key: cord-334881-x9nxxled
authors: Di Lorenzo, Giuseppe; Di Trolio, Rossella; Kozlakidis, Zisis; Busto, Giuseppina; Ingenito, Concetta; Buonerba, Luciana; Ferrara, Claudia; Libroia, Annamaria; Ragone, Gianluca; Ioio, Concetta dello; Savastano, Beatrice; Polverino, Mario; De Falco, Ferdinando; Iaccarino, Simona; Leo, Emilio
title: COVID 19 therapies and anti-cancer drugs: A systematic review of recent literature
date: 2020-05-21
journal: Crit Rev Oncol Hematol
DOI: 10.1016/j.critrevonc.2020.102991
sha: 
doc_id: 334881
cord_uid: x9nxxled

BACKGROUND: It is reasonable to think that cancer patients undergoing chemotherapy, targeted therapy or immunotherapy could have a more aggressive course if positive for Coronavirus disease CoV-2 (COVID- 19). METHODS: We conducted a literature review on https://www.ncbi.nlm.nih.gov/pubmed/, https://scholar.google.com, www.arxiv.org, www.biorxiv.org, of all articles published using the keywords COVID-19 therapy or treatment and cancer until May 2, 2020. A total of 205 articles were identified and 53 were included in this review. RESULTS: We describe the ongoing COVID-19 therapies that should be known by oncologists and highlight the potential interactions with antineoplastic drugs, commonly used in clinical practice. The main drug interactions were found with tocilizumab, ruxolitinib and colchicine. Conclusions. The literature provides an inconclusive picture on potential preferred treatments for COVID-19 and their interactions with antineoplastic agents. Future clinical trials are needed to better understand the interactions between different drugs in the context of COVID-19 pandemic.

In our recent history there have been three epidemics related to coronavirus infections: the SARS-CoV (severe acute respiratory syndrome), 2002-03; the MERS-CoV (Middle-East-Respiratory-Syndrome), 2012; and currently the SARS-CoV-2, (2019-2020) (1) . Until May 2, 2020, there were approximately 209000 confirmed cases, with 28 000 deaths due to coronavirus disease CoV-2 (COVID- 19) in Italy, according to the Italian Civil Protection bulletin (2). According to the World Health Organization (WHO) as of May 2 2020 due to COVID-19, in Spain there were 215000 confirmed cases and 25000 deaths; in the United States, 1 milion confirmed cases and 57000 deaths; France has 128000 confirmed cases with 24000 deaths while United Kingdom has 177000 cases and 27000 deaths (3).

From the available scientific literature it is evident that about 19.4% of the deaths with the coranavirus had an oncological pathology as comorbidity (4, 5) . Thus, during this COVID-19 crisis, cancer patients are regarded as a highly vulnerable group. It was found that within 14 days, anti-cancer treatments were significantly associated with occurrence of severe clinical events in J o u r n a l P r e -p r o o f COVID-19 infection (6) . The cancer population subjected to chemotherapy and/or radiotherapy is more exposed to infections in general and, therefore, also to that from Coronavirus primarily due to the effect of the cytotoxic action on the hematopoietic and immune systems with a reduction in the number of neutrophils, the first bulwark of infections, and decreased immune capacity (4) . Although there is no data yet on the risks of contracting coronavirus infection or on the clinical course of the infection during immunotherapy and/or immunosuppressive treatment with chemotherapy. It is reasonable to think, by analogy of what happens in the case of seasonal flu, due to the presence of immunosuppression, that in treated cancer patients, there may be a greater number of complications and the clinical course to be more serious (1) .

