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Department of Pulmonary Diseases GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
2 Both authors contributed equally to the work and are considered last author.
Astrid A.M. van der Veldt
Correspondence
Corresponding author: Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands.
1 Both authors contributed equally to the work and are considered first author. 2 Both authors contributed equally to the work and are considered last author. 3 DOCC Investigators are listed in appendix 1 (page 31–32).
Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19).
•
This nationwide study investigated risk factors for fatal outcome of COVID-19.
•
Among 442 registered patients with cancer, 32.3% of patients died of COVID-19.
•
Haematological malignancy and lung cancer increased the risk of fatal outcome.
•
These results can guide treatment and vaccination decisions in patients with cancer.
Abstract
Aim of the study
Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19.
Methods
This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible.
Results
Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years).
Conclusion
The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered.
]. In particular, the consequences for oncological care are extensive, as the effects of malignancy or cancer treatments on the outcome of COVID-19 are yet unknown [
]. These treatment adjustments were made according to COVID-19 guidelines of (inter)national oncological societies, which were primarily based on expert opinions [
Awaiting the development of vaccines against SARS-CoV-2, new outbreaks are expected worldwide. A nationwide registry was initiated by the Dutch Oncology COVID-19 Consortium (DOCC). It aims to identify characteristics of patients with cancer and/or their treatments associated with a worse outcome of COVID-19 to facilitate evidence-based decisions in oncological care during this ongoing pandemic. In the Netherlands, all patients have equal access to medical care and open discussions with patients and their families about treatment restrictions, i.e. do-not-intubate or do-not-resuscitate orders, are daily practice.
2. Methods
2.1 Study design
The registry is executed by DOCC, which is a nationwide consortium of oncology physicians (haematologists, medical oncologists, neuro-oncologists and pulmonologists) in the Netherlands. This observational cohort study was designed as a national quality of care registry to support rapid clinical decision-making in oncological practice. A questionnaire was developed to collect pseudonymised patient data on four topics: baseline patient characteristics, diagnosis and treatment of cancer, characteristics of COVID-19 and treatment and outcome of COVID-19 (appendix 2). Some patients with COVID-19 were transferred to another hospital because of capacity issues. Therefore, data of transfer of patients between hospitals were requested to avoid duplicates. This registry was approved by the ethics committee and the Privacy Knowledge Office at Erasmus Medical Centre. According to local hospital guidelines, additional approval was obtained by local committees when needed.
2.2 Inclusion criteria of DOCC registry
All patients with COVID-19 and a cancer diagnosis or cancer treatment in the past 5 years were eligible for inclusion in the DOCC registry. Besides, patients with a diagnosis or treatment more than 5 years ago could be included if the diagnosis or treatment was expected to have had an impact on COVID-19 outcome (e.g. bone marrow transplantation, chest radiation therapy). The diagnosis of COVID-19 was defined as a positive test for SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) and/or radiological findings on computed tomography (CT) and/or clinical symptoms of COVID-19. However, as a diagnosis of COVID-19 based solely on clinical symptoms is insecure and subject to bias, it was decided to restrict eligibility to a PCR and/or CT-based COVID-19 diagnosis for this analysis.
2.3 Collection of data
The DOCC registry was initiated on March 27th, 2020, and supported by the Dutch societies of medical oncologists, pulmonologists and neuro-oncologists [
]. Dutch oncology physicians in all 69 hospital organisations in the Netherlands were informed about the registry by communications via different cancer societies. Physicians were encouraged to identify cancer patients with COVID-19 and to collect pseudonymised data using the questionnaire. Subsequently, the data provided were centrally entered into an electronic clinical record form (eCRF) using a secured digital database (ALEA Clinical).
2.4 Data processing
For the first analysis, an update on the course and outcome of COVID-19 was requested for all patients diagnosed with COVID-19 ≥ 4 weeks before May 4th, 2020. Also, all clinical data in eCRFs were checked for inconsistencies by experienced oncology physicians (D.D., P.M., A.V.), and the queries generated were sent to the participating hospitals. The returned queries and updated data were processed in eCRFs. Clinical data were both annotated and cleaned, including the processing of transfer data to avoid duplicates.
2.5 Distribution of COVID-19 in the Netherlands
In the Netherlands, the COVID-19 pandemic is monitored by The National Institute for Public Health and the Environment [
]. All patients with a positive RT-PCR test for SARS-CoV-2 are centrally registered. The 12 geographic regions of the Netherlands were classified according to the number of COVID-19 positive patients per 100,000 inhabitants. This allows evaluation of the national coverage of the DOCC registry according to regional incidence of COVID-19.
