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      The official French guidelines to protect patients with cancer against SARS-CoV-2 infection

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          Abstract

          On request of the French Health Ministry, the French High Council for Public health (Haut Conseil de Santé Publique [HCSP]) entrusted a representative group of French medical oncologists and radiation oncologists, working across academic and private practice, with the task of preparing guidelines to protect patients with cancer against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while maintaining the possibility of cancer treatment. After finalisation of the guidelines on March 10, 2020, the coordinator of the group (BY) was interviewed by HCSP on March 11, 2020. The guidelines were adopted and published by HCSP on March 14, 2020. The preparation of these guidelines is justified by data 1 suggesting patients with cancer are at high risk of respiratory complications related to SARS-CoV-2 infection. The susceptibility of patients with cancer to influenza was described 2 before the emergence of SARS-CoV-2. For patients with cancer infected with influenza, the risk of hospital admission for respiratory distress is four times higher, and the risk of death ten times higher than patients without cancer. This exacerbation seems to be particularly marked in those with neutropenia or lymphopenia, a feature commonly seen in patients with cancer treated with multiple therapies. 2 A Comment 1 from Wenhua Liang and colleagues, published in The Lancet Oncology, on the situation in China suggests that patients with cancer are at higher risk of infection with SARS-CoV-2 than the general population (1% of patients with COVID-19 in the study had cancer, whereas the incidence of cancer in the Chinese population is 0·29%), which could be related to the closer medical follow-up of these patients. More concerning is the increased risk of severe respiratory complications requiring time in the intensive care unit in patients with cancer, as compared with patients without cancer (39% vs 8%, respectively; p=0·0003). A covariate significantly associated with this risk was a history of chemotherapy or surgery in the month preceding infection (odds ratio 5·34, 95% CI 1·80–16·18; p=0·0026), a factor that includes the majority of patients with cancer. Finally, patients with cancer deteriorated more rapidly than those without cancer (median time to severe events 13 days vs 43 days; p<0·0001; hazard ratio 3·56, 95% CI 1·65–7·69). The following guidelines apply to adult patients with solid tumours only, and should be considered complementary to the standard rules adopted by the French health authorities for the general population. First, some prevention measures can be implemented in oncology departments. The basic principle is for patients with cancer and oncology or radiotherapy departments to avoid—as much as possible—any contact with people with coronavirus disease 2019 (COVID-19). Oncology and radiotherapy departments should ideally remain COVID-19-free sanctuaries. The admission of patients with COVID-19 in oncology or radiotherapy departments should be avoided. If, despite this principle, such patients were admitted to hospital in oncology or radiotherapy departments, they should be isolated from other patients with cancer and referred to departments specialised in the fight against COVID-19 as quickly as possible. Given the susceptibility of patients with cancer to SARS-CoV-2 infection, their presence at hospitals should be minimised. Any measures that would enable management of patients with cancer at home should be encouraged. This includes telemedicine and phone calls to replace safety visits, as well as replacement of intravenous drugs with oral drugs (eg, chemotherapy and hormone therapies) where possible, along with infrastructure and logistics to allow home administration of intravenous and subcutaneous anticancer agents. Adjustment of dosing schedules of chemotherapy or radiotherapy treatments can be considered to reduce the frequency of hospital admissions (eg, every 3 weeks, rather than weekly administration, of the same regimens or hypofractionated radiotherapy). Moreover, some patients with slowly evolving metastatic cancers could be given temporary breaks in their treatment at the discretion of the referring oncologist, with disease assessment extended to every 2–3 months, to avoid hospital admissions. Despite these measures, some patients with cancer will have to be admitted to hospital for systemic treatment or radiotherapy. The caregivers are advised to organise daily phone calls to patients with cancer planned to be admitted the following day, to ensure these patients do not present any symptoms compatible