Globally, the incidence of colorectal cancer ranks third and the mortality ranks second.
In China, the incidence of colorectal cancer has jumped to the second place, and the mortality rate ranks fifth.
Since1960s, the chemotherapy regimen of 5-Fu combined with oxaliplatin or irinotecan has been the basis for the treatment of metastatic colorectal cancer.
In recent years, anti-angiogenic drugs (such as anti-VEGF monoclonal antibody and bevacizumab) and anti-EGFR monoclonal antibody (such as cetuximab) have been gradually approved for first-line and second-line treatment of metastatic colorectal cancer in combination with chemotherapy.
In addition, Trifluorouridine/Tipiracetam (TAS- 102), rifenib and Gu Lei tinib were used for third-line treatment and rescue treatment.
How to accurately treat colorectal cancer according to its molecular biological characteristics, tumor site, previous treatment, patient status and other factors is very important for the treatment of metastatic colorectal cancer.
Below, let's take a look at how to accurately treat colorectal cancer and maximize the benefits for patients.
0 1 surgical treatment
For colorectal cancer patients with liver metastasis or lung metastasis, after surgical evaluation, if surgical resection is possible, surgical resection is performed.
For patients with potentially resectable metastatic colorectal cancer, about 40% patients can undergo surgery after switching treatment. But there is still a recurrence rate of 75% after operation.
There is no clear standard treatment scheme for conversion treatment, which is usually:
A. For patients with wild-type RAS gene, dual-drug chemotherapy (FOLFOX/FOLFIRI)+ EGFR antibody (cetuximab) was used.
B For patients with RAS gene mutation and right colon cancer, double or triple chemotherapy (Folfoxiri) and VEGF monoclonal antibody (bevacizumab) were used.
02 first-line therapy
The standard first-line treatment for most metastatic colorectal cancer is two different combinations of dual-drug chemotherapy:
A. fluoropyrimidine (5-FU/ folinic acid)+irinotecan, that is, FOLFIRI combination.
B.5-FU/ folinic acid or capecitabine+oxaliplatin, namely FOLFOX or CapOX.
The two kinds of chemotherapy have the same efficacy, but the adverse reactions are different. Chemotherapy combined with irinotecan has a high incidence of gastrointestinal adverse reactions, while chemotherapy combined with oxaliplatin is easy to cause serious peripheral neuropathy.
Chemotherapy combined with FOLFOXIRI and other three drugs may be more effective than the two drugs, but the side effects are also greater. It is suitable for patients who have no serious complications or need to reduce the tumor volume urgently.
In the first-line treatment of metastatic colorectal cancer, chemotherapy is often combined with EGFR monoclonal antibody, such as cetuximab, or VEGF monoclonal antibody, such as bevacizumab, in order to further enhance the curative effect.
EGFR monoclonal antibody is used in patients with left colon cancer whose RAS gene and BRAF gene are wild type, and the scheme is: FOLFOX/FOLFIRI)+ EGFR monoclonal antibody (cetuximab).
VEGF monoclonal antibody has no biomarker as medication guidance, and is usually used for patients with r as gene mutation. The regimen is: double or triple chemotherapy (FOLFOXIRI)+VEGF monoclonal antibody (bevacizumab).
In addition, the location of the lesion also affects the choice of treatment plan.
Colorectal cancer located in the right colon (cecum, ascending colon and transverse colon) usually has specific histological and molecular characteristics: low differentiation, high mucin expression, BRAF mutation and MSI, and the overall prognosis is relatively poor.
Because EGFR monoclonal antibody did not show the benefit to patients with right colon cancer, VEGF monoclonal antibody was used instead of EGFR monoclonal antibody in the first-line treatment of patients with right colon cancer, regardless of RAS mutation.
03 maintenance therapy
As shown in table 1, patients who respond to the first-line induction therapy but cannot be resected usually switch to maintenance therapy within 4-6 months due to the toxicity of chemotherapy.
Compared with drug withdrawal, 5-FU patients combined with bevacizumab can benefit from PFS.
04 second-line therapy
After the progress of first-line treatment, most patients have to receive second-line treatment to prolong their survival.
The choice of second-line treatment depends on the patient and the disease, as well as the first-line treatment.
As for monoclonal antibody therapy, patients who receive EGFR monoclonal antibody therapy in the first line usually switch to bevacizumab, an antiangiogenic drug, in the second line.
Bevacizumab is used in the first-line treatment, and it can still be used in combination with bevacizumab after changing the chemotherapy regimen in the second-line treatment.
For wild-type RAS patients, second-line therapy with anti-EGFR monoclonal antibody or combined chemotherapy has therapeutic effect. However, if EGFR monoclonal antibody has been used in the first line, it is not recommended to continue to use it in the second line treatment, but to use bevacizumab instead.
In addition, consistent with the recommendation of first-line treatment, anti-EGFR monoclonal antibodies are not recommended for patients with right colon cancer who are treated with second-line treatment.
Three-line and four-line therapy
The third-line and fourth-line treatments after the second-line progress mainly include nucleoside drugs TAS- 102 (tripyrimidine), multi-tyrosine kinase inhibitor Regifinib, furosemide and so on.
Clinical research shows that the combined application of TAS- 102 and bevacizumab can benefit patients, so it can also be considered in the back-line treatment.
Immunotherapy
In addition to chemotherapy and targeted therapy, immunotherapy has become the third important choice for the treatment of metastatic colorectal cancer.
About 5% patients with metastatic colorectal cancer carry MSI-H/dMMR. These patients can choose PD- 1 monoclonal antibody treatment.
The results showed that the response rates (ORR) of PD- 1 monoclonal antibodies pembrolizumab and nivolumab reached 40% and 3 1% respectively.
