What Is Folfox Chemotherapy?

Before and after surgical treatment and radiotherapy of body tumors, chemotherapy is used to shrink the primary tumor. At the same time, it may eliminate the remaining small metastatic lesions, reduce the chance of tumor recurrence and metastasis, and improve the cure rate. Chemotherapy.

Adjuvant chemotherapy

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Before and after surgical treatment and radiotherapy of body tumors, chemotherapy is used to shrink the primary tumor. At the same time, it may eliminate the remaining small metastatic lesions, reduce the chance of tumor recurrence and metastasis, and improve the cure rate. Chemotherapy.

Chinese name

Adjuvant chemotherapy

Foreign name

Adjuvant Chemotherapy

Colorectal cancer adjuvant chemotherapy began in the 1950s. After nearly 30 years of exploration and controversy, until 1988, Buyse et al. Published the first meta-analysis report on the effectiveness of adjuvant chemotherapy for colorectal cancer. A consensus was reached on the effectiveness of chemotherapy. For more than 10 years, many scholars have devoted themselves to the development of new drugs and design of new schemes for adjuvant chemotherapy for colorectal cancer, and have carried out a series of large-scale clinical studies. Adjuvant chemotherapy for colorectal cancer has made great progress and gradually changed some traditional concepts of people. .

The purpose of adjuvant chemotherapy is to kill tiny lesions that cannot be removed by surgery, reduce recurrence, and improve survival. Therefore, patients with tumors that are more likely to have metastasis and recurrence should receive chemotherapy after surgery. The traditional concept is that for colon cancer, only stage III chemotherapy can prolong survival and is an indication for chemotherapy. For rectal cancer, stage I does not require chemotherapy, and it is best to perform chemotherapy and stage II surgery at the same time. Radiotherapy. Michael and others studied the cost-effectiveness ratio of various colorectal cancer chemotherapy regimens, and found that adjuvant chemotherapy was the most reasonable for all stage II and III colorectal cancer.

The length of chemotherapy is related to drug treatment, price, effects, and quality of life. Most effective treatments are active treatments for colorectal cancer for 1 year. A study of NCCTG is completely aimed at the time limit of medication. Patients were randomly included in the following four groups: 5-Fu + Lev (levamisole) for 1 year; 5-Fu + Lev (levamisole) for 6 months; 5-Fu + Lev ( Levamisole) + Levl years; 5-Fu + Lev (levamisole) + LeV for 6 months. A total of 915 patients were followed up for 5 years. The results show that the effect of 5-Fu + LeV for 6 months is the same as that of 5- Fu + Levl year. The three drugs combined for 1 year did not improve overall survival. At present, 5-Fu + Lev has been applied internationally for 6 months as the standard scheme for adjuvant chemotherapy after colorectal cancer surgery.

1.Fluorouracil 5-Fu and its derivatives

Fluorouracil antitumor drugs (5-Fu) have been synthesized by Duschinsky et al. Since 1957, and they are one of the most widely used clinical drugs. 5-Fu plays an important role in the treatment of a variety of malignancies, including gastrointestinal cancer, including colorectal cancer. 5-Fu is an anti-metabolic tumor drug, which can mimic normal metabolites and specifically antagonize related metabolites. 5-Fu's mechanism of action is mainly to inhibit deoxythymidylate synthetase (TS), which is activated and converted to fluorodeoxyuridine (FdUMP). FdUMP replaces deoxyuridine (duMP) with TS and 5-Fu, 10- Tetrahydrofolate formate (CH2FH4) forms a triple complex that is not easy to dissociate, and cannot synthesize deoxythymidylate (dTMP), which affects the synthesis of DNA, thereby exerting an antitumor effect. 5-Fu mainly affects the S phase of cells, but it can also interfere with protein synthesis after being converted into 5-fluorouracil nucleoside in vivo, so it also has effects on cells in other phases. Several enzymes that affect 5-Fu: (1) Deoxythymidylate synthetase (TS): According to the foregoing and a large number of clinical and preclinical studies confirmed: TS is related to the sensitivity of tumors to 5-Fu chemotherapy, so Fluorouracil is an indicator of the efficacy and prognosis of basic chemotherapy. The main mechanism of fluorouracil resistance is Ts overexpression. It can be said that in patients with colorectal cancer surgery, regardless of the stage, 5-Fu-based chemotherapy, patients with low TS expression have higher efficiency and median survival time. However, in a review at the 2005 ASCO Annual Meeting, 1326 patients with stage II and III postoperative surgery only found that patients with low TS expression in the stage IIIC subgroup could benefit from 5-Fu-based chemotherapy. This may be related to the expression of Ts in micrometastases. So patients with high expression of Ts are not enough for surgery alone, and adjuvant chemotherapy is also needed. (2) Dihydropyridine dehydrogenase (DPD): DPD is a rate-limiting enzyme for 5-Fu metabolism. Most 5-Fu entering the human body is metabolized in the liver, and more than 80% is metabolized to dihydrofluorouracil through DPD, and then decomposed and eliminated. in vitro. It is closely related to the 5-Fu clearance rate, the toxicity of chemotherapy, and the efficacy of chemotherapy. Patients with DPD deficiency may have fatal toxicity. It has been reported that DPD activity in tumors is an important factor in determining whether tumors are sensitive to 5-Fu in both in vitro and in vivo metastatic tumor models. McLcod et al. Reported that the ratio of DPD activity of colon tumor tissue to normal colon tissue is about 0.76, which can be used as a marker to predict whether the tumor is resistant to 5-Fu. The higher the ratio, the greater the possibility of drug resistance. Research on the relationship between the expression of DPD in tumor tissues and the benefit of adjuvant chemotherapy. There are documents in patients with low DPD expression in stage II and III colorectal cancer. 5-Fu-based adjuvant chemotherapy can improve 5-year survival compared with surgery alone. Rate, which is mainly due to the low expression of DPD tumors that grow faster and are sensitive to 5-Fu chemotherapy.

