Myelosuppression, also known as bone marrow suppression or myelotoxicity, is a decline in the activity of the bone marrow, resulting in decreased numbers of WBCs, platelets, and RBCs. Myelosuppression is one of the most commonly observed side effects of chemotherapy and radiotherapy, and it is also a listed side effect of many chemotherapy drugs. Patients are usually given these medications anyway because dying from cancer poses a more immediate threat. Therefore, the possibility of myelosuppression must be considered and monitored when using a chemo- or radiotherapy treatment plan.
Once patients undergo myelosuppression, the bone marrow cannot make the normal level of blood cells. Given that many blood cells have a very short life in the body, patients start to suffer medical complications almost immediately. These include anemia from a low number of RBCs, hemorrhage due to thrombopenia, and immunosuppression caused by a low number of WBCs. Patients will be at risk of developing fatal infections and will not be able to fight them off [
It is crucial to avoid damaging nonmalignant cells during the clinical application of chemotherapy and radiotherapy to reduce morbidity and mortality from infections due to myelosuppression. There have been many research attempts to find safe agents that can reduce myelosuppression and improve the immune response in chemotherapy- or radiotherapy-treated patients. One treatment that has become increasingly attractive in recent years is the use of alternative therapies, especially CHM, as an adjunctive treatment to prevent myelosuppression. Numerous studies have already reported the myelosuppression reduction effects in cancer patients who received CHM during their chemotherapy or radiotherapy treatment. These studies had a variable design and have generally reported inconclusive or conflicting results, making the clinical decision of whether to recommend or omit the use of CHM during chemotherapy/radiotherapy in cancer patients difficult [
It would be worthwhile to assess the quality and evaluate the efficacy of data from trials according to the principles and measurements of evidence-based medicine. There is no previously published systematic review examining the role of CHM to prevent myelosuppression caused by chemotherapy or radiotherapy. In the present study, we sought to perform a systematic review of RCTs on the use of CHM during chemotherapy or radiotherapy of cancer patients to generate a more precise estimate of the possible therapeutic value of CHM on preventing myelosuppression.
Our review was restricted to RCTs that compared CHM plus chemotherapy/radiotherapy with placebo plus chemotherapy/radiotherapy or chemotherapy/radiotherapy alone.
We included all patients with any type of solid tumor or hematologic malignancy, who accepted chemotherapy or radiation therapy combined with CHM, irrespective of the patient’s sex, age, ethnicity, and occupation. All appropriate definitions of myelosuppression included decreased peripheral blood WBCs, RBCs, platelets, or hemoglobin. Patients with serious medical conditions were excluded.
The intervention was required to be a clinical trial evaluating all forms of CHM (herbal formula, single herb, herbal extractions, or compounds including herbs and other supplements), which were administered either orally or intravenously, used alone or in combination with other herbs for subjects in the treatment and placebo groups or without additional intervention except chemotherapy or radiotherapy in the control groups.
The outcome measures included changes in the peripheral blood WBCs as the primary outcome and changes in the peripheral blood RBCs, platelets, and hemoglobin as the secondary outcomes.
The methodological quality of all included trials was independently assessed by two reviewers according to “Risk of Bias table,” which is recommended by Cochrane Handbook 5.1.0. Reviewers were not blinded with respect to the authors, institution, and journal because they were familiar with the literature. Two review authors (Youji Jia and Huihui Du) independently assessed the risk of bias with the criteria in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (
Exclusions included case or experience reports, preclinical studies (e.g.,
We searched PubMed, EMBASE, the Cochrane Library, the CNKI, Wanfang Data, the VIP, and the CBM, a total of 7 electronic databases, from the date of database creation to April 2014.
We followed the research strategy using the following key words: (I) Neoplasm OR Tumor OR Neoplasia OR Cancer; (II) Chemotherapy OR Pharmacotherapy OR Adjuvant Drug Therapy OR Drug Polytherapy OR Drug Therapy; (III) Radiosurgery OR Radiotherapy OR radiation therapy OR radioisotope therapy OR X-ray therapy OR Radioisotope Brachytherapy OR Radioisotope Plaque Therapy OR Curietherapy; (IV) Erythrocyte OR Red Blood Corpuscle OR Red Blood Cell OR Erythrocytopenia OR Erythropenia OR Anemia; (V) Granulocytopenia OR Agranulocytosis OR Granulopenia OR White Blood Corpuscle OR Leukocyte OR White Blood Cell; (VI) Soterocyte OR Platelet OR Haematoblast OR Thrombocyte OR Thrombocytopenia OR Thrombopenia; and (VII) (trial OR randomly OR clinical trials OR placebo OR randomized OR randomized controlled trial OR controlled clinical trial) NOT (animals NOT humans), regardless of the language and publication status.
