Cancer patients with COVID-19: a retrospective study of 51 patients in the district of Piacenza, Northern Italy

Background: Cancer patients are considered a highly fragile group in the current coronavirus disease 2019 (COVID-19) pandemic. Material & methods: In this study, patients with COVID-19 and cancer, hospitalized in Piacenza, Italy, from 4 April to 4 May 2020 were included. Risk factors for death were analyzed. Results: Fifty-one COVID-19 cancer patients were included, of which the median age was 71.02 years (range: 51–86) and 70.59% were male. Cancer types included gastrointestinal (25.49%), genitourinary (25.49%) and lung (23.53%). Forty-five (88.24%) patients received hydroxychloroquine-based therapy. In addition, 25 of 51 patients died (49%): 12 of 51 (23.53%) owing to cancer and 13 of 51 (25.49%) owing to COVID-19. Conclusion: The risks for death were related to later onset of treatment for COVID-19, severe/critical COVID-19, age, elevated basal CRP and elevated lactate dehydrogenase.

However, the district of Piacenza in the Emilia Romagna Region is very near to the epicenter of the outbreak of COVID-19 in Italy (10 min by car); the catastrophic nature of that North Italy outbreak has been widely publicized [9,10]. Many oncology patients coming from the epicenter of the outbreak of COVID-19 were actively receiving treatment at the oncologic department of the hospital of Piacenza. We recently reported the first 25 cancer patients complicated with COVID-19 [11], and the aims of the present study are to collect the medical information of an additional 51 cancer patients with COVID-19 admitted to the hospitals within the district of Piacenza and to report the clinical characteristics and outcome of these patients. Thus, the total number of cancer patients with COVID-19 hospitalized between 21 February and 4 May 2020 in the district of Piacenza is 76 cases. We report clinical and laboratory data such as CRP and LDH values that could have prognostic significance [12,13]. After all, data on cancer patients and COVID-19 in western countries are still fragmentary and sometimes contradictory [11,[14][15][16]; thus, we believe that more information is likely to be helpful in improving the management of these patients.

Patients
We conducted this retrospective study at the three hospitals of the district of Piacenza, Emilia Romagna Region, North Italy. We reviewed the medical records of 973 patients with COVID-19 hospitalized between 4 April 2020 and 4 May 2020; we retrieved a total of 51 cancer cases (5.24%). In all of these patients the COVID-19 infection was diagnosed with laboratory-confirmed SARS-CoV-2 infection, with reverse-transcription PCR in nasopharyngeal swabs. The medical records of patients were analyzed by a team of oncologists, and data were obtained with data collection forms from electronic medical records and included demographic and clinical features, laboratory findings and chest radiological images. The COVID-19 severity was divided into two groups: mild/moderate and severe/critical in accordance with the diagnosis and treatment of COVID-19 guidelines of China [17]. The severe/critical group included patients with respiratory illness defined as an oxygen saturation of 94% or less while they were breathing ambient air, or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mmHg that required oxygen treatment [18].

Statistical analysis
Continuous variables were presented by mean values ± standard deviation, and categorical ones were presented by percentages. Categorical variables were analyzed using the chi-square test or Fisher's exact test, and continuous variables were analyzed using Student's t-test or the Mann-Whitney test. Variables were included in a univariate Cox analysis using R language with packages 'survival' and 'survminer'. For all Cox regression models, we tested for evidence against the proportional hazard assumption on the basis of Schoenfeld residuals after fitting a model with Cox regression. The results of this regression analyses were reported as hazard ratio (HR) with 95% CI. Time to mortality was analyzed using Kaplan-Meier survival analysis, and the log-rank test was used for comparison between the two groups. A p < 0.05 was considered statistically significant. The Rstudio-1.2.1335 program was used for the analysis.

Laboratory tests
Nasopharyngeal swab specimens were collected and analyzed with the PCR result according to CDC guidelines [19].
Diagnostic kits for IgM antibodies to Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila was used for detecting three kinds of common respiratory pathogens. Other laboratory tests were part of the standard performed during hospitalization (lymphocytes, CRP, LDH, blood count with formula and platelets, liver, kidney analysis). ECG was performed in all patients, and echocardiogram was performed when required. All patients received radiological evaluation of the chest by x-ray or computed tomography.

Treatment
Hydroxychloroquine with or without antiviral treatment has been incorporated in our regional guideline to treat COVID-19 [11,20].
Three physicians (L Cavanna, I Toscani, M Ambroggi) independently reviewed the data. The study was approved by the Local Ethics Committee of Area Vasta Emila Romagna (institutional review board approval number 494/2020/OSS*/AUSLPC).

