A Narrative Review of the Safety of Anti-COVID-19 Nutraceuticals for Patients with Cancer

Simple Summary Dietary supplement use has increased more than 35% globally since the COVID-19 outbreak. While some nutraceuticals are potentially efficacious against severe disease from COVID-19, their indiscriminate use by patients with cancer without medical supervision is concerning. The aim of this narrative review was to evaluate the data on safety of “anti-COVID-19” nutraceuticals for patients with cancer. We found that the use of vitamin C, vitamin D, and selenium supplements is likely safe and even potentially beneficial at typically recommended doses. However, caution is advised regarding the use of omega-3 fatty acids and zinc, as risks from their use may outweigh the benefits. Abstract Interest in dietary supplements and their efficacy in treating and preventing disease has increased greatly since the outbreak of the COVID-19 pandemic. Due to the risk of severe COVID-19 in patients with cancer, we conducted a narrative review aiming to better understand the data on the safety of the most efficacious “anti-COVID-19” nutraceuticals for patients with cancer. We conducted a PubMed database search aimed at identifying the most effective nutrients for use against COVID-19. For the identified nutraceuticals, we searched PubMed again regarding their safety for patients with cancer. Fifty-four total records (52 independent studies) were retrieved, pertaining to vitamin D, vitamin C, selenium, omega-3 fatty acids, and zinc. Vitamin D results from 23 articles indicated safe use, but two articles indicated potential harm. All 14 articles for vitamin C and five out of six articles for selenium indicated the safety of use (one study for selenium suggested harm with high-dose supplementation). Results for omega-3 fatty acids (seven articles) and zinc (one article), however, were rather mixed regarding safety. We conclude that vitamin D, vitamin C, and selenium supplements are likely safe or even beneficial at typically recommended doses; however, caution is urged with omega-3 fatty acid supplements, and zinc supplements should likely be avoided. More experimental research is needed, and nutraceutical use by patients with cancer should always be under the supervision of a healthcare team.


Introduction
In December 2019, a novel virus of unknown etiology was detected in Wuhan, China [1]. The virus, which most often manifests as a severe respiratory syndrome, quickly spread from Wuhan, with cases appearing globally by 30 January 2020 [2]. It was quickly labeled by the World Health Organization as a public health outbreak of international concern and was later declared a pandemic [2,3]. This novel airborne pathogen, since named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes the disease now known as COVID- 19 [2]. Despite containment efforts and the introduction of a vaccine in late 2020, by November 2021, over 5 million deaths had been attributed to the virus [4]. such, many individuals, immunocompromised and healthy alike, have sought out ways to improve immunity [30]. Concurrently, popular media outlets have promoted the use of a variety of dietary supplements with putative immune-boosting potential that may help against COVID-19 infection [31,32]. This has led to a major increase in dietary supplement use during the pandemic, with a roughly 35% increase in North and South America, a 40% increase in Asia, and a 38% increase in Europe [30,33]. Concerningly, only 40% of these individuals consume supplements at the recommendation of a licensed medical professional [30].
Increased supplement use during the COVID-19 pandemic, especially without appropriate medical supervision, is troubling for oncologists and other oncology specialists. Specifically, one concern relates to the potential dampening of the cytotoxicity of chemotherapy by antioxidants and other supplements. The Diet, Exercise, Lifestyle, and Cancer Prognosis (DELCaP) study, a correlative study to the phase III SWOG SO221 [34], examined supplement use in patients with breast cancer and survivorship. This study found that the use of any antioxidant supplements, before or during breast cancer treatment, was associated with an increased risk of breast cancer recurrence and that vitamin B12 use during treatment was associated with poorer survival rates and poorer disease-free survival [34]. Results such as these indicate that nutraceutical use during or around chemotherapy may not be benign.
Given the rise in oral supplement use during the COVID-19 pandemic, as well as the increased interest in the efficacy of nutraceuticals in preventing or reducing the severity of COVID-19, we conducted a narrative review focusing on the safety of the most efficacious "anti-COVID-19" oral supplements for patients with cancer. As COVID-19 is still a present threat, individuals with cancer and their providers need up-to-date, evidence-based guidance for supplement use around their respective treatments.