Two independent reviewers (Youji Jia and Huihui Du) evaluated the title and abstract of every document retrieved from the literature searches. The full text of all potentially relevant articles was explored in any language. For confusing or missing information, we contacted the authors, where possible. For duplicate publications, the original one was used.
Two reviewers (Youji Jia and Huihui Du) independently extracted the study characteristic data from all eligible articles, including the authors, publication date, study type, participants, sample size, interventions, outcomes, baseline treatment, type of CHM, and follow-up. The authors were contacted for more information, as needed. Two review authors (Min Yao and Xuejun Cui) checked and entered data into Review Manager (RevMan 5.2.1).
Statistical analysis was performed using RevMan 5.2.1. The results were pooled and continuous data were expressed as the weighted mean difference (WMD) or standardized weighted mean difference (SMD) with a 95% CI.
The chi-square test (
Funnel plots were made to assess the publication bias, when at least 10 trials were included in the meta-analysis.
In total, 646 articles were retrieved following the search strategy described above (259 in English and 387 in Chinese). Potential studies, including 14 in English and 303 in Chinese, were identified by title and abstract screening to exclude trials that were duplicates [
Flow of the included studies.
These eight trials were all RCTs using CHM, and the duration of studies ranged from 1 to 3 years. Six of the studies were performed in mainland China, and two of them were conducted in Taiwan.
A total of 818 subjects (429 males and 389 females) were included in the eight trials. The number of patients included in each study ranged from 58 to 235, and there was an average sample size of 103.5. There are seven adult patients and one pediatric patient, who had a total of 13 different types of cancer, including breast cancer, colon cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, stomach cancer, leukemia, esophageal cancer, pancreatic cancer, prostate cancer, neuroblastoma, Wilms tumor, and hepatoblastoma. The baselines of all eight randomized studies were compared between the treatment and control groups, and there were no statistically significant differences.
The intervention varied noticeably across the trials. All eight trials included a basic chemotherapy or radiotherapy in both the test and control groups and five of the trials described the type of chemotherapy drugs used. Two [
Details of the included studies.
Author, year | Study types | Participants | Sample size (T/C) | Intervention | Outcome | Baseline treatment | Detail content of CHM | Lost to follow-up |
---|---|---|---|---|---|---|---|---|
Zhuang et al., 2009 [ |
Randomized, double-blind | Breast/nasopharyngeal/colon/lung | 55/50 | Extract of CHM versus placebo | PLT, RBC, and Hb | Chemotherapy or radiotherapy |
|
16 incomplete, 7 giving up, 1 and poor compliance |
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Zhuang et al., |
Randomized, double-blind | Breast cancer | 31/27 | Extract of CHM versus placebo | PLT, RBC, and Hb | Chemotherapy or radiotherapy |
|
6 therapeutic regimen changed, 1 erythra, and 1 intolerance in capsules taste |
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Chen and Shen, |
Randomized | Colon/rectal cancer | 60/60 | CHM plus chemotherapy versus chemotherapy | WBC, PLT, RBC, and Hb | Chemotherapy | Qisheng Mixture (Astragalus, angelica, Cimicifuga rhizome, and Rhizoma Polygoni Cuspidati) |
Not described |
|
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Xu et al., |
Randomized | Lung/breast/gastric/intestinal cancer | 55/57 | CHM plus chemotherapy versus chemotherapy | WBC | Chemotherapy | Shuanghuang Shengbai Granule |
Not described |
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Li et al., |
Randomized, double-blind | Refractory acute leukemia | 118/117 | CHM plus chemotherapy versus chemotherapy | WBC, PLT, and Hb | Chemotherapy | Compound Zhebei granules. |
Not described |
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Shi et al., |
Randomized | Neuroblastoma tumors, nephroblastoma, and hepatoblastoma | 30/30 | CHM plus chemotherapy versus chemotherapy | WBC, PLT, and Hb | Chemotherapy | (1) Millet sprout, rice sprout, Qu Jian, Alpinia katsumadai, Costas, Amomum villosum. |
Not described |
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Chu, |
Randomized | Lung/breast/gastric/colorectal/esophageal/pancreatic | 36/36 | CHM plus chemotherapy versus chemotherapy | WBC, PLT, and Hb | Chemotherapy | Bushen Shengxue recipe |
Not described |
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Liu, |
Randomized | Lung/breast/stomach/prostate | 28/28 | CHM plus chemotherapy versus chemotherapy | WBC | Chemotherapy | Licorice root, deerhorn glue, Radix Rehmanniae Preparata, Fructus Psoraleae, Himalayan teasel root, Poria, Atractylodes, Radix Pseudostellariae, Angelica, and Astragalus sunburn |
Not described |
All eight trials showed routine blood reports, including the WBCs, RBCs, and hemoglobin (Hb) and platelet (PLT) values.
