Safeguarding COVID-19 and cancer management: drug design and therapeutic approach.

Plain language summary

To create an evidence-based therapeutic approach and to build clinical protocols for treating patients affected both by cancer and SARS-CoV-2 infection, systematic clinical research of the implications of acute COVID-19 and malignant neoplasms is required. In addition, a comprehensive understanding of the comorbid patient care required beyond the acute phase of COVID-19 is also urgently needed. New therapy protocols combining anticancer, antiviral, antifungal, and other supporting medications will aid in providing integrated multispecialty patient care. The most recent clinical cohort studies discussed in this review suggest that managing cancer patients infected with SARS-CoV-2 require a substantial revision of the current pharmacological treatments. Furthermore, the interpretation of cancer-relevant mechanisms engaged by the SARS-CoV-2 infection is essential for evidence-based cancer therapeutics, while the links between SARS-CoV-2 infection, tumorigenesis, and cancer patient immunosuppression must be predicted in epidemiological settings. Contextually, the adoption of highly advanced approaches such as those based on the application of artificial intelligence (AI) to COVID-19/cancer combinations could be highly beneficial, as AI can reduce the development timelines of new protocols, a critical issue in the current health emergency. Many national and international health authorities including the European Centre for Disease Prevention and Control (ECDC), the European Medicines Agency (EMA), the United States Center for Disease Control and Prevention (CDC), the National Health Service (NHS) in the United Kingdom, and the National Institute of Infectious Diseases (NIID) in Japan have issued protocol guidelines for the treatment of patients affected by cancer/COVID-19 comorbidity. All authorities specifically advise that chemotherapeutic, antiviral, and steroid doses be used in a controlled manner. Furthermore, continued usage of investigational drugs must be context-dependent and adhere to the highest clinical trial standards.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to spread globally at an alarming rate. The coronavirus disease 2019 (COVID-19) pandemic has dramatically affected cancer management, and has had an impact on diagnosis, treatment, and related therapeutic protocols 1 , 2 . COVID-19 has caused overall morbidity and mortality in cancer patients at an unprecedented scale. Clinical database evidence is evolving on the subacute and long-term effects of COVID-19 on cancer patients. Among all types of COVID-19 comorbidities, cancer is one of the diseases with a poorer patient outcome if compared to individuals afflicted by diabetic, cardiac, or chronic illnesses, or those without other underlying malignancies. Recent clinical studies have reported mortality rates that are significantly different among continents, ranging from 3.7% to 61.5% 3 for developed and underdeveloped countries, respectively. Evidence from prospective trials has suggested a link between cancer and impact of COVID-19 in comorbid patients. A cohort study including all types of cancers, with 82% of patients having solid tumors, recorded 35.5% mortality in the United Kingdom (UK) for the year 2020 3 . Contextually, a very recent update for the year 2021 from the COVID-19 and Cancer Consortium (CCC19) highlighted a comorbidity-related death rate of 15.8% 4 – 6 . Overall, the mortality rate of cancer patients infected with SARS-CoV-2 has been reported to vary between 13% to 40.5% in large national/international cohort studies 7 . Factors associated with a high risk of mortality in cancer/COVID-19 patients are older age, ever-smoking status, coexistence of additional comorbidities (e.g., diabetes), and presence of chronic health conditions.

Cancer patients are more likely to be infected by COVID-19, and clinical outcomes across the globe have evidenced that SARS-CoV-2 infection leads to significant adverse events in oncological patients; as a result, this comorbidity unavoidably reflects an increased mortality rate, and SARS-CoV-2 and cancer have been indicated as real partners of a single crime 8 . Many national population-based modelling studies support the concept that patients undergoing anticancer therapeutic regimens against all types of solid tumours (including breast, brain, lung, prostate, head and neck, and malignant neoplasms) and haematological malignancies, have a poorer therapeutic response and higher mortality rate after COVID-19 infection 9 . Potential cohort clinical studies involving cancer patients are currently being evaluated with the purpose of answering the crucial question of whether SARS-CoV-2 virus infections develop extreme or life-threatening complications 10 , 11 . The ability of cancer patients to combat external infections is markedly reduced due to their immunocompromised conditions; therefore, the risk of serious events associated with COVID-19 is remarkably greater in the oncological population. In addition, cancer patients are subjected to a higher risk of SARS-CoV-2 infection not only because of age or other pre-existing life style factors (e.g., smoking) but also because of cancer-associated metabolic disorders and chemotherapy/radiotherapy side effects that might exacerbate COVID-19 symptoms. Because of these pre-existing health conditions, cancer patients require timely diagnosis and faster intensive care admission in comparison to other comorbidities. The schematic correlation of cancer and COVID-19 comorbidity and its consequences in the current clinical settings is shown in Figure 1 .

With the purpose of counteracting the COVID-19 pandemic, strong measures including national lockdowns were introduced by almost all countries in March 2020 and many countries are still imposing major restrictions on citizen mobility. Unfortunately, during lockdown cancer screening campaigns were interrupted, regular diagnostic investigations postponed, and only late stage oncological conditions were scheduled for priority intervention. In addition, hospitals and oncology centres around the world have restricted cancer patient mobility, aiming to limit patient exposure to COVID-19 12 . Clearly, setting aside the direct threats to patients with cancer brought about by SARS-CoV-2 infection, late diagnosis and sub-standard oncological therapeutic regimens of care may largely and negatively affect cancer-afflicted individuals 1 .

The main focus of this data-driven review is to provide insights to scientists and general readers on the one-year consequences of the COVID-19 pandemic on cancer management. Another purpose is to offer some important criteria that clinical oncologists might follow while making decisions about cancer therapies to be administered under the extra pressure exerted by this unprecedented viral spreading. Furthermore, the impact of the COVID-19 pandemic on cancer management and therapeutic approaches is discussed, as we surmise that the role of multimodal therapies for cancer COVID-19 and new drug developments may have been underestimated so far. Finally, this review covers the concept of anticancer drug repurposing or repositioning in the combined treatment of COVID-19 and cancer comorbidity. The mortality (%) of hospitalized cancer (major) patients due to COVID-19 across the world is given in Table 1 .

