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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 5  |  Page : 29-34

Systemic therapy for thoracic malignancies during the COVID-19 pandemic

Department of Medical Oncology, Tata Memorial Centre, HBNI, Mumbai, Maharashtra, India

Date of Submission03-Apr-2020
Date of Decision06-Apr-2020
Date of Acceptance08-Apr-2020
Date of Web Publication25-Apr-2020

Correspondence Address:
Nandini Menon
Department of Medical Oncology, Tata Memorial Hospital, E Borges Road, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_110_20

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People with cancer are particularly vulnerable during this pandemic and are at high risk of developing a serious COVID-19-related illness. The data that are available suggest that patients with cancer, especially those who are undergoing treatment, are at a higher risk for severe COVID-19 infection and death. These patients need increased surveillance, screening, and better personal protection strategies. Patients with lung and esophageal cancers often require aggressive multidisciplinary treatment. In the era of the COVID-19 pandemic, we face new challenges in delivering systemic therapies (chemotherapy/targeted therapy/immunotherapy) to patients with thoracic malignancies. This review aims to highlight the common issues faced and measures that need to be taken to effectively deliver systemic therapy to patients with thoracic malignancies.

Keywords: COVID-19 pandemic, esophageal cancer, lung cancer, NSCLC, esophagus, SARS

How to cite this article:
Menon N, Noronha V, Joshi A, Patil V, Prabhash K. Systemic therapy for thoracic malignancies during the COVID-19 pandemic. Cancer Res Stat Treat 2020;3, Suppl S1:29-34

How to cite this URL:
Menon N, Noronha V, Joshi A, Patil V, Prabhash K. Systemic therapy for thoracic malignancies during the COVID-19 pandemic. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Jun 3];3, Suppl S1:29-34. Available from: http://www.crstonline.com/text.asp?2020/3/5/29/283284

  Introduction Top

In December 2019, an outbreak of the novel coronavirus, also known as the SARS CoV-2 that caused COVID-19 infection, occurred in Wuhan, in China's Hubei province. In a short span of 3 months, the virus spread to 203 countries across the globe leading to a large number of deaths. At the time of writing, there were 754,948 cases and 36,571 deaths worldwide. In India, 2303 cases have tested positive for COVID-19 till date. People with cancer are particularly vulnerable during this pandemic and are at a high risk of developing a serious COVID-19-related illness.[1],[2],[3] In a densely populated country like India where cancer patients flock to tertiary care centers often far from their homes for the treatment of cancer, the COVID-19 pandemic poses a far bigger threat.

  Covid-19 Infection in Patients With Cancer Top

Most of the data available on COVID-19 infection in patients with cancer are from retrospective studies from China. In one of the earliest reports by Liang et al., 18 of 1590 COVID-19 positive cases (1%) had a history of cancer, which was higher than the incidence of cancer in the overall Chinese population (0.29%). Another study reported a COVID-19 infection rate of 0.79% in patients with cancer (12 of 1524) which was higher than the cumulative incidence of all diagnosed COVID-19 cases reported in Wuhan over the same time period (0.37%).[2] Patients with cancer and COVID-19 had rapid clinical deterioration and a higher incidence of intensive care unit (ICU) admission, invasive ventilation, or death (39% vs. 8%; hazard ratio [HR], 3.56, P = 0·0003).[1] Similar results were also reported in other studies. Yu et al. reported a 25% incidence of severe acute respiratory distress syndrome (SARS) and 1 patient required admission to the ICU,[2] while Zhang et al. reported severe events in 53.6%, ICU admission in 21.4%, life-threatening complications in 35.7%, and death in 28.6% of patients.[3] It was noted that the risk of developing severe events was higher in those who had received tumor-directed treatment (chemotherapy, targeted therapy, immunotherapy, and radiation) within 2–4 weeks of the COVID-19 diagnosis (Liang et al.: odds ratio, 5.34, P = 0.0026; Zhang et al.: HR, 4.079; P = 0.037).[1],[3]

