Management of Metastatic Colorectal Cancer

Introduction

Colorectal cancer is currently the third most common cancer in the United States, and in 2015 it is estimated that 140,000 persons will be diagnosed with this disease. More than 50,000 patients die from colorectal cancer each year, making it second only to lung cancer as a cause of cancer-related death. Risk factors for colorectal cancer include inflammatory bowel disease, tobacco, consumption of red and processed meats, alcohol, diabetes, inactivity, and obesity. Inherited genetic syndromes account for fewer than 10% of new cases. Colorectal cancer can spread by lymphatics or blood vessels, or by transperitoneal or direct spread. The most common site of hematogenous dissemination is the liver, followed by the lungs and bone. Rectal cancer can initially metastasize to the lungs as a result of inferior rectal vein drainage into the inferior vena cava. Approximately 20% of patients with colorectal cancer are found to have metastatic disease at the time of presentation. Most of these patients cannot be cured.

In the past three decades we have seen great progress in treatment options for metastatic disease. In the 1990s, 5-fluorouracil (5-FU) was the only agent approved for this indication, and median survival was less than 1 year. Now, with nearly 10 agents approved, median survival in the most recent randomized trials is approaching 30 months. This progress is a result of new cytotoxic agents and biomarker-based therapies targeting specific molecules, including vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR).

One major advance in the treatment of metastatic colorectal cancer involves a greater understanding of sequential systemic and local therapies, including resection in patients with oligometastatic disease. For such patients, some estimates suggest that 20% to 25% can be offered potentially curative treatment with the combination of surgical resection and chemotherapy. Furthermore, improvements in response rates with chemotherapy have allowed patients who present with unresectable disease to be downstaged, and some patients eventually may be offered curative resection. However, the timing and sequence of treatment remains an art, and data from large clinical trials are lacking. In this chapter we will review the management of patients with metastatic disease, focusing on systemic chemotherapy and potentially curative approaches incorporating liver-directed therapy.

Chemotherapy

The standard first-line approach for patients with metastatic colorectal cancer is systemic chemotherapy, which is given with the intent to palliate symptoms and prolong life. Initial treatment is composed of several standard cytotoxic drugs given as the chemotherapy “backbone” that are often combined with more recently approved targeted agents. These conventional agents are 5-FU, capecitabine, oxaliplatin, and irinotecan, as depicted in Table 62-1 .

Capecitabine

Capecitabine is a fluoropyrimidine carbamate, a prodrug of 5-FU designed to be dihydropyrimidine dehydrogenase (DPD) resistant. Once absorbed into the gastrointestinal tract, it undergoes a three-step activation process into 5-FU. Capecitabine was first compared with bolus 5-FU/LV in a randomized trial of patients with metastatic disease. It was found to have a superior response rate and was equivalent with respect to progression-free survival (PFS) and overall survival (OS). Capecitabine was also studied in a European trial and found to be equivalent to 5-FU.

The current standard of care for first-line treatment in metastatic colon cancer involves administration of either 5-FU and LV in combination with oxaliplatin (FOLFOX) or 5-FU and LV in combination with irinotecan (FOLFIRI) ( Fig. 62-1 ). Several versions of FOLFOX exist, distinguished by the dosing schedule of individual drugs. Alternatively, capecitabine can be substituted for 5-FU and LV and combined with either oxaliplatin or irinotecan.