Colorectal cancer is one of the common malignant tumors of the digestive system, second only to gastric cancer and esophageal cancer in terms of incidence rate, and its incidence rate is increasing year by year in China, meanwhile, its incidence age tends to be older. Its etiology and pathogenesis are not completely clear. Besides factors related to immunity, genetics and viral infection, many environmental factors such as diet, living habits, weight and hormones are closely related to the development of colorectal tumors. In recent years, with the development of medicine, colorectal cancer has made great progress in treatment, from the basic treatment methods such as surgery, chemotherapy and radiotherapy in the past to new methods such as molecular targeted therapy and immunotherapy nowadays, thus bringing great changes to the treatment of colorectal cancer patients. The following is an overview of several treatment methods.
I. Surgical treatment
For a long time, surgical resection has been recognized as the primary treatment method for colorectal cancer. After years of development, the surgical treatment of colorectal cancer has undergone the transformation from “biological model” to “bio-social-psychological model”, from simply pursuing “curing cancer and saving life” to “curing cancer and saving life”. It has changed from simply pursuing “curing cancer and saving life” to the dual standard of “curing cancer and improving life”, and improving quality of life has become a factor that cannot be ignored when deciding on the surgical procedure. At present, total rectal mesenteric resection, colonic pouch anastomosis and pelvic autonomic nerve preservation are the most important advances in the surgical treatment of rectal cancer [1].
New advances in surgical treatment of local recurrence of colorectal cancer: In the past, local recurrence of colorectal cancer was considered to be advanced and not suitable for surgery, and only palliative treatments such as chemotherapy and radiotherapy were used to relieve symptoms, but recent studies have reported [2]: the use of preoperative chemotherapy and radiotherapy + surgery + postoperative chemotherapy or preoperative chemotherapy and radiotherapy + surgery + intraoperative chemotherapy + postoperative chemotherapy has made most of the original unresectable lesions resectable, and more than 50% of them have implemented radical chemotherapy. Therefore, active and effective surgical treatment can significantly prolong the survival time of patients with recurrence, improve symptoms and enhance the quality of survival.
Second, radiotherapy method
Preoperative radiotherapy can inhibit the proliferation of tumor cells, whether they are localized lesions or those that spread outside the pelvis during surgery. Well-oxygenated tumor cells are more sensitive to radiation than hypoxic cells. Since surgery destroys blood transport, the oxygenation of tumor cells is poor, so the effect of postoperative radiotherapy is not as good as preoperative.
Chemotherapy: At present, the early diagnosis rate of colorectal cancer is low, and most patients are already in advanced stage when diagnosed, which brings certain difficulties to radical surgery, and even if surgical resection is performed, about 50% of patients will have recurrence or metastasis after surgery, therefore, most patients with colorectal cancer need comprehensive treatment. In recent years, the status of chemotherapy for colorectal cancer has been gradually emphasized. The commonly used chemotherapeutic drugs include the following categories: 1. antimetabolites; 2. botanicals; 3. alkylating agents; 4. platinum; 5. antitumor antibiotics. The effect of treatment with one class of drugs alone is not good. In order to improve the efficacy, the combination of multiple cytotoxic drugs is often used, such as 5-fluorouracil (5-FU) in combination with oxaliplatin (L-OHP). In addition, new generation anticancer drugs such as capecitabine are also used in clinical practice. Capecitabine has the advantages of intratumoral activation, convenient oral administration, high efficiency and low toxicity, and is expected to replace the 5-FU/LV intravenous drug regimen. Simultaneous treatment of capecitabine with radiotherapy can significantly improve the efficacy of colorectal cancer. Capecitabine in combination with new chemotherapeutic agents or new targeted therapeutic agents, such as in combination with oxaliplatin (XELOX regimen), in combination with irinotecan (XELIRI regimen), in combination with COX-2 inhibitors, in combination with Cetuximab or Bevacizumab, is expected to further improve the outcome of colorectal cancer. A recent study showed [3] that capecitabine in combination with radiation therapy is effective in locally unresectable advanced colorectal cancer.
Molecular targeted therapy
With the continuous research on the pathogenesis of colorectal cancer and the continuous development of therapeutic drugs, molecular targeted therapy has become a new method to treat colorectal cancer in addition to surgery, chemotherapy and radiotherapy. The combination of molecularly targeted drugs such as anti-vascular endothelial growth factor monoclonal antibody and anti-epidermal growth factor receptor monoclonal antibody can significantly improve the effect of chemotherapy and is better tolerated.
Studies have demonstrated that vascular endothelial growth factor and epidermal growth factor receptor have a large role in the development of colorectal cancer [4].
