Abstract
Aims:
This study aimed to assess the habits and knowledge of cancer patients regarding the use of herbal medicines and dietary supplements in cancer patients receiving immune checkpoint inhibitors (ICI).
Methods:
The data of 181 cancer patients who were over 18 years old and received ICIs were collected. The usage patterns, anticipated benefits and harms, and sources of supply were evaluated by filling researcher-prepared forms.
Results:
Most patients did not use any kind of herbal medicine (91.2%) or dietary supplements (75.9%) during their immunotherapy. Boosting the immune system is the primary motivation for use among users. Multivitamins are the most frequently used supplements. Family members and TV advertisements were the main sources of information, in addition to limited advice from healthcare professionals. A minority of participants reported gastrointestinal side effects. Herbal medicine and dietary supplement use were more prevalent among patients with stage IV cancer and renal cell carcinoma (RCC).
Discussion:
This study revealed that the limited uptake of herbal medicines and dietary supplements alongside ICI treatment among cancer patients. The lack of adequate information from healthcare professionals poses potential risks to patients. Improved communication with patients, education regarding herbal medicine and dietary supplement use, potential interactions, and associated risks during ICI treatment are essential. Further research is needed to identify the specific needs of patients, anticipated benefits, and potential harms of herbal medicine and dietary supplement use, together with ICIs.
Introduction
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by enhancing the immune system of the body to fight cancer cells. They are used either as monotherapy or in combination with conventional chemotherapy and radiotherapy and have shown promising results in certain types of cancer1 -3 There are several factors that can enhance the effectiveness of immune checkpoint inhibitors (ICIs). 4 There is evidence that diet and nutrition can also enhance the effectiveness of immune checkpoint inhibitors (ICIs). 5
Herbal medicine and dietary supplements are frequently used as supportive care for cancer patients. According to a multi-center study, 12.1% of cancer patients use herbal medicine, 5.1% use vitamin/mineral dietary supplements, and 1.9% use other dietary supplements. 6
Herbal medicine is defined as a type of medicine that uses the roots, stems, leaves, flowers, or seeds of plants to improve health, prevent disease, and treat illness. Dietary supplements are defined as products that may contain vitamins, minerals, amino acids, fatty acids, probiotics, and other nutritional substances. 7 Dietary supplements can be used to address deficiencies, support general health, or achieve specific health goals. Common dietary supplements include multivitamins, omega-3 fatty acids, protein powders, and probiotics. 8 The main difference between these two terms is that herbal medicine focuses on plant-based treatments, while dietary supplements are generally used to address nutritional deficiencies or provide health support. 9
Some herbal medicines have been shown to stimulate the immune system to eliminate cancer cells, whereas others may reduce the side effects of ICIs. 10 For example, reishi mushroom contains beta-glucan, and studies have suggested that this polysaccharide increases the anticancer activity of immune cells.11 -13 However, there is still insufficient evidence to support the use of herbal products together with conventional cancer treatments such as ICIs. Some herbal products may interact with ICIs, potentially enhancing their effectiveness. However, it is important to be aware of possible toxicity.14,15 It may be beneficial for the patients to consult healthcare professionals before any use of herbal medicines and dietary supplements.16,17 Furthermore, the frequency and motivations for herbal medicine and dietary supplements product use in conjunction with ICIs are not fully understood. There is insufficient information about cancer patients’ habits of using these products, as well as their potential benefits and risks. Further research is required in this area.18,19
The aim of our study was to evaluate cancer patients’ habits of herbal medicine and dietary supplements use and their knowledge regarding the potential benefits and risks of these products in combination with immune checkpoint inhibitors.20,21
Method
This study was conducted using a cross-sectional and multicenter design. Data were gathered from June 1, 2022, to December 31, 2022, using forms developed by the researchers (see “Supplement”). The survey included questions about demographic characteristics such as age, gender, and level of education, as well as the utilization patterns of herbal medicine and dietary supplements: frequency of use, product types, financial impact of these products, and information sources regarding herbal medicine and dietary supplements. Prior to the survey, the characteristics and differences between herbal medicine and dietary supplements were explained to the patients. The questions regarding the demographic information were selected under the investigation of the prevalent populations who are known from previous studies to use a lot. Likewise, the main questionnaire comprising the nature and motivation of their use was prepared according to the well-described previous data from the studies conducted on oncologic patients. 6
The participants were selected among the patients who were on their routine oncologic follow-up visits. Any kind of oncologic background and age over 18 were the eligibility criteria. Patients with intellectual disabilities or illiteracy were excluded. The forms were distributed to the patients after they were informed about the study, agreed to participate, and signed a consent form. The identities of the participants enrolled in the survey were kept anonymous. Patients filled out the survey while waiting in the outpatient clinic for their physicians or during their treatment. Upon completion, patients either dropped the questionnaire into a box or handed it to a local researcher. Owing to the multicentered scope of the study, it was not feasible to ascertain the number or characteristics of those who chose not to participate. Participants who wished to participate in the survey were informed that their participation was voluntary, and that their consent was obtained on the first page of the survey form.
