Colorectal cancer is the more common malignant tumor of the gastrointestinal tract, and the statistics in 2000 showed that colorectal cancer ranked the third in cancer incidence and death in the United States. In recent years, the incidence rate of colorectal cancer in China has been increasing year by year, and there is a trend of rejuvenation, and the incidence rate in big cities has ranked third in malignant tumors.
I. Diagnostic points
(A) Clinical manifestations
1.Blood in stool
Blood in stool is one of the most common symptoms of colorectal cancer, and it is often the first symptom of rectal cancer, and it is fresh blood. Jiang Min, Department of General Surgery, Shanghai Hospital of Traditional Chinese Medicine
2.Change of defecation habit
It includes the change of defecation time and frequency, as well as constipation or unexplained diarrhea. Patients may have more frequent bowel movements, but the volume of each bowel movement is not much, and it may be mucus blood stool, mucus pus blood stool or loose thin stool, which may be accompanied by a feeling of urgency. Some patients have diarrhea as the first symptom, or repeatedly alternate between constipation and diarrhea.
3.Abnormality of stool properties
The normal stool is cylindrical in shape, but the cancer protrudes in the rectal cavity and presses the stool, which may cause indentation or thinning of the stool, accompanied by difficulty in defecation and anal pain.
4.Abdominal pain
Some patients have vague abdominal pain as the first or prominent symptom, while others show typical abdominal pain of incomplete intestinal obstruction, i.e. the pain is paroxysmal colic and accompanied by abdominal distension.
5.Lack of energy and anemia
Bleeding from tumors in the upper part of the large intestine, especially in the ascending colon area, is not easy to be detected. Due to long-term blood in stool, patients will have unexplained anemia and weakness.
(II) Examination means
1.rectal finger examination
It is a simple but very important diagnostic method. During the examination, attention should be paid to whether the base of the mass is fixed and whether the prostate and bladder are involved. When the surface of the tumor has been ulcerated, the finger sleeve is often stained with blood and mucus.
2.Tumor markers
There are several tumor markers used in the diagnosis of colorectal cancer, CEA is one of the earlier and more used in China, but its sensitivity and specificity are not high, so it is mostly used to estimate the prognosis of colorectal cancer.
3.Barium enema
Especially air-barium double contrast colonography can clearly show ulcerative, bulging lesions and strictures of intestinal mucosa and other lesions.
4.Imaging examination
Ultrasound, CT and other imaging examinations are not significant to confirm the diagnosis of colorectal cancer itself, but they are superior in determining the invasion of adjacent tissues, distant organ metastasis, lymphatic metastasis, postoperative review, etc. They are important supplementary means to barium enema and fiber colonoscopy for the diagnosis of colorectal cancer.
5.Colonoscopy
The diagnostic value of colonoscopy has been further improved in the past 20 years, and the whole colon examination should be done as far as possible in clinical examination.
(III) TNM staging (2002 International Union Against Cancer)
TX The condition of primary lesion cannot be assessed
NX Unable to assess regional lymph nodes
MX Unable to assess distant metastasis
Tis carcinoma in situ, intraepithelial or intramucosal carcinoma that has not penetrated the mucosal muscle layer but reached the submucosa
N0 No regional lymph node metastasis
M0 No distant metastasis
T1 Invasion of submucosa
N1 1~3 regional lymph node metastases
M1 distant metastasis
T2 Invasion of the intrinsic muscular layer of the intestinal wall
N2 ≥4 regional lymph node metastases
T3 Invasion beyond the intrinsic muscular layer to the subplasma layer or invasion of paracolon or pararectal tissue when the primary lesion is located in the colon or rectum without a plasma layer
T4 penetration of visceral peritoneum or direct invasion of other organs or structures (T4 is also considered when other segments of the colon are involved after penetrating the plasma membrane, for example, when cecum cancer invades the sigmoid colon) II.
The treatment methods of colorectal cancer include surgery, chemotherapy, radiotherapy and biological therapy, among which surgery is the main treatment method. The role of chemotherapy in the treatment of colorectal cancer has two aspects, namely adjuvant chemotherapy after radical surgery and dividend chemotherapy for advanced colorectal cancer.