COVID-19 and cancer: immuno-oncological perspectives

Although many of the details of the SARS-CoV-2 virus and its effect on patients who suffer from cancer have still to be clarified, a few remarkable, common features are emerging between COVID-19 pathophysiology and cancerous malignancies. In particular, the onset of inflammation, dysregulation of the immune system and impaired clot formation (also known as coagulopathy) are three hallmarks of both diseases. People living with cancer are more prone to become infected by SARS-CoV-2, and this is strongly linked to their weakened immune system ( Figure 2 ). Infections with SARS-CoV-2 can elicit host inflammation, leading to cytokine-induced vasodilation, extravasation of neutrophils, and plasma leakage into the affected tissue 13 . In addition, SARS-CoV-2 replication within infected cells stimulates increased levels of the pro-inflammatory mediators, including several interleukins (e.g., interleukin (IL)-6, IL-1β, IL-2 and IL-10), interferon (IFN)-γ, and tumour necrosis factor (TNF)-α. Within the vast majority of affected organs, the growth pattern of cancer cells is abnormal and uncontrolled, and ultimately these cells leave the primary site tumour to migrate to other body parts, where they originate secondary lesions known as metastases. Current chemo- or-radio-based anticancer therapies rely on the principle of killing fast-dividing cells either by cytotoxic drugs or radiation, with the ultimate aim of controlling metastasis growth and spread. However, other non-malignant rapidly-growing cells – including leukocytes (white blood cells or WBCs) and lymphocytes such as T and B cells 9 – can also be killed by such treatments, and this additional attack to the immune system of cancer patients render these individual less responsive to ongoing therapies. Additionally, cancer patients’ weak immunity itself cannot provide the powerful weapon required to face external threats such as viral or bacterial infections. Hence, these patients are undoubtedly exposed to an increased risk of SARS-CoV-2 infection, and have a three to four-fold higher mortality rate due to COVID-19 compared to other non-malignant comorbidities 27 , 28 .

Several clinical data analysis reports have addressed the incidence of COVID-19 patients with cancer across all continents. Among the cancer types, haematological and thoracic cancers have been associated with worse mortality rates since the beginning of the COVID-19 outbreak 29 . Recent studies have also shown that type 2-diabetes is linked to deaths from COVID-19 among cancer patients, the majority of affected individuals having liver, pancreatic or endometrial malignant neoplasms 30 . On the other hand, pre-existing lung comorbidities such as lower respiratory reserve, smoking and age status, and a clinical history of thoracic cancer and or anticancer treatments were shown to be connected with worse COVID-19 outcomes in populations from both USA and China. In detail, reports published from the USA demonstrated that lung cancer patients have a 55% higher risk of mortality from COVID-19 when compared with patients suffering from other cancer types (28%) 14 , while studies from China reported lung cancer patients are more vulnerable (18.8% mortality) to COVID-19 when compared with other cancer types (11.1% mortality) 28 .

The most prominent therapeutic challenge for cancer patients with COVID-19 is age as shown in Figure 3 . Aging is primarily responsible for increasing cumulative mortality incidence within the oncological population, due to the combination of immunosuppressive effects - induced by the disease itself and chemotherapeutic drugs - and physiological immunosenescence. Since SARS-CoV-2 infections already promote systemic changes and damage to the immune system of healthy individuals, its role in weakening the already-waning innate immunity of cancer patients is clearly a prevailing factor compared to non-cancer patients. Thus, the lack of effective immunity to combat SARS-CoV-2 infection is among the prime reasons for high COVID-19-related mortality in oncological patients 31 . Notably, SARS-CoV-2 infection not only reduces T cell counts but also stimulates polarization of age-induced immune cells and expression of inflammatory-related genes 30 . Furthermore, aging-associated immune response dysregulation was confirmed in older individuals diagnosed with both COVID-19 and cancer, and this unavoidably concurs both in weakening the host ability to suppress SARS-CoV-2 infections but also to mount effective responses to anticancer therapies, thus leading to the vulnerability of cancer patients to COVID-19 32 . Additionally, the generation of naive T cells through thymopoiesis and their priming by tumour specific antigens and SARS-CoV-2 infections are compromised with aging 33 , 34 . Unregulated mitochondrial functions are involved in inflammation and dysfunctional response to SARS-CoV-2 infection 33 ; as a result, older persons are more susceptible to cancer and SARS-CoV-2 infections, as well as being less able to build adaptive immune responses after COVID-19 treatment.

COVID 19: Compromised cancer management

Early on in the COVID-19 pandemic, the World Health Organization (WHO) found that cancer care (including diagnosis and therapy) has been severely negatively impacted in more than 150 countries worldwide 35 . Figure 4 shows the cancer and COVID-19 comorbidity scenario. Contextually, all European nations and the United States reported partial or complete interruption of cancer services. For instance, a 46.4% decrement in cancer diagnosis protocols was reported in the first month of COVID-19 outbreak in the USA (March 2020) 36 . In the European territory, many national health services also reported a substantial decline in the number of cancers diagnosed at the beginning of the COVID-19 pandemic (e.g., the Netherlands and Belgium reported a 30–40% decline in diagnosis, while the UK reported a decline of up to 84%) 37 . Similarly, India reported a 50% decline 38 in new diagnoses; Japan, Korea, Canada and Australia reported declines of nearly 45%, and China along with African countries reported a 10% decline in March–April 2020 in new diagnoses of cancer 39 , 40 . Such delayed cancer diagnosis and treatments are projected to result in an increase in the number of cancer-related deaths, in particular from colorectal cancer (+15%) and breast cancer (+9%) over the next five years 11 . Under this perspective, the concrete fear of a further medical emergency linked to noncommunicable diseases (including cancer) brought on by the pandemic is currently emerging.

