Colorectal cancer is one of the malignancies with the highest incidence and mortality rates in the world. According to WHO Dr. Parkin [1.2] and others, in 2002, 1.02 million new cases of colorectal cancer were diagnosed worldwide, accounting for the 3rd highest incidence rate and 529,000 deaths, accounting for the 4th highest mortality rate. In western countries colorectal cancer mortality accounts for the 2nd highest death rate of oncology patients. In recent years, the incidence of colorectal cancer has been on the rise, and its 5-year incidence ranks the 3rd in malignant tumors. The annual incidence of colorectal cancer in China is 150,600 and the annual death rate is 86,100. Among malignant tumors in China, colorectal cancer ranks 5th in both incidence rate and mortality rate, with women ranking 6th (WHO, 2002). Both incidence and mortality rates are on the rise. Colorectal cancer ranks 5th among the 8 malignant tumors listed as priorities for prevention and control in the Outline of China’s Cancer Prevention and Control Plan (2004-2010) promulgated by the Ministry of Health of China in December 2003. Colorectal cancer is still one of the malignant tumors that countries focus on preventing and treating.
I. Research on the etiology of colorectal cancer
In the past decade or so, with the progress of research on colorectal cancer-related genes and gene mechanisms and the emergence of many new related genes, the understanding of the genetic mechanism of colorectal cancer has been improved.
The occurrence and development of colorectal cancer is a complex process regulated by multiple genes and steps, which is often related to uncontrolled cell proliferation and apoptosis, involving oncogenes, oncogenes, mismatch repair genes and some modifying genes.
1. Oncogenes
The Ras gene, the majority of whose mutations are K – Ras gene mutations, accounts for about 50% of colorectal cancer patients [3]. the expression product of the Ras gene, P21, can bind to GTP /GDP and has GTPase activity. When normal cells are stimulated by growth factor receptors, Ras protein separates from GDP and binds to GTP. Activated RAS protein P21 transmits growth factor information to the nucleus via Raf-1 and stimulates MAPK pathway, while GTP is hydrolyzed to GDP and P21 is inactivated. In contrast, the protein product of the mutated Ras gene cannot hydrolyze the GTP bound to it, and the RAS protein remains in an activated state, thus continuously stimulating cell proliferation. Ras mutations are also found in normal epithelial cells adjacent to tumor tissue, suggesting that Ras mutations are an early event in colorectal carcinogenesis. The presence of different Ras mutations in the same tumor indicates that there are many conditions leading to Ras mutations. Also, mutated Ras can downregulate the oncogene COX-2. K-Ras gene activation mutations are highly correlated with methylation of oncogene P16 promoter region [3]. activation of Ras gene functions through three transduction pathways, RAS/Raf, RAS/P I3 – K and RAS/RAL [4]
2. oncogenes
p53 gene: p53 gene mutation is present in 75% of sporadic colorectal cancers, and the frequency of mutation correlates with the malignant biological behavior of the tumor. p53 gene variation is related to the degree of differentiation of colorectal cancer, the presence or absence of liver metastasis or lymph node metastasis and Dukes’ stage, which has important implications for patient prognosis [5].
APC gene (adenomatous polyposis coli): APC gene is in 5q21, and familial adenomatous polyposis (FAP) is caused by mutation or loss of this gene, while about 35% – 60% of colorectal cancer patients without family history also have loss of this gene. The APC gene is responsible for the self-stabilization of colorectal epithelial cells and is a rate-limiting factor in colorectal cancer.
Other oncogenes such as TGFβIIR, DCC and MCC (mutated in colorectal cancer) have also been shown to be associated with the occurrence of colorectal cancer.
