key: cord-0688175-h6kb0nsr
authors: Seneviratne, Suranjith L; Wijerathne, Widuranga; Yasawardene, Pamodh; Somawardana, Buddhika
title: COVID-19 in cancer patients
date: 2022-03-11
journal: Trans R Soc Trop Med Hyg
DOI: 10.1093/trstmh/trac015
sha: dcf1006daead16896bab1fe83ff7d55596683be2
doc_id: 688175
cord_uid: h6kb0nsr

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has currently affected >220 million individuals worldwide. The complex interplay of immune dysfunction, active malignancy, the effect of cancer treatment on the immune system and additional comorbidities associated with cancer and COVID-19 all affect the outcomes of COVID-19 in patients with cancer. We have discussed the published findings (through the end of September 2021) on the effects of cancer on the morbidity and mortality of COVID-19, common factors between cancer and COVID-19, the interaction of cancer and COVID-19 treatments, the impact of COVID-19 on cancer clinical services, immune test findings in cancer patients with COVID-19 and the long-term effects of COVID-19 on cancer survivors.

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has currently affected >220 million individuals worldwide. 1 has been shown to cause more severe disease and increased mortality in patients with active cancer. [2] [3] [4] [5] The complex interplay of immune dysfunction, active malignancy, the effects of cancer treatment on the immune system and additional comorbidities associated with cancer and COVID-19 all affect the outcomes of COVID-19 in patients with cancer. The emergence of the Delta variant, which has been shown to have higher transmissibility, cause more severe disease among the unvaccinated and have somewhat less responsiveness to current COVID-19 vaccines 6 may further alter the current landscape with regard to COVID-19 infections in patients with cancer. The effect of cancer on COVID-19 has also been shown to vary according to the type of cancer. 7 The emergence of variants of SARS-CoV-2 has also led to changes in clinical presentations in cancer patients. In this article we discuss what is known about the effect of cancer on the morbidity and mortality of COVID-19, common factors that are shared between cancer and COVID-19, the interaction of cancer and COVID-19 treatments, the impact of COVID-19 on cancer clinical services, immune test findings in cancer patients with COVID-19 and the long-term effects of COVID-19 on cancer survivors.

The PubMed and Google Scholar databases were searched from 1 January 2020 to 30 September 2021 using the search terms 'COVID AND cancer screening OR cancer diagnosis OR cancer management', 'COVID AND cancer AND seroconversion OR immunity OR antibodies' and 'COVID AND cancer AND mortality OR outcomes OR clinical characteristics'. Retrospective and prospective observational and cohort studies describing clinical outcomes and changes in the immunity of cancer patients with COVID-19 and the impact on cancer services due to COVID-19 were included in the review after eliminating duplicates and irrelevant articles ( Figure 1 ). Studies included in qualitative synthesis growth and tumours are forced to edit the immune components that surround it, which is known as cancer immunoediting. There are three phases of cancer immunoediting: tumour dormancy/equilibrium, where the immune system fights against the cancerous cells and both are at an equilibrium; tumour immunity/elimination, where the immune system eliminates the cancerous cells; and tumour progression/escape, where the tumour overtakes the immune system and evades the immune surveillance. 9 Tumour cells evade immune attack by avoiding immune recognition and instigating an immunosuppressive tumour microenvironment. 8 Tumour-induced immune defects may weaken the host immune response, and this is a common feature in patients with haematologic malignancies such as leukaemia. 10 In certain haematologic malignancies, such as multiple myeloma and chronic lymphocytic leukaemia (CLL), the tumour cells need to share the same developmental space with normal immune cells and this may lead to immunoparesis. Some haema-tologic malignancies are characterised by systemic involvement of secondary lymphoid organs. The bone marrow represents a distinct immune tissue and haematopoietic stem cell involvement in leukaemia leads to cytopenia. 11 These distinct biological characteristics of haematologic malignancies reflect the immunosuppression associated with these malignancies. Cancer treatments such as chemotherapy, immunotherapy, targeted therapy and haematopoietic stem cell transplantation (HSCT) may also lead to myelosuppression and immunosuppression in cancer patients.

The viral envelope of SARS-CoV-2 is typically made up of three proteins that include the membrane, envelope and spike proteins. The latter helps the virus to bind to and enter host cells. 12, 13 Here it multiplies and then spreads from cell to cell and person to person. The immune system is activated in different ways, including increased or decreased proliferation of various cells and secretion of cytokines and downstream effects due to this. The immune system produces different CD4 and CD8 T cells against different Transactions of the Royal Society of Tropical Medicine and Hygiene parts of the virus and the process of vaccination tries to mimic this before the infection occurs. 12, 13 Thus a person with cancer, in whom the immune system is weak due to the cancer and the various treatments received, may be more prone to getting COVID-19 and getting severe disease with adverse clinical outcomes including death.