Neoadjuvant chemotherapy for colorectal cancer is mainly used in combination with radiotherapy for rectal cancer, which can increase the rate of anal preservation, improve patients’ quality of life and reduce postoperative recurrence.
Adjuvant chemotherapy is an important part of the comprehensive treatment of colorectal cancer. The mechanism of adjuvant chemotherapy is to destroy residual lesions after radical surgery or radiotherapy. However, not all patients need adjuvant chemotherapy, and adjuvant chemotherapy is not required for stage II patients with low risk of recurrence. Therefore, correct postoperative staging is very important to guide adjuvant chemotherapy, especially for lymph nodes, which should be above 12. In the treatment of rectal cancer, radiotherapy and chemotherapy are inseparable. Adjuvant chemotherapy can not only play the role of decreasing the distant micro metastases, but also increase the radiosensitivity of local residual lesions. The combination of radiotherapy and chemotherapy significantly improves the tumor-free survival rate and overall survival rate of patients with rectal cancer after radical surgery.
For some colorectal cancer patients who have distant metastases at the time of diagnosis or recurrent metastases after surgery, chemotherapy can prolong the survival and improve the quality of life of patients.
III. Treatment strategies
(I) Neoadjuvant chemotherapy for colorectal cancer
Neoadjuvant chemotherapy for colorectal cancer is generally used for rectal cancer, the purpose of which is to increase the rate of anal preservation and improve patients’ quality of life, and for T3~4 patients, it can also reduce the rate of local recurrence after surgery. It is usually used in combination with 54Gy dose of radiotherapy.
1. Irinotecan 50mg/m2, iv gtt, 1 time per week
Fluorouracil 225mg/m2, iv gtt, 5d per week
Radiotherapy 54Gy
2.Oxaliplatin 30~60mg/m2 iv gtt (2h), once a week
Fluorouracil 200mg/m2, iv gtt, qd
Radiotherapy 54Gy
3. Capecitabine 1000mg/m2, bid, po, d1~14, rest 1 week.
Oxaliplatin 130mg/m2, iv gtt, qd 3 weeks
Combined radiotherapy/chemotherapy after 12 weeks. Capecitabine 825mg/m2, bid, po, radiotherapy 54Gy
According to the clinical study results obtained so far, combined radiotherapy can obtain an efficiency of 70%~80%, and most patients can obtain complete surgery through neoadjuvant radiotherapy, increasing the rate of anal preservation and reducing postoperative recurrence.
(II) Adjuvant chemotherapy for colorectal cancer
Adjuvant treatment for colorectal cancer has undergone more than 30 years of research and has made remarkable progress, and postoperative adjuvant treatment can improve the 5-year survival rate by about 15%. It is generally believed that the fluorouracil-based chemotherapy regimen is the basis of chemotherapy for colorectal cancer, and the application of oxaliplatin further enhances the effect of fluorouracil/calcium folinic acid, and the application time of adjuvant chemotherapy is six months.
A chemotherapy regimen based on fluorouracil + calcium folinic acid and combined with oxaliplatin has been listed as the standard adjuvant chemotherapy regimen for stage III colorectal cancer and is recommended for stage IIB colorectal cancer, especially for stage II colorectal cancer with high-risk factors that can benefit from postoperative adjuvant chemotherapy. These high-risk factors include intestinal obstruction, intestinal perforation, T4, poorly differentiated tumors, presence of vascular invasion, and <12 lymph nodes sent for examination.
1. De Gramont regimen
Calcium folinic acid 200mg/m2, iv gtt, d1, 2
Fluorouracil 400mg/m2, iv, d1, 2
Fluorouracil 600mg/m2, iv gtt (22h), d1, 2
Repeated 1 time in 2 weeks.
