key: cord-0970330-01w038rb authors: Ali, Jamshed; Sajjad, Kashif; Rehman Farooqi, Amer; Tahir Aziz, Muhammad; Rahat, Ayesha; Khan, Sarah title: COVID-19 Positive Cancer Patients Undergoing Active Cancer Treatment: An Analysis of Clinical Features and Outcomes date: 2020-12-24 journal: Hematol Oncol Stem Cell Ther DOI: 10.1016/j.hemonc.2020.12.001 sha: 0452685fd9582b4b2fb62d3f76dafdf9c99f18b4 doc_id: 970330 cord_uid: 01w038rb Background Cancer patients particularly those on active anti-cancer treatment have been reported to be at a high risk of severe COVID-19 infection and deaths. This study aimed to describe the clinical characteristics and outcomes of patients diagnosed with COVID-19 whilst on anti-cancer treatment in a developing country. Methods This is a retrospective observational study of all adult cancer patients at SKMCH & RC Pakistan, from 15th March - 10th July,2020 diagnosed with COVID-19 within 4 weeks of receiving anti-cancer treatment, where a purposive sampling was carried out. Cancer Patients who did not receive anti-cancer treatment and clinical or radiological diagnosis of COVID-19 without a positive RT-PCR test were excluded. The primary endpoint was all-cause mortality after 30 days of COVID‐19 test. Data was analyzed through SPSS version 23. Categorical parameters were computed using Chi-Square test, keeping p-value <0.05 as significant. Results A total of 201 cancer patients with COVID‐19 were analyzed. The median age of patients was 45 (18-78) years. Mild symptoms were present in 162(80.6%) patients and 39(19.4%) had severe symptoms. The risk of death was statistically significant (p-value <0.05) amongst patients above 50 years of age, with metastatic disease and on palliative anti-cancer treatment. Anti-cancer treatment (chemotherapy, radiotherapy, hormonal therapy, targeted therapy and surgery) recieved within preceding 4 weeks, had no statistically significant (p-value >0.05) impact on mortality. Conclusion In cancer patients with COVID-19, mortality appears to be principally driven by age, advanced stage of the disease and palliative intent of cancer treatment. We did not identify evidence that cancer patients on chemotherapy are at significant risk of mortality from COVID-19 correlating to those not on chemotherapy. Individuals with a background of cancer have been identified to be at high risk of severe infection. The case fatality rate amongst the cancer patients has previously been shown to be almost double than the normal population at 5.6%. 1 Moreover, this is assumed that the risk of mortality is further amplified if the cancer patients are on active anti-cancer therapy. A st udy from China has established an increased risk of severe infection and poorer outcomes in cancer patients. 2 In the UK Coronavirus Cancer Monitoring Project (UKCCMP), COVID-19 positive Cancer patients with advanced age and comorbidities had a significantly higher mortality. 3 This study did not reveal a significant impact of cancer treatment on mortality. Another European study revealed Karnofsky performance status <60, relapsed cancer, male gender and respiratory manifestations as selfreliant risk factors for death in patients that are on active anti-cancer treatment. 4 The above studies described the impact of COVID-19 infection in cancer patients on active anti-cancer treatment, but all these studies are from developed countries. This correlation has not been studied in low and middleincome countries. This study PakOncCovid19(POC19) is the first study in Pakistan, which evaluated the clinical features and outcomes of cancer patients, who were diagnosed as COVID-19 within 4 weeks of anti-cancer treatment. We also focused on identifying the possible risk factors in these patients which can lead to complications or death. This will aid in early recognition and timely management of the COVID-19 positive patients, who are on active anti-cancer treatment. The study population includes all adult patients who received cancer treatment within 4 weeks of COVID-19 diagnosis, selected through non-probability purposive sampling. We evaluated all histologically confirmed cancer patients, who became COVID-19 positive from 15th March till 10th July, 2020. The active anti-cancer treatment includes chemotherapy, targeted therapy, radiotherapy, hormonal therapy and cancer-related surgery. We have excluded the patients not undergoing active cancer treatment, and COVID-19 suspected patients based on radiological or clinical suspicion with a negative RT-PCR. The primary outcome of our study was 30-day all-cause mortality. The study variables included age, gender, indications for COVID-19 testing (COVID-19 symptoms, pre-procedure screening and incidental radiological finding confirmed with RT-PCR), primary cancer status (primary site localized, primary site advanced, and metastatic), type of malignancy (solid and haematological), the intent of treatment (palliative, curative) and severity of COVID-19 infection (mild/severe course). We defined primary cancer as localized where the solid organ tumor was deemed surgically resectable. Primary cancer advanced was defined as the primary tumor not being suitable for complete resection and metastatic cancer was a tumor with distant metastasis. The intent of anti-cancer treatment was defined as palliative where the intent was disease control, whereas curative anticancer treatment included radical intent involving surgery, neoadjuvant and adjuvant treatment modalities. The severity of the clinical course was divided into mild and severe. We modified the national criteria for the severity of the clinical course to ascertain the patient groups. 