Almost 55% of colorectal cancer cases worldwide occur in more developed countries. Its incidence continues to rise in developing countries36. As with most cancer types, surgery is the main treatment method. For metastatic cancer, cytotoxic methods, such as neoadjuvant therapy and adjuvant therapy, are used before or after it. The main treatment options include fluoropyrimidine, oxaliplatin, and irinotecan. TAS-102 is an anti-cancer drug that has entered people's field of vision in recent years. Because of its excellent clinical efficacy and safety, it is often added to the treatment of colorectal cancer, gastric cancer in the middle and late stages and anti-cancer treatment programs for metastatic tumors.
Our study found that the mOS of patients treated with TAS-102 was 7.74 (95%CI: 6.09–9.85) and the mPFS was 2.91 (95%CI: 2.38–3.57). The mOS in patients treated by TAS-102 combined with bevacizumab is 10.41 (95%CI: 8.40-12.89) and the mPFS is 4.35 (95%CI: 3.05–6.20). Combination therapy may have better effectiveness. As the current targeted drug for the treatment of metastatic colorectal cancer, it is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), which plays an anti-tumor effect by blocking the formation of tumor blood vessels and regulating the immune function of patients37. In 2004, the FDA approved bevacizumab combined with chemotherapy drugs as the first-line treatment for mCRC. A study showed that bevacizumab combined with first-line chemotherapy for metastatic colorectal cancer can significantly prolong the survival and PFS of patients with mCRC, improve the quality of life, increase the resectable rate of metastases, and improve the survival outcome of patients with mCRC38,39. The number of adverse events has also been significantly reduced.
Although uncontrolled trials can observe the survival of patients, they cannot specify the improvement in survival. We included 16 studies that included two controlled protocols (TAS-102 + B VS. TAS-102 AND TAS-102 VS. Placebo). In either scenario, we found a significant increase in mOS and mPFS. Surprisingly, we found that TAS-102 combined with bevacizumab will increase the incidence of grade ≥ 3 AEs (OR = 2.19, 95%CI: 1.40–3.44) compared to TAS-102 alone. The safety of bevacizumab is worthy of further consideration. This indicates that clinicians need to make careful decisions when making treatment options for patients with metastatic colorectal cancer, considering the patient's tolerance to anticancer drugs.
It is necessary to optimize the design plan when evaluating the efficacy of new drugs. Randomized controlled trials such as resource and TERRA are conducted in homogeneous populations, which can minimize the risk of bias40. In the current study, we have included real observational studies aimed at evaluating the effectiveness of a relatively small homogeneous population. These studies have the shortcomings of non-randomized controlled studies. The studies we included included controlled and uncontrolled experiments. And the demographic characteristics and disease manifestations of the participants in the experiment are also quite different. This will actually affect the accuracy of our final results. Therefore, more rigorous and appropriate randomized controlled experiments need to be proposed. The published meta-analysis of TAS-102 involves comparison of the effectiveness and safety of multiple therapeutic drugs40–45. Regorafenib, TAS-102, fruquintinib, panitumumab and cetuximab are recommended single-agent chemotherapy regimens for patients exhibiting disease progression. The safety of these drugs is difficult to assess. But the safety of the drug does affect the confidence of patients in the treatment plan. The most important thing is the improvement of symptoms and the management of side effects47,48.
In a retrospective study, potential predictive or prognostic biomarkers for the efficacy of regorafenib were evaluated46. The results indicate that the mutation status of KRAS and PIK3CA may be a predictor of the clinical benefit of regorafenib treatment. However, no biomarkers have been found to predict the efficacy and safety of TAS-102. The frequency of KRAS mutations should be worth exploring, because mOS and mPFS are independent of KRAS status in resource and TERRA, but are highly dependent on KRAS mutations in the second phase of trials in Japan5.
Although this study gives the survival status of TAS-102 as a single treatment, it is worth looking forward to the application of the drug combination program may further improve the efficacy of FTD/TPI, and some clinical trials are currently underway.