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Vong et al. J Cancer Metastasis Treat 2020;6:54 I http://dx.doi.org/10.20517/2394-4722.2020.116 Page 5 of 11

CoV-2 antibody production (seroconversion) in cancer versus non-cancer patients after symptomatic
[16]
COVID-19 .

Patients with lung cancers are thought to be at disproportionately increased risk of death from COVID-19,
[17]
with mortality ranging from 25%-33% . However, the increase in mortality is thought to be related to
patient-specific features as outlined above, rather than cancer-specific features or specific anti-cancer
treatments such as tyrosine kinase inhibitors (TKIs), cytotoxic chemotherapy, or immune checkpoint
inhibitors (ICIs), albeit compared to cancer instead of non-cancer controls. The ongoing TERAVOLT study
is the largest cohort study of patients with thoracic malignancies including non-small cell lung cancer
(NSCLC), small cell lung cancer (SCLC), mesothelioma, thymic epithelial tumours and other pulmonary
[17]
neuroendocrine neoplasms . Preliminary results have been reported from the first 200 patients enrolled,
of whom 151 (76%) had NSCLC, 29 (15%) had SCLC, 36 (18%) and 147 (74%) had stage III and stage IV
disease respectively, and 147 (74%) were on active anticancer therapy. Forty-eight (33%), 34 (23%), and
28 (19%) were on chemotherapy, ICIs or TKIs alone respectively, and 20 (14%) were on chemotherapy
in combination with ICIs. The majority of patients received therapy administered for a median of 7 days
(interquartile range 0-17) before COVID-19 diagnosis. Eighty percent of patients developed pneumonia
or pneumonitis, and 27% of patients developed acute respiratory distress syndrome. The mortality rate
was 33%. In multivariable analysis, only smoking was significantly associated with an increased risk of
death. Although the findings above are highly relevant and have allowed quick dissemination of real-time
data and guidance in the midst of a global pandemic, observational studies are associated with inherent
limitations such as confounders and biases such as selection and recall bias. Larger patient cohorts and
longer-term follow-up are required to confirm the findings as well as ascertain long-term effects on lung
cancer mortality.

Another key consideration in managing patients with lung cancers during the COVID-19 pandemic lies in
their overlapping clinical and radiological features, which poses unique challenges in the identification of
suspect cases of COVID-19 and calls for a high index of suspicion. Overlapping symptoms include cough,
dyspnoea, fever, arthralgia/myalgia and fatigue or malaise [9,10,14,15,17,18] . Furthermore, immunocompromised
lung cancer patients, especially those on myelosuppressive chemotherapy, may present atypically without
fever. In addition to clinical symptoms, a detailed history of possible exposure to suspected or confirmed
cases of COVID-19 is critical. Patients with thoracic malignancies often have thoracic imaging performed
routinely as part of follow-up and response assessment. Chest radiography (CXR) and computed
tomography (CT) appearances overlap amongst patients with primary thoracic malignancies, pulmonary
metastases, treatment-related pneumonitis (from TKIs, ICIs, or radiotherapy), and COVID-19, with
common features such as the presence of unilateral or multifocal ground glass opacities. In COVID-19,
ground glass opacities are usually peripheral and/or bibasal. Pulmonary nodules, pleural effusions and
mediastinal lymphadenopathy which are seen in thoracic malignancies are less commonly observed in
[19]
patients with COVID-19 . SARS-CoV-2 RT-PCR from nasopharyngeal or respiratory tract (e.g., sputum)
samples remains the gold standard for COVID-19 diagnosis.

The unique clinical challenges relating to clinical risk and overlapping presenting features as described
above require the use of distinct surveillance protocols from non-cancer patients. On 8 May 2020, the
Singapore MOH amended its enhanced Swab-and-Send-Home (SASH) criteria to mandate SARS-CoV2
RT-PCR testing for all cancer patients on chemotherapy presenting with ARI with or without fever. Patients
who are not medically unstable nor assessed to require inpatient admission can be managed under the
enhanced SASH protocol when they are seen at primary care, instead of being referred to NCID or hospital
EDs. Patients with positive results will be recalled and conveyed to NCID. The capacity for diagnostic
testing of COVID-19 has been gradually increased nationwide, with expansion from hospitals to Public
Health Preparedness Clinics (PHPCs) and polyclinics in the community. From 1 July 2020, the SASH