Highlights
- •Cancer patients are vulnerable to severe acute respiratory syndrome coronavirus 2 infection and severe COVID-19.
- •Comprehensive management strategies are required in care for cancer patients.
- •Evidence-based recommendations help clinicians make informed treatment decisions.
- •Providing state-of-the-art cancer care is possible during COVID-19 pandemic.
Abstract
Since its first detection in China in late 2019 the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated infectious disease COVID-19 continue to have a major impact on global healthcare and clinical practice. Cancer patients, in particular those with haematological malignancies, seem to be at an increased risk for a severe course of infection. Deliberations to avoid or defer potentially immunosuppressive therapies in these patients need to be balanced against the overarching goal of providing optimal antineoplastic treatment. This poses a unique challenge to treating physicians. This guideline provides evidence-based recommendations regarding prevention, diagnostics and treatment of SARS-CoV-2 infection and COVID-19 as well as strategies towards safe antineoplastic care during the COVID-19 pandemic. It was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO) by critically reviewing the currently available data on SARS-CoV-2 and COVID-19 in cancer patients applying evidence-based medicine criteria.
Keywords
1. Introduction
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a betacoronavirus first described in China in late 2019 as the causative agent of a coronavirus disease (COVID-19) [
[1]
,[2]
]. Since then, SARS-CoV-2 has spread around the globe putting a major strain on healthcare worldwide. While many people infected by SARS-CoV-2 seem to remain asymptomatic or oligosymptomatic, SARS-CoV-2 can cause significant upper respiratory tract infectious disease (URTID) and lower respiratory tract infectious disease (LRTID). After an incubation period of about 3–5 days, typical symptoms of an influenza-like illness may occur and include fever, dry cough and myalgia. Olfactory or taste disorders occur frequently, which are rarely observed after infections with other community-acquired respiratory viruses [[1]
,[3]
]. In contrast to SARS-CoV or Middle East respiratory syndrome-related coronavirus (MERS-CoV) infection, gastrointestinal symptoms occur less frequently following SARS-CoV-2 infection [[1]
,[4]
]. In case of viral pneumonia, rapidly progressing impairment of oxygenation and life-threatening respiratory failure may occur [[4]
]. This progressive hypoxaemia may be clinically silent, characterised by exceedingly low blood oxygen saturation levels without signs of dyspnoea [[5]
]. Further complications include renal and cardiac impairment as well as hypercoagulopathy resulting in pulmonary embolisms or stroke [[6]
,[7]
].Pathophysiologically, after infection, the increasing viral replication leads to local and systemic activation of the innate immune response. In severe courses, progressive viral cytopathic damage, fluid leakage and innate immune activation of resident and invading macrophages coincide with impaired gas exchange, respiratory failure as well as systemic involvement resulting from endothelial dysfunction, complement activation and hypercoagulopathy [
[8]
,[9]
]. Abundant viral antigens, pro-inflammatory cytokines, and antigen-presenting cells activate the SARS-CoV-2–specific adaptive immunity consisting of SARS-CoV-2–specific T cells and neutralising antibodies permitting to eventually clear SARS-CoV-2 replication. Accordingly, treatment emphasis should shift from initially antiviral curtailing, to dampening anti-inflammatory responses and supporting specific lymphocyte effector function [[10]
].It is generally assumed that cancer patients may be at an increased risk of severe COVID-19 [
11
, 12
, 13
, 14
]. In addition to the underlying disease impairing virus-specific immunity, which is presumably more prominent in haematological malignancies, many antineoplastic therapies, but also the underlying malignancy itself, can lead to significant immunosuppression and thus contribute to patient vulnerability towards severe infection [- Cook G.
- John Ashcroft A.
- Pratt G.
- Popat R.
- Ramasamy K.
- Kaiser M.
- et al.
Real-world assessment of the clinical impact of symptomatic infection with severe acute respiratory syndrome coronavirus (COVID-19 disease) in patients with multiple myeloma receiving systemic anti-cancer therapy.
Br J Haematol. 2020; 190: e83-e86
[15]
]. Cancer patients on active therapy, e.g. those receiving intravenous chemotherapy, may require more frequent interactions with healthcare providers than the general population, potentially increasing the opportunity of exposure to SARS-CoV-2. Thorough hygiene measures and implementation of adequate organisational strategies are therefore important to minimise patients’ risk. However, it should also be noted that in most publications cancer patients are older and have more comorbidities than patients of the non-cancer cohort [[13]
]. To address this point, a recent publication compared age-matched groups of cancer and non-cancer patients detecting no difference in mortality [[16]
]. Moreover, some publications even describe a below average mortality in cancer populations [- Shoumariyeh K.
- Biavasco F.
- Ihorst G.
- Rieg S.
- Nieters A.
- Kern W.V.
- et al.
Covid-19 in patients with solid and hematological cancers at a Comprehensive Cancer Center in Germany.
Cancer Medicine. 2020; https://doi.org/10.1002/cam4.3460
17
, - Engelhardt M.
- Shoumariyeh K.
- Rosner A.
- Ihorst G.
- Biavasco F.
- Meckel K.
- et al.
Clinical characteristics and outcome of multiple myeloma patients with concomitant COVID-19 at Comprehensive Cancer Centers in Germany.
