Introduction
Severe acute respiratory syndrome-related coronaviruses (SARS-CoVs) are single-stranded,
positive-sense, nonsegmented, enveloped RNA viruses. In the past, the world has seen
three other “novel” CoV outbreaks that caused substantial destruction. The recent
outbreak of COVID-19 has created an alarming fear, apprehension, and worry world over.
With the number of confirmed cases on the rise, governments and health-care workers
are faced with the challenge of curbing its spread and the resultant damage.
The first pandemic of the 21st century was caused by the SARS-CoV-1.[1] It presented as atypical pneumonia in the latter half of 2002[2],[3] in Foshan, Guangdong Province, mainland China, from where it spread to Hong Kong,[4] Vietnam, Canada, and Singapore.[5] The epidemic lasted about a year infecting over 8000 individuals and resulting in
774 deaths with a case fatality rate of 9.5%.[6]
A decade later, another CoV emerged in the Middle East called the Middle East respiratory
syndrome-CoV (MERS-CoV). MERS-CoV was a zoonotic virus that entered into the human
lineage from dromedary camels in the Arabian Peninsula.[7] In comparison to SARS-CoV, MERS-CoV had a much higher case fatality rate of around
35%, but it has allowed control due to low R 0 (basic reproduction number).[6] It claimed around 858 lives with 2494 laboratory-confirmed cases.
In December 2019, reports emerged of a cluster of cases in Wuhan, China, ailing with
pneumonia of unknown etiology. In the following week, a strain of CoV was isolated
from these patients. It was initially referred to as novel CoV 2019 but was officially
named by the World Health Organization (WHO) on 11 February 2020 as COVID19. The incubation
period of the virus ranges from 2 to 14 days (median 5 days). Angiotensin-converting
enzyme-2 (ACE2) has been found as the receptor through which the virus invades the
respiratory mucosa.[8]
In the last century, the world has faced pandemics such as the plague; smallpox; cholera;
yellow fever; and Spanish-, Russian-, Hong Kong- and Asian-flu that claimed millions
of lives. The H1N1 swine flu pandemic which originated in Mexico in 2009 spread across
the rest of the world infecting roughly 1.4 billion people and killing between 151,700
and 575,400 according to the Centers for Disease Control and Prevention (CDC). Ebola
spread across Guinea, Liberia, and Sierra Leone between 2014 and 2016 reporting 28,610
cases and 11,308 deaths.
Cancer patients receive special consideration as they represent a subgroup that is
immunocompromised and is under high risk. While coping up with the fears associated
with the diagnosis of cancer, the COVID-19 pandemic places another hurdle in their
path. It is, therefore, necessary to analyze factors that predict outcomes in these
patients so that they can be treated effectively.
Methodology
A systematic search was performed to identify all relevant studies on PubMed, Embase,
and Google Scholar published until April 5, 2020, as per the PRISMA guidelines. The
following MESH terms were used: Beta coronavirus or severe acute respiratory syndrome
coronavirus 2 or COVID-19 or Coronavirus Infections or Coronavirus and Neoplasms or
Cancer Care Facilities or Cancer Survivors or Radiation Oncology or Drug Therapy or
Chemotherapy, Adjuvant or Chemotherapy, Cancer, Regional Perfusion or Induction Chemotherapy
or Maintenance Chemotherapy. Additional searches were done from reference lists of
included studies to avoid any missing articles.
Relevant articles that reported the incidence, demographic and clinical characteristics,
treatment, and outcomes of cancer patients infected by COVID-19 were included in the
analysis. Articles were graded as per the level of evidence they reported using the
Oxford Centre for Evidence-Based Medicine system. The search resulted in 559 articles
that were further screened according to the inclusion and exclusion criteria. Articles
based on influenza and SARS were excluded, which resulted in 14 articles which were
dealt with cancer during the COVID-19 pandemic, however demographic data were available
only in three studies. As the sample size was less with limited data available from
the quoted studies, statistical analysis was not done.
Results
The search resulted in 559 articles that were further screened by the authors. Out
of these, 14 articles fulfilled the inclusion criteria.
Demographics
The demographic details about the cancer patients in various studies are tabulated
in [Table 1].
