Abstract
A novel coronavirus, or severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), was identified as the causative agent of coronavirus
disease 2019 (COVID-19). In early 2020, the World Health Organization
declared COVID-19 the sixth public health emergency of international
concern. The COVID-19 pandemic has substantially affected many groups
within the general population, but particularly those with extant
clinical conditions, such as having or being treated for cancer. Cancer
patients are at a higher risk of developing severe COVID-19 since the
malignancy and chemotherapy may negatively affect the immune system, and
their immunocompromised condition also increases the risk of infection.
Substantial international efforts are currently underway to develop
specific methods for diagnosing and treating COVID-19. However, the risk
profiles, management, and outcomes of cancer patients are not yet well
understood. Thus, the main objective of this review is to discuss the
relevant evidence to understand the prognosis of COVID-19 infections in
cancer patients more clearly, as well as helping to improve the clinical
management of these patients.
Keywords: COVID-19; Cancer; SARS-CoV-2; Immunodeficiency
Introduction
Since the emergence of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), many infected individuals and the high mortality rate have
caused a significant burden on public health worldwide (1-3). All of the
risk factors which increase the severity or mortality of the current
coronavirus disease 2019 (COVID‑19) have not yet been identified but are
more severe in immunocompromised patients (4). Patients with malignant
tumors are one important immunosuppressed group in the population.
Cancer patients with hematologic malignancies who are receiving T
cell‑depleting therapies or immunosuppressive therapy, or have had
allogeneic hematopoietic cell transplantation (HCT), are at a higher
risk of acquiring severe infection (5). Furthermore, increased
hospitalization and nosocomial transmission of SARS-CoV-2 is another
reason for a surge in infections in this group. Additionally,
glucocorticoids, which are used in various therapy protocols, suppress
both humoral and cellular immunity.
Moreover, surgery is another factor that makes cancer patients more
susceptible to all kinds of infections, including viral diseases (6).
Finally, psychological disorders caused by the COVID-19 pandemic, such
as anxiety and depression, could negatively affect adherence to
chemotherapy or other treatments, making this population more vulnerable
(7). All the above problems increase COVID-19 severity, chances of
hospitalization, the likelihood of intensive care unit (ICU) admission,
need for mechanical ventilation, and mortality in this high-risk
population. The worst COVID-19 outcomes, including acute respiratory
distress syndrome (ARDS), septic shock, acute myocardial ischemia (AMI),
and death, would also be more likely in cancer patients undergoing
surgery or chemotherapy 14-30 days before getting infected with the
virus (8, 9).
Immunopathogenesis of more severe SARS-CoV-2 infection in
cancer patients
The humeral and cellular immune systems play an essential role in
defending against viral infections. Neutralizing antibodies effectively
prevent viral entry, whereas cellular immunity is vital in activating
CD4+ helper T cells, required for triggering humoral
immunity, and CD8+ cytotoxic T cells, which are vital
for the recognition and destruction of infected cells (10). Studies on
previous coronavirus infections, such as Middle-East Respiratory
Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), have shown
that CD8+ T cell responses are directly linked to the
severity of the disease (11). Thus, cancer patients are at exceptionally
high risk of COVID‑19 infection because of the therapies they receive,
such as anti-CD20 medications, Janus kinase inhibitors (JAKi), or Bruton
tyrosine kinase inhibitors (BTKi), which weaken humoral immunity through
inhibiting B cell function. These immunosuppressive agents can also
cause T cell dysfunction and inhibition (12). Patients on active
cytotoxic chemotherapy or who recently had hematopoietic stem cell
transplants (HSCT) usually suffer from myelosuppression, resulting in an
innate and adaptive immunodeficiency.
Furthermore, the development of cancer itself often weakens the immune
system (13). It has also been proposed that having a history of smoking,
which may include a substantial proportion of those with cancer,
aggravates the situation by overexpressing immunosuppressive cytokines,
suppressing the induction of pro-inflammatory danger signals, impairing
dendritic cell maturation, and enhancing immunosuppressive regulatory T
lymphocyte numbers (14). Tobacco use also leads to a significant
increase in the gene expression of angiotensin-converting enzyme 2
(ACE2), the binding receptor for SARS-CoV-2, further elevating
susceptibility to COVID-19 infection (15).
