The NCCN clinical guideline for colon cancer is divided into four parts: clinical decision tree, key problem statement, manuscript, and references. The clinical decision tree is the core of the colon cancer treatment guidelines, and the various types follow the conventional clinical diagnosis and treatment process of first examination, pre-treatment assessment, treatment, post-treatment assessment, adjuvant treatment, and follow-up, respectively. Key problem statements include principles of pathological assessment (detection of K-ras mutations), principles of surgical treatment, chemotherapy for advanced or metastatic colon cancer, principles of risk assessment for stage II colon cancer, adjuvant therapy, and radiation therapy.
Interpretation 1] Treatment of early colon cancer in situ cancer and T1-2N0M0 stage can be treated without chemotherapy after surgery stage II should be treated with chemotherapy as appropriate
A comprehensive study on the benefits of adjuvant chemotherapy for colon cancer patients after radical surgery published by Gill et al. in the American Journal of Clinical Oncology in 2004 showed that adjuvant chemotherapy containing fluorouracil improved the survival of stage II patients by no more than 5%, therefore, in deciding whether stage II colon cancer patients need to receive adjuvant chemotherapy, clinicians should use discretionary chemotherapy. adjuvant chemotherapy, clinicians should consider whether patients have adverse prognostic factors (including stage T4 lesions, bowel perforation, peritumoral vascular lymphovascular infiltration, poor differentiation, and less than 12 postoperative lymph nodes) and evaluate patients for other comorbidities and life expectancy.
After patients are fully informed, patients staged as T3N0M0 with no high-risk factors can choose capecitabine or fluorouracil + calcium folinic acid chemotherapy, or participate in clinical trials, or choose clinical observation and regular follow-up; for patients with high-risk factors at T3~4N0M0, or with local perforation at T3, or with positive, indeterminate and too close cut margins at T3 can be considered for administration of fluorouracil + calcium folinic acid Fluorouracil + calcium folic acid + oxaliplatin combination chemotherapy, or capecitabine/fluorouracil + calcium folic acid monotherapy, or participate in clinical trials or choose to observe.
[Interpretation 2] Treatment of stage III colon cancer FOLFOX regimen as the recommended postoperative adjuvant chemotherapy for patients with stage III colon cancer
The MOSAIC clinical trial by De.Gramont et al. in France showed that postoperative adjuvant chemotherapy containing fluorouracil + calcium folinate + oxaliplatin regimen (FOLFOX regimen) in patients with stage III colon cancer can improve disease-free survival, therefore FOLFOX regimen is recommended as postoperative adjuvant chemotherapy for patients with stage III colon cancer (Class 1 evidence), and for patients who cannot receive strong regimen chemotherapy Patients may consider capecitabine/fluorouracil + calcium folinic acid monotherapy.
In recent basic studies, microsatellite instability, 18q heterozygous deletion and TGF-β1RII were shown to be prognostic factors for patients with stage III colon cancer receiving fluorouracil-based adjuvant chemotherapy regimens. The 5-year overall survival rate after receiving adjuvant chemotherapy containing fluorouracil was about 75%, otherwise the 5-year overall survival rate was only about 50%. Further studies will continue to search for valid molecular indicators to predict the efficacy and determine the prognosis.
[Interpretation 3] Treatment of advanced colon cancer
Treatment of patients with suspected or confirmed concurrent metastatic colon cancer
These patients are subdivided into three categories according to the examination results: simple liver metastasis, lung metastasis or abdominal metastasis. For patients with operable simultaneous liver or lung metastases, simultaneous or staged resection of primary and metastatic foci can be chosen, i.e. neoadjuvant chemotherapy followed by surgery, or the primary foci can be removed first followed by chemotherapy and then the metastatic foci. The new version of the guidelines recommends that the duration of neoadjuvant chemotherapy be 2-3 months to avoid complications at the time of surgery due to drug-related adverse reactions from excessive chemotherapy or to miss the best time for surgery due to excessive chemotherapy. For patients with concurrent liver or lung metastases who are temporarily inoperable, systemic chemotherapy can be given first.