2.6 Statistical analysis
The characteristics of patients with resolved COVID-19 versus a fatal outcome of COVID-19 were analysed. Descriptive statistics were used for baseline characteristics. To analyse the risk for different age categories, patients were categorised into three age groups; i.e. <65 years, ≥65–75 years and ≥75 years. Pearson's chi-square test was used to identify univariable risk factors for a fatal outcome of COVID-19, and odds ratios were presented with 95% confidence intervals. Variables with p ≤ 0.10 in univariable analysis were included in multivariable logistic regression analyses. This was done with backward selection with a threshold of p < 0.05. All statistical tests were performed two-sided. Data were analysed using IBM SPSS statistics 25.
As patients with metastatic disease and/or active cancer treatment could be more susceptible to a severe course of COVID-19, a separate analysis was performed for this subgroup of patients. Active malignancy was defined as metastatic disease in patients with solid tumours and/or recent cancer treatment (<90 days before diagnosis of COVID-19). In patients with an active malignancy, the impact of cancer treatment on COVID-19 severity was also evaluated. For this group, treatment was defined as any cancer treatment 30 days before COVID-19 diagnosis. Finally, the impact of steroid use was analysed as a possible risk factor for fatal outcome of COVID-19. For this specific analysis, steroid use (30 days before COVID-19 diagnosis) as supportive medication for cytotoxic treatment (e.g. part of the chemotherapeutic regime or anti-emetic medication) versus steroid use not related to cancer treatment was analysed.
3. Results
3.1 COVID-19 in the Netherlands
At initiation of the registry, March 27th 2020, all Dutch regions experienced an outbreak of COVID-19. At that time, the Southern region of the Netherlands had the highest incidence of COVID-19. Forty-five out of the 69 Dutch hospital organisations participated in the registry. All hospitals that provided care for the majority of patients with COVID-19 participated. The distribution of COVID-19 and the location of participating hospitals show nationwide coverage of this registry (Figure 1).
Fig. 1Prevalence of COVID-19 in the Netherlands. Patients with a positive test for SARS-CoV-2 at start of the DOCC registry March 28th, 2020 (a) and one day after the database lock on (b) May 5th, 2020. The black bullets indicate the hospitals that participated in the registry (n = 45).
3.2 Characteristics of COVID-19 patients with cancer
Between March 27th and May 4th, 442 patients were registered. Data from 409 cancer patients were complete for the current analysis. In addition, the following patients were excluded form analyses: one duplicate case, 30 patients because of unconfirmed diagnosis of COVID-19 and 27 patients because of ongoing COVID-19 with unknown outcome. For this first analysis, 351 patients were included (Figure 2).
Fig. 2Patient selection. Flowchart of patient selection for the current analysis.
Detailed baseline characteristics are presented in Table 1. Overall, the median age was 70 years (interquartile range [IQR] 61–77) and 187 (53.3%) patients were male. The main cancer diagnoses were non-small cell lung cancer (13.4%), breast cancer (13.4%) and chronic lymphocytic leukaemia (8.8%). Metastatic disease was present in 112 (47.1%) out of 238 patients with solid tumours. In more than half of all patients (53.6%), the last cancer treatment was with non-curative intent. Besides cancer diagnosis, most patients had one or more relevant comorbidities, and 51% of the patients had a history of smoking.
Table 1Patients' characteristics.