Risk factors influencing infection severity in oncology
patients
Recent studies have shown that cancer patients with COVID-19 are more
likely to be admitted to the ICU, require mechanical ventilation, or die
(16). In addition, a delayed admission time, due to the similarity
between COVID-19 and cancer symptoms, might be another reason for the
more likely progression to severe disease. In one study, the case
fatality rate reached 5.6% among cancer patients, while the
COVID-related mortality in the general population has been reported to
be 2.3% (17). Therefore, the risk factors that may worsen -the outcomes
among cancer patients should be carefully examined. In a study
investigating risk factors for developing severe complications in cancer
patients, among those receiving anti-tumor treatment within 14 days of a
COVID-19 diagnosis, undergoing chemotherapy, radiotherapy, targeted
therapy, immunotherapy, and the presence of patchy consolidation in the
first computed tomography (CT) scan of the lungs on admission were
identified as significant risk factors (18). Moreover, due to the more
potent myelosuppressive therapy they receive, patients with hematologic
malignancies are more likely to develop a severe infection than those
with solid tumors (19).
As components of a chemotherapy regimen, treatment with high-dose
corticosteroids and immune checkpoint inhibitors have also been
independently associated with SARS-CoV-2 infection-related severity and
mortality (20). Treatment regimens containing JAKi or BTKi may also put
these patients at a higher risk of developing severe infections (21).
Studies conducted among patients with various malignancies have
demonstrated that the three most common malignancies in
COVID-19-infected patients were gastrointestinal, thoracic (particularly
non-small-cell lung carcinoma), and head and neck cancers (22). With
this in mind, patients with lung neoplasms should be one of the top
priority groups for COVID-19 prevention programs, such as vaccination.
Therefore, during the COVID-19 pandemic, these patients should be
actively screened for fever and respiratory symptoms and be kept
separately from suspected cases of COVID-19 (23).
Challenges of oncologists during the COVID-19 pandemic
The epidemic spread of this novel coronavirus has imposed significant
challenges on the clinical practice of oncologists, especially for
diagnosis and therapy. Studies have shown that the rate of cancer
diagnosis and newly detected malignancies were significantly lower
during the pandemic than for the same period before this outbreak (24).
Oncologists must carefully determine the risk of COVID-19 exposure in
their patients. Since a diagnosis of cancer places infected patients at
significantly increased risk of morbidity, including the need for
mechanical ventilation, or mortality, it would be appropriate to
decrease unnecessary exposure to COVID-19 for cancer patients in the
health care system. However, the consequences of delayed diagnosis or
treatment in common cancers must also be carefully considered (25, 26),
and the decision about whether to continue maintenance therapy should be
made individually. Some hematologic cancers, such as acute leukemia, and
many solid tumors, including lung or pancreatic cancers, require urgent
diagnosis and therapy.
In contrast, other common early-stage neoplasms (e.g., breast, prostate,
cervical, or non-melanoma skin cancers) do not need immediate
intervention (27). For example, maintenance rituximab in follicular and
mantle cell lymphomas are clear examples of where changes to maintenance
therapy are necessary, as this anti-CD20 agent could significantly
inhibit B cells, resulting in a much lower immune response to pathogens
like SARS-CoV-2. Nevertheless, a delay in treating metastatic cancers
can result in a much worse prognosis, significantly higher disease
progression, and more hospitalizations. However, it is worth mentioning
that some early-stage hormone-positive breast cancer patients can be
kept on their hormone therapy if needed (28).