Anti-vascular epidermal growth facor (VEGF) monoclonal antibody: bevacizumab is a recombinant humanized, human-mouse chimeric VEGF monoclonal antibody, which directly blocks the binding and activation of VEGF and its receptor to exert anti-angiogenic effects.Hurwitz et al [5] reported that bevacizumab + chemotherapy in first-line treatment of colorectal The study randomized 815 patients with primary colorectal cancer to receive bevacizumab + chemotherapy (irinotecan + 5-fluorouracil + calcium folinic acid in 403 cases) or ditto chemotherapy + placebo (412 cases), with an efficiency of 44.8% and 34.8%, respectively, P<0.05. The results confirmed that bevacizumab + chemotherapy improved efficiency, prolonged prolonged survival and progression-free survival of patients with good tolerability.
Epidermal growth factor receptor (EGFR) monoclonal antibody: Cetuximab is a chimeric human and murine EGFR monoclonal antibody that competitively inhibits EGFR binding to its ligand, blocks phosphorylation of receptor-associated enzymes, inhibits cell growth, induces apoptosis, and reduces production of matrix metalloproteinases and VEGF. In vitro and animal studies have shown that cetuximab inhibits the growth of tumor cells overexpressing EGFR, but has no antitumor activity in human tumor cells lacking EGFR expression, and that cetuximab + chemotherapy is superior to chemotherapy alone in some patients. Studies have shown [6] that there is a link between the efficacy of EGFR monoclonal antibodies and K-ras gene status. k-ras introns can produce mutations in codons 12 and 13, which can be found in about 30-50% of colorectal cancer patients, and anti-EGFR therapy is ineffective in patients carrying the K-ras gene.
Despite the efficacy of molecular targeted therapy, there are some questions to be solved, such as: how can the drugs of targeted therapy act specifically on tumor cells and not on normal cells? How to combine targeted therapy with chemotherapy to obtain the best efficacy, and the problem of drug resistance of targeted drugs, etc.
4.Laparoscopic colorectal cancer resection
Laparoscopic resection of colorectal cancer began in the 1990s, including both total laparoscopic surgery and laparoscopic-assisted surgery. Laparoscopic surgery has the advantages of small trauma, fast recovery and short hospitalization time, and there is not much controversy about its use for surgery of benign colorectal lesions, but there are more differences about its use for cancer, the biggest differences being the possibility of tumor cell implantation at the traumatic site and lymph node clearance.
(a) Single-port laparoscopy: At present, transumbilical single-port laparoscopic rectal colon cancer surgery has been widely accepted and recognized at home and abroad, and many prospective studies and evidence-based medicine have confirmed that it can achieve the same or even better long-term efficacy than open surgery. Compared with multiport laparoscopy, single-port laparoscopy has the advantages of fewer incisions on the body surface, lower incidence of postoperative complications, less postoperative pain and shorter hospital stay, but there are also some problems, such as the single-port laparoscopic surgical conditions will increase the difficulty of surgery, and there is no advantage in operation time, and it puts forward new requirements on the operator’s operating experience and skills, and the reasonable selection of indications should not be deliberately pursued for single-port effect to the neglect of indications [7 ].
(ii) Pneumoperitoneum-free laparoscopy: Since the 1990s, the application and research of pneumoperitoneum-free laparoscopy in the treatment of colorectal cancer have been greatly developed. Its advantages do not affect diaphragmatic movement, do not increase cardiac load, reduce the adverse hemodynamic effects of laparoscopic surgery, reduce the risks of surgery and anesthesia for some patients who are relatively contraindicated to surgery, and expand the indications for surgery. It is a surgical method worthy of further exploration because it is free of the hazards associated with pneumoperitoneum and saves time, with rapid postoperative recovery, and is minimally invasive, safe, and effective [8].
V. Immunotherapy
In recent years, it has been found that the occurrence of colorectal cancer has a great relationship with immune factors; therefore, immunotherapy provides a new method for colorectal cancer treatment. Immunotherapy is divided into active immunotherapy and passive immunotherapy, and the former is further divided into specific and non-specific active immunotherapy.
In specific active immunotherapy, due to the development of molecular pathology, a series of colorectal cancer antigens can be identified and their properties recognized, and vaccines against these antigens can stimulate the immune system, and a large number of clinical studies on tumor vaccines have been conducted or are underway, such as: autologous colon cancer cells amended with a certain virus or BCG semi-antigen, synthetic RAS peptide-binding antigen-presenting cells, etc. .
