The Use of Herbal Medicine and Dietary Supplements in Cancer Patients Receiving Immune Checkpoint Inhibitors: A Multicenter Cross-Sectional Study

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.

Keywords

complementary and alternative medicine herbal immune checkpoint inhibitors

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 cancer^1
-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.

Table 1.

Distribution of Sociodemographic and Clinical Variables of Patients (n = 181).

Variables	Mean or median (min-max)	% or mean ± SD
Age (y)	62.0 (21.0-89.0)	60.68 ± 13.52
Age group
18-44 y	23	12.7
45-59 y	52	28.7
60 y and older	106	58.6
Gender, n (%)
Female	61	66.3
Male	120	33.7
Education, n (%)
Pre-high school	87	48.0
High school	47	26.0
University and higher	47	26.0
Living arrangements
Alone	21	12.0
Spouse	72	41.1
Spouse + children	82	46.9
Smoking status
Never smoked	72	39.8
Current smoker	39	21.5
Former smoker	70	38.7
Immune checkpoint inhibitors used
Nivolumab	127	70.2
Pembrolizumab	50	27.6
Atezolizumab	4	2.2
Marital status
Married	165	91.2
Single	16	8.8

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).

Table 2.

Frequency Analysis of the Sociodemographic and Various Variables of the Participants.

Question	Response	Herbal Medicine Users n (%)	Dietary Supplements Users n (%)
Have you used any herbal medicine/dietary supplements while receiving chemotherapy?	Yes	10 (5.5)	20 (11.0)
	No	171 (94.5)	161 (89.0)
Did you use any herbal medicine/dietary supplements while receiving Immune checkpoint inhibitors?	Yes	16 (8.8)	27 (24.1)
	No	165 (91.2)	85 (75.9)
How often do you use the herbal medicine/dietary supplements you are using?	Regularly, every day	9 (56.25)	18 (64.3)
	Once a week or occasionally	4 (25)	8 (28.6)
	Rarely	3 (18.75)	2 (7.1)
Where did you obtain information about the herbal medicine/dietary supplements you use while receiving Immune checkpoint inhibitors?	Household	6 (37.5)	10 (35.7)
	Friends	4 (25)	2 (7.1)
	TV	4 (25)	7 (25)
	Doctor	1 (6.25)	8 (28.6)
	Internet	1 (6.25)	1 (3.6)
Did you experience any side effects related to the herbal medicine/dietary supplements during using Immune checkpoint inhibitors?	No	10 (62.5)	20 (71.4)
	Gastrointestinal side effects	4 (25)	6 (21.4)
	Rash and itching	2 (12.5)	2 (7.1)
What is your purpose for using herbal medicine/dieatry supplements during Immune checkpoint inhibitors?	I believe they are effective against cancer.	5 (31.25)	6 (21.4)
	I use them to treat symptoms related to the disease.	3 (18.75)	1 (3.6)
	I use them to combat the side effects of oncologic treatments.	2 (12.5)	4 (14.3)
	I use them to strengthen my immune system.	6 (37.5)	17 (60.7)
How much money do you spend monthly on the herbal medicine/dietary supplements during using Immune checkpoint inhibitors?	I didn’t spend any money.	1 (6.25)	9 (32.1)
	<3 dollars	4 (25)	10 (35.7)
	3-15 dollars	7 (43.75)	8 (28.6)
	15-30 dollars	4 (25)	1 (3.6)
Which herbal medicines/dietary supplements did you use?		Curcumin 6 (38)Nigella Sativa 2 (12)Reishi mushroom 3 (19)St. John’s wort. 3 (19)Panax Ginseng 2 (12)	Vitamins 14 (52)Omega-3 7 (26)Probiyotik. 5 (19)Protein powders 1 (3)

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).

Table 3.

Use of Herbal Medicine/Dietary Supplements During Immune Checkpoint Inhibitor Treatment.