Table 1
Demographic distribution of COVID‑19‑positive cancer patients
|
Parameters
|
Zhang et al.,[9]
n (%)
|
Liang et al.,[10]
n (%)
|
Yu et al.,[11]
n (%)
|
|
CHD: Coronary heart disease, COPD: Chronic obstructive pulmonary disease
|
|
N
|
28
|
18
|
12
|
|
Male:female
|
17 (60.7): 11 (39.28)
|
12 (66.7): 6 (33.3)
|
10 (83.33): 2 (16.7)
|
|
Mean age (years)
|
65
|
63.1
|
66
|
|
Comorbidity
|
11 (39.28)
|
22.2%
|
-
|
|
Diabetes
|
4 (14.3)
|
2 (11.11)
|
-
|
|
Chronic cardiovascular and cerebrovascular disease (including hypertension and CHD)
|
4 (14.3) 3 (16.7)
|
-
|
|
Chronic pulmonary disease (including COPD and asthma)
|
1 (1.36)
|
1 (5.5)
|
-
|
|
Chronic liver disease (including chronic hepatitis B and cirrhosis)
|
2 (7.1)
|
-
|
-
|
|
Chronic renal disease
|
1
|
1 (5.5)
|
-
|
A nationwide analysis in China by Liang et al.
[10] found that cancer patients were of advanced age and more likely to be associated
with a history of smoking, severe baseline computed tomography (CT) manifestation,
and a higher risk of progressing to severe events (hazard ratio [HR]: 3.56, 95% confidence
interval [CI] [1.65–7.69]; P < 0.0001).
The most common symptom on admission in Zhang et al.'s study was fever (n = 23, 82.1%), followed by cough (n = 22, 81%) and fatigue (n = 18, 64.3%). Blood parameters were suggestive of anemia in 21 (75%), lymphopenia
in 23 (82.1%), and leukopenia in 9 (32.1%) patients. Levels of albumin were on the
lower side in 25 (89.3%) patients, and 92.9% of the patients had normal prolactin
levels. Levels of serum globulin (11 [39.3%]), lactate dehydrogenase (10 [50%]), C-reactive
protein levels (23 [82.1%]), erythrocyte sedimentation rate (16 [57.1%]), and D-Dimer
(11 [39.3%]) were found to be elevated. Chest CT on admission was abnormal in the
entire cohort.
Higher dose of corticosteroids was administered for longer duration in patients with
severe events, but it failed to demonstrate any statistically significant difference
(dose [mg/kg/day]: 1.0 vs. 0.6, period [day]: 3.0 [2.0–4.8] vs. 5.0).
A significant number of severe cases required mechanical ventilation (noninvasive:
53.3% vs. 0%, P < 0.001) as compared to nonsevere intensive care unit (ICU) cases (noninvasive: 13.3%
vs. 0%, P < 0.001). The median period of mechanical ventilation for noninvasive ventilation
was 2.5 days (1.0–5.0 days) and 2.5 days for invasive cases.
Incidence of cancer among COVID-19 patients
Eight studies have specified the number of cancer patients being infected in the COVID-19
pandemic. The results are summarized in [Table 2].
Table 2
Incidence of cancer among COVID‑19‑positive patients
|
Study
|
n
|
Malignancy
|
Incidence rate (%)
|
|
Huang et al.
[12]
|
41
|
1
|
2.43
|
|
Chen et al.
[13]
|
99
|
1
|
1.01
|
|
Wang et al.
[14]
|
138
|
10
|
7.24
|
|
Guan et al.
[15]
|
1099
|
10
|
0.90
|
|
Liang et al.
[10]
|
1590
|
18
|
1.1
|
|
Wu et al.
[16]
|
80
|
1
|
1.25
|
|
Liu et al.
[17]
|
137
|
2
|
1.45
|
|
Wu and McGoogan[18]
|
20,982
|
107
|
0.5
|
Single-institutional studies from China like that of Huang et al.,[12] Chen et al.,[13] Wang et al.,[14] and Wu et al.
[16] have reported the incidence of cancer among the various other COVID-19-positive
cases.
Distribution of various cancers
The studies which looked into the distribution of various cancers among the COVID-19
patients are summarized in [Table 3].
