Impact of Hesitancy on Cancer Care and COVID-19: Comparison
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Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Damian Abel Laber.

The COVID-19 pandemic disrupted the optimal management of outpatient appointments, scheduled treatments, and hospitalizations for cancer patients because of hesitancy among patients and health-care providers. Travel restrictions and other factors likely affected medical, surgical, and radiation treatments during the COVID-19 pandemic. Cancer patients were more likely to be affected by severe illness and complications if they contracted COVID-19. A compromised immune system and comorbidities in cancer patients may have contributed to this increased risk. Hesitancy or reluctance to receive appropriate therapy or vaccination advice might have played a major role for cancer patients, resulting in health-care deficits. 

  • COVID-19
  • cancer
  • hesitancy
  • management
  • treatment

1. COVID-19 and Cancer

Patients with cancer and other immunocompromised states were considered susceptible to COVID-19 infection. The diagnosis of COVID-19 in 1% of 1590 patients with cancer was much higher than the incidence of COVID-19 (0.29% per 100,000 people) in the historical control [2][1]. Patients with cancer were found to have a fatality rate of 5.6% according to COVID-19 outcome data. According to records obtained from the Public Health England National Cancer Registration and Analysis Service, patients with stage II or III bladder, lung, esophagus, ovary, liver, pancreas and stomach cancers with COVID-19 infection experienced a >30% reduction in survival at 6 months and a >17% reduction in survival at 3 months [9][2]. The Chinese Center for Disease Control and Prevention described the epidemiological characteristics of 72,314 COVID-19 cases in mainland China as of February 11, 2020. They reported that 107 patients (0.5%) had cancer, and 6 of them died. The case fatality was 5.6%, which is higher than the overall reported case fatality (2.3%) from COVID-19 [2][1]. In a retrospective study of 1253 patients with cancer, the all-cause 30-day mortality was 2.4%, 38.3% and 69.4% in patients with mild, moderate, and severe COVID-19, respectively. COVID-19 was mild in 81% of patients, moderate in 13%, and severe in 6%. The severity of COVID-19 or death was independently associated with increasing age, smoking history, concurrent comorbidities, and palliative intent of treatment [10][3]. In a study of 128 hospitalized patients with hematological cancers in Wuhan, there was a 10% incidence of COVID-19, significantly higher than the 1% incidence reported for patients with other cancers [11][4].
During the COVID-19 pandemic, patients with cancer had a higher mortality rate. In a systematic review and meta-analysis of 22 studies that evaluated the prevalence of cancer among patients infected with COVID-19, cancer patients were found to have a higher risk of severe/critical COVID-19 disease, mortality, ICU admission, and mechanical ventilation [12][5]. A multicenter study of patients with cancer and COVID-19 reported a nearly three-fold increase in the death rate compared to COVID-19 patients without cancer, and patients with cancer also had a much higher severity of illness [13][6]. There were 9385 deaths reported in New York State in April 2020 from COVID-19. Out of these individuals, cancer patients comprised 8.4% [14][7]. There was a higher overall case-fatality rate reported in Italy (7.2%) than in China (2.3%) [15][8]. In another systematic review of 52 studies involving 18,650 patients with COVID-19 and cancer, there were 4243 deaths recorded in this population, with a mortality rate of 25.6% [16][9].
However, in a study by Mehta et al., out of 3101 cancer patients who were admitted to the hospital, 186 of them tested positive for COVID-19 and the mortality rate was 14.52%. A univariate analysis showed that the risk of death was significantly associated with the presence of comorbidities, especially diabetes and cardiovascular diseases. Anticancer treatments, including chemotherapy, surgery, radiotherapy, targeted therapy, and immunotherapy, administered within a month before the onset of COVID-19 symptoms had no significant effect on mortality [17][10]. An analysis of 1590 patients studied in 570 Wuhan hospitals showed that COVID-19 infections occurred in 12 patients who had recovered from their previous cancer. It was concluded that COVID-19 is a highly contagious infection for everyone, and cancer survivors are not particularly prone to this infection [2][1]. Other comorbidities, including age, may skew the incidence of COVID-19 in cancer patients. The median age was 63.1 years in cancer patients versus 48.7 years in subjects without cancer [18][11]. A study of 890 patients diagnosed with COVID-19 and cancer revealed a mortality rate of 33.6%. This was influenced by the male gender, age 65 or older, and comorbidities. There was no worsening of COVID-19 severity or mortality because of chemotherapy, targeted therapy, or immunotherapy [19][12]. In a racially diverse group of 27 patients with breast cancer and COVID-19, the majority (74%) did not require hospitalization unless there were multiple co-morbidities [20][13]. In a prospective study of 800 patients with a diagnosis of cancer and symptomatic COVID-19, there was no significant effect on mortality found for patients with immunotherapy, hormonal therapy, targeted therapy and radiotherapy used within the previous 4 weeks. Mortality from COVID-19 in cancer patients was found to be principally driven by age, gender, and comorbidities [21][14].