Variable
Resolved (n = 237)
Fatal (n = 114)
Total group (n = 351)
Sex—n (%)
Male
112 (47.3)
75 (65.8)
187 (53.3)
Female
125 (52.7)
39 (34.2)
164 (46.7)
Age
Median age in years (interquartile range)
68 (59–76)
74 (68–80)
70 (61–77)
<65 years—n (%)
99 (41.8)
12 (10.5)
111 (31.6)
≥65 years < 75 years—n (%)
71 (30.0)
46 (40.4)
117 (33.3)
≥75 years—n (%)
67 (28.3)
56 (49.1)
123 (35.0)
Smoking—n (%)
All smokers
112 (47.3)
67 (58.5)
179 (51.0)
Current smoker
12 (5.1)
12 (10.5)
24 (6.8)
History of smoking
100 (42.2)
55 (48.2)
155 (44.2)
Comorbidities—n (%)
Cardiovascular disease
119 (50.2)
71 (62.3)
190 (54.1)
BMI ≥ 30
48 (20.3)
16 (14.0)
64 (18.2)
COPD
26 (11.0)
20 (17.5)
46 (13.1)
Diabetes mellitus
34 (14.3)
21 (18.4)
55 (15.7)
Autoimmune disease
13 (5.5)
9 (7.9)
22 (6.3)
Prior/other malignancy
31 (13.1)
32 (28.1)
63 (17.9)
Use of steroids at COVID-19 diagnosis
53 (22.4)
40 (35.1)
93 (26.5)
As part of cancer treatment (<1 week)
32 (13.5)
23 (20.2)
55 (15.7)
Use >1 week (not related to cancer treatment)
21 (8.9)
17 (14.9)
38 (10.8)
Cancer type—n (%)
Non-small-cell lung cancer
25 (10.5)
22 (19.3)
47 (13.4)
Breast cancer
40 (16.9)
7 (6.1)
47 (13.4)
Chronic lymphocytic leukaemia
22 (9.3)
9 (7.9)
31 (8.8)
Colorectal cancer
26 (11.0)
5 (4.4)
31 (8.8)
Prostate cancer
19 (8.0)
10 (8.8)
29 (8.3)
Multiple myeloma
14 (5.9)
14 (12.3)
28 (8.0)
Non-Hodgkin lymphoma
17 (7.2)
11 (9.6)
28 (8.0)
Urinary cell cancer
8 (3.4)
5 (4.4)
13 (3.7)
Myeloproliferative neoplasms
7 (3.0)
3 (2.6)
10 (2.8)
Myelodysplastic syndrome
4 (1.7)
5 (4.4)
9 (2.6)
Renal cell cancer
6 (2.5)
3 (2.6)
9 (2.6)
Melanoma
7 (3.0)
1 (0.9)
8 (2.3)
Endometrial cancer
6 (2.5)
1 (0.9)
7 (2.0)
Neuro-endocrine tumour
6 (2.5)
1 (0.9)
7 (2.0)
Oesophageal cancer
1 (0.4)
5 (4.4)
6 (1.7)
Chronic myeloid leukaemia
4 (1.7)
1 (0.9)
5 (1.4)
Ovarian cancer
4 (1.7)
0 (0)
4 (1.1)
Pancreatic cancer
4 (1.7)
0 (0)
4 (1.1)
Small-cell lung cancer
1 (0.4)
3 (2.6)
4 (1.1)
Other
14 (5.9)
8 (7.0)
24 (6.8)
Last oncological treatment—n (%)
Surgery
25 (10.5)
17 (14.9)
42 (12.0)
Radiotherapy
43 (18.1)
24 (21.1)
67 (19.1)
Thoracic radiotherapy
27 (11.4)
16 (14.0)
43 (12.3)
Chemotherapy
104 (43.9)
49 (43.0)
153 (43.6)
Immunotherapy
41 (17.3)
16 (14.0)
57 (16.2)
Targeted therapy
39 (16.5)
17 (14.9)
56 (16.0)
Hormonal therapy
35 (14.8)
13 (11.4)
48 (13.7)
Disease stage solid tumours—n (%)
Metastatic
81 (34.2)
31 (27.2)
112 (47.1)
Intention most recent cancer treatment given—n (%)
Curative
105 (44.3)
45 (39.5)
150 (42.7)
Non-curative
122 (51.5)
66 (57.9)
188 (53.6)
Unknown
10 (4.2)
3 (2.6)
13 (3.7)
Treatment restrictions—n (%)
Do-not-intubate
82 (34.6)
95 (83.3)
177 (50.4)
BMI, body mass index; COPD, chronic obstructive pulmonary disease.
Before the COVID-19 diagnosis, cancer treatment had been completed in 108 (30.8%) patients. In 101 (28.8%) patients, cancer treatment was not adjusted during the COVID-19 outbreak. Adjustments before the COVID-19 diagnosis included dose reduction (n = 4, 1.1%), premature withdrawal of treatment (n = 14, 4.0%), administration of higher dose (e.g. immunotherapy or radiotherapy) at longer interval (n = 16, 4.6%), cancellation of recent treatment cycle (n = 35, 10.0%) and/or temporarily interruption of treatment (n = 70, 19.9%).
3.3 Outcome of COVID-19 in patients with cancer
In total, 114 (32.3%) of the patients died from COVID-19. Patients with a fatal outcome of COVID-19 had a higher median age as compared with patients with non-fatal outcome (74 [IQR 68–80] versus 68 [IQR 59–76] years). Patients with age ≥65 years had an increased risk of fatal outcome (p < 0.001). In univariable analyses (Table 2), male gender, smoking, cardiovascular disease, chronic obstructive pulmonary disease, prior or other malignancy, use of steroids at COVID-19 diagnosis, a current diagnosis of haematologic malignancy and lung cancer were associated with fatal outcome of COVID-19.
Table 2Univariable analysis of features of patients related to a fatal outcome of COVID-19.