Table 3
Distribution of various cancers among the COVID‑19‑positive patients
|
Types of cancer
|
Zhang et al.
[9] (n=28), n (%)
|
Liang et al.
[10] (n=18), n (%)
|
Yu et al.
[11] (n=12), n (%)
|
|
Lung cancer
|
7 (25.0)
|
5 (28)
|
7 (58.3)
|
|
Esophagus cancer
|
4 (14.3)
|
-
|
-
|
|
Breast cancer
|
3 (10.7)
|
3 (16.6)
|
1 (8.3)
|
|
Larynx
|
2 (7.1)
|
-
|
-
|
|
Liver cancer
|
2 (7.1)
|
-
|
-
|
|
Prostatic cancer
|
2 (7.1)
|
-
|
-
|
|
Cervical cancer
|
1 (3.6)
|
-
|
-
|
|
Gastric cancer
|
1 (3.6)
|
-
|
-
|
|
Colorectal cancers
|
2 (7.1)
|
4 (22.2)
|
2 (16.7)
|
|
Adrenal neoplasm
|
-
|
1 (5.5)
|
-
|
Among the several sites of cancer in the study by Zhang et al.,[9] lung (25%, n = 7) was the most common site, and it was observed that symptoms of dyspnea occurred
much earlier in cancer patients compared to that in the general population (1.0 [0.0–3.5]
vs. 8.0 [5.0–13.0] days)[19] and other cancer patients (1.0 [0.0–3.5] vs. 5.0 [4.0–7.0] days).
Lung was also the most frequent site (28% n = 5) in the study by Liang et al.,[10] however, compared to other sites, patients with lung cancer (1/5, 20% vs. 8/13,
62%) did not have much likelihood of developing severe events.
Treatment history
The treatment protocol among the various studies was according to their institutional
protocols. Detailed treatment history was not available in all the studies. [Table 4] summarizes the antitumoral treatment history received by patients across the various
studies.
Table 4
Antitumoral treatment details of COVID‑19‑positive cancer patients
|
Treatment
|
Zhang et al.
[9] (n=28), n (%)
|
Liang et al.
[10] (n=18), n (%)
|
Yu et al.
[11] (n=12), n (%)
|
|
Surgery
|
21 (75.0)
|
13 (72.2)
|
1 (8.3)
|
|
Chemo/radiotherapy
|
25 (89.3)
|
9 (50)
|
7 (58.3)
|
|
Target/immunotherapy
|
6 (21.4
|
3 (16.7)
|
1 (8.3)
|
|
Best supportive care
|
-
|
-
|
4 (33.3)
|
|
Details not available
|
-
|
1 (5.6)
|
1 (8.3)
|
Staging of the tumor was presented only in the study by Zhang et al.
[9] where 18 (64.3%) patients were in Stages I–III and 10 (35.7%) patients in Stage
IV disease. On descriptive analysis, it was found that 70% (7/10) of Stage IV cancer
patients had developed severe events, whereas only 44.4% of the rest had such events
with no statistically significant association on univariate analysis. The tumor stage
could not be included in multivariate cox model analysis due to a high correlation
between stage and the antitumor treatment within 14 days (correlation coefficient
r = −0.518, P = 0.005).
In the study by Zhang et al.,[9] the patients receiving antitumoral treatment within 2 weeks, 5 (83%), developed
severe events.
Multivariate analysis adjusted for gender and age revealed that those patients who
received antitumor treatment within 2 weeks before COVID-19 infection had a greater
risk of developing severe events with marginal statistical significance (HR: 4.079,
95% CI: 1.086–15.322; P = 0.037).
Nearly 75% of the patients (3/4) who underwent surgery or chemotherapy in the previous
month had a high risk of developing clinically severe events than those (6/14) not
receiving chemotherapy or surgery in the study by Liang et al.
[10] It was additionally confirmed by logistic regression (odds ratio [OR]: 5.34, 95%
CI: 1.80–16.18; P = 0.0026) after adjusting for other risk factors such as smoking, age, and other
comorbidities.
In the study by Yu et al.,[11] fewer than half of these COVID-19 patients were undergoing active treatment for
malignancy.
