Q1: Where can colorectal cancer usually metastasize to?
A1: Colorectal cancer most often metastasizes to the liver, with more than half of colorectal cancer patients experiencing liver metastases either synchronously or asynchronously. The lung is the second most common organ to which colorectal cancer metastasizes, followed by the abdomen. Peritoneal involvement is considered peritoneal carcinomatosis and in some cases as peritoneal pseudomucinous tumors, especially primary tumors originating from the appendix. Brain and bone metastases are less common. So, is it possible for colorectal cancer to metastasize only to the lungs and not to the liver? Of course it can be presented this way, but it is only relatively rare.
Q2: How long can a patient with metastatic colorectal cancer live?
A2: The survival period of patients is mainly determined by the stage of the tumor. The 5-year relative survival rate of patients with localized colorectal cancer is 90%, while the 5-year relative survival rate of those with distant metastases from colorectal cancer is only 12% to 19%.
Q3: How should patients with metastatic colorectal cancer be treated?
A3: At present, the main treatment for stage I-III colorectal cancer is still surgery, and high-risk stage II and III colorectal cancer patients also undergo postoperative adjuvant chemotherapy, while chemotherapy is the main treatment for stage IV colorectal cancer; however, surgical resection or interventional treatment can also be performed in some patients with single metastases.
Simultaneous liver metastases from colorectal cancer may be resected simultaneously or in stages for both the primary tumor and liver metastases. In some cases, surgical resection may be considered for isolated pulmonary metastases with no other metastases. Unresectable intrapulmonary metastatic colorectal cancer can be treated like liver metastases. Palliative treatment is used for peritoneal carcinoma, and systemic chemotherapy is used for advanced metastatic colorectal cancer.
Q4： How long can a patient with metastatic colorectal cancer who can undergo surgery live?
A4： Surgical resection is the only decisive method to treat metastatic colorectal cancer, which can increase the survival rate of patients by 25%~50%. However, only 10-20% of patients with liver metastases have resectable tumors.
Of course, the definition of resectable is currently evolving, i.e., the ability to obtain complete resection of the tumor with negative tumor margins with minimal requirements, while preserving enough liver tissue to maintain its normal liver function. Patients with resectable or potentially resectable liver metastases benefit from perioperative chemotherapy, such as preoperative neoadjuvant chemotherapy and postoperative adjuvant chemotherapy.
The advantages of neoadjuvant chemotherapy are preoperative removal of micrometastases, assessment of chemotherapy response and providing time to evaluate whether additional metastases will form outside the liver. The disadvantages of neoadjuvant chemotherapy are that there is a risk of tumor progression, thereby depriving the patient of a surgical window, full radiological validity (although live tumors are still histopathologically detectable) can make surgical resection difficult, and chemotherapy-induced fatty liver and sinusoidal damage can increase postoperative mortality and disability. This requires close collaboration between radiologists and medical oncologists and surgical oncologists to determine the appropriate timing of surgery.
Q5： Is there any way to turn inoperable metastatic colorectal cancer into surgically resectable one?
A5： Yes, for some patients. Selected patients may be able to turn unresectable metastases into resectable tumors with “remodeling chemotherapy” (to distinguish it from neoadjuvant chemotherapy). The goal of remodeling chemotherapy is to reduce the size of the tumor to create the opportunity for surgical resection. Like neoadjuvant chemotherapy, the duration of remodeling chemotherapy should be as short as possible, and surgery should be done as soon as possible to exclude the risk of chemotherapy-related fatty liver and liver sinus injury.
Q6: How long can a patient with inoperable metastatic colorectal cancer live?
A6: As I said before, how long to live depends on the stage of the tumor. Stage IV colorectal cancer refers to colorectal cancer with distant metastasis, where stage IVA refers to colorectal cancer confined to a single organ or site, while stage IVB refers to colorectal cancer involving more than one organ, site or peritoneum.
Over the past 10 years, there has been a significant shift in the treatment of stage IV colorectal cancer or metastatic colorectal cancer, resulting in a significant increase in overall survival time for these patients, from less than 6 months to nearly 2 years. This is largely due to newer chemotherapeutic approaches, the increased use of hepatic resection for patients with single metastases, and the identification of new molecular targets and their associated inhibitors.
Q7: What if liver metastatic colorectal cancer cannot be surgically resected?
A7: The direct treatment of hepatic metastatic colorectal cancer remains controversial and is an evolving field. Oncologists tend to perform direct treatment of the liver when the liver is the only site of metastases. The following are the main modalities currently available for non-surgical treatment.
Hepatic Arterial Infusion (HAI) is the surgical placement of a hepatic arterial chemotherapy tube used to infuse chemotherapeutic agents, taking advantage of the increased arterial blood supply to the metastases to create a selective high-dose infusion. proponents of HAI believe it aids in local tumor control.
Transaterial Radioembolization with Yttrium-90 Microspheres is used in refractory patients with no significant extrahepatic metastases on first- and second-line therapy.
