One-Year and Consequences of COVID-19 in Cancer Patients: a Cohort Study

The study aim was to investigate one-year all-cause mortality and health consequences of cancer COVID-19 patients in China, stratied by primary tumor subtype. In this multicenter cohort study, 166 cancer COVID-19 patients were studied along with 498 gender- and age-matched non-cancer COVID-19 patients in four hospitals in Wuhan, China, admitted 2020/01/01-2020/03/18, as well as with 498 parallel gender-, age-, and cancer subtype- matched non-COVID cancer patients hospitalized between 2019/01/01-2020/03/17. All patients were followed-up with a telephone survey to assess health consequences. Cox proportional hazards regression were used for risk analysis.

thyroid, breast, female genital, genitourinary tumor had low risk mortality which was similar to non-cancer patients.

Background
As of 30 March 2021, the number of COVID-19 cases and deaths continued to rise with 127.3 million cumulative cases and 2.8 million deaths globally [1]. The global cancer burden is estimated to have risen to 19.3 million new cases and 10.0 million deaths in 2020 [2]. Initial reports suggested that patients with active malignancy might be at increased risk of contracting SARS-CoV-2 and have an increasing risk of short-term mortality [3][4][5][6].
However, these initial reports were restricted by follow-up time [6]. As some patients remained hospitalized for some time, longer-term follow-up is needed to better understand the effect of COVID-19 on outcomes in cancer patients[6, 3,7]. Cancer encompasses a diverse array of primary tumor subtypes with different outcomes [8,9]. To the best of our knowledge, there are no reports to study long-term prognostic of cancer patients with COVID-19, and few studies comparing them with cancer patients without COVID-19, and with different tumor subtypes.
To address this knowledge gap, we compared 166 cancer patients with COVID-19 with 498 COVID-19 patients without cancer, and with 498 cancer patients without COVID-19 from 4 hospitals in Wuhan, a China 'hot spot' of COVID-19. All survival patients were followed up for at least 12 months post hospital admission.

Study Design and Patients
In this multicenter ambidirectional comparative cohort study, we enrolled sequential cancer patients who were admitted with COVID-19 (Cancer COVID-19 Cohort) to the four hospitals in Hubei Province, China, the epicenter of the rst COVID-19 outbreak, between January 1, 2020, and March 18, 2020 (Supplementary Table 1). Eligibility criteria for enrollment were laboratory con rmation of SARS-CoV-2 virus infection by RT-PCR test and hospitalized patients with active cancer (Supplementary Table 2). COVID-19 disease severity was de ned according to WHO guidelines [10]. Primary tumor subtypes were classi ed by the World Health Organization (WHO) Classi cation of Tumors series [11]. Each Cancer COVID-19 patient was matched in a 1:3 ratio based on age (± 5 years) and sex, to a comparator patient without cancer from the same COVID-19-positive population (COVID-19 Cohort). Another parallel comparator patient served as uninfected controls were chosen in a 1:3 ratio with age (± 5 years), gender, and cancer subtype, from cancer patients admitted to the same four hospitals between January 1, 2019 and March 17, 2020. All data were de-identi ed. This study was done in accordance with the STROBE statement [12].

Study Variables and Outcomes
We de ne the acute phase as the time between symptom onset and hospital discharge. Data were collected on site by trained coordinators manually reviewing the electronic medical records and importing into a secure online database using a standardized case report form (Supplementary Case Report Form).
Demographic characteristics, coexisting conditions, presenting symptoms, vital signs, biochemical nding, treatment practices, and a variety of hospital outcome data were collected. To ensure enrollment of an unbiased population, the consecutive eligible patients were recruited from each site from Jan 1, 2020, to March 17, 2020.
All survivors who had discharged from hospital were selected onto follow-up study to observe their health consequences in recovery from COVID-19 (Supplementary Follow-Up Studies). Some patients were done follow-up interview in outpatient clinic and asked to complete a series of questionnaires. We followed up patients until death, or February 18, 2021, whichever came rst.
The primary outcomes included the 1-year all-cause mortality rate, sequelae. Secondary outcomes variables included: the hospital mortality rate, the length of hospital stay, and the 12-month all-cause post-discharge mortality rate.

Statistical Analysis
We aimed to generate a representative sample of cancer patients with COVID-19 by starting with at least 5,500 patients with COVID-19 and 38335 cancer patients from the four hospitals ( Supplementary Fig. 1).
To describe baseline characteristics, treatment, and outcome, we prespeci ed the following covariates for inclusion in the models. Continuous variables were presented as median and interquartile range [IQR] while categorical variables presented as number (percentage).

Twelve-Month Post-Discharge Mortality
Median follow-up of cancer COVID-19 patients from the point of hospital discharged was11.2 (IQR10.8-11.6) months among who were discharged alive (Table 3 and Figure 1B).