Morbidity and mortality in cancer patients
According to the study by Zhang et al.,[9] out of the 28 cancer patients, 53.6% of the patients advanced to severe events,
21.4% required ICU admission, 35.7% had life-threatening complications, and 28.6%
of the patients succumbed to death. The cause of death encompassed acute respiratory
distress syndrome (ARDS) in about 62.5% (5/8), pulmonary embolism in 12.5% (1/8),
septic shock in 12.5% (1/8), and acute myocardial infection in 12.5% (1/8) of patients.
On multivariate analysis for the risk of developing severe events, there was no statistically
significant correlation with age (HR: 1.455; 95% CI: 0.478–4.430; P = 0.509) and gender (HR: 0.574; 95% CI: 0.162–2.038; P = 0.390).
Liang et al.
[10] used Cox regression model to estimate the time-dependent hazards of progressing
to severe events, and it was seen that cancer patients deteriorated more rapidly (median
time to severe event – 13 days) (interquartile range: 6–15) than those without cancers
(median time to severe event – 43 days) (20 – not reached), P < 0. 0001, HR: 3.56, 95% CI: 1. 65–7.69, after adjusting for age.
The only risk factor for developing severe events in the study by Liang et al.
[10] was found to be old age (OR: 1.43, 95% CI: 0.97–2.12; P = 0.072). While comorbidities such as hypertension (OR: 1.878, 95% CI: 1.217–2.898;
P = 0.004), chronic obstructive pulmonary disease (COPD) (OR: 3.397, 95% CI: 1.373–8.409;
P = 0.008), and diabetes mellitus (OR: 2.206, 95% CI: 1.331–3.656; P = 0.002) were not associated with the risk of developing severe events.
In a case series by Grasselli et al.,[19] the demographic details of COVID-19 patients admitted to ICUs in Lombardy, Italy,
were gathered telephonically by the ICU network team. Data were collected from February
to March 18, 2020. Among 1591 patients requiring admission into ICU, 81 had a history
of malignancy either in active or remission stage, with 69 of those patients above
60 years.
In a large case series of 72,314 patients published by the Chinese CDC,[18] the overall case fatality was around 2.3% and in patients with a history of malignancy,
it was 5.6%.
The WHO China Joint Mission on COVID-19 reported a case fatality rate of 7.6% for
cancer.
Onder et al.
[20] analyzed a subsample of 355 patients who died due to COVID-19 in Italy. The mean
age was found to be 79.5 years (standard deviation 8.1) and 72 patients died due to
cancer, leading to a case fatality rate of 20.3%.
Biological basis of susceptibility
Cancer patients are more susceptible to infection due to their immunocompromised status
owing to multiple reasons such as the disease itself, malnutrition, postsurgical status,
or the anticancer treatment that they receive.
In a review article by Galluzzi et al.,[21] they have reported that as tumors evolve, they favor the release of myeloid-derived
suppressor cells (MDSCs) from the bone marrow, which exerts immunosuppressive effects
both intratumorally and systemically. In addition, myelosuppression due to cytotoxic
chemotherapy or early phase of hematopoietic stem cell transfer, conventional chemotherapy,
and targeted therapy drugs such as rituximab may alter both humoral and T-cell-mediated
immunity, making the individual more susceptible to COVID-19.
Cai[22] analyzed transcriptomic databases of lung tissue and found that smoking tobacco
increases the gene expression of ACE2 in the lung, which is also the binding receptor
for COVID-19. This could explain the reason for smokers being susceptible to COVID-19
as they both share the same receptor.
Malnutrition in a cancer patient can be due to multiple reasons such as nausea and
vomiting because of chemotherapeutic drugs, loss of appetite, the morbidity associated
with surgery, or long-term hospitalization. Moreover, 20%–80% of cancer patients become
malnourished during their clinical course.[23],[24],[25] This can adversely affect the immunity of a patient, making him/her more prone to
infection by respiratory pathogens.
In the study by Zhang et al.,[9] lung cancer patients showed reduced lung volume due to tumor co-existing with features
of pneumonia.
Quality of life
Quality-of-life assessment is a multidimensional paradigm measuring subjective assessment
of well-being and health status including both mental and physical health. A qualitative
survey was done by Casanova et al.