3. mismatch repair genes (m isma tch repa ir gene, MMR gene)
MMR genes, including hMSH2, hMSH3, hMSH6, hMLH1, hPMS1, hPMS2, are considered as “caretaker genes” responsible for genomic stability; mutations in this system can lead to an increase in the mutation rate of all genes, including the APC gene, and eventually lead to colorectal cancer. The microsatellite sequence alterations caused by MMR mutations are called microsatellite instability (MSI) and can usually be corrected by some mismatch repair proteins. However, in some tumors, mutations in mismatch repair genes resulting in decreased mismatch repair protein function can lead to repair failure [6]. The genetic pathogenesis of hereditary nonpolyposis colorectal cancer (HNPCC) is based on microsatellite instability, i.e., the recurrence of mismatched sequences, and mutations in at least one known MMR gene in the HNPCC family. The most frequent are hMLH1 and hMSH2 [ 7 ], both of which are mutated in up to 85% of patients with HNPCC. mutations in the MMR gene also cause 15% to 20% of sporadic colorectal cancers [8]. Mismatch repair gene mutations can also lead to allele-shifting mutations in Bax, which is a core gene in the apoptosis pathway.
4. modifying genes
In addition to the above genes, many other genes play an important role in colorectal carcinogenesis.COX-2 is one of the 2 members of the COXs (cyclooxygenases) family.COX-2 is overexpressed in colon cancer cells, and colon cancer cells overexpressing COX-2 in tissue culture systems produce factors that promote angiogenesis. COX – 2 appears to be more important due to the presence of antagonists of this gene.
Nuclear receptor peroxisome proliferator-activated receptors ( PPARs): a subtype of PPARs, PPARs-γ, is expressed at high levels in colorectal cancer cells. The number of colonic tumors was significantly increased after administration of a ligand for PPARs-γ in intestinal tumor-prone mice. It has also been shown that increased activation of PPARs-γ is associated with mutations in the APC gene.
II. Surgical treatment of colorectal cancer
1.Radical surgery
At present, the first choice of treatment for colorectal cancer is still radical surgery, but its therapeutic effect is not satisfactory enough, and the improvement has not been significant in the past thirty years.
American Cancer Society Cutler statistical analysis of 25,000 cases of colorectal cancer data, surgical treatment of colon cancer 5-year survival rate from 1940 – 1960 from 48% to 56%, rectal cancer from 44% to 50%. The Clinical Trials Research Centre at the University of Oxford, UK, collected data on all clinical randomized treatments for colorectal cancer from 1960-1987 from a total of 97 groups of 154 studies containing more than 32,000 cases worldwide. The 3-year survival rates were 74% for colon cancer and 65% for rectal cancer; the 5-year survival rates were 56.1% and 45.1%, respectively. Recently, the 5-year postoperative survival rates reported in a large number of cases are around 70% (colon cancer) and 50% (rectal cancer) [9].
2. Laparoscopic surgery
Since the world’s first laparoscopic-assisted resection of colon cancer was performed in 1990, laparoscopy has increasingly shown its advantages in colorectal surgery. The magnifying effect of laparoscopic images allows for clearer identification of important structures such as blood vessels and nerves and more precise operation, especially in pelvic surgery operations, which are quite advantageous, all of which are beyond the reach of open surgery.
From the current research results, most scholars believe that laparoscopic surgery is safe and efficacious. Whether laparoscopic or open surgery is performed for colorectal cancer patients, the determining factor for postoperative tumor recurrence and long-term postoperative survival is whether the surgery follows the tumor-free principle of radical resection for colorectal cancer. Large randomized controlled trials have shown that laparoscopy can achieve the same curative results as open surgery.
The results of the CLASICC (conventional versus laparoscopic assisted surgery in colorectal cancer) RCT, conducted by the Medical Research Council (MRC) in 27 medical centers in the UK, showed that patients in the laparoscopic group had a similar time to recovery of bowel function and return to normal diet as those in the open group, but the mean length of stay was shorter than that in the open group [10]. The in-hospital morbidity and mortality rates were essentially the same between the two groups. The results of an RCT conducted by the COST (Clinical Outcomes of Surgical Therapy) study group, which included 863 colon cancer patients (435 in the laparoscopic group and 428 in the open group) from 48 medical centers [11], showed that the perioperative recovery in the laparoscopic group was better or not worse than that in the open group: the laparoscopic group had a shorter hospital stay (P < 0. 001) and less postoperative analgesia (P = 0. 02); the overall complication rate and the perioperative mortality rate in both groups were not significantly higher than those in the open group. There was no significant difference in the overall complication rate and perioperative morbidity and mortality rate between the two groups (P = 0. 64, P = 0. 40). Although the intraoperative complication rate appeared to be higher in the laparoscopic group than in the open group (1.8% vs. 0.2% for intraoperative bleeding, 1.4% vs. 0.5% for bowel injury, 0% vs. 0.5% for splenic injury, and 0.7% vs. 0.7% for other intraoperative complications), there was no significant difference in the overall rate of intraoperative complications (3.7% vs. 1.9%, P = 0. 10), nor was there a significant difference in the overall rate of postoperative complications between the two groups (18.7% vs. 18.6%, P = 0. 98). Based on the findings of the COST large sample, multicenter, prospective RCT clinical study, in 2005, the American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal Endoscopic Surgeons (SAGES) signed a joint statement that for curable colon cancer, laparoscopic colectomy performed by experienced surgeons can achieve the same tumor-related survival rates as open surgery.