Xia et al. countered that merely observing a higher percentage of patients with cancer in the COVID-19 cohort than the overall population was not sufficient evidence to conclude that patients with cancer had a higher risk of COVID-19.[4] They opined that there could be other factors such as a higher incidence of smoking and chronic obstructive pulmonary disease (COPD) which could explain the increased susceptibility and worse prognosis in cancer patients.[4] It is important to note that in the study by Liang et al., only 4 of 18 patients had received treatment in the month prior to the COVID-19 diagnosis; half of these patients had a disease course longer than 4 years and some of these patients could have been cured.[4] Hence, we cannot generalize these findings to all cancer patients.[3],[4] In all the studies above, cancer patients with COVID-19 infection were older than those without cancer (median age ranged from 63.1 to 66 years) and had other risk factors such as smoking.[1],[2],[3] These studies also had a small heterogeneous (different cancer types, stage, and disease biology) population of cancer patients with other risk factors and this may not be representative of the entire cancer population. However, they provide valuable information and highlight the fact that patients with cancer, especially those who are undergoing treatment, are at a higher risk for severe COVID-19 infections and death. These patients need increased surveillance, screening, and better personal protection strategies.[1],[2],[3]

  Clinical Features of Covid-19 in Cancer Patients Top

The symptoms of COVID-19 infection include fever, dry cough, fatigue, myalgia, and dyspnea.[3],[5],[6] However, the infected persons could also be asymptomatic and yet continue to shed the virus. In a study of cancer patients with COVID-19 infection, 39.2% had one or more comorbidities other than cancer.[3] Tian et al. described two patients of lung cancer who underwent lobectomy and were later diagnosed with COVID-19. They developed symptoms on the 16th and 9th postoperative days, respectively; the first patient never had a fever during the entire course of disease till death from COVID-19.[7]

It is important to note that:

  • Not all patients have symptoms
  • Fever may not be a manifestation in all patients
  • Patients may be in the incubation period while they are admitted for surgery/chemotherapy and may develop symptoms later.

  Pathological Findings of Covid-19 Pneumonia in Cancer Patients Top

There is a lack of information on the pathological findings of COVID-19 pneumonia from autopsy or biopsy. Tian et al. reported the pathological findings of two patients with adenocarcinoma of the lung who underwent lobectomy and were retrospectively diagnosed to have COVID-19 at the time of surgery.[7] Features of diffuse alveolar damage were noted – alveolar edema and proteinaceous and fibrin exudates were seen in the lung tissue. Vascular congestion and mild inflammatory infiltration consisting of mononuclear cells and multinucleated giant cells were seen in the air spaces. There was no significant neutrophil infiltration. Patchy type II pneumocyte hyperplasia and proliferation of interstitial fibroblasts leading to interstitial thickening were noted. Suspected viral inclusion bodies were also seen in some cells. The authors noted that the exudative and proliferative phases of acute lung injury seen in the two cases (edema, inflammatory infiltrates, type II pneumocyte hyperplasia, and organization) were similar to the pathological findings seen at autopsy in SARS cases. However, hyaline membrane formation and squamous metaplasia were not seen in the COVID-19 cases. They concluded that since the pathologic changes seen in the two cases reported by them preceded the onset of clinical symptoms, they could represent an earlier phase of the disease. More studies are needed to learn about the pathology of COVID-19 pneumonia.[7]

  Radiological Features of Covid-19 Pneumonia in Patients With Cancer Top

The common radiological (computed tomography [CT] scan) findings of COVID-19 pneumonia reported in various studies are described below:

  • Majority of patients have bilateral involvement on CT scan; some may have focal unilateral involvement initially (Zhang et al. −21.4%)[3],[8]
  • Ground-glass opacities (GGOs) are the predominant patterns seen on CT scans in various studies (Pan et al. −75%[8] and Zhang et al. −75%[3]). GGOs seem to appear early in the course of the illness, even before symptoms appear and even in the absence of a positive reverse transcriptase–polymerase chain reaction test[7]
  • Crazy-paving pattern: GGO with superimposed inter- and intralobular septal thickening[8]
  • Consolidation: Initially patchy and later diffuse and dense.[3],[8] Zhang et al. reported that the presence of patchy consolidation on the first CT scan increased the risk of developing severe events (HR, 5.0)[3]
  • Interstitial findings: Reticular appearance, fibrous strands, and interlobular thickening.[3]

The evolution of CT scan findings in patients with COVID-19 pneumonia[8]

  • Early stage (0–4 days after onset of the initial symptoms): The predominant feature is the presence of unilateral or bilateral GGOs distributed subpleurally in the lower lobes
  • Progressive stage (5–8 days after the onset of the initial symptoms): Diffuse GGOs, crazy-paving pattern, and consolidation with a bilateral multilobe distribution
  • Peak stage (9–13 days after the onset of the initial symptoms): The area of lung involvement increases. Dense consolidation, diffuse GGOs, crazy-paving pattern, and residual parenchymal bands are seen
  • Absorption stage (≥14 days after the onset of the initial symptom): Once the infection is controlled and the consolidation is gradually absorbed. No crazy-paving pattern seen. However, extensive GGOs may be seen during the absorption of the consolidation.

Polverari et al. described 18-fluorodeoxyglucose (FDG) positron-emission tomography/CT findings in an asymptomatic elderly male with COVID-19, which revealed bilateral, diffuse, intense FDG uptake in the lower lobes and less intense uptake in the other lobes. This corresponded to peripheral predominant GGOs observed in low-dose CT scan. An increased mediastinal lymph node uptake was also noted.[9]

  Lung Cancer and Covid-19 Infection Top

Since most cases of lung cancer are diagnosed late, a large number of patients are present at an advanced stage. Hence, a large number of patients are treated with systemic therapy which includes chemotherapy, immunotherapy, and targeted therapy (e.g., tyrosine kinase inhibitors [TKIs] and anti-angiogenic agents). The question that arises is whether lung cancer patients are at increased risk during the COVID-19 epidemic. There are little data specific to lung cancer and COVID-19 infections at present, but as we navigate through this pandemic, more data will become available.

Three retrospective studies from China reported that lung cancer was the most common cancer (Liang et al. –28%, Yu, et al. –58.3% nonsmall-cell lung cancer [NSCLC], and Zhang – 25%) in patients with COVID-19 infection.[1],[2],[3] In comparison with other cancers, patients with lung cancer did not have a higher probability of severe events.[1] One of the factors which could predispose patients with lung cancer to severe COVID-19 infection could be the higher incidence of smoking among these patients.[4] Angiotensin-converting enzyme 2 (ACE2) is the binding receptor for SARS-CoV2.[10] Cai reported a significantly higher ACE2 gene expression in both the large airway and small airway epithelium of smokers. This could explain the increased susceptibility of smokers to the virus.[11] COPD caused by smoking is an independent risk factor in severe COVID-19 cases.[4],[12] Patients with lung cancer developed dyspnea much earlier in the course of COVID-19 infection as compared to the general population (1.0 vs. 8.0 days)[3],[6] and other cancer patients (1.0 vs. 5.0 days). Patients with lung cancer who have worse baseline lung function and endurance are more likely to develop severe anoxia and progress rapidly. Hence, COVID-19-infected lung cancer patients need urgent attention.[12]

  Specific Issues in Patients With Lung Cancer Top

  • Many lung cancer patients have smoking history and compromised lung function (e.g., COPD) which makes them high risk for COVID-19-related serious events including death[11],[12]
  • Patients on chemotherapy are immunosuppressed and may be at an increased risk for infection with COVID-19
  • Immunotherapy is commonly used for the treatment of advanced lung cancer. Immune-mediated pneumonitis is a potentially life-threatening adverse effect of immunotherapy. The concerns with the use of immunotherapy during the COVID pandemic are:

    1. The potential overlaps between the clinical manifestations of coronavirus-related interstitial pneumonia and the immune-mediated pneumonitis due to programmed death receptor-1 (PD-1)/PD-ligand-1 (/PD-L1) inhibitors. Immune-related pneumonitis could be a confounding factor in patients on immunotherapy who are suspected of having COVID-19 infection. Underlying lung disease, especially interstitial pneumonitis, is considered a risk factor for immune-related pneumonitis. This should be considered while planning treatment with immune checkpoint inhibitors (ICIs). Although hypothetical, the synergy between the lung injury caused by ICI and COVID-19 cannot be ruled out completely[13]
    2. The hypothesis is that synergy between ICI mechanism and COVID-19 pathogenesis may lead to immune hyperactivation and cytokine release syndrome (CRS), leading to acute respiratory distress syndrome (ARDS) or even multiple organ failure.[13]
  • In patients with lung cancer treated with chemoradiation, it is not known whether preexisting radiation pneumonitis in these patients could predispose them to a severe form of COVID-19 infection and ARDS
  • Although the recommendation is to delay chemotherapy, it is not feasible in all cases of lung cancer, especially in small-cell lung cancer, superior vena cava obstruction (SVCO) syndrome, or patients who have significant symptoms due to the disease. If we postpone systemic therapy in these situations, we might lose the window of opportunity to treat these patients; here, starting chemotherapy early may be necessary
  • Lung cancer patients, especially those with advanced disease, require supportive care. In these times of social distancing, access to additional palliative/supportive care including home care is difficult in our setting
  • The impact of delaying adjuvant chemotherapy on survival outcomes in patients with early-stage lung cancer who have undergone surgery is yet to be determined
  • The risk of inhospital transmission of COVID-19 infection to cancer patients.[6],[12]

  Esophageal Cancer and Covid-19 Top

Esophageal cancer is a common cancer in our setting and is often detected in advanced stages. Patients with esophageal cancer suffer from malnutrition, often have significant dysphagia, and are at a risk for aspiration. Poor nutrition and the catabolic state due to cancer lead to the development of hypoalbuminemia, anemia, and vitamin deficiency. These patients are therefore predisposed to infections which lead to higher treatment toxicity. There are no data available to guide the management of esophageal carcinoma during the COVID-19 pandemic.

Specific Issues in patients with esophageal cancer

  • Poor nutritional status and performance status might make them more susceptible to infections
  • Almost all cases of esophageal cancer need to be treated with chemotherapy at some time point during the course of the disease. Delaying chemotherapy, especially in the neoadjuvant/perioperative setting, could adversely impact survival outcomes
  • Aspiration pneumonia is common in esophageal cancer, and patients may present with symptoms similar to that of COVID-19 infection
  • Patients with radiation pneumonitis are at increased risk for severe/complicated COVID-19 illness
  • Patients may need endoscopic procedures which could expose the patient and health-care workers to the risk of COVID-19 infection.

  Recommendations for Systemic Therapy for Thoracic Cancer Therapy during the Covid-19 Epidemic Top

Although there are no formal guidelines for systemic therapy for thoracic cancers, multiple experts from all over the world have put forth recommendations,[14],[15],[16],[17] [Table 1] and these are similar to the protocol that we have followed at our institute.
Table 1: Challenges in cancer care delivery during the coronavirus-19 pandemic

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  1. Prevention

    • Patients with cancer should avoid contact with people with suspected/confirmed COVID-19 infection
    • Decrease the number of hospital visits and inpatient admissions
    • Telemedicine/telephone consultation can be used to decrease the number of hospital visits and for long-term follow up
    • Outpatient chemotherapy (day-care) centers should institute separation measures, for example, sufficient space between seats, use partitions/screens, and wearing of masks by patients and staff. Minimize visits to day-care facilities
    • Better personal protection strategies for patients and their caregivers[3]
    • Currently, there is no strong evidence to recommend the use of prophylactic antivirals or hydroxychloroquine in cancer patients[14]
    • Educate patients and their families about hand hygiene, social distancing, and symptoms of COVID-19 infection.[14]
    • Some authors recommend that patients should stay in an observation ward isolated from other patients for at least 7 days prior to antitumor treatment to minimize the risk of COVID-19 infection.[3] However, this may not be feasible in all cases.

