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ORIGINAL RESEARCH

published: 13 April 2022


doi: 10.3389/fonc.2022.857076

Outcomes and Risk Factors of


Edited by:
Hajo Zeeb,
Leibniz Institute for Prevention
Patients With COVID-19 and Cancer
Research and Epidemiology (LG),
Germany
(ONCORONA): Findings from The
Reviewed by:
Helena Carreira,
Philippine CORONA Study
University of London, United Kingdom
Deniz Can Guven, Adrian I. Espiritu 1,2,3*†‡, Ramon B. Larrazabal Jr.4†‡, Marie Charmaine C. Sy 1†,
Hacettepe University, Turkey Emilio Q. Villanueva III5, Veeda Michelle M. Anlacan 1† and Roland Dominic G. Jamora 1,6*†
*Correspondence: 1Department of Neurosciences, College of Medicine and Philippine General Hospital, University of the Philippines Manila,
Roland Dominic G. Jamora
Manila, Philippines, 2 Department of Clinical Epidemiology, College of Medicine, University of the Philippines Manila,
rgjamora@up.edu.ph
Manila, Philippines, 3 Division of Neurology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto,
Adrian I. Espiritu
ON, Canada, 4 Division of Medical Oncology, Department of Medicine, College of Medicine and Philippine General Hospital,
aiespiritu@up.edu.ph
University of the Philippines Manila, Manila, Philippines, 5 Department of Pathology, College of Medicine and Philippine

ORCID: General Hospital, University of the Philippines Manila, Manila, Philippines, 6 Institute for Neurosciences, St. Luke’s Medical
Roland Dominic G. Jamora Center, Taguig, Philippines
orcid.org/0000-0001-5317-7369
Adrian I. Espiritu
orcid.org/0000-0001-5621-1833 Background: A study conducted in China on patients with coronavirus disease 2019
Ramon B. Larrazabal Jr. (COVID-19) showed that cancer conferred a five times increased risk for needing intensive
orcid.org/0000-0003-4538-416X
Marie Charmaine C. Sy
care admission and mortality; No data has yet been collected and published from the
orcid.org/0000-0003-1135-6400 Philippines. Thus, the investigators conducted this substudy to determine the association
Veeda Michelle M. Anlacan
of having a history of cancer with clinical outcomes among patients included in the
orcid.org/0000-0002-1241-8805

Philippine CORONA Study.
These authors share first authorship
Methodology: Multi-center, retrospective cohort design
Specialty section:
This article was submitted to
Results: A total of 244 patients had a history of cancer, out of 10,881 COVID-19
Cancer Epidemiology and Prevention, hospital admissions. After adjusting for different confounding variables of interest, having
a section of the journal
cancer was significantly associated with a 75% increased odds of having severe/
Frontiers in Oncology
critical COVID-19 at nadir (CI 95% 1.32, 2.33; p < 0.001). After adjusting for different
Received: 18 January 2022
Accepted: 21 March 2022 confounding variables of interest, having cancer was significantly associated with the
Published: 13 April 2022 following time-to-event outcomes: 72% increase in hazard of in-hospital mortality (CI 95%
Citation: 1.37, 2.16; p < 0.001), 65% increase in hazard of respiratory failure (CI 95% 1.31, 2.08;
Espiritu AI, Larrazabal RB Jr, Sy MCC,
Villanueva EQ III, Anlacan VMM and
p < 0.001), and 57% increase in hazard of being admitted to ICU (CI 95% 1.24, 1.97;
Jamora RDG (2022) Outcomes and p < 0.001).
Risk Factors of Patients With COVID-19
and Cancer (ONCORONA): Findings Conclusion: A history of cancer conferred poorer clinical outcomes on adult, hospitalized
from The Philippine CORONA Study. COVID-19 patients.
Front. Oncol. 12:857076.
doi: 10.3389/fonc.2022.857076 Keywords: cancer, mortality, respiratory failure, intensive care unit admission, outcomes, COVID-19

Frontiers in Oncology | www.frontiersin.org 1 April 2022 | Volume 12 | Article 857076


