1 INTRODUCTION

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many infected individuals and the high mortality rate have caused a significant burden on public health worldwide.1 All of the risk factors which increase the severity or mortality of the current coronavirus disease 2019 (COVID‑19) have not yet been identified but are more severe in immunocompromised patients.2 Patients with malignant tumors are one important immunosuppressed group in the population. Cancer patients with hematologic malignancies who are receiving T cell‑depleting therapies or immunosuppressive therapy, or have had allogeneic hematopoietic cell transplantation, are at a higher risk of acquiring severe infection.3 Furthermore, increased hospitalization and nosocomial transmission of SARS-CoV-2 are another reason for a surge in infections in this group. Additionally, glucocorticoids, used in various therapy protocols, suppress both humoral and cellular immunity.

Moreover, surgery is another factor that makes cancer patients more susceptible to all kinds of infections, including viral diseases.4 Finally, psychological disorders caused by the COVID-19 pandemic, such as anxiety and depression, could negatively affect adherence to chemotherapy or other treatments, making this population more vulnerable.5 All the above problems increase COVID-19 severity, chances of hospitalization, the likelihood of intensive care unit (ICU) admission, need for mechanical ventilation, and mortality in this high-risk population. The worst COVID-19 outcomes, including acute respiratory distress syndrome, septic shock, acute myocardial ischemia, and death, would also be more likely in cancer patients undergoing surgery or chemotherapy for 14–30 days before getting infected with the virus.6, 7

2 IMMUNOPATHOGENESIS OF MORE SEVERE SARS-COV-2 INFECTION IN CANCER PATIENTS

The humoral and cellular immune systems play an essential role in defending against viral infections. Neutralizing antibodies effectively prevent viral entry, whereas cellular immunity is vital in activating CD4+ helper T cells, required for triggering humoral immunity, and CD8+ cytotoxic T cells, which are vital for the recognition and destruction of infected cells.8 Studies on previous coronavirus infections, such as Middle-East Respiratory Syndrome (MERS) and SARS, have shown that CD8+ T cell responses are directly linked to the severity of the disease.9 Thus, cancer patients are at exceptionally high risk of COVID‑19 infection because of the therapies they receive, such as anti-CD20 medications, Janus kinase inhibitors (JAKi), or Bruton tyrosine kinase inhibitors (BTKi), which weaken humoral immunity through inhibiting B cell function. These immunosuppressive agents can also cause T cell dysfunction and inhibition.10 Patients on active cytotoxic chemotherapy or who recently had hematopoietic stem cell transplants (HSCT) usually suffer from myelosuppression, resulting in an innate and adaptive immunodeficiency.

Furthermore, cancer development often weakens the immune system.11 It has also been proposed that having a history of smoking, which may include a substantial proportion of those with cancer, aggravates the situation by overexpressing immunosuppressive cytokines, suppressing the induction of pro-inflammatory danger signals, impairing dendritic cell maturation, and enhancing immunosuppressive regulatory T lymphocyte numbers.12 Tobacco use also leads to a significant increase in the gene expression of angiotensin-converting enzyme 2 (ACE2), the binding receptor for SARS-CoV-2, further elevating susceptibility to COVID-19 infection.13

3 RISK FACTORS INFLUENCING INFECTION SEVERITY IN ONCOLOGY PATIENTS

Recent studies have shown that cancer patients with COVID-19 are more likely to be admitted to the ICU, require mechanical ventilation, or die.14 In addition, a delayed admission time, due to the similarity between COVID-19 and cancer symptoms, might be another reason for the more likely progression to severe disease. In one study, the case fatality rate reached 5.6% among cancer patients, while the COVID-related mortality in the general population has been reported to be 2.3%.15 Therefore, the risk factors that may worsen the outcomes among cancer patients should be carefully examined. In a study investigating risk factors for developing severe complications in cancer patients, among those receiving antitumor treatment within 14 days of a COVID-19 diagnosis, undergoing chemotherapy, radiotherapy, targeted therapy, immunotherapy, and the presence of patchy consolidation in the first computed tomography (CT) scan of the lungs on admission were identified as significant risk factors.16 Moreover, due to the more potent myelosuppressive therapy they received, patients with hematologic malignancies are more likely to develop a severe infection than those with solid tumors.17