Therefore there remains an urgent need to answer whether COVID-19-positive cancer patients will have worse outcomes, such as death, from the coronavirus-induced pneumonia for example, and whether cancer patients should receive anti-cancer treatments. Additionally, oncologists are required to know the toxic effects of the drugs used in the experimental therapy of COVID-19 and the possible interactions of these drugs with the commonly used antineoplastic drugs. The systematic review followed the PRISMA guidelines (figure 1) (7) . Two investigators (EL and RDT) independently conducted literature search using as combined keywords COVID-19 therapy or treatment and cancer on https://www.ncbi.nlm.nih.gov/pubmed/, www.arxiv.org (8), www.biorxiv.org (9) and https://scholar.google.com (10) . The database search was run of all the published articles from database inception until May 2, 2020. In Pubmed the following strategy was used: (COVID-19 OR Novel Coronavirus-Infected Pneumonia OR 2019 novel coronavirus OR 2019-nCoV or SARS-CoV-2 therapy or treatment) AND cancer.

The strategy was then adapted for the other databases, including website of Italian Medicines Agency (AIFA) for ongoing trials ( https://www.aifa.gov.it/emergenza-covid-19 ) (11).

All studies reporting information on both COVID-19 therapy/treatment and cancer were included. 205 articles were identified and reviewed independently by two authors (EL AND RDT) and 53 articles were considered relevant to the scope of the current review, as described in figure 1 (6, . Any inconsistencies were resolved by consensus with a third author (GDL). All health outcomes were included, due to the anticipated scarcity of data.

The lists of the drugs being tested and their side-effects are listed in Table 1 . They are presented below in more detail.

Considering the etiological therapy of SARS-CoV-2, antiviral agents, already on the market and in use for other viral pathologies, in monotherapy or in combination are currently being tested.

It has a mechanism of action related to the selective inhibition of the Viral polymerase-RNAdependent RNA and is used as a backup drug when other therapies do not work (42) .

Commonly used for the treatment of hepatitis C and for inflammatory lung diseases, such as bronchiolitis, this antiviral drug is always used in combination with other medicines, such as interferon alfa and peginterferon alfa and can be used both in the treatment of adult patients and in the treatment of pediatric patients (49).

It is an antiviral drug in the class of nucleotide analogues. It was developed as a treatment for Ebola virus disease and Marburg virus infections. It has also been shown to have antiviral activity against RNA viruses such as human respiratory syncytial virus and coronaviruses, including viruses that cause the MERS and SARS (42) .

On 29 April, the director of the US National Institute of Allergy and Infectious Diseases (NIAID), announced the results of a study in which patients taking remdesivir recovered in 11 days compared with 15 days for those on a placebo. The shortened recovery time was so significant that investigators decided to stop the trial (50).

This news contradicts previous mixed results on the drug. Gilead Sciences announced that in a non-randomized trial, more than half of participants with severe COVID-19 had recovered from their disease within two weeks of receiving treatment. Another smaller trial in China announced that it had found no benefits from remdesivir when compared with a placebo. The NIAID did not release informations on safety data (50).

Lopinavir and Ritonavir is indicated, in combination with other antiretroviral medicines, for the treatment of adults, and children over the age of 2 years with human immunodeficiency virus (HIV-1) infection (42) . Lopinavir-Ritonavir in association with Ribavirin is being evaluated.

It is a drug that counteracts the over-reaction of the immune system, at the origin of some of the most serious complications of COVID-19 and which in these days seems to offer hope to patients with coronavirus-induced pneumonia. In addition to rheumatoid arthritis therapy, the medicine is also used to treat cytokine release syndrome, a side effect of CAR-T anticancer therapy which consists of a massive release of inflammatory molecules in response to the immune cells used in the treatment (51).

It is an anti-interferon gamma. This drug keeps children with hemophagocytic lymphohistiocytosis (HLH) alive, awaiting transplantation. The administration of emapalumab is able to "turn off" the abnormal and excessive inflammatory response in patients with HLH, neutralizing the effects deriving from the excessive production of interferon-gamma (52).

Sarilumab is an interleukin-6 (IL-6) receptor antagonist indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs) (53).

It is a member of the drug class selective immunosuppressants and is used to treat Hemolytic Uremic Syndrome, Myasthenia Gravis, Neuromyelitis Optica and Paroxysmal Nocturnal Hemoglobinuria (54).