The impact of COVID-19 on cancer throughout the world is complex, and has been referred to as a “deadly interplay” by WHO 35 . Unexpected travel restrictions, as well as the risk of SARS-CoV-2 infection among patients, have interrupted cancer services around the world, reducing the odds of a cure or survival for millions of cancer patients. Another issue in cancer management is drug shortages, which have resulted in a considerable decline in the number of new diagnoses and pre-planned therapy, even in nations with the strongest health-care systems. Treatment is extremely expensive for both COVID-19 and cancer, posing a challenge to the health-care systems of all emerging, developing, and high-income countries.

Throughout 2020, data from multiple cohort studies revealed that lung cancer was the most common malignancy linked to poor outcomes during the COVID-19 pandemic 41 , 42 . Among these patients, persons over the age of 60 are more likely to have lung cancer and SARS-CoV-2 comorbidity in comparison to their younger counterparts. One of the prevalent reasons for this outcome is the SARS-CoV-2 host-cell entry mechanism. Indeed, this pathogen targets lung tissue and enters lung cells via the angiotensin-converting enzyme 2 (ACE2) receptor. The viral load overwhelms other organs over time, leading in a cytokine storm and organ crosstalk that is dependent on the expression of the ACE2 receptor. Lung cancer patients have symptoms comparable to COVID-19 patients, such as systemic inflammation, fever, cough, and shortness of breath, as well as additional cancer consequences that can lead to multi-organ failure; thus COVID-19 mortality is more likely in this comorbidity 43 . Following lung cancer, other blood, bone marrow, and lymph node (haematological) malignancies were linked to increased vulnerability and accounted for up to 10-39% of global mortality from SARS-CoV-2 infections 44 – 46 . The characteristics of lung and haematological cancer patients, for example haemoptysis, loss of weight, loss of appetite, dyspnoea, thoracic pain, their age and the co-existence of further chronic diseases (both known or unknown), set further hurdles in any of these malignant clinical settings, with the COVID-19 pandemic resulting in much worse outcomes 47 . In line with this, patients with a haematological malignancy and lung cancer have an elevated risk of a poor outcome of COVID-19 in Europe and other parts of the world, according to studies carried out throughout the year 2020 by the Dutch Oncology COVID-19 group in the Netherlands 17 , 48 – 52 . As a result, the advice to clinicians with these vulnerable individuals as patients is to minimize their exposure to SARS-CoV-2 during treatment changes and, when possible, immunization should also be considered for continuing cancer patients.

Increased mortality among older adults is also associated with infection anxiety, leading to delayed hospital admissions and other supportive care ( Figure 5 ). In addition, after the COVID-19 outbreak, more than 34% of cancer surgical procedures were cancelled, and reduced monitoring and normal follow-up for adverse reactions to chemotherapy has suppressed therapeutic plans for older persons around the world 53 . According to the European Commission report on cancer management and COVID-19 54 in the European region, early cancer diagnosis awareness campaigns were either suspended or cancelled, not only in older patients but also in younger patients. Breast and cervical cancer-screening services in women and vaccination programmes (e.g. against human papillomavirus, HPV) continued during the first wave of COVID-19. This has been proposed in response to an impending health crisis caused by an overabundance of cancer patients, which is predicted to increase the strain on health systems globally, not just in Europe.

Associations of COVID-19 and cancer therapies

The management of cancer patients during the COVID-19 pandemic is mainly based on the provision of adjunctive support, including antiviral drugs, oxygen therapy, chemotherapy and radiotherapy, which represents the main treatment course. Despite the fact that novel anti-SARS-CoV-2 curative medications have yet to be discovered, the administration of anti-inflammatory, anticancer, and antiviral therapy is currently recommended 55 . WHO has recently updated interim guidance for cancer comorbidity, with the major aims of designing standard care to: (i) attenuate and prevent COVID-19 transmission in cancer patients; (ii) develop new antiviral and anticancer therapy protocols that can provide optimal care for all patients; (iii) develop fast-track solutions to promote effective multiple treatments; and (iv) ensure cancer research and care continuity while battling COVID-19 35 .

An association between cancer and SARS-CoV-2 infections, as well as a direct relationship between SARS-CoV-2 and cancer therapeutics, is still not well studied and elaborated in the literature. As discussed above, the weakened immune system of cancer patients is a key player in the individual outcome of SARS‑CoV‑2 infection. Many immune boosters, antiviral medications, and reciprocal anticancer medications with possible multifunctional therapeutic qualities have recently been examined for mild to severe COVID-19 cases, based on a number of clinical cohort studies and data from cancer patients with COVID-19 56 . A higher viral load, which may favour immunosuppression, also predisposes cancer patients to more intense viral replication 57 . The activation of T cells, which detect and destroy SARS-CoV-2-infected cells, is required for a powerful immune response against COVID-19. Additionally, T cell activation by cancer therapy also improves the ability of our own immune cells to fight cancer. This dual nature of T cells drew the attention of researchers and physicians, who devised a treatment protocol applying T cell-activated immunotherapy to this comorbidity. In contrast, recent observational clinical studies in oncological cohorts with confirmed severe COVID-19 comorbidity reported a reduced number of CD4 + cells (i.e., T-helper cells active against infections) and CD8 + cells (specialized in killing cancer cells and other antigens) 58 . Because T cells play such an important role in virus-infected cells, having a larger functionally protected T cell pool may help to lessen the severity of COVID-19 in cancer patients. This led to the development of integrated immunotherapy protocols for cancer and COVID-19 patients, which included immune-checkpoint blockers (pembrolizumab, nivolumab, cemiplimab) that might increase T cell immune responses against SARS-CoV-2 infected cells and malignant cells at the same time 59 . Encouragingly, recent retrospective cohort studies in haematological cancer patients with COVID-19 demonstrated positive outcomes of immunotherapy and endocrine therapy 60 . These clinical data strongly suggest that immunotherapy is somewhat beneficial to cancer patients with COVID-19. Similarly, large-cohort studies from the UK Coronavirus Cancer Monitoring Project and CCC19 reported that immunotherapy is advantageous to control COVID-19 in cancer patients 61 . In contrast, in a study of 275 patients, undergoing immunotherapy, particularly among lung cancer patients, was linked to an increased likelihood of intensive care unit (ICU) admission 62 . As a result, extended immunotherapy could be a big issue for COVID-19 cancer patients, as immune-mediated pneumonitis is a common adverse effect. In addition, clinical protocols involving steroid-based therapies for treating cancer/SARS‑CoV‑2 infection comorbidities have become established trends in the management of COVID-19 63 – 65 .

