There were approximately 1.2 million new cases of colorectal cancer worldwide in 2008, accounting for approximately 10% of all new cancers, and their associated deaths exceeded 600,000 [1]. Colorectal cancer is common in economically developed countries and regions such as North America, Western Europe, and Australia, with a crude incidence rate of 40/100,000-66/100,000, accounting for more than two-thirds of all new cases. In developing countries such as China, where the economy is rapidly emerging, the incidence of colorectal cancer is also rising rapidly year by year.
Although the burden of colorectal cancer on people’s health and society remains heavy, significant progress has been made in its treatment in the last two decades, with the 5-year survival rate increasing from 50% in the past to 63%, and patients’ quality of life has also improved significantly. These achievements are largely attributed to the breakthroughs in the drug treatment of colorectal cancer and the rational and standardized use of drugs.
Since the 1950s, fluorouracil (5-FU) has been widely used as the basic chemotherapeutic drug for colorectal cancer treatment, and in the mid-1990s, new highly effective chemotherapeutic drugs such as oxaliplatin, irinotecan, capecitabine, and molecularly targeted drugs such as cetuximab and bevacizumab were developed and marketed, making significant progress in the drug treatment of colorectal cancer. In this paper, we will review the six drugs used for colorectal cancer. In this paper, the mechanism of action, therapeutic regimen, dosage and usage of the above six drugs for colorectal cancer treatment, namely fluorouracil, capecitabine, oxaliplatin, irinotecan, cetuximab and bevacizumab, as well as related clinical studies, will be outlined and summarized to provide guidance and reference for the standardized use of drugs in colorectal cancer.
1.1
5-FU is a derivative of uracil with hydrogen substituted by fluorine at the 5-position, which is converted into deoxyfluoro-uracil monophosphate (FdUMP) after entering cells. synthesis, which acts as an inhibitor of tumor cell growth.
In a retrospective analysis of 25 randomized controlled studies of nearly 1000 patients with colorectal cancer, Buyse et al. found a slight survival advantage of adjuvant chemotherapy containing 5-FU over surgery alone [2].The INT0035 randomized controlled study enrolled 1200 patients with stage II or III colon cancer and randomized them to the surgery alone group, the levamisole (LEV) group, and the 5-FU/ LEV group. The results showed that 5-FU/LEV reduced the risk of recurrence by 40% (P0.0001) and the risk of death by 33% (P = 0.0007) compared with surgery alone [3]. Therefore, 5-FU/LEV was once used as a standard adjuvant chemotherapy regimen for colon cancer. the NSABP C-04 study analyzed colon cancer patients who received 5-FU combined with calcium folinic acid (LV) and 5-FU/LEV adjuvant chemotherapy for 1 year and found that the 5-year DFS was better in the 5-FU/LV group than in the 5-FU/LEV group (65% vs 60%, P = 0.04) [4]. Based on the results of this study, the 5-FU/LV regimen replaced 5-FU/LEV as the standard adjuvant chemotherapy regimen. In addition, the INT0089 study showed that 5-FU combined with high-dose LV compared with low-dose LV and 9-12 months compared with 6-8 months of adjuvant chemotherapy did not show any advantage [5]. The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for colon cancer recommend 6 months of 5-FU/LV as the standard adjuvant chemotherapy regimen for low-risk stage II colon cancer.
5-FU has been used for more than 40 years for the treatment of advanced colorectal cancer. Its single-agent regimen has limited efficacy, with an efficacy rate of only 10-15%. A meta-analysis including 3300 patients in 18 clinical trials showed that 5-FU in combination with LV increased the efficacy from 11% to 21% (p0.0001) [6]. In addition, several studies have investigated the effects of different administration methods and doses of 5-FU on efficacy and toxicity. A related meta-analysis showed that 5-FU was significantly more effective when administered intravenously than by push (22% vs. 14%, P0.0002) and had a lower incidence of GI side effects [7-8]. Therefore, the NCCN recommends 5-FU combined with intravenous continuous LV drip as the standard method of 5-FU administration. Some commonly used doses and methods of 5-FU administration are listed in Table 1.
1.2 , Capecitabine
Capecitabine is an orally administered fluorouracil drug that can be converted to 5-FU by the higher expression of thymidine phosphorylase (TP) in tumor tissues, which is more active in tumor tissues than in normal tissues to achieve selective intra-tumor activation, thus maximizing tumor killing effect and minimizing damage to normal human cells. A simultaneous 2 times/day dosing pattern mimics continuous infusion of 5-FU to provide steady-state blood concentrations at the site of drug action.
The X-ACT study included 1987 postoperative stage III colon cancer patients randomized to the capecitabine and 5-FU/LV groups and showed that disease-free survival (DFS) in the capecitabine group was at least comparable to that in the 5-FU/LV group with lower toxic side effects (P0.001) [12]. Therefore, capecitabine monotherapy may also be one of the standard regimens for adjuvant therapy after colon cancer.NCCN recommends capecitabine 1250 mg/m2 orally twice daily on days 1-14, repeated every 2 weeks for a total of 24 weeks as an adjuvant regimen after colon cancer surgery.