The reports of all trials mentioned randomization, but only five described the method of randomization [
Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.
There were 6 RCTs [
Meta-analysis of studies evaluating the effect of CHM on preventing WBC loss in cancer patients undergoing chemotherapy or radiotherapy.
Meta-analysis of studies evaluating the effect of CHM on preventing WBC loss in cancer patients undergoing chemotherapy or radiotherapy after one study was dropped.
Two trials that included an RBC examination conducted a placebo-controlled test and were combined in a meta-analysis (Figure
Meta-analysis of studies evaluating the effect of CHM on preventing RBCs from decreasing in cancer patients undergoing chemotherapy or radiotherapy.
Only one included study investigated the change in the RBCs between CHM combined with chemotherapy and chemotherapy, which also showed no statistically significant difference (
Six reports with platelet measurements were divided into two subgroups. One subgroup included two studies that compared the effects of CHM versus placebo during chemotherapy or radiotherapy in clinical cancer patients [
Meta-analysis of studies evaluating the effect of CHM on preventing platelets from decreasing in cancer patients undergoing chemotherapy or radiotherapy.
Six studies included measurements of the serum hemoglobin levels. Two of the studies compared the effects of CHM and placebo during chemotherapy or radiotherapy in clinical cancer patients [
Meta-analysis of studies evaluating the effect of CHM on preventing hemoglobin from decreasing in cancer patients undergoing chemotherapy or radiotherapy.
Funnel plots could not be performed due to the small number of studies evaluated.
In this systematic review of articles published in English and Chinese, we have identified eight randomized studies using CHM. A total of 818 subjects were included and the duration of studies ranged from 1 to 3 years. Six of these studies were performed in mainland China and 2 of them were conducted in Taiwan. The baselines of these eight randomized studies were compared between the treatment and control groups, and there was no significant difference. Although we searched both English and Chinese databases, we still cannot promise that all relevant trials were found, so the publication bias could not be ignored.
We have tried to identify all RCTs on CHM for prevention of chemotherapy- or radiotherapy-induced myelosuppression, although this might be limited by incomplete citation tracking, as is the case with most systematic reviews. We were able to review studies performed and published in China and English-speaking countries, and a small number of studies performed in Japan and Korea were written in English. We could not include all trials from Korea or Japan written in their native language even though traditional Chinese medicine (TCM) is extensively used in these two countries.
Herbal formulae used in studies performed in China generally showed a good tolerability, while CHM intervention used in studies performed outside China was likely to have more side effects [
CHM generally uses multiple herbs, which may produce complementary and antagonistic effects to balance the benefits and adverse effects. Even with these positive results, some over-the-counter Chinese remedies have been used together with Western medications, which may increase the chance of side effects [
Given that myelosuppression mainly results from the use of symptomatic therapy, the application of TCM is a possible strategy to address this unmet therapeutic area. Myelosuppression is graded according to anticancer drugs in acute and subacute toxicity of classificatory criteria (WHO criteria) as described in Table
Anticancer drugs in acute and subacute toxicity of classificatory criteria (WHO criteria).