Espiritu et al. COVID-19 and Cancer

INTRODUCTION Patient Selection


We included a total enumeration of all patients that fulfilled the
On the 11th of March 2020, the World Health Organization inclusion criteria, as follows: adults older than or of 19 years of
declared that the coronavirus disease 2019 (COVID-19), caused age; confirmed cases via COVID-19 real-time reverse
by the severe acute respiratory syndrome coronavirus 2 (SARS- transcription polymerase chain reaction (RT-PCR) of patients’
CoV-2), was a global pandemic (1). Since then, it has affected nasopharyngeal swab samples which were performed by testing
more than 420 million people, causing 5.86 million deaths, as of centers accredited by the Department of Health (Philippines);
February 19, 2022 worldwide (2). At the same time in the clinical symptoms/signs ascribed to COVID-19 infection;
Philippines, this pandemic has affected an estimated 3.65 patients with the appropriate disposition by the end of the data
million people with more than 55 thousand deaths (3). collection period (e.g., discharged, transferred to another
Studies have been conducted worldwide that evaluated the hospital, or died). Individuals who were transferred to another
demographic profiles, clinical characteristics and clinical outcomes hospital were excluded to prevent duplication of data. Adult
among COVID-19 patients. There are other specific subgroups, COVID-19 patients who had new-onset neurological symptom/s
such as those with cancer, that are susceptible to the disease and are (NNS) were grouped under the exposed cohort while those
associated with poorer clinical outcomes such as requiring oxygen without NNS (non-NNS) were classified under the unexposed
support, needing intensive care, and increased mortality (4). A study cohort. The information on the patient selection is detailed in the
conducted in Italy supported this when they showed that cancer published study protocol (8).
conferred a near-doubled death rate among patients with cancer
than those without who were infected with COVID 19 (5). Data Collection Procedure and
Furthermore, the published data from the COVID-19 in patients Management
with thoracic malignancies study and clinical impact of COVID-19 All investigators, sub-investigators, and hired data collectors
patients with cancer study, both being registries from different obtained pertinent information for this study. An electronic
countries, showed that age, smoking, male sex, functional status, data collection form was formulated using Epi Info™ Software
and the presence of active cancer were associated with higher (Version 7.2.2.16). The form was pilot-tested and a formal
mortality. Specifically, the COVID-19 study done by the Gustave orientation and workshop was conducted to ensure accurate
Roussy Hospital identified that those older than 70 years old, with a data collection as explained in the published protocol (8).
smoking history, advanced cancer (metastatic), those undergoing Moreover, the data collection forms used did not contain any
cytotoxic chemotherapy, and those having an Eastern Cooperative information that could identify the patients.
Oncology Group performance status of more than or equal to 2 are The following pertinent data were obtained: demographic
risk factors that increased the risk of death (6). data; other clinical profile data/comorbidities; neurological
The studies mentioned were conducted in Europe, South history; date of illness onset; respiratory and constitutional
America, United States of America, Japan, and China; and no symptoms associated with COVID-19; COVID-19 disease
data was collected and published from the Philippines, a severity25 at nadir; data if neurological manifestation/s were
developing country with a different healthcare system (7). Thus, present at onset prior to respiratory symptoms and the specific
the investigators in collaboration with the Philippine CORONA neurological manifestation/s present at onset; neurological
Study Group conducted a substudy on the cohort of COVID-19 symptoms; date of neurological symptom onset; new-onset
patients with a history of cancer; looking at their clinical outcomes neurological disorders or complications; date of new
(i.e., mortality, respiratory failure, duration of ventilator neurological disorder or complication onset; imaging done;
dependence, intensive care unit (ICU) admission, length of ICU cerebrospinal fluid analysis; electrophysiological studies;
and hospital stay compared to those with no history of cancer (8). treatment given; antibiotics given; neurological interventions
given; date of mortality and cause/s of mortality; date of
respiratory failure onset, date of mechanical ventilator
MATERIALS AND METHODS cessation and cause/s of respiratory failure; date of first day of
ICU admission, date of discharge from ICU and indication/s for
Study Design ICU admission; other neurological outcomes at discharge; date
This was a retrospective substudy of patients with cancer of hospital discharge; and final disposition.
enrolled in the Philippine CORONA study, which was a
nationwide, multicentre, comparative, retrospective, cohort Statistical Analysis
study of hospitalized patients with COVID-19 from February Baseline characteristics and clinical outcomes of the patients
2020 to December 2020. The study protocol was registered in were summarized by descriptive statistics. Numerical variables
ClinicalTrials.gov (NCT04386083) and published previously (8). were described as mean and standard deviation, if the data were
normally distributed as assessed by the Shapiro-Wilk test for
Study Setting normality, and as median and interquartile range, if otherwise.
This substudy was based on the data gathered from 37 major Categorical variables were described as frequency and proportion.
hospitals/study sites from various regions in the Philippines. The These different baseline characteristics and clinical outcomes were
specific sites are listed in the published study protocol (8). compared between the two groups: with cancer, and without

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Espiritu et al. COVID-19 and Cancer

