COVID-19 and cancer: an extensive review ONCOLOGY

Emerging data postulates that cancer is an important risk factor for disease severity and higher in-hospital mortality amongst patients with COVID-19. From a pathophysiological perspective, COVID-19 induces an overproduction of inflammatory cytokines, causing systemic inflammation, hypercoagulability, and multiple organ dysfunction syndrome. The exact pathophysiological mechanisms associated with severe COVID-19 disease in patients with cancer is uncertain. Moreover, the challenge of implementing social distancing in patients requiring speciﬁc anticancer treatments urged international societies to issue recommendations regarding the adoption of safety measures to reduce transmission risk and optimize anticancer treatment during the COVID-19 pandemic. We provide an extensive review of the clinical outcomes, prognosis and management of patients with cancer and COVID-19 infection. ABSTRACT de inflamatórias, inflamação hipercoagulabilidade e múltiplos órgãos. Os mecanismos ﬁsiopatológicos exatos COVID-19 pacientes câncer são incertos. que tratamentos tratamento anticâncer pandemia Nós extensa dos prognóstico e de com câncer e infecção por COVID-19.


INTRODUCTION
Currently, the world is facing the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 . In this century, two coronavirus epidemics occurred, the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 1 . In late December 2019, several local health facilities reported clusters of patients with pneumonia of unknown cause that were epidemiologically linked to a seafood and wet animal wholesale market in Wuhan, Hubei Province, China 2 . In March 2020, due to its fast dissemination, COVID-19 was declared a pandemic by the World Health Organization (WHO) 3 . In early March of 2021, the world had already registered more than 116 million individuals infected, with more than 2.5 million deaths.
In 2018 cancer was responsible for an estimated 9.6 million deaths, making it the second highest cause of death worldwide 4 . Every year 18 million new cases are diagnosed 4 . Particular attention was immediately given to patients with cancer in the Chinese nationwide cohort, representing about 1% of the COVID19-infected population, who were particularly vulnerable, with a case fatality rate (CFR) of 5.6% compared to 2.3% in the general population 5 . This increased susceptibility is partially due to the cancer itself, exerting a chronic immunosuppressive state, and exacerbated by cytotoxic therapies. Therefore, it is expected that cancer patients are at higher risk, both of infection and complications, during the COVID-19 pandemic 6 .
It is well established that early diagnosis and therapy are associated with better results in cancer morbidity and mortality. Due to COVID-19, many cancer diagnosis and treatments are being delayed which may result in worse outcomes for patients 7 . Maintaining cancer wards has been challenging in healthcare institutions currently focusing on the short-term emergency in response to COVID-19 5 .
In this review we will discuss the stages, pathophysiology, clinical evolution and management of COVID-19 of patients with cancer.

METHODOLOGY
We performed a critical literature review based on the PubMed electronic bibliographic database. The following descriptors were used in the search engines advanced tool: "COVID-19" or "SARS-CoV-2" and "cancer", resulting in 4,376 articles. Utilizing article type filters to include retrospective studies, prospective studies, meta-analysis, and clinical guidelines regarding the association of Cancer and COVID-19, obtained 941 results. Articles with a central theme diverging, or not related to  or the association between Cancer and SARS-CoV-2 infection were excluded from the revision. After title and abstract evaluation, 43 COVID-19 and Cancer articles were thoroughly reviewed, in addition to 25 articles on essential COVID-19 aspects used for contextualization, totaling 68 citations. Preprints articles were also included. A description of the methodology is depicted in Figure 1.

Clinical Evolution of COVID-19 patients
COVID-19´s clinical spectrum comprises three main phases that can range from asymptomatic carriers to individuals with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation 8 .
To comprehend the pathophysiology of this disease and apply it to patients diagnosed with an active or previously treated cancer, the clinical and laboratorial evolution will be discussed and exemplified in detail. Different studies show that about 86% of patients do not present disease severity, only about 14% require oxygen therapy in a hospital unit, and less than 5% of this group require intensive care 9 .

