asymptomatic disease (positive SARS CoV-2 PCR test without clinical signs of infection), mild disease (symptoms of acute upper respiratory tract infection without pneumonia), moderate disease (radiological evidence of pneumonia), severe disease (pneumonia with dyspnea and hypoxemia), and critical disease (pneumonia with acute respiratory distress syndrome, respiratory failure, shock, and multiple organ dysfunction) [2]. More than 80% of COVID-19 cases in adults were classified as mild/moderate, while the majority of infections in children are asymptomatic [2]. Conversely, patients with comorbidities (age ≥ 65 years, smoking habits, chronic cardiovascular and pulmonary diseases, renal insufficiency, sickle cell disease, diabetes, obesity, pregnancy, and cancer) have been associated with a higher risk of progressing to the severe/critical disease stages [3].
The known routes of COVID-19 transmission were droplets as well as direct physical contact, while the possibility of fecal transmission has not been confirmed yet [4]. Vertical transmission has been described only in a small subgroup of cases and has been mainly related to the third trimester of pregnancy [5]. Infected individuals may be contagious before the onset of symptoms [6]. The estimated incubation period is up to 14 days from the time of exposure, with a median incubation ranging from four to five days [6]. Asymptomatic infection, particularly in children, is an important source of disease for the community, as these asymptomatic patients can easily cause familial clusters.
Considering the dramatic increase of the number of COVID-19 confirmed cases, the World Health Organization initially declared this epidemic a public health emergency of international concern on the 30 January 2020, while the COVID-19 disease was definitively declared a pandemic on the 11 March 2020. To date, more than 240 million cases of COVID-19 and about 4.9 million deaths have been reported worldwide [7].
1. Epidemiology, Transmission and Clinical Features of SARS-CoV-2 Infection
In December 2019, a pneumonia cluster of unknown etiology appeared in the city of Wuhan (China’s Hubei). Virus isolation and molecular analysis allowed a novel coronavirus (CoV) to be identified, named SARS-CoV-2, by the International Committee on Virus Taxonomy, representing the seventh member of the Coronaviridae family to infect humans. Initial investigations suggested that it could be originally transmitted by bats, as SARS CoV-2 had a nucleotide identity that was a 96% match with bat coronavirus, although the real origin of the infection is still debated [1].
The main clinical features of SARS CoV-2 disease (COVID-19) are fever, cough, muscle pain, and dyspnea, while atypical symptoms include diarrhea and vomiting. The clinical severity of COVID-19 was graded as follows: asymptomatic disease (positive SARS CoV-2 PCR test without clinical signs of infection), mild disease (symptoms of acute upper respiratory tract infection without pneumonia), moderate disease (radiological evidence of pneumonia), severe disease (pneumonia with dyspnea and hypoxemia), and critical disease (pneumonia with acute respiratory distress syndrome, respiratory failure, shock, and multiple organ dysfunction) [2]. More than 80% of COVID-19 cases in adults were classified as mild/moderate, while the majority of infections in children are asymptomatic [2]. Conversely, patients with comorbidities (age ≥ 65 years, smoking habits, chronic cardiovascular and pulmonary diseases, renal insufficiency, sickle cell disease, diabetes, obesity, pregnancy, and cancer) have been associated with a higher risk of progressing to the severe/critical disease stages [3].
The known routes of COVID-19 transmission were droplets as well as direct physical contact, while the possibility of fecal transmission has not been confirmed yet [4]. Vertical transmission has been described only in a small subgroup of cases and has been mainly related to the third trimester of pregnancy [5]. Infected individuals may be contagious before the onset of symptoms [6]. The estimated incubation period is up to 14 days from the time of exposure, with a median incubation ranging from four to five days [6]. Asymptomatic infection, particularly in children, is an important source of disease for the community, as these asymptomatic patients can easily cause familial clusters.
Considering the dramatic increase of the number of COVID-19 confirmed cases, the World Health Organization initially declared this epidemic a public health emergency of international concern on the 30 January 2020, while the COVID-19 disease was definitively declared a pandemic on the 11 March 2020. To date, more than 240 million cases of COVID-19 and about 4.9 million deaths have been reported worldwide [7].
