IX. Principles of treatment of metastatic disease
Metastases occur in 50-60% of patients and unresectable liver metastases in 80-90% of patients. Metastatic disease often emerges after regional treatment, with the liver being the most frequently involved site, and simultaneous liver metastases in 20-34% of patients. Patients with liver metastases who do not undergo surgery have a low 5-year survival rate. Some clinicopathological factors such as extrahepatic metastasis, more than 3 tumors, and DFS less than 12 months have poor prognosis.
1. Surgery for colorectal cancer metastasis
Studies have shown that surgical resection of colorectal cancer liver metastases is potentially curable for selective patients, and the 5-year disease-free survival can reach 20%. Colorectal cancer can also occur with pulmonary metastases, and most of the recommended treatment strategies for liver metastases are also applicable to pulmonary metastases, and combined hepatopulmonary resection is only suitable for highly selective patients. There are also data suggesting re-surgical resection for metastatic lesions with recurrent hepatic recurrence, but 5-year survival decreases with each surgery, and the presence of extrahepatic disease at the time of surgery is an independent poor prognostic factor.
Simultaneous resection or staged resection is feasible for both primary and metastatic lesions that are resectable. For unresectable metastases and in the absence of acute obstruction of the primary tumor, palliative resection of the primary site is a rare indication, and chemotherapy is the treatment of choice.
2. Liver treatment
Although the standard treatment for resectable metastatic disease is surgical resection, local non-surgical treatment of the liver can also be performed for a particular patient.
(1) Hepatic artery infusion (HAI)
The side effects of HAI therapy include biliary toxicity. The committee believes that HAI therapy is appropriate for elective patients and should only be used where there is extensive experience with both surgical and oncologic treatment.
(2) Arterial embolization therapy
Transarterial chemoembolization (TACE) includes hepatic artery cannulation to cause obstruction to facilitate local administration of chemotherapy. The available evidence is insufficient to recommend TACE for colorectal cancer liver metastases, except in clinical trials.
(3) Radiotherapy
Radiotherapy includes either intra-arterial placement of radioactive particles for embolization or confocal external irradiation. The former is only used for highly selected patients, while the latter is only suitable for patients with limited hepatopulmonary metastases or patients with significant symptoms or clinical trials, and should not irradiate the surgical site, and radiotherapy techniques should be chosen from 3D focused radiotherapy, intensity-modulated radiotherapy and IMRT.
(4) Tumor ablation
For patients who cannot physically tolerate resection surgery, ablation therapy can be considered. Ablation techniques include radiofrequency ablation, microwave ablation, and cold ablation. The committee does not recommend the use of ablation as a substitute for surgery in resectable patients. Surgery or ablation or ablation combined with surgery is not recommended for patients whose lesions cannot be completely removed.
3. Abdominal metastases
Colorectal metastases are seen in about 17% of patients and only peritoneal metastases in 2% of patients, and PFS and OS are usually shorter in such patients than in patients without peritoneal metastases. Treatment is mostly palliative in nature. The committee warned that patients treated with bevacizumab using colorectal stents are at increased risk of perforation.
Studies have been done describing cytoreductive surgery and perioperative warmed intraperitoneal chemotherapy (HIPEC) for abdominal metastases with high treatment-related complications, mortality of 8%, and seemingly no improvement in long-term survival, and the committee currently believes that the use of cytoreductive surgery combined with HIPEC for diffuse abdominal metastases is only appropriate for clinical trials. However, the committee also recognized the need for additional trials to confirm this treatment.
4. Determining resectability
Patients diagnosed with potentially resectable colorectal cancer should undergo a multidisciplinary evaluation, including a surgical consultation to assess resectability status. The criteria for determining the resectability of a patient with metastatic disease are complete resection of all disease with negative margins and adequate liver function. Preoperative portal embolization of the affected liver may be performed to increase liver preservation in those with inadequate residual liver function. It should be noted that tumor size alone is not a contraindication to tumor resection. The purpose of resection of liver metastases is to cure the disease and there is no benefit to debulking surgery.
5. Transformation to resectable
Most patients diagnosed with metastases have unresectable disease; however, limited liver metastases such as those involving key structures are feasible for surgical resection after tumor regression, and such patients should be highly considered for chemotherapy to reduce metastases and convert them to resectable; those with multiple metastases in the liver or lungs, where R0 resection cannot be obtained with chemotherapy alone, such should be considered unresectable lesions that cannot be converted.
Any chemotherapy regimen used to treat metastatic disease can be used for conversion therapy with the aim not to remove micrometastases but to try to obtain tumor regression. Importantly irinotecan and oxaliplatin containing regimens can cause hepatic steatohepatitis and sinusoidal liver injury. To reduce hepatotoxicity, it is recommended that this be performed as soon as surgery is available. For chemotherapy for initial unresectable disease, the committee recommends reassessment of disease every two months.