5-Fu derivatives include three types: (l) Fluorinated pyrimidine derivatives that need to be metabolized by liver drug enzymes: fluorofuridine (FT-207) and bispyridine, all of which are inactive precursors of 5-Fu In vivo, it is gradually converted to 5-Fu by liver drug enzymes and cytochrome (P-50) system degradation. Others include Ufodine (UFD), Tigio (Sl) and so on. UFD is a composite preparation of FT-207 and uracil 1: 4. Uracil can block the degradation of FT-207 and specifically increase the concentration of 5-Fu and its active metabolites in tumor tissues. Sl was developed by Japan and has been approved by the US FDA for use in colorectal cancer phase II and III clinical studies. Sl is composed of FT-207 plus 5-chloro-2,4-hydroxypyridine (CDHP) and Oxonic acid. CDHP can inhibit the catabolism of 5-Fu released from FT under the action of dihydropyrimidine dehydrogenase. It helps to maintain 5-Fu in blood and tumor tissue effectively for a long time, and then prolongs the maintenance time of 5-Fu blood concentration, so as to obtain a similar effect to 5-Fu continuous intravenous infusion. Oxonic acid can block the phosphorylation of 5-Fu. After oral administration, Oxouic acid has a high distribution concentration in the gastrointestinal tissue, which affects the distribution of 5-Fu in the gastrointestinal tract, thereby reducing the digestion of 5-Fu Road toxicity. The anti-cancer effect exceeds 5-Fu or UFD, and has a high synergy with cisplatin. Ohtsu [l4] reported the results of a phase II clinical study of 62 cases of newly diagnosed colorectal cancer in Japan, S-1 usage: body surface area <1.25 m2, 40mg, bidx28d;

2.Biochemical regulators

Calcium folinate (LV) is an important coenzyme for nucleic acid synthesis and has no effect on tumors. Waxmans first reported its enhanced 5-Fu activity as a dUMP-incorporated inhibitor enhancer since 1978, and is considered to be the most effective biological regulator discovered in the past 20 years. LV mainly forms stable tri-plexes with 5-fluorouracil deoxynucleotide (5-FdUMP) and TS, thereby inhibiting DNA synthesis and enhancing the cytotoxic effect of 5-Fu on colorectal cancer and other tumors, clinically effective 18.8% ~ 48%, which is significantly higher than 5-Fu single dose (7% ~ 16.9%), and the median survival time is also prolonged. The blood concentration reached 2 hours after Lv administration. At this time, 5-Fu intravenous drip was used to continuously affect the S phase of cancer cells and increase the inhibitory effect. The combination of the two has become the basic drug for colorectal cancer chemotherapy. Other biochemical regulators such as carbamidine (MTX), cisplatin (DDP), interferon, and levamisole can also produce cytotoxic effects.

