Introduction
We are now nearly 2 years into the coronavirus disease 2019 (COVID-19) pandemic. As
we learn to exist and move ahead, embracing the “new normal” with COVID-19, both at
a professional and personal level, it is time to reflect on some of the challenges
and lessons from the pandemic. COVID-19, one of the most devastating health emergencies
of the century, has laid bare the inefficiencies of modern health systems and led
to 5 million deaths worldwide.[1] The varying case fatality rates of 0.5 to 2.5% and the absolute numbers of deaths
reported from different countries are still lower than the mortality due to noncommunicable
diseases and other infectious diseases.[1] This is not to belittle the devastation caused by the pandemic but to draw attention
to the impact that COVID-19 and the response to the pandemic have had on systems needed
for prevention and management of these other illnesses. In this article, we explore
the complex interplay between cancer and COVID-19, the impact of cancer on COVID-19
severity and outcomes, and how COVID-19 affected several levels of care in the diagnosis
and management of cancer.
Cancer Burden in India and Other Low- and Middle-Income Countries
It is important to have a perspective on the burden of cancer and the challenges which
are faced by patients, their families, oncologists, and institutions in our country
and other low- and middle-income countries (LMICs) even prior to the pandemic. As
per GLOBOCAN data, the global incidence of all cancers is 19 million cases annually
with nearly 10 million deaths per year.[2] Though the overall incidence of cancer is more in high-income countries, LMICs account
for nearly two-thirds of cancer deaths.[2] This high mortality-to-incidence ratio is largely due to delayed diagnosis, late-stage
presentation, inadequate access to care, and unaffordability of treatment.[3] Cancer care is limited to the larger cities with wide variations in infrastructure
and expertise between centers. Access to cancer care requires considerable amount
of travel, long stays away from home, loss of wages, and significant out-of-pocket
expenditure that unfortunately results in high rates of treatment abandonment. Another
important issue is the poor distribution of palliative care services and access to
opioids which result in poor quality of life in advanced-stage cancers.
COVID-19 in Patients with Cancer
Cancer has been identified as a risk factor for severe COVID-19 and poor outcomes
after COVID-19. During the course of pandemic, several studies evaluated the possible
risk factors for adverse outcomes in patients with COVID-19 and cancer—these included
advanced age, multiple comorbidities, smoking, hematological cancers, and the use
of systemic anticancer therapy.[4] Patients with cancer who developed COVID-19 have been reported to have fatality
rates between 10 and 30%.[5]
[6]
[7]
[8]
[9]
[10]
[11] As data emerged on the high risk of developing COVID-19 and its complications in
patients with cancer, most professional bodies advised delays or modification of intensive
treatment, including postponement of elective surgeries and hypofractionation of radiation
therapy.[12]
COVID-19 in India
As on November 11, 2021, India has seen nearly 35 million cases of COVID-19.[1] The overall case fatality has been 1.3%, which is considerably lower than in many
other countries.[1] This difference in outcomes has been attributed to several reasons: underreporting
of cases, unreliable death certification, and possible cross-immunity due to previous
coronavirus infection.[13]
[14] There are very little data from India on the outcomes of patients with both cancer
and COVID-19. Mehta et al reported a 14.5% case fatality rate, with presence of comorbidities
being the only significant risk factor for mortality.[15] Recent systemic cancer therapy had no impact on COVID-19 outcomes. Ramaswamy et
al looked at 236 patients with cancer on active therapy; the all-cause mortality rate
was 10%. Independent predictors of mortality were advanced-stage cancer treated with
palliative intent, severe COVID-19, and uncontrolled cancer status.[16] Radhakrishnan et al reported on COVID-19 in 15 pediatric patients with cancer, all
of whom had an uneventful recovery.[17] Unpublished data from our center evaluating 1,253 patients with cancer found that
the majority of them (90%) had mild COVID-19, and the mortality rate was around 10%.