Studies have assessed the effects of SARS-CoV-1 and Middle East respiratory syndrome-related coronavirus (MERS-CoV) infections in cancer patients. Information on the mortality and morbidity of cancer patients following SARS-CoV-1 infection are sparse. A patient with acute myeloid leukaemia (AML) and SARS-CoV-1 infection developed bilateral infiltrates on chest radiography but did not require intubation and was discharged uneventfully from the hospital. 14 On the other hand, there is high morbidity and mortality among cancer patients infected with MERS-CoV, especially in those with haematologic malignancies. Atypical presentations of MERS-CoV infections were seen in those with a current or recent history of blood cancers. These included delayed symptom development, 20-d incubation period and persistent viral shedding without clinical deterioration. 15 Multiple studies have found higher mortality rates among blood cancer patients who developed MERS-CoV infection. One study found MERS-CoV infection in blood cancer patients to have a very poor prognosis regardless of the status of the underlying disease. 16 Other studies found the disease to be more severe among patients with cancers, 17 with a 100% case fatality rate among patients with haematologic malignancies and advanced solid cancers. The major causes of death were multi-organ failure and septic shock. 18 

Cancer is a genetic disease that is influenced by the tissue microenvironment and COVID-19 is an infectious disease. 19 There are several similarities between cancer and COVID-19 with regards to risk factors for severe disease and immune changes, such as overproduction of some cytokines (e.g. interleukin-6 [IL-6] and type I interferon [IFN-I]), the involvement of androgen receptors and immune checkpoint signalling. 20 Studies have clearly shown gender, age, ethnicity, comorbidities (including cardiovascular and respiratory), obesity, smoking and various medical conditions significantly impact the morbidity and mortality rates in 21, 22 The same factors are known to have a significant adverse impact on cancer patients as well. Socioeconomic factors, including the gross domestic product, may also affect the association between cancer and COVID-19. 20, 23 Further similarities between cancer and COVID-19 have been elucidated at a molecular level by Zong et al. 20 Four major signalling pathways-androgen receptor (AR), cytokine, IFN-I and immune checkpoint signalling-have been shown to govern the incidence and severity of both diseases. 19 Angiotensin-converting enzyme 2 (ACE2) expression in lung tissue has been found to increase with age. 24, 25 Since most cancers occur in older individuals, high ACE expression has been suggested as a mechanism mediating adverse clinical outcomes in older cancer patients. 26 Furthermore, smoking increases ACE2 expression in the lung tissue. There is a dose-response relation-ship between the number of pack-years of smoking and ACE2 expression. 27, 28 Smoking also correlates with adverse outcomes in patients with COVID-19. 29 The S protein of coronavirus consists of two components, S1 and S2. S1 is involved in recognizing and binding the virus to the host cell surface, while S2 is involved in fusing the viral and cell membranes, allowing viral entry into the cell. TMPRSS2 is the protease that mediates S protein cleavage, setting S1 and S2 apart. This event is called S protein priming and is believed to be essential for the interaction of SARS-CoV-2 with ACE2 and cell entry. 30 Co-expression of ACE2 and TMPRSS2 in such cells as type II pneumocytes, absorptive enterocytes of the small intestine and nasal goblet secretory cells reflects the high susceptibility of these cells to SARS-CoV-2. 31 ACE2 is also highly expressed in males, especially in urogenital organs such as the prostate. It was demonstrated in a recent study that patients with chronic urinary diseases are highly prone to SARS-CoV-2 infection. 32 Further, expression of TMPRSS2, one of the target genes of ARs, has an impact on both cancer and COVID-19. TMPRSS2 expression is modulated by the ARs in normal prostate secretory epithelium and prostate cancer. TMPRSS2 has also been found to be expressed in lung tissue. 33 Recent studies suggest that patients with prostate cancer treated by androgen deprivation therapy (ADT) were less likely to be infected by SARS-CoV-2 compared with those not on ADT or those with other tumour types. 34 They are also less likely to develop adverse clinical outcomes (hospitalization and oxygen supplementation). 35 Patients with pre-existing primary or secondary immune dysregulation are at an increased risk of adverse or severe outcomes following COVID-19. 36 Severe COVID-19 is associated with increased levels of cytokines such as IL-6, leading to a cytokine storm. 26,37-40 IL-6 is also overexpressed in almost all types of tumours and is one of the major cytokines in the tumour microenvironment and a driver of tumour progression. 41 On the other hand, one study showed that IFN-I levels are reduced in COVID-19 infection. 42 IFN-I is implicated in inhibiting tumour growth and promoting tumour cell senescence and death. 43 Decreased levels of IFN-I and IFNstimulated genes along with increased levels of IL-6 has been demonstrated in peripheral blood samples from critical COVID-19 patients. 44 In contrast, a few studies have demonstrated elevated IFN-I levels along with high IFN-stimulated genes in bronchoalveolar lavage or peripheral blood mononuclear cells of COVID-19 patients. 45, 46 Immune checkpoint molecules are expressed on a considerable proportion of tumour cells in many different cancers, including some haematologic malignancies such as Hodgkin lymphoma and primary mediastinal B cell lymphoma. 47 Several studies have shown an upregulation of checkpoint receptors in association with T cell exhaustion and lymphopenia in severe COVID-19 cases. [48] [49] [50] [51] Both cancer and COVID-19 have an increased risk of venous thromboembolic events (or, more rarely, arterial thromboses). 52 The mechanisms involved in COVID-19 coagulopathy include inflammation and activation of the innate immune system that in turn activates the systemic coagulation pathways. [52] [53] [54] Viral endotheliopathy and microcirculatory dysfunction may further contribute to the thrombotic complications seen in COVID-19. [53] [54] [55] In cancer patients, local or systemic therapy, multiple comorbidities and cancer cells expressing coagulation factors have been implicated in the pro-coagulant state. 56 S.L. Seneviratne et al.