At the pandemic’s beginning, the overall desire was to postpone
non-urgent chemotherapy interventions in cancer patients. However, it is
currently believed that routine antineoplastic therapy should not be
delayed or stopped in patients without suspected or confirmed SARS-CoV-2
(29). Conversely, suppose a SARS-CoV-2 infection is suspected. In that
case, the patient should be quarantined. The antineoplastic therapy
should be delayed for up to 14 days (30), but if the infection is
confirmed, delaying or discontinuing chemotherapy is strongly
recommended, as it significantly increases the risk of morbidity and
mortality (6). Moreover, surgery or radiotherapy in cancer patients is
strongly discouraged in the acute phase of SARS-CoV-2 infection (30,
31). Moreover, although more studies are required, another concerning
issue is the interactions between anti-COVID-19 therapies (e.g.,
antiviral agents and monoclonal antibodies) with antineoplastic
regimens, such as chemotherapy, hormonotherapy, targeted therapy, and
immunotherapy (32).
Another critical issue to be considered is the similarity between some
symptoms of COVID-19 and cancer at the time of diagnosis (e.g., fever or
cough), which may result in a misdiagnosis or delayed diagnosis of some
malignancies, such as acute leukemia, primary mediastinal lymphoma, or
lung cancer (33). In addition, the predominant peripheral ground-glass
opacities (GGOs) or predominant lung consolidations of the lower lobes
are a common radiographic presentation of metastatic lung cancers,
differentiating a new COVID-19 infection from the so-called neoplasms
would be challenging. In these cases, positron-emission
tomography/computed tomography (PET/CT) scans would be appropriate
diagnostic options for differentiating active lesions from new
infections imposed upon the underlying malignant lesions (34).
Challenges of cancer surgery during the pandemic
During this outbreak, specific surgical recommendations have been made
for common malignancies in cancer-specific guidelines. For instance, for
gynecological cancers, surgeries are recommended to be postponed, with
only emergent or urgent surgeries to be performed. Radiotherapy and
concomitant chemoradiotherapy could be used instead, particularly for
digestive neoplasms, laparoscopic surgery could also be undertaken with
strict precautions. Furthermore, palliative therapy, such as stenting
for esophageal cancers, can also be considered. However, it should be
noted that delayed oncologic surgery may lead to cancer progression that
may result in the tumor no longer being resectable, with the associated
worse survival outcomes (35, 36). Thus, it is recommended that patients
who need to be operated on should at least have an adverse reverse
transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 (5).
Also, in this situation, high-risk aerosolizing procedures should be
avoided, appropriate personal protective equipment (PPE), such as N95
masks, goggles, gowns, and gloves, should be donned by all health care
workers, and such procedures should be performed in unfavorable pressure
rooms, where possible (21).
Challenges for chemotherapy during the pandemic
Chemotherapeutic agents predispose patients to infections through
impairing bone marrow function, leading to thrombocytopenia and
neutropenia. The risk of infection is highest when their absolute
neutrophil count (ANC) is the lowest, usually 7–12 days after each
chemotherapy session (21). Some cytotoxic agents (e.g., temozolomide,
cyclophosphamide, paclitaxel, cisplatin, methotrexate, and fludarabine)
may induce severe damage to the bone marrow and alemtuzumab, leading to
lymphopenia and an increased risk of infection (37). Interactions
between antineoplastic agents and potential SARS-CoV-2 infection
therapies should also be considered. For example, some chemotherapeutic
agents, such as vinca alkaloids (vincristine and vinblastine) and
taxanes (docetaxel and paclitaxel), show significant interactions with
protease inhibitors (e.g., atazanavir, lopinavir, and ritonavir), which
were commonly used for treating SARS-CoV-2-infected patients at the
beginning of the pandemic. Moreover, many other agents, such as tyrosine
kinase inhibitors (dasatinib and ibrutinib), may interact with heparin,
a commonly used anticoagulant in hospitalized patients. In addition,
rituximab, a monoclonal anti-CD20 antibody, has significant interactions
with tocilizumab, an approved interleukin-6 (IL-6) antagonist commonly
used in severe COVID-19 patients (38).
A potential solution to the increased risk of infection and increased
severity in patients undergoing chemotherapy could be through the use of
low-dose metronomic chemotherapy with different agents and schedules.
This intervention can hopefully control the tumors and has more
favorable safety profiles. In addition to the approaches mentioned
above, the continuation of cancer care during the pandemic would be
enhanced if oral administration of the medication were possible (39).