Variable
Odds ratio (95% CI)
p value
Sex (male)
2.15 (1.35–3.41)
0.001
Age (years)
<65 years
–
–
≥65 years < 75 years
5.35 (2.64–10.81)
<0.001
≥75 years
6.90 (3.44–13.84)
<0.001
Smoking
All smokers
–
–
History of smoking
1.72 (1.03–2.88)
0.040
Active smoker
3.13 (1.28–7.64)
0.012
Comorbidities
Cardiovascular disease
1.64 (1.04–2.58)
0.034
BMI ≥ 30
0.64 (0.35–1.19)
0.158
COPD
1.73 (0.92–3.25)
0.087
Diabetes mellitus
1.35 (0.74–2.45)
0.325
Autoimmune disease
1.48 (0.61–3.56)
0.383
Prior/other malignancy
2.59 (1.49–4.52)
0.001
Use of steroids at COVID-19 diagnosis
–
–
As part of cancer treatment (<1 week)
1.94 (1.06–3.57)
0.033
Use >1 week (not related to cancer treatment)
2.18 (1.08–4.41)
0.029
Cancer type
Other
–
–
Haematological malignancy
2.15 (1.30–3.57)
0.003
Lung cancer
3.13 (1.64–5.95)
0.001
Last oncological treatment
Surgery
1.49 (0.77–2.88)
0.238
Radiotherapy
1.20 (0.69–2.10)
0.516
Thoracic radiotherapy
1.27 (0.65–2.47)
0.479
Chemotherapy
0.96 (0.61–1.51)
0.874
Immunotherapy
0.78 (0.42–1.46)
0.437
Targeted therapy
0.89 (0.48–1.65)
0.712
Hormonal therapy
0.74 (0.38–1.47)
0.390
Disease stage
Metastatic
0.87 (0.54–1.41)
0.575
Intention most recent cancer treatment given
Non-curative
1.30 (0.83–2.03)
0.259
BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval.
In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and an active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) remained independent risk factors for a fatal outcome of COVID-19 (Table 3).
Table 3Multivariable analysis of features of patients related to a fatal outcome of COVID-19.
Treatment restrictions with a do-not-intubate order were reported in 117/351 (50.4%) patients and in 95/114 (83.3%) patients with fatal COVID-19 outcome.
3.4 Active malignancy
A subgroup analysis was performed in 227 patients with active malignancy. The characteristics and results of the univariable analysis are shown in Table 4. Patients with a haematological malignancy or lung cancer had an increased risk of a fatal outcome of COVID-19 compared with patients with other cancer types. In addition, male patients, age ≥65 years, smoking, cardiovascular disease and use of steroids as part of anticancer treatment remained risk factors for fatal outcome in univariable analysis. In this subgroup analysis, treatment in non-curative setting was also associated with fatal outcome.
Table 4Univariable analysis for the subgroup of patients with active malignancy and COVID-19.
Variable
Total group (n = 227)
Frequency n (%)
Odds ratio (95% CI)
p value
Sex (male)
115 (50.7)
1.79 (1.01–3.17)
0.045
Age (median age in years)
<65 years
84 (37.0)
–
–
≥65 years < 75 years
77 (33.9)
4.72 (2.12–10.55)
<0.001
≥75 years
66 (29.1)
6.55 (2.89–14.86)
<0.001
Smoking
All smokers
115 (50.7)
–
–
History of smoking
99 (43.6)
1.20 (0.64–2.26)
0.579
Active smoker
16 (7.0)
2.63 (0.89–7.78)
0.082
Comorbidities
Cardiovascular disease
107 (47.1)
1.86 (1.06–3.29)
0.031
BMI ≥ 30
39 (17.2)
0.61 (0.27–1.36)
0.225
COPD
23 (10.1)
1.47 (0.61–3.58)
0.392
Diabetes mellitus
30 (13.2)
1.12 (0.49–2.52)
0.794
Autoimmune disease
10 (4.4)
1.49 (0.41–5.46)
0.543
Prior/other malignancy
38 (16.7)
1.77 (0.87–3.63)
0.115
Use of steroids at COVID-19 diagnosis
134 (59.0)
–
–
As part of cancer treatment (<1 week)
53 (23.3)
2.26 (1.16–4.40)
0.017
Use >1 week (not related to cancer treatment)
25 (11.0)
1.65 (0.67–4.09)
0.275
Cancer type
Other
127 (55.9)
–
–
Haematological malignancy
62 (27.3)
3.64 (1.89–7.04)
<0.001
Lung cancer
38 (16.7)
2.53 (1.16–5.53)
0.020
Last oncological treatment
Surgery
15 (6.6)
1.51 (0.52–4.41)
0.451
Radiotherapy
49 (21.6)
0.85 (0.42–1.70)
0.645
Thoracic radiotherapy
31 (13.7)
0.88 (0.39–2.03)
0.772
Chemotherapy
117 (51.5)
0.88 (0.50–1.54)
0.648
Immunotherapy
46 (20.3)
0.84 (0.41–1.71)
0.621
Targeted therapy
49 (21.6)
1.22 (0.63–2.38)
0.560
Hormonal therapy
39 (17.2)
0.72 (0.33–1.57)
0.404
Disease stage for solid tumours
Metastatic
118 (52.0)
0.93 (0.53–1.63)
0.795
Intention most recent cancer treatment given
Non-curative
148 (65.2)
1.89 (1.01–3.53)
0.044
Treatment restrictions
Do-not-intubate
121 (53.3)
–
–
BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval.