Discussion
To our knowledge, this study represents the longest follow-up on mortality and the health consequences of hospitalized cancer patients with COVID-19. One-year mortality (30%) among Cancer COVID-19 Cohort was nearly 2 times of Cancer Cohort (16%) and more than 3 times of COVID-19 Cohort (9%), even slightly higher than them combined. Compared with the COVID-19 Cohort, patients with hematologic, brain, nasopharyngeal, digestive system, and lung malignancies showed a signi cantly high risk of mortality.
While patients with breast and endocrine, genitourinary and female genital tumors showed moderate risk mortality just similar with the COVID-19 Cohort As it was di cult to determine if COVID-19 was the direct cause of death for a patient, or the death was inevitably caused by a terminal event for a patient who was approaching the end of the cancer care, we are reporting the all-cause case fatality rate. All COVID-19 patients in our cohort had nished their clinical course. The hospital mortality among the Cancer COVID-19 Cohort was 20%, which was 2.5 times of the COVID-19 Cohort (8%) and was higher than the Cancer Cohort (2% We found that at 12 months after hospital admission, 23% cancer COVID-19 patients endorsed at least one symptom, which had similar risk with 30% of COVID-19 Cohort. Cough (9%) or dyspnea (8%) were common among Cancer COVID-19 Cohort, while fatigue (12%) or chest congestion (9%) were common in COVID-19 Cohort. Huang and colleagues found that Fatigue or muscle weakness (63%) were the most common symptoms in a 6-month follow-up survey of 1733 COVID-19 patients [17]. A 3-month follow-up survey of 538 COVID-19 patients reported that Fatigue (28%) were the most common symptoms in [18]. Interesting, we found that fatigue, depression or anxiety, and chest congestion were more common in COVID-19 Cohort than Cancer COVID-19 Cohort.
Many of the predictive risk factors for mortality in the Cancer COVID-19 Cohort were similar to data reported among all patients with COVID-19 [19]. In the adjusted Cox proportional hazards model, we observed signi cant associations of death from COVID-19 patients with chronic diseases including hypertension, diabetes, hyperuricemia, COPD, cardiovascular disease, and cerebrovascular disease [20,21]. Serologic predictors in our dataset predictive for mortality included anemia at the time of infection, and elevated LDH, D-dimer, and lactic acid, which correlated with available data from all COVID-19 patients [22].

Limitation
This study has several limitations. First of all, this study population only included hospitalized COVID-19 patients within Hubei Province, China, therefore, the cohort might not exactly represent all cancer patient population, such as patients who were on end-of-life care and/or residing in nursing homes, which may potentially bias our study to more severe cases of COVID-19. Secondly, our Cancer Cohort were admitted into hospital for active cancer during a different time frame (01/01/2019-03/17/2020) from the COVID-19 Cohorts (01/01/2020-03/17/2020), the hospitals might be under different stress levels and operation modes during these two time frames, although it shouldn't affect the patient care signi cantly. Nonetheless it would be desired to use contemporaneous control groups when these data become available. Lastly it would be ideal to have cancer stages identi ed and matched between cohorts in addition to the cancer subtypes. However, the cancer staging information required extensive manual review and veri cations, eventually becoming prohibitively time-consuming and technically di cult for the involved COVID-19 clinicians to collect and con rm on, especially on the deceased patients. Also the sample size of strati ed populations would be too limited to be meaningful. Hopefully our larger sample size of controls compensates some of the potential skews.

Conclusion
Our data showed a signi cant increase in mortality among cancer patients with COVID-19, especially in higher risk group, patients with hematologic, brain, nasopharyngeal, digestive system and lung malignancies. It supports that, as an acute respiratory infectious disease, COVID-19 brings a high risk on cancer patients in the acute phase of the disease, but it probably does not affect the long-term prognosis of patients after they are discharged from hospital.

Declarations
Ethics approval and consent to participate The study was approved by the Institutional Ethics Committee of Union Hospital (2021-0005-01) and Institutional Ethics Committee of the Central Hospital of Wuhan (2020-7), Tongji Medical College, Huazhong University of Science and Technology. The data used were de-identi ed. No reference has been made at any point to individually identi able data. All of the data used in this study come from Wuhan Union Hospital and its a liated hospitals and the Central Hospital of Wuhan.

Consent for publication
Not applicable.

Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available due Data Protection Laws and Regulations in China but are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This work was supported by grants from the Natural Science Foundation of Hubei Province, China (2020CFB804 to Z. T.).

Role of the funder
The funder had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.

Conflicts of interests
All authors declare no potential con icts of interests.
Availability of data and material The data underlying this article cannot be shared publicly because subsequent follow-up investigations for COVID-19 are in progress. The data will be shared on reasonable request to the corresponding author.

Supplementary Files
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