Acknowledgments
Dr. Khorana acknowledges research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research, the Scott Hamilton CARES Initiative, the Porter Family Fund for Biliary Genomics Research, and the National Heart, Lung and Blood Institute (1R34HL127156). Dr. Noel serves on the speakers bureau for Taiho Pharmaceutical.
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 .
| Category | Mechanism | Adverse Effects |
|---|---|---|
| Fluoropyrimidines (5-fluorouracil/capecitabine) | A pyrimidine analog antimetabolite that interferes with DNA and RNA synthesis | Mucositis Diarrhea Hand-foot syndrome |
| Irinotecan | Converted by carboxylesterase to its active metabolite (SN38), which binds reversibly to topoisomerase 1-DNA complex, preventing regulation of the cleaved DNA strand | Diarrhea Alopecia |
| Oxaliplatin | An alkylating agent that binds DNA, forming cross-links that inhibit DNA replication and transcription | Neurotoxicity |
5-Fu
5-FU has remained an integral part of the treatment in colorectal cancer after its first approval more than 50 years ago. 5-FU is a prodrug that requires multiple enzymatic steps prior to its conversion into the active phosphorylated form. The key metabolite is 5-fluorodeoxyuridylate monophosphate (F-dUMP), which is a competitive inhibitor of thymidylate synthase (TS). TS is an obligatory step in the synthesis of thymidine, and its inhibition has a potent effect on DNA synthesis. 5,10-Methylene tetrahydrofolate (leucovorin; LV) accentuates the inhibition of TS therapy by stabilizing the ternary complex, thus enhancing the activity of 5-FU. 5-FU is administered in several ways, including bolus and continuous infusion.
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.
Irinotecan
Irinotecan, a semisynthetic derivative of the plant alkaloid camptothecin, works by inhibiting topoisomerase I, which is necessary for DNA self-replication and RNA transcription. Inhibition of topoisomerase I results in DNA strand breaks and cytotoxicity. Initial clinical trials with irinotecan were notable for response rates of up to 25% and clinical benefit in patients previously treated with fluoropyrimidines. Two randomized clinical trials led to U.S. Food and Drug Administration approval of irinotecan in 1996. In one trial, nearly 300 patients were randomized to irinotecan versus best supportive care, and the treatment group was found to have an increase in 1-year survival (36% vs. 14%, P = .0001). In the second trial, 267 refractory patients were randomized to either irinotecan or infusional 5-FU; survival in the irinotecan group was increased at 1 year from 32% to 45% ( P = .035).
Once irinotecan was established as an active agent in colorectal cancer, the next step was to combine it with 5-FU with the hope of increasing response rates and survival. After successful completion of phase 1 trials, two large randomized studies were conducted in first-line metastatic disease. The first study randomized 387 patients to irinotecan plus 5-FU versus 5-FU alone. Response rates increased from 31% to 49% ( P <.001), PFS increased from 4.4 to 6.7 months ( P <.001), and OS increased from 14.1 to 17.4 months ( P = .031). The second trial, based in North America, randomized 683 patients to one of three groups: irinotecan combined with 5-FU and LV, 5-FU and LV alone, or irinotecan alone. The combination regimen was superior to both 5-FU and LV and single-agent irinotecan with regard to the response rate (50% vs. 28% vs. 29%, P <.001), PFS (7.0 vs. 4.3 vs. 4.2 months, P = .004), and OS (14.8 vs. 12.6 vs. 12 months, P = .04). Although manageable, the combination regimen is notable for toxicity, including diarrhea and neutropenia.
Oxaliplatin
A second key agent that changed the landscape of treatment for this disease was oxaliplatin. Oxaliplatin is a third-generation platinum analog that has substantial clinical activity in colorectal cancer. Oxaliplatin exerts its effect by the formation of covalent DNA adducts involving the complexed platinum atom. As a single agent, oxaliplatin was found to have response rates of 10% to 20% and demonstrated synergy with 5-FU in preclinical testing. Multiple clinical trials have evaluated oxaliplatin combined with 5-FU in a randomized setting. De Gramont and colleagues randomized 420 chemotherapy-naïve patients to infusional 5-FU/LV with or without oxaliplatin (85 mg/m 2 every 2 weeks). The combination group was found to have superior response rate (51% vs. 22%, P = .0001), PFS (9.0 vs. 6.2 months, P = .0003), and a trend toward improved survival (16.2 vs. 14.7 months, P = .12) It is likely that overall survival did not reach statistical significance because patients were allowed to cross over after disease progression occurred upon treatment with 5-FU.
In 2004, a randomized clinical trial compared FOLFOX6 versus FOLFIRI in the first-line setting. At the time of disease progression, 220 patients were randomized to the opposite regimen. For patients who received FOLFOX6 followed by FOLFIRI, the response rate was 54%, whereas in patients treated with FOLFIRI followed by FOLFOX, it was 56%. No statistically significant difference was found in either median PFS or OS between the groups. First-line FOLFOX6 yielded a PFS and OS of 8.0 months (95% confidence interval [CI], 6.2-9.4), and first-line FOLFIRI yielded a PFS and OS of 8.5 months (95% CI, 7.0-9.5). The decision to use one combination versus the other therefore rests in the hands of the treating oncologist and is individualized primarily on the basis of the adverse effect profile. Treatment with oxaliplatin is associated with high rates of neuropathy and thus should be used with caution in patients with poorly controlled diabetes or pre-existing neuropathy. Irinotecan is associated with a higher incidence of diarrhea and alopecia, which are important determinants of quality of life.
Once FOLFOX and FOLFIRI were established as the standard chemotherapy backbone for metastatic disease, the question of combining three chemotherapeutic agents arose. A total of 508 patients who were chemotherapy-naïve were randomized to FOLFIRI plus bevacizumab versus folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. In the FOLFOXIRI group, the response rate was increased from 53% to 65% ( P = .006), and PFS was increased from 9.7 to 12.1 months ( P = .003). There was a trend but a nonsignificant increase in OS from 25.8 to 31 months ( P = .054). The incidence of grade 3 and 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly increased in the FOLFOXIRI arm. This regimen is quite popular in Europe but is used sparingly in the United States at this time.
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