2. Immune-Pathophysiology of SARS-CoV-2 Lung Injury and Risk of Infection in Lung Cancer Patients
Cancer patients have been associated with an increased risk of COVID-19 infection compared to the general population, due to the systemic immunosuppression caused by both the tumor itself and the anti-cancer treatments [8]. Specifically, lung cancer patients may have an increased risk of pulmonary complications from COVID-19 (such as admission to the intensive care unit for invasive ventilation) with worse survival outcomes [9][10]. A descriptive analysis of patients entering the hospital emergency department for symptoms related to SARS-CoV-2 infection showed that COVID-positive cancer patients were older, harboring ≥ 2 comorbidities, more frequently developing respiratory failure, at higher rates of hospitalization, compared to the general population [11]. Liang et al., in collaboration with the National Health Commission of the People’s Republic of China, identified a prospective cohort of patients hospitalized following the diagnosis of COVID-19 disease. Just 1% of these patients had a history of cancer, with lung cancer accounting for 5 out of 18 cancer patients [12]. A retrospective analysis of 1524 oncological patients by Yu et al. showed an increased risk of SARS-CoV-2 infection (odds ratio (OR), 2.31; 95% confidence intervals (CI), 1.89 to 3.02) compared with the general population [13]. The risk appeared to be increased both in patients with and without active anticancer treatment, with non-small cell lung cancer (NSCLC) patients aging ≥ 60 years old being the most likely to develop COVID-19 [13].
Severe COVID-19 can be considered a hyperinflammatory disorder characterized by a massive activation of the immune system, thus explaining the worse survival outcomes observed in both elderly people and cancer patients. The pathophysiology of COVID-19 has not been entirely clarified yet. In some cases, SARS-CoV-2 induces an excessive and aberrant ineffective host immune response resulting in a severe and potentially fatal lung injury [14]. In severe cases, infection may be associated with the hyperactivation of tissue macrophages that release a storm of cytokines leading to rapidly progressive organ dysfunction. Macrophage activation syndrome (MAS) can be fatal due to pancytopenia, tissue hemophagocytosis, disseminated intravascular coagulation, and hepatobiliary and central nervous system dysfunction [15].
Qin and colleagues investigated the immune response of 452 patients with COVID-19 and reported an increased neutrophil/lymphocyte ratio (NLR) and T lymphopenia, which were more pronounced in severe disease than in mild disease [14]. Patients with severe COVID-19 also reported higher serum levels of pro-inflammatory cytokines (TNF-α, IL-1 and IL-6) and chemokines (IL-8), suggesting a possible role for hyper-inflammatory responses in the pathogenesis of COVID-19 disease [14]. The differentiation of naïve CD4+ T cells into effector and memory cells as well as the balance between these elements is crucial for maintaining an efficient cell-mediated immune response [16]. Patients with severe disease seem to have a dysregulated immune system, with a higher ratio of naive cells to memory cells and a decreased number of regulatory T cells [14]. Regulatory T cells play a crucial role in regulating the activity of a wide range of immune cells to maintain self-tolerance and immune homeostasis [17]. Both helper T and suppressor T cells in patients with COVID-19 were decreased, but a lower level of helper T cells was found in the severe group [14]. An increased expression of pro-inflammatory cytokines and chemokines along with a consumption of CD4+ and CD8+ T cells, could result in severe inflammatory responses in COVID-19 patients. A detailed characterization of natural killer (NK) cells in COVID-19 patients reported elevated plasma levels of interferon (IFN)-α in severe disease resulting in an intense and prolonged IFN-α-induced NK cell response [18]. NK cells appeared to also play a specific role in the development of lung fibrosis for those patients harboring severe COVID-19 disease, as they had impaired antifibrotic activity [18].
Following the characterization of the immune response to SARS-CoV-2 infection, a series of immune-biological biomarkers have been investigated for predicting the outcomes of patients who develop COVID-19 disease. A recent study by Del Valle and colleagues showed that elevated levels of immune-biomarkers involved in the cytokine storm induced by COVID-19 at the time of hospitalization, like both IL-6 and TNF-α, were significantly associated with patients’ survival [19].
