New concepts and progress of adjuvant chemotherapy for colorectal cancer
With the improvement of living standard, the incidence rate of colorectal cancer in China is increasing at an average annual rate of 4.2%, which seriously threatens people’s life and health. The recognized treatment method for colorectal cancer is comprehensive treatment with surgery as the first choice. Adjuvant chemotherapy is an important part of the comprehensive treatment and the main means to prevent and treat distant metastasis. However, the therapeutic role of chemotherapy in colorectal cancer has long been questioned. In recent years, with the development of modern pharmacology and modern molecular biology, the status of adjuvant chemotherapy in colorectal cancer is gradually increasing. At present, adjuvant chemotherapy for colorectal cancer has become one of the most active areas of clinical research in oncology.
I. History of adjuvant chemotherapy for colorectal cancer
Adjuvant chemotherapy for colorectal cancer began in the 1950s and has been explored and debated for nearly 30 years until 1988 when Buyse et al. published the first meta-analysis report on the effectiveness of adjuvant chemotherapy for colorectal cancer, and only then did we reach a consensus on the effectiveness of adjuvant chemotherapy for colorectal cancer. In the past 10 years, many scholars have devoted themselves to the development of new drugs and new protocols for adjuvant chemotherapy for colorectal cancer, and a series of large-scale clinical studies have been carried out, thus making great progress in adjuvant chemotherapy for colorectal cancer and gradually changing some traditional concepts.
New concepts of adjuvant chemotherapy for colorectal cancer
(A) Biochemical modulation of 5-Fu (biochemical modulation) concept
All kinds of information show that 5-Fu + tetrahydrofolic acid (leucovorin, CF) is the most effective combination and has been considered the standard therapy for colorectal cancer worldwide.
(II) New concept of 5-Fu administration method
1.Low-dose prolonged continuous infusion (PVI) therapy with 5-Fu
2.Temporal therapy of 5-Fu
Chronotherapy refers to the administration of anti-tumor drugs at the time of minimal toxicity to cells according to their efficacy, tolerability and the difference in efficacy between day and night. This therapy can increase the tolerance of the body to the drugs, increase the dose of chemotherapy drugs, and also minimize the toxic side effects of the drugs.
(C) Application scope of adjuvant chemotherapy for colorectal cancer
The purpose of adjuvant chemotherapy is to kill microscopic lesions that cannot be removed by surgery, reduce recurrence and improve survival rate. Therefore, patients with tumors with a greater possibility of metastasis and recurrence should receive chemotherapy after surgery. The traditional concept is that for colon cancer, only stage III chemotherapy can prolong survival, which is the indication for chemotherapy; while for rectal cancer, stage I also does not require chemotherapy, and stage II and III are best treated with both chemotherapy and radiotherapy after surgery. Michael et al. studied the efficacy ratio of various chemotherapy regimens for colorectal cancer, and found that adjuvant chemotherapy is most reasonable for all stage II and III colorectal cancers.
(IV) Time frame of adjuvant chemotherapy for colorectal cancer
The length of chemotherapy time frame involves issues such as drug therapy, price, effect and quality of life. Most effective treatment is active treatment of colorectal cancer for one year. The current international application of 5-Fu + CF for 6 months has been adopted as the standard regimen of postoperative adjuvant chemotherapy for colorectal cancer.
(E) Timing of adjuvant chemotherapy for colorectal cancer
The traditional concept of adjuvant chemotherapy for colorectal cancer refers mostly to postoperative chemotherapy, which still occupies a central position in adjuvant chemotherapy so far. In recent years, preoperative and intraoperative chemotherapy for colorectal cancer has also received more and more attention from surgeons.
Preoperative chemotherapy: also known as neoadjuvant chemotherapy, is a new development of adjuvant chemotherapy for colorectal cancer. There are few reports of preoperative systemic intravenous chemotherapy alone, which is mainly used to shrink the mass and reduce the adhesion of surrounding tissues through regional arterial infusion chemotherapy and preoperative radiotherapy, so as to improve the success rate of anal preservation surgery for middle and lower rectal cancer.
2.Intraoperative chemotherapy: it refers to intraoperative application of anti-cancer drugs to kill microscopic lesions or shed cancer cells to prevent or reduce the occurrence of postoperative liver metastasis, abdominal implantation and anastomotic recurrence. Intraoperative chemotherapy does not delay the surgical arrangement or affect the postoperative recovery, and it takes less time and has few side effects. At present, the main intraoperative chemotherapy methods are intestinal chemotherapy, abdominal chemotherapy, systemic intravenous chemotherapy and portal vein infusion chemotherapy.