Nevertheless, SARS-CoV-2 RT-PCR testing should be carried out before
initiating the treatment in all cases with an urgent need for
chemotherapy.
Challenges of radiotherapy during the pandemic
Radiation therapy is one of the main treatment options for malignancies.
This intervention can lead to immunosuppression by inducing bone marrow
suppression and lymphopenia. Therefore, radiotherapy can put the patient
at increased risk of infection, morbidity, or mortality (40). Patients
undergoing this type of treatment would usually continue their treatment
for several weeks. However, as most staff at radiotherapy centers had
been off work since the beginning of the pandemic, the intervals between
radiotherapy sessions have increased, possibly leading to a decrease in
their therapeutic efficacy. Thus, if treatments were postponed, like
elective surgeries, adverse clinical outcomes may become inevitable, as
this modality usually consists of multi-fraction courses of therapy that
require daily visits to the clinic (41). Moreover, some of the typical
and nonspecific side effects of radiotherapy, and even some cancer
manifestations (e.g., low-grade fever, cough, sore throat, and
rhinorrhea), mimic COVID-19 symptoms; differentiating between the two
can be challenging (42).
Several protocols have been implemented in different centers in an
attempt to reduce the burden of this epidemic. Many centers provide
radiotherapy for patients with negative COVID-19 screening results,
while others recommend asymptomatic patients to wait until a sufficient
isolation period has passed following close contact with a suspected or
confirmed patient. For confirmed COVID-19 patients who have fully
recovered, almost all centers recommend starting radiotherapy after
being quarantined for at least 14 days. However, it should also be noted
that unnecessarily delaying these sessions would adversely affect cancer
management (43). Furthermore, almost all radiotherapy centers have
planned areas for previously infected COVID-19 patients to undergo
treatment, separated from non-infected patients. Patients should also be
instructed to keep the interpersonal spacing of at least 2 meters in the
general waiting areas. Disinfecting the treatment bed and surrounding
accessories during the treatments would also be helpful. Some centers
may classify cancer patients into confirmed and suspected cases of
COVID-19, cases that should be medically isolated, and cases with
negative screening results. In the early stages of malignancy,
negatively screened patients should only receive radiation therapy if
deemed absolutely necessary. At the same time, those with locally
advanced tumors are recommended a neoadjuvant chemotherapy regimen or
hormone therapy first and then to continue with radiotherapy after some
delay (44). Patients already receiving radiotherapy should be
individually assessed about whether to continue therapy with the
previous dose or reduce the dose’s intensity (45). Moreover, using
proton beam therapy, stereotactic body radiation, or a hypo-fractionated
schedule can also be considered to decrease the risk of
radiation-related immunosuppression (37).
High-risk patients who are mandated to undergo radiotherapy should be
treated as the last cases of the day, with all personnel wearing
appropriate PPE, including N95 respirators, surgical masks, and gloves,
depending on medical policies, available supplies, and procedural risks.
All patients and accompanying individuals must also be required to wear
surgical masks. Some centers even implement mandatory twice daily
monitoring of temperature for all staff. Educational information about
personal hygiene, the importance of handwashing, and the appropriate
methods of wearing masks should be highly prioritized in the patient
care programs. Moreover, interventional radiology staff should follow
the standard precautions, primarily including personal and hand hygiene,
proper ward ventilation, and disinfection of instruments, to minimize
the risk of nosocomial infections (41, 46).
Challenges of immunotherapy during the pandemic
Immunotherapy is another therapeutic modality for treating specific
cancer types. This therapeutic option includes vaccines, immune
checkpoint inhibitors, T-cell transfer therapy, and immunomodulators.