Biomarker studies coming from Gustave Roussy Cancer Centre cohort of cancer patients managed for COVID-19 found that high levels of C-reactive protein (PCR) and lactate dehydrogenase (LDH) were associated with the disease severity, while levels of PCR and D-dimer predicted an increased risk of death from COVID-19 disease [20].
Tian et al. demonstrated that pro-inflammatory biomarkers, including TNF-α, IL-6, procalcitonin, and PCR, as well as levels of leukocytes, neutrophils, LDH, coagulation factors and NT-proBNP were significantly associated with an increased severity of COVID-19 disease in cancer patients admitted to a hospital department [21]. In contrast, both albumin levels and albumin-to-globulin ratio were associated with lower disease severity. The TNF-α, NT-proBNP, albumin-to-globulin ratio, and CD4+ T-cells were also associated with an increased risk of death from COVID-19 [21]. In patients with non-severe disease, CD4+ T cells decreased during the first 3 weeks of hospitalization and then progressively increased. The decrease in CD4+ T cells among patients with severe COVID-19 has shown to be more pronounced and prolonged over time [21].
The inflammatory response, along with endothelial dysfunction and microvascular damage, may underlie the effects of COVID-19 infection, including pulmonary fibrosis and subsequent reduced respiratory function [22]. It was observed that 3 months later an acute infection, some patients had CT abnormalities including ground glass opacities (GGO) and subpleural bands [23]. Conversely some patients experienced GGOs resolution at six months while developing fibrosis with or without parenchymal distortion [23]. Pulmonary function tests showed a decreased forced vital capacity (FVC), total lung capacity (TLC), and carbon monoxide diffusing capacity (DLCO) < 80% [22]. Coronavirus infection could directly promote pulmonary fibrosis through two different mechanisms. The nucleocapsid protein of SARS-CoV-1, more than 90% similar to that of SARS-CoV-2, increases levels of transforming growth factor-beta (TGF-β), which acts as a potent promoter of pulmonary fibrosis. Coronaviruses also appear to induce downregulation of the angiotensin-converting-enzyme-2, reducing angiotensin II clearance in the lungs. Angiotensin II may in turn upregulate TGF-β and connective tissue growth factor [22]. Post infection pulmonary fibrosis can be estimated at 2–6% after moderate disease [24]. One year later, the incidence rate of impaired DLCO and persistent radiological lung damage still exceeds 30% [24]. Despite the efforts of the worldwide medical community, there are no treatment options for COVID19-induced pulmonary fibrosis.
Recent studies investigated the critical role of reactive oxygen species (ROS)-associated inflammation pathways (in particular the redox-sensitive transcription factor NRF2) in both COVID-19 and lung cancer, showing some similarities but relevant differences [25]. Indeed, NRF2 is usually activated in lung cancer, facilitating the immune escape of tumor cells, while it is downregulated in COVID-19-positive patients, causing immunosuppressive effects that may worsen COVID-19 symptoms in lung cancer patients [25].
Westblade and colleagues conducted a multicenter study including more than 3000 hospitalized COVID-19-positive patients with the aim of demonstrating the correlation between SARS-CoV-2 viral load and COVID-19 mortality [26]. Results showed a mortality rate of 38.8%, 24.1%, and 15.3% among patients with a high, medium, and low viral load, respectively [26]. Similar results have also been observed in cancer patients, suggesting that the SARS-CoV-2 viral load on admission to hospital could be highly predictive of cause-specific mortality in both patients with and without cancer [26].
A recent retrospective analysis by Luo et al. reported a longer and more severe course of COVID-19 disease in lung cancer patients than in the general United States (US) population, which is consistent with most recent literature data [27]. Both smoking habits and chronic obstructive pulmonary disease were found to be associated with infection severity, whereas tumor characteristics and anticancer treatments did not influence patients’ symptoms. Despite the burden of COVID-19 disease in lung cancer patients, more than half of them achieved recovery, including those who initially required invasive ventilation. Interestingly, only a small fraction (11%) of the overall deaths occurring in lung cancer patients during the pandemic could be ascribed to COVID-19 [27]. The multicenter observational TERAVOLT study showed a COVID-19 mortality rate of 33% along with a 76% hospitalization rate in patients with pleuropulmonary neoplasms [28]. Among the hospitalized patients, 88% met the criteria for intensive care unit admission, but only 10% had access to the intensive care unit. In line with previous data, cigarette smoking has been confirmed to be significantly associated with patients’ mortality in multivariate analysis, whereas the type of systemic anticancer therapy did not influence the survival outcomes of COVID-19-positive patients [28].