Discussion
The clinical characteristics of 51 cancer patients with laboratory-confirmed COVID-19 from three hospitals in the district of Piacenza (Italy) are described.
The complex care of cancer patients requiring multidisciplinary approaches with surgery, chemotherapy, targeted therapy, immunotherapy and radiation during the COVID-19 pandemic poses unprecedent ed challenges. Oncologists, in addition to caring for cancer patients, must also protect patients and their caregivers from unnecessary exposure [21]. It has been reported from China that approximately 1% of patients infected with COVID-19 had cancer, and it was five-times higher than the general incidence in China [22]. In addition, a report from Italy provides evidence that approximately 20% of deceased patients with COVID-19 had a cancer in the past 5 years [15]. We recently reported a small series of 25 cancer patients and COVID-19 [11]. All of these 25 patients showed fever,     of cancer patients with COVID-19 were severe/critical cases; this percentage is higher than in the general population, and it is well known that the mortality rate is higher in patients with severe/critical COVID-19. However, the mortality rate of patients with COVID-19 and cancer versus patients without cancer is still controversial, as reported previously [24]. In our study, the medical records of 973 patients with COVID-19 admitted to the hospitals of Piacenza were reviewed and 51 cases with cancer were retrieved (5.24%). This infection rate of COVID-19 in our series of cancer patients is much higher than the general population, as reported previously [22,23,[25][26][27]. It must be emphasized that Italy was the first country in Europe to experience an outbreak of COVID-19, and the city of Piacenza is very near to the epicenter of the Lombardy outbreak (only 10 min by car). In our series, the median age of patients with cancer and COVID-19 was higher when compared with other reported series: 71.02 years (range: 50-86) versus 63 years (range: 56-70) [26] or 65 years (range: 34-98) [23]. It is well known that cancer patients may be susceptible to infection during the COVID-19 pandemic secondary to their impaired immune function [23]. However, it must be emphasized that it has been reported that cancers such as colon, breast and lung cancer do not typically cause immune suppression that is not treatment related [27]. The main symptoms of our patients were fever 38 • C or higher (100%), dyspnea (70.59%) cough and fatigue (33.33%) that were similar to those of previous reports and of the general population infected by COVID-19 [26]. Among the 51 cancer patients with COVID-19, the main sites of cancer were gastrointestinal (25.49%) and genitourinary (25.49%), followed by lung (23.53%), then breast and undefined origin (7.8%) and hematological (9.8%) cancers. Thirty-eight of 51 patients (74.51%) showed comorbidities, with hypertension being the most common in 34 of 51 patients (66.67%), followed by diabetes in 12 of 51 patients (23.53%) and chronic obstructive pulmonary disease in 11 of 51 cases (21.57%); those data are similar to the previous report [23]. Comorbidities seem to play an important role in the prognosis of cancer patients with COVID; in fact, 84% of our patients who died had one or more comorbidities as reported previously [26]. The majority of patients were male. Thus, that could have contributed to the high death rate [28].
In a small series of 28 cancer patients with COVID-19, it was identified that recent anticancer treatment within 14 days of infection, such as chemotherapy, immunotherapy or radiation, was an independent predictor of death or other severe events with a HR greater than 4 [26].
However, in the largest multicenter studies, no interactions between anticancer treatment within 4 weeks prior to COVID-19 diagnosis and COVID-19-related mortality were found [29,30]. Our data are in agreement with these studies, since in our series 24 of 51 (47.06%) cancer patients received anticancer treatment within 4 weeks before testing positive for COVID-19, and no interaction was found in patients' outcome. However, more recent results presented at European Society for Medical Oncology (ESMO) by CCC19 have suggested that chemoimmunotherapy was associated with a high mortality rate [31].
Currently, there are no clinical data on the efficacy and safety of antiviral prophylaxis for COVID-19 in cancer patients and little is known about the treatment of COVID-19 in cancer patients [32].
Although no vaccine or specific antiviral treatment for COVID-19 has yet been demonstrated to be effective in Phase 3 randomized clinical trials, hydroxychloroquine with or without antiviral treatment has been incorporated in some national or regional guidelines to treat COVID-19 [11,20], and our patients with cancer were treated for COVID-19 as were noncancer COVID-19 patients, with hydroxychloroquine-based therapy [11,20].
Hydroxychloroquine has received worldwide attention as a potential treatment for COVID-19 because of positive results from some studies [33,34]. However, other studies do not support its use in patients admitted to the hospital with COVID-19 [35,36]. Moreover, recent positive research supports the use of dexamethasone in COVID-19 patients [37].

Conclusion & future perspective
In this retrospective study, we confirmed the well-known risk factors of death for cancer patients and COVID-19, such as advanced age, severe/critical type of COVID-19 and laboratory data (elevated CRP, LDH). In addition, we acknowledge some limitations to the study (retrospective study, small size, monoinstitutional study and the disparity between the type of cancers that our study included [most common were gastrointestinal, genitourinary and lung] versus the normal incidence of cancers) may indicate that this study may be not representative of the effects of COVID-19 on cancer. With the limitations of univariate analysis, we reported that treatment with hydroxychloroquine-based therapy was significantly associated with favorable outcome.
The COVID-19 outbreak is a major global public health pandemic, and it can have catastrophic consequences for cancer patients. We believe that physicians, caregivers and patients, while waiting for a vaccine, should research prevention, early diagnosis and therapeutic pragmatic approaches to improve cancer patient outcome. Oncologists, in addition to providing care for cancer patients, must also protect patients and their caregivers from unnecessary exposure, particularly considering that mortality from COVID-19 is greater in cancer patients than for patients without cancer.

Summary points
• Mortality for coronavirus disease 2019 (COVID-19) appears greater in cancer patients when compared with noncancer patients. • Cancer patients receiving anticancer treatment in the previous 4 weeks were not at an increased risk of mortality from COVID-19 when compared with patients not on active treatment. • High basal C-reactive protein and lactate dehydrogenase values showed an unfavorable prognostic role. • Mortality was driven by age (specifically older age) and severity of COVID-19: 90.91% of patients with mild/moderate type overcame COVID-19, whereas 60% with severe/critical COVID-19 died.

Acknowledgments
The authors dedicate this work to all of the patients who died in the district of Piacenza as a result of COVID-19.
Financial & competing interests disclosure L Cavanna holds a consulting or advisory role for AstraZeneca and Merck, and received travel and accommodation expenses from Celgene, Pfizer and Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research
The study was conducted in compliance with local ethic regulations, approved by the institutional ethics committee or audited by the review boards. This work is in line with the recommendations for biomedical research of the Declaration of Helsinki of the World Medical Association. Informed consent procedures were conducted according to local regulations, and patient data were anonymized. Each patient or legal representative signed an institutional informed consent in which he or she expressed his or her will to allow the use of clinical history data, diagnostic images, photographs and the publication of such information for research purposes.

Open access
This work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/