Colorectal cancer is one of the highly prevalent malignant tumors of the gastrointestinal system, and its incidence rate is in the third place of malignant tumors worldwide, and has risen to the second place in economically developed regions. The main treatment for recurrent metastatic colorectal cancer is internal medicine, including chemotherapy and molecular targeted therapy. Chemotherapy can prolong the survival of patients and improve the quality of life.
In recent years, many studies have focused on the application of small molecule targeted drugs and monoclonal antibodies in recurrent metastatic rectal cancer, and encouraging results have been achieved. molecular targeted therapy combined with chemotherapy for recurrent metastatic rectal cancer has reached a consensus, and the standard first-line chemotherapy regimen has gradually become clear. 2008 NCCN guidelines expended that the first-line treatment for metastatic colorectal cancer: those who can receive intensive treatment FOLFOX, CapeOX, FOLFIRI, 5-FU/CF, can be combined with bevacizumab. For those who cannot receive intensive therapy, capecitabine or intravenous infusion of 5-FU/CF and/or in combination with bevacizumab. This article reviews the new standards of first-line treatment for advanced colorectal cancer.
I. Fluorouracil and its derivatives
Since 1957, fluorouracil (5-FU) has been the predominant drug in the treatment of colorectal cancer, and its combination with calcium folinic acid (CF) can significantly improve the efficacy. In the treatment of advanced colorectal cancer, 5-FU with CF remains the standard of care for advanced colorectal cancer, with an efficiency rate of approximately 20% and an extension of the use of locoregional survival from 6 months to 11 months with best supportive care. To overcome the toxic side effects of 5-FU, especially myelotoxicity, the hematologic and gastrointestinal systemic toxicities were significantly reduced by using a partial continuous intravenous drip of 5-FU (5-FU 400 mg/m2+CF 200 mg/m2, followed by a continuous drip of 5-FU 600 mg/m222 hours on day 1.2). Continuous dosing, either alone or in combination with a new generation of anticancer drugs, is more effective than rapid dosing. There is a recent trend to use all 5-FU as continuous IV, such as the AIO regimen of CF 500 mg/m22 hours followed by 5-FU (2.6 g/m2) continuous IV for 24 hours once a week (6 times/8 weeks).
Tegafur/uracil (UFT) has gained renewed attention recently due to its high efficiency, low toxicity and ease of application, and a phase III clinical study was communicated at the 2005 ASCO Congress. The study enrolled 58 patients over 75 years of age with colorectal cancer on oral UFT 100 mg/m2 and CF 300 mg once every 8 hours for 28 days with a 7-day break. The regimen had very mild toxic effects. 3.5% CR, 15.5% PR median tumor progression time was 19 weeks and overall survival time was 11.8 months. The authors concluded that the oral regimen of UFT combined with CF is safer for grandmother’s colorectal cancer patients and has similar efficacy to intravenous 5FU/CF. TS-1 is a modification of tegafur, which includes tegafur and two modulators – gemcitabine and octreotide. CDHP inhibits 5-FU catabolism and helps maintain effective 5-FU concentrations in blood and tumor tissue, thereby obtains phosphorylation with 5-FU and affects 5-FU distribution in the gastrointestinal tract, thereby reducing the GI toxicity of 5-FU. Two phase II clinical studies of S1 first-line chemotherapy for advanced colorectal cancer showed that the application of S1 dose of 40 mg/m2 twice daily, administered for 2 weeks with a 2-week break, resulted in remission rates of 35.5% and 39.5% in 63 patients, respectively. clinical trials of S1 combination regimen for advanced colorectal cancer are ongoing.
II. Irinotecan
The study of irinotecan (irinotecan,CPT-11) in combination with 5-FU/CF for advanced colorectal cancer is based on the availability of clear results on the efficacy of second-line therapy. Clinical trials including Saltz and Douillard (V302 trial). The study compared the efficacy of CF/5-FU+/- irinotecan as first-line treatment for advanced colorectal cancer. The results found statistically significant differences in efficiency, median progression-free survival time and overall survival time between treatment with and without irinotecan, whether administered as an intravenous or continuous intravenous 5-FU drip. Based on these studies, the irinotecan/5-FU/LV (IFL) regimen was first approved in the United States as the standard regimen for advanced colorectal cancer.
A multicenter clinical study of intermittent or continuous use of the FOLFIRI regimen was reported at the 2006 ASCO Congress. The results showed that the intermittent FOLFIRI regimen (two months off for two months) was similar to the continuous FOLFIRI regimen in terms of improved survival, but reduced the toxic side effects of chemotherapy and treatment costs. This dosing regimen needs to be validated in more clinical studies.
Oxaliplatin
The efficacy of oxaliplatin in advanced colorectal cancer has been largely confirmed, especially after the combination of 5-FU/CF, the efficacy has been significantly improved. Studies have confirmed that the combination chemotherapy regimen of oxaliplatin + CF/5-FU is able to increase the efficiency, prolong disease-free survival, compared with the combination chemotherapy of CF/5-FU. improved progression-free survival time, improved survival time, and improved quality of survival, but there was no statistically significant difference in extending overall patient survival time, despite the absence of a survival advantage, and the improved efficacy and progression-free survival time of oxaliplatin on top of 5-FU/LV led to oxaliplatin 2000 being recommended by the FDA for first-line treatment of advanced colorectal cancer, and for the peripheral neurotoxicity of oxaliplatin, the The OPTIMOXL regimen was introduced to reduce the peripheral neurotoxicity of oxaliplatin by intermittent treatment. 2006 ASCO Congress reported this large-scale phase II randomized clinical trial, which showed no significant difference in efficacy between the two groups, but maintenance treatment with LV5FU was able to improve progression-free survival time.