Specific anti-viral drugs were administered to hospitalized patients affected by severe forms of infection, including also cancer patients undergoing active antineoplastic treatments. A recent systematic review of the literature did not find a high rate of interactions [29], reporting cardiological side effects with chloroquine/hydroxychloroquine and chemotherapy or trastuzumab [29]. Tocilizumab seems to interfere with the activity of several checkpoint inhibitors, decreasing the concentration of some tyrosine kinase inhibitors (TKIs) (ceritinib, crizotinib, brigatinib, and gefitinib) and docetaxel [29]. Finally, literature currently provides an inconclusive picture of potential interactions between anti-viral drugs and antitumor therapies in cancer patients.
3. Management of Lung Cancer Patients’ Care during the COVID-19 Pandemic
Since the beginning of the pandemic, the oncology community has been pushed to find a balance between protecting cancer patients from the risk of infection and ensuring adequate anti-cancer treatment. In order to comply with social distancing and general public health measures to mitigate the spread of SARS-CoV-2, outpatient oncology services have been thoroughly reorganized. Triage areas have been set up at the entrance of the hospitals in order to administer COVID-19-related symptom questionnaires and provide body temperature checks [30]. Non-essential outpatient visits were postponed or performed via telemedicine (e.g., long-term follow-up visits in surgically resected patients with low risk of relapse). For some patients on active treatment, whenever possible, blood tests were performed at home.
Several leading global professional organizations, including the European Society of Medical Oncology (ESMO), provided recommendations for the diagnosis, treatment, and follow-up of lung cancer patients during the COVID-19 pandemic, as a guide for prioritizing cancer care issues and mitigating potential harm related to the state of health emergency [31]. The proposed recommendations considered three levels of priority (high, medium, and low) for therapeutic interventions, according to the Cancer Care Ontario criteria, Huntsman Cancer Institute, and Magnitude of Clinical Benefit Scale, taking into account patients’ clinical stability, the magnitude of benefit in terms of survival, quality of life, or both, and the negative impact that delayed treatment might have on the overall outcomes [32][33].
Clinical decision making within a multidisciplinary setting has been strongly recommended for a multifactorial risk/benefit assessment, including the extent of the outbreak in the country, the resources of the local health facility, and the risk of individual infection.
Patients with a high suspicion of newly diagnosed lung cancer should be managed within standard diagnostic pathways, without delaying radiological imaging as well as the rest of the diagnostic work-up.
It has been necessary to prioritize early stage disease requiring surgery among the different surgical procedures, while maintaining the highest possible standards, even if both surgical activities and ICU access have been dramatically limited. Considering the risk of SARS-CoV-2 infection in surgically resected patients and the potential immunosuppressive status induced by peri-operative chemotherapy, it has been recommended that the role of adjuvant treatment be reconsidered following thorough discussion with individual patients. The indication should be denied in frail, elderly patients, who are affected by significant comorbidities.
2. Immune-Pathophysiology of SARS-CoV-2 Lung Injury and Risk of Infection in Lung Cancer Patients
Cancer patients have been associated with an increased risk of COVID-19 infection compared to the general population, due to the systemic immunosuppression caused by both the tumor itself and the anti-cancer treatments [8]. Specifically, lung cancer patients may have an increased risk of pulmonary complications from COVID-19 (such as admission to the intensive care unit for invasive ventilation) with worse survival outcomes [9,10]. A descriptive analysis of patients entering the hospital emergency department for symptoms related to SARS-CoV-2 infection showed that COVID-positive cancer patients were older, harboring ≥ 2 comorbidities, more frequently developing respiratory failure, at higher rates of hospitalization, compared to the general population [11]. Liang et al., in collaboration with the National Health Commission of the People’s Republic of China, identified a prospective cohort of patients hospitalized following the diagnosis of COVID-19 disease. Just 1% of these patients had a history of cancer, with lung cancer accounting for 5 out of 18 cancer patients [12]. A retrospective analysis of 1524 oncological patients by Yu et al. showed an increased risk of SARS-CoV-2 infection (odds ratio (OR), 2.31; 95% confidence intervals (CI), 1.89 to 3.02) compared with the general population [13]. The risk appeared to be increased both in patients with and without active anticancer treatment, with non-small cell lung cancer (NSCLC) patients aging ≥ 60 years old being the most likely to develop COVID-19 [13].