As of today, COVID-19 is being treated with a class of anticancer medications with antiviral characteristics that may raise or decrease vulnerability to SARS-CoV-2 infections. Administration of anticancer treatments to COVID-19 patients carries the risk of toxicity and infection severity due to the immunosuppressive nature of anticancer medications. As a result, numerous chemotherapeutic medications have been linked to an increased chance of severe COVID-19 56 , while infected individuals who received immune checkpoint inhibitors or targeted anticancer chemotherapeutics were shown to be more resistant to SARS-CoV-2 infections, whether mild or severe 56 . In rare cases, oncological patients subjected to extensive chemotherapy with various medications may experience immune-related side effects of the lung including pneumonia; clearly, this constitutes an additional risk factor in cancer patients impacted by COVID-19 and chemotherapeutic regimens.

New cancer chemotherapeutics are improving the host immune system's ability to recognize and eliminate cancer cells. The strong link between oncology drugs that enhance antitumor immune responses and promote better outcomes in SARS-CoV-2 infected individuals is now convincingly demonstrated by several clinical cohort studies, as shown in Table 2 . Intrinsic immune responses induced by anticancer therapies confer extra antiviral immunity and are critical for developing optimal COVID-19/cancer comorbidity therapeutic strategies. Antiviral immunity is also efficiently triggered by the delivery of chemotherapeutics in patients with a cancer burden via in situ techniques 66 . Chemotherapeutic medicines have long been known for their anticancer properties, but they are now also being recognized for their antiviral and immunotherapeutic properties. During SARS-CoV-2 infection, the effects of antiviral immune responses can be amplified using chemotherapeutics via the subsequent immune cascade; indeed, the internalization of chemotherapeutics into the bloodstream and lymphatic system activates the first line immune response as well as recruits second line responders (e.g., neutrophils and macrophages) to the infection site. Hence, the efficacy of antiviral therapy is dependent on the recruitment of immune cells caused by the anticancer chemotherapeutics. Beside anticancer drugs, other antiviral, antibiotic, and antimalarial active principles - along with plasma therapy - have also been tested to avoid severe SARS-CoV-2 infections 56 . Regardless of a lack of strong clinical evidence, multiple COVID-19 treatment protocols have been adopted in clinical practice across the world. Interestingly, some preliminary findings show promising results for these protocols against COVID-19 and cancer in comorbid patients. Although clinical trials remain the mainstay practice in cancer treatment, in the current COVID-19 pandemic drug repurposing can be a compelling and promising method to control SARS-CoV-2 infections.

Assessing the road ahead

To create an evidence-based therapeutic approach and to build clinical protocols for treating patients affected both by cancer and SARS-CoV-2 infection, a systematic clinical investigation of the implications of acute COVID-19 and malignant neoplasms is required. In addition, a comprehensive understanding of comorbid patient care required beyond the acute phase of COVID-19 is urgently needed. New therapy protocols combining anticancer, antiviral, antifungal, and other supporting medications will aid in providing integrated multispecialty patient care. The most recent clinical cohort studies discussed in this review suggest that managing cancer patients infected with SARS-CoV-2 requires a substantial revision of current pharmacological treatments. Furthermore, the interpretation of cancer-relevant mechanisms engaged by the SARS-CoV-2 virus is essential for evidence-based cancer therapeutics, while the links between SARS-CoV-2 infection, tumorigenesis, and cancer patient immunosuppression must be predicted in epidemiological settings. Contextually, the adoption of a highly advanced approach such as those based on the application of artificial intelligence (AI) to COVID-19/cancer comorbidities could be highly beneficial, as AI can reduce the timeline of new protocol development, a critical issue in the current health emergency 67 . During such an evolving and dramatic period, AI could not only decrease development time but also the costs of these therapeutic strategies, allowing for equal treatment options to be available worldwide. AI could use cutting-edge computational algorithms and clinical data for network medicine, which allows existing drugs to be tested across multiple diseases. In the big-data age, AI-guided drug repurposing or repositioning can overcome illness severity using early prognostic platforms, making it possible to define disease, medicine, therapies, and target identification with the least amount of mistakes in a very short amount of time.

At the current time, a network-based method for the systematic identification of targeted therapeutic and drug combinations for a prospective treatment of COVID-19 and cancer is a matter of urgency, given the lack of complete illness information about COVID-19 and its effects on cancer patients. Integration of drug and SARS-CoV-2 target networks, virus-host interactions, cancer induced immunosuppression in patients and antiviral-anticancer drug interactome networks are essential for such identification ( Figure 6 ). The current pharmacology model of anticancer drugs used to treat COVID-19 cannot separate antiviral-anticancer effects from those predictions due to a lack of detailed pharmacokinetics of drug targets and consequences of virus–host interactions 68 . The wide- ranging biological effects of different drug combinations as well as drug repurposing for both diseases will significantly improve the accuracy of the treatment combinations for the quick recovery of COVID-19 patients.