When CTLA-4 monoclonal antibody (epimuzumab, which has not been approved for marketing in China) is used in combination with navuzumab, the curative effect is further improved. The effective rate (ORR) is 55%, the disease control rate (DCR) is 80%, and the 12-month survival rate is 85%.
Based on the above data, FDA has approved CTLA-4 monoclonal antibody combined with PD- 1 monoclonal antibody for first-line and second-line treatment of patients with MSI-H/dMMR metastatic colorectal cancer.
For most (95%) patients who do not carry MSI-H/dMMR, the effect of using immune checkpoint inhibitors alone is not significant. For this part of patients, many clinical studies are trying to use immune checkpoint inhibitors in combination with other drugs.
Different joining methods are as follows:
07 EGF/MAPK pathway small molecule inhibitor
Molecular mutation of EGF/MAPK pathway is very common in colorectal cancer. The most common mutant molecules are KRAS, NRAS and BRAF.
The following figure shows monoclonal antibodies and small molecule drugs against MAPK signaling pathway mutation.
Some drugs in the figure below, such as ADC drugs (T-DXd and T-DM 1), MEK inhibitors (Binimetinib and Trimetinib) and PI3K inhibitors (Alpelisib), have not been approved for the treatment of advanced colorectal cancer, and are currently in clinical trials or have potential therapeutic effects on advanced colorectal cancer in theory.
(1) targeted therapy of HER2 overexpression
It is reported that the frequency of HER2 overexpression is 20-25% in breast cancer and 10- 15% in gastroesophageal adenocarcinoma, but it only exists in about 3-5% of colorectal cancer patients.
If conditions permit, HER2 status can be detected in patients with colorectal cancer who have failed standard treatment.
Monoclonal antibodies and small molecule drugs against HER2(ERBB2) have become part of the standard treatment of breast cancer and gastric cancer. At present, it is gradually expanding to the treatment of colorectal cancer.
Patients with colorectal cancer who overexpress RAS wild-type HER2 have poor prognosis and are resistant to EGFR antibody therapy. This makes it necessary to treat colorectal cancer with overexpression of HER2.
A phase II clinical trial explored the efficacy of trastuzumab (a monoclonal antibody targeting HER2) combined with rapatinib (a small molecule HER2 inhibitor) in patients with colorectal cancer resistant to standard treatment (including cetuximab). The treatment response rate (ORR) of patients in HER2 activation (amplification, overexpression and activation mutation) subgroup reached 38%, and the progression-free survival (PFS) was 5.6 months. This shows that targeted therapy for HER2 activation can benefit patients in clinic.
At present, ADC (antibody-drug conjugate drug) drugs for overexpression of HER2, such as T-DXd and T-DM 1 in Figure 2, have also been shown to be beneficial to patients with colorectal cancer.
Therefore, targeted HER2 therapy is a feasible treatment option for RAS wild-type colorectal cancer that is ineffective in standard treatment.
(2) targeted BRAF mutation therapy
BRAF mutation occurred in 5- 10% of colorectal cancer, mainly V600E type.
The typical features of BRAF V600E mutant colorectal cancer are right colon cancer, poorly differentiated tumor, peritoneal metastasis, DNA hypermethylation and microsatellite instability (MSI).
Because of the poor curative effect and prognosis of BRAF V600E mutant colorectal cancer, the first-line treatment usually adopts 3-drug chemotherapy (FOLFOXIRI) combined with bevacizumab.
In the second-line treatment, the mutation of BRAF V600E often coexists with MSI-H. If MSI-H is detected, immune checkpoint inhibitor treatment is preferred.
For patients with BRAF-V600E mutation without MSI-H, the European and American Food and Drug Administration approved Encorafenib combined with cetuximab as second-line treatment.
(3) Other mutation inhibitors
NTRK gene fusion is very rare in colorectal cancer, and the incidence rate is about 0.35%.
For the patients whose disease progresses after the first-line and second-line standardized treatment and whose NTRK gene fusion mutation is found, larotrectinib or entrectinib can be used to target NTRK for treatment.
RAS mutation and TP53 mutation are common in colorectal cancer, but it is very difficult to develop inhibitors because of their special molecular structure and functional characteristics.
At present, there are two inhibitors of KRAS G 12 C mutation: Sotorasib and Adagrasib. Early clinical trials showed that the remission rate (ORR) of advanced colorectal cancer was 7. 1% and 22% respectively.
abstract
In recent years, the treatment of metastatic colorectal cancer has been greatly improved.
With the latest chemotherapy and targeted therapy, some patients with metastatic colorectal cancer have the opportunity to remove the metastatic focus or even be cured by surgery.
For patients with metastatic colorectal cancer who have lost the opportunity of surgery, different treatment schemes are selected according to the type of gene mutation (RAS/RAF/MSI) and clinical characteristics (whether the lesion is in the right colon or the left colon and the patient's physical condition), which obviously optimizes the treatment effect.
Detection of biomarkers, such as dMMR/MSI-H, HER2 amplification, BRAF V600E mutation and NTRK fusion, will further enable patients to get accurate treatment opportunities and benefit from corresponding immunotherapy or targeted therapy (Table 2).
However, there is still much room for improvement in the precise treatment of metastatic colorectal cancer, and more biomarkers and corresponding precise treatment drugs need to be developed.
refer to
[1] Accurate medical treatment of metastatic colorectal cancer in clinical practice. Advances in Oncology, 2022, Vol. 14:1–25.
[2] The prospect of immunotherapy for colorectal cancer: beyond the current knowledge and future prospect of immune checkpoint blocking. Life 2022,12,229.
[3] HER2 targeted therapy for colorectal cancer: a new perspective. Cancer treatment revised on February 22, 2022; 105: 102363.
[4] CSCO Guidelines for Diagnosis and Treatment of Colorectal Cancer in 2020