cancer. A significant difference in the mean/median/mean-rank of reaction) from February to December 2020 were included in
the different numerical variables between the two groups was the study. Initially, there were 118 patients who did not meet the
determined by Student’s t test for the variables with normally age criteria, and were excluded in the final analysis in
distributed data, while Mann-Whitney U test was done for non- the published paper (9). Out of the 10,881 patients included in
normally distributed variables. Comparison of the proportions of the final analysis, 244 of them had a history of cancer
the different categorical variables between the two groups was (see Figure 1).
determined by chi-squared test or Fisher exact test.
The associations between having cancer and the different Demographic and Clinical Profile
individual dichotomous outcome variables of interest were The participants’ age were divided into 2 categories: those aged
determined by multivariable binary logistic regression. Survival 60 years and above and those aged 18-59 years. The cancer group
analysis was also done for time-to-event data of mortality, had equal participants for both age groups [122 (50%) vs 122
respiratory failure, and admission to ICU. The time-to-event (50%)], while majority of the group without cancer were
were right-censored on time-to-discharge as the exit from the belonged to the less than 60 years old age group [6925 (65.1%)
time-at-risk among those who have not experienced the event, vs 3,712 (34.9%), p < 0.001]. There was a considerable number of
i.e., mortality, respiratory failure, or admission to ICU, during women in the study and significantly more reported having no
the hospital stay. The associations between having cancer and the history of cancer [4950 (46.5%), p < 0.001].
different time-to-event outcome variables of interest were The most common non-neurologic co-morbidity reported
determined by multivariable Cox proportional hazards was hypertension in both groups with and without cancer. There
regression. The logistic and Cox proportional hazards was a significant difference between groups, with those with a
regression models were adjusted for the following pre- history of cancer reporting to have more hypertension [113
determined confounders: age group, sex, smoking status, (46.3%) vs 3534 (33.2%), p < 0.001]. The most common
hypertension, chronic cardiac disease, chronic respiratory neurologic co-morbidity reported was a history of stroke which
disease, chronic kidney disease, and chronic neurologic disease. was significantly different between both groups [14 (5.7%) vs 307
A cutoff of p < 0.05 identifies having cancer as a significant (2.9%), p 0.009], higher in those with a history of cancer than
predictor of the different outcomes of interest. Kaplan-Meier those without.
curves were constructed to visualize the survival curves of those The group of patients with cancer (or a history of cancer) was
with cancer versus without cancer; adjusted for the different noted to have a significantly higher incidence of respiratory
confounding variables of interest, and also for the different time- symptoms: cough [128 (52.5%) vs 4,283 (40.3%), p < 0.001],
to-event outcome variables. dyspnea [98 (40.2%) vs 2605 (24.5%), p < 0.001), and increased
sputum production [28 (11.5%) vs 609 (5.7%), p < 0.001]. It also
showed that the cancer group was given more glucocorticoids [93
RESULTS (38.1%) vs 2751 (25.9%), p < 0.001], antiviral medications [60
(24.6%) vs 1842 (17.3%)], and antibiotics [221 (90.6%) vs 8793
A total of 10,999 patients were hospitalized who tested positive (82.7%), p < 0.001] as treatment for COVID 19, compared to
for COVID 19 (by reverse transcription polymerase chain those patients without a history of cancer. The cancer group

FIGURE 1 | Flow of patients.

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Espiritu et al. COVID-19 and Cancer