Early reports of COVID-19 outcomes in cancer patients have been largely derived in retrospect from small cohorts of SARS-CoV-2 infected individuals. Therapeutic conclusions, such as an increased risk of death from immunotherapy and chemotherapy, were taken from a small number of clinical studies and patient subgroups (as an understandable obvious consequence of COVID-19 constraints). Much of the research discussed in this article shows that systemic chemotherapy treatment choices for higher-risk SARS-CoV-2 infected patients are limited, which may lead to poorer results rather than curative treatment. While anticancer drugs and chimeric antigen receptor (CAR) T cell therapy summarized in Table 2 could indeed be effective in combatting the cytokine storm induced by COVID-19, the risk associated with some of these treatments is controversial due to reported side effects of fever, malaise and myalgias, severe organ toxicity, lung failure 83 . Anti-cancer medications and other immune-modulating active principles, whether used as a supplement or as part of a cancer therapy plan, may have different effects in COVID-19 patients; moreover, SARS-CoV-2 infections are being treated with other medicines that are routinely used in cancer therapeutic settings (e.g., steroids) that, in turn, affect host immunity 84 . An excessive usage of steroids in COVID-19 patients, however, was recently linked to a mucormycosis outbreak in India: according to media sources, hundreds of COVID-19 patients perished in India alone in the third week of May 2021 owing to mucormycosis fungal infection following steroid-based anti-SARS-CoV-2 treatments. This clearly highlights the necessity of low-dose steroidal regimens in managing cancer/COVID-19 patients during the present and possible future health emergencies. In order to reduce risk and enhance cancer treatment results, clinicians and policymakers must possess an essential, multidisciplinary knowledge of the complex and delicate interplay of SARS-CoV-2 virology, tumour biology, immune system physiology and anticancer therapeutic mechanisms in order to operate in the wider context of global healthcare.

Conclusion: key recommendations for safeguarding SARS-CoV-2 and cancer management

One of the most important questions that physicians and researchers have had to answer was whether COVID-19 patients with cancer comorbidity have worse outcomes owing to chemotherapeutic drugs than patients who were not treated with the same medications. The definitive answer to this question will aid clinicians in developing novel COVID-19 treatment protocols based on life-saving chemotherapeutics or antiviral drugs. Many national and international health authorities including the European Centre for Disease Prevention and Control (ECDC) 85 , the European Medicines Agency (EMA) 86 , the United States Center for Disease Control and Prevention (CDC) 87 , the National Health Service (NHS) in the UK 88 , and the National Institute of Infectious Diseases (NIID) 89 in Japan issued protocol guidelines for the treatment of patients affected by cancer/COVID-19 comorbidity ( Table 3 ). All authorities specifically advise that chemotherapeutic, antiviral, and steroid doses be used in a controlled manner. Furthermore, continued usage of investigational drugs must be context-dependent and adhere to the highest clinical trial standards.

The clinical world is speeding up the therapeutic inventions of many treatments to combat COVID-19, and all authorities have warned about the dangers of such haste, suggesting appropriate safety monitoring and in-depth preclinical study of the investigational product before conducting clinical trials on patients. Converting physical visits for therapy consultation to phone or video calls, and maintaining the highest standards of clinical safety during cancer surgeries, radiation, and chemotherapy treatments are all practical methods that could reduce viral spreading within the oncological population.

Data availability

No data are associated with this article.

Funding Statement

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 840964. This article is based upon work from COST Action CA 17140 "Cancer Nanomedicine from the Bench to the Bedside" supported by COST (European Cooperation in Science and Technology).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

[version 1; peer review: 2 approved]

References

1. Richards M, Anderson M, Carter P, et al. : The impact of the COVID-19 pandemic on cancer care. Nat Cancer. 2020;1(6):1–3. 10.1038/s43018-020-0074-y

2. Nalbandian A, Sehgal K, Gupta A, et al. : Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601–615. 10.1038/s41591-021-01283-z

3. Saini KS, Tagliamento M, Lambertini M, et al. : Mortality in patients with cancer and coronavirus disease 2019: A systematic review and pooled analysis of 52 studies. Eur J Cancer. 2020;139:43–50. 10.1016/j.ejca.2020.08.011

4. Bhaskaran K, Bacon SCJ, Evans SJW, et al. : Factors associated with deaths due to COVID-19 versus other causes: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform. MedRxiv. 2021; 2021.01.15.21249756. 10.1101/2021.01.15.21249756

5. Williamson EJ, Walker AJ, Bhaskaran K, et al. : Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430–436. 10.1038/s41586-020-2521-4

6. The OpenSAFELY Collaborative; Williamson EJ, Tazare J, et al. : Predicting COVID-19 related death using the OpenSAFELY platform. MedRxiv. 2021; 2021.02.25.21252433. 10.1101/2021.02.25.21252433

7. Lee AJX, Purshouse K: COVID-19 and cancer registries: learning from the first peak of the SARS-CoV-2 pandemic. Br J Cancer. Springer Nature,2021;124(11):1777–1784. 10.1038/s41416-021-01324-x

8. van Dam PA, Huizing M, Mestach G, et al. : SARS-CoV-2 and cancer: Are they really partners in crime? Cancer Treat Rev. W.B. Saunders Ltd,2020;89:102068. 10.1016/j.ctrv.2020.102068

9. Pathania AS, Prathipati P, Abdul BA, et al. : COVID-19 and cancer comorbidity: Therapeutic opportunities and challenges. Theranostics. Ivyspring International Publisher,2021;11(2):731–753. 10.7150/thno.51471

10. Maringe C, Spicer J, Morris M, et al. : The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study. Lancet Oncol. 2020;21(8):1023–1034. 10.1016/S1470-2045(20)30388-0

11. Hanna TP, King WD, Thibodeau S, et al. : Mortality due to cancer treatment delay: systematic review and meta-analysis. BMJ. 2020;371:m4087. 10.1136/bmj.m4087