Both cancer and COVID-19 may have some common predisposing factors, including increased age, obesity and immunosuppression, and these may also increase the chance of a person getting severe COVID-19. In cancer, there may be a greater chance of the immune system becoming further dysregulated by COVID-19 as compared with a healthy person. The outcomes in patients with cancer who develop COVID-19 can be divided into three facets: clinical, laboratory and general management outcomes. Table 1 outlines the significant findings with regard to changes in outcomes of patients with solid and/or haematologic malignancies following COVID-19 infection. 3, 5, 7, 21, 22, 29, 

In studies that included solid cancer patients, those who got COVID-19 had a higher probability of death compared with patients without cancer. 7,57,60 Several risk factors for increased mortality have been identified, including advanced age, male sex, smoking history, metastatic cancer, the presence of lung or bone metastases, higher C-reactive protein levels, the number of comorbidities and poor performance status. 7,21 Some studies found the age cut-off for worse prognosis to be 65 y, 96 while others found it to be 75 y. 21 Severe lung involvement due to cancer is an important determinant, 22 and those from ethnic minorities have a worse prognosis. 3 Those with lung, digestive (excluding colorectal), nasopharyngeal, brain and skin cancers had high mortality, with lung cancer as the highest. 7,57,101 Moderately higher mortality was noted with genitourinary, female genital tract, breast and thyroid cancers. 57 One study found genitourinary malignancies to not have a higher risk for mortality compared with the general population 91 and another found those with gynaecologic cancer to have a similar age-specific mortality risk. 71 Non-metastatic cancer patients experience similar frequencies of severe conditions as patients without cancer. 63 Another study reported gastrointestinal tract cancer (together with lymphoma or other haematologic neoplasms) had the highest excess of hospitalization, while cancers of the urinary tract, female genital organs and melanoma had the highest excess mortality. 97 Those with solid cancers had a higher risk of thromboembolism and sepsis, 59 acute respiratory and kidney failure, venous thrombosis, atrial fibrillation, 7 acute respiratory distress syndrome (ARDS), 60 liver injury, myocardial injury, renal insufficiency and multi-organ dysfunction syndrome (MODS). 81

Owing to high immunosuppression as a result of underlying disease, patients with haematologic malignancies are at significantly higher risk of a variety of severe infections, including COVID-19. They often receive myelosuppressive and immunosuppressive treatment, which further reduces their immune responses and further increases their risk of infections.

Increased mortality from COVID-19 infection has been reported in patients with immunosuppression (including those taking methotrexate). In particular, those with haematologic malignancies had a 2.5-fold increased risk. 109 A retrospective study found that patients with both COVID-19 infection and progressive cancer had a fivefold increase in the risk of 30-d mortality compared with COVID-19-positive cancer patients who were in remission or had no evidence of cancer. 29 A retrospective Italian study early in the pandemic also showed higher mortality in haemato-oncology patients with COVID-19 infection on the order of 39.2%, which was significantly higher when compared with rates for non-haematologic patients with COVID-19 (23.5%) and uninfected haematologic controls (3%). 61 A large retrospective study by Passamonti et al. 110 from Italy revealed increased mortality of patients with haematologic malignancies infected with COVID-19 when compared with a non-COVID-19 cohort with haematologic malignancies. Older age, progressive disease status, diagnosis of AML, indolent non-Hodgkin lymphoma, aggressive non-Hodgkin lymphoma or plasma cell neoplasms and severe or critical COVID-19 were associated with worse overall survival in this study. A meta-analysis of 34 adult and 5 paediatric studies from Asia, Europe and North America that included 3377 predominantly hospitalised haemato-oncology patients reported a comparable risk of death on the order of 34%. 111 Patients >60 y of age had a significantly higher relative risk of death compared with those <60 y of age. Several more studies have demonstrated higher mortality in patients with haematologic malignancies following COVID-19 infection compared with solid cancer patients. 73, 79, 82, 90 Children with blood cancers seem to have a low risk of death and the risk is higher in those with blood compared with solid organ cancers. 111 A multicentre audit in six National Health Service (NHS) centres revealed that patients with haematologic malignancies treated with chemotherapy in the preceding 28 d to COVID-19 diagnosis and nosocomial COVID-19 infection had a significantly higher mortality rate than those with solid malignancies. 112 In contrast, the aforementioned Italian study by Passamonti et al. 110 found that recent therapy had no association with mortality. This finding is consistent with the studies of patients with cancer in general and provides reassurance of the general safety of cancer treatment during the pandemic, although it is not a guarantee for every specific treatment in every clinical scenario. 27 Several studies have shown haematologic malignancies adversely affect COVID-19 severity. A study conducted at two centres in Wuhan, China among haematologic malignancy patients found no differences in baseline characteristics between those who did or did not develop COVID-19. However, the haematologic malignancy patients with COVID-19 had a higher mortality rate than those without COVID-19. 113 Patients with haematologic malignancies have significantly more admissions to the intensive care unit (ICU) than those without cancer. 7 Factors that adversely affected prognosis were advanced age, male sex, presence of lung or bone metastases, higher C-reactive protein levels, lymphopenia, non-Hispanic black race and Hispanic ethnicity, the number of comorbidities and poor performance status. 3,7,21 following COVID-19 to be lower in patients with haematologic malignancies and those who had received rituximab or a stem cell transplant. 124 Thus a differential rate of seroconversion was seen in different cancer patient groups. Another study found survival to be lower in patients with blood cancers compared with those with solid organ cancers. In this study there was greater impairment of B cell and SARS-CoV-2-specific antibody responses in those with blood cancers compared with solid cancers. 86 Significantly reduced immunoglobulin G (IgG) and IgM antibodies to SARS-CoV-2 are seen among blood cancer patients compared with solid cancer patients following COVID-19. 86 However, a subset of patients developed good CD4 + and CD8 + T cell responses and those with good CD8 + T cell responses were able to compensate for the weak antibody responses. 86 Impairment of B cells has been found in other studies as well. 121, 123 In one study there were heterogeneous humoral responses and an exhausted T cell phenotype in blood cancer patients. There is compelling evidence from case reports and series that immunosuppressed patients, including those with cancers, are also at increased risk of prolonged, persistent SARS-CoV-2 infection and viral shedding, accelerated viral evolution during infection and treatment, emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies and low antibody titres to SARS-CoV-2 variants. [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] The immunophenotypes of recovered solid cancer patients were similar to non-virus-exposed cancer individuals, while recovered blood cancer patients showed a weak immune response. 117 Anti-cancer therapy has been reported to be associated with impaired seroconversion. Patients receiving anti-CD20 therapy and chimeric antigen receptor (CAR) T cell therapy have absent seroconversion. 124 However, some studies reported SARS-CoV-2-specific IgG antibody detection did not differ between cancer patients and healthy individuals. 122, 136 Furthermore, immune disruption is higher in symptomatic COVID-19 patients, while asymptomatic carriers have normal immunity and lymphocyte counts. 114 Finally, the resolution of any immune dysfunction that follows COVID-19 occurs faster and better in those with a solid cancer. There is delayed or absent antibody responses in patients with haematologic malignancies and these patients will take longer time to clear the virus. 137