5 The patients diagnosed as mild COVID-19 infection were either asymptomatic or had symptoms with oxygen saturation of ≥94% on room air at the time of diagnosis. The severe group was the patients with oxygen saturation of ≤ 93% on room air, septic shock or any organ failure requiring treatment in the intensive care unit. The analysis was done through SPSS Version 23. Chi-square test was applied using severity (mild and severe) and outcome (recovered and death) as dependent variables to see their association with different demographics (age and gender) and clinical characteristics like type of anti-cancer treatment, the intent of treatment, stage at presentation, the severity of symptoms of COVID-19 and presence of comorbidities. The significance level was demarcated as a two-tailed p-value <0.05. The OS was updated as of 10th August 2020, follow up calls were made after 30 days of the initial presentation of each cancer patient with COVID-19 infection. A total of 510 cancer patients diagnosed with COVID-19 were reviewed at SKMCH & RC Pakistan from 15th March till 10th July, 2020. We identified 201 cancer patients infected with COVID-19 and receiving active cancer treatment. The median age of the patients was 45 years, ranging from 18 to 78 years. This includes 86(42.8%) males and 115(57.2%) females, with 162(80.6%) mild cases and 39(19.4%) severe cases. As shown in figure-1, the majority of the patients 145(72.1%) were symptomatic with COVID-19 infection, 48(23.9%) patients were found to be COVID-19 positive on pre-procedure screening and 8(4.0%) patients were tested positive on RT-PCR for COVID-19 after they were found to have incidental radiological features suggestive of COVID-19. The breakdown of active cancer treatment patients included in the study is as follows; chemotherapy 146 (72.6%), hormonal therapy 18(9.0%), radiation therapy 13(6.5%), cancer-related surgical treatment 22(10.9%) and targeted agents 2(1.0%). The Breast Cancer 74(36.8%) was the most common cancer, followed by Gastrointestinal Cancer 28(13.9%), Genitourinary Cancer 21(10.4%) and others (see Table 1 ). Haematological cancer was present in 33(16.4%) and 168(83.6%) patients had solid malignancy. There were 137(68.2%) patients with localized cancer, 20(10.0%) with locally advanced cancer and 44(21.9%) with metastatic disease. The most common COVID-19 related symptoms were: fever 104(51.7%), cough 67(33.3%) and shortness of breath 24(11.9%). Comorbidities were observed in 52 patients and hypertension was the most common comorbidity present in 44 patients, followed by diabetes in 10 patients. While 4 patients had hypertension along with diabetes and ischemic heart disease in 2 patients. All patient outcomes (dead or recovered) were updated after 30 days of their initial presentation with COVID-19 infection. None of the patient was lost to follow up. As shown in Table- The mortality was statistically significant (p-value < 0.05) in patients who were above 50 years of age as compared to the patients with 50 years or below, as shown in table 3. The overall mortality was 10/55 patients (18.2 %) in those cancer patients who were above 50 years of age and 6 /146 patients (4.1 %) below the age of 50 years. There were a total of 16 deaths out of which 12 patients were post-chemotherapy, 2 patients were on hormonal therapy and 2 patients who received radiotherapy in a period of 4 weeks of their COVID-19 detection. No case of fatality was reported in patients who had cancer-related surgery or targeted anticancer therapy. Most of the deceased patients 8/44 (18.2%) had metastatic disease, followed by locally advanced 3/20 (15.0%) and only 5/137 (3.65%) patients in the localized group. As compared to the patients who had localized disease, mortality was statistically significant (p-value <0.05) in the patients who had locally advanced and metastatic disease. Mortality was also statistically significant (p-value <0.05) among the patients with severe COVID-19 infection at presentation and who were on palliative intent anti-cancer treatment. Of all those COVID-19 positive cancer patients, 7/161 (4.3%) patients who died received curative anticancer treatments and 9/40 (22.5%) patients received palliative treatment. The type of anti-cancer treatment received with in preceding 4 weeks of COVID 19 infection was not statistically significant on the severity of the disease (p-value > 0.05). Patients with cancer and particularly those on active cancer treatment are at a greater risk for a severe form of COVID-19 infection, due to their immunosuppression. 6 In Pakistani population, the mortality from COVID-19 is between 2-3%. 5 The worldwide COVID-19 related mortality is much higher in cancer population. 7 To the best of our knowledge, POC19 is the first retrospective observational study and this is also the largest study from a developing country to describe the clinical features and outcomes in cancer patients who received anti-cancer treatment within the preceding 4 weeks of COVID-19 diagnosis. In a cohort study of patients from Wuhan, China, with COVID-19, the risk of severe disease was more than three times higher amongst the 230 patients with cancer compared with matched controls. 2 Furthermore, the course of COVID-19 is much more severe in cancer patients on active cancer treatment. 3 This study showed a similar percentage of severe infection in cancer patients with COVID-19, as described in previously observed studies. The majority of patients in our study were less than 50 years of age, which is a characteristic feature of the cancer population in Pakistan 8 . A 10-year data of breast cancer patients from Pakistan highlighted the age of presentation being one and a half decade earlier in Pakistan as compared to the developed countries 9 . Similar trend was shown in oral cavity cancer and in colonic cancer 10, 8 . In COVID19 disease, age has been an important determinant of mortality, as shown in a Meta-analysis of 611,583 patients, with exponential increase in mortality after 50 years of age 11 The old age is a significant independent risk factor of mortality in COVID-19 patients. 