3. Platinum anticancer drugs

The main representatives are cisplatin, carboplatin, and oxaliplatin (L-OHP), of which cisplatin [cis-dichlorodiammine platinum (II) cisplatin] is the first generation of platinum anticancer drugs, which has obvious anti-cancer effects. Cancer activity, and clinically verified, it has a good therapeutic effect on a variety of tumors, has become one of the most effective clinical anti-cancer drugs in countries around the world, but it is affected by renal function damage, gastrointestinal reactions, ototoxicity Such as toxic side effects, the use is limited. Carboplatin [l, l-cyclobutanedicarboxylic acid diaminoplatinum (II), Carboplatin] is the second-generation platinum anticancer agent, which was launched in 1986 and has been widely used in clinical practice. Compared with platinum, carboplatin has better water solubility and is less toxic to nerves and kidneys. However, in clinical studies, it has cross-resistance with cisplatin. Oxaliplatin (L-OHP) is the third-generation platinum anticancer drug after cisplatin and carboplatin. Its molecular formula is C8H14N2O4Pt. The amino ring on the cisplatin structure is replaced by 1,2-diaminocyclohexane group. With DNA as a target, it covalently combines with G on the DNA strand to form intra-chain, inter-chain cross-links, and DNA protein linkage, which damages DNA, blocks its replication and transcription, and causes cancer cell death. Pre-clinical studies in vitro and in vivo have shown that L-OHP has anti-tumor effects on a variety of tumor cells, including cell lines that are resistant to cisplatin, and especially have significant inhibitory effects on colorectal cancer cell lines. Clinical studies have also shown that L-OHP has synergistic or additive effects with fluorouracil drugs, including tumors that are resistant to 5-Fu. The main toxic and side effects of L-OHP are neurotoxicity, which is manifested as paresthesia, dullness, numbness, and even pain in peripheral and peripheral sensations, which can be exacerbated by cold. It can usually be subsided during treatment, can be tolerated by patients, mild bone marrow suppression, and no renal toxicity The conventional dosage does not require hydration, and the incidence of nausea and vomiting is lower than that of cisplatin, which does not produce cardiotoxicity and severe hearing impairment. Because L-OHP has the characteristics of high water solubility, low toxicity, and broad anticancer spectrum, foreign countries have entered phase II clinical trials. Studies have confirmed that single-agent oxaliplatin (L-OHP) first-line treatment has entered phase II clinical trials. Confirmed that the single-agent oxaliplatin (L-OHP) is effective in 20% to 25% of first-line treatment of advanced colorectal cancer and 10% in the second-line treatment of advanced large intestine, combined with 5-fluorouracil (5-Fu) and calcium folinate (LV) The effective rate of second-line treatment of advanced colorectal cancer is 32% ~ 58%. As a result of domestic multi-center phase II clinical trials, the effective rate of combination therapy is 34.4%. The chemotherapy regimen containing L-OHP and 5-fluorouracil (5-Fu) + calcium folic acid (LV) is considered to be a classic scheme for colorectal cancer at this stage.

A single chemotherapeutic drug is less effective in treating colorectal cancer, and most of them are partial remission (PR); the application of a combination of chemotherapeutic drugs can significantly improve the median survival time and prolong the patient's life.

1. The basic plan of adjuvant chemotherapy

In recent years, in improving the efficacy of 5-Fu in colorectal cancer, the most innovative and active research is to use biological modulators to improve the anti-tumor activity of 5-Fu, and on this basis, continue to innovate and obtain Great progress has been made. Clinically used programs include: De Gramont program, Mayo program, AIO program, PIV program, etc.

DeGramont protocol (5-Fu / LV biweekly therapy): In 1997, the French de Gramont organization collaboration group GERCOD proposed a 48-hour regimen of LV combined with 5-Fu bolus and continuous infusion. LV200 mg / m2.d, iv2h, dl ~ d2; 5-Fu400 mg / m2.d, first bolus, then 5- Fu600 mg / m2.d, continuous intravenous infusion for 22h, d1 ~ d2, q2w. Randomized phase III clinical trials have shown that the De Gramont regimen is more effective and less toxic than the Mayo regimen, but there is no evidence to extend overall survival. Mayo regimen (Mayo Clinic Regimen): It is a generally recognized first-line regimen, including LV mg / m2.d, 5- Fu425 mg / m2.d, iv, d1-d5, and a course of treatment every 4 to 5 weeks. After six cycles of treatment for patients with high-risk factors after colorectal cancer surgery, the recurrence and overall survival were significantly longer than those in the control group.

AlO scheme: LV500 mg / m2 infusion, 5- Fu1500 mg / m2-2000 mg / m2 infusion for 24h, qlw, continuous 6w, 8w for 1 cycle. This program was designed by wehHJ et al. The application of high-dose 5-Fu once a week can improve the partial response rate and time to disease progression of patients with metastatic colorectal cancer.

PIV protocol (protracted IV 5-Fu): a single application of 5-Fu300 mg / m2.d continued infusion for a total of 12w. A French study compared the efficacy of PIV regimen and Mayo regimen for postoperative adjuvant chemotherapy in patients with stage II and III colon cancer, and the results showed that the two were similar in efficacy, while PIV regimen III-IV had significantly fewer side effects.