Similar results have been reported in some of the following other foreign studies.
Lujan et al [12] conducted a single-center, retrospective study including 102 patients undergoing laparoscopic colorectal cancer surgery with a follow-up period of 1 to 111 months with a mean of 64. 4 months, and their 5-year survival rates for patients with TNM stages I, II, III, and IV were 73%, 61%, 55%, and 0%, respectively, compared with the National Cancer Data Base (NCDB The corresponding survival rates in the National Cancer Data Base (NCDB) were 70%, 60%, 44%, and 7%, respectively; Leroy et al [13] conducted a prospective clinical study on laparoscopic radical resection of rectal cancer with a follow-up time of 6 to 96 months, averaging 36 months, and no recurrence at the poke site was found, and the local recurrence rate of tumor was only 6%, with a tumor-related 5-year survival rate of 75%. These results were essentially comparable to those of open surgery; Lacy et al [14] in Spain conducted a clinical study of RCT including 219 cases of resectable colon cancer with a follow-up time of 27 to 85 months and a median of 43 months. Although the difference in overall survival between the two groups was not significant ( P = 0. 16), the tumor-related survival rate was significantly higher in the laparoscopic group than in the open group ( P = 0.02); for colon cancer at TNM stage I and II, the differences in recurrence and survival rates between the two groups were not significant, but for colon cancer at TNM stage III, the recurrence, overall and tumor-related survival rates were better in the laparoscopic group than in the open group ( P = 0.04, P = 0.02, and P = 0.006). The difference in incisional recurrence rates between the two groups was not significant; Patankar et al [15]], USA, conducted a prospective, non-randomized, controlled clinical study of 344 cases (172 each in the laparoscopic and open groups) of colorectal cancer surgery over a 10-year period, with a follow-up period of 3 to 128 months and a mean of 52 months; the difference in postoperative local recurrence rates between the laparoscopic and open groups was not significant ( 3.5% vs 2.9%, P = 0.76). Notably, 1. 7% (3 cases) of recurrences in the laparoscopic group were incisional, poked-hole tumor recurrences; the difference in the incidence of distant metastases between the two groups was not significant (P = 0.61), nor was the difference in overall survival between the two groups (P = 0. 23); the prospective, non-randomized, controlled clinical study by Feliciotti et al [16] in Italy concluded that the difference in long-term survival between laparoscopic and open radical colon cancer surgery was not significant. The results of a follow-up of 74 laparoscopic versus 75 open surgery patients for 36 to 96 months (mean 48.9 months) showed that the differences in local recurrence rate, incidence of distant metastases in a different time, and cumulative survival rate between the laparoscopic and open groups were not significant (P = 0.105, 0.563, 0. 513); the results of a prospective study by Poulin et al [17] in Canada showed that laparoscopic surgery for rectal cancer at TNM stage I to III was not significant. The results of a prospective study by Poulin et al [17] in Canada showed that the 5-year survival rate after laparoscopic radical resection (TME) for stage I-III rectal cancer was 72.1%, with a local recurrence rate of 4.3% and no poke site recurrence. This is basically comparable to the results of open surgery.
A few small-sample, single-center, retrospective studies on the intermediate and long-term outcomes of laparoscopic radical colorectal cancer have been reported in China; no large-sample, multicenter, prospective studies have been reported, and no RCT studies have been reported. The reported results suggest that the adoption of laparoscopic resection is safe, with no significant difference between the recent and long-term follow-up results and open surgery.