COVID-19 AND CANCER
The presentation of COVID-19 is predominantly mild and asymptomatic, which is exemplified as the first phase or nonpneumonia / mild pneumonia 10 . This stage occurs in the first 7 days containing a benign evolution, with symptoms characteristic of upper respiratory tract infection such as: dry cough, sore throat, rhinorrhea and respiratory secretion as well as headache, mild fever, fatigue, myalgia and malaise 11 . Nonspecific symptoms were also identified such as anosmia, ageusia and gastrointestinal manifestations: diarrhea, abdominal pain, nausea and vomiting. Early in the disease, chest computed tomographic (CT) imaging findings in approximately 15% of individuals and chest radiograph findings in approximately 40% of individuals can be normal 12 . In this phase, a complete blood count may reveal a lymphopenia and neutrophilia without other significant abnormalities and in dealing with these patients, approximately 80% of the cases are resolved 13 .
The second phase occurs after the first week in which the disease progresses to a moderate pneumonia, revealing a pulmonary involvement which can be divided into two subgroups, patients with and without hypoxia 14 . This phase occurs in approximately 15% of the patients and usually from the tenth day on, when the symptoms begin to worsen, with dyspnea, cough, and oxygen saturation decrease suggesting a progression to lower respiratory tract infection 13 . This progression is associated with the extreme increase of inflammatory cytokines, including interleukins IL-2, IL-7, IL-10, granulocytes colony stimulating factor (G-CSF), interferon gamma-induced protein of 10 KDa (IP-10), monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein 1α (MIP-1α), and transforming growth factor α (TGF-α) 15 . During this stage, patients develop a viral pneumonia, with cough, fever, and possibly hypoxia leading to dyspnea (defined as PaO2/FiO2 < 300 mm Hg). Imaging with chest roentgenogram or CT may reveal a bilateral peripheral pulmonary infiltrate in a ground-glass opacity pattern demonstrating the development of the viral pneumonia. Blood tests may reveal increasing lymphopenia along with transaminases. Laboratory evaluations also reveal an increase of inflammatory reagents such as C-reactive protein (CRP), ferritin, and D-dimer, evidencing an important systemic inflammatory and prothrombotic activity, also increasing the risk of bleeding by disseminated intravascular coagulation (DIC), in which both may be elevated, but not remarkably so 14 .
The third and last phase occurs after the second week of clinical evolution, representing approximately 5% of the patients infected with COVID-19. These COVID-19 patients that transition into this third and most severe stage of the illness manifest a severe pneumonia, as well as hypercapnia which is associated with an advanced respiratory failure established by the COVID-19 ARDS. In chest CT, there is an exacerbation of the bilateral multifocal pulmonary ground-glass opacities, with possible concomitant foci of consolidation and pleural effusion, and an augmentation of the ventilatory ratio, which reflects an increase in pulmonary dead space and inadequacy of ventilation, demanding oxygen therapy and ventilatory support; in addition, extra pulmonary systemic hyper inflammation syndrome is also noted 16 .
In this stage, markers of systemic inflammation are significantly elevated, and this systemic infection is characterized by a fulminant and fatal hypercytokinaemia (cytokine storm) with multiorgan failure 17 . Studies reveal that in this specific stage of the disease, inflammatory cytokines