Percutaneous Ablation of liver metastases (Percutaneous Ablation) is used in patients who are not candidates for surgery due to co-morbidity, lack of adequate future residual liver, or in combination with surgery to obtain a tumor-free state, such as radiofrequency ablation, cryoablation, and microwave ablation. Radiofrequency ablation is most widely used for local ablation procedures because of its low disability and lethality rates; however, several retrospective studies have found that radiofrequency ablation is inferior to surgical resection in patients with resectable tumors because of its higher recurrence rate.
Q8: What treatment can be done for patients with advanced metastatic colorectal cancer?
A8: Systemic chemotherapy, which is a kind of palliative chemotherapy. About 80% to 90% of metastatic colorectal cancer are unresectable tumors. The current treatment for most unresectable and disseminated metastatic colorectal cancer is palliative chemotherapy. The cytotoxic chemotherapeutic agents used for metastatic colorectal cancer are 5-FU/LV (leucovorin), capecitabine (capecitabine), oxiliplatin (oxaliplatin), and irinotecan (irinotecan). All of these drugs are often used in combination and are rarely used individually for treatment. Currently, the most widely used first-line treatment regimens for metastatic colorectal cancer are 5-FU/LV in combination with oxiliplatin (FOLFOX) and 5-FU/LV in combination with irinotecan (FOLFIRI). Sequential treatment of metastatic colorectal cancer with FOLFOX and FOLFIRI improved the median survival time of patients by approximately 20 months. Although the two regimens cannot be distinguished for their post-treatment efficacy, they have distinctly different toxicities: FOLFOX can cause nephropathy, while FOLFIRI can cause severe diarrhea. For patients with non-incisional tumors, oncologists administer individualized treatment to each patient, continuing with the same regimen as long as the patient tolerates it and radiologically evaluates it well. Chemotherapy intervals are necessary due to toxicity of chemotherapy drugs and patient fatigue and weakness. The oncologist will change the chemotherapy regimen when there is definite radiological evidence of tumor progression.
Q9: What exactly is the effectiveness of molecular targeted therapy for metastatic colorectal cancer?
A9: Molecular targeted therapy actually means that a protein (such as antibody) has a one-to-one correspondence with a specific protein (such as receptor) on the tumor, and the targeted drug binds to a specific protein on the tumor in the human body.
Bevacizumab, a monoclonal antibody bound to Vascular Endothelial Growth Factor (VEGF), was approved by the FDA in 2004 as a first-line treatment for metastatic colorectal cancer. Recent NCCN guidelines also recommend adding bevacizumab to FOLFOX, FOLFIRI and 5-FU/LV first-line combination chemotherapy.
Cetuximab, a chimeric human-mouse monoclonal antibody, and panitumumab, a fully human monoclonal antibody, were approved by the FDA in 2004 and 2006, respectively, for the treatment of metastatic colorectal cancer. Both drugs are anti-EGFR antibodies that inhibit intracellular signaling like the RAS/RAF/MAPK pathway by binding to the extracellular region of the Epidermal Growth Factor Receptor (EGFR).
Recent studies have shown that mutations in one intracellular signaling protein, KRAS (seen in 35-45% of colorectal cancer cases), can lead to activation of the EGFR pathway and determine the response of anti-EGFR antibodies. Compared to colorectal cancers without KRAS mutations (i.e., wild-type KRAS), colorectal cancers with KRAS mutations do not respond to EGFR inhibition by cetuximab and panitumumab.NCCN guidelines recommend KRAS genotyping for all patients with stage IV colon cancer.B-RAF (V600E) is another intracellular protein seen in 5% to 9% of colon cancer cases, and its mutations have effects similar to those of KRAS mutations.
Abciximab (Ziv-aflibercept) is a recombinant protein composed of human VEGF receptor 1 and receptor 2, which fuses to the Fc segment of human immunoglobulin G1 by inhibiting ligand binding and organizing the activation of the VEGF receptor. Abciximab in combination with FOLFIRI has been shown to be an effective second-line treatment option when tumor progression occurs with first-line non-irinotecan-containing regimens such as FOLFOX.
Regorafenib is a multi-targeted kinase inhibitor with the ability to inhibit the VEGF receptor, Kit, platelet-derived growth factor receptor, and several other kinases. Recent clinical trials have shown a moderate 6-week survival benefit with Regorafenib in patients with metastatic colorectal cancer that is resistant to all chemotherapy agents and was approved by the US FDA in 2012.
Q10: What are the drug complications and toxicities associated with the treatment of metastatic colorectal cancer?
A10: Cytotoxic chemotherapeutic agents can cause hepatotoxicity (fatty liver and hepatic sinusoidal obstruction syndrome, etc.), interstitial lung disease, nephropathy and bone marrow suppression (opportunistic infections and neutropenic colitis). Molecularly targeted therapeutic agents can cause pneumatization of the intestinal wall, perforation, tumor-enteric fistula, thromboembolism, cholecystitis, pancreatitis, and interstitial lung disease.