As components of a chemotherapy regimen, treatment with high-dose corticosteroids and immune checkpoint inhibitors (ICIs) have been independently associated with SARS-CoV-2 infection-related severity and mortality.18 Treatment regimens containing JAKi or BTKi may also put these patients at a higher risk of developing severe infections.19 Another vital point to consider is that symptoms and radiological features of ICI-induced pneumonitis can be overlapping with those of COVID-19-related pneumonia. For the latter, dexamethasone and remdesivir have shown encouraging results.20 On the other hand, the mainstay of treatment in ICI-induced pneumonitis is immunosuppressive therapy. It has been speculated that immunosuppression may be associated with an increased risk of progression to severe COVID-19, especially during the early stage of infection.20 Therefore, although the distinction between these two entities could be challenging for clinicians, it is highly warranted.

On the other hand, the sensitivity of the SARS-CoV-2 RT-PCR test is quite low, and the consequences of wrong interpretation can be too severe, to fully trust a negative result in clinically suspicious cases. Thus, additional parameters must be considered when assessing patients treated with ICIs with suspicion of COVID-19.20 Based on imaging modalities, laboratory assays, SARS-CoV-2 RT-PCR test, and if necessary, bronchoscopy with bronchoalveolar lavage, a diagnostic blueprint can be proposed to aid clinicians in daily practice to establish the right diagnosis between these two similar diseases, leading to the initiation of the correct course of treatment.20 Moreover, studies conducted among patients with various malignancies have demonstrated that the three most common malignancies in COVID-19-infected patients were gastrointestinal, thoracic (particularly non-small-cell lung carcinoma), and head and neck cancers.21 With this in mind, patients with lung neoplasms should be one of the top priority groups for COVID-19 prevention programs, such as vaccination. Therefore, during the COVID-19 pandemic, these patients should be actively screened for fever and respiratory symptoms and be kept separately from suspected cases of COVID-1922 (Figure 1).

The risk factors influencing infection severity in cancer patients. Several factors can increase the risk of COVID-19 in cancer patients. These risk factors are delayed admission, low sensitivity, or wrong interpretation of the SARS-CoV-2 RT-PCR tests. In some cases, the initial diagnosis may not be correct due to the similarity of cancer symptoms and COVID-19. There are also risk factors for cancer treatment, including chemotherapy, targeted therapy, radiotherapy, immunotherapy, and treatment regimens containing JAKi or BTKi. Treatment with high-dose corticosteroids and ICIs can also increase the chance of infection. Observing patchy consolidation in the first CT scan of the lungs on admission is also a risk factor for increasing the severity of infection. Also, patients with some cancers are more susceptible to infection than others. Abbreviations: BTKi, Bruton tyrosine kinase inhibitors; CT, computed tomography; ICIs, Immune checkpoint inhibitors; JAKi, Janus kinase inhibitors. *Gastrointestinal, thoracic (particularly non-small cell lung carcinoma), and head and neck cancers

4 CHALLENGES OF ONCOLOGISTS DURING THE COVID-19 PANDEMIC

The epidemic spread of this novel coronavirus has imposed significant challenges on the clinical practice of oncologists, especially for diagnosis and therapy. Studies have shown that the rate of cancer diagnosis and newly detected malignancies were significantly lower during the pandemic than for the same period before this outbreak.23 A systematic review of 62 studies measured and reported at least one delay or disruption in cancer health care because of the COVID-19 pandemic.24 The studies addressed 38 different categories of delays and disruptions with established or potential impact on the treatment plan, diagnosis, or health-service process. Most of the delays and disruptions in this study were as follows: reduction in any routine activity of cancer services, including the visits; reduction in the number of cancer surgeries; delay in radiotherapy; and delay, reschedule, or cancellation of outpatient visits. According to this survey, up to 77.5% of the patients reported interruption in any stage of treatment.24 Another interesting study by Ghahramani-Asl et al25 indicated the possible beneficiary effect of partial lung irradiation in COVID-19 patients. In this study, the authors imported the CT images of 10 COVID-19 patients into a specific treatment planning .system to anatomically define and contour the volumes of the pulmonary lesions, the lungs, and other nearby organs.25 For the first time, they report the feasibility and acceptability of using this treatment planning system in the volumetric assessment of COVID-19 lung lesions and its validity in determining the location of pulmonary lesions as a target for 3D conformal radiation therapy. Thus, if proven safe and effective in future studies, this modality could also be considered in COVID-19 patients’ treatment plans.25