Note: The regimen was designed by Prof. De Gramont, France, once every 2 weeks. Adjuvant treatment with fluorouracil combined with calcium folinic acid for stage III and IIB colon cancer increased the tumor-free survival rate by 17% and 8%, respectively, compared to the surgery-only group. Since a series of clinical studies found that continuous intravenous fluorouracil has less toxic side effects and higher efficacy than the intravenous approach. Therefore, the Mayo Clinic and Roswell Park regimens are no longer recommended for clinical use.
2.Modified De Gramont regimen
Calcium folinic acid 400mg/m2, iv gtt, d1
Fluorouracil 400mg/m2, iv, d1
Fluorouracil 2400mg/m2, iv gtt (46h), d1
Repeat 1 time in 2 weeks.
Note: With the intensive study of fluorouracil usage, it was recognized that continuous administration of fluorouracil has greater advantages than sedation, thus giving rise to this regimen, which is a modification of the De Gramont regimen.
3.AIO regimen
Calcium folinic acid 500 mg/m2, iv gtt, d1
Fluorouracil 2.6~3.0g/m2, iv gtt (24h), d1
1 time per week, 2 weeks break after 6 weeks of application.
4.Capecitabine regimen
Capecitabine 1250mg/m2, bid, po, d1~14
Repeat once every 3 weeks.
5.Ufadine/calcium folinic acid regimen
Euphradine 200 mg/m2, tid, po
Calcium folinic acid 30 mg, tid, po, (30 min after eflornithine administration)
4 weeks of application and 1 week of rest
Note: A study of thousands of patients organized by NSABP proved the difference in efficacy and toxicity of Ufadin compared with fluorouracil/calcium folinic acid.
6.FOLFOX4 regimen
Oxaliplatin 85mg/m2, iv gtt (2h), d1
Calcium folinic acid 200mg/m2, iv gtt, d1, 2
Fluorouracil 400mg/m2, iv, d1, 2
Fluorouracil 600mg/m2, iv gtt (22h), d1, 2
Repeat every 2 weeks.
Note: Fluorouracil/calcium folinate alone is not advocated for patients who are able to receive potent chemotherapy, but should be combined with oxaliplatin. For patients who cannot tolerate potent chemotherapy or are allergic to oxaliplatin, fluorouracil/calcium folinic acid or a derivative of fluorouracil can be used alone for safety.
7. mFOLFOX6 regimen
Oxaliplatin 85mg/m2, iv gtt (2h), d1
Calcium folinic acid 400mg/m2, iv gtt, d1
Fluorouracil 400mg/m2, iv, d1
Fluorouracil 2400mg/m2, iv gtt (46h), d1
Repeat every 2 weeks.
Note: This regimen is an improvement on the FOLFOX6 regimen, with a reduced dosage of oxaliplatin and better safety, and a modified De Gramont regimen for the use of fluorouracil/calcium folinate.
8.CapeOX (XELOX) regimen
Oxaliplatin 130mg/m2, iv gtt, d1
Capecitabine 850~1000mg/m2, bid, po, d1~14
Repeat every 3 weeks.
Description: ①Many clinical trials have demonstrated that capecitabine (Xyroda) is close to the efficacy of continuous intravenous fluorouracil, is less myelosuppressive and safer for elderly or infirm patients, and the convenience of dosing is also one of the advantages of capecitabine relative to intravenous chemotherapy. ②For postoperative adjuvant therapy in support of cancer, combined radiotherapy should be preferred. Due to the effectiveness of radiotherapy, adding oxaliplatin to fluorouracil does not further reduce local recurrence, but for stage III patients, oxaliplatin can reduce the incidence of distant metastases. ③So far, irinotecan is still not recommended for postoperative adjuvant chemotherapy. (iv) Clinical trials about monoclonal antibodies combined with chemotherapy as adjuvant therapy are underway, and there is no evidence that monoclonal antibodies are effective for adjuvant therapy.
(iii) Chemotherapy for advanced colorectal cancer
Compared with supportive therapy alone, chemotherapy for advanced colorectal cancer has advantages in terms of survival and quality of life, and early treatment is more beneficial to patients and can prolong median survival. In recent years, the use of irinotecan and oxaliplatin has significantly improved the efficacy of combination chemotherapy.