The Statistical Package for Social Sciences (SPSS) version 22.0 was used for data analysis. Descriptive data are presented as mean, standard deviation, and percentage values. Chi-square and Fischer exact tests were used for comparisons between groups, and a significance level of P < .05 was used for all statistical analyses.
The study was conducted with strict adherence to ethical considerations and was approved by the ethics committee of Hacettepe University, with decision number: SBA 24/591 and date: 04.04.2024.
Results
A total of 181 patients from 4 institutions were enrolled, aged 21 to 89 (mean 60.68 ± 13.52). Fifty-eight percent were 60 years of age or older, and the gender distribution was 120 (66.3%) male and 61 (33.7%) female. The demographic data and clinical characteristics of the patients included in the study are presented in Table 1.
Distribution of Sociodemographic and Clinical Variables of Patients (n = 181).
Abbreviations: n, number; %, frequency; Median, median; Min, minimum; Max, maximum; Mean, mean, SD, standard deviation.
Of the participants, 16 (8.8%) reported the use of herbal medicine during ICIs treatment. Of these, 6 (37.5%) aimed to strengthen the immune system, and 5 (27.7%) believed in effective against cancer. The frequency of use was variable; some were using it daily (9; 56.2%), while others used it rarely (3; 18.7%). Dietary supplements were used during cancer treatment in 27 (24.1%) of ICI patients, with the highest percentage being motivated to strengthen the immune system 17 (60.7%), mostly administered daily (64.2%). The most commonly used herbal medicine was curcumin 6 (38%) and the most commonly used dietary supplements were multivitamins 14 (52%). The most common sources of information about herbal medicine and dietary supplements were household members 6 (37.5%), television 4 (25%), and friends 4(25%). Most patients 10 (62.5%) reported no side effects, while 4 (25%) experienced gastrointestinal issues and 2 (12.5%) had skin reactions. In terms of monthly expenditure, 6.25% (n = 1) of patients did not spend any money, 25% (n = 4) spent less than 3 dollars, 43.75% (n = 7) spent between 3 and 15 dollars, and 25% (n = 4) spent between 15 and 30 dollars (presented in Table 2).
Frequency Analysis of the Sociodemographic and Various Variables of the Participants.
There was no significant difference in herbal medicine use according to age, sex, smoking status, marital status, diagnosis, and stage of the disease (presented in Table 3). The dietary supplements used were related to the disease stage (P = .002) and diagnosis (P = .001).
Use of Herbal Medicine/Dietary Supplements During Immune Checkpoint Inhibitor Treatment.
Discussion
To the best of our knowledge, this study is the first to search for the use of herbal medicine and dietary supplements in conjunction with ICIs. This study also analyzed patients’ perspectives on the potential benefits and drawbacks of these products when combined with ICIs. Our findings indicate that the majority of cancer patients didn’t use herbal medicine or dietary supplements in addition to their treatment regimen during ICIs. Most of the patients motivated mainly by the intent to boost their immune systems. The rate of herbal medicine and dietary supplements usage among patients with cancer may vary depending on cultural beliefs, nationwide healthcare systems, and socioeconomic status. It is important to consider these contextual factors when interpreting the results of studies.