with COVID-19 before being admitted to oncology or radiotherapy wards. Patients with cancer who have symptoms of COVID-19 should be referred to departments specialised in the fight against COVID-19. To protect patients with cancer, open-space chemotherapy outpatient centres should integrate separation measures (eg, minimum space between seats, mobile walls, wearing of masks by patients and staff). Patients with cancer who do not have COVID-19, or who have recovered, can continue treatment, with the aforementioned adjustments to limit their presence at the hospital. If access to hospital cancer care is reduced because of requisition of facilities for management of patients with COVID-19, or if the likelihood of viral infection and life-threatening complications were deemed too high, a selection of patients to be admitted to hospital for cancer treatment, prioritised by type of care or treatment, might be required. The prioritisation in the management of patients will integrate the essence of curative or non-curative intent therapeutic strategy, age of patients, life expectancy, time since diagnosis (eg, early setting recently diagnosed or first-line treatment, or late setting in patients who have been treated with multiple lines of chemotherapy), and symptoms. The following priority order is proposed (but remains at the discretion of the patient's clinician and team): (1) patients with cancers managed with curative intent treatments (favouring those patients aged ≤60 years or life expectancy ≥5 years, or both); (2) patients with cancers managed with non-curative intent treatments, and aged 60 years or younger, or life expectancy of 5 years or more, or both, and in first-line of the therapeutic strategy (early setting); and (3) other patients with cancers managed with non-curative intent treatments, favouring those whose cancerous lesions extend or whose symptoms might jeopardise their lives quickly in the case of treatment discontinuation. Patients with cancer who need to be hospitalised for supportive care (eg, pain management, bacterial infection, or palliative care before death) could be referred to non-specialised cancer departments, or home care. In summary, patients with cancer are at high risk of severe and urgent clinical complications and patients with cancer with COVID-19 should discontinue their systemic anticancer treatments until complete resolution of symptoms (at clinician discretion). If hospital admission is deemed necessary, the patient should be admitted to departments involved in the fight against COVID-19 so that oncology and radiotherapy departments remain COVID-19-free sanctuaries. For patients with cancer without COVID-19, hospital admission for in-patient cancer care should be minimised, and management at home favoured. In a situation where available care facilities are scarce, prioritisation should involve the patients managed with curative-intent therapeutic strategies, and those with a life expectancy of 5 years or more, acknowledging that final decisions lie with the referring clinicians. Patients with cancer should be closely monitored owing to their susceptibility to SARS-CoV-2 infection. © 2020 Gustoimages/Science Photo Library 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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          Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China

          China and the rest of the world are experiencing an outbreak of a novel betacoronavirus known as severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). 1 By Feb 12, 2020, the rapid spread of the virus had caused 42 747 cases and 1017 deaths in China and cases have been reported in 25 countries, including the USA, Japan, and Spain. WHO has declared 2019 novel coronavirus disease (COVID-19), caused by SARS-CoV-2, a public health emergency of international concern. In contrast to severe acute respiratory system coronavirus and Middle East respiratory syndrome coronavirus, more deaths from COVID-19 have been caused by multiple organ dysfunction syndrome rather than respiratory failure, 2 which might be attributable to the widespread distribution of angiotensin converting enzyme 2—the functional receptor for SARS-CoV-2—in multiple organs.3, 4 Patients with cancer are more susceptible to infection than individuals without cancer because of their systemic immunosuppressive state caused by the malignancy and anticancer treatments, such as chemotherapy or surgery.5, 6, 7, 8 Therefore, these patients might be at increased risk of COVID-19 and have a poorer prognosis. On behalf of the National Clinical Research Center for Respiratory Disease, we worked together with the National Health Commission of the People's Republic of China to establish a prospective cohort to monitor COVID-19 cases throughout China. As of the data cutoff on Jan 31, 2020, we have collected and analysed 2007 cases from 575 hospitals (appendix pp 4–9 for a full list) in 31 provincial administrative regions. All cases were diagnosed with laboratory-confirmed COVID-19 acute respiratory disease and were admitted to hospital. We excluded 417 cases because of insufficient records of previous disease history. 