4
and biomarkers such as IL-2, IL-6, IL-7, G-CSF, macrophage inflammatory protein 1-alpha, tumor necrosis factor-alpha, CRP, ferritin, and D-dimer are significantly elevated 18 . Also in this phase, procalcitonin (PCT) and erythrocyte sedimentation rate (ESR) increase gradually as the clinical status deteriorates, as does creatine kinase (CK), creatine kinase-MB fraction (CK-MB), Lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, and serum amyloid A protein (SAA) as well as prothrombin time in contrast with seric albumin which instead decreases 19 . When focusing in the immune response, other studies also show that in consequence to this state of hypercytokinaemia a decrease in CD4, CD8, suppressor, and regulatory T cell counts occur 20 . In this phase of the disease, these patients have critical manifestations such as septic shock, vasoplegia, unremitting fever, cytopenia and respiratory failure; cardiopulmonary collapse is also discernable, and/or multiple organ dysfunction syndrome 21 . Therefore, complications of COVID-19 include impaired function of the heart, brain, lung, liver, kidney and coagulation system, due to the endothelial damage possibly leading to disseminated intravascular coagulation. Concerning prognostic significance is the Sequential Organ Failure Assessment (SOFA) score, which predicts intensive care unit (ICU) mortality based on laboratory results and clinical data 22 . It is noteworthy that patients in this late stage of the disease have a dissociation between their relatively well-preserved lung mechanics and the severity of hypoxemia. This wide discrepancy is virtually never seen in most forms of ARDS 16 .
Although most patients progress with a good prognosis, it is essential to highlight that in the case of the elderly or individuals with comorbidities, such as diabetes, chronic lung diseases, cardiovascular (CV) and kidney diseases and cancer, COVID-19 can progress more aggressively, leading to multiple organ dysfunction 23 .

COVID-19 and Cancer-Pathophysiological Mechanisms
The SARS-CoV-2 infection is essentially initiated by the coupling of a host TMPRSS2 viral Spike-1 primed receptor with angiotensin-converting enzyme 2(ACE2), an anti-inflammatory receptor mostly present in the pulmonary alveolar epithelial type II cells 24 . Given that these cells produce surfactant and play a key role in pulmonary gas exchange, infection resulting in direct damage by pyroptosis and indirect lesion by inflammatory cell infiltration and secretion production, can result in lung injury 25,26 and cause dyspnea by hypoxemia, a cardinal symptom of COVID-19 27 .
SARS-CoV-2 also induces a decrease of ACE2 expression, thereby worsening lung injury 28 and increasing the already present pro-inflammatory host response, resulting in fever and feverrelated symptoms (myalgia, chills, fatigue) and cough possibly due to the release of inflammatory mediators such as Histamine, Prostaglandin E2 and Prostaglandin F 29 . Interaction of SARS-CoV-2 with ACE2 in other tissues such as the heart, intestines, and blood vessels could account for other manifestations of the disease such as myocarditis, diarrhea and multi-organ failure in critical patients 25,30 . SARS CoV-2 infection also provokes enhanced pro-thrombotic activity related to increased direct platelet activation and platelet-monocyte aggregates formation (thrombocytopathy) 31 , coagulation abnormalities (coagulopathy) 32 , complement activation with cytokine release (inflammation), and endothelial dysfunction (endotheliopathy).
Despite the mechanisms of thrombocytopathy and endotheliopathy in COVID-19 still being poorly understood, the clear clinical association is the presence of CV risk factors. The role of thromboinflammation is well known and highlights the crucial importance of endotheliopathy and thrombocytopathy to the morbimortality of this disease 33,34 .
Compared to the general population, cancer patients will display a higher risk of thromboembolic complications due to a cancer related increase in general thromboinflammation 35 , which could result in higher morbimortality in this group compared to the general population 36, 37 . However, this high risk of adverse outcomes of SARS-CoV-2 infection in cancer patients is also possibly explained through a series of immunologic mechanisms such as the immunosuppressive state caused by both the tumor itself and the cytotoxic therapies commonly used in this group. These therapies result in blunting of the immune response through lymphopenia and/or neutropenia and tumoral-induced exhaustion of antiviral lymphocytes 38 . This impaired immune response leads to the persistence of the virus ensuring continuous cytokine release probably by leukocytes other than T lymphocytes 39 . It causes and/or intensify the "cytokine storm" leading to severe lung damage. In addition, viral replication with consequent direct tissular lesion in other ACE2 rich biological sites such as the heart, intestine, and kidneys is also favored by this exacerbated immune response. Ultimately, it contributes to worsen the overall prognosis of the neoplasm patient when infected by SARS-CoV-2 40 .