Severe COVID-19 can be considered a hyperinflammatory disorder characterized by a massive activation of the immune system, thus explaining the worse survival outcomes observed in both elderly people and cancer patients. The pathophysiology of COVID-19 has not been entirely clarified yet. In some cases, SARS-CoV-2 induces an excessive and aberrant ineffective host immune response resulting in a severe and potentially fatal lung injury [14]. In severe cases, infection may be associated with the hyperactivation of tissue macrophages that release a storm of cytokines leading to rapidly progressive organ dysfunction. Macrophage activation syndrome (MAS) can be fatal due to pancytopenia, tissue hemophagocytosis, disseminated intravascular coagulation, and hepatobiliary and central nervous system dysfunction [15].
Qin and colleagues investigated the immune response of 452 patients with COVID-19 and reported an increased neutrophil/lymphocyte ratio (NLR) and T lymphopenia, which were more pronounced in severe disease than in mild disease [14]. Patients with severe COVID-19 also reported higher serum levels of pro-inflammatory cytokines (TNF-α, IL-1 and IL-6) and chemokines (IL-8), suggesting a possible role for hyper-inflammatory responses in the pathogenesis of COVID-19 disease [14]. The differentiation of naïve CD4+ T cells into effector and memory cells as well as the balance between these elements is crucial for maintaining an efficient cell-mediated immune response [16]. Patients with severe disease seem to have a dysregulated immune system, with a higher ratio of naive cells to memory cells and a decreased number of regulatory T cells [14]. Regulatory T cells play a crucial role in regulating the activity of a wide range of immune cells to maintain self-tolerance and immune homeostasis [17]. Both helper T and suppressor T cells in patients with COVID-19 were decreased, but a lower level of helper T cells was found in the severe group [14]. An increased expression of pro-inflammatory cytokines and chemokines along with a consumption of CD4+ and CD8+ T cells, could result in severe inflammatory responses in COVID-19 patients. A detailed characterization of natural killer (NK) cells in COVID-19 patients reported elevated plasma levels of interferon (IFN)-α in severe disease resulting in an intense and prolonged IFN-α-induced NK cell response [18]. NK cells appeared to also play a specific role in the development of lung fibrosis for those patients harboring severe COVID-19 disease, as they had impaired antifibrotic activity [18].
Following the characterization of the immune response to SARS-CoV-2 infection, a series of immune-biological biomarkers have been investigated for predicting the outcomes of patients who develop COVID-19 disease. A recent study by Del Valle and colleagues showed that elevated levels of immune-biomarkers involved in the cytokine storm induced by COVID-19 at the time of hospitalization, like both IL-6 and TNF-α, were significantly associated with patients’ survival [19].
Biomarker studies coming from Gustave Roussy Cancer Centre cohort of cancer patients managed for COVID-19 found that high levels of C-reactive protein (PCR) and lactate dehydrogenase (LDH) were associated with the disease severity, while levels of PCR and D-dimer predicted an increased risk of death from COVID-19 disease [20].
Tian et al. demonstrated that pro-inflammatory biomarkers, including TNF-α, IL-6, procalcitonin, and PCR, as well as levels of leukocytes, neutrophils, LDH, coagulation factors and NT-proBNP were significantly associated with an increased severity of COVID-19 disease in cancer patients admitted to a hospital department [21]. In contrast, both albumin levels and albumin-to-globulin ratio were associated with lower disease severity. The TNF-α, NT-proBNP, albumin-to-globulin ratio, and CD4+ T-cells were also associated with an increased risk of death from COVID-19 [21]. In patients with non-severe disease, CD4+ T cells decreased during the first 3 weeks of hospitalization and then progressively increased. The decrease in CD4+ T cells among patients with severe COVID-19 has shown to be more pronounced and prolonged over time [21].