The treatment of cancer patients with COVID-19 may be complicated by changes in immunity when using certain medications and drug interactions. In Hodgkin lymphoma, bleomycin needs to be used with caution, owing to its lung toxicity. 138 Immune checkpoint inhibitor (ICI)-induced pneumonitis has made clinicians cautious about using this class of medicines. Concomitant ICI-induced pneumonitis and COVID-19 pneumonia may potentially increase the risk of lung damage. 139 Among those with cancer that develop COVID-19, those receiving ICI therapy had worse outcomes in some studies 40 but not in others. 102 Several cancer treatment protocols or regimens do not affect the outcomes of COVID-19 and have thus been recommended for use in cancer patients during the pandemic. 140 Immunotherapy, hormone therapy or radiotherapy in the month prior to SARS-CoV-2 infection is not associated with an increased risk of mortality among cancer patients with COVID-19. 34 Androgen therapy reduces the risk of contracting COVID-19 among patients with prostate cancer.

The Bruton tyrosine kinase inhibitors (BTKis) are used to treat CLL, Waldenström macroglobulinaemia and chronic graftvs-host disease and have been shown to have potent antiinflammatory effects resulting in decreased levels of proinflammatory cytokines that are commonly elevated in severe COVID-19. 141 Thus some authors have suggested a protective role of BTKis from severe COVID-19 morbidity due to an attenuated inflammatory response. 142, 143 It is recommended that granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) be stopped in patients with cancer and COVID-19 who do not have bacterial or fungal infections, to avoid the potential risk of increasing inflammatory cytokine levels and pulmonary inflammation. 144, 145 On the other hand, it is recommended that G-CSF be given with chemotherapy regimens to reduce the risk of febrile neutropenia in patients with COVID-19. 146 Thus, further trials on this aspect are urgently needed.

With CAR T cell and bispecific T cell engineer therapy, cytokine release syndrome is a known complication and shares many similarities with the COVID-19-associated cytokine storm. 147 The optimal time interval between resolution of infection and initiating or restarting cancer-directed therapy is still to be determined. Currently it has been recommended that treatment be withheld until COVID-19 symptoms have resolved. 140 With radiation therapy, hypofractionation has been suggested to minimize the number of hospital visits during the pandemic. 148 The overall recommendations for treating COVID-19 in cancer patients are similar to those for the general population. 140 Dexamethasone has been found to reduce mortality rates in patients with COVID-19 who require supplemental oxygen or invasive mechanical ventilation. 149 In cancer patients, dexamethasone is used for several reasons, including preventing chemotherapyinduced nausea and to treat inflammation associated with brain metastasis or spinal cord compression and as part of treatment protocols in acute lymphoblastic leukaemia and multiple myeloma. The side effects of dexamethasone are expected to be similar in patients with cancer to those without. 140 However, as dexamethasone is a weak to moderate cytochrome P450 (CYP3A4) inducer, possible interactions do need to be considered. 140 Interactions are seen between medications that are used to treat cancer and COVID-19. 150 Tocilizumab is known to interact with vincristine and doxorubicin. Some COVID-19 treatments may cause QT interval prolongation and thus need to be used with caution in patients receiving a bcl-2 inhibitor (venetoclax) or tyrosine kinase inhibitors (such as gilteritinib or nilotinib). Lopinavir/ritonavir are CYP3A4 inhibitors and may increase methotrexate, vincristine or ruxolitinib concentrations. 151, 152 