experienced more symptoms and needed more medications of patients done in New York City (12, 13). The investigators
(see Table 1). attribute this high mortality in our study to a difference in
healthcare systems. In the Philippines the universal health care
Comparison of Outcomes of the law is partially and poorly implemented (14) and majority of the
Patients According to Whether They Filipinos belong to the lower socioeconomic status (15). Since
Have Cancer or Not 1992, the Philippine Government has devolved the management
Our study showed that there was significantly higher proportion and delivery of health services from the national Department of
of patients with cancer with the following outcomes of interest Health to locally elected provincial, city, and municipal
than those patients without cancer: severe/critical COVID-19 at governments. This was highlighted in a review of studies on
nadir [125 (52.1%) vs 3936 (37.5%), p < 0.001], in-hospital the health care cost and financing of patients with malignancies
mortality [80 (32.8%) vs 1622 (15.3%), p < 0.001], respiratory (especially for those with central nervous system malignancies).
failure [76 (31.1%) vs 1532 (14.4%), p < 0.001], intensive care The cost of care (especially in cancer care) in the country is not
unit (ICU) admission [78 (31.9%) vs 1662 (15.6%), p < 0.001], covered by most insurance companies and is scarcely subsidized
hospital stay > 14 days [113 (46.3%) vs 4191 (39.4%), p 0.026], by the state, which means that cancer care is an out-of-pocket
and neurologic presentation or complication [80 (32.8%) vs 2211 cost for most if not all Filipinos (14, 15).
(20.8%), p < 0.001] (see Table 2). Our cohort also analyzed multiple centers nationwide, with
Additionally, there were significantly lower proportion of varying levels of healthcare services, and not just a single-center
patients with cancer with the following outcomes of interest study (9). There was also the consideration of poorer
than those patients without cancer: IMV dependence >5 days socioeconomic factors (residence in rural areas and low level of
[234 (95.9%) vs 10,429 (98%), p < 0.032] and full/partial income) which are associated with increased mortality (16). The
neurologic recovery among patients with neurologic other outcomes of interest in this study were consistent with
presentation at admission or neurologic complication during other studies such as respiratory failure and needing intensive
hospital stay [34 (72.3%) vs 1605 (86.3%), p < 0.001]. care which, along with increased mortality, all portend to poor
clinical outcomes shown in patients with cancer (6, 7).
The Relationship of Clinical Outcomes In response to the surge of cases in the country, the Philippine
of Interest Among Patients With and General Hospital (PGH) was designated by the Philippine
Without Cancer Department of Health as a COVID-19 referral center. The
After adjusting for the different confounding variables of interest, Department of Health also designated other institutions in
having cancer was significantly associated with the following different regions as COVID-19 referral centers. This meant
outcomes: those with cancer have 75% increased odds of having that since March 31, 2020 non-emergency clinics, elective
severe/critical COVID-19 at nadir [OR 1.75, 95% CI 1.32, 2.33], a procedures and surgeries and non-COVID-19 admissions were
54% increased odds of having neurologic presentations/ intermittently being suspended or limited depending on the
complications [OR 1.54, 95% CI 1.17, 2.03], and a 54% threat of the COVID surge. Realizing the possible detrimental
decreased odds of having full/partial neurological improvement effects of the cessation of oncologic care, the Cancer Institute
if they have neurologic presentations/complications [OR 0.46, adapted strategies that allowed the continuation of cancer care
95% CI 0.22, 0.93] (see Table 3). and maintained the safety and well-being of both the patients
After adjusting for the different confounding variables of and the health professionals. Patients seen at the clinic were
interest, having cancer was significantly associated with the limited and appointments given were based on a prioritization
following time-to-event outcomes (see Table 4): 72% increase scheme. The Philippine government has relegated the duty of
in hazard of in-hospital mortality [HR 1.72, 95% CI 1.37, 2.16], vaccinating individuals to the local governments. As of this
65% increase in hazard of respiratory failure [HR 1.65, 95% CI writing, 62.2 million people (56.8%) have been fully
1.31, 2.08], and a 57% increase in hazard of being admitted to vaccinated (2).
ICU [HR 1.57, 95% CI 1.24, 1.97]. The following outcomes are The pandemic has a profound impact on cancer care in all
depicted in the Kaplan-Meier curves (see Figure 2). aspects. Specifically, the screening, diagnosis, and treatment in
both medical and surgical oncology. With the participants
recruited many months into the pandemic, those patients with
DISCUSSION cancer might have had their treatment delayed due to the burden
the pandemic imposed on the healthcare system (i.e. prioritizing
Previous literature have shown that patients with cancer are as patients with COVID-19) as well as the government response
susceptible to being infected with the SARS-CoV-2 virus as those (i.e. logistics problem due to the numerous and repeated
without (10, 11). This study emphasized that the cohort of lockdowns imposed) (16). With these roadblocks to cancer
COVID-19 patients with cancer had a higher risk for in- care, an international collaborative group recommended a
hospital mortality, respiratory failure, and needing intensive prioritization scheme that can maximize health benefits, taking
care. This was consistent with early studies reported in China into consideration the patient, their disease, and prognosis (17).
(4–7). There was a 72% increase in in-hospital mortality was in In our study, we were able to show a significant difference of
stark contrast to the other studies that analyzed a similar cohort neurologic manifestations between patients with and without

Frontiers in Oncology | www.frontiersin.org 4 April 2022 | Volume 12 | Article 857076


Frontiers in Oncology | www.frontiersin.org

Espiritu et al.
TABLE 1 | Clinicodemographic characteristics of the stratified according to having cancer or without.

With cancer (n = 244) Without cancer (n = 10,637) p-value

Socio-demographic data
Age group <0.001
19 – 59 y, n (%) 122 (50.0) 6925 (65.1)
≥ 60 y, n (%) 122 (50.0) 3712 (34.9)
Female, n (%) 149 (61.1) 4950 (46.5) <0.001
Ever-smoker (past/current), n (%) 31 (12.7) 995 (9.4) <0.001
Non-neurologic comorbidities, n (%)
Hypertension 113 (46.3) 3534 (33.2) <0.001
Diabetes mellitus 64 (26.2) 2127 (20.0) 0.016
Chronic cardiac diseasea 20 (8.2) 492 (4.6) 0.009
Chronic respiratory diseaseb 12 (4.9) 604 (5.7) 0.611
Chronic kidney disease 24 (9.8) 587 (5.5) 0.004
Chronic liver disease 1 (0.4) 59 (0.6) 1.000
HIV/AIDS 1 (0.4) 36 (0.3) 0.569
Past neurologic history, n (%)
Stroke/cerebrovascular 14 (5.7) 307 (2.9) 0.009
Epilepsy 1 (0.4) 26 (0.2) 0.458
Neurodegenerativec 3 (1.2) 41 (0.4) 0.075
Headache syndrome - 5 (0.05) 1.000
Demyelinating disorder - 2 (0.02) 1.000
Central nervous system infection - 5 (0.05) 1.000
Peripheral nervous system disordersd - 15 (0.1) 1.000
Respiratory and constitutional symptoms, n (%)
5