Methods
We conducted our initial literature search on 8 September 2021 focusing on the efficacy of nutraceuticals for the treatment and prevention of COVID-19. We performed the search in the PubMed database and included variations of the search terms "SARS-CoV-2" or "coronavirus" or "COVID-19" AND "supplement" or "phytonutrient" or "nutraceutical" AND "review." There were no restrictions on time period, language, or place of publication, and only review articles were included. This yielded 137 review articles after removing duplicates, from which titles and abstracts were reviewed. Sixty-seven articles were then removed for not pertaining to the research question and 25 for not being review articles, leaving 45 articles for full-text review and data extraction.
Our data extraction tool at this step focused on determining which nutraceuticals are most efficacious for the treatment or prevention of COVID-19 and included the name of the nutraceutical considered, the type of studies included in the review (e.g., in vitro, in vivo, animal or human studies), and the evidence for use against  For the purpose of our review, a nutraceutical was considered efficacious if our data extraction tool resulted in two or more reviews in favor of that nutraceutical's ingestion for COVID-19, either through food or supplement form, and no reviews indicating harm from use. Nutraceuticals for which there was only one review in favor were searched again in PubMed for original articles. If this secondary search yielded two or more original results in its favor, that nutraceutical was also included. This process resulted in the inclusion of the following nutraceuticals for review of the safety of single-nutrient supplements in patients with cancer: vitamin D, vitamin C, zinc, selenium, omega-3 fatty acids, and quercetin (see Supplementary Materials).
At the next step of the process, for each of the identified "anti-COVID-19" nutrients, we conducted a new PubMed search regarding safety for use in patients with cancer. The search was performed using the nutraceutical name (e.g., "vitamin D") AND "supplement" AND "cancer" AND "survivorship" or "safety" or "recurrence" or "disease progression" or "mortality" or "adverse events." Additional articles were sourced from a hand-search of

Results
Out of 470 articles reviewed, 406 were excluded, leaving a total of 52 independent studies across all included nutraceuticals for data extraction (two of which included data for two nutraceuticals, resulting in a total of 54 records [35,36]). From those 52 studies, we extracted information about the authors, type of study, participants, cancer studied, nutraceutical dosing, and results. The search and selection process is graphically illustrated in Figure 1, and extracted information from the retrieved studies is shown in Tables 1-5.
At the next step of the process, for each of the identified "anti-COVID-19" nutrients, we conducted a new PubMed search regarding safety for use in patients with cancer. The search was performed using the nutraceutical name (e.g., "vitamin D") AND "supplement" AND "cancer" AND "survivorship" or "safety" or "recurrence" or "disease progression" or "mortality" or "adverse events." Additional articles were sourced from a hand-search of related literature by the included authors. After duplicate removal, this yielded 470 articles in total across all included nutraceuticals for review.

Results
Out of 470 articles reviewed, 406 were excluded, leaving a total of 52 independent studies across all included nutraceuticals for data extraction (two of which included data for two nutraceuticals, resulting in a total of 54 records [35,36]). From those 52 studies, we extracted information about the authors, type of study, participants, cancer studied, nutraceutical dosing, and results. The search and selection process is graphically illustrated in Figure 1, and extracted information from the retrieved studies is shown in Tables 1-5.