12. Gosain R, Abdou Y, Singh A, et al. : COVID-19 and Cancer: a Comprehensive Review. Curr Oncol Rep. Springer,2020;22(5):53. 10.1007/s11912-020-00934-7

13. Saini KS, Lanza C, Romano M, et al. : Repurposing anticancer drugs for COVID-19-induced inflammation, immune dysfunction, and coagulopathy. Br J Cancer. Springer Nature,2020;123(5):694–697. 10.1038/s41416-020-0948-x

14. Mehta V, Goel S, Kabarriti R, et al. : Case fatality rate of cancer patients with COVID-19 in a New York Hospital system. Cancer Discov. 2020;10(7):935–941. 10.1158/2159-8290.CD-20-0516

15. Mehta A, Vasudevan S, Parkash A, et al. : COVID-19 mortality in cancer patients: A report from a tertiary cancer centre in India. PeerJ. 2021;9:e10599. 10.7717/peerj.10599

16. Fernandes GA, Feriani D, França E Silva ILA, et al. : Differences in mortality of cancer patients with COVID-19 in a Brazilian cancer center. Semin Oncol. 2021; S0093-7754(21)00003-8. 10.1053/j.seminoncol.2021.01.003

17. Pinato DJ, Scotti L, Gennari A, et al. : Determinants of enhanced vulnerability to coronavirus disease 2019 in UK patients with cancer: a European study. Eur J Cancer. 2021;150:190–202. 10.1016/j.ejca.2021.03.035

18. Lee LY, Cazier JB, Angelis V, et al. : COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: A prospective cohort study. Lancet. 2020;395(10241):1919–1926. 10.1016/S0140-6736(20)31173-9

19. Erdal GS, Polat O, Erdem GU, et al. : The mortality rate of COVID-19 was high in cancer patients: a retrospective single-center study. Int J Clin Oncol. 2021;26(5):826–834. 10.1007/s10147-021-01863-6

20. Stroppa EM, Toscani I, Citterio C, et al. : Coronavirus disease-2019 in cancer patients. A report of the first 25 cancer patients in a western country (Italy). Future Oncol. 2020;16(20):1425–1432. 10.2217/fon-2020-0369

21. Vuagnat P, Frelaut M, Ramtohul T, et al. : COVID-19 in breast cancer patients: A cohort at the Institut Curie hospitals in the Paris area. Breast Cancer Res. 2020;22(1):55. 10.1186/s13058-020-01293-8

22. Bernard A, Cottenet J, Bonniaud P, et al. : Comparison of cancer patients to non-cancer patients among covid-19 inpatients at a national level. Cancers (Basel). 2021;13(6):1436. 10.3390/cancers13061436

23. Yang F, Shi S, Zhu J, et al. : Clinical characteristics and outcomes of cancer patients with COVID-19. J Med Virol. 2020;92(10):2067–2073. 10.1002/jmv.25972

24. Nakamura S, Kanemasa Y, Atsuta Y, et al. : Characteristics and outcomes of coronavirus disease 2019 (COVID-19) patients with cancer: a single-center retrospective observational study in Tokyo, Japan. Int J Clin Oncol. 2021;26(3):485–493. 10.1007/s10147-020-01837-0

25. Sorouri M, Kasaeian A, Mojtabavi H, et al. : Clinical characteristics, outcomes, and risk factors for mortality in hospitalized patients with COVID-19 and cancer history: a propensity score-matched study. Infect Agent Cancer. 2020;15(1):74. 10.1186/s13027-020-00339-y

26. Liu Y, Lu H, Wang W, et al. : Clinical risk factors for mortality in patients with cancer and COVID-19: a systematic review and meta-analysis of recent observational studies. Expert Rev Anticancer Ther. 2021;21(1):107–119. 10.1080/14737140.2021.1837628

27. Kuderer NM, Choueiri TK, Shah DP, et al. : Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020;395(10241):1907–1918. 10.1016/S0140-6736(20)31187-9

28. Dai M, Liu D, Liu M, et al. : Patients with cancer appear more vulnerable to SARS-CoV-2: A multicenter study during the COVID-19 outbreak. Cancer Discov. 2020;10(6):783–791. 10.1158/2159-8290.CD-20-0422

29. Lee LYW, Cazier JB, Starkey T, et al. : COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study. Lancet Oncol. 2020;21(10):1309–1316. 10.1016/S1470-2045(20)30442-3

30. Derosa L, Melenotte C, Griscelli F, et al. : The immuno-oncological challenge of COVID-19. Nat Cancer. 2020;1(10):946–964. 10.1038/s43018-020-00122-3

31. van de Haar J, Hoes LR, Coles CE, et al. : Caring for patients with cancer in the COVID-19 era. Nat Med. Nature Research,2020;26(5):665–671. 10.1038/s41591-020-0874-8

32. Bajaj V, Gadi N, Spihlman AP, et al. : Aging, Immunity, and COVID-19: How Age Influences the Host Immune Response to Coronavirus Infections? Front Physiol. Frontiers Media S.A,2021;11:571416. 10.3389/fphys.2020.571416

33. Moreno Fernández-Ayala DJ, Navas P, López-Lluch G: Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. Exp Gerontol. Elsevier Inc,2020;142:111147. 10.1016/j.exger.2020.111147

34. Tian Y, Qiu X, Wang C, et al. : Cancer associates with risk and severe events of COVID-19: A systematic review and meta-analysis. Int J Cancer. 2021;148(2):363–374. 10.1002/ijc.33213

35. Statement - Catastrophic impact of COVID-19 on cancer care.2021. Reference Source

36. Kaufman HW, Chen Z, Niles J, et al. : Changes in the Number of US Patients With Newly Identified Cancer Before and During the Coronavirus Disease 2019 (COVID-19) Pandemic. JAMA Netw Open. 2020;3(8):e2017267. 10.1001/jamanetworkopen.2020.17267

