Colorectal cancer is one of the most common malignant tumors. In China, the incidence of colorectal cancer is ranked 4th and 3rd among men and women, respectively. Entering a state of advanced disease, the treatment strategy for these patients is chemotherapy-based comprehensive treatment. Compared with the best supportive treatment, it can significantly prolong the survival period and improve the quality of life. In the past two years, with the deepening of cancer molecular targeting research, the efficacy of targeted drugs is getting better and better, and the side effects are small, so that clinicians and patients have more treatment options. Let us take a look at the colorectal What are the current medication options for cancer?
Colorectal cancer treatment plan
(1) It is recommended to detect the gene status of tumor K-ras, N-ras and BRAF before treatment, and EGFR is not recommended as a routine test item.
(2) Combined chemotherapy should be used as the first- and second-line treatment for patients with metastatic colorectal cancer that can tolerate chemotherapy. The following chemotherapy regimens are recommended: FOLFOX or FOLFIRI, or combined with cetuximab (recommended for patients with wild-type K-ras, N-ras, BRAF genes), CapeOx, FOLFOX or FOLFIRI, or combined with bevacizumab.
(3) Patients with more than third-line chemotherapy are recommended to try targeted drugs or participate in clinical trials. For patients who do not use targeted drugs in first- and second-line therapy, irinotecan combined with targeted drug therapy can also be considered.
(4) Regofinil or clinical trials are recommended for patients who have failed third-line and above standard system treatment. For patients who do not use targeted drugs in first- and second-line treatment, irinotecan combined with cetuximab (recommended for wild-type K-ras, N-ras, BRAF genes) can also be considered.
(5) For patients who cannot tolerate combination chemotherapy, the fluorouracil + calcium folinate scheme or capecitabine single drug or combination targeted drugs are recommended. Patients with advanced colorectal cancer who are not suitable for the fluorouracil + calcium leucovorin regimen may consider single-agent treatment with raltrexone.
(6) Patients whose disease is stable after 4 to 6 months of palliative treatment but still have no chance of R0 resection can consider entering maintenance treatment (such as the use of less toxic fluorouracil + calcium leucovorin, or capecitabine single drug combined targeting Treatment, or suspend systemic system treatment) to reduce the toxicity of combined chemotherapy.
(7) For patients with BRAF gene V600E mutation, if the general condition is better, FOLFOXIRI or first-line therapy combined with bevacizumab can be considered.
(8) If the general condition or organ function is very poor in advanced patients, the best supportive treatment is recommended.
(9) If the metastasis is limited to the liver and / or lung, refer to the treatment principles of liver metastasis and lung metastasis.
(10) For patients with local recurrence of colorectal cancer, a multidisciplinary assessment is recommended to determine whether they have the opportunity to be resected or radiotherapy again. If it is only suitable for chemotherapy, the above principles of drug treatment for advanced patients are adopted.
Choice of chemotherapy for patients with colorectal cancer
Chemotherapy drugs currently used to treat advanced colorectal cancer include: fluorouracil (including oral
Capecitabine), oxaliplatin and irinotecan .
One
Induction therapy
1. Three-drug plan
FOLFOXIRI [23]: irinotecan 165 mg / m2, intravenous infusion, d1; oxaliplatin 85 mg / m2, intravenous infusion, d1; LV 400 mg / m2, intravenous infusion, d1; 5-FU 1 600 mg / (m2 · d) × 2 d continuous intravenous infusion (total 3 200 mg / m2, infusion for 48 hours), starting on the first day. Repeat every 2 weeks.
2. Dual drug regimen
(1) Oxaliplatin-based programs, such as FOLFOX and CapeOx, see the adjuvant treatment of colon cancer.
(2) Irinotecan-based regimen: FOLFIRI: irinotecan 180 mg / m2, intravenous infusion for 2 hours, d1; LV 400 mg / m2, intravenous infusion for 2 hours, d1; 5-FU 400 mg / m2 , Intravenous bolus injection, d1, then 2 400 mg / m2, continuous intravenous infusion for 46 to 48 hours. Repeat every 2 weeks.
3. Single drug regimen
If the patient cannot tolerate strong initial treatment, 5-FU / LV or capecitabine infusion (see adjuvant therapy for specific details) or the single-agent irinotecan (125 mg / m2 irinotecan, intravenous infusion 30 ~ 90 minutes, d1, d8, repeated every 3 weeks; or irinotecan 300-350 mg / m2, intravenous infusion 30-90 minutes, d1, repeated every 3 weeks). Or irinotecan 180 mg / m2, intravenous infusion for 2 hours, d1, repeated every 2 weeks.