New progress of adjuvant chemotherapy for colorectal cancer
(I) New progress of chemotherapy drugs
In recent years, effective new drugs for colorectal cancer chemotherapy have been introduced, which have attracted widespread clinical attention. Among them, the representative ones are Capecitabine (Xeloda, Siroda), Camptothecin (CPT-11, Irinotecan, Kepto), Oxaliplatin (L-OHP, oxaliplatin, platinum oxalate, lexadrine, Ehren) and Raltitrexed (Tomudex ZD1694), etc.
1. Xeloda: It is the only fluoropyrimidine drug that can achieve or even exceed the efficacy of intravenous administration with oral formulation. Its pharmacological mechanism is unique in that it is converted into 5-DFUR at the tumor site and finally metabolized into 5-Fu through the catalytic metabolism of thymidylate phosphorylase, which can selectively kill tumor cells. Studies have confirmed that the concentration of Xeloda administered orally in colorectal cancer is close to 6 times that in adjacent healthy tissues. xeloda is used as postoperative adjuvant chemotherapy, usually usage: 2500mg/m2/d for 2 weeks, stop for 1 week, 3 weeks as a course of treatment.
2. CPT-11: It is a specific DNA topoisomerase inhibitor, which specifically inhibits the DNA reconnection step by binding stably to the complex formed by topoisomerase and DNA, causing DNA single-strand breaks and irreversible DNA damage. It is used as first-line treatment for colorectal cancer with an efficiency of 15% to 32%, and in second-line treatment with an efficiency of 17.7% to 27.0%, which is similar to the efficacy of 5-Fu/CF. CPT-11 remains effective in those who fail 5-Fu treatment. The main toxicity is delayed diarrhea, which can be controlled by high-dose Emmenthal.
3.L-OHP: It is the third generation platinum anticancer drug, its chemical structure is different from CDDP (cisplatin), which can cause intra- and inter-strand DNA cross-linking and stronger DNA inhibition. There is no cross-resistance with CDDP, and L-OHP can still be effective for those who fail CDDP treatment. It has synergistic effect with 5-Fu, CDDP, CTX, TPT, CPT-11, etc [13]. The recommended dose is 130-150 mg/m2 once every 3 weeks. Monotherapy is effective in 10% of 5-Fu-resistant advanced colorectal cancer. Efficacy is improved when combined with FU/CF. common adverse effects of L-OHP are peripheral neurotoxicity, which is aggravated by cold and reversible. Gastrointestinal reactions and bone marrow suppression are less common.
4, Tomudex: is a folic acid-like thymidylate synthase (TMPS) inhibitor, direct inhibition of TMPS, without metabolic activation, not easy to rapidly decompose, no insertion into nucleic acids to interfere with DNA, RNA synthesis
(II) New advances in chemotherapy regimens
In recent years, the chemotherapy regimen for colorectal cancer has been innovated on the basis of the standard regimen (5-Fu+CF applied for 6 months) and has made great progress.
1.Mayo regimen (Mayo Clinic Regimen): It is a generally recognized first-line regimen, including CF 200mg/m2/d, 5-FU 425mg/m2/d, iv, static push, day 1 to 5, every 4 to 5 weeks for 1 course of treatment.
2. de Gramont regimen (5-Fu/CF biweekly therapy): In 1997, the French de Gramont Organization Collaborative Group GERCOD proposed a 48-hour regimen combining CF with 5-Fu push and continuous perfusion. 200 mg/m2/d of CF, iv perfusion for 2 h, d1-2; 5-Fu 400 mg/m2/d, push, followed by 5-Fu 600 mg/ m2/d, continuous intravenous infusion (civ) for 22h, d1-2, q2w. The de Gramont regimen was shown to be more effective and less toxic than the Mayo regimen in a randomized phase III clinical trial. However, there was no evidence of prolonged overall survival.
3. New combination regimens
(1) CPT-11 combined with 5-Fu/CF regimen
(1) Saltz regimen (IFL regimen): The US FDA approved Saltz regimen as the first-line treatment for advanced colorectal cancer.
② Another weekly regimen of CPT-11 combined with 5-Fu/CF: CPT-11 80mg/m2, qw, 5-Fu 2.3g/m2, 24h, civ, CF 500mg/m2, iv, 2h, d1.
(3) Two-week regimen of CPT-11 combined with 5-Fu/CF (FOLFIRI regimen), i.e. CPT-11 + de Gramont regimen: CPT-11 180mg/m2, d1, combined with de Gramont regimen.