Fever 107 (43.8) 3820 (35.9) 0.011


Cough 128 (52.5) 4283 (40.3) <0.001
Dyspnea 98 (40.2) 2605 (24.5) <0.001
Rhinorrhea 9 (2.7) 598 (5.6) 0.193
Sputum production 28 (11.5) 609 (5.7) <0.001
Sore throat 15 (6.2) 736 (6.9) 0.638
Diarrhea 19 (7.8) 578 (5.4) 0.111
Fatigue 16 (6.6) 697 (6.6) 0.998
Others 53 (21.7) 1621 (15.2) 0.006
New onset neurological symptoms, n (%)
Headache 10 (4.1) 597 (5.6) 0.308
Nausea or vomiting 8 (3.3) 150 (1.4) 0.026
Seizure 5 (2.0) 91 (0.9) 0.064
Altered mental statee 28 (11.5) 490 (4.6) <0.001
April 2022 | Volume 12 | Article 857076

Olfactory or taste dysfunction 14 (5.7) 649 (6.1) 0.814


Dysfunctions of other sensesf 9 (3.7) 157 (1.5) 0.012
Bulbar symptomsg 3 (1.2) 119 (1.1) 0.755
Motor symptoms 13 (5.3) 233 (2.2) 0.001
Sensory symptoms 4 (1.6) 49 (0.5) 0.031
Myalgia 5 (2.0) 251 (2.4) 0.752

COVID-19 and Cancer


Othersh - 33 (0.3) 1.000
New-onset neurological disorders/complications, n (%)
Encephalopathyi 35 (14.3) 609 (5.7) <0.001
Symptomatic seizure/status epilepticus 7 (2.9) 118 (1.1) 0.022
Stroke/cerebrovasculari 13 (5.3) 354 (3.3) 0.087

(Continued)
Espiritu et al. COVID-19 and Cancer

p-value cancer. Only altered mental status was shown to be more in those

<0.001
1.000
1.000

0.385
0.003
0.001
0.255
with cancer. The presence of new-onset neurologic

Includes acute disseminated encephalopmyelitis, optic neuritis, sensory ganglionitis, radiculitis, anterior horn syndrome, peripheral neuritis (Guillain-Barre Syndrome [GBS], other than GBS), neuromuscular disorder, and myositis.
manifestations could be explained by the COVID-19 infection
itself, as reported in a meta-analysis showing that COVID 19
may manifest primarily or initially with neurologic
manifestations (18). This neurologic involvement was also seen
neuropathologically, where direct central nervous system
involvement was documented (19). Although the direct
relationship between COVID 19 and its effect on the nervous
system is yet to be fully established, it has been postulated that
there is the presence of severe hemorrhage and hypoxia,
increased thrombotic events (as seen in infections like COVID
Without cancer (n = 10,637)

19), acute disseminated encephalomyelitis – like changes,


encephalitis, and meningitis. Lastly, there have been reports of
2751 (25.9)

1842 (17.3)
8793 (82.7)
3809 (35.9)
1002 (9.4)
14 (0.1)

SARS-CoV-2 (the causative agent of COVID 19) reactivity in the


7 (0.1)

brain (19). While COVID-19 patients present with abnormal


electroencephalograms, these are not specific for COVID 19
alone and may be attributed to COVID-19 causing
inflammation in the brain or other extracranial causes of
encephalopathy (20).
A study done in Europe analyzed 1044 patients with active
cancer diagnosed with COVID 19 and their outcomes, around
30.6% patients in the study died, while 92.5% of whom had a
cause of death recorded as due to COVID-19. Furthermore, the
all-cause case–fatality rate in patients with cancer who were
infected with COVID-19 was significantly associated with sex
and older age (21). A meta-analysis done in China included 15
Includes peripheral nervous system infection, peripheral nerve disease, neuromuscular junction disorder, and muscle disorder.
Includes bronchial asthma. chronic obstructive pulmonary disease, restrictive lung disease, and other pulmonary conditions.

studies from different countries around the world showed that


With cancer (n = 244)

Includes facial paresthesia, facial weakness, dysarthria, dysphonia, dysphagia, tongue weakness, and neck weakness.

the overall case fatality rate of COVID 19 patient with cancer was
Any acute cerebrovascular disease (no need to distinguish between cerebrovascular disease infarction, hemorrhagic).

22.4% (22). The relationship between cancer an COVID 19 was


Includes heart failure, coronary artery disease, prior history of myocardial infarction, and other cardiac conditions.
221 (90.6)
93 (38.1)
27 (11.1)
60 (24.6)

96 (39.3)

further established by another study which analyzed patients



with cancer who were recently and had infection with COVID
19. It showed cancer patients who underwent recent
chemotherapy and were associated with worse outcomes. This
is explained by the possible immunosuppressive effects of
chemotherapy (4).
Includes chloroquine, hydroxychloroquine, convalescent plasma, and other therapies.

The other effects of the pandemic on patients with cancer


Includes tremor, dystonia, choreoathetosis, bradykinesia, ataxia, and meningisimus.

include tumor stage migration and higher early mortality which


are both directly and indirectly caused. A study showed that
there were more patients seen during the pandemic that
presented to have inoperable or metastatic cancer (49.8% vs
39%). This meant poorer prognosis and that these patients most
likely would only warrant palliative care (chemotherapy and/or
Includes encephalitis, meningitis, and meningoencephalitis.

radiotherapy) instead of being seen at an earlier stage or less


Includes visual, hearing, and vestibular dysfunctions.

extensive disease in which curative treatment (surgery,


Includes encephalopathy, and anoxic brain injury.

chemotherapy, and/or radiotherapy) maybe be offered (23).