Despite being beneficial in treating malignancies, these agents have
side effects like hyperactivated T cell responses, directly affecting
and harming normal tissues. Hence, the decision to initiate or continue
immunotherapy during this outbreak or during the acute phase of
SARS-CoV-2 infection should be made individually. These agents’ most
significant adverse effects include thrombocytopenia, prolonged
lymphopenia, pneumonitis, cytokine release syndrome (CRS), and increased
vascular permeability, leading to pleural effusion or pulmonary edema
(47). More recently, targeted therapies, such as selective Fms-related
receptor tyrosine kinase 3 (FLT3, also known as CD135) inhibitors (e.g.,
midostaurin, quizartinib, crenolanib, and gilteritinib), BCL-2
inhibitors (e.g., venetoclax), or isocitrate dehydrogenase (IDH)
inhibitors (e.g., ivosidenib and enasidenib), have been used for some
neoplasms (e.g., acute myeloid leukemia or acute lymphocytic leukemia).
The risk of severe respiratory failure in patients treated with these
agents, who are concurrently infected with SARS-CoV-2, has been raised
and should be validated in future studies (48).
Challenges of bone marrow transplantation during the pandemic
Patients who are candidates for bone marrow transplantation are better
to defer their surgery due to the subsequent need for long-term
immunosuppression. This treatment modality weakens the immune system,
which predisposes the patient to an increased risk of infection for
three months after the transplant, although complete recovery may take
up to a year in some cases (49). HSCT (hematopoietic stem cell
transplantation) has been dramatically affected by the COVID-19 pandemic
in some ways since donors and recipients must both test negative for
COVID-19 for the procedure to be feasible and successful. If potential
donors are infected with SARS-CoV-2, the donation should be delayed
until a full recovery has been made. Thus, having a backup donor might
help in this situation (50).
Preventive measures against SARS-CoV-2 infection in cancer
patients
The first question would be whether protective measures needed for
cancer patients are any different from those needed for immunocompetent
individuals. It should be emphasized that standard personal protection,
similar to healthy individuals, should be worn by cancer patients on
active therapy and those who are cancer-free (51). However, more
vigilant and intensive provisions or treatment plans should be
considered for SARS‑CoV‑2-infected cancer patients, especially the
elderly or those with other comorbidities. In addition,
SARS‑CoV‑2-induced pneumonia rapidly spreads through person-to-person
transmission by droplets, and because cancer patients should usually be
hospitalized for their therapy and disease surveillance, they are at
higher risk of exposure to SARS-CoV-2. Therefore, the most sensible
strategy for these patients in this outbreak would be to suspend
adjuvant chemotherapy or elective surgery for stable patients to
decrease hospitalization and the need for multiple hospital visits and,
subsequently, close contacts COVID-19 suspected patients or healthcare
workers (52).
Nevertheless, if cancer therapy must be undertaken, self-isolation
following treatment may enable patients to delay or avoid being infected
with COVID-19, which is particularly important following chemotherapy.
It would also be helpful if outpatient clinics used telehealth options,
such as telephone- or video-conferencing appointments for their patients
(53). However, if attending the clinics cannot be avoided, patients
should be asked to wait outside until their turn to avoid crowding in
one area and reduce their exposure to other patients and healthcare
personnel. Precautions could also include screening patients and
visitors for COVID-19 upon arrival (54).
Oral chemotherapy may be another good way of avoiding unnecessary
hospital admissions (54). For patients who require urgent malignancy
treatment, proper isolation measures should be considered, such as
reducing chemotherapy intensity, decreasing the frequency of cancer care
sessions, or establishing off-site cancer care facilities (55). The most
important and effective strategy to prevent COVID-19 is “social
distancing,” the primary intervention to reduce the spread of this
infection. This strategy is significantly disrupted by any engagement of
cancer patients with the health care settings, including clinic visits,
surgical stays, infusion sessions, radiation planning, treatment
appointments, hospital admissions, phlebotomies for laboratory tests,
and radiographic studies, all of which provide potential opportunities
for viral transmission (56). In addition to receiving COVID-19 vaccines,
these patients should take other precautions to reduce their risk of
infection (57). Since secondary bacterial infections may superimpose on
viral infections, vaccination against Streptococcus pneumoniaeshould be recommended for this at-risk population (58).