Taking into account the impact of COVID-19 on cancer clinical services, clinicians have had to rethink and remodel the provision of curative care for such patients. Table 3 outlines important findings with regard to the impact on clinical services and psychological aspects of cancer patients due to the COVID-19 Transactions of the Royal Society of Tropical Medicine and Hygiene pandemic. 137, [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] [164] [165] [166] [167] One study suggested that while appropriate therapy is continuing, physicians should take steps to reduce the risk from COVID-19, such as the selection of oral over intravenous treatment regimens wherever there is equipoise, the more judicious use of growth factor support and reducing surveillance laboratory and radiologic evaluations when possible. 144, 145, 148 Another study discussed the use of tele-oncology services to reduce the risk of cancer patients being exposed to SARS-CoV-2. 168 There is a need for clear communication and education about hand hygiene, infection control measures, high-risk exposure and awareness of the signs and symptoms of COVID-19. Some have suggested the need to individually evaluate the necessity of active intervention, postponing elective surgery or adjuvant chemotherapy for patients with a low risk of progression and minimizing outpatient visits to mitigate exposure and transmission. 169 Optimal protection of healthcare staff is important during the pandemic. Rapid response by institutions, adjustments to organizational structure, strategic planning, developing and implementing effective guidelines and providing effective and alternative ways to protect and support clinical staff, employees and patients are key to achieving good care during the pandemic.

Many patients with haematologic malignancies rely on clinical trials to receive their care, but during the pandemic the conduct of several clinical trials has been affected. The risk of adverse events from cancer therapies is unlikely to be increased. 170 Haematologic malignancy treatment units should be SARS-CoV-2 free zones, dedicated solely to haematologic treatment. Patients should strictly comply with social distancing and hospital outpatient visits should be reduced.

During the pandemic, cancer patients may experience adverse impacts from a screening, treatment or psychological perspective. Two-thirds of new cancer patients have presented at a more advanced stage. Nearly 75% missed their cancer screening appointment and two-thirds of patients who are already on cancer treatment have had their treatment interrupted. 171 A significant proportion of screening and diagnostic investigations have had to be postponed due to the pandemic. There has been a large effect on endoscopic services, leading to reductions in cancer detection. 165 Significant disruption has been seen in lung cancer screening 167 and imaging studies. 161 Urgent referrals for early cancer diagnosis were significantly reduced. 137 National screening programmes for breast, colorectal and cervical cancer were temporarily stopped or reduced due to the pandemic. 153 An Israeli national survey among haemato-oncology patients reported a delay in treatment among 9.1% of patients. 172 Interruptions to treatment at any stage have been reported by 77.5% of breast cancer patients during the pandemic. 156 A systematic review of 62 descriptive studies showed that interruptions and disruptions largely affected facilities up to 77.5%, the supply chain up to 79% and personnel availability up to 60%. 173 Despite repeated reassurances from officials that the UK's NHS remained open for urgent care, it was estimated that 45% of those with potential cancer symptoms did not contact their doctor during the UK's first wave of the pandemic from March to August 2020. The main reasons cited were fear of contracting COVID-19 and avoiding placing extra strain on the NHS. Consequently, suspected cancer referrals fell by 350 000 compared with the same period in 2019. 174 By April 2021, the UK NHS had >4.6 million cases on the waiting list for surgery and >300 000 have a waiting time of >12 months, a considerable proportion of which are for cancer. 174 There have been disruptions to interventional procedures, palliative care services 154 and therapeutic surgeries, 158, 164, 175 with decreases in admissions for chemotherapy. 137 One study found the delay occurred among newly diagnosed patients with breast, prostate and non-metastatic cancers. 162 Some of the reasons for delayed and disrupted care included an overwhelmed health system, lack of personal protective equipment, staff shortages, restricted access to medications 155 and barriers to consulting a general practitioner. 153 A 20% increase of cancer deaths has been predicted in England due to COVID-19 because of delays in patients seeking care, getting referred or receiving their chemotherapy. 137 During the COVID-19 pandemic, adverse psychological effects have been noted among cancer patients. A high prevalence of mental health problems among cancer patients has been observed. 160 Patients with breast cancer were reported to have high rates of anxiety, depression, distress and insomnia. 156 COVID-19-related anxiety among breast cancer patients may affect their decision-making process, such as attending diagnostic and therapeutic procedures. 159 The aforementioned Israeli national survey including >400 haemato-oncology patients recorded high rates of depression, and it was more evident among patients with chronic myeloid leukaemia. 172 A prospective study that included 77 lymphoma patients from Italy reported anxiety in 36% of patients, depression in 31% when the Hospital and Anxiety Depression Scale was administered and posttraumatic stress disorder (PTSD) among 36%. 176 Some may develop issues with a range of addictions. 177