Oncologists must carefully determine the risk of COVID-19 exposure in their patients. Since a diagnosis of cancer places infected patients at significantly increased risk of morbidity, including the need for mechanical ventilation, or mortality, it would be appropriate to decrease unnecessary exposure to COVID-19 for cancer patients in the health care system. However, the consequences of delayed diagnosis or treatment in common cancers must also be carefully considered,26, 27 and the decision about whether to continue maintenance therapy should be made individually. Some hematologic cancers, such as acute leukemia, and many solid tumors, including lung or pancreatic cancers, require urgent diagnosis and therapy. In contrast, other common early-stage neoplasms (e.g., breast, prostate, cervical, or non-melanoma skin cancers) do not need immediate intervention.28 For example, maintenance rituximab in follicular and mantle cell lymphomas are clear examples of where changes to maintenance therapy are necessary, as this anti-CD20 agent could significantly inhibit B cells, resulting in a much lower immune response to pathogens like SARS-CoV-2. Nevertheless, a delay in treating metastatic cancers can result in a much worse prognosis, significantly higher disease progression, and more hospitalizations. However, it is worth mentioning that some early-stage hormone-positive breast cancer patients can be kept on their hormone therapy if needed.29

A study on the effect of the current pandemic on cancer patients in Iran argued that cancer patients in developing countries with limited resources encounter more serious problems during outbreaks.30 This is mainly because the healthcare systems do not prioritize these patients. In addition, the lack of appropriate guidelines for their condition worsens the situation. Other problems in these countries include using radiation treatment centers as COVID-19 referral centers, lack of available hospital beds because they are allocated to cancer care, and deployment of the same nursing and hospital staff in cancer treatment centers COVID-19 wards.30 Moreover, timely delivery of radiotherapy is essential for patients, and any interruptions in radiation therapy may lead to cancer recurrence. Thus, another important issue is the irregular visits of patients for their treatments due to the fear of getting infected.30

At the pandemic’s beginning, the overall desire was to postpone nonurgent chemotherapy interventions in cancer patients. However, it is currently believed that routine antineoplastic therapy should not be delayed or stopped in patients without suspected or confirmed SARS-CoV-2.31 Conversely, suppose a SARS-CoV-2 infection is suspected. In that case, the patient should be quarantined. The antineoplastic therapy should be delayed for up to 14 days,31 but if the infection is confirmed, delaying or discontinuing chemotherapy is strongly recommended, as it significantly increase the risk of morbidity and mortality.4

Moreover, surgery or radiotherapy in cancer patients is strongly discouraged in the acute phase of SARS-CoV-2 infection.32, 33 Moreover, although more studies are required, another concerning issue is the interactions between anti-COVID-19 therapies (e.g., antiviral agents and monoclonal antibodies) with antineoplastic regimens, such as chemotherapy, hormonotherapy, targeted therapy, and immunotherapy.34 Another critical issue to be considered is the similarity between some symptoms of COVID-19 and cancer at the time of diagnosis (e.g., fever or cough), which may result in a misdiagnosis or delayed diagnosis of some malignancies, such as acute leukemia, primary mediastinal lymphoma, or lung cancer.35 In addition, the predominant peripheral ground-glass opacities (GGOs) or predominant lung consolidations of the lower lobes are a common radiographic presentation of metastatic lung cancers, differentiating a new COVID-19 infection from the so-called neoplasms would be challenging. In these cases, positron-emission tomography/CT scans would be appropriate diagnostic options for differentiating active lesions from new infections imposed upon the underlying malignant lesions.36 Comorbidities are another vital determinant of morbidity in cancer patients. A previous study showed that mortality was significantly higher in SARS-CoV-2-infected cancer patients, although the comorbidities, especially diabetes mellitus, were more prevalent in nonmalignant patients.37 Moreover, the probability of a positive SARS-CoV-2 RT-PCR test was significantly higher in nonmalignant patients. Regression analysis showed that the risk of death in COVID-19 cancer patients was about nine times greater than in other patients. Also, the patients who needed mechanical ventilation had a significantly higher mortality rate.37