Haematologica. 2020; https://doi.org/10.3324/haematol.2020.262758
18
, 19
]. On the other hand, as uncontrolled malignancy seems to be an independent risk factor for severe COVID-19 [[20]
], administration of state-of-the art cancer therapy to reach the best possible remission remains an essential goal. Treating physicians must balance all these aspects to safely provide optimal antineoplastic care for their patients. In any case, the risk of infection and the disease COVID-19 itself should not be taken lightly, especially not in cancer patients. However, unnecessary precautions must by no means jeopardise the administration of the required antineoplastic treatment. It has been shown to be possible to find the right balance during the COVID-19 pandemic [[17]
,- Engelhardt M.
- Shoumariyeh K.
- Rosner A.
- Ihorst G.
- Biavasco F.
- Meckel K.
- et al.
Clinical characteristics and outcome of multiple myeloma patients with concomitant COVID-19 at Comprehensive Cancer Centers in Germany.
Haematologica. 2020; https://doi.org/10.3324/haematol.2020.262758
[21]
].This guideline aims to help clinicians make informed decisions with regard to prevention, diagnostics and treatment of SARS-CoV-2 infection and COVID-19 as well as devising strategies towards safe antineoplastic care during the current pandemic. These recommendations apply to adult patients with solid tumours or haematological malignancies. For specific considerations regarding stem cell transplantation, we kindly refer to the current guidelines by the European Society for Blood and Marrow Transplantation [
[22]
].- Ljungman P.
- Mikulska M.
- de la Camara R.
- Basak G.W.
- Chabannon C.
- Corbacioglu S.
- et al.
The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy.
Bone Marrow Transplant. 2020; https://doi.org/10.1038/s41409-020-0919-0
2. Methods
This guideline was developed by an expert panel from the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). The panel consisted of 18 specialists certified in haematology, medical oncology, infectious diseases, critical care, emergency medicine and virology.
2.1 Search strategies and selection criteria
After definition of topics and formation of subgroups, a systematic search of MEDLINE for publications in English language was performed using one of the following search terms: “coronavirus”, “SARS-CoV-2”, or “COVID-19”. Given the current dynamic of research into COVID-19, publications on the preprint server www.medRxiv.org were also evaluated; however, the lack of formal peer review in these cases was taken into consideration with regard to grading of quality of evidence. Publications were evaluated that appeared online until August 19th 2020.
2.2 Guideline process
The relevant literature was thoroughly reviewed; the data were extracted and rated. Based on the results of data assessment, preliminary recommendations were first discussed within subgroups and then discussed and revised in a step-by-step process by the specialist panel. Strength of recommendation and quality of evidence were graded applying the scale proposed by the European Society of Clinical Microbiology and Infectious Diseases ESCMID(Table 1) [
[23]
]. In short, recommendations were graded as follows: A, AGIHO strongly supports a recommendation for use; B, AGIHO moderately supports a recommendation for use; C, AGIHO marginally supports a recommendation for use; and D, AGIHO supports a recommendation against use. The final recommendations presented in this guideline were discussed and agreed upon by the AGIHO general assembly in a web meeting on June 23rd 2020 and again on July 9th 2020.Table 1Grading system for strength of recommendation (SoR) and quality of evidence (QoE) as proposed by the European Society of Clinical Microbiology and Infectious Diseases [
[23]
].| Strength of recommendation | |
|---|---|
| A | AGIHO strongly supports a recommendation for use |
| B | AGIHO moderately supports a recommendation for use |
| C | AGIHO marginally support a recommendation for use |
| D | AGIHO supports a recommendation against use |
| Quality of evidence | |
| I | Evidence from at least one properly designed randomised, controlled trial |
| II∗ | Evidence from at least one well-designed clinical trial, without randomisation; from cohort– or case–control analytic studies (preferably from more than one centre); from multiple time series; or from dramatic results from uncontrolled experiments |
| III | Evidence from opinion of respected authorities, based on clinical experience, descriptive case studies, or report of expert committees |
| ∗added index for level II | |
| R | Meta-analysis or systematic review of randomised controlled trials |
| T | Transferred evidence, i.e. results from different patients' cohorts or similar immune status situation |
| H | The comparator group is a historical control |
| U | Uncontrolled trial |
| A | Abstract published at an international meeting or manuscript available on preprint server only |
AGIHO, Infectious Diseases Working Party
3. Risk factors
Cancer patients are generally assumed to be at an increased risk of severe illness by respiratory virus infections when compared with healthy individuals, amongst others as they tend to be older and more frequently suffer from comorbidities than the general population [
[24]
]. However, in case of SARS-CoV-2, both healthy and immunocompromised individuals are immunologically naïve to this infection. Data on SARS-CoV-2 infection rates vary among patients with malignant diseases [- von Lilienfeld-Toal M.
- Berger A.
- Christopeit M.
- Hentrich M.
- Heussel C.P.
- Kalkreuth J.
- et al.
Community acquired respiratory virus infections in cancer patients-Guideline on diagnosis and management by the Infectious Diseases Working Party of the German Society for haematology and Medical Oncology.