The inflammatory response, along with endothelial dysfunction and microvascular damage, may underlie the effects of COVID-19 infection, including pulmonary fibrosis and subsequent reduced respiratory function [22]. It was observed that 3 months later an acute infection, some patients had CT abnormalities including ground glass opacities (GGO) and subpleural bands [23]. Conversely some patients experienced GGOs resolution at six months while developing fibrosis with or without parenchymal distortion [23]. Pulmonary function tests showed a decreased forced vital capacity (FVC), total lung capacity (TLC), and carbon monoxide diffusing capacity (DLCO) < 80% [22]. Coronavirus infection could directly promote pulmonary fibrosis through two different mechanisms. The nucleocapsid protein of SARS-CoV-1, more than 90% similar to that of SARS-CoV-2, increases levels of transforming growth factor-beta (TGF-β), which acts as a potent promoter of pulmonary fibrosis. Coronaviruses also appear to induce downregulation of the angiotensin-converting-enzyme-2, reducing angiotensin II clearance in the lungs. Angiotensin II may in turn upregulate TGF-β and connective tissue growth factor [22]. Post infection pulmonary fibrosis can be estimated at 2–6% after moderate disease [24]. One year later, the incidence rate of impaired DLCO and persistent radiological lung damage still exceeds 30% [24]. Despite the efforts of the worldwide medical community, there are no treatment options for COVID19-induced pulmonary fibrosis.
Recent studies investigated the critical role of reactive oxygen species (ROS)-associated inflammation pathways (in particular the redox-sensitive transcription factor NRF2) in both COVID-19 and lung cancer, showing some similarities but relevant differences [25]. Indeed, NRF2 is usually activated in lung cancer, facilitating the immune escape of tumor cells, while it is downregulated in COVID-19-positive patients, causing immunosuppressive effects that may worsen COVID-19 symptoms in lung cancer patients [25].
Westblade and colleagues conducted a multicenter study including more than 3000 hospitalized COVID-19-positive patients with the aim of demonstrating the correlation between SARS-CoV-2 viral load and COVID-19 mortality [26]. Results showed a mortality rate of 38.8%, 24.1%, and 15.3% among patients with a high, medium, and low viral load, respectively [26]. Similar results have also been observed in cancer patients, suggesting that the SARS-CoV-2 viral load on admission to hospital could be highly predictive of cause-specific mortality in both patients with and without cancer [26].
A recent retrospective analysis by Luo et al. reported a longer and more severe course of COVID-19 disease in lung cancer patients than in the general United States (US) population, which is consistent with most recent literature data [27]. Both smoking habits and chronic obstructive pulmonary disease were found to be associated with infection severity, whereas tumor characteristics and anticancer treatments did not influence patients’ symptoms. Despite the burden of COVID-19 disease in lung cancer patients, more than half of them achieved recovery, including those who initially required invasive ventilation. Interestingly, only a small fraction (11%) of the overall deaths occurring in lung cancer patients during the pandemic could be ascribed to COVID-19 [27]. The multicenter observational TERAVOLT study showed a COVID-19 mortality rate of 33% along with a 76% hospitalization rate in patients with pleuropulmonary neoplasms [28]. Among the hospitalized patients, 88% met the criteria for intensive care unit admission, but only 10% had access to the intensive care unit. In line with previous data, cigarette smoking has been confirmed to be significantly associated with patients’ mortality in multivariate analysis, whereas the type of systemic anticancer therapy did not influence the survival outcomes of COVID-19-positive patients [28].
Specific anti-viral drugs were administered to hospitalized patients affected by severe forms of infection, including also cancer patients undergoing active antineoplastic treatments. A recent systematic review of the literature did not find a high rate of interactions [29], reporting cardiological side effects with chloroquine/hydroxychloroquine and chemotherapy or trastuzumab [29]. Tocilizumab seems to interfere with the activity of several checkpoint inhibitors, decreasing the concentration of some tyrosine kinase inhibitors (TKIs) (ceritinib, crizotinib, brigatinib, and gefitinib) and docetaxel [29]. Finally, literature currently provides an inconclusive picture of potential interactions between anti-viral drugs and antitumor therapies in cancer patients.