In a comprehensive analysis of two phase III clinical studies comparing capecitabine alone with a 5-FU/LV intravenous push regimen for advanced colorectal cancer, Van Cutsem et al. found that capecitabine alone had a higher efficiency rate (25.7% vs. 16.7%, P0.0002), with no statistically significant differences between the two groups in terms of time to disease progression and overall survival [13]. The dose of capecitabine alone in advanced or metastatic colorectal cancer was 2000-2500 mg/m2/day in 2 oral doses on days 1-14, followed by a 7-day break and repeated every 3 weeks.
1.3. Oxaliplatin
Oxaliplatin is a new 3rd generation platinum-based chemotherapeutic drug, which, like other platinum-based drugs, acts on DNA as the site of action, with platinum atoms forming intra- and inter-strand cross-links with DNA strands, blocking DNA replication and transcription. Oxaliplatin binds more rapidly to DNA and also has an effect on RNA. In vivo and in vitro tests have shown no cross-resistance with cisplatin and carboplatin, and its mild myelosuppression makes it easier to use in combination with other antitumor agents.
The international multicenter MOSAIC study in Europe demonstrated for the first time the superiority of oxaliplatin combined with 5-FU chemotherapy, i.e. FOLFOX regimen for 6 months of adjuvant chemotherapy, over the 5-FU/LV regimen. A total of 2246 patients with stage II or III colon cancer were enrolled in this study. The NSABP-C07 study further confirmed the role of oxaliplatin in adjuvant therapy. 2047 patients with stage II and III colon cancer were randomized to receive adjuvant chemotherapy with FOLX or 5-FU/LV regimens after surgery, and the 4-year DFS in the two groups was 73.2% and 73.2%, respectively. were 73.2% and 67.0%, respectively (P0.004) [15]. The NCCN currently recommends FOLFOX or FLOX regimens of oxaliplatin combined with 5-FU/LV for the adjuvant treatment of stage II or III colorectal cancer after radical surgery except for stage IIA (no high-risk factors).
The N9741 randomized phase III study compared the FOLFOX4, irinotecan combined with intravenous push 5-FU/LV (IFL) regimen and oxaliplatin combined with irinotecan (IROX) regimen for the first-line treatment of advanced metastatic colorectal cancer.The FOLFOX regimen was superior to the latter two regimens in terms of efficiency, PFS and overall survival (OS) [16]. The NCCN recommends FOLFOX as the standard first-line chemotherapy regimen for advanced or metastatic colorectal cancer. The currently widely used mFOLFOX6 regimen, oxaliplatin, is administered intravenously at 85 mg/m2 for 2 hours on day 1 and repeated every 2 weeks.The NO16966A phase III study compared the efficacy of the CapeOX regimen of oxaliplatin in combination with capecitabine to the FOLFOX regimen in 2034 patients with metastatic colorectal cancer. PFS was similar in both groups (8.0 months vs. 8.5 months), indicating that the CapeOX regimen is not inferior to the FOLFOX regimen in the first-line treatment of advanced colorectal cancer [17].
1.4 , Irinotecan
Irinotecan is a semi-synthetic derivative of natural camptothecin that exerts cytotoxic effects by inhibiting topoisomerase. It selectively acts on topoisomerase I, which has a very important function in interfering with DNA spatial conformation, replication, recombination, transcription and mitosis processes, causing DNA single- and double-strand breaks and thus inducing apoptosis in cancer cells.
The CALGB 89803 study compared the efficacy of irinotecan combined with intravenous push 5-FU/LV (IFL) regimen and 5-FU/LV alone in the treatment of stage III colon cancer. The results showed no improvement in OS (P = 0.74) or DFS (P = 0.84) in the IFL group and a greater risk of neutropenia, febrile neutropenia and death in the IFL group [18]. In addition, the PETACC-3 study and the FFCD9802 study found that irinotecan combined with an intravenous 5-FU/LV (FOLFIRI) regimen for adjuvant chemotherapy in colon cancer was not superior to the 5-FU/LV regimen [19-20]. Therefore, irinotecan-containing regimens are not suitable for adjuvant chemotherapy in colorectal cancer.
Evidence for the efficacy of the FOLFIRI regimen in first-line treatment of advanced colorectal cancer relative to FOLFOX comes from the GERCOR crossover study. In this study, patients started treatment with either the FOLFIRI or FOLFOX regimen and switched to the other regimen when their disease progressed. The results showed similar remission rates (56% vs 54%) and time to disease progression (progression-free survival,PFS) (8.5 months vs 8.0 months, P = 0.26) for both regimens as first-line treatment [21]. This conclusion is further supported by the phase III clinical study by Colucci et al, which compared the efficacy and toxicity of the FOLFOX and FOLFIRI regimens for primary treatment of metastatic colorectal cancer. There were no significant differences between the two groups in terms of remission rates, PFS and OS [22]. Based on the above evidence, the NCCN recommends the FOLFIRI regimen (irinotecan 180 mg/m2 IV drip, day 1; LV 400 mg/m2 IV drip over 2 hours, day 1, followed by 5-FU 400 mg/m2 IV push, then 5-FU 1200 mg/m2/day x 2 days continuous IV drip over 46-48 hours; repeated every 2 weeks) for palliative chemotherapy in advanced or metastatic colorectal cancer.