After the above treatment, if the patient’s general condition has not improved, the best supportive treatment should be given.
Two
Maintenance treatment
The OPTIMOX1 trial showed that in patients with metastatic colorectal cancer receiving FOLFOX as first-line treatment, the intermittent use of oxaliplatin’s “stop and go” strategy can reduce neurotoxicity but does not affect Survival [26]. Therefore, after 3 to 6 months of dual-agent combination chemotherapy, such as the disease CR / PR / SD, oxaliplatin or irinotecan with greater adverse reactions can be discontinued, and other drug maintenance treatments in the regimen continue. Until the tumor progresses, progression-free survival can be extended, but the overall survival benefit is not obvious.
Three
Second, third and subsequent chemotherapy options
The choice of second-line chemotherapy depends on the first-line treatment plan. The oxaliplatin-based and irinotecan-based programs can be the first and second line of each other. According to the patient’s physical condition, choose a single drug or combination treatment plan.
Patients with more than third-line chemotherapy are recommended to try targeted drugs or participate in clinical trials. For patients who do not use targeted drugs in first- and second-line therapy, irinotecan combined with targeted drug therapy can also be considered.
Targeted treatment for colorectal cancer
The list of targeted and immunotherapy drugs for colorectal cancer that have been approved so far at home and abroad.
1. Bevacizumab
Common name: An Wei Ting
English name: Avastin
Molecular structure name: Bevacizumab
Main indications: colorectal cancer
Origin: Roche
Bevacizumab (Avastin®) is a recombinant humanized monoclonal antibody. It was approved by the FDA on February 26, 2004, and it was the first drug approved in the United States to suppress tumor angiogenesis.
The effectiveness of bevacizumab as a single agent is low, and it is generally recommended to be used in combination with chemotherapy.
Combined chemotherapy regimen: IFL, FOLFIRI, FOLFOX and CapeOX; doses used: 5 mg / kg (2-week regimen) and 7.5 mg / kg (3-week regimen).
The combination of IFL and bevacizumab in the treatment of advanced colorectal cancer increased OS from 15.6 months to 20.3 months (AVF2107 study).
Bevacizumab combined with FOLFIRI regimen as first-line treatment, the effective rate was 58.7%, PFS was 10.3 months (FIRE3 study).
Bevacizumab combined with FOLFOX or FOLFIRI as first-line treatment, PFS reached 11.3 months, OS reached 31.2 months (CALGB80405 study).
2. Cetuximab
Common name: Erbitux
English name: CETUXIMAB SOLUTION FOR INFUSION
Molecular structure name: Cetuximab
Main indications: colorectal cancer
Place of Origin: Merkelion, Germany
Before treatment with cetuximab, the RAS gene must be tested before all wild-type patients can use cetuximab. The effective rate of cetuximab is only about 20%, and it is usually recommended to be used in combination with chemotherapy.
FOLFIRI and FOLFOX; dosage: 400mg / m2 250mg / m2 per week after the first dose.
In RAS wild-type patients, cetuximab combined with FOLFIRI regimen or FOLFOX regimen brings significantly longer PFS and OS than chemotherapy alone.
3. Regafini
Common name: Baivango
English name: regorafenib
Molecular structure name: Regefenib
Main indications: metastatic colorectal cancer
Place of Origin: Bayer Corporation
Applicable people: In September 2012, Regefini was approved by the FDA to treat advanced colon cancer. In May 2017, China’s CFDA has also approved regorafenib for the treatment of fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and anti-VEGF therapy 1. Anti-EGFR therapy (RAS wild-type) patients with metastatic colorectal cancer (mCRC).
4. Panitumumab (panitumumab)
Common name: Viktibi
English name: Erbitux cetuximab
Molecular structure name: panitumumab
Main indications: metastatic colorectal cancer
Place of Origin: American Amgen
Colorectal cancer treatment drugs Vectibix (panitumumab) and panitumumab are the first fully humanized monoclonal antibodies that target the epidermal growth factor receptor (EGFR). In July 2005, Panitumumab received FDA fast track approval. At the end of 2005, Amgen and its partner Abgenix jointly submitted a license application for this product to the FDA for the treatment of metastatic colorectal cancer after chemotherapy failure.