Low anti-SARS-CoV-2 IgG antibody titers are another important risk factor in cancer patients, making them more vulnerable to the infection. Although numerous studies have already discussed this phenomenon,38-40 little is known about the pathophysiology of this condition.41 Moreover, there was a significant difference in SARS-CoV-2 IgG seroconversion among cancer patients undergoing various treatment plans. For instance, Thakkar et al.42 showed that cancer patients with hematological malignancies who received anti-CD20 antibody regimens and undergone stem cell transplantation had significantly lower seroconversion than other cancer patients. Furthermore, interestingly, their findings concluded that cancer patients who received immunotherapy, including anti-PD-1/PD-L1 monoclonal antibodies, developed 100% seroconversion for SARS-CoV-2. Thus, these lower seroconversion rates in cancer patients necessitate the importance of rigorous clinical monitoring and vaccination strategies in these susceptible populations.42 Nevertheless, even though such decreased anti-SARS-CoV-2 antibodies were not detected in asymptomatic COVID-19 cancer patients, more clinical studies are mandated to better understand this difference in asymptomatic patients since they play an essential role in the COVID-19 transmission chain.43

In summary, the unprecedented burden of COVID-19 on healthcare systems worldwide has a significant impact on cancer care. First, despite limited data, cancer patients seem to be more susceptible to the more catastrophic outcomes from the infection, including increased need for mechanical ventilation6 and mortality rates37, 44-47 (Table 1). Second, the diagnosis might be withheld as screening programs and diagnostic services have been decreased or suspended in many countries, and patients, wary of exposing themselves to the risk of infection, have been more reluctant to present to healthcare services.48 Third, Treatment routes have been modified to minimize potential exposure of cancer patients to SARS-CoV-2 and to reduce the risk during surgery or radiation therapy. Fourth, certain aspects of ongoing care have been deprioritized to enable health systems to respond to the current pandemic, resulting in suboptimal or delayed care for cancer patients. Fifth, many clinical trials have been suspended, reducing current therapy options for their participants, and jeopardizing longer-term therapy development 48 (Figure 2).

TABLE 1. The outcome of cancer patients in different COVID-19 studies First author, year Location Type of malignancy included Duration of study, weeks Total number of patients with malignancy Total number of hospitalized patients with malignancy Median age of patients with malignancy, year Deceased patients, N (%) Deceased patients with malignancy, N (%) Cook, 202049 UK and Italy Myeloma 15 75 72 73 30 (40) 41 (55) Ferrara, 202050 UK and Italy AML 4 10 10 60 5 (50) 5 (50) Mato, 202051 Multiple countries CLL 11 198 178 71 73 (37) 66 (33) Yigenoglu, 202052 Turkey Hematological malignancies 15 740 452 56 343 (46) 102 (14) Song, 202053 China Multiple cancers 12 248 101 63 38 (15) 2 (0.8) Chai, 202054 China Multiple cancers 52 166 166 65 60 (36) 49 (29) Mousavi, 202055 Iran Multiple cancers 8 33 33 64 16 (48) 13 (39) Aboueshia, 202056 USA Multiple cancers 8 57 57 59 40 (70) 7 (12) Condom, 202057 Spain Multiple cancers 12 24 24 69 11 (45) 11 (45) Biernat, 202058 Poland Hematological malignancies 4 10 10 58 8 (80) 7 (70) Aries, 202059 Netherlands Hematological malignancies 8 35 24 69 12 (34) 14 (40) Booth, 202060 UK Hematological malignancies 8 66 66 73 25 (38) 34 (52) Engelhardt, 202061 Germany Multiple myeloma 12 21 17 59 4 (19) 0 (0) Fox, 202016 UK Hematological malignancies 4 54 51 63 18 (33) 19 (35) He, 202062 China Hematological malignancies 3 13 13 35 6 (46) 8 (62) Hultcrantz, 202063 USA Myeloma 7 100 74 68 42 (42) 18 (18) Infante, 202064 China Hematological malignancies 4 41 29 76 19 (47) 15 (37) Lattenist, 202065 Belgium Hematological malignancies 8 12 12 74 3 (25) 6 (50) Malard, 202066 Multiple countries Hematological malignancies 4 25 25 72 8 (32) 10 (40) Martin-Moro, 202067 Spain Hematological malignancies 5 34 34 73 15 (44) 11 (32) Passamonti , 202068 Italy Hematological malignancies 12 536 451 68 196 (37) 198 (37) Razanamahery, 202069 France Hematological malignancies 8 20 20 69 7 (35) 6 (30) Sanchez-Pina, 202070 Spain Hematological malignancies 4 39 34 65 16 (41) 14 (40) Scarfo, 202071 Multiple countries CLL 10 190 169 72 64 (34) 56 (29) Shah, 202072 UK Hematological malignancies 8 80 80 73 28 (35) 28 (35) Wang, 202073 USA Myeloma 8 58 36 67 28 (48) 14 (24) Abbreviations: AML, Acute myeloid leukemia; CLL, Chronic lymphocytic leukemia.