Eur J Cancer. 2016; 67: 200-212
[1]
,[13]
,26
, 27
, 28
]. Overrepresentation of cancer patients among hospitalised patient populations may contribute to a higher reported prevalence of SARS-CoV-2 infections among cancer patients compared with the general population, which is supported by a study showing similar infection rates in hospitalised patients with haematological malignancies and a comparator group of healthcare workers (HCWs) [[29]
].In cancer patients, uncontrolled malignancy seems to confer a higher risk of severe or even fatal outcome of COVID-19 [
[20]
,[30]
]. With regard to specific cancer types, both haematological malignancies and lung cancer were repeatedly identified as factors for poor prognosis compared with other (solid) cancers [[12]
,29
, 30
, 31
, 32
, 33
, 34
, 35
]. Interestingly, myeloid or lymphoid malignancies as underlying disease do not appear to differ in their impact on COVID-19 mortality [[36]
]. Among cancer patients, advanced stage [[11]
,[12]
] and recent antineoplastic therapy within the last 2–4 weeks were reported as risk factors [37
, 38
, 39
]. However, data on the impact of different cancer treatment modalities (immunotherapy, endocrine therapy, targeted therapy, radiotherapy, chemotherapy or surgery) on the outcome of COVID-19 are contradictory [[11]
,[20]
,[39]
,[40]
].Of note, patients with lymphopenia [
[11]
,41
, - Yang F.
- Shi S.
- Zhu J.
- Shi J.
- Dai K.
- Chen X.
Clinical characteristics and outcomes of cancer patients with COVID-19.
J Med Virol. 2020; https://doi.org/10.1002/jmv.25972
42
, 43
] and granulocytosis [[33]
,[44]
] were reported to be at an increased risk for severe or fatal COVID-19. Further factors with possible impact on the COVID-19 course and outcome are listed in Table 2.Table 2Risk factors for severe COVID-19 in cancer patients.
| Risk factors | Comments | References |
|---|---|---|
| Patient-related | ||
| Age | Higher age associated with a higher risk for severe disease or death (OR = 1.04–1.84) | [ [11] , [20] , [31] , [33] ] |
| Male sex | Male sex associated with a higher risk for death (OR 1.63–3.86, HR = 2.75) | [ [20] ,[39] ,[42] ] |
| ECOG | A higher ECOG score associated with a higher risk for death (OR 2.80–3.89, HR = 4.87) | [ [11] , [20] , [42] ] |
| Comorbidities | A higher number of comorbidities associated with a higher risk for death (OR = 4.50) | [ [20] ,[31] ,[33] ] |
| Smoking | Smoking associated with a higher risk for death (OR = 1.60–3.18) | [ [20] ,[145] ] |
| Cancer-related | ||
| Cancer history | Cancer history associated with a higher risk for death (OR = 2.98) | [ [146] ] |
| Cancer type | A higher death rate for haematological (31–62%, OR = 2.40) and lung cancers (55%, OR = 1.80) than for other (solid) cancers (25%) | [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , [147] ] |
| Active cancer | Active cancer associated with a higher risk for death (OR = 5.20, HR = 14.29) | [ [20] ,[30] ] |
| Stage IV cancer | Metastatic cancer associated with a higher risk for severe disease or death (OR = 2.60) | [ [11] ,[147] ] |
| Cancer treatment <2–4 weeks | Cancer treatment before disease associated with a higher risk for severe disease or death (OR = 3.51–3.99, HR = 4.10) | [ [37] , [38] , [41] ]
Clinical characteristics and outcomes of cancer patients with COVID-19. J Med Virol. 2020; https://doi.org/10.1002/jmv.25972 |
| Blood counts | ||
| Lymphopenia | A lower lymphocyte count associated with a higher risk for severe disease or death (OR = 2.99, HR = 3.05) | [ [11] , 41 ,
Clinical characteristics and outcomes of cancer patients with COVID-19. J Med Virol. 2020; https://doi.org/10.1002/jmv.25972 42 , 43 ] |
| Granulocytosis | A higher neutrophil count associated with a higher risk for death | [ [32] ,[44] ] |
| Summary of risk factors Increased risk of death was reported for patients of higher age, male sex and with limitations in daily activity and comorbidities. Both history of cancer and active cancer, particularly haematological and lung cancer and advanced-stage cancer, as well as lymphopenia and granulocytosis were associated with a higher risk of death in COVID-19 patients. | ||
Abbreviations: ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; OR, odds ratio.
4. Prevention
4.1 Hygiene measures
Given the current lack of herd immunity, an effective vaccine, or antiviral prophylaxis, hygiene measures and contact precautions are the cornerstones in preventing SARS-CoV-2 infection and transmission (Table 3). Community-wide face masks and physical distancing measures were effective in several population-based studies and are thus strongly recommended (AIIu) [
45
, 46
, 47
, 48
, 49
]. A distance of at least 1.5 m (6 ft) is usually considered appropriate; however, depending on environmental conditions a wider distance may be considered [[50]
].Table 3Recommendations regarding prevention of SARS-CoV-2 infection and COVID-19 in cancer patients during the COVID-19 pandemic.
