Systematic evaluation of clinical and experimental evidence for the application of Chinese herbal medicines in the management of colorectal cancer

Chen, M 2018, Systematic evaluation of clinical and experimental evidence for the application of Chinese herbal medicines in the management of colorectal cancer, Doctor of Philosophy (PhD), Health and Biomedical Sciences, RMIT University.

Document type: Thesis
Collection: Theses

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Title Systematic evaluation of clinical and experimental evidence for the application of Chinese herbal medicines in the management of colorectal cancer
Author(s) Chen, M
Year 2018
Abstract Worldwide, colorectal cancer (CRC) is the third most common cancer in men and the second in women. CRC is curable by surgical resection if it is diagnosed in early stage but requires more complex therapeutic approaches including chemotherapy at more advanced stages. Although overall patient survival is improving, survival rates for advanced CRC are poor and adverse events (AEs) associated with multi-drug combination chemotherapy can severely compromise quality of life in CRC sufferers.

In China, integrative treatments which combine herbal medicines (HM) and chemotherapy are applied in hospital settings with the aim of enhancing the benefits of conventional treatments and alleviating the side effects of chemotherapy. Outside China, there is widespread use of HMs by cancer patients. However, the number of different HMs in use is large, they are often used in combination, and the evidence for their effects (if any) is limited.

Hence, the primary objectives of this study were to:

Evaluate the efficacy and safety of HMs in the clinical management of CRC;
Identify potentially effective HMs and combinations of HMs that warrant further research;
Investigate the actions and mechanisms of action of promising HMs in experimental models of CRC; and
Determine directions for future research.
The first stage of the project involved a comprehensive systematic review of randomised controlled trials (RCTs) that evaluated HMs in patients with CRC. Eighty-eight (88) RCTs were included (Chapter 4). The majority of studies were of integrative treatments for CRC. Meta-analyses found the addition of HM interventions to conventional chemotherapy provided benefits for tumour response, survival, alleviation of chemotherapy-related AEs and improved quality of life. This suggested that at least some of the included HMs improved clinical outcomes and warranted further study. However, the variety of HMs and chemotherapy regimens tested in the studies was considerable, participants were at different stages of the disease and there was potential for bias in the published studies (publication 1 Chen et al 2018).

To further explore the effects of HMs, more focussed meta-analyses were conducted of RCTs that only enrolled people with advanced CRC and all employed FOLFOX4, which is the most commonly used regimen (Chapter 5, publication 5 Chen et al 2014). The result showed that even in advanced CRC patients, the addition of HMs to FOLFOX4 enhanced the tumour response rate by 9% based on data from 12 RCTs (880 participants) without statistical heterogeneity, and improved Quality of Life based on Karnofsky Performance Status. Importantly, there were significant reductions in severe (grade 3/4) chemotherapy-induced AEs for nausea & vomiting (9.5% reduction, 9 RCTs) and neutropenia (8.7% reduction, 10 RCTs) without heterogeneity. Both AEs are clinically important since they can lead to cessation of treatment which shortens overall survival.

The HMs were composed of multiple ingredients, so the question was which of these ingredients made greater contributions to the overall effects detected in the pooled data in the meta-analyses? To approach this question, a larger meta-analysis pool was identified and a novel approach to sensitivity analyses was developed. The inclusion criteria for studies were broadened to encompass other oxaliplatin-based chemotherapies besides FOLFOX4, since these are known to have similar effects on tumour response and similar AE profiles. The resultant studies were all of Chinese HMs, most of which used orally administered formulae. Meta-analyses of the oral HM studies were conducted for tumour response rate (31 studies, 2,145 participants), nausea and vomiting (21 studies, 1,322 participants) and neutropenia (24 studies, 1,319 participants) (Chapter 6). In each case, there were significant improvements in the oral HM plus chemotherapy groups compared to the chemotherapy alone groups for all grades of the AE without important heterogeneity, based on large sample sizes. This lack of statistical heterogeneity combined with large sample sizes provided the opportunity for a series of sensitivity analyses aimed at determining which (if any) specific herbs, or combinations of herbs, improved the meta-analysis results of the pool of studies in which the herb was an ingredient. If a herb consistently improved the outcome, whenever it was included in a formula along with a variety of other herbs, it was considered a candidate for further research.

The above meta-analyses and sensitivity analyses identified promising herbs for reducing chemotherapy-induced nausea and vomiting (publication 3 Chen et al 2016b) and chemotherapy-induced neutropenia (publication 2 Chen et al 2016c); and improving tumour response rate (publication 4 Chen et al 2016a). Of these outcomes, tumour response was selected as particularly relevant for further research. Of the three herbs identified as most likely to have contributed to improved tumour response (ku shen, chi shao and e zhu), one was selected for further research. This herb (ku shen) is always derived from the root of the plant Sophora flavescens, is well characterised, and some of its constituent compounds have been identified. Of these, the alkaloid matrine has been reported to have antitumour effects, so this was selected for a series of experiments.

Matrine was tested in four human CRC cell lines: LS 174T, Caco-2, SW1116 and RKO (Chapter 7). Cell viability, measured using CCK-8 assays, showed that matrine inhibited proliferation of these cell-lines, time- and dose-dependently. Optical microscopy of cell morphology indicated cells underwent apoptosis rather than necrosis. Matrine was much less cytotoxic than oxaliplatin. Flow cytometry was used to measure DNA content for cell cycle analysis, and Annexin V-FITC/PI double staining was used to measure cellular apoptosis. The results showed that matrine induced cell cycle arrest at the G1 phase, and induced apoptosis in each cell-line in a time- and dose-dependent manner.

To explore the likely molecular mechanisms of action of S. flavescens and its various constituent compounds, including matrine, a detailed review was conducted of published in vitro and in vivo studies in models of CRC (Chapter 8). This identified a number of intracellular signalling pathways, including WNT signalling, MAPK signalling, TGF-β signalling, and p53 signalling, as likely to be central to the anti-proliferative actions of this HM. In conclusion, matrine and other S. flavescens compounds show important bioactivities in CRC. Future studies in CRC cell-lines and in vivo models of CRC could investigate the effects of Sophora alkaloids and flavonoids on the protein components of the above pathways (Chapter 9).
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Health and Biomedical Sciences
Subjects Traditional Chinese Medicine and Treatments
Keyword(s) colorectal cancer
integrative medicine
herbal medicine
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