1.Fluorouracil combined with irinotecan
(1) FOLFIRI regimen
Irinotecan 180mg/m2, iv gtt (90min), d1
Calcium folinic acid 200mg/m2, iv gtt, d1, 2
Fluorouracil 400mg/m2, iv, d1, 2
Fluorouracil 600mg/m2, iv gtt (22h), d1, 2
Repeat every 2 weeks
This regimen uses irinotecan in combination with the De Gramont regimen, with an efficiency of 45% for first-line treatment and 5% to 10% for second-line treatment, for a clinical benefit rate of approximately 25%.
(2) AIO/irinotecan regimen
Irinotecan 80mg/m2, iv gtt (90min), once a week
Calcium folinate 500mg/m2, iv gtt, once a week
Fluorouracil 2.4g/m2, iv gtt (24h), 1 time per week, 2 weeks break after 6 weeks of application.
2.Fluorouracil combined with oxaliplatin regimen
(1) FOLFOX4 regimen
(2) mFOLFOX6 regimen
(3) CapeOX regimen
Note: Oxaliplatin-based combination regimen and irinotecan-based combination regimen can be used as second-line drugs, and patients who can complete these two regimens can have a median survival of more than 20 months.
(4) FOLFOXIRI regimen
Irinotecan 165mg/m2, iv gtt (90min), d1
Oxaliplatin 85mg/m2, iv gtt (2h), d1
Calcium folinic acid 200mg/m2, iv gtt, d1
Fluorouracil 3200mg/m2, iv gtt (48h), d1
Repeat every 2 weeks
Note: Compared with the FOLFOX regimen, the FOL FOXIRI regimen significantly improves the near-term efficiency, radical resection rate of metastases, and progression-free survival time, but has a greater toxic response and is not recommended for routine clinical use. This regimen can be used for patients who are in good health and have the hope of receiving powerful chemotherapy to shrink the lesions and gain access to surgery.
3.The combination program of monoclonal antibodies
(1) Bevacizumab / FOLFIRI
Bevacizumab 5mg/kg, iv, once every 2 weeks
Irinotecan 180mg/m2, iv gtt (90min), d1
Calcium folinic acid 200mg/m2, iv gtt, d1, 2
Fluorouracil 400mg/m2, iv, d1, 2
Fluorouracil 600mg/m2, iv gtt (22h), d1, 2
(2) Bevacizumab/FOLFOX4
Bevacizumab 5mg/kg, iv, every 2 weeks
Oxaliplatin 85mg/m2, iv gtt (2h), d1
Calcium folinic acid 200mg/m2, iv gtt, d1, 2
Fluorouracil 400mg/m2, iv, d1, 2
Fluorouracil 600mg/m2, iv gtt (22h), d1, 2
Note: The combination regimen of the above 2 bevacizumab can be used as first-line or second-line without bevacizumab. The application of bevacizumab must be combined with effective chemotherapeutic drugs, therefore it is not recommended in the third line.
(3) Cetuximab/FOLFIRI
Cetuximab 400 mg/m2, iv gtt, week 1, followed by 250 mg/m2, iv gtt, once a week
Irinotecan 180 mg/m2, iv gtt (90min), d1
Calcium folinic acid 200 mg/m2, iv gtt, d1, 2
Fluorouracil 400mg/m2, iv, d1, 2
Fluorouracil 600mg/m2, iv gtt (22h), d1, 2
Note: ①Cetuximab is currently approved by the FDA only for use in combination or alone in patients who have failed irinotecan. Recent clinical trials have demonstrated that the combination of cetuximab with either FOLFOX or FOLFIRI can be used in first-line therapy with satisfactory efficacy. The chemotherapy dose remains unchanged when the combination is used. Cetuximab can be used alone for patients who are in poor physical condition and cannot tolerate chemotherapy. ②The combination of cetuximab with regimens such as FOLFOX or FOLFIRI can be effective for first-line, second-line or third-line treatment.