The main side effects of 5-Fu are related to the method of administration. Intravenous rapid infusion every 4 or 5 weeks for 5 consecutive days, neutropenia and stomatitis are the most common; and once a week rapid intravenous infusion of diarrhea is obvious; patients with continuous intravenous infusion have more hand and foot syndrome. Although it is thought that continuous intravenous infusion is expensive and inconvenient for patients, recent analysis has shown that the cost and impact on life are not much different, and continuous intravenous infusion is more effective than intravenous infusion. Better. ASCO conference in 2006 on 24 weeks and 36 weeks of 5-Fu adjuvant chemotherapy efficacy new views: Fluorouracil is still one of the most important drugs for colorectal cancer, adjuvant chemotherapy in stage III patients can reduce the risk of postoperative recurrence. The GERCOR team reported at the conference a 5.9-year follow-up of 5-Fu / LV for adjuvant treatment of DukesB and C colon cancer. This phase III clinical study compared the results of the LV5FU2 regimen with the monthly 5-Fu / LV regimen for the mg / m2.d and adjuvant treatment of stage C colon cancer. 905 patients with Dukes B and C colon cancer were randomly assigned to the standard LV5FU group or the monthly 5-Fu / LV group for 24 or 36 weeks of treatment. The results showed that the 5-year disease-free survival (DFS) and overall survival (OS) were 67% and 80%, and there were no significant differences in DFS and OS between 24 and 36 weeks of chemotherapy. It is suggested that adjuvant chemotherapy after 5-Fu / LV can be used for 24 weeks.

Clinical study of capecitabine (Xeloda) in the treatment of colorectal cancer

Early fluorouracil oral medications were ineffective, and randomized controlled trials considered intravenous medication to be more effective. According to pharmacokinetics, intestinal mucosa is caused by different concentrations of dihydropyrimidine dehydrogenase. Dihydropyrimidine dehydrogenase is the main metabolic enzyme of oral fluorouracil, which leads to incomplete drug absorption. The fluorouracil prodrug developed to overcome this shortcoming can be completely absorbed through the intestinal tract, and then metabolized into an active drug or a dihydropyrimidine dehydrogenase inhibitor drug can be simultaneously used to reduce the decomposition of the oral preparation. The emergence of a new oral fluorouracil preparation, capecitabine (Xeloda, Capecitabine, xeloda), is a major development in the history of chemotherapy. Capecitabine is a 5-Fu precursor. After oral administration, 5-deoxyfluorocytidine (5'-DFCR) is produced by carboxylesterase in the liver, and 5-deoxyfluorouridine (5-deoxyfluorouridine) is produced by cytosine deaminase ( 5'-DFUR), which produces 5-Fu under the action of high amounts of thymidine phosphorylase (TP) in tumor tissues.

Capecitabine (Xeleda) is a new generation of 5-Fu oral preparations. Because of its convenient administration, good absorption, high selectivity and high stability, it is widely used in colorectal cancer chemotherapy, especially in advanced stages. Case. Progressive cases refer to advanced cases where the primary tumor cannot be removed, or cases where recurrence after surgery is not suitable for reoperation, or cases with distant metastases that cannot be reoperated.

The X-ACT trial (xeloda Adjuvant Chemotherapy Trial) randomized comparison of capecitabine and Mayo regimens for chemotherapy in patients with stage III colon cancer. A total of 1987 patients were enrolled in the trial. One hundred and four patients in the test group received capecitabine 1250 mg / m2 orally twice a day for 1 to 14 days, with each 2 ld as a cycle. 983 patients in the control group were treated with Mayo. Results Capecitabine could prolong the tumor-free survival time (hazard ratio 0.86; 95% confidence interval 0.74 ~ 0.99; P: 0.04), and its chemotherapy side effects were lighter (P <0.001). Oral capecitabine is considered to be an effective adjuvant chemotherapy for colon cancer. The side effects of capecitabine are similar to the intravenous infusion of 5-Fu. Hand and foot syndrome is common. Other toxic side effects include diarrhea, nausea, vomiting, and bone marrow suppression. A phase III clinical trial of capecitabine in combination with new-generation chemotherapy drugs oxaliplatin, irinotecan, or molecularly targeted drugs is ongoing.

The X-ACT trial showed that capecitabine or 5-Fu / Lv (Mayo regimen) adjuvant chemotherapy was similarly effective for patients with Dukes C colon cancer who could be completely resected. The ASCO conference in 2006 continued to report the 4.3-year follow-up results of the X-ACT trial. The DFS in the two groups was comparable, and capecitabine was slightly better than the Mayo protocol in terms of recurrence-free survival (RFS). Most of the experts at the meeting believed that capecitabine should not be used alone for postoperative adjuvant chemotherapy, but a combination of oxaliplatin based clear evidence-based medical evidence should be used for adjuvant chemotherapy in order to effectively reduce postoperative recurrence. Mayo Hospital Grothy also pointed out that because the Mayo regimen is significantly worse than the continuous intravenous drip fluorouracil regimen, it is also not recommended for adjuvant chemotherapy.

