Though the incidence of colorectal cancer is dropping, colorectal cancer remains the third most common cancer in the United States, as well as the third leading cause of cancer death. While the outcome of those patients diagnosed with early stage disease remains very good, with 5-year survival of 70-90%, only 12.5% of those patients diagnosed with metastatic disease are alive at 5 years[1]. For those patients who present with limited metastatic disease, in particular hepatic metastasis, there is compelling data to support that aggressive treatment of the primary tumor as well as the hepatic metastasis improves outcomes. Advances in chemotherapy over the last decade have allowed for broadening of the definition of resectability, potentially extending this benefit in outcomes to a larger proportion of our colorectal cancer patients. While the optimal chemotherapy cocktail is not firmly established, 6 months of peri-operative FOLFOX has been demonstrated to improve progression free survival in those patients who present with initially resectable disease[2]. Those patients with initially resectable disease should generally be treated with the minimal necessary duration of neo-adjuvant chemotherapy, given that an increase in major responses is generally not observed after more than 8 cycles of chemotherapy, though with further treatment, rates of hepatic toxicity continue to rise[3]. Thus, it is critical to involve a surgical oncologist early in the treatment planning for these patients.
A larger proportion of patients present with unresectable hepatic-only or hepatic-predominant metastatic disease. In this group of patients, there may remain a hope of conversion to resectability through systemic therapy. Admittedly, with the current armamentarium of chemotherapy, many patients will not become resectable. Investigations of regimens beyond FOLFOX have recently been reported. At the 2013 ASCO Annual meeting, the initial results of the TRIBE trial were reported, comparing FOLFOXIRI + bevacizumab with FOLFIRI + bevacizumab. While response rates and progression free survival were significantly increased, rates of R0 resection were no different between the two regimens. This is in contrast to earlier reports suggesting marked improvement in rates of conversion to resectability through use of FOLFOXIRI. At the same meeting, the data from FIRE-3 was presented, supporting increased response rates through the addition of cetuximab rather than bevacizumab to FOLFIRI. However, again in contrast to other reports, the EPOC study of peri-operative FOLFOX +/- cetuximab in patients with initially resectable hepatic metastasis actually demonstrated inferior progression free survival with the addition of cetuximab, though a trend toward improved response rates was maintained. It is important to point out that these data are still immature and have not yet undergone peer review. However, as a standard is yet to be established, multiple chemotherapeutic options remain available. Either way, it stands that a large portion of patients will not undergo resection of their disease with current options.
Our center is currently part of a multi-center trial evaluating the addition of radioembolization (SIR-spheres) to initial FOLFOX-based chemotherapy for patients with unresectable liver only or liver-predominant metastatic colorectal cancer. The FOXFIRE trial, as it is known, offers an intriguing new option for our patients with liver-predominant metastatic disease. While two radioembolization treatments, Yttrium-90(90Y)-labeled resin microspheres (SIR-spheres) and 90Y-labeled glass microspheres (Therasphere), are utilized in the United States, use has typically been limited to this population of patients after failure of standard chemotherapies, in the refractory setting. It is hoped that the addition of this therapy to initial chemotherapy will increase long-term disease control, response rates and potentially hepatic resection rates.
References
[1]Siegel, R., et al., Cancer statistics, 2014. CA Cancer J Clin, 2014. 64(1): p. 9-29.
[2]Nordlinger, B., et al., Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet, 2008. 371(9617): p. 1007-16.
[3]Kishi, Y., et al., Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol, 2010. 17(11): p. 2870-6.