18 (1%; 95% CI 0·61–1·65) of 1590 COVID-19 cases had a history of cancer, which seems to be higher than the incidence of cancer in the overall Chinese population (285·83 [0·29%] per 100 000 people, according to 2015 cancer epidemiology statistics 9 ). Detailed information about the 18 patients with cancer with COVID-19 is summarised in the appendix (p 1). Lung cancer was the most frequent type (five [28%] of 18 patients). Four (25%) of 16 patients (two of the 18 patients had unknown treatment status) with cancer with COVID-19 had received chemotherapy or surgery within the past month, and the other 12 (25%) patients were cancer survivors in routine follow-up after primary resection. Compared with patients without cancer, patients with cancer were older (mean age 63·1 years [SD 12·1] vs 48·7 years [16·2]), more likely to have a history of smoking (four [22%] of 18 patients vs 107 [7%] of 1572 patients), had more polypnea (eight [47%] of 17 patients vs 323 [23%] of 1377 patients; some data were missing on polypnea), and more severe baseline CT manifestation (17 [94%] of 18 patients vs 1113 [71%] of 1572 patients), but had no significant differences in sex, other baseline symptoms, other comorbidities, or baseline severity of x-ray (appendix p 2). Most importantly, patients with cancer were observed to have a higher risk of severe events (a composite endpoint defined as the percentage of patients being admitted to the intensive care unit requiring invasive ventilation, or death) compared with patients without cancer (seven [39%] of 18 patients vs 124 [8%] of 1572 patients; Fisher's exact p=0·0003). We observed similar results when the severe events were defined both by the above objective events and physician evaluation (nine [50%] of 18 patients vs 245 [16%] of 1572 patients; Fisher's exact p=0·0008). Moreover, patients who underwent chemotherapy or surgery in the past month had a numerically higher risk (three [75%] of four patients) of clinically severe events than did those not receiving chemotherapy or surgery (six [43%] of 14 patients; figure ). These odds were further confirmed by logistic regression (odds ratio [OR] 5·34, 95% CI 1·80–16·18; p=0·0026) after adjusting for other risk factors, including age, smoking history, and other comorbidities. Cancer history represented the highest risk for severe events (appendix p 3). Among patients with cancer, older age was the only risk factor for severe events (OR 1·43, 95% CI 0·97–2·12; p=0·072). Patients with lung cancer did not have a higher probability of severe events compared with patients with other cancer types (one [20%] of five patients with lung cancer vs eight [62%] of 13 patients with other types of cancer; p=0·294). Additionally, we used a Cox regression model to evaluate the time-dependent hazards of developing severe events, and found that patients with cancer deteriorated more rapidly than those without cancer (median time to severe events 13 days [IQR 6–15] vs 43 days [20–not reached]; p<0·0001; hazard ratio 3·56, 95% CI 1·65–7·69, after adjusting for age; figure). Figure Severe events in patients without cancer, cancer survivors, and patients with cancer (A) and risks of developing severe events for patients with cancer and patients without cancer (B) ICU=intensive care unit. In this study, we analysed the risk for severe COVID-19 in patients with cancer for the first time, to our knowledge; only by nationwide analysis can we follow up patients with rare but important comorbidities, such as cancer. We found that patients with cancer might have a higher risk of COVID-19 than individuals without cancer. Additionally, we showed that patients with cancer had poorer outcomes from COVID-19, providing a timely reminder to physicians that more intensive attention should be paid to patients with cancer, in case of rapid deterioration. Therefore, we propose three major strategies for patients with cancer in this COVID-19 crisis, and in future attacks of severe infectious diseases. First, an intentional postponing of adjuvant chemotherapy or elective surgery for stable cancer should be considered in endemic areas. Second, stronger personal protection provisions should be made for patients with cancer or cancer survivors. Third, more intensive surveillance or treatment should be considered when patients with cancer are infected with SARS-CoV-2, especially in older patients or those with other comorbidities.