Adam et al. showed that neoadjuvant chemotherapy could convert 10% of patients with originally unresectable liver metastases to resectable, and patients who could be surgically resected after neoadjuvant chemotherapy had a survival comparable to that of patients with originally resectable metastases, which was significantly better than those who had no chance of resection. In addition, the new guidelines recommend that the resectability of the lesion should be evaluated every 2 months during neoadjuvant chemotherapy to avoid missed surgery due to over-chemotherapy.
Management of liver metastases
The new version of the guidelines adds the following for the management of hepatic metastases.
(1) The principle of radical resection must be followed for both primary and liver metastases, and the use of simultaneous or staged resection depends on the complexity of the hepatectomy or colectomy, the patient’s comorbidities, surgical exposure, and the experience of the clinical surgeon;
(2) If the residual liver volume is insufficient for resection of liver metastases, preoperative portal vein embolization or staged hepatectomy may be considered;
(3) Intra-arterial embolization may be considered for some patients with significant liver metastases but not significant systemic lesions and who are resistant to chemotherapy or have refractory bowel cancer, but the evidence level for this management is only category 3;
(4) Conformal external radiation therapy is not routinely recommended, unless the patient is symptomatic or required for clinical trials.
Management of pulmonary metastases
The new version of the guidelines adds the following to the management of pulmonary metastases.
(1) If pulmonary metastases are unresectable, radiofrequency may be considered;
(2) Concurrent resectable pulmonary metastases may be considered for simultaneous or staged surgical resection of the primary and metastatic foci.
If patients with concurrent abdominal metastases have intestinal obstruction or are at risk of intestinal obstruction, colon resection, bypass colostomy or bypass, stenting and other surgeries can be considered; for patients without risk of intestinal obstruction, systemic chemotherapy is recommended first.
Treatment for patients with recurrent metastatic colorectal cancer
There are many factors affecting the elevation of tumor marker carcinoembryonic antigen (CEA), and it is not yet possible to determine the recurrence or metastasis of tumor based on the elevation of CEA, but the elevation of CEA should be used as a signal to remind clinicians to conduct comprehensive review of patients, including colonoscopy and CT examination of chest, abdomen and pelvis, and PET examination if necessary to exclude the possibility of recurrence and metastasis. If there are no positive findings, review is still required every 3 months; if there is imaging evidence to support recurrent metastasis, the resectability of the lesion should be fully evaluated. Patients with resectable recurrent metastatic colon cancer can be operated directly or receive neoadjuvant chemotherapy before surgery. Postoperatively, patients still need to receive systemic chemotherapy.
Patients with unresectable recurrent metastatic colon cancer who have received chemotherapy with FOLFOX regimen for less than 1 year should be considered to have failed chemotherapy with oxaliplatin-containing regimen and considered to switch to chemotherapy with FOLFIRI regimen (irinotecan + fluorouracil + calcium folinic acid) ± bevacizumab. Patients who have been off FOLFOX regimen chemotherapy for more than 1 year, or who have received only fluorouracil + calcium folinic acid/capecitabine monotherapy, or who have not received chemotherapy may choose aggressive regimen chemotherapy for surgical opportunities.
Regimen selection for palliative chemotherapy The new version of the guideline adds the following first-line chemotherapy regimens for patients with locally advanced or metastatic colon cancer who can tolerate chemotherapy: FOLFOX, FOLFIRI, XELOX (capecitabine + oxaliplatin) ± cetuximab (K-ras wild-type patients), while the FOLFOXIRI regimen (irinotecan + oxaliplatin + fluorouracil/calcium folinic acid) ‘s recommendation level is in category 2B. In Italy, Colucii et al. compared the efficacy of FOLFOX and FOLFIRI regimens in patients with advanced colorectal cancer and showed comparable efficacy rates. the V308 study by Tournigand et al. showed that FOLFOX and FOLFIRI regimens can be used interchangeably as first- and second-line regimens in patients with advanced colorectal cancer.