Tan Min et al [19] reported 78 laparoscopic colorectal cancer resections with a follow-up time of 2 to 60 months and cumulative survival rates of 95.0%, 68.8%, and 58.8% for patients with tumor stages Dukes B, C1, and C2, respectively; Fu Wei et al [20] reported the long-term follow-up results of 9 laparoscopic combined abdominoperineal resections for rectal cancer (5 cases with Dukes stage B and 4 cases with stage C) The follow-up time ranged from 40 to 94 months, with a median of 80 months and a 5-year survival rate of 77. 8%, and no tumor recurrence at the poke hole was found; Zheng Minhua et al [21] compared radically resectable colon cancer non-randomly divided into two groups (30 cases in the laparoscopic group and 34 cases in the open group), with a follow-up time of 8 to 36 months, no incisional implantation metastasis in both groups, and a non-significant difference in the 3-year cumulative survival rate ( 84% vs 84%, P > 0.05); Guan Jinghong [22] and Du Yanfu [23.24] reported 80 and 137 cases of laparoscopic colorectal cancer surgery, respectively, with a mean follow-up time of about 1 year, and no incision or poke hole tumor implantation was seen, which also achieved better recent survival results.
III. Chemotherapy for colorectal cancer
About 30% of newly diagnosed colorectal cancer cases belong to progressive or metastatic lesions (about 20% of patients have liver metastases), and another 20-30% of cases will have recurrence or metastatic lesions after surgery. Ultimately, 50% of cases will be classified as progressive or metastatic colorectal cancer. The prognosis of these cases is extremely poor and also the reason why the 5-year survival rate has been hovering around 50%. It is clearly not possible to alter the prognosis by expanding resection alone. Chemotherapy is currently the main tool available for the treatment of such patients.
Colorectal cancer is a relatively sensitive tumor to chemotherapy. Advances in chemotherapy methods for colorectal cancer in the past decade have improved the effectiveness of chemotherapy for progressive colorectal cancer. Progressive colorectal cancer chemotherapy includes preoperative, intraoperative and postoperative adjuvant chemotherapy. The most effective drugs include 5-fluorouracil, capecitabine, camptothecin, oxaliplatin, etc. Targeted drugs Avastin and Cetuximab have also shown good efficacy.
1. Preferred drug 5-FU
For many years, 5-FU has been the drug of choice for the treatment of advanced colorectal cancer. 5-FU combined with tetrahydrofolic acid (FA) is internationally recognized as the standard first-line treatment regimen for progressive or metastatic colorectal cancer, with an efficiency of about 30-40%. In addition, several new agents such as platinum oxalate (Oxaliplatin, L-OHP), irinotecan (CPT-11), capecitabine (Xeloda) and hydroxylcamptothecine (HCPT), with established effects alone, have been used in combination with 5 C Fu/CF The preliminary results of the combination were encouraging.
Xeloda, also known as capecitabine, the predecessor of 5-FU, is a fluoropyrimidine deoxynucleoside carbamate that is administered orally and mimics continuous intravenous 5-FU. domestic and international studies have shown that Xeloda is effective in the treatment of advanced or recurrent colorectal cancer and recurrent metastatic breast cancer and is well tolerated by patients [25.26]. It is at least as effective as 5-Fu/CF (Mayo regimen) in the treatment of advanced colorectal cancer, and even Xeloda is effective when 5-Fu/CF is not effective. X-ACT clinical trials were initiated in November 1998. By November 2001, 164 medical centers participated, enrolling 1,987 cases (Dukes’ stage C colon cancer) randomly assigned to two groups: Xeloda group – oral Xeloda 1 250 mg/m2 Bid d1-14, stopping for 7 days, each course of 3 weeks, for a total of 8 courses;5 C Fu/CF group –CF 20 mg/ m2 5 – Fu 425 mg/ m2 IV qdd1-5, 4 weeks per course, 6 courses in total. The main observation was the disease-free survival (DFS) after surgery. By 2005, with a median follow-up of 4.3 years (51 months), the results showed that Xeloda was at least as effective as 5-Fu/CF (3-year disease-free survival rate of 64.2%). However, as adjuvant chemotherapy, relapse-free survival was superior to that of 5-Fu/CF, and toxic side effects (e.g., diarrhea, nausea, vomiting, gastritis, alopecia, leukocyte decline, etc.) were less than those of 5-Fu/CF, with only hand-foot syndrome and hyperbilirubinemia being more frequent (P< 0.001) [27]. Since Xeloda is equivalent to 5-Fu/CF , the Xelox regimen, i.e. Xeloda plus Oxaliplatin, is also commonly used clinically.
