Process of Metastasis
Cancer cells can travel from the primary tumor site to distant organs, such as the liver, lungs, and bone. This dynamic process requires an environment in which tumor cells can proliferate, invade surrounding tissues, be released into the circulation, invade a distant organ, establish their own blood supply (angiogenesis), and grow. Mutations in oncogenes and tumor suppressor genes play important roles in hereditary and sporadic cancer development.

Metastasis and Survival
Nearly half of patients with newly diagnosed CRC develop metastases. Almost 25% of patients have stage IV (metastatic) disease at diagnosis, and their predicted 5-year survival is less than 10%.¹ Approximately 30% to 50% of patients diagnosed with stage II or III CRC will develop local or distant metastases within 5 years.²

Figure 1. Liver and peritoneal metastases.
Intra-abdominal seeding model of A, liver, and B, abdominal wall. C, Photomicrograph of HT-29 cell tumor implant of the parietal peritoneum. D, Photomicrograph showing tumor invasion through the liver capsule. (From Scaife et al,³ with permission.)



Sites of CRC Metastasis
CRC tends to metastasize to the liver; among patients with CRC, liver metastases represent the major cause of death. Depending on the stage of the primary tumor at diagnosis, liver metastases may occur in 20% to 70% of patients, and lung metastases in 10% to 20%. Spread to bone is relatively rare, affecting fewer than 2% of CRC patients.⁴

Mechanism of CRC Metastasis
CRC generally spreads through the lymphatics or portal venous system to the liver.⁵ Other mechanisms of spread include transperitoneal metastasis (seeding through the serosa) or intraluminal metastasis (seeding into the lumen, as a blood vessel), which is rare (Figure 1).^3,6 One theory of metastasis that may account for spread beyond the lymphatic or portal venous system is “seed and soil,” proposed in 1889 by Stephen Paget.⁷ Paget theorized that cells are carried in all directions in the bloodstream but deposit and grow only if they fall on congenial “soil.” Emerging gene expression microarrays suggest that tumor cells may be programmed early on and that an individual’s cancer already carries a particular prognostic signature.⁸

Site of Primary CRC and Prognosis
Some investigators have explored the possible link between the location of the primary CRC and the occurrence and site of metastatic disease. Wang et al⁹ reported that cancer of the right side of the colon correlates significantly with liver recurrence (P = .0071). However, extensive evidence from the Gastrointestinal Tumor Study Group (GITSG) showed that tumor location (left, right, rectosigmoid, or sigmoid) was of low prognostic value.¹⁰

Treatment of CRC Metastasis
Treatment of CRC metastasis is often a multimodality approach involving surgery, chemotherapy, ablation of liver metastases, or radiotherapy and may be completed over a finite period of time or continue until progression or intolerable side effects decrease the patient’s quality of life.

Controversies in the treatment of CRC metastasis include appropriate identification of patients who should be considered for staged resection of metastatic disease at the time primary disease is resected or for resection of metastatic lesions at recurrence, selection of the most effective chemotherapy and biologic therapy regimen for neoadjuvant or adjuvant therapy to debulk metastatic deposits and provide disease control following resection, respectively, and selection of palliative chemotherapy for patients with nonresectable metastases.¹¹

Resection of CRC Liver Metastasis: Benefits
Unlike other solid tumor types, CRC metastatic to the liver may be cured by surgical resection followed by chemotherapy. Resection of CRC liver metastases can yield 5-year survival rates between 25% and 40%, although only 7% to 10% of patients with CRC liver metastases ultimately benefit from resection. Best results are seen with a solitary liver lesion.¹² In addition to surgical resection, options for local control of liver metastases may include

Link to information on Local Ablation of Liver Metastases on this Web site.

A select group of patients with CRC metastatic to the lung only may also be considered curable by staged thoracotomy with resection of lung nodules followed by chemotherapy. Assuring adequate pulmonary function prior to and following resection is essential.¹³

Nonresectable Metastases
When stage IV disease includes multiple sites or nonresectable tumor, patients may undergo surgical resection of the primary tumor, resection of the entire colon (colectomy), or removal of a segment of the colon (hemicolectomy). If the colon is obstructed by tumor, a diverting colostomy may be required. Following surgical resection, or if resection is not an option, systemic chemotherapy can be considered. The choice of regimen depends on the patient’s general condition, comorbidities, and tolerance.^13,14

The median survival for stage IV CRC with FOLFOX4 plus bevacizumab (10 mg/kg) chemotherapy is approximately 12.5 months versus 10.7 months in patients treated with FOLFOX4 alone.¹⁵

Hurwitz et al¹⁶ compared irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg/kg) with IFL plus placebo The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, compared with 15.6 months in the group given IFL plus placebo.¹⁶

Treatment Guidelines for Metastatic CRC
Guidelines for chemotherapy regimens for stage IV CRC are located at: http://www.cancer.gov/cancertopics/pdq/treatment/colon/HealthProfessional/page10

The National Comprehensive Cancer Network (NCCN) guidelines for treatment of metastatic CRC can be found here.

Web Resources
C3: Colorectal Cancer Coalition is a patient advocacy organization that fights colorectal cancer through research, empowerment and access. http://fightcolorectalcancer.org/

Colon Cancer Alliance is a patient advocacy organization providing patient support, education, research, and advocacy across North America. http://www.ccalliance.org/

Oncology Nursing Society 

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13. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Colon Cancer, v.2.2009. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed July 20, 2009.
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15. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539-1544.
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colostomy—surgical procedure that brings the end of the large intestine through the abdominal wall. Stools moving through the intestine drain into a bag attached to the abdomen

oncogene—a gene that played a normal role in the cell as a proto-oncogene and that has been altered by mutation and now may contribute to the growth of a tumor

serosa—thin membrane lining the closed cavities of the body; has 2 layers with a space between that is filled with serous fluid

thoracotomy—surgery to open the chest wall

tumor suppressor gene—a protective gene that normally limits the growth of tumors. When a tumor suppressor gene is mutated (altered), it may fail to keep a cancer from growing