6. Neoadjuvant and adjuvant therapy for resectable disease
The committee recommends that systemic chemotherapy be administered to metastatic patients after resection to remove residual disease, with a perioperative treatment period of approximately 6 months. The choice of preoperative and postoperative chemotherapy regimens is dependent on chemotherapy history and response, safety, and consistency between adjuvant and neoadjuvant chemotherapy recommendations. If the tumor continues to grow at the time of neoadjuvant chemotherapy, it is switched to another regimen or observed. The appropriate sequence of chemotherapy is unclear. Resectable patients should undergo hepatic resection followed by postoperative adjuvant chemotherapy or perioperative chemotherapy.
Possible advantages of preoperative chemotherapy are: earlier treatment of micrometastatic disease, determination of response to chemotherapy, and avoidance of local treatment in patients with early disease progression. The disadvantage is that if progression or complete remission occurs during treatment, the opportunity for surgery may be missed. Therefore, preoperative chemotherapy patients need frequent evaluation and close communication between multidisciplinary specialists and patients to optimize preoperative treatment strategies and appropriate timing for surgical intervention. Other risk of preoperative chemotherapy is hepatotoxicity, so neoadjuvant chemotherapy is best limited to 2-3 months.
7. Chemotherapy for progressive or metastatic disease
Drugs used to treat multiple metastatic colorectal cancers can be used in combination or alone, including 5-FU/LV, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, abciximab, and regifinib. Treatment selection is based on the purpose of treatment, type and duration of previous treatment, and toxicity of the treatment drug. If the patient’s physical status, etc., can tolerate more intense chemotherapy, one of the following five regimens is recommended: FOLFOX, FOLFIRI, CapeOX, 5-FU/LV, or FOLFOXIRI.
(1) Treatment sequence and timing
Prior to the era of targeted therapy, studies have shown that there was little difference in clinical outcomes whether strong chemotherapy or weaker chemotherapy was given first. For metastatic disease, all of the above regimens are equal, with no priority recommendation, nor for initial treatment with biologics.
(2) Regimens not recommended
The IFL regimen is not recommended because of its toxicity and reduced effectiveness; the CapeIRI regimen or the CapeIRI/bevacizumab regimen is not recommended for first-line treatment of metastatic colorectal cancer; the combination of biological agents is not recommended because it does not improve outcomes but increases toxicity.
(3) Toxicity of capecitabine
The committee noted: patients with decreased creatinine clearance can develop drug accumulation, so dose adjustment should be made; the incidence of hand-foot syndrome is higher than 5-FU/LV; North American patients may have a higher chance of side effects and should be closely monitored and dose adjusted based on side effects. A recent study showed that hand-foot syndrome was associated with improved OS.
(4) Toxicity of irinotecan
The main ones include early and late diarrhea, dehydration and severe neutropenia. Irinotecan is caused by the inactivation of an enzyme called UGT1A1, which is involved in bilirubin conversion and can lead to elevated indirect bilirubin in deficiency. Therefore, caution should be exercised when using irinotecan in the presence of UGT1A1 deficiency or when indirect bilirubin is elevated.
Some UGT1A1 deficiencies lead to decreased metabolic inactivation of irinotecan, drug accumulation, and increased toxicity. The maximum tolerated dose of irinotecan is 850 mg, 700 mg and 400 mg for the following phenotypes *1/*1, *1/28 and *28/*28, respectively.
(5) 5-FU/LV or capecitabine treatment
For patients who cannot tolerate strong chemotherapy, the guidelines recommend treatment with 5-FU/LV or capecitabine, with or without bevacizumab. If such less intense therapy does not improve the patient’s functional status, it is appropriate to change to supportive therapy; if the status improves, a more intense regimen as recommended above should be used.
(6) FOLFOXIRI
This strong chemotherapy should only be used in highly selected patients who are likely to convert to resectable disease.
(7) Bevacizumab
It is a humanized monoclonal antibody that is used to block tumor angiogenesis. Studies have shown benefit of bevacizumab for first-line treatment of metastatic colorectal cancer, and there are no data clarifying whether bevacizumab should be used in the perioperative treatment of resectable metastatic disease. The committee does not recommend bevacizumab for the adjuvant treatment of stage IV disease after resection unless a response to bevacizumab therapy is seen with neoadjuvant therapy.
The FDA agreed to add a warning to the bevacizumab insert that there is a risk of necrotizing fasciitis, which can sometimes be fatal, usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation following bevacizumab administration.
The use of bevacizumab may interfere with wound healing. The committee recommends a minimum of 6 weeks between elective surgery and the last bevacizumab treatment. Previous clinical studies showed that discontinuation of anti-VEGF therapy may accelerate recurrence, make recurrent tumors more aggressive, and increase mortality, but recent findings suggest no rebound effect.
(8) Cetuximab and panitumumab
Both are monoclonal antibodies that act on EGFR to inhibit its downstream signaling. They can be treated with serious infusion reactions including allergy; they can also produce skin toxicity, which is associated with treatment response and survival; in addition, both can cause venous thrombosis and other serious side effects.