5.Ziv-aflibercept (Abercept)
English name: Zaltrap (ziv-aflibercept for solution for infusion)
Molecular structure name: Abecip
Main indications: metastatic colorectal cancer
Origin: Sanofi
Abecip was approved by the US FDA for the treatment of advanced colorectal cancer in 2012. It is a chimeric protein drug that restricts the supply of tumor nutrients by inhibiting human vascular endothelial growth factor VEGF, thereby inhibiting tumor proliferation.
Aflibercept binds to circulating VEGF in the body and acts like a “VEGF trap”. Therefore, they inhibit the activity of vascular endothelial growth factor subtypes VEGF-A and VEGF-B and placental growth factor (PGF), respectively, and inhibit the growth of new blood vessels in chorionic cysts or tumors. It can be said that the purpose of Aflibercept is to “starve” tumor tissue.
6. Ramolimumab (Cyramza)
English name: ramucirumab
Molecular structure name: Remolumumab
Main indications: colorectal cancer
Origin: Eli Lilly and Company
Cyramza was approved by the US FDA in 2014 to treat gastric cancer, colorectal cancer and non-small cell lung cancer.
As the tumor tissue enlarges, it will undergo the process of angiogenesis, that is, the formation of new blood vessels around the tumor tissue to transport nutrients to the tumor cells. Therefore, inhibiting this process can inhibit the proliferation of most tumors.
Cyramza is a monoclonal antibody drug, which mainly inhibits the formation of new blood vessels around the tumor and inhibits the supply of nutrients to the tumor by binding to the vascular endothelial growth factor receptor (VEGFR2), thereby inhibiting tumor proliferation.
7. Fruquintinib
Product Name: Aiyoute
Applicable symptoms: Approved in China on September 5 for the treatment of previous fluorouracil, oxaliplatin and irinotecan-based chemotherapy, as well as previous or unsuitable treatment with anti-vascular endothelial growth factor (VEGF) 1. Patients with metastatic CRC treated with anti-epidermal growth factor receptor (EGFR) (RAS wild-type).
7.opdivo
English name: nivolumab
Molecular structure name: nivolumab
Main indications: colorectal cancer
Place of Origin: Bristol-Myers Squibb
Ono and Bristol Myers Squibb (BMS) joint research and development, in July 2014 by the Japanese Pharmaceutical and Medical Devices Agency (PMDA) approval, December 2014 by the US Food and Drug Administration (FDA) Approved, approved by the European Medicines Agency (EMA) in June 2015, approved by the China Food and Drug Administration (CFDA) for marketing in June 2018, and sold by Ono Pharmaceuticals in Japan, Bristol-Myers Squibb in the United States, It is sold in Europe and China under the brand name Odivo®.
The latest treatment progress of colorectal cancer
1) TAS-102 (Lonsurf)
TAS102 is an oral chemotherapeutic drug composed of the anti-tumor nucleoside analog FTD (trifluorothymidine, trifluridine) and thymidine phosphorylase inhibitor TPI.
The mPFS of the TT-B group treated with TAS102 + bevacizumab was 9.2 months, which was significantly higher than the 7.8 months of the traditionally treated capecitabine + bevacizumab CB group. Progression-free survival. It is expected to become a new first-line treatment option for such patients.
2) What are the benefits of breakthrough therapy in the three-drug combination?
The combination of encorafenib, binimetinib and cetuximab for BRAF mutation patients is a big change, because multiple studies have shown that the combination of BRAF inhibitors and MEK inhibitors in refractory patients, It can be seen that the reaction rate exceeds 30%, which is unheard of.
Recent data submitted at the 2018 World Congress of Gastrointestinal Cancer show that the three-drug combination not only has a high response rate, but also has a long PFS and OS. This is why trials are being developed in first-line therapy. Interestingly, this triplet does not contain cytotoxic targeted drugs. This shows that it can intelligently identify tumor molecules and produce significant clinical effects without generating a lot of toxicity.
3) What are the progress of immunotherapy?
For MSI-H tumors, the combination of nivolumab and ipilimumab has the opportunity to obtain first-line treatment, because the efficacy data seems very convincing.
For microsatellite stable tumors, should we combine immunotherapy with standard chemotherapy-FOLFOX / bevacizumab in combination with nivolumab.