5 – Fu/CF plus Oxaliplatin has also yielded good results in the treatment of early colon cancer, and the FOLFOX4 regimen is currently the standard adjuvant therapy for colon cancer. A multicenter international study of postoperative adjuvant Oxaliplatin/5-Fu/CF treatment for stage II and III colon cancer (the MOSAIC trial) was initiated in October 1998. A total of 146 hospitals in 20 countries participated in the study, and 2,246 patients were enrolled by January 2001. The control group was treated with CF 200 mg/m2 for 2 hours, followed by 5-Fu 400 mg/m2 intravenously; then 5-Fu 600 mg/m2 was infused intravenously for 22 hours for 2 days, 14 days per cycle. In addition to the above regimen, Oxaliplatin 85 mg/m2 was added to the trial group for 2 hours on the first day. preliminary MOSAIC results presented at ASCO 2004 showed that the trial group had a better 3-year disease-free survival rate of 78.2% than the control group (72.9%) and a 23% reduction in the risk of recurrence. in 2005, De Gramont et al. reported 4-year follow-up results with a median follow-up of 48.6 months for In 2005, De Gramont et al. reported a 4-year follow-up with a median follow-up of 48.6 months and a 4-year disease-free survival rate of 69.7% for stage III patients in the FOLFOX4 group, which was better than that of the control group (61%), with a 25% reduction in the risk of recurrence; for stage II patients, the 4-year disease-free survival rate was 84.3%, which was also better than that of the control group (82.7%), with a 20% reduction in the risk of recurrence [28].
2. CPT-11
CPT-11 is a semi-synthetic derivative of camptothecin, which has been recommended as a second-line drug for advanced colorectal cancer in the absence of 5-FU treatment in clinical studies conducted in Europe, the United States, and Japan, and was found to be effective in advanced colorectal cancer without cross-resistance to 5-FU. achieve significant improvements in efficiency, time to disease progression, and overall survival over the 5-FU/FA regimen alone. Guan Zhongzhen et al. reported that the efficiency of single-agent CPT-11 in advanced colorectal cancer was 16% and 48% had stable disease, and some patients who had failed with previous treatment with 5-FU [30] could still achieve a 20% remission rate, suggesting that there was no cross-resistance between CPT-11 and 5-FU.
The FOLFIRI regimen, in which Irinotecan (CPT-11) is added to 5-FU/CF, is a semi-synthetic derivative of camptothecin that is metabolized in the liver to an active SN-38, which inactivates topoisomerase I (Topo-Ⅰ), causing irreversible single-strand breaks in DNA and cancer cell death. FOLFIRI has been clinically proven to be effective in advanced colorectal cancer alone or in combination with 5-Fu/CF. Is FOLFIRI more effective than 5-Fu/CF as postoperative adjuvant therapy for stage II and III colon cancer? Since the initiation of a randomized trial in January 2000, the PETACC-3 trial (V307), 3,005 postoperative patients with stage II and III colon cancer from 340 sites in 32 countries were randomized. By the preliminary summary in 2005, this regimen showed a trend toward improved 3-year tumor-free survival in patients with stage III colon cancer, with overall survival to be further observed; the trial results also showed that this regimen had no unexpected toxicity, with a low incidence of diarrhea and neutropenia and an acceptable range of toxic reactions [31].
3. Targeted therapy
Two targeted drugs, Bavacizumab (Avastin) and Cetuximab (C-225), have been approved by the US FDA (2004) and the European Commission (early 2005) for use in metastatic colorectal cancer. Avastin is a monoclonal antibody against vascular epithelial growth factor A (VEGF- A); C-225 is a monoclonal antibody against epithelial growth factor receptor (EGFR). Clinical trials have confirmed that they are combined with chemotherapeutic agents to significantly improve the survival rate of patients with advanced colorectal cancer.