The use of herbal medicines is increasing worldwide. 22 The most notable derivatives include echinacea, ginseng, curcumin (an extract of turmeric), reishi mushrooms, and green tea. 23 A study conducted by the Cochrane Review in 2014 indicated the potential efficacy of echinacea in alleviating symptoms of the common cold or influenza, although the results varied significantly, and further studies are necessary. 24 In the context of ginseng, a randomized controlled trial demonstrated the potential benefits of ginseng extract in improving cognitive functions. 25 However, another meta-analysis did not find sufficient evidence to support the claim that ginseng improves fatigue and physical performance. 25 Curcumin, the active ingredient in turmeric, has potential efficacy in managing inflammatory conditions such as osteoarthritis and metabolic syndrome. 26 Reishi mushroom (Ganoderma lucidum) is known for its immunoregulatory effects.27,28 However, a review study in 2012 concluded that G. lucidum has not been proven to be an effective first-line treatment for cancer or to significantly improve long-term survival. It may be considered an adjunct to conventional treatment because of its potential to enhance tumor response and stimulate the immune system. 6 Lastly, green tea, or Camellia sinensis, has been studied extensively, and many studies in cell lines have demonstrated the modulation of signal transduction and metabolic pathways by (−)-epigallocatechin-3-gallate (EGCG), the most abundant and active polyphenol in green tea.
The general population, particularly individuals diagnosed with cancer, shows a significant and increasing interest in the use of herbal medicine and dietary supplements. This category encompasses herbal medicine, which can lead to undesirable herb-drug interactions with conventional treatments such as chemotherapy, subsequently causing adverse effects and potentially resulting in treatment failure. Research in this field often adopts the broader term “Complementary and Alternative Medicine (CAM) use,” which, in addition to herbal medicine, includes various treatment modalities such as massage, prayer, and acupuncture. Our study sought to investigate not only the use of herbal medicine for CAM purposes but also the use of dietary supplements.
Herbal medicine is frequently used in various areas worldwide for numerous reasons. Among cancer patients, it is employed for specific purposes, including enhancing physical and mental well-being and fighting cancer. These findings are consistent with the results of a study conducted by Wode et al, 29 which identified that herbal medicine was most frequently used to enhance physical and mental well-being and fighting cancer. Similarly, a study conducted by Molassiotis et al revealed a similar pattern, with herbal medicine primarily being employed to strengthen the immune system and fight cancer. In another study conducted by Kessel et al, CAM was found to be used with the hope of improving the immune system, reducing side effects, becoming more physically active, and enhancing the impact of oncological therapy. It is important to note that the differences in survey design across these studies may have contributed to the observed variations.
Patients often learn about herbal medicine and dietary supplements from various sources. According to a study by Wode et al, 29 the most common sources of information about CAM among both CAM users and non-CAM users were media, family, friends, and the media. Another study by Molassiotis et al 30 found that friends were the most common source of information, followed by family and media. Other sources of information included the patient’s physician, CAM practitioners, the internet, nurses, religious groups, personal knowledge, and other patients who used CAM. According to a study conducted by Kessel et al 31 on a German population, patients identified the most common sources of medical information gathering as their treating physician/therapist. During therapy, 50.0% of patients relied on their healthcare providers for information, while 48.2% sought information from their healthcare providers before starting therapy. In our study, we found that most patients learned about herbal medicines and dietary supplements from family members and from television. This finding is consistent with those of previous studies.