  2. Screening

    • Multiple on-site temperature checks performed at the entrances of the hospital, outpatient clinics, and wards[15]
    • Elicit contact and travel history of all patients and relatives[15]
    • Some authors recommend vigorous screening (including a chest CT scan and nucleic acid testing) of all cancer patients for whom cancer-directed therapy has been planned.[3] Ideally, caregivers and close contacts of cancer patients on treatment should also be tested for COVID-19. However, this may not feasible in all settings due to the limited availability of testing kits. Screening and testing of patients should be as per the national guidelines
    • Patients with symptoms associated with COVID-19 infection, such as fever, cough, or CT scan features suggestive of pneumonia should be considered for testing.[15]

  3. Treatment decisions

    • Immunosuppressive chemotherapy should be avoided if possible or the doses decreased to minimize immunosuppression.[1],[3] The decision to defer chemotherapy has to be individualized both for lung cancer and esophageal cancer.[16] Replace intravenous drugs with oral drugs whenever possible, for example, can consider using epidermal growth factor receptor TKI like gefitinib in advanced NSCLC on compassionate grounds in patients who are not fit to receive chemotherapy[17]
    • Consider modifying intravenous chemotherapy dosing schedules (especially adjuvant or maintenance therapy) to reduce the frequency of hospital visits/admissions, for example, three weekly doses rather than weekly doses of the same regimen if feasible[15],[17]
    • Patients with slowly evolving metastatic cancers who are clinically stable could be given a “drug holiday,” i.e., temporary break in treatment at the discretion of the oncologist, with disease assessment extended to every 2–3 months[17]
    • Immunotherapy (e.g., PD-1/PD-L1 inhibitors) does not cause immunosuppression like chemotherapy and hence could be a choice for the treatment of metastatic lung cancer. However, there are concerns about immune-mediated pneumonitis and CRS leading to severe forms of COVID-19 disease if patients on immunotherapy are infected.[13] Bonomi et al. reported rapid clinical deterioration leading to death in a patient with COVID-19 and metastatic NSCLC in partial remission with immunotherapy (nivolumab) for 7 years. However, it was not clear if the rapid worsening was due to hyperactivation of the immune response due to ICI or coexisting emphysema[18]
    • Patients whose general condition is poor should not receive highly immunosuppressive or aggressive therapy.[3]

  4. Prioritizing patients[17]

  5. During the COVID-19 crisis, resource constraints will lead to the reallocation of medical infrastructure to care for infected patients and routine cancer care will be affected. Oncologists need to prioritize which patients need early treatment and in whom treatment can be deferred.

    The French have proposed guidelines for prioritizing the treatment of cancer patients. Patients who meet the criteria below should be given priority for early treatment:[17]

    • Patients who are being treated with a curative intent, favoring patients aged ≤60 years or with a life expectancy ≥5 years, or both
    • Patients with being treated with a non-curative intent, aged ≤60 years or younger, or life expectancy of 5 years or more, or both, and in the first line setting, for example, patients with driver mutation-positive NSCLC who can be treated with systemic therapy, i.e., TKIs which have no/minimal immunosuppressive effects
    • Patients who are being treated with non-curativeintent, especially those with extensive disease causing significant symptoms or whose symptoms could be life-threatening if treatment is delayed or discontinued, for example, SVCO in lung cancer.

  6. Psychological support

The diagnosis of cancer (especially lung and esophageal cancer) and the adverse effects of cancer-directed therapy can cause significant psychological distress in patients. Patients with cancer and COVID-19 infection will need psychological support to help them cope with their disease.