Variables	Herbal medicine			Dietary supplements
	No	Yes	P-value	No	Yes	P-value
	n (%)	n (%)	P-value	n (%)	n (%)	P-value
Age group
18-44 y	20 (87)	3 (13)	.44	10 (66.7)	5 (33.3)	.31
45-59 y	46 (88.5)	6 (11.5)		24 (85.7)	4 (14.3)
60 y and over	99 (93.4)	7 (6.6)		51 (73.9)	18 (26.1)
Gender
Male	108 (90)	12 (10)	.44	64 (79)	17 (21)	.212
Female	57 (93.4)	4 (6.6)		21 (67.7)	10 (32.3)
Diagnosis	58 (86.6)	9 (13.4)	.12	35 (76.1)	11 (23.9)	.001
Lung	16 (88.9)	2 (11.1)		4 (57.1)	3 (42.9)
Melanoma	58 (98.3)	1 (1.7		41 (89.1)	5 (10.9)
RCC	33 (89.2)	4 (10.8)		5 (38.5)	8 (61.5)
Others
Stage
Non-stage 4	7 (87.5)	1 (12.5)	.71	2 (25)	6 (75)	.002
Stage 4	158 (91.3)	15 (8.7)		83 (79.8)	21 (20.2)
Education
Pre-high school	81 (93.1)	6 (6.9)	.49	41 (78.8)	11 (21.2)	.609
High school	43 (91.5)	4 (8.5)		23 (69.7)	10 (30.3)
University and higher	41 (87.2)	6 (12.8)		21 (77.8)	6 (22.2)
Living with
Alone	19 (90.5)	2 (9.5)	.96	10 (62.5)	6 (37.5)	.366
Spouse	65 (90.3)	7 (9.7)		32 (78)	9 (22)
Spouse and children	75 (91.5)	7 (8.5)		42 (79.2)	11 (20.8)
Smoking
None	65 (90.3)	7 (9.7)	.81	34 (75.6)	11 (24.4)	.381
Yes	35 (89.7)	4 (10.3)		13 (65)	7 (35)
Quit	65 (92.9)	5 (7.1)		38 (80.9)	9 (19.1)
Marital status
Married	150 (90.9)	15 (9.1)	.70	79 (77.5)	23 (22.5)	.446
Single	15 (93.8)	1 (6.3)		6 (60)	4 (40)

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 al³⁰ 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 al³¹ 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 al²⁹ 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 al³⁰ 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.

ORCID iD

Fatih Kus

References

Chae

Arya

Iams

, et al. Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018;6:39.

Bondhopadhyay

Sisodiya

Chikara

, et al. Cancer immunotherapy: a promising dawn in cancer research. Am J Blood Res. 2020;10:375-385.

Wang

, et al. Effective combinations of immunotherapy and radiotherapy for cancer treatment. Front Oncol. 2022;12:809304.

Longo

Brunetti

Azzariti

, et al. Strategies to improve cancer immune checkpoint inhibitors efficacy, other than abscopal effect: a systematic review. Cancers. 2019;11:539.

Golonko

Pienkowski

Swislocka

, et al. Dietary factors and their influence on immunotherapy strategies in oncology: a comprehensive review. Cell Death Dis. 2024;15:254.

Jermini

Dubois

Rodondi

, et al. Complementary medicine use during cancer treatment and potential herb-drug interactions from a cross-sectional study in an academic centre. Sci Rep. 2019;9:5078.

National Cancer Institute. NCI Dictionary of Cancer Terms. Cancer.gov. National Cancer Institute; 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/herbal-medicine

National Cancer Institute. NCI dictionary of cancer terms. Cancer.gov. (n.d.). https://www.cancer.gov/publications/dictionaries/cancer-terms/def/dietary-supplement#

Johns Hopkins Medicine. 2024. Accessed June 29, 2024. https://www.hopkinsmedicine.org/health/wellness-and-prevention/herbal-medicine#:~:text=Plant%2Dbased%20products%20used%20to,is%20called%20an%20herbal%20supplement

10.

Zhong

Vong

Chen

, et al. Immunomodulatory potential of natural products from herbal medicines as immune checkpoints inhibitors: helping to fight against cancer via multiple targets. Med Res Rev. 2022;42:1246-1279.

11.

Jin

Ruiz Beguerie

Sze

DMY

Chan

GC.

Ganoderma lucidum (Reishi mushroom) for cancer treatment. Cochrane Database Syst Rev. 2016;2019:Cd007731.

12.

Tavakoli

Miar

Majid Zadehzare

Akbari

Evaluation of effectiveness of herbal medication in cancer care: a review study. Iran J Cancer Prev. 2012;5:144-156.

13.

Jeitler

Michalsen

Frings

, et al. Significance of medicinal mushrooms in integrative oncology: a narrative review. Front Pharmacol. 2020;11:580656.

14.

Dong

Guo

Han

Wang

Emerging role of natural products in cancer immunotherapy. Acta Pharm Sin B. 2022;12:1163-1185.

15.

Yang

S-Y

Chun

, et al. Evaluation of the potential herb-drug interaction between Bojungikki-tang and PD-L1 immunotherapy in a syngeneic mouse model. Front Pharmacol. 2023;14:1181263.

16.

Yin

Wei

Jian

Yang

NS.

Therapeutic applications of herbal medicines for cancer patients. Evid Based Complement Alternat Med. 2013;2013:302426.

17.

Berretta

Dal Lago

Tinazzi

, et al. Evaluation of concomitant use of anticancer drugs and herbal products: from interactions to synergic activity. Cancers. 2022;14:5203.

18.

Krejbich

Birringer

The self-administered use of complementary and alternative medicine (CAM) supplements and antioxidants in cancer therapy and the critical role of nrf-2-a systematic review. Antioxidants. 2022;11:2149.

19.

Olaku

White

JD.

Herbal therapy use by cancer patients: a literature review on case reports. Eur J Cancer. 2011;47:508-514.

20.

Damery

Gratus

Grieve

, et al. The use of herbal medicines by people with cancer: a cross-sectional survey. Br J Cancer. 2011;104:927-933.

21.