Cancer patients are at an increased risk of developing post-COVID complications, 178 mainly affecting their heart, lung, kidney, skin and brain. 179 At least 15% of patients with cancer who have recovered from COVID-19 experience at least one post-infection sequelae, 180 such as respiratory symptoms, fatigue, neurocognitive dysfunction and weight loss. 181 Those at higher risk of longterm sequalae include men, those ≥65 y of age, having two or more comorbidities and a history of smoking. 178 One study found that if cancer patients with COVID-19 survive the immediate sequelae, their long-term sequalae and mortality are similar to those of cancer patients without COVID-19. 57 Interestingly, due to mounting evidence that SARS-CoV-2 is able to modulate certain oncogenic pathways, promote chronic low-grade inflammation and cause tissue damage, it has been hypothesised that long COVID-19 may predispose recovered patients to cancer development and accelerate cancer progression. 182 Comprehensive studies are urgently required to elucidate the effects of long COVID-19 on cancer susceptibility.

COVID-19 has significant adverse clinical, laboratory, socioeconomic and psychological effects among patients with malignancies. This is more prominent in those with haematologic S.L. Seneviratne et al. malignancies compared with solid malignancies and the magnitude of the risk has implications for clinical decision making. Those with lung cancer have the highest mortality among solid cancers from COVID-19. COVID-19 and cancer intersect at a molecular level, which may have therapeutic implications in cancer patients with COVID-19. Certain oncogenic molecular pathways commonly involved by cancer are also affected by COVID-19. Autoantibodies against IFN-I have been found in patients with life-threatening COVID-19. 183 Comprehensive studies are required to elucidate long-term sequelae of COVID-19 on cancer survivors. The COVID-19 pandemic has caused major disruptions to clinical services for cancer patients worldwide. Delayed presentations and diagnosis due to strained health systems and patients' reluctance to seek medical care during the pandemic have caused a considerable impact on cancer survival. In order to mitigate the catastrophic effects of the pandemic on cancer care, a thorough and collaborative effort is required at the national and international level. Findings from various studies have important policy implications, including, but not limited to, the need for increased surveillance and testing for SARS-CoV-2, minimising healthcare system exposure and reconsideration of procedures and treatments in patients with cancer in order to minimise the morbidity and mortality caused by COVID-19. Vaccination is an important preventive measure for patients with solid and haematologic malignancies against getting severe COVID-19.

Authors' contributions: SLS, WW, PY and BS designed the study. WW and PY conducted the search. WW, PY, SLS and BS assessed the article titles, abstracts and full texts. SLS, WW, PY, and BS wrote the first version of the manuscript and SLS and BS performed the final editing. All the authors reviewed and approved the final version. All authors had full access to the data in the study and final responsibility for the decision to submit for publication.

World Health Organization. Coronavirus disease (COVID-2019) situation reports

Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak

Immune modulation in hematologic malignancies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): an overview of viral structure and host response

COVID-19 vaccine landscape

An indolent case of severe acute respiratory syndrome

Atypical presentations of MERS-CoV infection in immunocompromised hosts

Middle East respiratory syndrome (MERS) infection in hematological and oncological patients: a case series from a tertiary care center in Saudi Arabia

Report of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in four patients with hematological malignancies treated at King Fahad Medical City

Outcome of oncology patients infected with coronavirus

Similarities in risk for COVID-19 and cancer disparities

The intersection of COVID-19 and cancer: signaling pathways and treatment implications

Cancer inpatients with COVID-19: a report from the Brazilian National Cancer Institute

The mortality rate of COVID-19 was high in cancer patients: a retrospective single-center study

Data regarding country-specific variability in Covid-19 prevalence, incidence, and case fatality rate

Asians do not exhibit elevated expression or unique genetic polymorphisms for ACE2, the cell-entry receptor of SARS-CoV-2

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

COVID-19 and cancer: current challenges and perspectives

Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract

Colorectal cancer statistics, 2020

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

TMPRSS2 activates the human coronavirus 229E for cathepsin-independent host cell entry and is expressed in viral target cells in the respiratory epithelium

SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues

Focus on the crosstalk between COVID-19 and urogenital systems

TMPRSS2 and COVID-19: serendipity or opportunity for intervention?

Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532)

Does androgen deprivation therapy protect against severe complications from COVID-19?