In the BOND study [32], conducted between July 2001 and January 2003 in 56 research centers in 11 European countries, 576 patients were screened and 474 ( 82.1%) patients expressed EGFR, of which 329 were enrolled and randomized in a 2:1 ratio into two groups, 218 patients received cetuximab in combination with irinotecan and 111 patients received cetuximab monotherapy. The initial dose of cetuximab The initial dose of cetuximab was 400 mg/m2 for the first week, followed by 250 mg/m2 once weekly, and irinotecan was administered at the same dose and regimen as recently used before enrollment. The single agent group was transferred to the combination therapy group after disease progression. All patients continued treatment until disease progression or unacceptable toxicities occurred. Results showed that cetuximab was 10.8% effective in the treatment of EGFR-expressed advanced colorectal cancer and 22.9% effective in combination with irinotecan. The median time to disease progression was 4.1 months in the combination group, significantly longer than that of 1.5 months in the single-agent group (P < 0.001), and survival was 8.6 months in the combination group, also longer than that of 6.9 months in the single-agent group (P = 0.48). In particular, for the subgroup of patients who progressed within 1 month of irinotecan treatment, the combination group was 25% more effective than the cetuximab monotherapy group (14.1%) (P=0.07). Notably, for the subgroup of patients who failed previous platinum oxalate and irinotecan treatment, the efficiency rate of the combination group was 22.2%, which was also significantly higher than that of the single-agent group (8.5%) (P=0.01).
IV. Adjuvant radiation therapy for colorectal cancer
For local recurrence of rectal cancer surgery, as early as the 1950s, some scholars tried to use effective preoperative radiotherapy as adjuvant therapy to control postoperative local recurrence in patients with advanced disease. The advantages of preoperative radiotherapy are mainly to reduce tumor inoculation at surgery, reduce tumor stage, increase the possibility of surgical resection and liver preservation, and favor radiotherapy with good blood and oxygen supply to the tumor bed. Although early retrospective studies suggest that preoperative radiotherapy has an encouraging effect on survival in patients with Dukes’ stage C rectal cancer, 37% versus 23% for those undergoing surgery alone. Several other randomized trials appeared to confirm the survival benefit of preoperative radiotherapy. However, 9 of the 10 subsequent randomized trials could not demonstrate a favorable effect of preoperative radiotherapy on survival, and a pooled analysis of randomized trials of preoperative radiotherapy published before 1987 supported that preoperative radiotherapy did not improve survival[33] . However, preoperative radiotherapy does enhance local control and can reduce staging and increase the chance of anus preservation.
Recently, the Colorectal Cancer Research Collaborative Group pooled 22 randomized trials, including 14 trials of preoperative radiotherapy in 6,350 cases and 8 trials of postoperative radiotherapy in 2,157 cases, and overall survival was slightly better with radiotherapy than with surgery alone (5-year survival 45% vs. 42.0%; 10-year survival 26.9% vs. 25.3%), with local recurrence rates of 12.5% and 16.7% at 5 and 10 years, respectively, in the preoperative radiotherapy group compared with 22.2% in surgery alone. The 5-year and 10-year local recurrence rates were 12.5% and 16.7% in the preoperative radiotherapy group, compared with 22.2% and 25.8% in the surgery-only group, respectively (P < 0. 00001); the 5-year local recurrence rate was 15.3% in the postoperative radiotherapy group, compared with 22.9% in the surgery-only group (P = 0. 0002). It can be seen that both preoperative and postoperative radiotherapy had a significant effect on enhancing local control and reducing recurrence. Deaths were slightly lower in the preoperative radiotherapy group than in the surgery-only group (45% vs. 50%, P = 0. 0003), but deaths from other causes increased within 1 year after treatment (8% vs. 4%, P < 0.0001). The authors also concluded that high-dose preoperative radiotherapy (>30 Gy) appeared to be superior to postoperative radiotherapy[34] .