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            Influenza vaccines in immunosuppressed adults with cancer

            This is an update of the Cochrane review published in 2013, Issue 10. Immunosuppressed cancer patients are at increased risk of serious influenza‐related complications. Guidelines, therefore, recommend influenza vaccination for these patients. However, data on vaccine effectiveness in this population are lacking, and the value of vaccination in this population remains unclear. To assess the effectiveness of influenza vaccine in immunosuppressed adults with malignancies. The primary review outcome is all‐cause mortality, preferably at the end of the influenza season. Influenza‐like illness (ILI, a clinical definition), confirmed influenza, pneumonia, any hospitalisations, influenza‐related mortality and immunogenicity were defined as secondary outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and LILACS databases up to May 2017. We searched the following conference proceedings: ICAAC, ECCMID, IDSA (infectious disease conferences), ASH, ASBMT, EBMT (haematological), and ASCO (oncological) between the years 2006 to 2017. In addition, we scanned the references of all identified studies and pertinent reviews. We searched the websites of the manufacturers of influenza vaccine. Finally, we searched for ongoing or unpublished trials in clinical trial registry databases. Randomised controlled trials (RCTs), prospective and retrospective cohort studies and case‐control studies were considered, comparing inactivated influenza vaccines versus placebo, no vaccination or a different vaccine, in adults (16 years and over) with cancer. We considered solid malignancies treated with chemotherapy, haematological cancer patients treated or not treated with chemotherapy, cancer patients post‐autologous (up to six months after transplantation) or allogeneic (at any time) haematopoietic stem cell transplantation (HSCT). Two review authors independently assessed the risk of bias and extracted data from included studies adhering to Cochrane methodology. Meta‐analysis could not be performed because of different outcome and denominator definitions in the included studies. We identified six studies with a total of 2275 participants: five studies comparing vaccination with no vaccination, and one comparing adjuvanted vaccine with non‐adjuvanted vaccine. Three studies were RCTs, one was a prospective observational cohort study and two were retrospective cohort studies. For the comparison of vaccination with no vaccination we included two RCTs and three observational studies, including 2202 participants. One study reported results in person‐years while the others reported results per person. The five studies were performed between 1993 and 2015 and included adults with haematological diseases (three studies), patients following bone marrow transplantation (BMT) (two studies) and solid malignancies (three studies). One RCT and two observational studies reported all‐cause mortality; the RCT showed similar mortality rates in both arms (odds ratio (OR) 1.25 (95% CI 0.43 to 3.62; 1 study, 78 participants, low‐certainty evidence)); and the observational studies demonstrated a significant association between vaccine receipt and lower risk of death, adjusted hazard ratio 0.88 (95% CI 0.78 to 1; 1 study, 1577 participants, very low‐certainty evidence) in one study and OR 0.42 (95% CI 0.24 to 0.75; 1 study, 806 participants, very low‐certainty evidence) in the other. One RCT reported a reduction in ILI with vaccination, while no difference was observed in one observational study. Confirmed influenza rates were lower with vaccination in one RCT and the three observational studies, the difference reaching statistical significance in one. Pneumonia was observed significantly less frequently with vaccination in one observational study, but no difference was detected in another or in the RCT. One RCT showed a reduction in hospitalisations following vaccination, while an observational study found no difference. No life‐threatening or persistent adverse effects from vaccination were reported. The strength of evidence was limited by the low number of included studies and by their low methodological quality and the certainty of the evidence for the mortality outcome according to GRADE was low to very low. For the comparison of adjuvanted vaccine with non‐adjuvanted vaccine, we identified one RCT, including 73 patients. No differences were found for the primary and all secondary outcomes assessed. Mortality risk ratio was 0.54 (95% CI 0.05 to 5.73; low‐certainty evidence) in the adjuvanted vaccine group. The quality of evidence was low due to the small sample size and the large confidence intervals for all outcomes. Observational data suggest lower mortality and infection‐related outcomes with influenza vaccination. The strength of evidence is limited by the small number of studies and low grade of evidence. It seems that the evidence, although weak, shows that the benefits overweigh the potential risks when vaccinating adults with cancer against influenza. However, additional placebo or no‐treatment controlled RCTs of influenza vaccination among adults with cancer is ethically questionable.There is no conclusive evidence regarding the use of adjuvanted versus non‐adjuvanted influenza vaccine in this population. Influenza (flu) vaccination for preventing influenza in adults with cancer Background 
 Adults with cancer are prone to serious complications from influenza, more than healthy adults. The influenza vaccine protects against influenza and its complications. However, its effectiveness among people with cancer is unclear, as immune dysfunction that accompanies cancer as a result of chemotherapy might lower immune response to the vaccine. People with cancer, therefore, do not have clear information on the importance and effectiveness of the vaccine. The aim of the review 
 This review focused on the effectiveness of influenza vaccination in adults with cancer who have a suppressed immune system because of cancer or chemotherapy. We searched the literature up to May 2017. What are the main findings? 