Herbal medicines are known to have immune-regulatory effects. 32 Curcumin, the active ingredient in turmeric, is well-known for its strong anti-inflammatory and immune-boosting effects. It can influence various immune cells like T cells, B cells, and macrophages, helping to strengthen the immune system. 33 Similarly, reishi mushroom (Ganoderma lucidum) contains compounds such as polysaccharides and triterpenes that have been shown to significantly enhance immune function by promoting the growth and activity of immune cells like natural killer cells and macrophages. 34 Ginseng, especially Panax ginseng, is rich in ginsenosides, which are known to boost both innate and adaptive immunity. 35 Similarly, there are other data on other herbal medicines with immune-regulatory effects. 32 However, the interactions between these herbal medicines and immunotherapies, as well as their contributions to immunotherapy, are not yet fully understood. Limited data on this topic include a case study of a 33-year-old male lung cancer patient who developed toxic hepatitis while taking herbal medicine alongside immunotherapy and chemotherapy. 36 This case report highlights the potential risks associated with combining herbal medicines with conventional cancer treatments.
Despite the potential benefits mentioned above, it is important to consider the literature regarding the side effects of various herbal remedies. These remedies, while offering health advantages, can potentially lead to adverse reactions. St. John’s Wort is well-known for its numerous drug interactions due to its impact on the cytochrome P450 3A4 enzyme. 37 In cancer patients, it is particularly known to interact with medications such as irinotecan, docetaxel, imatinib, and methotrexate.38 -41 Although it does not interfere with immune checkpoint inhibitors (ICIs) that patients might be using, it can interact with certain medications frequently used by cancer patients, such as paracetamol, oxycodone, omeprazole, and selective serotonin reuptake inhibitors.42 -45 Ginseng, a commonly used herb comprising P. ginseng and Panax quinquefolius, has not been associated with significant side effects. However, some patients reported vaginal bleeding and mastalgia, which may be attributed to the estrogenic effects of ginseng. High doses of P. ginseng (more than 2.5 g/day) have been linked to central nervous system (CNS) effects, such as insomnia, tachyarrhythmias, hypertension, and nervousness. Other reported adverse effects of P. ginseng include headaches and gastrointestinal disorders. 46 Curcumin, the active compound in turmeric, may also cause gastrointestinal problems. 36 Reishi mushrooms can cause dizziness and stomach upset and, in some cases, may induce liver toxicity. 47 In our study, the most common side effects were gastrointestinal (GI)-related. However, most patients do not experience any side effects. Similarly, Wode et al 29 found that only 5.6% of patients experienced side effects, with the most common being GI-related, in addition to cough and fever. Molassiotis et al 30 reported that only 4.4% of patients experienced side effects with CAM therapy, with GI-related side effects being the most common.
In conclusion, our study revealed mixed beliefs among patients about the risks of using herbal products and dietary supplements during treatment with immune checkpoint inhibitors. While some patients expressed concerns about an increase in side effects, others were worried about a possible decrease in treatment effectiveness. Patients should be informed that some herbal products can interact with immunotherapies, such as by reducing their effectiveness and causing adverse effects. The risk of herb-drug interactions is higher in patients on polypharmacy. The most commonly seen mechanisms of this interaction are herb-mediated inhibition and induction of enzymes, leading to an alteration in the pharmacokinetics of these chemotherapeutics. 48
It is important to acknowledge the limitations of our study, which include its limited geographical scope and reliance on self-reported data, thus introducing the possibility of recall bias. Additionally, due to differences in healthcare coverage, some cancer types were overrepresented while others were underrepresented. We also did not investigate the dosages of herbal products and dietary supplements used by the participants. Furthermore, the small number of patients in certain subgroups limits the statistical power of our analyses. Despite these limitations, our study provides an initial overview of the use of herbal medicine and dietary supplements in patients undergoing immunotherapy. Future research should address these limitations to enhance our understanding of herbal medicine and dietary supplement use, and to guide healthcare providers in effectively managing their integration with conventional cancer treatment.
Footnotes
Author Contributions
Collecting data: F.K, B.A, S.K, O.S, E.C, A.A, B.K, Y.B.S, O.A.K, N.T.Z, F.S/. Data curation: F.K, Y.B.S, N.T.Z, F.S. Statistical analysis: F.K. Writing: F.K. Review and editing: D.C.G., H.C.Y., O.Y., S.Y.
Data Availability
The data sets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