Includes dementia and movement disorders

Includes remdesivir, lopinavir, and ritonavir.

The 90-day mortality after the diagnosis of cancer was also


Includes altered sensorium and confusion.

higher during the pandemic at 10.5% vs 6.6%. The reason cited in


k
Central nervous system infection

the study was the higher rate of advanced disease at first referral/
Treatment/s received, n (%)

diagnosis which was attributed to the indirect effect of the


pandemic from the lockdowns and logistical limitations for
TABLE 1 | Continued

patients to seek consult and have work-up done (23). Another


study supported the findings of the study cited earlier wherein, as
Glucocorticoids

Antibacterial
Tocilizumab

compared to the pre-pandemic times, the diagnosis of the six


Antiviralm

most common types of cancers were lesser (24). It does not mean
Othersn
Othersl

that the actual incidence of cancer has decreased but most likely,
the ability of patients to seek consult and the facilities to conduct
m
b

n
a

k
f

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Espiritu et al. COVID-19 and Cancer

TABLE 2 | Clinical outcomes of COVID-19 patients stratified according to having cancer or without.

Outcomes With cancer Without cancer p-value

(n = 244) (n = 10,637)
COVID-19 severity at nadir <0.001
Mild/moderate, n (%) 115 (47.9) 6575 (62.6%)
Severe/critical, n (%) 125 (52.1) 3936 (37.4%)
In-hospital mortality, n (%) 80 (32.8) 1622 (15.2%) <0.001
Time to in-hospital mortality in days, median (IQR) 15 (9) 15 (14) 0.613
Respiratory failure, n (%) 76 (31.2) 1532 (14.4) <0.001
Time to respiratory failure in days, median (IQR) 5 (4) 5 (4) 0.815
Duration of IMV in days, median (IQR) 13 (10.5) 13 (12) 0.899
IMV dependence ≤ 5 days, n (%) 10 (4.1) 208 (2) 0.032
IMV dependence > 5 days, n (%) 234 (95.9) 10,429 (98)
Admitted to ICU, n (%) 78 (32) 1662 (15.6) <0.001
Time to ICU admission in days, median (IQR) 4.5 (3) 5 (4) 0.721
Length of ICU stay in days, median (IQR) 15 (10) 15 (12) 0.996
ICU stay ≤ 7 days, n (%) 9 (11.5) 263 (15.8) 0.308
ICU stay > 7 days, n (%) 69 (88.5) 1399 (84.2)
Length of hospital staya in days, median (IQR) 14 (10) 13 (9) 0.026
Hospital stay ≤ 14 days, n (%) 131 (53.7) 6446 (60.6) 0.029
Hospital stay > 14 days, n (%) 113 (46.3) 4191 (39.4)
Neurologic presentation or complication, n (%) 80 (32.8) 2211 (20.8) <0.001
Neurologic outcomeb 0.006
Full/partial neurologic recovery, n (%) 34 (72.3) 1605 (86.4)
No recovery, n (%) 13 (27.7) 253 (13.6)

ICU, intensive care unit; IMV, invasive mechanical ventilation; IQR, interquartile range.
a
Derived from overall length of stay for patients who were never admitted to ICU; excludes length of ICU stay for those who were admitted in the ICU.
b
Patients with recorded data for neurologic outcome (n=1905).

the work-up for the diagnosis of cancer have been hampered due to those who were deemed to have been cured of their cancer, with
to the logistic limitations caused by the pandemic. the latter having comparable outcomes to those with no cancer (25).
The results of this study allowed us to understand the Second, only the history of cancer was noted; with no data on the
consequences of COVID-19 on adult patients with cancer. type of cancer, site, stage, and treatment history. The retrospective
First, mortality rate of adult hospitalized cancer patients with nature of the study was also subject to recall and selection bias. With
COVID-19 was high, with estimates at around 32-33%. Second, the limitations identified, we recommend that a more detailed
cancer was also associated with longer hospital stays, respiratory cancer history be taken with a prospective study design to
failure, and needing ICU admission. Third, COVID-19 patients corroborate our conclusions.
with cancer needed more interventions like steroids, antivirals, The findings in this study raise the need to further investigate
and antibiotics. These pieces of information may provide context patients with cancer, focusing on the type and stage of their
and ideas for other investigators to write and conduct cancer, as well as the status of their needs and treatment in
prospective studies and/or randomized clinical trials for this relation to the pandemic. The data also stresses the importance of
specific vulnerable subgroup. giving more support to vulnerable groups like patients with
The investigators have identified several limitations of this study. cancer during this time of the pandemic, in order to improve
First, a detailed history on the cancer of the participants could have their outcomes. Furthermore, this study adds to the body of
given us more insight on other relevant variables and their knowledge regarding COVID 19 and cancer. Physicians will be
relationships; Since poorer functional status and those presently able to prognosticate this cohort of patients and government
receiving cytotoxic chemotherapy had poorer outcomes compared agencies in charge of the pandemic response will be able to

TABLE 3 | Association of having a cancer with the different outcomes of interest.