 We identified six clinical studies (2275 participants) addressing this question, half of which were randomised controlled trials, where patients were randomly selected to get or not to get the vaccine. Two other studies showed that adults with cancer who were vaccinated were found to have lower rates of death, but these studies were not randomised. One small randomised study showed a similar mortality rate in vaccinated and non‐vaccinated patients. Pooling (combining) results from the different studies was not possible because of different methods or different ways the results were reported. There was a lower rate of influenza‐like illness (any febrile respiratory illness), pneumonia, confirmed influenza and hospitalisation for any reason, among vaccinated people in at least one study. No side effects to the vaccine were reported in these studies. The review also included a trial comparing the regular vaccine to a vaccine containing an adjuvant that is supposed to increase the immune response. This randomised trial was small and did not find differences in all clinical outcomes examined. Quality of the evidence 
 The strength of evidence is limited by the low number of studies and by their low methodological quality (high risk of bias). What are the conclusions? 
 It is unlikely that there will be any future large‐scale controlled trials to investigate this issue. The current evidence, although weak, suggests a benefit for influenza vaccination amongst adults with cancer and the vaccine was not found to be harmful. Influenza vaccines given to adults with cancer contain an inactivated virus that cannot cause influenza or other viral infection.
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              Author and article information

              Contributors
              Journal
              Lancet Oncol
              Lancet Oncol
              The Lancet. Oncology
              Elsevier Ltd.
              1470-2045
              1474-5488
              25 March 2020
              25 March 2020
              :
              Affiliations
              [a ]Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon, Centre d'Investigation des Thérapeutiques en Oncologie et Hématologie de lyon, Université Claude Bernard Lyon 1, Lyon 69495, France
              [b ]Medical Oncology, Bordeaux University Hospital, Bordeaux, France
              [c ]Service d'hygiene, Centre de Lutte Contre le Cancer François Baclesse, Caen, France
              [d ]Clinique Victor Hugo-Centre Jean Bernard, Le Mans, France
              [e ]Radiotherapy Department, Hôpital Européen Georges Pompidou, Sociéré Francaise de Radiothérapie Oncologique, France
              [f ]Oncologie Médicale Digestive, CHU de Toulouse, Toulouse, France
              [g ]Centre Hospitalier Public du Cotentin, Cherbourg-en-Cotentin, France
              [h ]Centre de Lutte Contre le Cancer Institut Bergonié, Bordeaux, Association Francophone pour les Soins Oncologiques de Support (AFSOS), France
              [i ]Oncologie médicale, Centre Georges Francois Leclerc, Dijon, AFSOS, France
              [j ]Centre hospitalier de la Côte Basque, Service D'Oncologie Médicale, Bayonne, France
              [k ]Tenon Hospital, Assistance Publique Hôpitaux de Paris, Sorbonne Université, Paris, France
              Article
              S1470-2045(20)30204-7
              10.1016/S1470-2045(20)30204-7
              7118635
              32220659
              ddb343d1-9195-4219-b92d-96c47704d408
              © 2020 Elsevier Ltd. All rights reserved.

              Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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