It inhibits the activity of interleukin-1 (IL-1), and has already been approved for the treatment of 

Siltuximab like tocilizumab, binds to interleukin-6 and is indicated for the treatment of adult patients with Castleman disease (56) . The SISCO study (Siltuximab In Serious COVID-19) is configured as an observational study conducted both on hospitalized patients and those already in intensive care (65). Table 2 shows Italian Medicines Agency (AIFA) approved experimental studies in COVID-19 therapy (66-76).

The main currently ongoing studies are: 1) TOCIVID-19, multicenter study on the efficacy and tolerability of Tocilizumab in the treatment of patients with COVID-19 pneumonia;

2) Sobi study, IMMUNO-101, a randomized, open, 3 parallel, multicenter, phase 2/3 groups, that evaluates the efficacy and safety of intravenous doses of Emapalumab, antiinterferon gamma monoclonal antibody (anti-IFNγ), and Anakinra, interleukin receptor antagonist-1 (IL-1), compared to standard therapy;

3) Sarilumab COVID-19 study: a randomized, double-blind, placebo-controlled phase 2/3 study evaluating the efficacy and safety of intravenous administration of Sarilumab, an interleukin receptor antagonist-6 (IL-6).

Other potential therapeutic agents.

The required urgency for the identification of potential treatments has necessitated the further investigation of a wide-range of potential therapeutic agents. The ones identified in this review are listed below in some detail. 

Ruxolitinib is an inhibitor of the signal transmission pathway mediated by Janus Kinase (Jak), with anti-inflammatory effects related to the inhibition of the release of cytokines. Normally ruxolitinib is used in the hematology field and is indicated for the treatment of splenomegaly or disease-related symptoms in adult patients with primary myelofibrosis. It is also approved for the treatment of adult patients with polycythemia vera who are resistant or intolerant to hydroxyurea (59) . A compassionate use of Ruxolitinib has also been approved by AIFA in Covid-19 patients with respiratory failure who do not require invasive assisted ventilation.

Baricitinib is another JAK inhibitor indicated for the treatment of active rheumatoid arthritis (59) .

AIFA has licensed a randomized phase 2 trial to evaluate the efficacy, safety and tolerability of J o u r n a l P r e -p r o o f baricitinib in addition to the usual treatment in patients with pneumonia in COVID-19 (Barcivid study) (74).

A new line of research comes from diabetologists. According to a study, in addition to the main entrance door of virus, the angiotensin-converting enzyme 2 (ACE2) receptor, the DPP4 receptor must be evaluated. The Dipeptidyl peptidase 4 (Dpp4) receptor is present on all human cell types (bronchi and hearth) and is the same on which many medicines for diabetes work (60) .

Colchicine is a molecule, capable of interfering with the inflammatory immune response observed in subjects with COVID-19. Colchicine is a drug that has been used for a long time and is effective for the treatment of acute attack of gouty arthritis. Specifically, it manages to reduce the release of cytokines, molecules that, like IL-6, are responsible for the inflammatory (48, 51). A study has recently started in Italy (75).

A reduction of up to 20% in mortality among COVID-19 patients with a marked increase in an indicator of the presence of blood clots, was achieve due to the use of an old drug, heparin (61).

This was reported by a study according to which the use of heparin in COVID-19 patients could have anticoagulant effects, as well as anti-inflammatory and potentially even antiviral ones. It has been shown that new coronavirus infections are associated with a high mortality in the presence of high value of D-dimer, a particularly important marker for coagulopathy (61) . However, it will be necessary to study in depth at what dosage the drug could have such potential antiviral properties. A recent study has been approved by AIFA with enoxeparin (INHIXACOVID) (76). Table 3 Table 4 shows interferences with tocilizumab, ruxolitinib and colchicine. Tocilizumab increases immunosuppressive action and inhibits Fluouracil-resistance (22) ; it interferes with pharmacodynamic activity and the therapeutic efficacy of durvalumab, nivolumab, atezolizumab (22, 27, 28) . Moreover it is important to emphasize that tocilizumab decreases the concentration of several medications as a cytochrome P450 (CYP), isoenzyme CYP3A4 inducer (16) (17) (18) (19) (20) (21) (22) 64) .