Based on increasing the effectiveness of radiotherapy and preventing distant metastases as well as further striving to improve survival, chemotherapy – preoperative or postoperative radiotherapy – is added to radiotherapy. The Gastrointestinal Tumor Study Group GITSG- 7175 randomized trial demonstrated significant benefits of postoperative radiotherapy over surgery alone, with a 5-year local recurrence rate of 11% versus 20%; a distant metastasis rate of 26% versus 36%; and a 5-year survival rate of 59% versus 44%[35] . Another study, the North Central Oncology Treatment Group Mayo 794751 trial, also confirmed the benefit of radiotherapy on local control and survival. The American Institute of Cancer Research consensus would recommend postoperative radiotherapy for rectal cancer with T3/4 or lymph node metastases [33].
In 2005 Gerard [36] et al. reported the results of a randomized trial that elucidated the efficacy of radiotherapy plus chemotherapy. From 1993 to 2003, 733 patients were randomized to the radiotherapy alone group (45 Gy/ 25 times/5 weeks) and the radiotherapy group (CF 20 mg/m2 IV, 5 – Fu 350 mg/m2 IV, d1 – 5, administered at weeks 1 and 5, in addition to the above regimen of radiotherapy), with surgery 3 – 10 weeks after radiotherapy. After surgery, patients in both groups received 4 courses of adjuvant chemotherapy (same protocol as before). The preoperative tumor disappearance (pCR) in the radiotherapy group was 11.7%, which was significantly better than that in the radiotherapy-only group (3.7%, P < 0. 0001), but the grade 3-4 toxic effects were also higher (14.6% vs. 2.7%, P < 0. 0001), and the 5-year overall survival rate was 67.8% vs. 66.6%, respectively, with no significant difference. As for the superiority of preoperative radiotherapy and postoperative radiotherapy, it has not been determined, but there is a tendency to favor preoperative radiotherapy.
Although preoperative radiotherapy is increasingly accepted and promoted by scholars, there are still many controversies about the specific radiotherapy regimen.
V. Treatment of colorectal cancer liver metastasis
Liver metastases from colorectal cancer are an important factor affecting the prognosis of colorectal cancer. 25% of colorectal cancer patients are diagnosed with liver metastases, and another 25% develop liver metastases after radical surgery, and the median survival of patients with unresectable liver metastases is only 6.9 months [37.38]. About 50% of colorectal cancer patients eventually die from this disease, and the cause of death is mainly related to colorectal cancer liver metastases. Therefore, the diagnosis and treatment of colorectal cancer liver metastases, especially the improvement of prognosis through active comprehensive treatment, has been a hot spot of research for scholars at home and abroad.
At present, there are many treatment options for colorectal liver metastases, including surgery, chemotherapy (systemic intravenous chemotherapy and interventional therapy), gene therapy and local treatment of liver metastases (radiofrequency ablation, laser ablation, anhydrous alcohol injection and cryodestruction), among which surgery is the only effective curative means at present.
The operative mortality rate of curative hepatectomy is reported to be 1%-2.8% and the 5-year postoperative survival rate is 34%-38% [39], but only 10%-25% of patients with colorectal cancer liver metastases are suitable for surgical resection at the time of diagnosis, so the role of various non-surgical treatments is receiving increasing attention [40]. Analysis) in 2001 showed that the 5-year and 10-year survival rates after surgery for liver metastases from colorectal cancer were 16%-49% and 17%-33%, respectively, and the operative mortality rate was 0-9% [41].
The most commonly used chemotherapy regimens are the FOLFOX regimen of calcium folinate (CF) + 5-Fu + oxaliplatin (OX) and the IFL regimen of 5-Fu + CF + irinotecan (IRI). The median time to tumor progression in the FOLFOX, IFL, and IROX groups was 8.7, 6.9, and 6.5 months, and the effective rates were 45%, 31%, and 35%, with median survival of 19.5, 15.0, and 17.4 months; the results showed that the FOLFOX group was significantly better than the other two groups; the incidence of serious side effects such as nausea, vomiting, diarrhea, hemocytopenia, and dehydration were significantly higher in the FOLFOX group. The incidence of serious side effects such as nausea, vomiting, diarrhea, hematocrit, and dehydration were also lower in the FOLFOX group; neurotoxicity and hematological toxicity were more common in the OX-containing group. The results of this study indicate that the FOLFOX regimen is a highly effective and low-toxicity regimen and should be recommended as the standard of care for patients with progressive colorectal cancer.