In China, traditional Chinese medicine (TCM) is one of the most common complementary and alternative medicines used in the treatment of patients with CRC. TCM can be used as an effective auxiliary method to reduce the incidence rate of CRC and can be combined with other chemotherapy agents to reduce the adverse reactions caused by chemotherapy and significantly improve the quality of life of patients.19 HCS is one of the TCMs commonly used to treat CRC and shows a wide range of in vitro and in vivo pharmacological effects, such as anti-inflammatory, antitumor, immunomodulatory and antinociceptive effects.10, 20, 21
In our study, we found that HCS combined with chemotherapy for CRC did not show superiority to chemotherapy alone in terms of OS of patients at 3 years. However, HCS combined with chemotherapy showed significant superiority to chemotherapy alone in DFS at 3 years. Our results show that HCS combined with chemotherapy can significantly reduce the recurrence and metastasis of CRC after surgery, especially for lung metastasis. This result is similar to those of previous small-sample clinical studies of colorectal cancer.18, 22 In contrast to this result, a previous study23 showed that HCS combined with gemcitabine can improve the ORR of patients with locally advanced and/or metastatic pancreatic cancer by 6% but did not improve the final outcome of patients. The reason may be related to the rapid progression of advanced pancreatic cancer, the small number of effective study samples in 79 cases and the short observation period of 4 months.
In terms of adverse events, the first-phase experiment of HCS showed its safety in multiple cancers, in which no dose-limiting toxicity (DLT) was observed with the use of HCS at doses up to 8 times higher than the typical dosage used in China.24 In the current study, no patients experienced grade 4 adverse events, and HCS combined with chemotherapy could reduce the incidence of leukopenia, neutropenia, and diarrhea. For leukopenia and neutropenia, a previous study showed similar results regarding dose intensity and toxicity.25 Interestingly, the present study showed that HCS relieved chemotherapy-induced diarrhea (CID). CID is the intestinal mucosal injury caused by chemotherapy, which is characterized by intestinal inflammation and mucosal barrier destruction. It can lead to changes in intestinal structure, function and immunity, mainly manifesting as diarrhea to different degrees.26, 27 Its incidence rate is 50–80%,28 especially in 5-FU or irinotecan-based regimens, which can reach 82%.29 Animal experiments have shown that HCS can ameliorate dextran sulfate sodium (DSS)-induced colitis in mice.30 The effect of HCS on CID still needs further exploration in the future.
The limitations of the current study must be noted. First, this study compared and observed the 3-year outcomes of patients in a single clinical center. However, the observation time of 3 years can reflect the long-term recurrence and metastasis time of CRC after operation because 80% of CRC patients experience recurrence in the first 3 years after surgical resection. Thus, 3-year DFS can be considered a valid surrogate (replacement) endpoint for 5-year OS in clinical trials of adjuvant chemotherapy for CRC.31 Second, clinical cases are selected for ≥ 3 months of chemotherapy instead of those who have completely completed 6 months of chemotherapy. The reason is that fewer CRC patients insist on the whole course of chemotherapy. A study showed that 3 months of oxaliplatin-containing adjuvant chemotherapy was noninferior to 6 months of the same therapy for patients with high-risk stage II and stage III CRC.32 Third, there was no direct comparison between HCS and conventional chemotherapy. There are still a small number of CRC patients who use HCS alone, but the compliance of patients is not high, and the number is not sufficient for statistical analysis.