Vitamin D
A total of 177 unique articles were retrieved for vitamin D through our PubMed search. We reviewed titles and abstracts, resulting in 35 for full-text review. After a full-text review, 26 articles remained for data extraction (Table 1).
Of those 26 studies, 23 reported results that indicated benefit, no harm, or null effects of vitamin D supplementation for patients with cancer. Two of the studies reported results with a negative impact for patients with cancer, and one study reported mixed results.
In the studies that found that vitamin D supplements were either beneficial or not harmful for patients with cancer, nine found that supplementation had no effect on a variety of outcomes including symptom management, risk of death, and risk of recurrence [43,51,52,54,[57][58][59][60][61].  • One RCT showed no effect of use on cancer mortality • One RCT showed no effect of use in breast or colorectal cancer incidence with vitamin D plus calcium • One RCT showed ↓ in total cancer incidence with vitamin D plus calcium vs. placebo (+)  11 Quality of Life, 12 Quality of Life Questionnaire-Core Questionnaire, 13 Functional Assessment of Cancer Therapy-Neurotoxicity, 14 Common Terminology Criteria for Adverse Events. The last column indicates the overall direction of the effects of vitamin D supplementation on safety: (+) no risks to health; (−) some risks to health outcomes; (+/−) mixed risk profile. Relative risks (RR) and odds/hazard ratios (OR/HR) are shown as means with 95% confidence intervals.   Abbreviations used: 1 Randomized Controlled Trial, 2 Body Mass Index, 3 External Beam Radiation Therapy. The last column indicates the overall direction of the effects of selenium supplementation on safety: (+) no risks to health; (−) some risks to health outcomes; (+/−) mixed risk profile. Relative risks (RR) and odds/hazard ratios (OR/HR) are shown as means with 95% confidence intervals.     Three of the studies found that vitamin D was associated with better quality-of-life outcomes, including better scores on the cancer quality-of-life questionnaire (QLQ-C30) for physical functioning, social functioning, fatigue, and appetite, and better scores on the colorectal cancer subscale of the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) tool [37,52,59]. Beyond quality-of-life measures, four studies reported a decrease in cancer mortality in those who took vitamin D supplements, and two showed a decrease in overall mortality [38,43,46,49,53,56]. One study found a lower risk of breast cancer recurrence in those who were supplemented with vitamin D post-diagnosis, but only among estrogen receptor (ER)-positive tumors and not among ER-negative tumors (HR = 0.64, 95% CI: 0.47-0.87 and HR = 1.25, 95% CI: 0.78-1.98; respectively) [35].
In the two studies that found vitamin D supplementation was harmful in patients with cancer, one found a positive association between vitamin D supplement use above 10 µg/day and cancer mortality (RR = 2.11, 95% CI: 1.18-3.77) [40], and the other found that vitamin D supplementation increased the risk of breast cancer mortality (HR = 1.47, 95% CI: 1.07-2.00) [48].
One RCT found mixed results for vitamin D supplementation with 200 IU/day in patients with digestive-tract cancer, post-curative surgery [55]. The study found that the effect of supplementation depended on the levels of serum Programmed Death Ligand 1 (PD-L1), a regulatory molecule expressed in T cells with immunosuppressive function [55]. Since PD-L1 is associated with a poorer cancer prognosis in various types of cancer (gastric cancer, small cell lung cancer, pancreatic cancer, breast cancer) [83][84][85][86], for those patients in the lowest PD-L1 concentration quintile, vitamin D supplementation seemed to have a detrimental effect by upregulating serum PD-L1 levels; however, for those in the highest quintile, vitamin D was beneficial and downregulated serum PD-L1 levels [55,87].

Vitamin C
A total of 190 unique articles were retrieved for vitamin C through our PubMed search. We reviewed titles and abstracts, resulting in 35 for full-text review. After a full-text review, 14 articles remained for data extraction (Table 2).
Of those 14 studies, all provided results in the direction of benefit, no harm, or null effects of vitamin C supplementation in patients with cancer. Six of the fourteen studies found no association between the use of vitamin C supplements and adverse cancer-related events, including recurrence, survival, overall mortality, and cancer-specific mortality [34,62,64,[67][68][69]. Additionally, a study on chemotherapy-induced peripheral neuropathy found no significant effect of pre-treatment vitamin C supplementation on neurotoxicity [61]. Three studies found that vitamin C intake was associated with decreased overall mortality, three found a decreased risk of cancer-specific mortality, and three found a decreased risk of recurrence [35,63,65,66,70,71]. None of the studies reported an increased risk to health from the use of vitamin C supplements.

Selenium
A total of 45 unique articles were retrieved for selenium through our PubMed search. We reviewed titles and abstracts, resulting in 28 for full-text review. After a full-text review, six articles remained for data extraction ( Table 3).
Five of these six papers showed no harmful effects of selenium supplementation in patients with cancer and included two meta-analyses [72,73], two reviews [62,76], and one RCT [75]. Three articles did not find a beneficial effect on the incidence or progression of gastrointestinal cancer [62], prostate cancer [73], or cervical and uterine cancer [75], but found selenium supplementation was not otherwise harmful. Beneficial effects were highlighted in a review that addressed an association between selenium supplementation and decreased edema volumes and incidence of skin infection in patients with breast cancer in an RCT of 179 post-mastectomy patients with secondary lymphedema, as well as decreased edema volumes in 10 out of 12 patients with breast cancer included in a 48-participant cohort study [76].
A meta-analysis of RCTs by Jenkins et al. concluded that selenium taken independently (i.e., not as a multivitamin or mixed with other supplements) was not associated with cancer mortality [72]. However, a prospective cohort study within the review found that high-dose selenium supplementation (≥140 µg/day) may be associated with a greater risk of prostate cancer mortality [72].