| Population/clinical situation | Intention | Intervention | SoR | QoE | References |
|---|---|---|---|---|---|
| Hygiene measures | |||||
| Any population | To prevent SARS-CoV-2 transmission and infection | Physical distancing measures | A | IIu | [ 45 , 46 , 47 , 48 , [50] ] |
| Any population | To prevent SARS-CoV-2 transmission and infection | Community-wide face masks | A | IIu | [ [49] ] |
| Any population | To prevent SARS-CoV-2 transmission and infection | Hand washing with soap | A | IIt | [ [51] ,[52] ] |
| Cancer patients, healthcare setting, and healthcare workers | To prevent SARS-CoV-2 infection | Hand disinfection with ethanol or 2-propanol at >30% concentration for 30s | A | IIu | [ [56] ] |
| Cancer patients, healthcare setting | To prevent SARS-CoV-2 infection | Disinfection of touched surfaces | A | IIr,u | [ 54 , 56 ] |
| Healthcare workers | To prevent SARS-CoV-2 infection | Surgical mask or FFP2/N95 respirator | A | IIr,t | [ 58 ,
Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19). Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa644 59 , 60 ] |
| Healthcare workers in contact with (confirmed/suspected) SARS-CoV-2-positive patients | To prevent SARS-CoV-2 infection | Personal protective equipment (PPE) incl. FFP2/N95 respirator | A | IIr,t | [ [22] ,
The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy. Bone Marrow Transplant. 2020; https://doi.org/10.1038/s41409-020-0919-0 61 , 62 , 63 , 64 ] |
| Cancer patients with (confirmed/suspected) SARS-CoV-2 infection | To prevent SARS-CoV-2 transmission | Surgical mask or FFP2/N95 respirator (without exhalation valve) | A | IIt | [ [22] ,
The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy. Bone Marrow Transplant. 2020; https://doi.org/10.1038/s41409-020-0919-0 [57] , [58] ]
Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19). Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa644 |
| Cancer patients with SARS-CoV-2 infection | To prevent SARS-CoV-2 transmission | Single room isolation, cohort isolation or self-quarantine | A | IIt,u | [ [65] ] |
| Cancer patients with SARS-CoV-2 infection | To prevent SARS-CoV-2 transmission | Requirement of negative SARS-CoV-2 test result prior to discontinuation of isolation | A | IIt,u | [ [66] , [68] , [69] , [70] , [71] ]
The issue of recurrently positive patients who recovered from COVID-19 according to the current discharge criteria: investigation of patients from multiple medical institutions in Wuhan, China. J Infect Dis. 2020; https://doi.org/10.1093/infdis/jiaa301 |
| Cancer patients, outside of healthcare setting | To prevent SARS-CoV-2 infection | Disinfection of frequently touched surfaces | B | IIr,u | [ 54 , 55 , 56 ] |
| Cancer patients | To prevent SARS-CoV-2 infection | Regular ventilation of rooms | B | III | [ [54] ] |
| Cancer patients | To prevent SARS-CoV-2 infection | Surgical mask or FFP2/N95 respirator | B | IIr,t | [ 58 ,
Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19). Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa644 59 , 60 ] |
| Cancer patients, outside of healthcare setting | To prevent SARS-CoV-2 infection | Hand disinfection with ethanol or 2-propanol at >30% concentration for 30s | C | IIu | [ [53] ] |
| Supportive measures | |||||
| Cancer patients with severe COVID-19 and hypogammaglobulinaemia | To reduce mortality | Adjuvant IVIG treatment <48 h | B | IIt,u | [ [77] , [148] ] |
| Cancer patients | To prevent SARS-CoV-2 infection | Vitamin D level (supply) | C | III | [ [75] , [76] , [149] ] |
| Cancer patients with RAAS inhibitors | To prevent SARS-CoV-2 infection | Discontinuation of RAAS inhibitors | D | IIu | [ [72] , [73] ] |
| Cancer patients with RAAS inhibitors and COVID-19 | To prevent hospitalisation and severe COVID-19 | Discontinuation of RAAS inhibitors | D | IIu | [ [73] , [74] ] |
Abbreviations: FFP, filtering facepiece; IVIG, intravenous immunoglobulin; QoE, quality of evidence; RAAS, renin-angiotensin-aldosterone system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SoR, strength of recommendation.
Hand hygiene is crucial for infection control, and regular washing of hands with water and soap is strongly recommended for any population (AIIt) [
[51]
,[52]
]. Alcohol-based hand rubs were shown to be virucidal to SARS-CoV-2 if applied for at least 30 s at a concentration of ethanol or 2-propanol ≥ 30% [[53]
]. We strongly recommend hand disinfection for HCWs and cancer patients in healthcare settings (AIIu).SARS-CoV-2 can remain viable on surfaces for up to 3 days [
[54]
,[55]
]. We strongly recommend disinfection of frequently touched surfaces such as doorknobs, elevator buttons or hand rails for cancer patients in healthcare settings (AIIr,u) and moderately outside of healthcare settings (BIIr,u) [54
, 55
, 56
].Surgical masks covering nose and mouths of an infected person reduce coronavirus RNA in expiration air [
[57]
,[58]
]. Particulate-filtering facepieces (FFPs) such as the US-regulated N95 respirators and the functionally-equivalent EU-regulated FFP2 masks are characterised by a tighter fit and a finer mesh. Several randomised trials in HCWs provide evidence of the protective effect of surgical masks against respiratory virus infections with a potential additional benefit of FFP2/N95 respirators [- Chan J.F.
- Yuan S.
- Zhang A.J.
- Poon V.K.
- Chan C.C.
- Lee A.C.
- et al.
Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19).
Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa644
59
, 60
, 61
]. If worn to prevent infection, FFP2/N95 masks may be equipped with an exhalation valve for greater comfort, whereas to prevent transmission they must not have an exhalation valve [[22]
].- Ljungman P.
- Mikulska M.
- de la Camara R.
- Basak G.W.
- Chabannon C.