COVID-19 and Cancer-Clinical Outcomes and Prognosis
Malignancy emerges as an important risk factor for disease severity and more adverse clinical outcomes amongst patients with SARS-CoV-2 infection. Impaired regulatory immune response observed in patients with cancer possibly enhances the cytokine storm and systemic inflammation observed in more severe forms of COVID-19. An initial report describing SARS-CoV-2 transmission in patients with cancer in a tertiary care hospital in Wuhan demonstrated a higher risk of COVID-19 infection. This example COVID-19 AND CANCER portrayed the vulnerability of these patients amid the COVID-19 pandemic raising initial concerns for oncologists and frontline doctors, which has been confirmed by several more recent reports 41 . Thus, it is of utmost importance to clearly understand the clinical manifestations, evolution, prognosis, mortality rates, and risk factors for severity and inhospital death in patients with COVID-19 and cancer

Clinical
Manifestations, Laboratory and
A multicenter retrospective cohort study evaluated the clinical characteristics and risk factors associated with COVID-19 disease severity in 232 cancer patients in Wuhan. It was evidenced that cancer predisposed patients to progress to severe COVID-19 when compared to non-cancer patients. Regarding clinical manifestations and symptomatology, SARS-CoV-2 infected cancer patients presented a higher prevalence of dyspnea 13.2 s, p=0.036) and activated partial thromboplastin time (35.5 vs. 34.1], p=0.046), and D-dimer levels (1.2 vs. 0.8 g/ml, p=0.054) were increased in cancer patients when compared to patients without cancer. These findings have revealed a direct association between cancer and systemic inflammation, immune hyperactivity and prothrombotic state, more critical forms of SARS-CoV-2 infection related to hypercytokinemia.

Cancer as a risk factor for severe COVID-19
Besides worse clinical features and a more adverse laboratory and radiographic profile, the retrospective analysis from Tian and colleagues also demonstrated that cancer is associated with a higher need of high-flow nasal cannula oxygen therapy (33.0% vs. 23.0%), and non-invasive mechanical ventilation (27.0% vs, 19.0%) or invasive mechanical ventilation (9.0% vs. 4.0%0) among patients with SARS-CoV-2 infection compared with non-cancer patients. Moreover, cancer was associated with severity increasing almost four-fold the risk of severe COVID-19 illness. The study also identified advanced tumor stage, elevated TNF, and increased NT-proBNP as novel predictors for poor prognosis among patients with cancer and SARS-CoV-2 infection. Multivariable logistic regression analysis revealed that target therapy and immunotherapy were correlated with 3 times increased risk of developing severe COVID-19, emphasizing that oncology teams must be attentive towards immunotherapy-related adverse events such as myocarditis and pneumonitis as they might contribute to worse prognosis in cancer patients with COVID-19 43,44 .
Thus, cancer seems to be also associated with worse clinical outcomes among patients with COVID-19. An early nationwide analysis in China evaluating the clinical characteristics and outcomes of cancer patients in SARS-CoV-2 infection depicted that those patients were observed to have a higher risk of severe events (composite endpoint including the percentage of patients admitted to ICU, requiring mechanical ventilation or death) compared to non-cancer patients (39.0% vs. 8.0%, p=0.0003). Moreover, besides malignancy per se, the association between anticancer therapy status and impact on COVID-19 severity is also a concern for intensivists and oncologists during the pandemic. The nationwide analysis from Liang and colleagues showed that patients with history of chemotherapy or surgery in the past month had increased risk of clinically COVID-19 severe events (75.0% vs. 43.0%) than patients that did not receive these types of anticancer therapy. This indicates a fivefold i of severe COVID- 19  In a multicenter, retrospective, cohort study including 205 patients with laboratory-confirmed severe SARS-CoV-2 infection evaluating the clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and COVID-19 in Hubei, China, revealed that cancer was associated with high case-fatality rate and unfavorable prognosis. In the study the most prevalent types of cancer were breast, colorectal, and lung carcinomas, while lymphoma was the most frequent hematological malignancy. Among the 205 cancer patients included, 30 patients (15.0%) were referred to the ICU and invasive mechanical ventilation was applied to 21 (66.0%) of patients that required mechanical ventilation. Moreover, complications occurred in 126 (63.0%) of 199 cancer patients, and the most common complications identified in these patients were abnormal liver function (17.0%), secondary infection (13.0%), ARDS (12.0%), coagulopathy (9.0%), acute renal failure (7.0%) and septic shock (6.0%). The median duration of hospitalization observed for cancer patients was 19  days for the total cohort of patients, 20