IV. Comparison of several combination regimens
To investigate the effect of oxaliplatin or irinotecan combined with CF/5-FU for I picked up colorectal cancer, the GERCOR trial was designed to start one group with POLFIRI as irinotecan + simplified LV/5-FU2 until disease progression, i.e., the irinotecan-oxaliplatin group; the other group used the opposite order, i.e., the oxaliplatin-irinotecan group; the results of the trial showed that the median survival time of the irinotecan- The median survival was 21.5 months in the oxaliplatin group and 20.6 months in the oxaliplatin-irinotecan group, and the first-line efficiency was 56% and 54% in the irinotecan-oxaliplatin and oxaliplatin-irinotecan groups, respectively, with similar overall survival and tolerable toxicity regardless of which order was used, and another phase III multicenter study comparing FOLFIRI and POLFOX4 in first-line treatment in metastatic colorectal cancer, ORR was 31% vs 34%, respectively, TTP was 7 months for both, effective duration made hard by 9 vs 10 months, OS was 14 vs 15 months, no statistical difference, toxic reactions were mild in both groups, and 3-4 toxic reactions were rare, indicating that both regimens were effective as first-line word well.
The results of the GONO study of a three-drug combination regimen were reported at the 2006 ASCO Congress, which compared the efficiency and impact on survival of a three-drug combination of irinotecan, oxaliplatin and 5FU/LV (FOLFOXIRI) with a two-drug combination of irinotecan + 5FU/LV (FOLFIRI) as first-line treatment for metastatic colorectal cancer. 244 patients with primary treatment of metastatic colorectal cancer were treated with a three-drug combination of irinotecan, oxaliplatin and 5FU/LV (FOLFIRI). The incidence of major toxicity was higher in the FOLFIRI group than in the POLFIRI group, and the recent efficacy was higher than in the FOLDIEI group. The rate of radical resection of viable metastases after chemotherapy was higher in the POLFOXIRI group than in the FOLFIRI group (14% vs. 6%, p=0.05). This indicates that the FOLFOXIRI regimen can significantly improve the efficiency, radical resection rate of metastases, progression-free survival time and overall survival time, and the toxic effects can be controlled, and it can be recommended for patients who are in good health and have the hope to undergo surgery by receiving potent chemotherapy to shrink the lesions.
V. Targeted drug therapy
Bevacizumab is a humanized monoclonal antibody that acts directly on VEGF. A foreign phase III clinical trial for first-line treatment of metastatic colorectal cancer proved its effectiveness. 813 patients with advanced colorectal cancer were randomly divided into two groups, IFL + placebo (411 cases) and IFL + bevacizumab (402 cases), and bevacizumab was 5mg/Kg, repeated every 2 weeks. The efficiency of the control group was 44.8% and 34.8%, PFS was 10.6 months and 6.2 months, os was 20.3 months and 15.6 months, respectively, and the application of bevacizumab was an increase of 4.4 months in disease-free progression survival and 4.7 months in overall survival, both differences were statistically significant. Based on the results of this study, the FDA approved bevacizumab as the first-line treatment for metastatic colorectal cancer in February 2004.
A pooled analysis of cross-sectional data from three independent trials of bevacizumab in combination with FU/LV showed that the median survival time was longer in the combination group (17.9 vs. 14.6 cm, P=0.008). Median PFS time was prolonged (8.8 vs. 5.6) (HR=0.63 (p
VI. Future directions
The clinical application of cytotoxic drug therapy on top of 5-FU and the development of fractionated self-targeted drugs have led to great progress in the treatment of advanced colorectal cancer in just a few years. The median life expectancy of patients with advanced colorectal cancer is no more than 6 months with best supportive care, which can be extended to 10-12 months with the combination of 5-FU plus CF, while the median survival can be increased to 14-16 months when irinotecan or oxaliplatin is added to the application of 5-FU/CF. If monoclonal antibodies are then applied in combination, the survival can be further extended to more than 24 months. In the near hu future, with the emergence of more novel drugs, including tumor vaccines, the efficacy will be further improved, which will surely bring new hope to the treatment of colorectal cancer.
The addition of other biologic agents to the two-combination therapy has also been shown to improve the prognosis of patients with HER2-positive metastatic breast cancer. Studies with the addition of bevacizumab patuximab and lapatinib are both in Phase III clinical stages. Currently, trastuzumab in combination with chemotherapy is the standard first-line treatment option for patients with HER2-positive breast cancer. The two-drug combination of trastuzumab and other chemotherapeutic agents, including capecitabine, gemcitabine, and vincristine, can also significantly improve patient prognosis. There is still disagreement as to whether trastuzumab should be continued in metastatic breast cancer with disease progression after trastuzumab treatment.
A retrospective analysis of reported clinical studies has shown that continuation of trastuzumab and switching to a combination of other chemotherapeutic agents remains effective in patients with initial disease progression. This provides preliminary evidence for the continuation of trastuzumab studies after progression. A prospective study (RHEA) is currently underway to assess the clinical significance of re-treatment in patients with recurrent metastases after adjuvant trastuzumab therapy, and the AVEREL and CLEOPATRA studies are beginning to enroll patients who have received adjuvant trastuzumab to evaluate the value of its continued use. Trastuzumab provides benefit for most patients with HER2-positive MBC. Each patient should be evaluated on a case-by-case basis for the best treatment option, and treatment decisions should be guided by the evidence.