The above-mentioned characteristics were all included in the multivariable analysis. The risk for a fatal outcome was mainly determined by tumour type and age, as older patients (≥65 years) and patients with a haematological malignancy or lung cancer had a worse outcome of COVID-19 (Table 5).
Table 5Multivariable analysis for the subgroup of patients with active malignancy and COVID-19.
In total, 165 patients were on active treatment (i.e. ≤30 days between the last treatment and date of COVID-19 diagnosis). In this group, there were no differences in the risk of a fatal outcome of COVID-19 between the different cancer therapies. The disease setting (non-metastatic versus metastatic) and treatment setting (curative versus non-curative) were not associated with an increased risk of fatal outcome of COVID-19.
4. Discussion
The DOCC registry was initiated to identify clinical characteristics of patients with cancer related to an increased risk of fatal outcome of COVID-19. An active diagnosis of haematological malignancy or lung cancer, age (≥65 years), male gender and diagnosis of a prior or other malignancy were independent risk factors for a fatal outcome of COVID-19. In the subgroup of patients with active malignancy, age (≥65 years) and a diagnosis of a haematological malignancy or lung cancer remained independent risk factors for increased mortality of COVID-19.
Although chemotherapy has previously been identified as a risk factor for mortality of COVID-19 in cancer patients [
]. However, steroid use at the time of COVID-19 diagnosis was associated with an increased risk of fatal outcome of COVID-19 in univariable analysis. This result is of particular interest, as a recent randomised clinical trial showed that dexamethasone decreases mortality of COVID-19 in patients requiring respiratory support [
]. Steroid co-medication is usually prescribed as supportive medication for haematological treatment and/or highly emetogenic chemotherapy regimens. Therefore, systemic treatment or disease itself cannot be excluded as confounding factor.
Apart from the current DOCC registry, other international registries have been published to identify the clinical characteristics of cancer patients with severe COVID-19 [
COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus.
]. As the design and data collection of these registries are significantly different, a comparison between results is challenging. Therefore, for appropriate interpretation of data published by these registries, attention should be paid to the different designs and patient selections (Table 6).
Table 6Overview of previously published registries.
COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus.
Or longer if the cancer treatment is expected to have an impact on COVID-19 outcome, for example after bone marrow transplantation or thoracic radiotherapy.
Age, smoking, comorbidity, cancer type, cancer treatment, COVID-19 symptoms.
Yes
Yes
Yes
Yes (including covid-19 severity)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Laboratory examination
Not reported
Not reported
Yes
Not reported
Yes
Not reported
Not reported
Yes
Yes
Yes
Yes
Abnormalities at baseline on X-ray or CT
Not reported
Yes
Yes
Not reported
Yes
Not reported
Not reported
Not reported
Not reported
Yes
Yes
Use of antibiotics
Yes
Not reported
Yes
Not reported
Yes
Not reported
Not reported
Yes
Yes
Yes
Yes
Use of antiviral s
Yes
Not reported
Yes
Not reported
Yes
Not reported
Yes
Yes
Yes
Yes
Yes
Use of hydroxychloroquine
Not reported
Not reported
Not reported
Not reported
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Use of glucocorticoids
Yes
Not reported
Yes
Not reported
Yes
Not reported
Not reported
Yes
Yes
Yes
Yes
Use of anti-IL6
Not reported
Not reported
Not reported
Not reported
Yes
Not reported
Yes
Yes
Yes
Yes
Yes
Use of anticoagulants
Not reported
Not reported
Not reported
Not reported
Yes
Not reported
Yes
Not reported
Yes
Not reported
Not reported
Admission to ICU
Yes
Yes
Yes
Yes
Yes
Yes
Not reported
Yes
Yes
Yes
Not reported
Invasive ventilation
Yes
Yes
Yes
Not reported
Not reported
Yes
Not reported
Yes
Yes
Yes
Not reported
Death
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Other
Length of hospital stay
COVID-19 management at home, COVID-19 resolution
Occurrence of complicated SARS-Cov-2 infection
Adjustment of oncological treatment, treatment restrictions regarding mechanical ventilation and admission to ICU
DOCC, Dutch Oncology COVID-19 Consortium; ICU, intensive care unit; SARS-Cov-2, severe acute respiratory syndrome coronavirus 2; CT, computed tomography.