COVID-19 and cancer in children
Although severe COVID-19 infection is believed only rarely in children,
some studies have shown a higher illness severity among
immunocompromised infants and younger children. Childhood cancers pose
many challenges during the current COVID-19 pandemic. Since most
childhood malignancies are aggressive and need urgent treatment,
delaying treatment might not be appropriate for these patients (59).
Therefore, strategies should be undertaken to prevent and decrease the
risk of exposure to SARS-CoV-2 in children receiving intensive
chemotherapy or stem cell transplants, with isolation being the best
option. Families are also advised to strictly adhere to standard
preventive precautions, such as social distancing (60).
Anti-tumor medications that can be potentially used for
COVID-19 treatment
A pro-inflammatory state resulting from a cytokine storm is believed to
deteriorate significantly COVID-19- patients’ condition. Hence, it is
proposed that a group of immunosuppressive therapies may have a
protective role in helping infected patients by reducing the intensity
of the cytokine storm and thereby preventing further lung tissue damage
(61). Several medications used for chemotherapy or immunotherapy in
cancer patients may also effectively inhibit COVID-19 by stimulating the
immune response (62). Important examples are certain TKIs, which have
proven effective in treating SARS, MERS, and COVID‑19 infections.
However, TKIs, such as erlotinib, an FDA-approved inhibitor of the
epidermal growth factor receptor (EGFR), which is used to treat
non-small cell lung (NSCLC) and pancreatic cancers, may have
interactions with antiretroviral agents, such as lopinavir, and
ritonavir, which were used to treat COVID-19 early in the pandemic.
Nonetheless, these agents can themselves be good options for the
management of SARS-CoV-2. Moreover, JAK inhibitors (e.g., ruxolitinib,
baricitinib, and tofacitinib) have also shown promise in managing
COVID-19 through hyper-reactivating the immune response to the infection
(63). However, the additive risk of thrombotic events caused by a
SARS-CoV-2 infection and the use of JAK inhibitors should be carefully
considered (64).
Interleukin inhibitors, which target IL-6 and other cytokines (e.g.,
tocilizumab and sarilumab), are effective in specific neoplasia,
including lymphoproliferative disorders, Castleman’s syndrome, and
smoldering multiple myeloma (65), are currently being successfully
utilized for suppressing the cytokine release syndrome (CRS) during the
SARS-CoV-2 infection (66). In addition, being a cytokine mediator that
is included in the treatment regimens of certain cancers, such as
chronic myelogenous leukemia (CML), hairy cell leukemia, melanoma, and
Kaposi sarcoma (67), interferons can reduce viral infections and improve
viral clearance (68). Immune checkpoint inhibitors (e.g.,
pembrolizumab), which have revolutionized the management of a variety of
solid tumors and hematological malignancies (69), have also been
evaluated to be effective therapeutic agents for SARS-CoV-2 infection
through decreasing viral load, and increasing antiviral-specific
function in both the CD4+ and CD8+ T
cells, leading to clinical improvement, viral clearance, and attenuating
lung injury (70). Furthermore, CCR5 inhibitors (e.g., leronlimab,
thalidomide, and lenalidomide), well-known FDA-approved therapeutics for
certain malignancies, have previously shown efficacy against SARS-CoV-2
infection (71, 72).
Considerations for COVID-19 vaccines in cancer patients
Patients with cancer are at increased risk of adverse outcomes from
COVID-19 infections, and therefore should be prioritized for vaccination
(73). Currently, no COVID-19 vaccine platform is preferred over others
in cancer patients. However, it is expected that the vaccine-induced
immune response in cancer patients, particularly those undergoing
immunosuppressive therapy, would be less favorable than among the
immunonormal population (74). However, except during the intensive phase
of chemotherapy, vaccine antibody responses are believed to be
sufficient enough to recommend vaccination for these patients (75). For
patients scheduled for cytotoxic chemotherapy, it is better to
administer the first dose of the vaccine at least two weeks before
chemotherapy. Nevertheless, the first dose of the vaccine can also be
administered during the interval between chemotherapy sessions (75).
Moreover, the COVID-19 vaccination seems safe and efficient in patients
undergoing radiation therapy (76).