37. Sud A, Torr B, Jones ME, et al. : Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study. Lancet Oncol. 2020;21(8):1035–1044. 10.1016/S1470-2045(20)30392-2

38. Sharma DC: Lockdown poses new challenges for cancer care in India. Lancet Oncol. NLM (Medline),2020;21(7):884. 10.1016/S1470-2045(20)30312-0

39. Al‐Shamsi HO, Alhazzani W, Alhuraiji A, et al. : A Practical Approach to the Management of Cancer Patients During the Novel Coronavirus Disease 2019 (COVID-19) Pandemic: An International Collaborative Group. Oncologist. 2020;25(6):e936–e945. 10.1634/theoncologist.2020-0213

40. Chen H, Wu X, Wang W, et al. : When cancer encounters COVID-19 in China: What have we suffered, experienced and learned. Jpn J Clin Oncol. 2020;50(6):712–717. 10.1093/jjco/hyaa077

41. Calabrò L, Peters S, Soria JC, et al. : Challenges in lung cancer therapy during the COVID-19 pandemic. Lancet Respir Med. 2020;8(6):542–544. 10.1016/S2213-2600(20)30170-3

42. van Haren RM, Delman AM, Turner KM, et al. : Impact of the COVID-19 Pandemic on Lung Cancer Screening Program and Subsequent Lung Cancer. J Am Coll Surg. 2021;232(4):600–605. 10.1016/j.jamcollsurg.2020.12.002

43. Wu L, Zhang C, Zhao X: The Impact of COVID-19 Pandemic on Lung Cancer Community. World J Oncol. 2021;12(1):1–6. 10.14740/wjon1367

44. Borah P, Mirgh S, Sharma SK, et al. : Effect of age, comorbidity and remission status on outcome of COVID-19 in patients with hematological malignancies. Blood Cells Mol Dis. 2021;87:102525. 10.1016/j.bcmd.2020.102525

45. Rahman A, Niloofa R, Jayarajah U, et al. : Hematological Abnormalities in COVID-19: A Narrative Review. Am J Trop Med Hyg. 2021;104(4):1188–1201. 10.4269/ajtmh.20-1536

46. Paul S, Rausch CR, Jain N, et al. : Treating Leukemia in the Time of COVID-19. Acta Haematol. 2021;144(2):132–145. 10.1159/000508199

47. Mohammed T, Ali I, Desai A: COVID-19 in Older Individuals with Cancer: Problem and Potential Solutions. Cancer Invest. 2021;39(3):214–216. 10.1080/07357907.2020.1852567

48. Guarneri V, Bassan F, Zagonel V, et al. : Epidemiology and clinical course of severe acute respiratory syndrome coronavirus 2 infection in cancer patients in the Veneto Oncology Network: The Rete Oncologica Veneta covID19 study. Eur J Cancer. 2021;147:120–127. 10.1016/j.ejca.2021.01.021

49. Indini A, Pinotti G, Artioli F, et al. : Management of patients with cancer during the COVID-19 pandemic: The Italian perspective on the second wave. Eur J Cancer. 2021;148:112–116. 10.1016/j.ejca.2021.01.040

50. Ladoire S, Goussot V, Redersdorff E, et al. : Seroprevalence of SARS-CoV-2 among the staff and patients of a French cancer centre after first lockdown: The canSEROcov study. Eur J Cancer. 2021;148:359–370. 10.1016/j.ejca.2021.02.027

51. Chin IS, Galavotti S, Yip KP, et al. : Influence of clinical characteristics and anti-cancer therapy on outcomes from SARS-CoV-2 infection: A systematic review and meta-analysis of 5,678 cancer patients. medRxiv. 2020; 2020.12.15.20248195. 10.1101/2020.12.15.20248195

52. de Joode K, Dumoulin DW, Tol J, et al. : Dutch Oncology COVID-19 consortium: Outcome of COVID-19 in patients with cancer in a nationwide cohort study. Eur J Cancer. 2020;141:171–184. 10.1016/j.ejca.2020.09.027

53. Onesti CE, Tagliamento M, Curigliano G, et al. : Expected Medium- and Long-Term Impact of the COVID-19 Outbreak in Oncology. JCO Glob Oncol. 2021;7(7):162–172. 10.1200/GO.20.00589

54. COVID-19 Consultation | BECA | Committees | European Parliament. 2021. Reference Source

55. Vivarelli S, Falzone L, Torino F, et al. : Immune-checkpoint inhibitors from cancer to COVID-19: A promising avenue for the treatment of patients with COVID-19 (Review). Int J Oncol. Spandidos Publications,2021;58(2):145–157. 10.3892/ijo.2020.5159

56. El Bairi K, Trapani D, Petrillo A, et al. : Repurposing anticancer drugs for the management of COVID-19. Eur J Cancer. Elsevier Ltd,2020;141:40–61. 10.1016/j.ejca.2020.09.014

57. Aldea M, Michot JM, Danlos FX, et al. : Repurposing of anticancer drugs expands possibilities for antiviral and anti-inflammatory discovery in COVID-19. Cancer Discov. 2021;11(6):1336–1344. 10.1158/2159-8290.CD-21-0144

58. Rogiers A, Tondini C, Grimes JM, et al. : Abstract S02-01: Clinical characteristics and outcomes of coronavirus 2019 disease (COVID-19) in cancer patients treated with immune checkpoint inhibitors (ICI). Clinical Cancer Research. 2020;26(18 Supplement):S02-01. 10.1158/1557-3265.covid-19-s02-01

59. Sullivan RJ, Johnson DB, Rini BI, et al. : COVID-19 and immune checkpoint inhibitors: Initial considerations. J Immunother Cancer. BMJ Publishing Group,2020;8(1):e000933. 10.1136/jitc-2020-000933