(2) FOLFOX regimen (i.e. L-OHP + de Gramont regimen)
(1) FOLFOX4 regimen: It is the de Gramont regimen plus L-OHP 85mg/m2, iv, 2h, d1 used as the first-line regimen for the treatment of progressive colorectal cancer (ACRC). de Gramont et al [16] randomized 420 cases of ACRC into two groups: 210 cases each in the de Gramont regimen group and the FOLFOX4 regimen group. In the FOLFOX4 group, the efficiency rate (CR+PR) was 50.7%, which was significantly higher than that of the de Gramont regimen group (22.3%), P=0.0001; PFS was also higher (9.0 months compared to 6.2 months), P=0.0003; however, WBC decline, diarrhea and hand-foot signs were higher in the FOLFOX4 group than in the de Gramont regimen group. The FOLFOX4 regimen was considered beneficial for first-line treatment of ACRC, with prolonged PFS, tolerable, and maintainable quality of survival.
② FOLFOX6 regimen: It is L-OHP plus a simplified de Gramont regimen as a second-line regimen used as a treatment for patients with 5-Fu/CF-resistant metastatic colorectal cancer. l-OHP 100mg/m2, 2h, d1, combined with CF 400mg/m2 both civ, 2h, d1, 5-Fu 400mg/m2, push (bolus), followed by 5-Fu 2.4g to 3g/m2, 46h, civ, q2w.
(3) L-OHP plus 5-Fu/CF hourly dosing regimen: Giacchetti et al. carried out this regimen used as first-line treatment for 200 cases of metastatic colorectal cancer (multicenter randomized phase III clinical trial). L-OHP was administered at a constant rate over 6 hours from 10:00 h to 16:00 h (close to the minimum toxicity time of L-OHP), while 5-Fu and CF were administered after L-OHP according to time-adjusted dosing. Methods and doses: 5-Fu 700 mg/m2/d, d1-5, CF 300 mg/m2/d , d1-5, with or without L-OHP 125 mg/m2/d, civ, 6 h. Repeated every 21 days. RESULTS: The effective rates were 16% and 53% in the 5-Fu/CF group and the plus L-OHP group, respectively, P<0.001; PFS was 6.1 and 8.7 months, respectively, P=0.048; median survival was 19.9 and 19.4 months, respectively; 21 and 32 metastases were resected after treatment, respectively. Diarrhea and peripheral neurotoxic reactions were higher in the plus L-OHP group. It is believed that this regimen of 5-Fu/CF plus L-OHP does not require dose reduction of L-OHP and significantly enhances the antitumor effect.
(4) 5-Fu/MTX/MMC regimen
(5) IO regimen (CPT-11+L-OHP)
IV. New advances in adjuvant chemotherapy for colorectal cancer liver metastases
Liver is the main target organ of colorectal cancer hematogenous metastasis, and simultaneous or heterochronic liver metastasis can reach 25% and 25%~50%, respectively. If colorectal cancer liver metastases can be surgically resected, the prognosis is better, however, the resection rate is only 30%. For unresectable hepatic metastases, because their blood supply mainly comes from hepatic artery, hepatic artery infusion chemotherapy (HAIC) is mostly administered by subcutaneous placement of fully buried drug pump, which can achieve palliative treatment effect. Usually 5-Fu is chosen for HAIC because its first pass is less than hepatic uptake, accounting for only 19%~55%, and the excess 5-Fu can enter the body circulation through hepatic vein overflow, which also has a certain role in preventing extrahepatic metastasis. In recent years, 5-Fu/CF combined with L-OHP or CPT-11 has been used as adjuvant chemotherapy for liver metastases from colorectal cancer in China, except for individual patients who underwent systemic intravenous chemotherapy, most of them were treated with HAIC through a fully buried drug pump placed under the skin, usually once every 2 weeks. Further studies are needed to evaluate the exact efficacy.
V. Review and outlook
Reviewing the development of adjuvant chemotherapy for colorectal cancer, we have reasons to believe that with the application of various new drugs, new methods and new technologies, the efficacy of colorectal cancer will be improved, the survival period of patients will be prolonged and the quality of survival will be improved. Looking ahead, adjuvant chemotherapy for colorectal cancer is expected to continue to develop and achieve breakthroughs in the following areas.
1. Finding new drugs that are more effective and less toxic;
2. More and more reasonable combinations of combination chemotherapy;
3.The route of drug administration gradually tends to be more reasonable;
4, individualized drug use more prominent;
5, further improvement and development of chemotherapy at the time;
6, the introduction of immunotherapy as adjuvant chemotherapy.