a Age, smoking, comorbidity, cancer type, cancer treatment, COVID-19 symptoms.
b <3 months, 1–3 months, 3–6 months, 6–12 months, 1–3 years, >3 year.
c On behalf of the National Clinical Research Center for Respiratory Disease.
d Or longer if the cancer treatment is expected to have an impact on COVID-19 outcome, for example after bone marrow transplantation or thoracic radiotherapy.
]. In summary, the national guidelines were rather reluctant to start or continue oncological therapies. In addition, treating physicians were encouraged to discuss treatment restrictions regarding intubation and ICU admission with their patients. Owing to these conservative guidelines, adjustments in oncological treatment were rather common [12] and probably even more frequent in vulnerable patients. Therefore, the lack of effect of oncological treatments on fatal outcomes of COVID-19 should be interpreted cautiously in the current study, and the impact of anticancer therapies on the course of COVID-19 cannot be excluded.
Moreover, discussing treatment restrictions with patients in the outpatient clinic was already common practice in the Netherlands prior to COVID-19, especially for patients with cancer in the non-curative setting. In the DOCC registry, more than 50% of patients had a do-not-intubate order prior to infection with SARS-CoV-2. Among patients with fatal outcome of COVID-19, more than 80% had a do-not-intubate order. In addition, in the Netherlands, patients with COVID-19 are almost solely admitted to the ICU when mechanical ventilation is required, whereas most other supportive treatments are given outside the ICU. As a result, <20% of patients with fatal outcome of COVID-19 was admitted to the ICU in the current study, despite the lack of capacity issues of ICUs in the Netherlands. Although discussing treatment restrictions is common practice in the Netherlands and probably more common as compared to other countries, the percentage of patients with a fatal outcome is comparable to other countries [
]. Therefore, early discussion of treatment restrictions with vulnerable patients is preferred during this ongoing pandemic.
As the DOCC registry is only executed by oncology physicians in hospitals, a limitation of this study is the potential selection bias. As a result, particular groups of patients may have been underreported. For instance, patients who already had completed oncological treatment, patients who were not admitted to the hospital or patients who died in an out-hospital setting, may not have been registered. Next, the Dutch testing policy for SARS-CoV-2 was restrictive in the beginning of the pandemic, which initially resulted in an underestimation of the total number of patients with COVID-19. Although a potential selection bias may have occurred, this does not directly affect the results of this analysis, as the potentially underreported patient groups mainly included patients without active malignancy and/or recent cancer treatment. In addition, the Dutch healthcare system provides equal access to medical care and cancer treatment decisions are based on the same national guidelines. Therefore, the results of the current study seem to be representative of a national cancer patient population.
As the COVID-19 pandemic overwhelmed healthcare systems worldwide, non-evidence–based decisions had to be made about the treatment of patients with non-COVID-19 diseases such as cancer. Therefore, it is essential to combine data from several international registries and to ensure the collection of new and more comprehensive data during this ongoing pandemic. In particular, more data concerning cancer treatment and supportive medication (e.g. steroids) should be collected.
In conclusion, the findings of the DOCC registry in cancer patients confirm previous findings that older, male patients with comorbidities have an increased risk of a fatal outcome of COVID-19 [
]. Besides, the results of this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a poorer outcome. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to SARS-CoV-2, whereas treatment adjustments and prioritising vaccination, when available, should be considered as well.
