I. Introduction
The International Agency for Research on Cancer estimates that the global cancer burden rose to 19.3 million cases in 20201 and suggests that more than 50 million people are living with cancer diagnosed within the last five years. The prevention and treatment of cancer is a significant public health challenge of the 21st century2. To reduce the overall mortality rate associated with cancer, combined success in cancer prevention, early detection, screening, and treatment is needed3.
Conventional cancer treatments, such as radiation therapy and chemotherapy, aim to cure the disease or prolong the patient’s life4. Nevertheless, they often lead to poor quality of life and dose delays because of their side effects and toxicities. Cytotoxic chemotherapy suppresses the hematopoietic system and increases the risk of life-threatening infections owing to neutropenia5.
Cancer immunotherapy has been a paradigm in modern oncology since 1985. The mechanism of action of this therapy blocks the way cancer cells develop and evade immunosurveillance6. However, the response rates to immunotherapy vary widely among different cancers. Approximately 15-30% of patients respond objectively to immune checkpoint inhibitors7.
Herbal medicine is a typical complementary and integrative medicine used in Asia to treat cancer4. Clinical trials using herbal medicines as adjuvant cancer treatments have shown effectiveness in reducing cancer-related fatigue, pain, and gastrointestinal side effects, such as vomiting, diarrhea, and nausea. A previous review showed that herbal medicine reduces respiratory tract infections, one of the most common complications of radiotherapy, and improves the symptoms of cachexia and quality of life in patients with cancer8.
In many pre-clinical studies, herbal medicine has demonstrated antitumor effects by upregulating immune responses in the immunosuppressive tumor microenvironment (TME)9. Furthermore, a clinical trial using herbal extracts evaluated changes in NK cell activity. The herbal intervention group had a higher immunoregulatory effect than the placebo group10.
Even so, clinical trials using herbal medicines to improve immune function in patients with cancer have yet to be systematically examined. Our study will review randomized controlled trials (RCTs) that evaluate the effectiveness of herbal medicines in improving immune function in patients with cancer4.
II. Methods
1. Study registration
This review’s protocol was registered in PROSPERO (registration number CRD42022354649).
We will conduct a systematic review according to this protocol, and the dates, changes, and rationales for each amendment will be tracked in PROSPERO if no protocol amendments are made. This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis guideline11.
2. Search method for identifying the studies
The following electronic databases will be searched: MEDLINE via PubMed, EMBASE via Elsevier, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI), and Korean databases, including Regional Information Sharing Systems (RISS), National Digital Science Library (NDSL), and Oriental Medicine Advanced Searching Integrated System(OASIS). The reference lists of the retrieved articles will be manually searched, and previous review articles will be examined. There will be no restrictions on the year or language of the reviewed publications.
The search strategy for Medline is shown in Table 1 and will be modified similarly for other databases.
Table 1
Medline Search Strategy
3. Inclusion criteria for this review
1) Types of studies
This systematic review will include prospective RCTs. These RCTs will evaluate the effectiveness of herbal medicines on immune functions in patients with cancer. Studies with other designs, such as observational studies, cohort studies, case reports, case series, non-RCTs, and animal and experimental studies, will be excluded.
2) Types of participants
Patients with all types of cancer, regardless of sex, age, and cancer stage, will be included in the review.
3) Types of interventions
Studies including orally (e.g., decoction, tablets, pills, or powders) administered herbal medicines will be included in this review. RCTs in which other interventions (e.g., chemotherapy, radiation, and hormone therapy) were administered to all groups using same protocol will be included. The exclusion criteria include studies involving herbal extracts, herbal injections, and RCTs in which herbal medicines were combined with other interventions.
There will be no restrictions on comparisons. Placebos, active control groups, no-treatment groups, and wait-list control groups will be used as control groups.