Challenges of oncologists in the face of COVID-19. Due to the COVID-19 pandemic, oncologists face many challenges in treating cancer patients. One of these challenges is using shared staff and beds for cancer patients with COVID-19 due to a lack of human resources and hospital equipment. Other challenges include the fear of developing COVID-19. Many patients delay seeing a doctor because of this fear, which delays diagnosis, treatment, or even radiation therapy. Lack of appropriate guidelines for their condition also worsens the condition of patients with cancer. Interactions between antineoplastic regimens and anti-SARS-CoV-2 treatment are a major challenge for physicians. One of the most important challenges was accurately detecting COVID-19 from the so-called neoplasms. Reducing or delaying any routine cancer care activity is also a challenge. *Including the visits, reduction in the number of cancer surgeries, delay in radiotherapy, and delay, reschedule, or cancellation of outpatient visits

5 CHALLENGES OF CANCER SURGERY DURING THE PANDEMIC

During this outbreak, specific surgical recommendations have been made for common malignancies in cancer-specific guidelines. For instance, for gynecological cancers, surgeries are recommended to be postponed, with only emergent or urgent surgeries to be performed. Radiotherapy and concomitant chemoradiotherapy could be used instead, particularly for digestive neoplasms, laparoscopic surgery could also be undertaken with strict precautions. Furthermore, palliative therapy, such as stenting for esophageal cancers, can also be considered. However, it should be noted that delayed oncologic surgery may lead to cancer progression, resulting in the tumor no longer being resectable, with the associated worse survival outcomes.74, 75 Another study provided initial estimates and reference points for future research on the impact of the COVID-19 pandemic on oncological resection rates.76 As expected, the participating surgical departments perceive a reduction in tumor resections of all types. On average, the number of resections (for all questioned cancer types) was reduced by almost a third, consistent with another publication77 that estimates 38% of all cancer surgeries in all disciplines worldwide were canceled due to the COVID-19 crisis.76 Thus, it is recommended that patients who need to be operated on should at least have an adverse reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2.3 Also, in this situation, high-risk aerosolizing procedures should be avoided, appropriate personal protective equipment (PPE), such as N95 masks, goggles, gowns, and gloves, should be done by all health care workers, and such procedures should be performed in unfavorable pressure rooms, where possible.19

6 CHALLENGES FOR CHEMOTHERAPY DURING THE PANDEMIC

Chemotherapeutic agents predispose patients to infections through impairing bone marrow function, leading to thrombocytopenia and neutropenia. The risk of infection is highest when their absolute neutrophil count (ANC) is the lowest, usually 7–12 days after each chemotherapy session.19 Some cytotoxic agents (e.g., temozolomide, cyclophosphamide, paclitaxel, cisplatin, methotrexate, and fludarabine) may induce severe damage to the bone marrow and alemtuzumab, leading to lymphopenia and an increased risk of infection.78 Interactions between antineoplastic agents and potential SARS-CoV-2 infection therapies should also be considered. For example, some chemotherapeutic agents, such as vinca alkaloids (vincristine and vinblastine) and taxanes (docetaxel and paclitaxel), show significant interactions with protease inhibitors (e.g., atazanavir, lopinavir, and ritonavir), which were commonly used for treating SARS-CoV-2-infected patients at the beginning of the pandemic. Moreover, many other agents, such as tyrosine kinase inhibitors (dasatinib and ibrutinib), may interact with heparin, a commonly used anticoagulant in hospitalized patients. In addition, rituximab, a monoclonal anti-CD20 antibody, has significant interactions with tocilizumab, an approved interleukin-6 (IL-6) antagonist commonly used in severe COVID-19 patients.79

A potential solution to the increased risk of infection and increased severity in patients undergoing chemotherapy could be through the use of low-dose metronomic chemotherapy with different agents and schedules. This intervention can hopefully control the tumors and has more favorable safety profiles. In addition to the approaches mentioned above, the continuation of cancer care during the pandemic would be enhanced if oral administration of the medication was possible.