The Effectiveness And Mechanism Of Tonifying Kidney And Spleen Method On Preventing And Treatment Of Myelosuppression Induced By Adjuvant Chemotherapy Of Colorectal Cancer Ⅴ

Part I: Systematic review and meta-analysis of oral Chinese medicine to improve bone marrow suppression caused by adjuvant chemotherapy for colorectal cancer

1 Research background

In 2021, the International Agency for Research on Cancer (IARC) of the World Health Organization released the latest cancer statistics: 1.9 million new cases of colorectal cancer were reported in 2020, and approximately 930,000 patients died of colorectal cancer[1]. The latest data from China show that in 2015, the incidence and mortality of colorectal cancer in China ranked fourth and fifth in the spectrum of tumor incidence and tumor mortality, respectively, and showed an increasing trend year by year[2]. 40%-50% of colorectal cancer patients are diagnosed in the early and middle stages[3-5], and radical surgery is the key to treatment[6]; among patients with metastatic colorectal cancer, 10%-20% are initially resectable cases, and radical surgery can improve the patient's prognosis to a certain extent[7-9]. For patients with postoperative pathological stage II (high risk)/III and stage IV patients after radical resection, postoperative adjuvant chemotherapy can further improve the clinical benefits of patients [10-15].

However, the toxicity of chemotherapy, such as gastrointestinal reactions and bone marrow suppression, often limits the application of chemotherapy. Taking CapeOX or FOLFOX adjuvant chemotherapy as an example, during the 6-month treatment, the incidence of neutropenia, thrombocytopenia, and anemia is about 50% [16,17], and the incidence of ≥3 bone marrow suppression exceeds 10% [16,17]. And ≥3 toxicity may lead to a reduction in chemotherapy drugs, chemotherapy delays, or even chemotherapy termination. Therefore, the chemotherapy completion rate of the 6-month CapeOX or FOLFOX regimen is only 60-70%; even with the 3-month adjuvant chemotherapy regimen, more than 10% of patients cannot complete the established chemotherapy regimen [17]. According to the NCCN guidelines and the expert consensus on chemotherapy-related hematopoietic function damage in China [18-201, it is recommended to use HGFs, such as G-CSF and GM-CSF, to prevent and treat chemotherapy-induced neutropenia; blood transfusion, erythropoietin (such as erythropoietin, EPO), iron supplementation, etc. to treat chemotherapy-related anemia; for chemotherapy-induced thrombocytopenia, platelet transfusion, platelet growth factor, thrombopoietin receptor agonist and other treatment measures can be considered. However, the use of HGFs often brings new clinical problems. For example, the use of G-CSF may cause common adverse reactions such as bone pain, myalgia, fever, and fatigue [21-23], and some cases even have serious adverse reactions such as spleen rupture 124].

NEW HERBS FOR TREATING COLORECTAL CANCER CHEMOTHERAPY-INDUCED BONE MARROW SUPPRESSION

The use of traditional Chinese medicine to prevent and treat colorectal cancer chemotherapy-induced bone marrow suppression has a long history. Although there are many related clinical studies based on evidence-based medicine, most of them are small sample clinical studies, and some research results are inconsistent. This study evaluated the efficacy of traditional Chinese medicine in preventing and treating bone marrow suppression caused by adjuvant chemotherapy for colorectal cancer through systematic review and meta-analysis, to provide evidence-based medicine for clinical practice.

2 Research methods

This study strictly followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) principles.

2.1 Data source and retrieval strategy

The data of this study mainly came from electronic retrieval. A total of 8 databases were searched, including China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP, China Biology Medicine disc (CBM disc), Pubmed, Embase, Cochrane Library, and Web of Science. The search time range is from database establishment to January 20, 2021. Taking Pubmed as an example, the search strategy is shown in Table 1:

2.2 Literature inclusion and exclusion criteria

2.2.1 Literature inclusion criteria

(1) Study type: randomized controlled clinical trials (RCTs), regardless of whether the blind method is used.

(2) Study subjects: patients with colorectal cancer confirmed by pathology, postoperative pathological stage TNM stage I-IIII, or Duke's stage A-C, after radical surgery, adjuvant chemotherapy, or preoperative neoadjuvant chemotherapy; or after stage IV radical surgery, adjuvant chemotherapy; pathological type is not limited; gender, age, and race of subjects are not limited.

(3) Intervention measures: Control group: systemic chemotherapy + conventional supportive treatment + Chinese medicine placebo; Experimental group: control group + oral Chinese medicine (decoction, granules) or Chinese patent medicine; other treatment measures except Chinese medicine must be consistent between the experimental group and the control group; chemotherapy regimen, number of chemotherapy cycles, and time of Chinese medicine intervention are clear; Chinese medicine can be given in advance before chemotherapy or simultaneously with chemotherapy.

(4) Outcome indicators: at least one of the following outcome indicators: incidence of myelosuppression, the incidence of grade I/II/III/IV myelosuppression, the incidence of leukopenia, the incidence of grade I/II/I/IV leukopenia, the incidence of thrombocytopenia, the incidence of grade I/II/II/IV thrombocytopenia, the incidence of hemoglobinemia, the incidence of grade I/II/II/IV hemoglobinemia, the incidence of erythrocytes, the incidence of grade I/I/II/IV erythrocytes, the incidence of neutropenia, the incidence of grade I/II/II/IV neutropenia, white blood cell count (WBC) (x±s), hemoglobin (HGB) (x±s), red blood cell count (RBC) (x±s), platelet count (PLT) (x±s).

[Chinese Databases]                      [International Databases]

CNKI (n=336)                             Pubmed (n=31)

Wanfang (n=818)                          Embase (n=123)

VIP (n=41)                               Cochrane (n=7)

Chinese Biomedical Literature            Web of Science (n=17)

Database (n=461)

         |                                       |

         ↓                                       ↓

   [Duplicate Removal]

         (n=1528)

              |

              ↓

[Title and Abstract Screening]  → [Excluded (n=1125):

         (n=1528)                 (1) Repeated (n=157)

              |                   (2) Reviews, systematic reviews, 

              |                      meta-analyses (n=170)

              |                   (3) Irrelevant (n=611)

              |                   (4) Non-RCT (n=100)

              |                   (5) Non-English/Chinese (n=71)

              |                   (6) Western medicine combined 

              |                      with other therapies (n=16)]

              ↓

     [Full-Text Reading]        → [Excluded (n=366):

          (n=403)                 (1) Disease period not matching (n=223)

              |                   (2) Non-English/Chinese (n=57)

              |                   (3) Outcome indicators not matching (n=31)

              |                   (4) Intervention measures, study period 

              |                      not matching (n=28)

              |                   (5) Treatment plan unclear (n=3)

              |                   (6) Data incomplete (n=19)

              |                   (7) Full text unavailable (n=5)]

              ↓

 [Included for Qualitative Analysis]

              (n=37)

              |

              ↓

 [Included for Quantitative Analysis 

     (Meta-analysis) (n=37)]

3.2 Characteristics of included literature

A total of 37 articles were included in the study, all of which were RCTs, all published in Chinese, involving a total of 2705 subjects, including 1355 in the experimental group and 1350 in the control group. The chemotherapy regimens included FOLFOX, XELOX (CapeOX), single-drug capecitabine, 5-Fu/LV, and L-OHP+CF+ tegafur, with FOLFOX and XELOX (CapeOX) as the main regimens; all studies were blank-controlled, with the shortest intervention period being 2 chemotherapy cycles and the longest being 12 chemotherapy cycles. (Table 1-3)