- Corbacioglu S.
- et al.
The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy.
Bone Marrow Transplant. 2020; https://doi.org/10.1038/s41409-020-0919-0
We strongly recommend that cancer patients and HCWs wear a surgical mask to prevent SARS-CoV-2 transmission and infection (AIIt) [
57
, 58
, - Chan J.F.
- Yuan S.
- Zhang A.J.
- Poon V.K.
- Chan C.C.
- Lee A.C.
- et al.
Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19).
Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa644
59
, 60
]. If caring for COVID-19 patients, we strongly recommend that HCWs wear FFP2/N95 respirators (AIIt) and personal protective equipment including gloves, gowns and eye protection such as goggles or face shields (AIIr) [[22]
,- Ljungman P.
- Mikulska M.
- de la Camara R.
- Basak G.W.
- Chabannon C.
- Corbacioglu S.
- et al.
The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy.
Bone Marrow Transplant. 2020; https://doi.org/10.1038/s41409-020-0919-0
61
, 62
, 63
, 64
]. Patients with COVID-19 are strongly recommended to wear a surgical mask or FFP2/N95 respirator without an exhalation valve (AIIt) taking into account the protective equipment of their surroundings [[22]
,- Ljungman P.
- Mikulska M.
- de la Camara R.
- Basak G.W.
- Chabannon C.
- Corbacioglu S.
- et al.
The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy.
Bone Marrow Transplant. 2020; https://doi.org/10.1038/s41409-020-0919-0
[57]
,[58]
].- Chan J.F.
- Yuan S.
- Zhang A.J.
- Poon V.K.
- Chan C.C.
- Lee A.C.
- et al.
Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19).
Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa644
Cancer patients diagnosed with SARS-CoV-2 infection should undergo either self-quarantine, single-room or cohort isolation (AIIt,u) [
[65]
]. While infectiousness of SARS-CoV-2 seems to decline significantly within 7–8 days after onset of symptoms [[66]
,[67]
], prolonged shedding of viral RNA for many weeks was observed, especially in immunocompromised patients and in severe COVID-19 [68
, 69
, 70
]. We strongly recommend requirement of a negative SARS-CoV-2 polymerase chain reaction (PCR) test result before discontinuation of isolation (AIIt,u), which should be considered no earlier than 14 days after onset of symptoms and 2 days after cessation of symptoms. The possibility of false-negative test results must be kept in mind. A positive test after one negative test was reported in up to 30% of COVID-19 patients, which declined to 5% after three consecutive negative tests [[68]
,[71]
]. Requirement of more than one consecutive negative test before discontinuation of isolation should therefore be considered, especially in patients with risk factors for prolonged viral shedding.- Zou Y.
- Wang B.R.
- Sun L.
- Xu S.
- Kong Y.G.
- Shen L.J.
- et al.
The issue of recurrently positive patients who recovered from COVID-19 according to the current discharge criteria: investigation of patients from multiple medical institutions in Wuhan, China.
J Infect Dis. 2020; https://doi.org/10.1093/infdis/jiaa301
With regard to participation in activities of daily life of cancer patients not in quarantine/isolation because of suspected or confirmed SARS-CoV-2 infection, special consideration should be given to current local epidemiology and requirements of local and national health authorities. As a general recommendation, restriction of activities to places that have adequate hygiene concepts implemented seems to be reasonable and a preference of outdoor versus indoor activities, where possible.
4.2 Supportive measures
Several large trials could not establish an association between renin-angiotensin-aldosterone system (RAAS) blockers and risk of SARS-CoV-2 infection or severe COVID-19 disease [
72
, 73
, 74
]. Discontinuation of RAAS blockers is therefore not recommended (DIIu).A correlation between vitamin D levels and risk of COVID-19 has not been established to date [
[75]
]. However, in other infectious diseases, supplementation has been shown to be beneficial [[76]
]. Thus, we marginally support appropriate vitamin D supplementation (CIII). For other nutrients such as iron, selenium or vitamin C, no conclusive data support supplementation with regard to COVID-19.Administration of intravenous immunoglobulin (IVIG) may be considered in cancer patients with hypogammaglobulinaemia and COVID-19 (BIIt,u) [
[77]
]. As specific antibodies against SARS-CoV-2 are most likely absent in current products because of low herd immunity at the moment, IVIG will primarily act against possible co-infections with other pathogens. However, with an increase of SARS-CoV-2 infections in populations over the course of the COVID-19 pandemic future IVIG preparations may contain specific antibodies against SARS-CoV-2 possibly allowing for a broader use of IVIG in COVID-19 patients than according to present recommendations.Prophylaxis with granulocyte colony-stimulating factor (G-CSF) might help in reducing vulnerability to infections due to shortened neutropenia. However, G-CSF has also been associated with a risk of hyperinflammation during neutrophil regeneration, and cases of severe COVID-19 have been reported after G-CSF administration [
[44]
]. We therefore do not recommend additional G-CSF prophylaxis on top of current recommendations (DIII) [[78]
].- Vehreschild J.J.
- Bohme A.
- Cornely O.A.
- Kahl C.
- Karthaus M.
- Kreuzer K.A.
- et al.
Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy-evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO).