Robilotti et al. characterized the epidemiology and clinical characteristics of COVID-19 in 423 patients with cancer at the Memorial Sloan Kettering Cancer
Center in New York to describe the determinants of COVID-19 disease severity in patients with cancer. In the total cohort of patients, 168 (40.0%) patients were hospitalized, and 87 patients (20.0%) evolved with ARDS being 47 (11.0%) who required highflow oxygen and 40 (9.0%) who needed mechanical ventilation. Regarding clinical manifestations, shortness of breath and diarrhea were predictors of subsequent hospitalization and severe respiratory illness for patients with COVID-19 and cancer. Additionally, PCT (>0.5ng/ml), lymphopenia (<0.5K/ mcL), interleukin-6 (>100pg/ml), D-dimer (>1mcg/ ml), and LDH (250U/L) were laboratory biomarkers predictors of severe infection amongst cancer patients. Age (>65 years)], smoking status, cardiac disorder, history of hypertension/chronic kidney disease, and ICI were also independent predictors of severe COVID-19 in patients with cancer by Cox proportional hazard univariate analysis 53 .
A multicenter study evaluating clinical outcomes and mortality among 105 patients with COVID-19 and cancer in Wuhan described poor clinical outcomes and heightened mortality, alerting clinicians and oncologists. Patients with cancer had higher observed death rates, higher rates of ICU admission, and higher chances of requiring mechanical ventilation. Lung cancer was the most prevalent cancer type (20.95%), followed by gastrointestinal cancer ( 54 .
Hence, cancer seems to be associated with a more severe SARS-CoV-2 infection with more adverse and unfavorable clinical outcomes. Intensivists and oncologists should screen for concomitant comorbidities, severe clinical manifestations and a laboratory profile denoting a more profound inflammatory and thrombotic profile in patients with COVID-19 and cancer, due to an augmented risk for severe illness and more adverse clinical outcomes during hospitalization.

Cancer as a risk factor for mortality in COVID-19
As already mentioned, cancer seems to be also associated with higher in-hospital mortality of patients with COVID-19. In a retrospective observational cohort study in Lombardy, including 3,988 critically ill patients with COVID-19 evaluating the risk factors associated with mortality among patients in ICUs, malignant neoplasm was associated with higher risk of death (HR 1.  12-5.42], p<0.0001) analysis of risk factors for mortality in 2,665 included patients, cancer history was an independent risk factor for in-hospital mortality in patients with COVID-19 58 . Likewise, in a prospective observational study analyzing 800 patients with a diagnosis of cancer and symptomatic COVID-19 risk of death was significantly associated with advanced age, male sex, and the presence of other preexisting comorbidities such as hypertension and CV disease, despite the latter not obtaining statistical significance. Also, patients received cytotoxic chemotherapy within 4 weeks before testing positive for SARS-CoV-2 infection.
After adjusting for age, gender, and comorbidities, the study demonstrated that past chemotherapy had no significant impact on in-hospital mortality in cancer patients with COVID-19 compared with patients who had not received chemotherapy (OR 1.18 [CI95% 0.81-1.72], p=0.380).
Hence, these studies confirm cancer as an important risk factor for mortality in patents with COVID-19 59 . A summary of the major studies describing the clinical characteristics and predictors associated with severe COVID-19 and mortality in patients with cancer can be found in Table 1.