Omega-3 Fatty Acids
A total of 21 unique articles were retrieved for omega-3 fatty acids through our search. We reviewed titles and abstracts, resulting in 17 for full-text review. After a full-text review, seven articles remained for data extraction (Table 4).
In five of these seven studies, there were no adverse effects of supplementation. One study found that supplementation with omega-3 fatty acids decreased aromataseinhibitor-related pain in patients with breast cancer and obesity [79]. Additionally, omega-3 supplementation showed promising antitumor activity in two prospective trials of patients with advanced lung and breast cancer, as reviewed by Vernieri et al. [81]. The same review, however, highlighted a pre-clinical study that reported that the 16:4 omega-3 (hexadeca-4,7,10,13-tetraenoic) fatty acid supplement, commonly found in commercial fish oils, may be unsafe for patients with cancer as it can hinder tumor-directed cytotoxicity of platinum compounds used in cancer treatments [81].
Furthermore, an RCT pointed towards an increased mortality rate 5 years after patients with colorectal cancer (from a country with traditionally high fish intake) took omega-3 supplements in the 7 days before and after colorectal resection surgery [80].

Zinc
A total of 25 unique articles were retrieved for zinc through our PubMed search. We reviewed titles and abstracts, resulting in 11 for full-text review. After a full-text review, only one article remained for data extraction ( Table 5).
The study found that zinc supplementation reduced the duration and severity of oral mucositis in patients with head and neck cancer but sometimes caused gastrointestinal distress, which suggests that zinc supplements should not be taken on an empty stomach [88].

Quercetin
A total of 12 unique articles were retrieved for quercetin through our PubMed search. We reviewed titles and abstracts, resulting in five for full-text review. After a full-text review, one was removed for being conducted in animals, and the remaining four were review articles that did not include human studies; therefore, no articles qualified for further consideration.

Discussion
This narrative review aimed to synthesize the currently available literature regarding the safety of the most efficacious "anti-COVID-19" nutraceuticals for patients with cancer. Our findings reveal heterogeneous results, with safety largely depending on the type of nutraceutical or supplement consumed, the dose consumed, and the type of cancer studied. Across nutraceuticals, our results were heavily based on observational studies. Taking the potential risk of confounding into consideration, clear conclusions could not be drawn, further emphasizing the need for caution from healthcare providers.
Vitamin D may decrease CRP, which has been implicated in the cytokine storm seen in severe cases of COVID-19 infection [18]. We identified an overwhelming majority of studies with results that point in favor of vitamin D use in patients with cancer, with positive effects seen in quality-of-life measures, mortality, recurrence, and pain indexes. However, the mechanism between vitamin D and these positive cancer-related outcomes was not always well characterized. Anderson et al. documented improved quality-of-life measures in an observational cohort of patients with breast cancer, but ultimately noted that it was unclear whether the supplement itself was responsible or whether participants who took vitamin D were in general more optimistic or more likely to take other actions towards improving their overall health and mood [37]. Similarly, Bjelakovic et al. reported decreased cancer mortality from vitamin D3 supplementation (RR = 0.88, 95% CI: 0.78-0.98) but noted the lack of RCTs made it hard to draw robust conclusions [38].
Only two studies point to an increased risk of vitamin D intake in patients with cancer; one noted this was observed only among those who were not deficient in vitamin D [40], and the other noted that the association of vitamin D supplementation with higher breast cancer mortality needed further exploration, as there was no clear mechanism behind this observation [48]. Given that the majority of evidence is in support of vitamin D use, oncologists can likely safely allow their patients to continue supplementation at typically recommended doses (600 IU/day).
Vitamin C, similar to vitamin D, may contribute to a decrease in the pro-inflammatory cytokines, which are a hallmark of severe COVID-19 infection [18]. The evidence for vitamin C also strongly points in the direction of supplementation being safe, or perhaps even beneficial, for patients with cancer. In fact, none of the included articles found an indication of harm. Given that there has been concern that the use of antioxidants, including vitamin C, may negatively impact the effect of chemotherapeutic agents, these results are encouraging [70]. Nevertheless, we urge caution as the studies are, by and large, observational in nature, which stresses the need for additional clinical trials [49]. At the present state of knowledge, supplementation with vitamin C at typically recommended doses (75-90 mg/day) is likely not harmful and could conceivably confer benefit.
Selenium may reduce the severity of COVID-19 infection by impeding viral entry into the cytoplasm and has promising results in patients with cancer [89]. All but one out of six studies addressing selenium supplementation demonstrated no adverse effects in patients with cancer. However, the type of cancer (i.e., prostate, uterine, cervical, gastrointestinal) and outcome of interest varied greatly across studies. One prospective cohort study in patients with prostate cancer noted that selenium supplementation might be associated with a higher risk of mortality if intake is high (≥140 µg/day) [72]. Given these results, it is likely that selenium use is safe for patients with cancer, though high-dose supplementation should be avoided (typically recommended doses: 40-70 mg/day).
Omega-3 fatty acids may play a role in decreasing the severity of COVID-19 infection by inhibiting cellular viral entry, suppressing the production of pro-inflammatory cytokines, and increasing the phagocytic capacity of the innate immune system [20]. Out of seven identified articles for omega-3 fatty acids, five found their use to be safe, though estimates of efficacy varied [39,77]. The seven articles addressed safety in a variety of different cancers, including skin cancer, prostate cancer, gastrointestinal cancer, breast cancer, esophageal cancer, glioblastoma, and colorectal cancer. Two studies evaluated the long-term effects of supplementation with omega-3 fatty acids. The first, a longitudinal cohort study, did not find an association between mortality and supplementation in glioblastoma patients [56]. In contrast, the other, an RCT, pointed towards an increased mortality rate after five years of intake in patients with colorectal cancer who supplemented one week before and one week after colorectal resection surgery [80]. Additionally, one review specifically warned against the indiscriminate use of fish oil supplements, which may be unsafe for patients with cancer if they contain hexadeca-4,7,10,13-tetraenoic acid; this omega-3 fatty acid can dampen the tumor-directed cytotoxicity of platinum compounds used to treat some cancers [81]. Based on this evidence, caution should be used as far as omega-3 fatty acid supplements are concerned. At the very least, scrutiny of the exact fatty acid composition of the supplement together with frequent patient monitoring is warranted.
For zinc, which may counteract inflammation associated with tumor necrosis factor-α in COVID-19 infection [90], results did not universally show harm-free supplementation. Although one study indicated a reduced incidence of oral mucositis with supplementation in patients with head and neck cancer, the same study also cited potential gastrointestinal distress at the same dosage [88]. Given the lack of a sufficiently large body of evidence on this nutraceutical, with only one study being relevant, it is hard to draw any conclusions. That said, at present, it is probably prudent to advise patients with cancer against supplementation with zinc.
While this review thoroughly and systematically assessed the literature regarding the safety of these supplements for patients with cancer, our conclusions are not without limitations. The heterogeneity of results may in part be due to our inclusion of all stages and types of cancer, as well as our inclusion of all treatment types and clinical settings. It is possible that a narrower scope would have revealed more homogenous results due to the vast differences in the biology of various cancers. However, at the current state of knowledge, there is not enough information for a cancer type-specific assessment. Additionally, our review did not consider in detail possible toxicity issues resulting from supra-supplementation but rather evaluated safety at typically recommended doses. Lastly, due to the relatively recent onset of the COVID-19 pandemic, there are limited clinical trials on the efficacy of nutraceuticals for SARS-CoV-2. As a result, data on only a limited number of nutraceuticals could be identified. As more research becomes available, it is possible that more nutraceuticals will be deemed efficacious, and an updated safety review may become necessary.