Ann Oncol. 2014; 25: 1709-1718
Several preclinical and early clinical trials on vaccine candidates against SARS-CoV-2 have shown promising results [
79
, 80
, 81
]. As cancer patients are usually not included in these trials, it is too early to make any specific deliberations on SARS-CoV-2 vaccine strategies in these patients. However, based on experiences from other vaccines, depending on the type of vaccine, efficacy and/or safety might be an issue in immunocompromised cancer patients, rendering vaccinations of HCWs, caregivers and relatives especially important [[82]
].- Rieger C.T.
- Liss B.
- Mellinghoff S.
- Buchheidt D.
- Cornely O.A.
- Egerer G.
- et al.
Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors-guideline of the infectious diseases working party (AGIHO) of the German society for hematology and medical oncology (DGHO).
Ann Oncol. 2018; 29: 1354-1365
5. Organisational aspects
The prevention of nosocomial SARS-CoV-2 transmission is of major importance during treatment of cancer patients. This relates to both inpatient and outpatient management. Therefore, we strongly recommend the implementation of specific organisational pathways in hospitals and outpatient clinics (AIII, Table 4) [
[21]
,[83]
,[84]
]. This includes precise scheduling of in-person appointments to reduce waiting times, increasing telemedical approaches including phone or video consultations when clinically possible and special routing and zoning for cancer patients. Particularly with regard to patient care in outpatient clinics we recommend to reduce the seating capacity in waiting areas and treatment rooms to ensure a distancing of at least 1.5 m. To reduce the number of visitors, relatives and non-essential other attendants should be advised to stay outside the clinic during the patient visit. In high-volume contact areas such as front desks, installation of transparent shields may offer additional protection for HCWs.Table 4Recommendations regarding organisational aspects of outpatient and inpatient management of cancer patients during the COVID-19 pandemic.
| Population/Clinical situation | Intention | Intervention | SoR | QoE | References |
|---|---|---|---|---|---|
| Healthcare providers | To prevent nosocomial SARS-CoV-2 transmission | Implement organisational strategies | A | III | [ [21] , [83] , [84] , [150] ] |
| Healthcare providers | To prevent nosocomial SARS-CoV-2 transmission | Consider surveillance screening taking into account local epidemiology | A | IIt,u | [ [85] , [151] ]
Screening for COVID-19 in asymptomatic patients with cancer in a hospital in the United Arab Emirates. JAMA Oncol. 2020; https://doi.org/10.1001/jamaoncol.2020.2548 |
| Healthcare providers | To provide best care for cancer patients with COVID-19 | Implement dedicated teams | A | III | [ [19] ] |
| Healthcare providers | To keep risk for cancer patients as low as possible | Strict adherence to guidelines; consider restrictive transfusion strategies, if possible | A | III | [ 88 , 89 , 90 , 152 , 153 ] |
| Healthcare providers | To prevent SARS-CoV-2 transmission and infection | Consider treatments with fewest and shortest visits to hospital/outpatient clinic | A | III | [ [21] ,[29] ,[86] , [87] , [155] ] |
| Healthcare providers | To provide best care for cancer patients with COVID-19 | Increase ICU and ventilation capacity | B | III | [ [19] ,[153] ] |
| Healthcare providers | To prevent SARS-CoV-2 transmission and infection | Consider erythropoietin as an alternative to red cell transfusion | B | III | [ [85] ,[151] ,
Screening for COVID-19 in asymptomatic patients with cancer in a hospital in the United Arab Emirates. JAMA Oncol. 2020; https://doi.org/10.1001/jamaoncol.2020.2548 [90] ] |
Abbreviations: ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SoR, strength of recommendation; QoE, quality of evidence.
To provide best care for cancer patients with COVID-19, intensive care unit (ICU) and respirator capacity should be increased (BIII). If possible, dedicated treatment teams should be implemented to ensure continued cancer care in case of infected medical personnel (AIII) [
[19]
]. Early detection of infected staff is crucial. Surveillance screening related to local epidemiology should be considered, especially in inpatients, to prevent presymptomatic transmission of SARS-Cov-2 (AIIt,u) [[85]
].The risk of transmission strongly correlates with the number of consultation and treatment appointments [
[21]
,[29]
,[86]
,[87]
]. However, optimal control of the underlying malignancy is considered favourable as patients with active cancer appear to have an increased risk of severe COVID-19 [[20]
]. To ensure high-quality cancer care, visits should by no means be avoided or unnecessarily delayed, but reduced if possible without interfering with treatment goals. We strongly recommend considering therapeutic strategies with the fewest and shortest clinic visits adapted to curative or palliative intent taking the patient's individual situation and risk into account (AIII). This might e.g. include substitution of intravenous by oral regimens (e.g. 5-fluorouracil/capecitabine) or hypofractionated radiotherapy. Transfusion strategies should be as restrictive as recommended per guidelines and iron, folic acid, vitamin B12 or erythropoietin should be supplemented rigorously as indicated (BIII) [88
, 89
, 90
]. Clinic visits for surveillance might be postponed or be substituted by telephone or video calls [[91]
].6. Management of cancer care
6.1 General recommendations
Given the immunocompromising effect of many cancer therapies and the fact that most cancer patients belong to high-risk groups regarding adverse outcome of COVID-19 it seems reasonable to debate whether it may be the safer course of action to delay or discontinue certain antineoplastic therapies. However, uncontrolled malignancy was identified as an independent risk factor for severe COVID-19 [
[20]
]. We therefore strongly recommend performing antineoplastic therapy to reach the best possible remission (AIIu, Table 5).Table 5Recommendations regarding management of cancer care during the COVID-19 pandemic.