COVID-19 in immunocompromised hosts: what we know so far

Cytokine storms: understanding COVID-19

Longitudinal analyses reveal immunological misfiring in severe COVID-19

Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China

Determinants of COVID-19 disease severity in patients with cancer

Role of interleukin-6 in cancer progression and therapeutic resistance

Imbalanced host response to SARS-CoV-2 drives development of COVID-19

Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Heightened innate immune responses in the respiratory tract of COVID-19 patients

A single-cell atlas of the peripheral immune response in patients with severe COVID-19

Tumor cell-associated immune checkpoint molecules -drivers of malignancy and stemness. Biochim Biophys Acta Rev Cancer

Immunological features of coronavirus disease 2019 in patients with cancer

Using IL-2R/lymphocytes for predicting the clinical progression of patients with COVID-19

Lymphocyte subset counts in COVID-19 patients: a meta-analysis

Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19)

COVID-19 and its implications for thrombosis and anticoagulation

Atypical presentations of COVID-19

Hematological abnormalities in COVID-19: a narrative review

Endothelial cell infection and endotheliitis in COVID-19

Coagulation and cancer: biological and clinical aspects

One-year mortality and consequences of COVID-19 in cancer patients: a cohort study

Higher severity and risk of in-hospital mortality for COVID-19 patients with cancer during the year 2020 in Brazil: A countrywide analysis of secondary data. Cancer

Clinical course of cancer patients with COVID-19: a retrospective cohort study

Outcomes of COVID-19 in patients with lung cancer treated in a tertiary hospital in Madrid

Clinical characteristics and risk factors for mortality in hematologic patients affected by COVID-19

COVID-19 in cancer patients on systemic anti-cancer therapies: outcomes from the CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London) cohort study

Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak

Impact of solid cancer on in-hospital mortality overall and among different subgroups of patients with COVID-19: a nationwide, population-based analysis

High mortality among hospitalacquired COVID-19 infection in patients with cancer: a multicentre observational cohort study

Prevalence and outcome of COVID-19 infection in cancer patients: a national Veterans Affairs study

Outcomes of COVID-19 in patients with a history of cancer and comorbid cardiovascular disease

Chemotherapy and COVID-19 outcomes in patients with cancer

Extent of prior lung irradiation and mortality in COVID-19 patients with a cancer history

COVID-19 mortality in cancer patients in a Madrid hospital during the first 3 weeks of the epidemic

COVID-19 outcomes of patients with gynecologic cancer in New York City

Case fatality rate of cancer patients with COVID-19 in a New York hospital system

Cancer history is an independent risk factor for mortality in hospitalized COVID-19 patients: a propensity scorematched analysis

Presenting features and early mortality from SARS-CoV-2 infection in cancer patients during the initial stage of the COVID-19 pandemic in Europe

COVID-19 in cancer patients from New York City: a comparative single center retrospective analysis

Covid-19 transmission, outcome and associated risk factors in cancer patients at the first month of the pandemic in a Spanish hospital in Madrid

Covid-19 and lung cancer: a greater fatality rate? Lung Cancer

Factors affecting COVID-19 outcomes in cancer patients: a first report from Guy's Cancer Center in London

Clinical characteristics, outcomes, and risk factors for mortality in hospitalized patients with COVID-19 and cancer history: a propensity score-matched study

Systematic investigations of COVID-19 in 283 cancer patients

Clinical characteristics and outcomes of cancer patients with COVID-19

Clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study

Characteristics and outcomes of 35 breast cancer patients infected with COVID-19

Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China

Clinical characteristics of hematological patients concomitant with COVID-19

CD8 + T cells contribute to survival in patients with COVID-19 and hematologic cancer

Immunological alternation in COVID-19 patients with cancer and its implications on mortality

Differences in mortality of cancer patients with COVID-19 in a Brazilian cancer center

Determinants of COVID-19 mortality in patients with cancer from a community oncology practice in Brazil

Characteristics and outcomes of patients with cancer and COVID-19: results from a cohort study

Cancer, mortality, and acute kidney injury among hospitalized patients with SARS-CoV-2 infection

Covid-19 intensive care admissions and mortality among Swedish patients with cancer

COVID-19 and cancer registries: learning from the first peak of the SARS-CoV-2 pandemic

Cancer and risk of COVID-19 through a general community survey

Clinical characteristics and risk factors for mortality in cancer patients with COVID-19

Multivariate mortality analyses in COVID-19: comparing patients with cancer and patients without cancer in Louisiana

Cumulative COVID-19 incidence, mortality and prognosis in cancer survivors: a populationbased study in Reggio Emilia, Northern Italy

Outcomes of renal transplant recipients with SARS-CoV-2 infection in the eye of the storm: a comparative study with waitlisted patients

Impact of SARS-CoV-2 in hematopoietic stem cell transplantation and chimeric antigen receptor T cell therapy recipients

Characteristics and outcomes of coronavirus disease 2019 (COVID-19) patients with cancer: Transactions of the Royal Society of Tropical Medicine and Hygiene a single-center retrospective observational study in

Clinical characteristics and risk factors for in-hospital mortality of lung cancer patients with COVID-19: a multicenter, retrospective, cohort study. Thorac Cancer

Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition

COVID-19 in cancer patients: clinical characteristics and outcome-an analysis of the LEOSS registry

Identifying the risk factors for mortality in patients with cancer and COVID-19 in Hamadan, the West of Iran

Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study

Rates of COVID-19-Related Outcomes in Cancer Compared With Noncancer Patients

Incidence and outcome of SARS-CoV-2 infection on solid organ transplantation recipients: a nationwide population-based study

Analyses of risk, racial disparity, and outcomes among US patients with cancer and COVID-19 infection