Outcomes* Crude OR 95% CI Adjusted OR* 95% CI

Severe/critical COVID-19 at nadir 1.82 1.41, 2.35 1.75 1.32, 2.33


Neurological presentation/complication 1.86 1.42, 2.44 1.54 1.17, 2.03
Full/partial neurological improvement 0.41 0.21, 0.79 0.46 0.22, 0.93
IMV dependence > 5 days 0.47 0.24, 0.89 0.58 0.3, 1.13
ICU stay > 7 days 1.44 0.71, 2.92 1.39 0.68, 2.83
Hospital stay > 14 days 1.33 1.03, 1.71 1.22 0.94, 1.58

IMV, invasive mechanical ventilation; ICU, intensive care unit.


*Individual univariate multiple logistic regression analysis with independent variable malignancy adjusted for age group, sex, smoking history, hypertension, diabetes, chronic cardiac
disease, chronic kidney disease, chronic respiratory disease, and chronic neurologic disease.

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Espiritu et al. COVID-19 and Cancer

TABLE 4 | Association of having cancer with the different outcomes of interest (time-to-event analysis).

Outcomes* Crude HR 95% CI Adjusted HR* 95% CI

In-hospital mortality 2.07 1.65, 2.59 1.72 1.37, 2.16


Respiratory failure 2.33 1.85, 2.94 1.65 1.31, 2.08
ICU admission 2.25 1.79, 2.83 1.57 1.24, 1.97

ICU, intensive care unit.


*Individual univariate multiple Cox proportional hazard regression analysis with independent variable malignancy adjusted for age group, sex, smoking history, hypertension, diabetes,
chronic cardiac disease, chronic kidney disease, chronic respiratory disease, and chronic neurologic disease.

A B

C D

FIGURE 2 | Kaplan-Meier failure plot of the full cohort (A), and the comparison of the probability of (B) mortality, (C) respiratory failure, and (D) ICU admission,
between COVID-19 patients with and without cancer.

appropriately categorize patients with cancer as a priority for AUTHOR CONTRIBUTIONS


vaccinations and should also be given exceptions to logistic
restrictions when seeking treatment. AE: Conceptualization, data curation, formal analysis, interpretation
of data, writing-original draft, writing-review, and editing. RL: Data
curation, formal analysis, interpretation of data, writing-original
draft, writing-review, and editing. MS: Conceptualization, data
CONCLUSION curation, formal analysis, interpretation of data, writing-review,
and editing. EV: Data curation, formal analysis, interpretation of
A history of cancer conferred poorer clinical outcomes on adult, data, and editing. VA: Conceptualization, data curation, formal
hospitalized patients with COVID-19 with increased mortality, analysis, interpretation of data, writing-review, and editing. RJ:
respiratory failure, and need for ICU admission. Other Conceptualization, data curation, formal analysis, interpretation of
demographic and clinical risk factors associated with cancer data, writing-original draft, writing-review, and editing. All authors
patients with COVID-19 were older age, female sex, multiple contributed to the article and approved the submitted version.
co-morbidities, and having more respiratory symptoms and
neurologic manifestations.

ACKNOWLEDGMENTS
DATA AVAILABILITY STATEMENT We would like to thank the members of the The Philippine
CORONA Study Group for their contributions: Asian Hospital
The raw data supporting the conclusions of this article will be and Medical Center, Muntinlupa City (Corina Maria Socorro A.
made available by the authors, without undue reservation. Macalintal, MD; Joanne B. Robles, MD), Baguio General Hospital

Frontiers in Oncology | www.frontiersin.org 8 April 2022 | Volume 12 | Article 857076