Capecitabine ± bevacizumab, fluorouracil + calcium folinic acid ± bevacizumab may be considered for patients who cannot tolerate more aggressive regimens of chemotherapy (Class 2A evidence); in addition, cetuximab monotherapy (K-ras wild-type patients) is recommended as a treatment option (Class 2B evidence).
The combination of two or more targeted agents does not have an efficacy advantage over a single targeted agent, and therefore the new NCCN guidelines do not recommend the combination of targeted agents. The data on the use of FOLFOXIRI regimens in combination with targeted agents is also immature and the evidence is insufficient.
The new NCCN guidelines add a note to all recommendations for the use of cetuximab – limited to patients with K-ras wild type – making the use of cetuximab more selective and targeted. benefit from anti-EGFR therapy is modest, and anti-EGFR combination chemotherapy appears to be less effective and has more pronounced toxicities than chemotherapy alone.
In contrast, wild-type patients have a significant survival advantage with cetuximab in combination with chemotherapy over chemotherapy alone, with a similar spectrum of adverse effects. Therefore, the expert group recommends that tumor tissue (primary tumor tissue or metastatic tumor tissue) be taken for gene mutation testing before deciding whether to use cetuximab treatment, and cetuximab treatment is not recommended for patients with mutations in the above sites.
[Interpretation 4] Regular follow-up and timely detection of recurrence and metastasis are beneficial to early intervention
In 2005, Sargent et al. published in the American Journal of Clinical Oncology a comprehensive analysis summarizing 18 randomized trials of 20,898 colon cancer patients who received adjuvant chemotherapy after surgery showed that more than 80% of colon cancer recurrence occurred within 3 years after surgery, and timely detection of recurrence and metastasis is beneficial for early intervention.
For patients with stage I to III colon cancer, regular postoperative follow-up, including physical examination and dynamic monitoring of CEA, should be performed every 3-6 months for 2 years, and then every 6 months for 5 years. Patients with risk factors for recurrence may be considered for CT examinations of the chest, abdomen, and pelvis once a year for 3 years. colonoscopy should be performed within 1 year. if colonoscopy was not performed due to preoperative obstruction, colonoscopy should be reviewed within 3 months after surgery. if abnormalities are found, it needs to be reviewed within 1 year; if the adenoma is advanced, it should be reviewed once in 3 years, and then every 5 years thereafter. Routine PET scans are not recommended.
Regular monitoring should also be done for patients with previously unresectable metastatic colon cancer who have been converted to resectable after adjuvant chemotherapy. CEA1 should be monitored dynamically every 3 months for 2 years, and then every 6 months for 5 years. CT examination of chest, abdomen and pelvis, once every 3~6 months for 2 years, and then once every 6~12 months for 5 years. colonoscopy within 1 year, if colonoscopy is not performed due to preoperative obstruction, if abnormalities are found in 3~6 months after surgery, colonoscopy needs to be reviewed within 1 year; if it is advanced adenoma, it should be reviewed once in 3 years, and then once every 5 years.
Summary]
The NCCN clinical guidelines have become an important reference for global clinical diagnosis and treatment of cancer with their rigorous and authoritative conclusions and timely updated consensus. However, while referring to the NCCN clinical guidelines for colon cancer, Chinese oncologists should take into account the domestic clinical experience and the characteristics of Chinese patients themselves, and make targeted reference to the contents of the guidelines to guide their clinical work.
The main update of the 2009 edition of the NCCN guidelines is the recommendation to test patients’ K-ras gene status before choosing targeted therapy (cetuximab), which is the first example of individualized treatment in colon cancer treatment. Second, the guidelines emphasize the importance of multidisciplinary collaboration in the development of a patient’s treatment plan, especially the need for experienced surgeons to be involved in decision-making when deciding the timing of a patient’s surgery. Third, the guidelines suggest that preoperative chemotherapy needs to be limited for patients with potential surgery to avoid missed surgery due to excessive chemotherapy.