12 This fact could be influenced by both the physiological ageing process and comorbidities that contribute to a higher risk of complications from COVID-19 infection. 13 It was also established that the age above 50 was an independent risk factor for increased fatality and severity of COVID-19 infection. A meta-analysis of data from four retrospective studies concluded that the patients who received active anti-cancer treatment within two to four weeks of developing COVID-19 were associated with a nearly fourfold increased rate of in-hospital death compared with not having received such treatment. 14 The mortality can be up to 20% in cancer patients with COVID19 in this meta-analysis. The Moratlity in UKCCMP is 27% in COVID 19 positive cancer patients on active treatment 3 . A unique aspect of our results is the lower mortality as compared to the above mentioned studies and this difference in mortality can be attributed to the younger age of cancer onset in Pakistan.Being a developing country, we also faced the issue of limited resources along with shortage of other supportive treatment modalities for covid 19, such as oxygen, antibiotics and availability of the latest trial drugs like Tocilizumab and Remedesivir. Accumulating data suggest that the likelihood of COVID-19 related severe illness and death is higher among the cancer patients with metastatic disease. The study by Souad et al showed an increased risk of mortality in metastatic and relapsed cancer patients with COVID-19. 4 The majority of cancer patients who died in our study also had locally advanced and metastatic disease and this difference was statistically significant in comparison to the patients who had localized disease at the time of diagnosis of COVID-19. In our study, there were 30 patients with severe and 116 with mild COVID-19 infection who received chemotherapy in the preceding 4 weeks. There were 12 deaths observed in the chemotherapy group with severe infection, while 18 patients recovered within the 30 days of the study period. In an analysis of international COVID-19 and Cancer Consortium registry data on over 900 patients with active malignancy who were diagnosed with COVID-19 infection over one month, the use of anti-cancer therapy within four weeks of infection was not related with higher 30-day mortality rates. 7 These results were supported by another analysis of UKCCMP registery of patients with active cancer and symptomatic COVID-19 infection. 3 In this study, it is also concluded that cytotoxic chemotherapy which is given 4 weeks prior to COVID-19 diagnosis is not a statistically substantial contributor to more severe disease or a predictor of death from COVID-19 infection, when correlated with patients having cancer who have not received chemotherapy in that period. Therefore, it is ideal to individualize decisions regarding anticancer therapy amidst COVID-19 pandemic, taking into account factors such as the curability of cancer, the risks of progression with treatment delay, and the local incidence of COVID-19 and availability of resources. We found that 52 out of 201 patients having cancer had comorbidities, with 41 patients in the mild group and 11 in the severe group. One or more comorbidities were observed in 9 severe patients who died. There was no significant statistical difference in deaths among the patients who had comorbidities in comparison to the patients who did not have comorbidties. There were some limitations in this study, as this was a retrospective analysis based on an observational design without a control group, also a limited number of patients received COVID-19 targetted therapies, hence its difficult to accurately comment about its impact on patient's outcome. We included only RT-PCR positive patients, which can exclude a significant number of patients due to false-negative results. Identifying the characteristics of patients having cancer with COVID-19 infection are at risk of a severe complication or death and would be convenient to come up with definitive precautionary measures and also to adapt to clinical trials. Further studies are needed to determine the optimal screening frequency for patients undergoing anticancer therapy cycles. Mortality rate in COVID-19 cancer patients at 30 days is higher amongst the patients with additional risk factors such as old age, metastatic disease and palliative intent anti-cancer treatment received in preceding 4 weeks of COVID-19 infection. Our study did not reveal higher COVID-19 related mortality in cancer patients undergoing active anticancer treatment in a developing country, comparable to existing evidence from developed countries, despite limited resources. Further studies dedicated to cancer patients on active cancer treatment will add in defining the future until preventive treatments, such as a vaccine, have been found. 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Asian Pacific J Cancer Prev Oral cavity cancer in developed and in developing countries: Population-based incidence. Head Neck The Effect of Age on Mortality in Patients With COVID-19: A Meta-Analysis With 611,583 Subjects Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Geriatric assessment for oncologists Poor clinical outcomes for patients with cancer during the COVID-19 pandemic LA=Locally advanced, yrs.=Years *No Chemotherapy=Radiation therapy, Hormonal therapy Metastatic=Locally advanced and metastatic deceased patient are