[26] in the Milan focal point of Italy on young cancer patients during COVID-19 in order
to assess their level of stress. According to the survey, it was found that a relatively
large proportion of these patients felt themselves to be at risk of severe complications.
A semi-structured questionnaire was developed by a committee consisting of Youth Project's
staff (psychologists and physicians) and was later approved by the ethics committee.
Questionnaires were given to patients receiving treatment, on follow-up, and healthy
peers. It was seen that a large proportion of patients who were receiving cancer treatment
and on follow-up were worried about severe complications compared to healthy peers.
Discussion
COVID-19 has spread rampantly across the globe originating from China. Patients with
cancers are undoubtedly affected severely due to the ongoing pandemic. The incidence
of cancer reported across various studies varies from 0.5% to 2.43%. The incidence
of cancer was higher than the overall incidence among the Chinese population (0.29%)
according to cancer epidemiology statistics 2015.[27] However, the following points should be considered:
-
Duration of the study was short, studies were conducted during the epidemic, and many
were single-institutional studies
-
Suspected or undiagnosed cases were not included
-
The data available were quite heterogeneous, and many of the studies are only from
China, especially from the area when the epidemic started, and hence cannot be extrapolated
to the population in other parts of the world
-
Immunocompromised cancer patients are more likely to acquire infections.
Among the retrospective studies exclusively analyzing COVID-19-positive cancer patients,
it was observed that lung cancer was common overall. Studies by Zhang et al.
[9] and Liang et al.
[10] were multicentric studies where the incidence of lung cancer was more or less similar.
Extensive prospective epidemiologic data have clearly established cigarette smoking
as the major cause of lung cancer.[28] Approximately 50% of ARDS can be directly attributed to smoking tobacco.[29] Smoking increases the expression of ACE2 in the lungs, which is a binding site for
COVID-19.[30] According to a recent meta-analysis by Emami et al.,[31] the pooled prevalence of COVID-19 patients admitted in hospitals with a history
of tobacco smoking was estimated to be around 7.63%. Smokers were observed to be more
susceptible to COVID-19 infection.
Previous studies on MERS-CoV-2 have demonstrated dipeptidyl peptidase IV to be a specific
receptor for the virus, and it is upregulated in COPD patients and smokers, making
them more vulnerable to this infection.[32]
Patients with lung cancer, with poor baseline pulmonary function and endurance, were
more likely to develop more severe anoxia and deteriorate more rapidly with COVID-19.[9] Lung injury can occur due to primary lung tumors, metastasis, or radiation pneumonitis.
These can explain the reason why lung cancer patients are the ones who are affected
by COVID-19 on a larger scale.
Smoking can lead to lung cancer and COPD and increase susceptibility to acquiring
COVID-19. Although smoking was predominantly more among cancer groups in the study
by Liang et al.,[10] it failed to establish any statistical significance.
Males were more than females among all studies with mean age ranging from 63 to 66
years, implying elderly age group being affected. Elderly individuals had the risk
of progressing to severe events.
Cardiovascular diseases and diabetes were among the most prevalent comorbidities.
A systematic review and meta-analysis by Emami et al.
[31] has summarized that cardiovascular diseases, hypertension, COPD, and chronic kidney
disease were among the most prevalent underlying comorbidities in hospitalized COVID-19
patients, which is similar to our findings in cancer patients.
Metabolic syndrome-related health conditions such as hypertension, cardiovascular
diseases, and diabetes are known to downregulate innate immunity in the host. However,
in the study by Liang et al.,[10] progression to severe events was not related to comorbidities. Given that COVID-19
has a relatively protracted incubation period and during this phase, the infected
person can transmit the virus to another without being symptomatic, it is strongly
recommended that elderly cancer patients with chronic or underlying diseases avoid
close contact with others in the community, especially in areas where the epidemic
is rampant.
Findings of ground-glass opacity and patchy consolidation on CT scan of cancer patients
were similar to overall COVID-19 infected patients.[33] The role of systemic steroids is controversial in viral pneumonia, as it is thought
to be an immunosuppressant. However, it failed to demonstrate any benefit in reducing
the incidence of severe events.[9]
In their study, cancer patients who had ongoing treatment or those who had completed
treatment within the past month were at risk of developing clinical severe events
such as ICU admissions, mechanical ventilation, or death. Zhang et al.