The clinical management of stage III NSCLC has been particularly challenging during the COVID-19 pandemic, considering the need to optimize timing and sequencing of chemoradiation without increasing the risk of exposure to SARS-CoV-2. Given its curative potential, the treatment of stage III NSCLC patients maintained the highest priority, considering a delayed 4 week interval for durvalumab consolidation infusions, where permitted by national regulatory agencies.
3. Management of Lung Cancer Patients’ Care during the COVID-19 Pandemic
Since the beginning of the pandemic, the oncology community has been pushed to find a balance between protecting cancer patients from the risk of infection and ensuring adequate anti-cancer treatment. In order to comply with social distancing and general public health measures to mitigate the spread of SARS-CoV-2, outpatient oncology services have been thoroughly reorganized. Triage areas have been set up at the entrance of the hospitals in order to administer COVID-19-related symptom questionnaires and provide body temperature checks [30]. Non-essential outpatient visits were postponed or performed via telemedicine (e.g., long-term follow-up visits in surgically resected patients with low risk of relapse). For some patients on active treatment, whenever possible, blood tests were performed at home.
Several leading global professional organizations, including the European Society of Medical Oncology (ESMO), provided recommendations for the diagnosis, treatment, and follow-up of lung cancer patients during the COVID-19 pandemic, as a guide for prioritizing cancer care issues and mitigating potential harm related to the state of health emergency [31]. The proposed recommendations considered three levels of priority (high, medium, and low) for therapeutic interventions, according to the Cancer Care Ontario criteria, Huntsman Cancer Institute, and Magnitude of Clinical Benefit Scale, taking into account patients’ clinical stability, the magnitude of benefit in terms of survival, quality of life, or both, and the negative impact that delayed treatment might have on the overall outcomes [32,33].
Clinical decision making within a multidisciplinary setting has been strongly recommended for a multifactorial risk/benefit assessment, including the extent of the outbreak in the country, the resources of the local health facility, and the risk of individual infection.
Patients with a high suspicion of newly diagnosed lung cancer should be managed within standard diagnostic pathways, without delaying radiological imaging as well as the rest of the diagnostic work-up.
It has been necessary to prioritize early stage disease requiring surgery among the different surgical procedures, while maintaining the highest possible standards, even if both surgical activities and ICU access have been dramatically limited. Considering the risk of SARS-CoV-2 infection in surgically resected patients and the potential immunosuppressive status induced by peri-operative chemotherapy, it has been recommended that the role of adjuvant treatment be reconsidered following thorough discussion with individual patients. The indication should be denied in frail, elderly patients, who are affected by significant comorbidities.
The clinical management of stage III NSCLC has been particularly challenging during the COVID-19 pandemic, considering the need to optimize timing and sequencing of chemoradiation without increasing the risk of exposure to SARS-CoV-2. Given its curative potential, the treatment of stage III NSCLC patients maintained the highest priority, considering a delayed 4 week interval for durvalumab consolidation infusions, where permitted by national regulatory agencies.
As for newly diagnosed metastatic disease, it has been suggested that potential alternative administration schedules for the immune checkpoint inhibitors be evaluated, using either nivolumab every 4 weeks or pembrolizumab every 6 weeks, where permitted, in order to reduce patients’ access to the oncological day hospitals [34,35]. A home delivery service was also recommended for patients receiving either tyrosine kinase inhibitors (TKIs) or oral chemotherapy, while venous or subcutaneous antiresorptive bone-protective therapy should be discontinued. Second-line therapies should be carefully evaluated at single patient level.
As for newly diagnosed metastatic disease, it has been suggested that potential alternative administration schedules for the immune checkpoint inhibitors be evaluated, using either nivolumab every 4 weeks or pembrolizumab every 6 weeks, where permitted, in order to reduce patients’ access to the oncological day hospitals [34][35]. A home delivery service was also recommended for patients receiving either tyrosine kinase inhibitors (TKIs) or oral chemotherapy, while venous or subcutaneous antiresorptive bone-protective therapy should be discontinued. Second-line therapies should be carefully evaluated at single patient level.