| Population/Clinical situation | Intention | Intervention | SoR | QoE | References |
|---|---|---|---|---|---|
| General recommendations | |||||
| Cancer patients during COVID-19 pandemic | To reduce risk of severe COVID-19 | Perform cancer therapy to reach best possible remission | A | IIu | [ [20] ,[30] ] |
| Cancer patients with suspected SARS-CoV-2 infection (e.g. contact patients, hot spots) | To reduce risk of severe COVID-19 | Quarantine and delay/discontinue anti-cancer therapy for up to 14 days, if not detrimental for cancer prognosis | A | III | No reference. |
| Cancer patients with suspected SARS-CoV-2 infection (e.g. contact patients, hot spots) | To reduce risk of severe COVID-19 | Test for SARS-CoV-2 | A | III | No reference. |
| Cancer patients with SARS-CoV-2 infection | To reduce risk of severe COVID-19 | Delay/discontinue cytotoxic chemotherapy, if possible | A | IIu | [ [11] ] |
| Cancer patients with SARS-CoV-2 infection | To reduce mortality | Delay surgery, if possible | A | IIu | [ [95] ] |
| Cancer patients with SARS-CoV-2 infection | To reduce risk of severe COVID-19 | Delay/discontinue radiotherapy, if possible | B | IIu | [ [11] ] |
| Cancer patients during COVID-19 pandemic with controlled disease | To reduce risk of severe COVID-19 | Consider to delay/discontinue cytotoxic chemotherapy, if not detrimental for cancer prognosis, taking into account local epidemiology | B | IIu | [ [6] , [11] , [13] , [37] ] |
| Cancer patients with SARS-CoV-2 infection | To reduce risk of severe COVID-19 | Delay/discontinue targeted therapy, if possible | C | III | [ [11] ] |
| Cancer patients during COVID-19 pandemic | To reduce risk of SARS-CoV-2 infection and severe COVID-19 | Routinely delay/discontinue anti-cancer therapy | D | IIu | [ [18] , [20] ,[31] ,[33] , [40] , 92 , 93 , 94 ] |
| Cancer patients during COVID-19 pandemic | To reduce mortality | Delay/discontinue radiotherapy, endocrine therapy, targeted therapy or surgery | D | IIu | [ [18] , [20] ,[31] ,[40] , [94] ] |
| Cancer patients with SARS-CoV-2 infection | To reduce mortality | Delay/discontinue endocrine therapy | D | III | [ [18] ] |
| Specific recommendations | |||||
| Cancer patients during COVID-19 pandemic | To reduce risk of severe COVID-19 | Consider to delay/reduce/discontinue steroids, if not detrimental for cancer prognosis | C | IIt,u | [ [98] ] |
| Lung cancer patients during COVID-19 pandemic | To reduce risk of severe COVID-19 | Delay/discontinue PD1 inhibitors | D | IIu | [ [99] , [100] ] |
| Lung Cancer patients receiving TKI with SARS-CoV-2 infection | To reduce risk of severe COVID-19 | Discontinue TKI | D | IIu | [ [100] ] |
| CML patients with SARS-CoV-2 infection | To reduce risk of severe COVID-19 | Discontinue TKI | D | III | [ [104] ] |
| Cancer patients receiving BTKi with SARS-CoV-2 infection | To reduce risk of severe COVID-19 | Discontinue BTKi | D | III | [ [101] , [102] ] |
| Cancer patients receiving ruxolitinib with SARS-CoV-2 infection | To reduce risk of severe COVID-19 | Discontinue ruxolitinib | D | IIt | [ [103] ] |
Abbreviations: BTKi, Bruton tyrosine kinase inhibitor; CML, chronic myelogenous leukaemia; QoE, quality of evidence; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SoR, strength of recommendation; TKI, tyrosine kinase inhibitor.
Routine delay or discontinuation of antineoplastic therapy in patients without suspected/confirmed SARS-CoV-2 infection is not recommended even in times of pandemic (DIIu) [
[18]
,[20]
,[31]
,[33]
,[40]
,92
, 93
, 94
]. In case of suspected SARS-CoV-2 infection, e.g. because of contact with a confirmed case or a high incidence in the area, we strongly recommend to quarantine the patient and delay antineoplastic therapy for up to 14 days, if not detrimental for cancer prognosis (AIII). Given the average incubation time of 3–5 days, a delay for a shorter time period and (re-)start of antineoplastic therapy under quarantine conditions may be considered especially in patients with significant prognostic impact of per-protocol administration of treatment. Obviously, these patients should be tested for SARS-CoV-2 (AIII) but the possibility of false-negative test results should be kept in mind.Cytotoxic chemotherapy was reported as a risk factor for severe COVID-19 by some [
[11]
,[13]
,[37]
,[39]
], although not consistently across all studies [[20]
,[40]
]. We therefore moderately recommend to consider to delay/discontinue chemotherapy in areas with high SARS-CoV-2 infection rates in patients with controlled malignancy if no significant detrimental impact on cancer prognosis is to be expected (BIIu). This might be especially relevant in the palliative setting, if the benefit of chemotherapy is marginal, and if other risk factors for severe COVID-19 are present. Furthermore, dose reductions might be a reasonable strategy in the palliative setting to reduce neutropenia. We do not recommend to delay/discontinue radiotherapy, targeted therapy, endocrine therapy or surgery in cancer patients without suspected/confirmed SARS-CoV-2 infection (DIIu) as no impact on mortality of such prior treatments was seen in several large cohort studies of COVID-19 patients [[18]
,[20]
,[31]
,[40]
,[94]
].In patients with COVID-19, it is strongly recommended to delay/discontinue chemotherapy, if possible, as chemotherapy within two weeks of admission was a major risk factor for severe COVID-19 in a large Chinese cohort study (AIIu) [
[11]
]. Similarly, we strongly recommend delaying surgery in COVID-19 patients (AIIu), as perioperative SARS-CoV-2 infection was associated with a high rate of pulmonary complications and increased mortality [[95]
]. We recommend to delay/discontinue radiotherapy in patients with COVID-19 with moderate strength (BIIu) taking into account field size, location and dosage [[11]
,[12]
,[31]
,[40]
].A small cohort study in breast cancer patients with COVID-19 reported very favourable outcomes in several patients who did not discontinue their endocrine therapy despite diagnosis of infection [
[18]
]. Given that endocrine therapy is usually not associated with significant immunosuppression, we do not recommend discontinuing endocrine therapy in patients with COVID-19 (DIII). It is important to note that this does not apply to CDK4/6 inhibitors jointly administered with endocrine therapy which can induce significant neutropenia [[96]
].- Ramos-Esquivel A.