Although 5-Fu / LV or single-agent capecitabine has made some progress in adjuvant chemotherapy for colorectal cancer, the 3a tumor-free survival rate after colorectal cancer is less than 2/3, and about 1/3 of patients still relapse or Metastases, and ultimately death, require more active chemotherapy drugs and chemotherapy regimens. The application of new-generation drugs (such as oxaliplatin, irinotecan, etc.) has given rise to new prospects for chemotherapy for colorectal cancer.

3. Research on L-OHP, 5-Fu, LV combined chemotherapy

Oxaliplatin is widely used and researched in non-fluorouracil new drugs. Oxaliplatin is a third-generation platinum-based compound, and L-OHP is a platinum-based compound of diaminocyclohexane, which forms a cross-link with the DNA strand, blocking its replication and transcription. L-OHP combined with LV / 5-Fu can restore the efficacy of advanced colorectal cancer that was previously resistant to LV / 5-Fu. L-OHP and 5-Fu also have a synergistic effect. In addition, L-OHP also has synergistic effects with thymidine synthase inhibitors, CPT-11 and Gemza. The recommended dose intensity of L-OHP is mainly 130 mg / m2, q3w and 85 mg / m2, q2w by de Gramomt. Comparison of FOLFOX4 (L- OHP 85mg / m2, d1; Lv200 mg / m2, d1, d2; 5- Fu400mg / m2 bolus d1, d2, 600 mg / m2, civ22h d1, d2, q2w), IFL ( (CPT-11 / Lv / 5F-u), L-OHP / CPT-ll, and LV / 5-Fu different chemotherapy regimens for 1467 cases of advanced colorectal cancer, which proves that the FOLFOX regimen has the highest efficiency (RR38% ~ 50%). Long (7.9 to 9.0 months) and the best overall survival time (18.6 months).

At the 41st ASCO Annual Meeting in the United States, the results of the FOLFOX4 regimen assisted with stage II / III colorectal cancer adjuvant chemotherapy after 12 cycles of follow-up for 4 years were compared. Compared with LV5FU2, FOLFOX4 reduced the risk of stage III colon cancer recurrence by 24% ( 4-year disease-free survival (69.7% vs 61.0%); 25% reduction in the risk of recurrence of stage II colon cancer (4-year disease-free survival 85.5% vs 81.3%); 4-year total survival 84.3% vs 82.7%. The US NCCN Clinical Guidelines for Oncology also considers FOLFOX4 as the standard adjuvant chemotherapy regimen for postoperative colon cancer. Although the MOSAIC study believes that the FOLFOX4 regimen is equally beneficial for the prevention of postoperative recurrence of stage II colon cancer, the NCCN expert committee believes that for stage II colon cancer, postoperative adjuvant chemotherapy cannot yet become the standard treatment. It is clear that for patients with T1T2N0M0, if there are adverse prognostic factors: such as pathological III / IV differentiation, lymphatic infiltration around the tumor, intestinal obstruction, colon perforation and incomplete sampling of lymph nodes, postoperative adjuvant chemotherapy should be given, but Whether to apply oxaliplatin-containing solutions is still controversial.

In addition, colon cancer chemotherapy regimens containing oxaliplatin also include: mFOLFOX6 regimen (modified de Gramont regimen: LV400 mg / m2, d1 intravenous drip for 2 hours, 5- Fu400 mg / m2, intravenous iv infusion of d1, after 5- Fu1200 mg / m2.d continuous intravenous infusion 2d; L-OHP85 mg / m2, d1), FOLFOX7 regimen (intravenous high-dose L-OHP130 mg / m2, combined with the improved de Gramont regimen), XELOX (cal Betastatin combined with oxaliplatin)). Although clinical trials have shown that mFOLFOX6 and FOLFOX7 regimens have shown higher activity and better tolerance in colon cancer patients with distant metastases, there is no phase III clinical evidence for the efficacy of postoperative adjuvant chemotherapy for colon cancer.

5-Fu / LV + L-OHP can reduce the risk of recurrence. The NSABPC-07 study continues to report the efficacy of standard weekly boluses of 5-Fu / LV and 5-Fu / LV + L-OHP in adjuvant chemotherapy for colon cancer. The median follow-up period of 34 months showed that weekly bolus 5-Fu / LV regimen with oxaliplatin significantly increased the 3-year DFS of patients with stage II and III colon cancer. Because of the evidence that continuous intravenous infusion of 5-Fu is superior to intravenous bolus, the results of the MOSAIC study published at this meeting using LV5FU2 and FOLFOX4 for adjuvant chemotherapy for colon cancer are particularly striking. The results of a median follow-up of 4 years show that FOLFOX4 treatment can significantly reduce the risk of recurrence and increase DFS in patients with stage II and III. Therefore, FOLFOX4 has now become the standard adjuvant chemotherapy regimen for early colon cancer.

For an anticancer drug, the different routes of administration and doses during the treatment process have different effects on the tumor, and the effects are different.