Cancer Management during COVID-19 Pandemic
The COVID-19 pandemic had a considerable impact on the overall delivery of health care since health care workers and facilities have a high viral spreading Table 1. Overview of oncologic patient management recommendations by ASCO and ESMO.

Before patient arrival prevention
Screening for symptoms between 48 and 72 hours before the appointment. If present, rescheduling or telemedicine consultation should ensue.
Adaptation to pandemic scenario. + Telemedicine as a feasible option.

During patient arrival prevention
Establishment of COVID-19 triage stations in every point of entry of the respective facility. + Referral to isolated Ward if screening is positive with physician evaluation for the necessity of molecular testing for SARS-CoV2.
Patients with fever and upper respiratory tract symptoms OR suggestive radiographical findings should be tested if testing is available. + Patients should be referred to different areas (COVID positive, COVID under investigation OR COVID-19 negative) according to their status.

Clinical inpatient management
Infusion therapy and radiotherapy in COVID-19 positive or suspected patients is conditioned to 2 negative tests done 24 hours apart. + Symptomatic inpatients have priority in case of scarce testing material for SARS-CoV2. + Providing surgical services for patients without immediately life-or limb-threatening conditions only after a local decrease of COVID-19 incidence for at least 14 days.
G-CSF criteria expansion to prevent febrile neutropenia during pandemic setting. + Prophylaxis with low molecular weight heparin or NOACs for all patients with cancer and COVID-19. + Constant individualization of therapy considering potential infection risk/ COVID-19 complication exacerbation and possible benefits. The European Society for Medical Oncology (ESMO) has a slightly different approach regarding in person medical consultation. ESMO highlights the importance of tailoring the intensity of care and social measures in cancer patients according to the local pandemic scenario. Telemedicine follow-up and triage may be a useful alternative to face-to-face appointments during the pandemic setting 63 .