Conflict of interest statement
D.D. reports personal fees from speakers fee MSD, personal fees from speakers fee Roche, personal fees from speakers fee AstraZeneca, personal fees from speakers fee BMS, personal fees from speakers fee Novartis, personal fees from speakers fee Pfizer, outside the submitted work; H.W. reports honoraria from Astellas and Roche and travel expenses from Ipsen, outside the submitted work; K.S. reports personal fees and advisory role for Novartis, personal fees from Roche, personal fees and advisory role for MSD, advisory role BMS, advisory role Pierre Fabre, advisory role Abbvie, outside the submitted work; L.H. reports other from Boehringer Ingelheim, other from BMS, other from Roche Genentech, other from BMS, grants from Roche Genentech, grants from Boehringer Ingelheim, other from AstraZeneca, personal fees from Quadia, grants from Astra Zeneca, other from Eli Lilly, other from Roche Genentech, other from Pfizer, other from MSD, other from Takeda, non-financial support from AstraZeneca, non-financial support from Novartis, non-financial support from BMS, non-financial support from MSD/Merck, non-financial support from GSK, non-financial support from Takeda, non-financial support from Blueprint Medicines, non-financial support from Roche Genentech, other from Amgen, outside the submitted work; A.D. reports personal fees from Roche, personal fees from Eli Lily, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from BMS, personal fees from Novartis, personal fees from Takeda, personal fees from Pharmamar, non-financial support from Abbvie, grants from BMS, grants from Amgen, outside the submitted work; A.V. reports advisory board of BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi, outside the submitted work.
All remaining authors declare no competing interests.
Acknowledgements
The authors thank all the oncology physicians and healthcare staff for their participation in the DOCC registry during this COVID-19 pandemic. They would like to thank S. Aammari and the Clinical Trial Center Rotterdam for the design and implementation of the study and S. Jeup for administrative support.
C.J. van Loenhout1, C.H. van der Leest2, A. Becker-Commissaris3, J.S.W. Borgers4, F. Terhegggen5, B.E.E.M. van den Borne6, L.J.C. van Warmerdam7, L. van Leeuwen8, F.S. van der Meer9, M.A. Tiemessen10, D.M. van Diepen10, Y. Klaver11, A.P. Hamberg12, E.J. Libourel13, L. Strobbe14, M. Cloos15, E.J. Geraedts16, J.C. Drooger17, R. Heller18, J.W.B. de Groot19, J.A. Stigt20, V.J.A.A. Nuij21, C.C.M. Pitz22, M. Slingerland23, F.J. Borm24, B.C.M. Haberkorn25, S.C. van ‘t Westeinde26, M.J.B. Aarts27, J.W.G. van Putten28, M. Youssef29, G.A. Cirkel30, G.J.M. Herder31, C.R. van Rooijen32, E. Citgez33, N.P. Barlo34, B.M.J. Scholtes35, R.H.T. Koornstra36, N.J.M. Claessens37, L.M. Faber38, C.H. Rikers39, R.A.W. van de Wetering40, G.L. Veurink41, B.W. Bouter42, I. Houtenbos43, M.P.L. Bard44, K.H. Herbschleb45, E.A. Kastelijn46, P. Brocken47, G. Douma48, M. Jalving49, T.J.N. Hiltermann50, O.C.J. Schuurbiers-Siebers51, K.P.M. Suijkerbuijk52, A.S.R. van Lindert53, A.J. van de Wouw54, V.E.M. van den Boogaart55, S.D. Bakker56, E. Looysen57, A.L. Peerdeman58, W.K. de Jong59, E.J.M. Siemerink60, A.J. Staal61, B. Franken62, W.H. van Geffen63, G.P. Bootsma.64
1Department of Pulmonology, Admiraal de Ruijter Hospital, Goes, the Netherlands; 2Department of Pulmonology, Amphia Hospital, Breda, the Netherlands; 3Department of Pulmonary Diseases, Cancer Center Amsterdam, Amsterdam Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; 4Department of Medical Oncology, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands; 5Department of Internal Medicine, Bravis Hospital, Bergen op Zoom, The Netherlands; 6Department of Pulmonary Diseases, Catharina Hospital, Eindhoven, Netherlands; 7Department of Internal Medicine, Catharina-Hospital, Eindhoven, The Netherlands; 8Department of Internal Medicine, Diakonessenhuis, Utrecht, The Netherlands; 9Department of Pulmonology, Diakonessenhuis, Utrecht, The Netherlands; 10Department of Pulmonology, Dijklander Hospital, Purmerend, The Netherlands; 11Department of Internal Medicine, Elisabeth-Tweesteden hospital, Tilburg, The Netherlands; 12Department of Oncology, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands; 13Department of Internal Medicine, Franciscus Hospital, Rotterdam, the Netherlands.; 14Department of Internal Medicine, Gelre Hospital, Zutphen, The Netherlands; 15Department of Internal Medicine, Groene Hart Hospital, Gouda, The Netherlands; 16Department of Pulmonology, Groene Hart Hospital, Gouda, The Netherlands; 17Department of Medical Oncology, Ikazia Hospital, Rotterdam, The Netherlands; 18Department of Pulmonology, Ikazia hospital, Rotterdam, The Netherlands; 19Department of Medical