1, 5-Fu administration

Since 5-Fu was used clinically in 1957, related research has continued to intensify, and the number of applied cases has continued to increase. Its single-agent effective rate is about 8% to 85%, which is mainly related to 5-Fu dosage, dosage form, administration method, and Different routes of administration are involved. 5-Fu or its analogs can be administered in a variety of dosage forms, including daily service (tablets, water injections, dry syrups, suspensions, etc.), intravenous boluses, intravenous drips, enemas, suppositories, and the like. Oral administration should also monitor the 5-Fu plasma concentration of the patient at the same time, in order to guide the oral administration dose to achieve the best therapeutic effect. Low-dose 5-Fu long-term continuous perfusion (PV1) therapy 5-Fu is a time-dependent drug with a short half-life (10-20 minutes) and is a cell cycle-specific drug that only acts on the s phase of the cell cycle. The traditional administration method of 5-Fu is divided bolus injection or intravenous infusion. As a result, the contact time between the drug and cancer cells is short, the anti-cancer effect is poor, and more than half of the patients will have adverse reactions to chemotherapy. In recent years, with the understanding of its metabolism, pharmacology and drug resistance mechanism, the method of administration has been improved to a small dose of protractive venous infusion (PVI), which has improved the efficacy of 5-Fu and reduced the toxicity of treatment. side effect. 5-Fu combined with LV for PVI chemotherapy has been extensively studied by foreign evidence-based medicine at the level of A level, and its efficacy is better than that of 5-Fu single-dose short-term infusion or rapid intravenous bolus. 5-Fu Chronotherapy Chronotherapy refers to the administration of anti-tumor drugs within the time period that produces minimal toxicity to cells, based on the difference in efficacy, tolerance, and efficacy between day and night. This kind of therapy can increase the body's tolerance to drugs, increase the dose of chemotherapeutic drugs, and can minimize the toxic and side effects of drugs. Levi et al. Concluded that L-OHP + 5-Fu + Lv conventional group (140 patients) and Chronotherapy group (138 patients) treated first-line metastatic colorectal cancer. As a result, the efficacy of Chronotherapy group (51%) was significantly higher than that of conventional treatment. Group (30%) (P <0.001); the resection rate of metastatic lesions after chemotherapy (23.2%) was also higher than that of conventional treatment group (12.8%) (P = 0.039), showing the superiority of chronotherapy.

2. Preoperative chemotherapy

Surgery is the main method for the treatment of colorectal cancer, but even after radical surgery, there is still the possibility of recurrence, especially for patients with T3 or lymph node metastasis. The occurrence of local recurrence is directly related to the depth of invasion of the intestinal wall and lymph node metastasis of the primary tumor. It is the most common uncontrolled site for colorectal cancer and requires comprehensive treatment. As an important measure of comprehensive treatment, neoadjuvant chemotherapy refers to the intravenous administration of antitumor drugs before surgery to reduce the local recurrence of tumors, control distant metastases, increase the success rate of surgery, and extend the overall survival time. Commonly used 5-Fu-based combined chemotherapy regimens, through its derivatives, adding biological response modifiers, changing the way fluorouracil is administered, and choosing different combinations, bring the role of fluorouracil drugs to Extreme, but its efficiency and median survival are not ideal. However, in recent years, the application of some new drugs, such as capecitabine and oxaliplatin, has achieved good results. Combined use of them in neoadjuvant therapy can make the pathological complete remission rate from 9% to 29 % Further increased to 19% ~ 37%, which is intensive neoadjuvant chemotherapy.

Discussion of other modes of administration

1. Regional arterial infusion chemotherapy

Regional arterial infusion chemotherapy includes preoperative regional arterial infusion chemotherapy and postoperative regional arterial infusion chemotherapy. Preoperative regional arterial infusion chemotherapy is targeted administration through the main blood-supplying arteries of the tumor, in addition to eliminating existing micrometastasis and subclinical lesions, reducing iatrogenic spread, and exerting the maximum effect of chemotherapy drugs to make patients resistant Affected by high-dose chemotherapeutic drugs and reducing the clinical stage to create conditions for surgery, it can also avoid the pre-operative systemic chemotherapy with low dosages, large toxic and side effects, and the inadequacy of surgery due to the delay of chemotherapy. At the same time, high selective intubation can be achieved to maximize the concentration of chemotherapy drugs around the tumor. The seldinger technique can be used to intubate the femoral artery to the superior (inferior) mesenteric or superior rectal arteries and the internal iliac arteries on both sides, and can be further intubated selectively according to the tumor site. This helps chemotherapy drugs return to the liver through the portal vein, which can prevent and treat liver metastases. Furthermore, anti-cancer drugs enter the systemic circulation through only a small part of the liver metabolism, thereby reducing the toxicity of the systemic circulation. The main reason that affects the survival rate after surgery is tumor recurrence and metastasis, and liver metastasis is one of the main causes of death. Postoperative regional arterial infusion chemotherapy can significantly reduce the incidence of tumor liver metastasis, reduce local recurrence, and is more effective than systemic chemotherapy, improving the 5-year survival rate. Furthermore, for unresectable liver metastatic cancer, direct hepatic arterial infusion chemotherapy is a reasonable treatment approach for two reasons: First, liver metastases mainly receive hepatic artery blood supply, while normal liver cells also receive portal vein. For blood supply, chemotherapeutic drugs for transcatheter arterial infusion chemotherapy can achieve high concentrations in liver metastases, and liver cells can avoid the attack of anticancer drugs. Second, when drugs such as 5-Fu and FUDR are infused through the hepatic artery, most of them are metabolized by the liver, and less drugs flow into the body, so the adverse reactions are slight.