Items | 0 degree | I degree | II degree | III degree | IV degree |
---|---|---|---|---|---|
Hemoglobin (g/100 ml) | >11.0 | 10.9–9.5 | 9.4–8.0 | 7.9–6.5 | <6.5 |
WBC (1000/m3) | >4.0 | 3.9–3 | 2.9–2.0 | 1.9–1.0 | <1.0 |
Granulocyte (1000/m3) | >2.0 | 1.9–1.5 | 1.4–1.0 | 0.9–0.5 | <0.5 |
Platelets (1000/m3) | >100 | 99–75 | 74–50 | 49–25 | <25 |
The following is a description of the conventional therapeutic methods. Recombinant human erythropoietin (rhEPO), with supplement of other iron agents (such as dextran), is used to promote erythropoiesis and eliminate the iron utilization obstacle for the RBC thrombocytopenia and anemia. Transfuse RBCs or whole blood when hemoglobin is less than 85 g/L. Reduce movement, control the blood pressure, avoid using antiplatelet drugs, and use interleukin-11 (IL-11) and rhTPO when patients have thrombocytopenia and bleeding. Transfuse blood components with platelets or whole blood when the platelet concentration is less than 20 × 109/L or bleeding is severe. Prevention is preferred for leukopenia/neutropenia, fever, or infection, and we can use conventional drugs to increase the WBCs or hematopoietic stem cell differentiation, promoting the effects of therapy. Apply recombinant human granulocyte colony-stimulating factor (rhG-CSF) to patients with severe symptoms, and use antibiotics to control infection, when necessary. Generally, patients with degree III or higher myelosuppression must be treated. However, there are currently no clear criteria for those belonging to degree II or lower, and treatment mainly focuses on symptomatic therapy [
This systematic review is based on a number of clinical RCTs, and the quality of included studies was strictly screened and controlled. In this meta-analysis, we concluded that CHM could effectively prevent radiotherapy- and chemotherapy-induced myelosuppression in cancer patients. The reduction in WBC counts during radiotherapy or chemotherapy in cancer patients was blocked by the administration of CHM, which controlled infection. Therefore, the use of CHM is recommended as a basic therapeutic remedy during radiotherapy and chemotherapy in cancer patients to prevent infection due to insufficient WBCs.
Among the six included RCTs that studied the protective effects of CHM on chemotherapy or radiotherapy affected WBCs, it looks like CHM had extremely strong protective effects on WBCs in Li et al.’s report [
After comparing the detailed information of the four convincing RCTs (Chen and Shen [
The higher the quality of the included studies is, the more we can draw scientific conclusions by meta-analysis. Some studies in the literature have limitations. For example, in some, the random method was not clear and blinding was not implemented. Some studies were performed in China or Taiwan, which did not have international registries, and there was a lack of scientific quality control. The same group in Taiwan performed two of the studies, which may have a performance bias. The included studies had heterogeneity in the type of cancer and use of CHM; as a result, the subgroup analyses could not be conducted. These may, to some extent, limit the scientific validity of the analyzed results.
In conclusion, we demonstrated that CHM significantly prevented peripheral WBCs from being damaged by chemotherapy and radiotherapy in cancer patients by comparing CHM plus chemotherapy or radiotherapy with chemotherapy or radiotherapy alone. However, these results provide no convincing evidence for the efficacy of CHM on recovering platelets, red blood cells, and hemoglobin, which were affected by chemotherapy and radiotherapy in cancer patients. However, this may be due to the small number, size, and methodological quality of the available RCTs that used CHM to prevent bone marrow suppression as a result of radiotherapy and chemotherapy. Further rigorous, multicenter RCTs with a large sample size are necessary to further examine these topics, but they must overcome the limitations present in the current publication. This will benefit patients with decreased bone marrow function.
There was no conflict of interests.
This study was supported by grants from (1) National Nature Science Foundation (81102851 and 81373667), (2) Shanghai Pujiang Program (12PJ1408100), (3) China Postdoctoral Science Foundation (2012M520919), (4) the Longhua Medical Team Project (LYTD-08), (5) Kyorin Scholars of Shanghai University of Traditional Chinese Medicine (2209.13.03), (6) Independent Innovation Program Supported by Science and Technology Innovation of the “085” First-Class Disciplines Construction of Shanghai University of TCM (085ZY1217), and (7) the National Basic Research Program of China (973 Program, 2010CB530400).