Passive immunization: There are 3 methods to isolate tumor-infiltrating lymphocytes from resected tumors and then stimulate their expansion in vitro with interleukin 2 and then infuse them back into the patient. In addition, highly specific monoclonal antibodies are imported into the host. These antibodies will lead to an antibody-dependent cell-mediated cytotoxic response that can result in complement-mediated cell lysis or apoptosis. Overseas study [9]: 189 patients were randomly divided into observation and immunotherapy groups, and after 7 years of follow-up, the results showed that the overall morbidity and mortality rate was 32% lower in the immunotherapy group compared to the control group, and monoclonal antibodies reduced the incidence of distant metastases in about 1/3 of patients.
Immunogene therapy: With the development of gene transfection technology, it is now possible to introduce exogenous genes, such as interleukin 2, tumor necrosis factor and gamma-interferon, directly into tumor cells through the human body. However, it is still difficult to predict the ideal cytokine gene therapy for human colon cancer because the anti-tumor response of cytokines depends not only on the specific cytokine and its concentration, but also on the intrinsic immune properties of tumor cells and the immune status of host.
VI. Sentinel lymph node biopsy technique
Sentinel lymph nodes are special lymph nodes in the lymph nodes in the drainage area of the primary tumor, and they are the first lymph nodes that must be passed by the primary tumor for lymph node metastasis. The clinical significance of the sentinel lymph node as a barrier to prevent the spread of tumor cells from the lymphatic tract has received much attention [10]. Firstly, sentinel lymph node biopsy is used to determine the lymphatic area where the tumor drains, and depending on whether there is metastasis in the detected sentinel lymph nodes, the decision of lymph node dissection in this area is further made. In the 1990s, the technique of sentinel lymph node biopsy for breast cancer became a milestone in the field of breast surgery. Colorectal cancer patients can accurately locate their sentinel lymph nodes, both in vivo and in vitro, and the detection of these lymph nodes can theoretically be performed using molecular techniques that may improve the detection of micrometastases. It is expected to become a routine method for detecting micrometastases in colorectal cancer patients and further improve the positive detection rate of lymph nodes. Although the biopsy technique of lymph nodes can clearly guide the scope of radical surgery that should be resected and minimize the lymph nodes with cancer metastasis left behind with a simple method, recent studies have proved that the lymphatic systems of different colorectal cancer patients are very different, and biopsy of anterior lymph nodes cannot replace biopsy of local lymph nodes in advanced colorectal cancer patients [11]. Therefore, sentinel lymph node biopsy may become a therapeutic method for the treatment of colorectal cancer, but there are still differences.
VII. Treatment of colorectal cancer metastasis
Liver is the most common metastatic organ of colorectal cancer, and liver metastasis is also the main cause of death in patients with advanced colorectal cancer; therefore, proper management of liver metastasis is one of the important measures to improve the overall outcome of colorectal cancer. Radical surgical resection is the best treatment for patients with liver metastases from colorectal cancer and the only chance of cure. However, a study reported [12] that although surgical resection is the accepted gold standard of treatment for patients with colorectal cancer liver metastases, the surgical resection rate is low, with only 15%-20% of patients with colorectal cancer liver metastases being suitable for surgical treatment at diagnosis. Therefore, palliative chemotherapy, targeted therapy, interventional therapy and radiotherapy are the treatment options for this group of patients, which can prolong the survival period and improve the quality of survival.
5-Fluorouracil (5-FU) is the drug commonly used for adjuvant and palliative treatment of colorectal cancer in the past, while some new drugs such as oxaliplatin, capecitabine and irinotecan have been introduced to provide more options for the treatment of colorectal cancer. At this stage, neoadjuvant chemotherapy for colorectal cancer liver metastases is advocated. Adam et al [13] reported a group of 1104 patients with inoperable colorectal cancer liver metastases who underwent aggressive chemotherapy (based on 5FU and CF with oxaliplatin or irinotecan as appropriate), and after an average of 10 courses, 12.5% of patients had shrunken lesions and underwent stage 2 surgical resection, with a 5-year survival rate of 33%. Therefore, for patients with liver metastases, the appropriate treatment plan should be used according to the characteristics of each patient’s condition and economic status.
In conclusion, there are various methods of colorectal cancer treatment, emphasizing the application of comprehensive and individualized treatment, and reasonable and effective treatment plans should be adopted according to patients’ specific conditions and disease stages, but the problems of over-treatment and under-treatment should also be guarded in the treatment of colorectal cancer. There are obvious anatomical differences between colon and rectum, resulting in different clinicopathological stages. There are some differences in the indications for adjuvant therapy for colon and rectal cancer. Locally progressive rectal cancer should receive neoadjuvant therapy, but current preoperative treatment options are controversial. As research continues to progress, some new treatments will be applied to the clinic.