2. Cancer, Immune Dysregulation, and Susceptibility to COVID-19 Infection

Cancer patients’ morbidity and mortality increased due to the immunosuppressive state associated with COVID-19 infection, in addition to immune derangement secondary to cancer. Immune escape in cancer is promoted by T-regulatory cells that inhibit transforming growth factor-β (TNF-β) signaling in intra-tumoral T-lymphocytes but not in the lymph nodes draining the tumor. As a result, the cytotoxic T-cell function is impaired [22][15]. The altered TNF-β signaling also suppresses the innate immune system and reprograms the tumor microenvironment [23][16]. COVID-19 patients may have poor clinical outcomes due to immune dysregulation and prolonged inflammation. COVID-19 infection alters four genes (ANXA3, GNS, HIST1H1C, RASA3) as well as three genes (HBA1, TFRC, GHITM) related to aging, both of which alter immune responsiveness, increasing susceptibility to infection and cancer [24][17]. Autopsy reports of patients with COVID-19 revealed low numbers of CD8-positive T-lymphocytes infiltrating the lung tissue as evidence of adaptive immune dysfunction [25][18]. Clinical reports have also indicated decreased CD4, CD8, and natural killer (NK) cell populations in peripheral blood in COVID-19 infection [26][19]. Compared to healthy controls, T-cells from patients with COVID-19 express significantly more of the inhibitory programmed death (PD1) molecules, with enhanced immune evasion in patients with cancer [27][20]. Hence, cancer as well as treatment for cancer, including chemotherapy, made patients more susceptible to COVID-19, resulting in increased mortality and morbidity [28][21].

3. Severity of COVID-19 with Cancer Therapy

Evidence has been mixed regarding COVID-19 severity in cancer patients [29][22]. According to the OnCovid registry in Europe, mortality rates in patients with cancer diagnosed with COVID-19 have improved over the last 6–8 months [29][22]. In a study of 1253 patients with cancer who contracted COVID-19, most patients had a mild form of the disease [10][3]. In a tertiary referral cancer center, out of 1088 tested patients, 186 were positive for COVID-19, although anticancer therapies were not associated with increased mortality [17][10]. It remains of concern that postponing cancer treatment reduces its therapeutic efficacy and curability rates [30][23].

4. COVID-19 Vaccination Status and Cancer

The vaccination status may affect the COVID-19 disease outcomes and mortality of cancer patients (Figure 2). COVID-19 vaccination was a continuation of the treatment paradigm during the COVID-19 pandemic. Patients with solid tumors with normal cellular immunity were prevented from receiving the COVID-19 vaccine, either because of patients’ reluctance or health-care providers’ hesitancy in giving the vaccine because of the immunocompromised state—further restricting the oncological treatment plan. COVID-19 is more likely to infect those who have undergone radiotherapy, chemotherapy, and immunotherapy, as well as those who have recently undergone bone marrow or stem cell transplant. These patients were considered unable to mount an immune response sufficient enough and so to have a greater chance of getting infected with COVID-19 [31][24]. There is a difference in response to COVID-19 vaccines among cancer patients. The COVID-19 vaccines are unlikely to induce a humoral response in lymphoma patients treated with an anti-CD20 antibody. The length of time since the last exposure to anti-CD20 antibodies predicts an elevated antibody titer and a more favorable response [32][25]. Immune response rates were described to be lower amongst cancer patients, especially those with hematologic cancers and those receiving chemotherapy, radiotherapy, or immunosuppressants. Patients with hematologic malignancies, especially lymphoproliferative disorders, have the lowest seroconversion rates. Even after complete immunization, patients with cancer are more likely to get COVID-19 [33][26]. Patients with multiple myeloma are immunocompromised due to disorders of humoral and cellular immunity as well as the use of immunosuppressive drugs. When compared to healthy controls, the antibody response to the COVID-19 mRNA vaccine appears to be attenuated and delayed after the initial dose in multiple myeloma patients [34][27]. Nevertheless, a sufficient immune response was still generated in many patients, and vaccination was overall described to be safe and well-tolerated [35][28]. Mori et al. found no significant difference between the seroconversion rates for AML in remission and MDS compared to healthy controls, with 94.7% and 100%, respectively [36][29]. COVID-19 is unlikely to be worsened by anti-cancer therapies in cancer patients, including those with hematological malignancies [37][30].