Factors associated with COVID-19-related death using OpenSAFELY

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients

Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort. Leuk Lymphoma

COVID-19 in persons with haematological cancers

Asymptomatic COVID-19 infection in patients with cancer at a cancer-specialized hospital in Wuhan, China -preliminary results

Low prevalence of IgG antibodies to SARS-CoV-2 in cancer patients with COVID-19

Lower detection rates of SARS-COV2 antibodies in cancer patients versus health care workers after symptomatic COVID-19

Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2

Humoral immune response of SARS-CoV-2-infected patients with cancer: influencing factors and mechanisms

Rare SARS-CoV-2 antibody development in cancer patients

CD8 T cells compensate for impaired humoral immunity in COVID-19 patients with hematologic cancer

Seroconversion in patients with cancer and oncology health care workers infected by SARS-CoV-2

SARS-CoV-2-specific antibody rearrangements in prepandemic immune repertoires of risk cohorts and patients with COVID-19

Patterns of seroconversion for SARS-CoV-2 IgG in patients with malignant disease and association with anticancer therapy

Persistent SARS-CoV-2 infection and increasing viral variants in children and young adults with impaired humoral immunity

Intractable coronavirus disease 2019 (COVID-19) and prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in a chimeric antigen receptor-modified T-cell therapy recipient: a case study

Prolonged severe acute respiratory syndrome coronavirus 2 replication in an immunocompromised patient

Persistence and evolution of SARS-CoV-2 in an immunocompromised host

SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms

SARS-CoV-2 evolution during treatment of chronic infection

Emergence of multiple SARS-CoV-2 mutations in an immunocompromised host

Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on hemodialysis

Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer

Prolonged viral shedding of SARS-CoV-2 in an immunocompromised patient

Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectiousness among three immunocompromised patients: from prolonged viral shedding to SARS-CoV-2 superinfection

American Society for Radiation Oncology, and Society of Surgical Oncology guideline for management of hereditary breast cancer

Estimating excess mortality in people with cancer and multimorbidity in the COVID-19 emergency

COVID-19 and Hodgkin lymphoma: frequently asked questions

Checkpoint inhibitor pneumonitis: mechanisms, characteristics, management strategies, and beyond

Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib -findings from an investigator-initiated phase II study

The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients

Protective role of Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukaemia and COVID-19

National Comprehensive Cancer Network. NCCN hematopoietic growth factors: short-term recommendations specific to issues with COVID-19 (SARS-CoV-2)

Granulocyte-colony stimulating factor in COVID-19: is it stimulating more than just the bone marrow?

NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020

Cytokine release syndrome

ILROG emergency guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic

Dexamethasone in hospitalized patients with COVID-19

COVID-19 resources

Favipiravir in Covid-19

Remdesivir and Covid-19

Fewer cancer diagnoses during the COVID-19 epidemic in the Netherlands

COVID-19 pandemic: changes in cancer admissions

Impact of the COVID-19 pandemic on cancer care: a global collaborative study

Patient-reported outcomes of patients with breast cancer during the COVID-19 outbreak in the epicenter of China: a cross-sectional survey study

The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study

Impact of COVID-19 on cancer care: how the pandemic is delaying cancer diagnosis and treatment for American seniors

Breast cancer and COVID-19: the effect of fear on patients' decision-making process

Epidemiology of mental health problems among patients with cancer during COVID-19 pandemic

Impact of COVID-19 on cancer diagnosis and management in Slovenia -preliminary results

Delayed care for patients with newly diagnosed cancer due to COVID-19 and estimated impact on cancer mortality in France

The COVID-19 pandemic and impact on breast cancer diagnoses: what happened in England in the first half of 2020

Impact of the COVID-19 pandemic on the detection and management of colorectal cancer in England: a population-based study

Impact of the COVID-19 pandemic on UK endoscopic activity and cancer detection: a National Endoscopy Database Analysis

Evaluating the feasibility of performing elective gastrointestinal cancer surgery during the COVID-19 pandemic: an observational study with 60 days followup results of a tertiary referral pandemic hospital

Impact of the COVID-19 pandemic on lung cancer screening program and subsequent lung cancer

Managing healthcare operations during COVID-19

A practical approach to the management of cancer patients during the novel coronavirus disease 2019 (COVID-19) pandemic: an international collaborative group

COVID-19 pandemic and impact on cancer clinical trials: an academic medical center perspective

Covid-19: cancer mortality could rise at least 20% because of pandemic, study finds

The impact of COVID-19 on patients with hematological malignancies: the mixed-method analysis of an Israeli national survey

Delays and disruptions in cancer health care due to COVID-19 pandemic: systematic review

COVID-19 and cancer: 1 year on

Gastrointestinal manifestations in COVID-19

Psychological distress in outpatients with lymphoma during the COVID-19 pandemic

Substance use disorders and COVID-19: multi-faceted problems which require multi-pronged solutions

Post COVID complications, long term effects of coronavirus after recovery 2021

Long-term effects of COVID-19 and cancer create population of 'dual survivors

Long-term COVID-19 effects impact 15% of patients with cancer, may impair outcomes

Neurological manifestations in COVID-19: a narrative review

Cancer as a prospective sequela of long COVID-19

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Funding: None.

Ethical approval: Not required.

The data underlying this article are available in the article.