The type of cancer and systemic anticancer therapy in last 30 days prior to COVID-19
diagnosis did not increase mortality, except in patients with advanced age who were
being treated with palliative intent. This suggests that at least in India, most patients
with cancer who develop COVID-19 have a favorable prognosis, and their cancer treatment
should continue without interruption. The data from children with cancers are more
reassuring. Most patients develop asymptomatic to mild infections, and continuation
of treatment in these patients does not result in excess mortality.[18]
[19]
Impact of COVID-19 on Cancer Care
The impact of COVID-19 on cancer care has been more widespread and substantial. A
systematic review by Riera et al included 62 studies across 15 countries reporting
substantial disruptions and delays in cancer services during the pandemic.[20] In India, multiple factors may have contributed to this. First, due to travel restrictions
during the national lockdown, and fear of travel during the pandemic, many patients
were unable to access cancer centers. Second, resources and manpower available for
cancer care were diminished for a multitude of reasons—reallocation of oncology beds
and health care workforce to facilitate COVID-19 management, travel restrictions preventing
staff from reaching the work place, staff-sparing strategies to minimize the risk
of infection, and infections or quarantine among staff. Third, most cancer centers
suspended their cancer prevention and screening programs due to the risk of infection,
and the need to divert staff and resources for COVID-19 management. The national cancer
screening program in India was also put on hold since May 2020.[21] Data from 41 cancer centers across the country showed that during the peak of the
pandemic (March–May 2020), there was a reduction by two-third in most cancer services,
whereas screening activities were almost at a standstill.[22] These reductions were across new patient registrations, follow-up visits, major
and minor surgeries, day care chemotherapy, diagnostic testing, and palliative care
referrals. The number of patients accessing radiotherapy services showed the least
reduction (23%).[22] These factors may have possibly led to stage migration and increased mortality due
to delays in diagnosis and treatment, and interruptions in ongoing treatments. Even
among patients who sought and received cancer care, modifications and deintensification
of treatment regimens could have resulted in compromised outcomes, more so in the
curative setting. Similarly, interruption of palliative care services and access to
opioids, which were already limited across the country, posed challenges in the care
of advanced cancers.
A systematic review has estimated that even a 4-week delay of cancer treatment is
associated with increased mortality across surgical, systemic treatment, and radiotherapy
indications for seven cancers.[23] While there are no data from India to quantify the impact of the disruptions in
care due to COVID-19, several global studies have used modeling techniques to estimate
the likely consequences. Maringe et al predicted that in England, there would be 3,620
avoidable cancer deaths in the next 5 years for four major cancers (breast, bowel,
lung, and esophageal) representing ∼40% of total burden.[24] These additional excess cancer deaths would amount to a loss of 32,700 quality-adjusted
life years and productivity losses of 103.8 million British pounds in the next 5 years.[25] Rutter et al reported a 58% decrease in cancer detection during the peak of the
pandemic due to reductions in endoscopy services in the United Kingdom.[26] Sud et al reported between 3,316 and 9,948 additional life years lost due to delays
in referral during the 3-month lockdown period in the United Kingdom.[27] Data from Australia estimate at a conservative level, 88 additional deaths and 12
million Australian dollars spent in excess health care costs over 5 years for all
patients diagnosed in 2020.[28] These numbers are staggering and reflect the profound impact that the pandemic is
likely to have on oncological outcomes in the next few years.
Cancer education has also been badly affected during the pandemic, with compromised
training in specialty areas due to involvement in COVID-19 care.[22] Reduced numbers of patients visiting cancer centers have resulted in trainees receiving
suboptimal exposure to various aspects of cancer management. Research in oncology
has been put on the backburner due to diversion of research staff to COVID-19 care,
reluctance of research participants to make nonessential hospital visits, global recommendations
to avoid intensive research interventions, and cuts in research funding.[22] As a result, several oncology research studies have reported protocol violations,
setbacks in initiation and accrual, and likely delays in study completion and analysis,
thereby postponing the availability of the results.
The treatment of COVID-19 has evolved over time. Keeping in mind the underlying pathophysiology
of cytokine storm and activation of downstream pathways, several clinical trials evaluated
the repurposing of some anticancer drugs such as imatinib, bruton tyrosine kinase
(BTK) inhibitors, and Janus kinase/Signal transducers and activators of transcription
(JAK-STAT) pathway inhibitors.[29] One of the underlying pathophysiological mechanisms responsible for several of the
sequelae of COVID-19 is vascular thrombosis. Patients with cancers have a high risk
of thromboembolic events. Infection with COVID-19 may further amplify this risk, warranting
prophylactic anticoagulation, based on the underlying factors. Treatment of moderate
to severe COVID-19 with dexamethasone and tocilizumab can have potential adverse outcomes
in those with concomitant neutropenic sepsis warranting a careful decision and close
monitoring.
Vaccination is the only long-term measure to gain control over the COVID-19 pandemic.
However, patients with cancer faced several hurdles for vaccination. Paradoxically,
limited data on the safety and efficacy of the vaccine in this category of patients
led to a delayed start of the vaccination process in the population which possibly
needed it the most. For patients with cancer on active cancer therapy, there was an
initial lack of clarity on eligibility criteria to receive the vaccine. Finally, it
is known that immunosuppressed patients may not have a robust serological response
to the vaccine, suggesting the need for booster doses, in a situation where vaccines
are already in short supply.