- Hernandez-Steller H.
- Savard M.F.
- Landaverde D.U.
Cyclin-dependent kinase 4/6 inhibitors as first-line treatment for post-menopausal metastatic hormone receptor-positive breast cancer patients: a systematic review and meta-analysis of phase III randomized clinical trials.
Breast Cancer. 2018; 25: 479-488
Targeted therapy was reported as a risk factor for severe COVID-19 in one study, although patient numbers for this subgroup were small [
[11]
]. Given that many targeted agents adversely affect immune function we marginally support discontinuation of targeted therapy in COVID-19 patients (CIII). In support, a recent small German study on multiple myeloma (MM) patients with COVID-19 reported favourable outcomes after discontinuation of various types of targeted anti-MM therapies until resolution of symptoms [[17]
]. However, the heterogeneity of drugs summarised as targeted therapy has to be acknowledged, and depending on the available data, substance-specific recommendations should be applied.- Engelhardt M.
- Shoumariyeh K.
- Rosner A.
- Ihorst G.
- Biavasco F.
- Meckel K.
- et al.
Clinical characteristics and outcome of multiple myeloma patients with concomitant COVID-19 at Comprehensive Cancer Centers in Germany.
Haematologica. 2020; https://doi.org/10.3324/haematol.2020.262758
6.2 Specific recommendations on some cancer treatments
In the following passages, we summarise current knowledge regarding specific cancer treatments. This summary is in no way complete and subject to change as knowledge accumulates.
While corticosteroid therapy can be beneficial to treat severe COVID-19,[
[97]
] long-term systemic steroids were identified as a risk factor to develop severe COVID-19 in a large registry study of patients with inflammatory bowel disease [- Group R.C.
- Horby P.
- Lim W.S.
- Emberson J.R.
- Mafham M.
- Bell J.L.
- et al.
Dexamethasone in hospitalized patients with covid-19 - preliminary report.
N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2021436
[98]
]. We marginally recommend considering to delay, discontinue or reduce treatment with systemic steroids in cancer patients during the COVID-19 pandemic (CIIt,u). Any potential impact of steroid reduction on treatment success needs to be carefully evaluated, most importantly in curative settings.Immune checkpoint inhibitors were initially suspected to increase the risk of severe COVID-19 [
[12]
]. However, later studies did not find a significant association after adjustment for smoking [[99]
,[100]
]. We therefore do not recommend delaying/discontinuing immune checkpoint inhibitors (DIIu).Prior treatment with tyrosine kinase inhibitors (TKIs) was not associated with adverse outcomes in a cohort study of lung cancer patients with COVID-19, although patient numbers in this subgroup were small and no further details on the type of TKIs were provided [
[100]
]. Routine delay/discontinuation of TKIs in patients with lung cancer is thus not recommended (DIIu).Two small case series reported a favourable outcome of patients with chronic lymphocytic leukaemia (CLL) or Waldenström macroglobulinaemia diagnosed with COVID-19 and continuous administration of Bruton tyrosine kinase inhibitors (BTKis) [
[101]
,[102]
]. We therefore recommend against discontinuation of BTKis in patients with COVID-19 (DIII).The JAK inhibitor ruxolitinib was evaluated in a small randomised controlled trial (RCT) against placebo for the treatment of severe COVID-19 given its anti-inflammatory properties. While no statistically significant difference in the outcome was observed, time to clinical improvement of patients receiving ruxolitinib was numerically shorter [
[103]
]. Discontinuation of ruxolitinib in patients with COVID-19 is therefore not recommended (DIIt).Further data on the risks of specific antineoplastic drugs with regard to COVID-19 are scarce at this time. In a small case series of five patients with chronic myelogenous leukaemia (CML) and COVID-19, TKI treatment could safely be continued [
[104]
]. Regarding the impact of rituximab on COVID-19, several cases are published reporting outcomes ranging from very mild to fatal [[105]
- Tepasse P.R.
- Hafezi W.