  Conclusion Top

The treatment of cancer, especially thoracic tumors, is challenging during the COVID-19 pandemic. As oncologists, we need to follow certain principles to enable us to deliver cancer care effectively during the pandemic. The decision to administer systemic therapy should be weighed carefully with the risks involved. As new evidence emerges, we need to incorporate it into our clinical practice.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: A nationwide analysis in China. Lancet Oncol 2020;21:335-7.  Back to cited text no. 1
Yu J, Ouyang W, Chua MLK, Xie C. SARS-CoV-2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China. JAMA Oncol Published online March 25, 2020. doi:10.1001/jamaoncol.2020.0980.  Back to cited text no. 2
Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, et al. Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Ann Oncol 2020. pii: S0923-7534(20)36383-3.  Back to cited text no. 3
Xia Y, Jin R, Zhao J, Li W, Shen H. Risk of COVID-19 for patients with cancer. Lancet Oncol 2020;21:e180.  Back to cited text no. 4
Zhang H, Huang Y, Xie C, The Treatment and Outcome of a Lung Cancer Patient Infected with SARS-CoV-2. J Thorac Oncol 2020. pii: S1556-0864(20)30191-X.  Back to cited text no. 5
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061.  Back to cited text no. 6
Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol 2020. pii: S1556-0864 (20) 30132-5.  Back to cited text no. 7
Pan F, Ye T, Sun P, Gui S, Liang B, Li L, et al. Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia. Radiology. 2020 Feb 13:200370. doi: 10.1148/radiol.2020200370. [Epub ahead of print].  Back to cited text no. 8
Polverari G, Arena V, Ceci F, Pelosi E, Ianniello A, Poli E, et al. 18F-FDG uptake in Asymptomatic SARS-CoV-2 (COVID-19) patient, referred to PET/CT for NonSmall Cells Lung Cancer restaging. J Thorac Oncol 2020. pii: S1556-0864(20)30286-0.  Back to cited text no. 9
Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 2020;63:457-60.  Back to cited text no. 10
Cai G. Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov. medRxiv 2020. [doi: 10.1101/2020.02.05.20020107].  Back to cited text no. 11
Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, Liu XQ. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020. doi: 10.1056/NEJMoa2002032. [Epub ahead of print].  Back to cited text no. 12
Bersanelli M. Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors. Immunotherapy. 2020 Mar 26. doi: 10.2217/imt-2020-0067. [Epub ahead of print].  Back to cited text no. 13
Shankar A, Saini D, Roy S, Jarrahi AM, Chakraborty A, Bharati SJ, et al. Cancer care delivery challenges amidst coronavirus disease – 19 (COVID-19) outbreak: Specific precautions for cancer patients and cancer care providers to prevent spread. Asian Pac J Cancer Prev 2020;21:569-73.  Back to cited text no. 14
Wang Z, Wang J, He J. Active and effective measures for the care of patients with cancer during the COVID-19 spread in China. JAMA Oncol 2020 Apr 1. doi: 10.1001/jamaoncol.2020.1198. [Epub ahead of print].  Back to cited text no. 15
Kutikov A, Weinberg DS, Edelman MJ, Horwitz EM, Uzzo RG, Fisher RI. A war on two fronts: Cancer care in the time of COVID-19. Ann Intern Med 2020 Mar 27. doi: 10.7326/M20-1133. [Epub ahead of print].  Back to cited text no. 16
You B, Ravaud A, Canivet A, Ganem G, Giraud P, Guimbaud R, et al. The official French guidelines to protect patients with cancer against SARS-CoV-2 infection. Lancet Oncol 2020 Mar 25. pii: S1470-2045(20)30204-7. doi: 10.1016/S1470-2045(20)30204-7. [Epub ahead of print].  Back to cited text no. 17
Bonomi L, Ghilardi L, Arnoldi E, Tondini CA, Bettini AC. A rapid fatal evolution of Coronavirus Disease-19 (COVID-19) in an advanced lung cancer patient with a long time response to nivolumab. J Thorac Oncol 2020. pii: S1556-0864(20)30285-9.  Back to cited text no. 18


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