An important area which has been inadequately focused on during the pandemic is mental
health.[30] Patients who have been quarantined or isolated during the pandemic have experienced
feelings of anxiety and depression. In addition, several health care workers have
faced emotional burnout due to the psychological burden of loss, fear of getting infected,
long working hours, difficulty due to continuous use of PPE, social stigma among family
and neighbors, and problems with staying away from their families after caring for
patients with COVID-19.[31]
It is now known that patients who recover from COVID-19 may continue to have persistent
debilitating symptoms for several months after the initial infection, known as “post-COVID-19
syndrome” or “long COVID-19.” The World Health Organization defines post-COVID-19
condition as “occurring in individuals with a history of probable or confirmed SARS-CoV-2
infection, usually 3 months from the onset of COVID-19, with symptoms that last for
at least 2 months and cannot be explained by an alternative diagnosis.”[32] Some systems further classify post-COVID-19 into subacute (lasting 4–12 weeks after
the initial diagnosis) and chronic (lasting beyond 12 weeks) conditions. The manifestations
of post-COVID-19 syndrome include fatigue, sleep disturbances, cognitive dysfunction,
respiratory symptoms with a restrictive pattern of lung disease, myocarditis, and
endothelial dysfunction, among many others. Pinato et al found that 15% of patients
with cancer who developed COVID-19 had post-COVID-19 sequelae, leading to treatment
modifications and discontinuations in a significant proportion.[33] Permanent treatment discontinuation was an independent risk factor for mortality.
Cancer centers are now seeing increasing numbers of patients who have recovered from
COVID-19 and presenting for management of their cancer. It is essential to recognize
the implications of the previous COVID-19 infection, advise appropriate evaluation
and risk stratification, before proceeding with cancer therapy. There are several
recommendations for the evaluation of COVID-19 survivors to identify sequelae of COVID-19
prior to initiating other therapies.[34]
[35]
[36]
[37] Recognition of the sequelae of COVID-19 is especially important while using systemic
anticancer therapy with potential cardiac, pulmonary, hepatic, or renal toxicity,
and would warrant appropriate assessment and close monitoring. Mucormycoses emerged
as another threat in patients who had severe COVID-19. The use of steroids, environmental
factors, poorly controlled blood sugar, and oxygen sources were implicated for this
outbreak. Mucormycosis has been a known enemy for patients with hematological cancers
who are treated with steroids and have underlying diabetes mellitus.[38] This makes it essential to monitor such patients who develop COVID-19 and maintain
stringent blood sugar control along with judicious use of steroids.
Lessons from the Pandemic
Amidst this picture of gloom, the pandemic has taught us several lessons and had many
positive outcomes. To circumvent the problems with access to cancer care, most centers
started the facility of teleconsultation enabling the continued delivery of care and
minimizing the need for in-person visits. The widespread acceptance and success of
these teleconsultations suggest that even in future, remote consultation should be
adopted wherever feasible. This can have remarkable benefit in reducing the need for
follow-up visits. This also has the potential to decentralize medical care with optimal
resource utilization using the “hub and spoke” model. The delivery of oral drugs through
courier facilitated the continuation of treatment, both for routine care and for patients
on research protocols—an ideal practice that should be continued even postpandemic.
COVID-19 resulted in the setting up of isolation wards and adoption of better infection
control practices. Several studies have reported reductions in hospital infections
as a result of these measures. These practices can help reducing the transmission
of multidrug-resistant organisms, a major threat in immunocompromised patients with
cancer.[39] Most centers ramped up their testing services during the pandemic. This investment
in infrastructure and manpower will be useful in the coming years, for other infectious
diseases as well as molecular diagnostics of cancer. The pandemic resulted in several
drugs being tested as a cure for COVID-19, with the establishment of multicentric
collaborations, development of pragmatic protocols, and initiation of research studies
within rapid timelines. The establishment of collaborative registries led to a better
understanding of the impact and outcomes of COVID-19 in patients with cancer.[40] Simultaneously, there were modifications in ethics committee processes to facilitate
new and ongoing research via adoption of telephonic consent, expedited and virtual
reviews, remote monitoring, drug delivery directly to the patient, and pragmatic response
assessment timelines.[41] All of these processes have shown us more efficient ways of conducting research.
Research studies such as the “RECOVERY” and “SOLIDARITY” trials are leading examples
of pragmatic clinical trials which have shown wide external validity, with a variety
of populations and settings, and the ability to accrue rapidly with minimal burden
on the existing infrastructure at research sites. Oncology trials can learn from these
studies to ensure better generalizability of their results.[42]
[43]
Educational activities shifted largely to the online format, enabling several who
could not have attended otherwise to participate.[44] Many international teaching programs and course materials were made accessible to
all. The use of simulation techniques to replace actual clinical experience has gained
popularity. These changes can be incorporated into future academic activities which
can be blended or hybrid (virtual and in-person), thereby increasing their scope and
reach. Another blessing in disguise has been the reduction in the carbon footprint
generated by the decrease in travel for meetings and conferences. The recognition
of mental health challenges during the pandemic and the establishment of support services
for those with psychological issues are a huge step forward.
Summary
COVID-19 has had a substantial impact on various aspects of cancer care, both through
the direct effects of the infection, via its repercussions on cancer management, and
the cancer care workforce. As we continue to find a balance between minimizing the
risk of COVID-19 infection and continuing care for patients with cancer, there are
several positive lessons that will stand us in good stead for the future.