1.5 , Cetuximab
Cetuximab is an IgG1 human-mouse chimeric monoclonal antibody targeting human EGFR. It competitively inhibits the binding of EGFR to its ligand, inhibits cell cycle progression and induces apoptosis by inhibiting the activation of receptor-related tyrosine kinases, reduces the production of matrix metalloproteinases and vascular endothelial growth factor (VEGF), and reduces tumor angiogenesis, cell migration and invasion. Secondly, cetuximab also has indirect antitumor effects by stimulating complement-mediated cell killing effects and antibody-dependent cell killing effects. Tumors with mutations in codon 12 or 13 of the KRAS gene have been extensively reported to be insensitive to treatment with the EGFR inhibitor cetuximab [23, 24]. Therefore, cetuximab should not be used in patients with known codon 12 or 13 mutations in the KRAS gene, either alone or in combination with other antitumor agents.
The CRYSTAL trial demonstrated the role of cetuximab as first-line treatment for metastatic colorectal cancer. Patients were randomized to receive FOLFIRI with or without cetuximab. The results showed that the addition of cetuximab resulted in a significant improvement in PFS in patients with KRAS wild type (9.9 months vs. 8.7 months, P = 0.02) [25]. A retrospective analysis of data from the randomized phase II trial OPUS found that for patients with KRAS wild-type, cetuximab in combination with FOLFOX resulted in a significantly higher objective remission rate (57% vs 34%, P = 0.0027) and PFS (8.3 months vs 7.2 months, P = 0.0064) compared to FOLFOX alone [26]. Notably, the results of some recent clinical trials showed that cetuximab combined with oxaliplatin-containing chemotherapy in first-line treatment of KRAS wild-type metastatic colorectal cancer did not provide any additional benefit, and the phase III study NORDIC-VII showed that the addition of cetuximab to the FLOX regimen did not result in a benefit in PFS or OS [27]. In addition, the COIN study also found that the combination of cetuximab with FOLFOX or CapeOX in first-line treatment of KRAS wild-type metastatic colorectal cancer did not prolong patient OS (17.0 months vs 17.9 months,P = 0.67) or PFS (8.6 months vs 8.6 months, P = 0.60) compared with chemotherapy alone [28]. Current NCCN guidelines recommend FOLFIRI in combination with cetuximab (400 mg/m2 for the first time and 500 mg/m2 thereafter, repeated every 2 weeks) for the first-line treatment of advanced or metastatic colorectal cancer.
1.6 , Bevacizumab
Bevacizumab is a 149-kD recombinant human monoclonal IgG1 antibody against VEGF-A. It can selectively bind VEGF in circulating blood, avoid VEGF binding to receptors on cell membranes, inhibit microangiogenesis, limit blood supply to tumor cells, reduce tissue interstitial pressure, increase vascular permeability, accelerate chemotherapeutic drug transport, and promote apoptosis of tumor endothelial cells.
The AVF2107 study is a phase III clinical study comparing IFL regimen alone with IFL plus bevacizumab in first-line treatment of metastatic colorectal cancer. The results showed that IFL combined with bevacizumab was significantly more effective (44.8% vs 34.8%, P = 0.004), PFS (10.6 months vs 6.2 months, P0.001) and OS (20.3 months vs 15.6 months, P0.001) than the IFL regimen alone [29]. Based on the results of this study, bevacizumab was approved by the US Food and Drug Administration (FDA) in 2004 for the first-line treatment of metastatic colorectal cancer, and by the European Medicines Agency (EMA) in 2005 for the first-line treatment of metastatic colorectal cancer with bevacizumab in combination with irinotecan. Currently, the NCCN recommends bevacizumab in combination with FOLFOX, FOFIRI or CapeOX regimens for advanced or metastatic colorectal cancer at 5 mg/kg, repeated every 2 weeks.
In summary, the current drug treatment for colorectal cancer mainly consists of the above six categories of drugs. The standardized and rational use of these drugs not only reduces the postoperative recurrence rate of stage II and III colorectal cancer patients, but also greatly prolongs the disease progression time and survival time of advanced stage patients and improves the quality of life. Rational drug use through standardization based on clinical study data is the key to treating colorectal cancer, and future treatment studies will continue to focus on optimizing chemotherapy regimens to improve efficacy and reduce toxic side effects, as well as implementing individualized treatment for different patients. A well-designed randomized controlled clinical drug study is an important reference for standardized drug use in colorectal cancer.