[9] reported 53.6% of cancer patients developing severe events, whereas Liang et al.
[10] had only 39% of people developing severe events. This discrepancy is due to the
following reasons:
-
The definition of severe events by both groups was different: Zhang et al.
[9] included ICU admission or mechanical ventilation or death, whereas Liang et al.
[10] defined it as ICU admission or invasive ventilation or death, narrowing the cohort
to only those requiring invasive ventilation
-
Zhang et al.
[9] included cases from Wuhan, whereas Liang et al.
[10] included patients from the entire nation. Wuhan, on the other hand, had to face
a dire shortage of resources due to the sudden outbreak and delay in delivering health
facilities, leading to an increase in mortality.
The study by Grasselli et al.
[19] had many limitations as newly setup ICUs were not included, it was telephonic data
collection, and the follow-up period was relatively short and hence, the outcomes
and mortality may change.
Death was seen in 28.6% of the patients who developed critical events in the study
by Zhang et al.
[9] In comparison to the general COVID-19 population, 5% reached clinically critical
status, and the case fatality was nearly half (49%).[18] Studies from China reported a case fatality of 5.6%–7.6%, whereas Onder et al.
[20] from Italy reported a case fatality rate of 20.3%. It is also to be considered that
a large proportion of people were aged 90 or above in Italy, and this group has a
very high case fatality rate (22.7%).
Zhang et al.
[9] reported that 28.6% of patients developed COVID-19 infection during hospital admission
suspecting nosocomial transmission. Nosocomial transmission is reported by Wang et al.
[14] to be around 41%. Cancer patients can acquire infections in hospitals during their
course of anticancer treatment. This emphasizes vigorous screening and isolation of
suspected patients at cancer centers. Precautionary measures should also extend to
the family members and the health-care personnel attending such patients to prevent
infection and transmission. The European Society for Medical Oncology recommends a
tiered approach according to the priority of intervention required, and also the benefit/risk
ratio, prognosis, patient preferences, and comorbidities should be taken into consideration.
While navigating through all these, an epidemic like COVID-19 has made their condition
even worse as the medical facilities are likely to be jeopardized due to the overwhelming
patients. Life in a pandemic is more disturbing due to social distancing, isolation,
lockdown, and fear of contracting infections, which lead to a cycle of concern, worry,
and mental agony. There are also groundless fears due to the fabricated news and information
circulated in social media. Delays in treatment may lead to fear of death, progression,
or recurrence in cancer patients.
Thus, the following points have to be borne in mind while managing cancer patients:
-
At present, there is no direct evidence to support withholding anti-tumor therapy.
Treatment that is likely to worsen the immune status of a patient should be postponed
or modified
-
Patients should be triaged according to type and stage of cancer and need for aggressive
treatment
-
The possible benefits and risks of infection have to be discussed with the patient
and family members. If continuing treatment is the need of the hour, then patients
should be guided accordingly
-
The diagnosis of cancer itself has a lot of psychosocial impact on a person. The journey
from diagnosis to treatment can affect relationships, finances, and the physical and
mental health of a person
-
Telemedicine can help in reaching many patients and decrease anxiety. Cancer patients
require follow-ups at regular intervals in order to treat early recurrence, to detect
new primaries, or for rehabilitation. Due to lockdown, asymptomatic patients can be
followed up telephonically. Any new symptoms or concerns can be dealt, and the necessary
solutions can be discussed
-
In certain parts of the country wherein there is no access to oncology facilities,
the referral centers can utilize tele-expertize.
Studies have shown that cancer patients have worse outcomes from COVID-19, providing
a reason to pay more timely attention to cancer patients in case they deteriorate
rapidly. As a result, more intensive surveillance should be considered when cancer
patients acquire COVID-19, especially elderly, patients with comorbidities, and patients
receiving ongoing treatment. Further prospective studies from different parts of the
world with a large sample size are warranted to validate the findings. More robust
evidence is required to address various factors such as screening, prevention, quality
of life, and treatment modalities.