2.Portal vein intubation chemotherapy

More than 50% of patients with colorectal cancer have metastasis at the time of initial treatment, more than 40% have recurrence or metastasis after radical operation, and nearly half die from metastasis. The incidence of liver metastasis in advanced colorectal cancer is 38% ~ 60%, so it can be passed Hepatic vein intubation adjuvant chemotherapy for colorectal cancer after surgery can kill micrometastasis of the liver, reduce liver metastasis, and improve postoperative survival. There are clinical reports showing that adjuvant chemotherapy after portal vein intubation can only improve the 5-year survival rate by about 5 %, Reducing mortality by 10% to 15%, does not reduce the occurrence of distant metastases, the liver metastasis rate is only reduced by 14%, which is no better than systemic chemotherapy. Therefore, it is not recommended as standard adjuvant chemotherapy, but it is practical for those with established liver metastases and requires systemic chemotherapy.

3.Intraperitoneal chemotherapy

Intraperitoneal chemotherapy includes preoperative, intraoperative, and postoperative. There are three main routes of administration: the Tenchkhhoff catheter system, the catheterization of a permanent subcutaneous pump, and the disposable puncture and catheterization of the abdominal cavity. For intraperitoneal implantation, liver metastasis, and local recurrence after colorectal cancer surgery, intraperitoneal chemotherapy is a good treatment. It can produce drug concentration in the abdominal cavity 200-400 times higher than intravenous administration, so that cancer cells and residual small lesions after surgery can be directly immersed in high-concentration anticancer drugs, increasing the lethality of anticancer drugs to tumor cells. . In addition, chemotherapeutic drugs are introduced into the liver through the portal vein, which helps prevent and treat liver metastases. Early in the postoperative period, adhesions have not yet formed, and cancer cells in high-risk recurrence areas such as the surgical area and the peritoneal surface can be fully exposed to anticancer drugs, which can maximize local toxicity. In the early postoperative period, the tumor load was minimal, tumor cells proliferated rapidly, and were sensitive to treatment. Some scholars have suggested that the best effect is the dose and volume of 1-2L.

Clinical studies conducted in the United States since 1979 have confirmed that Levamisole Lev combined with 5-FU in the treatment of advanced colorectal cancer can increase the inhibitory effect of 5-Fu on thymidine synthase, and later found that tetrahydrofolate (Lv) can increase 5 -Fu for metastatic colorectal cancer. In subsequent large-scale clinical studies, compared with the 5-Fu radical postoperative adjuvant chemotherapy compared with the control group observed after surgery, adjuvant chemotherapy reduced the 5-year recurrence rate by 40% and the mortality rate by 33%. .