60. Thakkar A, Pradhan K, Jindal S, et al. : Patterns of seroconversion for SARS-CoV-2 IgG in patients with malignant disease and association with anticancer therapy. Nat Cancer. 2021;2(4):392–399. 10.1038/s43018-021-00191-y

61. Kuderer NM, Choueiri TK, Shah DP, et al. : Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020;395(10241):1907–1918. 10.1016/S0140-6736(20)31187-9

62. Robilotti EV, Babady NE, Mead PA, et al. : Determinants of COVID-19 disease severity in patients with cancer. Nat Med. 2020;26(8):1218–1223. 10.1038/s41591-020-0979-0

63. Rogiers A, Da Silva IP, Tentori C, et al. : Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition. J Immunother Cancer. 2021;9(1):e001931. 10.1136/jitc-2020-001931

64. Westblade LF, Brar G, Pinheiro LC, et al. : SARS-CoV-2 Viral Load Predicts Mortality in Patients with and without Cancer Who Are Hospitalized with COVID-19. Cancer Cell. 2020;38(5):661–671.e2. 10.1016/j.ccell.2020.09.007

65. Sica A, Casale D, Rossi G, et al. : The impact of the SARS-CoV-2 infection, with special reference to the hematological setting. J Med Virol. 2021;93(1):223–233. 10.1002/jmv.26197

66. Gujar S, Pol JG, Kim Y, et al. : Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies. Trends Immunol. Elsevier Ltd,2018;39(3):209–221. 10.1016/j.it.2017.11.006

67. Zhou Y, Wang F, Tang J, et al. : Artificial intelligence in COVID-19 drug repurposing. Lancet Digit Health. Elsevier Ltd,2020;2(12):e667–e676. 10.1016/S2589-7500(20)30192-8

68. Zhou Y, Hou Y, Shen J, et al. : Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020;6(1):14. 10.1038/s41421-020-0153-3

69. Huet T, Beaussier H, Voisin O, et al. : Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2(7):e393–e400. 10.1016/S2665-9913(20)30164-8

70. PRINCIPLE Trial Collaborative Group: Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;397(10279):1063–1074. 10.1016/S0140-6736(21)00461-X

71. Kalil AC, Patterson TF, Mehta AK, et al. : Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021;384(9):795–807. 10.1056/NEJMoa2031994

72. Pang J, Xu F, Aondio G, et al. : Efficacy and tolerability of bevacizumab in patients with severe Covid-19. Nat Commun. 2021;12(1):814. 10.1038/s41467-021-21085-8

73. Malard F, Mohty M: Management of patients with multiple myeloma during the COVID-19 pandemic. Lancet Haematol. Elsevier Ltd,2020;7(6):e435–e437. 10.1016/S2352-3026(20)30124-1

74. Stip E, Rizvi TA, Mustafa F, et al. : The Large Action of Chlorpromazine: Translational and Transdisciplinary Considerations in the Face of COVID-19. Front Pharmacol. 2020;11:577678. 10.3389/fphar.2020.577678

75. Geleris J, Sun Y, Platt J, et al. : Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020;382(25):2411–2418. 10.1056/NEJMoa2012410

76. Assaad HS, Assaad-Khalil S: Imatinib a Tyrosine Kinase Inhibitor: a potential treatment for SARS- COV-2 induced pneumonia. Alex J Med. 2020;56(1):68–72. 10.1080/20905068.2020.1778417

77. Goldstein DA, Ratain MJ, Saltz LB: Weight-Based Dosing of Pembrolizumab Every 6 Weeks in the Time of COVID-19. JAMA Oncol. American Medical Association,2020;6(11):1694–1695. 10.1001/jamaoncol.2020.2493

78. Martin WR, Cheng F: Repurposing of FDA-Approved Toremifene to Treat COVID-19 by Blocking the Spike Glycoprotein and NSP14 of SARS-CoV-2. J Proteome Res. 2020;19(11):4670–4677. 10.1021/acs.jproteome.0c00397

79. Hadjadj J, Yatim N, Barnabei L, et al. : Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369(6504):718–724. 10.1126/science.abc6027

80. Thibaud S, Tremblay D, Bhalla S, et al. : Protective role of Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukaemia and COVID-19. Br J Haematol. 2020;190(2):e73–e76. 10.1111/bjh.16863

81. Hu Y, Tan Su Yin E, Yang Y, et al. : CAR T-cell treatment during the COVID-19 pandemic: Management strategies and challenges. Curr Res Transl Med. Elsevier Masson SAS,2020;68(3):111–118. 10.1016/j.retram.2020.06.003

82. Lara PC, Burgos J, Macias D: Low dose lung radiotherapy for COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment. Clin Transl Radiat Oncol. 2020;23:27–29. 10.1016/j.ctro.2020.04.006

83. Bersanelli M: Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors. Immunotherapy. Future Medicine Ltd,2020;12(5):269–273. 10.2217/imt-2020-0067

84. van Paassen J, Vos JS, Hoekstra EM, et al. : Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. Crit Care. 2020;24(1):696. 10.1186/s13054-020-03400-9

85. Risk factors and risk groups.2020. Reference Source

86. Pottegård A, Kurz X, Moore N, et al. : Considerations for pharmacoepidemiological analyses in the SARS-CoV-2 pandemic. Pharmacoepidemiol Drug Saf. John Wiley and Sons Ltd,2020;29(8):825–831. 10.1002/pds.5029

87. CDC COVID Data Tracker.2020. Reference Source

88. Coronavirus » Urgent cancer diagnostic services during COVID-19.2020. Reference Source

89. Yazaki S, Yoshida T, Kojima Y, et al. : Difference in SARS-CoV-2 Antibody Status Between Patients With Cancer and Health Care Workers During the COVID-19 Pandemic in Japan. JAMA Oncol. 2021;e212159. 10.1001/jamaoncol.2021.2159