Healthcare
Upon patient arrival at the healthcare service, ASCO recommends the establishment of triage stations outside of the facility screening for COVID-19 symptoms and fever. The process should guarantee social distancing of a minimum of six feet between every person accessing the facility, with educational materials about infection prevention available and use of masks being obligatory. The suspected COVID-19 patients should receive a wristband before entry and be escorted to designated isolation areas. Testing for SARS-CoV-2 should be considered by the oncologist that would evaluate if a treatment delay is a necessity or whether patient is manifesting confounding symptoms (tumor fever) and further COVID-19 related action is not necessary 62 .
ESMO conditions COVID-19 testing to the availability of laboratory resources in the respective healthcare facility. It also suggests dividing outpatients into three separate wards: COVID-19 positive, COVID-19 under investigation, and COVID-19 negative and suggests that patients COVID-19 positive or under investigation for COVID-19 should not be allowed to have access to the cancer center facilities 63 .
ESMO also suggests expanding the criteria for the use of G-CSF (prevention and treatment of febrile neutropenia) during the pandemic setting especially in intermediate (10%-20%) risk, high risk (>20%), and elderly patients with comorbidities. Due to the increased risk of a thromboembolic event in COVID-19 cancer patients, ESMO also suggests prophylaxis with low molecular weight heparin or novel oral anticoagulants (NOACs) for all patients with these conditions. Constant evaluation of patient risk of infection and complications by COVID-19 infection and the benefits of specific therapies are heavily emphasized in the ESMO guidelines 63 .
According to ASCO, infusion therapy and radiotherapy for COVID-19 positive patients or patients under investigation for COVID-19, should be conditioned to two negative COVID-19 tests performed at least 24 hours apart. In the case of scarce testing material, the priorities according to ASCO should be: (1) hospitalized symptomatic patients/symptomatic residents of congregated living settings; (2) symptomatic patients; (3) asymptomatic patients awaiting for immunosuppressive therapy/deemed a priority by public health departments or clinicians. Also, ASCO supports ACS measures about elective surgeries. ACS suggest resuming elective surgery only after at least a consecutive 14-day decline in local COVID-19 incidence rates 62,64 .
Furthermore, given that there is a considerable overlap between initial presentations of COVID-19 and febrile neutropenia in the oncologic patient, the Multinational Association of Supportive Care in Cancer (MASCC) released a position paper regarding clinical screening, evaluation and patients in the risk of febrile neutropenia with confounding symptoms, such as fever and dyspnea 65 . MASCC supports the notion that screening interviews that address responses indicative of at least one symptom including exposure risk, fever, and respiratory symptoms without other known causes are imperative to determine whether patients might be infected with COVID-19. If the interview reveals at least one symptom or exposure risks to SARS-CoV-2, the patient should be referred to a contact isolation room for blood collection, clinical examination by a physician wearing personal protective equipment, and COVID-19 testing. If the patient presents a high risk for febrile neutropenia (myeloablative therapy within the last 6 weeks), cultures of possible infection foci (blood, urine, sputum) should be performed, and a first dose of broad-spectrum antibiotics provided. After the results of the blood count, if signs of febrile neutropenia are present (single oral temperature of higher than 38.3 °C (101 °F), or greater than or equal to 38.0 °C over at least 1 hour and absolute neutrophil count less than 500/μL or less than 1000/ μL with a predicted rapid decline to less than 500/μ), the patient should be stratified with the MASCC risk score for febrile neutropenia. If the MASCC score is less or equal to 21, the patient should be admitted to the hospital in the general wards/ ICU if tested negative for COVID-19, to the shared COVID-19 inpatient facilities if positive for COVID -19 or to the individual COVID-19 inpatient facilities if tested negative for COVID-19 but presenting highly suggestive clinical symptoms (flu-like symptoms, bilateral lung infiltrates with peripheral distribution on CT, high-risk travel/exposure). In the latter cases, follow-up testing should be repeated in 24-48 hours. MASCC management recommendations for febrile neutropenia in the COVID19 pandemic are in line with ESMO guidelines 65 .
It is remarkable the discordance between the numerous published articles in that matter due to a multitude of factors, such as differences in the national healthcare systems and demographics of the publishing institutions. The scarcity of literature on cancer and COVID-19 at the time of publication and the need for a rapid response to the pandemic blunted the multicentric discussion during the formulations of these policies 66,67 .
Despite the absence of a consensus between the multiple published guidelines and recommendations, these share common ground in recognizing that a delay of unnecessary treatment, the reduction of toxicity, and the identification of priorities for surgery, radiotherapy, and systemic therapies as fundamental for cancer treatment during the pandemic setting. The notion of primum-non-nocere (first, do no harm) in conjunction with adequation of optimal care with demographic, structural, and organizational difficulties seem to be the main driving idea behind these ideals 66,67,68 . The main recommendations regarding oncologic patient management during the COVID-19 pandemic proposed by ASCO and ESMO are summarized in Table 2.    58 2,665 Retrospective --

COVID-19 AND CANCER
In contrast to the abundant number of publications about the management of cancer during the pandemic setting, no data on specific management of COVID-19 for cancer patients besides thromboembolic prophylaxis could be found while writing of this article. Given the complexity of oncologic patients and the high mortality that ensues for those infected with SARS-CoV-2, further studies addressing this particular issue are required.

CONCLUSION
Cancer seems to be associated with more adverse clinical outcomes, critical disease, higher mortality, and poorer prognosis amongst patients with SARS-CoV-2 infection. Moreover, history of cancer must be taken into consideration during the risk stratification of patients with confirmed or suspected COVID-19. Additionally, as cancer seems to be associated with an increased risk of severe disease and fatality, the implementation of preventive measures to reduce the probability of SARS-CoV-2 transmission and proactive strategies to guarantee a precocious diagnosis is vital to decrease the vulnerability of cancer patients during the COVID-19 pandemic. Further studies are still required to completely elucidate the clinical profile and prognosis of cancer patients with COVID-19.