4) Type of outcome measures
All outcomes related to immune functions of cancers (e.g., CD3, CD4, CD8, CD4/CD8 ratio, CD19 (B cells), dendritic cells (CD11), CD56 (NK cells), and macrophages) will be included in this review. However, RCTs that did not report the measured values before and after treatment will be excluded.
4. Data collection, extraction, and assessment
1) Selection of studies
Two authors (YC and SJ) will independently screen the titles and abstracts of studies retrieved from the databases after excluding duplicate articles. The full texts of the selected articles will then be reviewed to ensure that each article meets the inclusion criteria for this review. Finally, a third reviewer (M-KJ) will provide the decisive factor if the two authors have a difference of opinion.
2) Data extraction
Two authors (YC and SJ) will extract the data, and a third author (M-KJ) will review the extracted data. Essential information for each article will be summarized, including the title, first author, published year, journal, study period, participants, interventions, comparisons, outcomes, results, and adverse events.
3) Assessment of risk of bias
Two reviewers (YC and SJ) will assess the quality of the included studies using the Cochrane Handbook risk of bias (RoB) assessment tool version 6.312. RoB will be assessed using the following seven items: 1) random sequence generation, 2) allocation concealment, 3) blinding of participants and personnel, 4) blinding of outcome assessment, 5) completeness of outcome data, 6) completeness of reporting, and 7) other sources of bias. In each RCT, items will be categorized as “high risk (H),” “unclear (U),” or “low risk (L).” In addition, an RoB graph will be generated using Review Manager (Cochrane Collaboration Software, RevMan), version 5.3 for Windows (Copenhagen, The Nordic Cochrane Centre, the Cochrane Collaboration, 2012).
5. Data synthesis
Differences between the intervention and control groups will be assessed. The mean differences (MDs) with 95% confidence intervals (CIs) will be used to measure the treatment effects for continuous data. In addition, we will convert other forms of data into MDs. For outcome variables on different scales, standard MDs (SMDs) with 95% CIs will be used. For dichotomous data, we will present treatment effects as relative risks (RRs) with 95% CIs; other binary data will be converted into RRs.
All statistical analyses will be conducted using RevMan version 5.3. We will contact the corresponding authors of studies with missing information to acquire and verify the data whenever possible. We will pool the data across studies to conduct a meta-analysis using fixed or random effects. Finally, we will use the GRADEpro software from Cochrane Systematic Reviews to create a summary of the findings.
III. Results
This review is expected to provide data on the effectiveness of herbal medicines on improving immune functions in patients with cancers.
IV. Discussion
One in five individuals worldwide develops cancer during their lifetime. One in eight males and one in eleven females will die from the disease. Effective strategies to treat cancer still need to be improved2. Various studies have suggested that herbal medicine is an effective complementary medicine that reduces the side effects of conventional cancer treatments13.
Herbal medicine can also be used to improve cancer-related fatigue, the most common symptom that affects the quality of life in patients with cancer14. Herbal medicine may work as an anti- cancer agent by exhibiting an anti-inflammatory and cytotoxic effect in tumors and by regulating the TME15. These mechanisms of action demonstrate the potential of herbal medicine to mitigate the limitations associated with conventional treatment methods4.
A previous review showed that herbal medicine regulates both innate and adaptive immunity9. Herbal medicine achieves this regulation by promoting the quantity of components involved in innate immunity and phagocytic capacity and the maturation and expression of antibodies in acquired immunity16.
Recent cancer immunotherapy targets the reactivation of the immune system by inhibiting tumor cell immune checkpoints. Understanding the interactions between tumor cells and immunomodulators in TME is needed to improve the reaction rate of cancer immunotherapy17. Herbal medicine is trend based on its multitarget compounds and antitumor effects on TME18. The clinical application of herbal medicines to improve immune function in the treatment of various cancer types is crucial. Eliminating cancer relies on restoration of the patient’s immune function. This systematic review will help patients and clinicians establish new management options for cancer treatment.
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