Therefore if drugs in lung cancer are used, such as ceritinib, crizotinib, brigatinib, gefitinib, docetaxel, a reduction in the anticancer drug may become noticeable, as well as paying attention in the case of concomitant use of tyrosine kinase inhibitors.

Anakinra and ruxolitinib could interfere with checkpoint inhibitors (CPI) in terms of antagonisms or synergy but this is not yet entirely clear (22, 28, 55) . Several drugs, such as CYP3A4 inhibitors, increase concentration of colchicine and attention should be paid when the latter is used with cisplatin or vinca alkaloids (48). Furthermore, one should not forget a concomitant use of antidiabetic drugs with antineoplastics that require cortisone (63) or cytostatic drugs that reduce the value of platelets with the concomitant use of heparin (61) .

Based on the increased risk of disease aggression of COVID-19 in patients with cancer it is important to describe which anti COVID-19 drugs could be administered and which not in cancer patients. The current review attempts to provide a first systematic glance at this issue. There are certain emergent points of attention that have already been described.

Specifically, particular attention to the potential cardiotoxicity of chloroquine with anthracyclines is necessary. Hydroxychloroquine is an antimalarial that has become a mainstay in the management of systemic lupus erythematosus and rheumatoid arthritis. Similar to chloroquine in structure, hydroxychloroquine is used more frequently because it confers lower toxicity. Cardiotoxicity manifests as restrictive or dilated cardiomyopathy or with conduction system abnormalities such as atrioventricular and bundle-branch block (43) . Recently, some doubts It is important also to note that some chemotherapeutic agents or hormonal therapies such as abiraterone require concomitant steroids that are immunosuppressive agents and could weaken anticitokines drugs such as tocilizumab (63) . However in some cases, the use of steroids could be reduced without interfering with the efficacy and toxicity profile. Tocilizumab decreases concentrations of many anticancer drugs due to interference with CYP (64).

Deserving to underline that today many patients carry out CPI, currently used in daily practice for the treatment of solid tumors. CPI, activating T-lymphocytes, increase the risk of autoimmune disease such as pneumoniae (46). Few case-reports have described significant reduction in IL-6 and CPI immunorelated toxicity after tocilizumab administration (47). To date the interaction between CPI and anti COVID-19 agents is not well-described. Consideration could be given to either extending the timing of the doses or delaying pretreated patients. Thirdly the data are based on retrospective findings, while the results of prospective cohorts are being awaited and expected to shed more light.

Moreover considering the rapid evolution of information related to the pandemic we conducted a search on 2 arxiv and biorxiv databases indentifying 50 articles of interest; these are preliminary reports that have not been peer-reviewed. Among the 50 articles only 2 were considered as relevant (40, 41) and subsequently 1 has been published in peer-reviewed journal (40) , testifying to the current urgent need of relevant, well-designed studies.

The literature so far available provides an inconclusive picture on potential preferred treatments for COVID-19 and their interactions with antineoplastic agents.

In order to continue treating cancer patients likely to be infected with COVID-19, we believe that it is appropriate to modify available therapeutic choices and arrive at a new therapeutic protocol that provides: 1) where there are no interactions to continue or delay antineoplastic therapy by 1-2 weeks; 2) where there are interactions and the patient has already done many cycles to stop the administration of the anticancer drug;

3) for newly diagnosed cancer patients to prefer antineoplastic drugs without interactions; 4) where further attention is given to CPI, the choice of which may vary from case to case.

This new therapeutic proposal awaits the constructive suggestions of the oncological community in order to make improvements, such as to better protect our patients, already 

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zip A phase 2/3, randomized, openlabel, parallel, 3-arm, multicenter study investigating the efficacy and safety of intravenous doses of emapalumab, a monoclonal antiinterferon gamma (anti-IFNγ) and anakinra antibody

All authors declare no conflict of interest

A randomized phase 3 study to evaluate the safety and antiviral activity of Remdesivir