A randomized study that analyzed adjuvant chemotherapy for 3,351 elderly patients with colon cancer and confirmed that postoperative adjuvant chemotherapy can reduce death by 24% and recurrence by 32%. The conclusion is that all patients with stage II and III colon cancer should receive adjuvant chemotherapy after radical operation. A recent author compared 5910 cases of colon cancer with 5-Fu / Lvl year, 5-Fu / Lv weekly regimen, with or without Lv for 8 consecutive months, and Mayo with or without Lv. The recurrence survival rate is 58% -65%, and the overall survival rate is 67% -74%. Further comparison of the mucosa of the Mayo regimen (Lv20 mg / m2, d1-d5, 5-Fu425 mg / m2, d1-d5) and the NCCTG regimen (Lv500 mg / m2 + 5-Fu500 mg / m2, weeklyx6 ~ 8w) The incidence of inflammation and leukocytopenia is the same, but the incidence of IV diarrhea is higher in the NCCTG weekly regimen. Therefore, most scholars recommend 5-Fu combined with LD-LV or HD-LV for 6 months as the standard adjuvant chemotherapy for radical colorectal cancer. Due to the excellent performance of oxaliplatin in the treatment of advanced colorectal cancer, Professor De Gramont has organized a multi-center international clinical collaborative study since October 1998. 2248 patients with stage IIB (40%) and stage III (60%) colorectal cancer were randomly divided into LV5-FU2 and FOLFOX regimens (L-OHP85 mg / m2 ivgtt dl; LV200 mg / m2 ivgtt 22h, 5-Fu400 mg / m2bolus, 5-Fu600 mg / m2, CIV 22h dl.2 :) The two groups of chemotherapy received a median of 10 cycles of treatment. Observation of grade III ~ IV toxicity reactions were vomiting (1%: 6%), diarrhea (6%: 11%), thrombocytopenia (1%: 2%), and leukopenia (46%: 40%); none for 3 years The disease survival rate was 77.9% in the FOLFOX group and 72.9% in the LV5-FU2 group. Among them, the stage III lesions were 71.8%: 65.5%: stage II lesions 86.6%: 83.9%; the FOLFOX group had a 27% reduction in recurrence at 3 years, so the FOLFOX regimen was considered to be safe as an adjuvant chemotherapy regimen after radical resection of colorectal cancer, and could be improved for 3 years. Survival, better than LV5-Fu2 (P <0.01). In recent years, research on adjuvant chemotherapy for stage II and III colorectal cancer in the United States and Europe has been conducted with LV / 5-Fu weekly regimen with or without CPT-11 (weekly) for a total of 8 weeks: LV / 5-Fu alone or Combined with Edrecolomab (anti-colon cancer monoclonal antibody); Lv / 5-Fu alone or in combination with autologous vaccine; LV / 5-Fu with or without intraperitoneal chemotherapy or hepatic artery chemotherapy; stage II colorectal cancer surgery with or without de More than 10 studies including Gsamont (biweekly) or AIO (weekly). After radical resection of rectal cancer, the local recurrence rate in stage I was 5% -10%; stage II 15% -30%; stage III> 50%. Postoperative adjuvant chemoradiotherapy is the standard treatment for stage II / III rectal cancer after radical surgery. The benefits of combined chemoradiotherapy for survival are significantly better than surgery alone or postoperative radiotherapy. Postoperative adjuvant radiation therapy has a 5-year survival rate of 33% to 61%; postoperative adjuvant radiotherapy and chemotherapy has a 5-year survival rate of 42% -81%.

In view of the above, the author believes that pathological reports of radical metastasis after colorectal cancer have positive lymph node metastasis, vascular tumor thrombus, invasion of nerves, invasion of serosa or surrounding tissues and organs, poor differentiation; Intestinal perforation, and the number of lymph node dissections are unknown or less than 12, and those with high levels of CEA after surgery are indications for adjuvant chemotherapy. Patients who meet the conditions for chemotherapy (the digestive tract function is basically restored, generally in good condition, peripheral blood signs, liver and kidney function, and heart function are basically normal, without chemotherapy contraindications) should undergo postoperative adjuvant chemotherapy as soon as possible (3 to 4 weeks after surgery) Months; for the above cases of rectal cancer, adjuvant radiotherapy should be performed first, and adjuvant chemotherapy should be continued after a short rest. It has been proven that the efficacy of 5-Fu or 5-Fu alone with Lev (levamisole) is lower than that of 5-Fu / LV; however, 5Fu / LV plus Lev have not seen more benefits, so the authors suggest that the large intestine Mayo (Lv20 mg / m2 combined with 5- Fu425 mg / m2) is the first choice for adjuvant chemotherapy after radical mastectomy, once a month for 6 consecutive cycles; or de Gramont (Lv200 mg / m2, iv 2 h combined with 5-Fu first 400 mg / m2, iv bolus then 600 mg / m2 civ 22h, d1 ~ d2) scheme, q2w, continuous 10-12 cycles. As elderly patients or those who may be intolerant to chemotherapy, oral capecitabine (capecitabine 2500 mg / m2.d) can be considered for oral administration, taking 2 consecutive weeks, rest for 1 week, a total of 6 cycles. For those with high risk factors (LNM> 12, a large number of vascular tumor emboli, direct invasion of surrounding tissues and organs, etc.), combined L-OHP or Capetop can be considered.

The authors believe that compared with the two-week regimen, the three-week, four-week, and weekly regimes have their own shortcomings. Therefore, the use of FOLFOX4 or FOLFIRI with L-OHP may be considered first. It is known that more than a quarter of patients with colorectal cancer undergo radical metastasis or recurrence after radical resection, so they should be reviewed regularly after surgery. The time and place of the review is very important. It is recommended that patients go to the oncology hospital, at least the oncology department of the general hospital. Experienced oncologists are required to assist in completing the necessary examinations. The review should be performed every 6 months within 2 years after surgery. It can be done once a year after 2 years. The re-examination included clinical symptoms and signs, tumor status (imaging examination, tumor marker examination), and important organ function status. If signs of relapse or metastasis are found, appropriate treatment should be performed promptly.