Oncology, Isala Oncology Center, Zwolle, The Netherlands; 20Department of Respiratory Medicine, Isala Hospital, Zwolle, The Netherlands; 21Department of Internal Medicine, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands; 22Department of Pulmonology, Laurentius Hospital, Roermond, The Netherlands; 23Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands; 24Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands; 25Department of Medical oncology, Maasstad Hospital, Rotterdam, The Netherlands; 26Department of Pulmonology, Maasstad Hospital, Rotterdam, The Netherlands; 27Department of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands; 28Department of Pulmonary Diseases, Martini Hospital, Groningen, The Netherlands; 29Department of Respiratory Medicine, Máxima Medical Centre, Veldhoven, The Netherlands; 30Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands; 31Department of Pulmonary Medicine, Meander Medical Center, Amersfoort, The Netherlands; 32Department of Internal Medicine, Medisch Spectrum Twente, Enschede, The Netherlands; 33Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede, The Netherlands; 34Department of Respiratory Medicine, Noordwest Ziekenhuisgroep, Alkmaar, the Netherlands; 35Department of Internal Medicine, Maasziekenhuis Pantein, Beugen, The Netherlands; 36Department of Internal Medicine, Rijnstate ziekenhuis, Arnhem, The Netherlands; 37Department of Respiratory Medicine, Rijnstate ziekenhuis, Arnhem, The Netherlands; 38Internal Medicine, Rode Kruis Hospital, Beverwijk, The Netherlands; 39Department of Pulmonology, Rode Kruis Hospital, Beverwijk, The Netherlands; 40Department of Internal Medicine, Slingeland Hospital, Doetinchem, The Netherlands; 41Department of Medical Oncology, Saxenburgh, Hardenberg, The Netherlands; 42Department of Pulmonology, Saxenburgh, Hardenberg, The Netherlands; 43Department of Internal Medicine, Spaarne Gasthuis, Haarlem, The Netherlands; 44Department of Pulmonology, Spaarne Gasthuis, Haarlem, The Netherlands; 45Department of Internal Medicine, St. Antonius Hospital Utrecht/Nieuwegein, Utrecht, The Netherlands; 46Department of Pulmonology, St. Antonius Hospital Utrecht/Nieuwegein, Utrecht, The Netherlands; 47Department of Pulmonary Diseases, Haga Ziekenhuis, den Haag, The Netherlands; 48Department of Pulmonary Diseases, Treant Zorggroep, Scheper hospital, Emmen, The Netherlands; 49Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 50Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 51Department of Pulmonary Diseases, Radboud university medical center, Nijmegen, The Netherlands; 52Department of Medical Oncology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands; 53Department of Respiratory Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands; 54Department of Internal Medicine, VieCuri Medical Center, Venlo, The Netherlands; 55Department of Respiratory Medicine, VieCuri Medical Center Venlo, The Netherlands; 56Department of Internal Medicine, Zaans Medical Center, Zaandam, The Netherlands; 57Department of Pulmonology, Zaans Medical Center, Zaandam, The Netherlands; 58Department of Internal Medicine, Bernhoven, Uden, The Netherlands; 59Department of Pulmonology, Hospital Gelderse Vallei, Ede, The Netherlands; 60Department of Internal Medicine, Ziekenhuis Groep Twente (ZGT), Hengelo, The Netherlands; 61Department of Pulmonary Diseases, ZGT Almelo/Hengelo, Hengelo, The Netherlands; 62Department of Hematology, Medical Center Leeuwarden, Leeuwarden, The Netherlands; 63Department of Respiratory Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands; 64Department of Pulmonology, Zuyderland Medical Center, Heerlen, The Netherlands.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
This study was supported by a grant from the Dutch Cancer Society, a non-profit organisation. The Dutch Cancer Society had no role in study design, data collection, data analysis, data interpretation or writing of the report.
Author contributions
K.J., D.D., J.T., H.W., L.B., F.B., P.M., N.D., O.V., E.O., H.B., H.L., L.H., J.H., E.V., A.D. and A.V. have contributed to the design of the study. All authors except for E.O. contributed to data collection. K.J., D.D., A.D., A.V. have contributed to literature search, data analysis, data interpretation and writing of the manuscript. D.D., P.M. and A.V. have checked all clinical data for inconsistencies. K.J. and E.O. have contributed to statistical analysis of the data. K.J., D.D., J.T., H.W., L.B., F.B., P.M., N.D., O.V., E.O., H.B., H.L., L.H., J.H., E.V., A.D. and A.V. participated in drafting the article and revising it critically for important intellectual content. All authors reviewed the manuscript and have given final approval of the submitted version.
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