5. COVID-19 Vaccination Hesitancy in Patients with Cancer

In a survey of 2691 people with solid organ tumors, it was found that hesitancy was higher among young, female, non-dominant English speakers and regional residents, as well as among those with non-genitourinary cancers. The vaccine uptake was higher in people who were older, male, metropolitan, spoke English as a first language, and had been diagnosed with cancer for more than six months [38][31]. In a cross-sectional online study of adults with a history of cancer, among 1073 respondents, 84% of them indicated positive intent toward COVID-19 vaccination, 10% were undecided, and 6% indicated negative attitudes [39][32]. In a two-wave survey of 2272 individuals between December 2020 and June 2021, among hematologic malignancy patients and survivors, being younger, unmarried, trusting local faith leaders, and not having a bachelor’s degree or more were negatively associated with getting vaccinated. Among those who were hesitant, those with a distrust of vaccines in general were least likely to get vaccinated [40][33]. Among a total of 424 families with childhood acute lymphoblastic leukemia in remission, 21.4% agreed, 39.6% hesitated, and 38.9% parents disagreed with the vaccination. The most common reason that kept parents from vaccinating their children was a lack of recommendations from professionals [41][34]. Mistrust of the health-care system, the misconception that COVID-19 vaccination is contraindicated in patients with breast cancer, not having a close acquaintance already vaccinated against COVID-19, noncompliance with prior influenza immunization, being aged younger than 60 years, having low educational attainment and not having a close acquaintance deceased due COVID-19 were all causes of the refusal of COVID-19 vaccines [42][35]. No study cited concerns about efficacy as a reason for refusal of the vaccine [43][36].
According to a study of 111 adult cancer patients from a single institution, the main reason for vaccine refusal was incompatibility with patients’ disease or treatment. In this study, 61.3% felt more vulnerable to COVID-19 than the general population. About 55% of the patients were ready to be vaccinated and 14.4% refused the vaccine. The researchers concluded that the majority of the patients in this institutional sample accepted the COVID-19 vaccine [44][37]. In another study of 1001 patients from five institutions, among those who participated in the survey, 293 were cancer patients. In this group, 53.9% were concerned about developing vaccine-related adverse events and 23.5% believed that the vaccine had a negative impact on cancer treatment [45][38].

6. Mitigation Strategies

There was a positive correlation between vaccination status and the trust respondents had for their oncologist, federal agencies, and pharmaceutical companies. It was reported that oncologists and primary care physicians were the most trusted sources of vaccines [40][33]. The major reasons behind vaccine hesitancy appear to be inadequate information about safety and seeing no reason for the vaccine. It may be possible to circumvent such barriers by providing appropriate information and counseling [46,47,48,49][39][40][41][42]. To effectively manage cancer patients during the COVID-19 pandemic, it is critical to effectively communicate and educate, providing positive reinforcement during the discussion [50,51,52][43][44][45]. The management strategies for treating cancer patients to avoid COVID-19 infection should include hand hygiene, infection control measures, avoiding high-risk exposure, and educating them about the signs and symptoms of COVID-19 [1][46]. The main reasons for hesitancy with regard to COVID-19 vaccines, including the rapid pace of vaccine development, safety of the vaccine, questionable long-term effects of the vaccine, misinformation on social media, doubts about the efficacy of the vaccine, general lack of trust in government and pharmaceutical industry, presumed harmless nature of COVID-19, the polarized sociopolitical environment, and the inherent complexities of large-scale vaccination, are all concerns for cancer patients [53][47]. To achieve a set target in terms of COVID-19 vaccination, each of the above issues must be addressed.
Several factors may complicate efforts to increase vaccine confidence among cancer patients. These factors include the underrepresentation of cancer patients in COVID-19 vaccine trials and specific recommendations concerning vaccine administration and timing for cancer survivors. A potential benefit of vaccine communication efforts targeting survivors is the consideration of social norms, perceptions of risk, and trust. Nevertheless, additional behavioral research is needed in order to better understand and respond to the drivers of vaccine hesitancy among survivors and ensure optimal protection against COVID-19 for this high-risk population [54][48].

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