Espiritu et al. COVID-19 and Cancer

and Medical Center, Baguio City (Paulo L. Cataniag, MD; Manolo MD; Al Inde John A. Pajantoy, MD; Josephine Cecilia V. Roque,
Kristoffer C. Flores, MD, MBA), Cagayan Valley Medical Center, MD; Paul Emmanuel L. Yambao, MD), Ospital ng Makati,
Tuguegarao City (Noreen Jhoanna C. Tangcuangco-Trinidad, Makati City (Christian Paul B. Banday, MD; Nehar A.
MD), Capitol Medical Center, Quezon City (Dan Neftalie A. Pangandaman, MD; Avery Gail C. Wasil, MD), Perpetual
Juango, MD; Giuliani Renz G. Paas, MD), Cardinal Santos Succour Hospital, Cebu City (Elrey P. Inocian, MD; Jarungchai
Medical Center, San Juan City (Audrey Marie U. Chua, MD, Anton S. Vatanagul, MD), University of the Philippines Manila,
Valmari Estrada, MD, Philip Rico P. Mejia, MD, Therese Franz B. Philippine General Hospital, Manila (Almira Doreen Abigail O.
Reyes, MD), Chong Hua Hospital, Cebu City (Maria Teresa A. Apor, MD; Carissa Paz Maligaso, MD), Philippine Heart Center,
Cañete, MD; Ferdinand Renfred A. Zapata, MD), De La Salle Quezon City (Prinz Andrew M. Dela Cruz, MD; Maricar P.
University Medical and Health Sciences Institute, Dasmariñas Yumul, MD) Research Institute for Tropical Medicine,
City, (Franko Eugenio B. Castillo, MD; Romulo U. Esagunde, Muntinlupa City (Ma. Alma E. Carandang-Concepcion, MD),
MD; Jean B. Gantioque, MD), Dr. Jose N. Rodriguez Memorial San Juan De Dios Educational Foundation Inc. Hospital, Pasay
Hospital, Caloocan City (Maritoni C. Abbariao, MD; Geramie M. City (Ma. Caridad V. Desquitado, MD; Carl Kevin L. Julao, MD),
Acebuque, MD; Eunice Lovelle R. Clarito, MD), Dr. Pablo O. San Lazaro Hospital, Manila (Dante P. Bornales, MD), Southern
Torre Memorial Hospital, Bacolod City (Evram V. Corral, MD), Isabela Medical Center, Santiago City (Generaldo D. Maylem,
East Avenue Medical Center, Quezon City (Marian Irene C. MD; Mark Joseph F. Cuntapay, MD), Southern Philippines
Escasura, MD; Marissa T. Ong, MD), Jose B. Lingad Memorial Medical Center, Davao City (Annabelle Y. Lao-Reyes, MD;
Regional Hospital, San Fernando City (Arnold A. Pineda, MD; Aileen Lee, MD; Nadia O. Manlegro, MD; Dave Mar Palere,
Khassmeen D. Aradani, MD), Jose R. Reyes Memorial Medical MD) St. Luke’s Medical Center, Bonifacio Global City, Taguig
Center, Manila (Joseree-Ann S. Catindig, MD; Mark Timothy T. City (Lina C. Laxamana, MD; Diana-Lynn S. Que, MD; Jeryl Ritzi
Cinco, MD; Mark Erving H. Ramos, MD), Lung Center of the T. Yu, MD), St. Luke’s Medical Center, Quezon City (Ma. Socorro
Philippines, Quezon City (Romulus Emmanuel H. Cruz, MD; C. Martinez, MD; Alexandria E. Matic, MD; John Angelo S. Perez,
Marita B. Dantes, MD; Norberto A. Francisco, MD; Rosalia A. MD), The Medical City, Pasig City (Glenn Anthony A.
Teleg, MD), Makati Medical Center, Makati City (Krisverlyn B. Constantino, MD; Aldanica R. Olano, MD; Liz Edenberg P.
Bellosillo, MD; Jean Paolo M. Delfino, MD; Cid Diesta, MD; Quiles, MD, Artemio A. Roxas, Jr, MD; Jo Ann R. Soliven, MD;
Rosalina B. Espiritu-Picar, MD; Julie Anne V. Gamboa, MD; Cara Michael Dorothy Frances Montojo-Tamayo, MD), University of
Camille M. Matute, MD; Franzelle P. Padilla, MD; John Joshua Q. Santo Tomas Hospital, Manila (Ma. Lourdes P. Corrales-Joson,
Punsalan, MD), Manila Doctors Hospital, Manila (Ma. Epifania MD; Jojo R. Evangelista, MD), University of the East Ramon
V. Collantes, MD; Charmaine B. Que, MD; Hanifa Ibrahim A. Magsaysay Memorial Medical Center, Inc., Quezon City (Ma.
Sampao, MD; Maxine Camela S. Sta. Maria, MD), Medical Center Clarissa B. Nuñez, MD; Marietta C. Olaivar, MD; Dominique Q.
Manila, Manila (Marita M. Fuentes, MD; Jennifer Justice F. Perez, MD), Veterans Memorial Medical Center, Quezon City
Manzano, MD; Rizza J. Umali, MD), New Era General (Mark Deneb O. Armeña, MD; Robert A. Barja, MD), Vicente
Hospital, Quezon City (Marc Conrad C. Molina, MD), Sotto Memorial Medical Center, Cebu City (Joshua Emmanuel E.
Northern Mindanao Medical Center, Cagayan de Oro City Abejero, MD; Maritzie R. Eribal, MD), Western Visayas Medical
(Hazel Claire M. Minerva-Ang, MD; Arturo F. Surdilla, MD; Center, Iloilo City (Ryndell G. Alava, MD), Zamboanga City
Loreto P. Talabucon Jr., MD; Natasha F. Wabe, MD), Quirino Medical Center, Zamboanga City (Muktader A. Kalbi, MD;
Memorial Medical Center, Quezon City (Maria Victoria Manuel, Nasheera W. Radja, MD; Mohammad Elshad S. Sali, MD).

Study. Lancet (2020) 395(10241):1907–18. doi: 10.1016/S0140-6736(20)


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