Conclusions
Patients with cancer are one of several co-morbid populations who are at increased risk of a severe course of disease if infected with COVID-19. While a number of nutraceuticals have attracted interest due to their potential "anti-COVID-19" activity, there is concern about the safety of their usage in patients with cancer due to the potential interactions with their treatment regimen and possible associations with an increased risk of recurrence, cancer incidence, or even death.
This review highlights the heterogeneity of results regarding the safety of nutraceuticals for patients with cancer. It is conceivable that a large part of this heterogeneity is due to different types and stages of cancer, different treatments, and different clinical settings among the identified studies. Our findings indicate that vitamin D, vitamin C, and selenium supplementation are likely safe at normal doses (i.e., the dosages typically recommended for the general population). However, caution should be used with omega-3 fatty acid supplementation due to a conflict in the results between two long-term studies and a paucity of data overall. Similarly, zinc supplementation should probably be avoided due to a lack of relevant studies and because the currently available evidence indicates potential for harm or discomfort in patients with cancer.
Overall, this work emphasizes a sizeable gap in the literature surrounding the safety of nutraceuticals in patients with cancer and underscores the potential danger of liberal use of supplements by this high-risk group. Furthermore, this review provides important and immediately relevant clinical guidance for cancer care practitioners during an ongoing public health crisis. It is important to note that any supplement intake by patients with cancer should be discussed with their healthcare team so their providers may more accurately monitor their health and assess potential risks. Lastly, though early evidence indicates a potential benefit of some nutraceuticals against COVID-19, and thus potentially to high-risk cancer populations, we do not recommend supplementation as a substitute for regular medical care and a balanced diet.