Mwaka

Abbo

Kinengyere

AA.

Traditional and complementary medicine use among adult cancer patients undergoing conventional treatment in sub-Saharan Africa: a scoping review on the use, safety and risks. Cancer Manag Res. 2020;12:3699-3712.

22.

Ekor

The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol. 2014;4:177.

23.

Williamson

Liu

Izzo

AA.

Trends in use, pharmacology, and clinical applications of emerging herbal nutraceuticals. Br J Pharmacol. 2020;177:1227-1240.

24.

Karsch-Völk

Barrett

Kiefer

, et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2014;2014:CD000530.

25.

Park

Jin

Zheng

, et al. Cognition enhancing effect of panax ginseng in Korean volunteers with mild cognitive impairment: a randomized, double-blind, placebo-controlled clinical trial. Transl Clin Pharmacol. 2019;27:92-97.

26.

Peng

Dong

, et al. Anti-inflammatory effects of curcumin in the inflammatory diseases: status, limitations and countermeasures. Drug Des Devel Ther. 2021;15:4503-4525.

27.

Chen

Nan

Liu

, et al. Evaluation of immune modulation by β-1,3; 1,6 D-Glucan derived from Ganoderma lucidum in healthy adult volunteers: a randomized controlled trial. Foods. 2023;12:659.

28.

Ekiz

Abd El-Aty

, et al. Exploring the potential medicinal benefits of Ganoderma lucidum: from metabolic disorders to coronavirus infections. Foods. 2023;12:1512.

29.

Wode

Henriksson

Sharp

Stoltenberg

Hök Nordberg

Cancer patients’ use of complementary and alternative medicine in Sweden: a cross-sectional study. BMC Complement Altern Med. 2019;19:62.

30.

Molassiotis

Fernández-Ortega

Pud

, et al. Use of complementary and alternative medicine in cancer patients: a European survey. Ann Oncol. 2005;16:655-663.

31.

Kessel

Lettner

Kessel

, et al. Use of complementary and alternative medicine (CAM) as part of the oncological treatment: survey about patients' attitude towards CAM in a university-based oncology center in Germany. PLoS One. 2016;11:e0165801.

32.

Wang

Liu

Bao

Advances in research on the effects of natural drugs with immune-promoting effects on immune function. Eur J Inflamat. 2020;18:2058739220926878.

33.

Allegra

Mirabile

Ettari

Pioggia

Gangemi

The impact of curcumin on immune response: an immunomodulatory strategy to treat sepsis. Int J Mol Sci. 2022;23:14710.

34.

Wang

Lin

Immunomodulating effect of Ganoderma (Lingzhi) and possible mechanism. Adv Exp Med Biol. 2019;1182:1-37.

35.

Zhao

Zhang

Pharmacological effects of ginseng and ginsenosides on intestinal inflammation and the immune system. Front Immunol. 2024;15:1353614.

36.

Lopes

Anne

Guillaume

, et al. A case of hepatitis induced by herbal medicine in non-small cell lung cancer patient treated by a combination of immunotherapy and chemotherapy. J Oncol Pharm Pract. 2022;28:1926-1929.

37.

Markowitz

Donovan

DeVane

, et al. Effect of St John’s Wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA. 2003;290:1500-1504.

38.

Mathijssen

Verweij

de Bruijn

Loos

Sparreboom

. Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst. 2002;94:1247-1249.

39.

Yang

Juang

Tsai

Chao

Hou

YC.

St. John’s wort significantly increased the systemic exposure and toxicity of methotrexate in rats. Toxicol Appl Pharmacol. 2012;263:39-43.

40.

Frye

Fitzgerald

Lagattuta

Hruska

Egorin

MJ.

Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther. 2004;76:323-329.

41.

Komoroski

Parise

Egorin

Strom

Venkataramanan

. Effect of the St. John’s wort constituent hyperforin on docetaxel metabolism by human hepatocyte cultures. Clin Cancer Res. 2005;11:6972-6979.

42.

Volak

Court

. Role for protein kinase C delta in the functional activity of human UGT1A6: implications for drug-drug interactions between PKC inhibitors and UGT1A6. Xenobiotica. 2010;40:306-318.

43.

Nieminen

Hagelberg

Saari

, et al. St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain. 2010;14:854-859.

44.

Parker

Wong

ABH

Boon

Seeman

MV.

Adverse reactions to St John’s wort. Can J Psychiatry. 2001;46:77-79.

45.

https://www.mayoclinic.org/drugs-supplements-st-johns-wort/art-20362212.

46.

Mancuso

Santangelo

Panax ginseng and Panax quinquefolius: from pharmacology to toxicology. Food Chem Toxicol. 2017;107:362-372.

47.

Unlu

Nayir

Kirca

, et al. Ganoderma Lucidum (Reishi Mushroom) and cancer. J BUON. 2016;21:792-798.

48.

Fasinu

Rapp

GK.

Herbal interaction with chemotherapeutic drugs-a focus on clinically significant findings. Front Oncol. 2019;9:1356.