CHICAGO-An overview of studies attests to the efficacy and safety of the combination of capecitabine(Drug information on capecitabine) (Xeloda) and oxaliplatin(Drug information on oxaliplatin) (Eloxatin) for the treatment of colorectal cancer and liver metastases that frequently develop after resection of the primary tumor. Additional studies are required, however, to determine the optimal dosing regimen and address quality of life and other issues. Data and implications from previous and ongoing studies and directions for future studies were presented at a symposium on integrating capecitabine in the management of colorectal cancer, sponsored by Roche and held in conjunction with the American Society of Clinical Oncology annual meeting. Charles Blanke, MD, of the Oregon Health Science University in Portland reviewed the rationale for combining capecitabine and oxaliplatin. "Both drugs have single-agent activity. There is very little overlap in the key toxicities," he said. "There is evidence of improvement when combining the drugs in humans. When you add oxaliplatin to fluorouracil(Drug information on fluorouracil) (5-FU) and leucovorin (LV), you can improve response rate and time to disease progression." Meaningful Response Rates Phase II studies of FOLFOX regimens (fluorouracil [5-FU], leucovorin, oxaliplatin) in previously treated colorectal cancer demonstrate clinical evidence of synergy, Dr. Blanke noted. The response to FOLFOX as second-line therapy in patients who had already failed chemotherapy generally tended to be quite high. "And if we add in the patients with stable disease, then tumor control exceeded 90% on a couple of the trials," he reported. "Median survival was also very striking for second-line therapy, as well. In several studies, patients actually got oxaliplatin added to the exact same 5-FU drug regimen they had already failed, and there was still a meaningful response rate, ranging from 25% to 50%. In the de Gramont trial (J Clin Oncol 18:2938, 2000), once again the 5-FU regimen was improved dramatically with the addition of oxaliplatin-the objective response rate doubled, and progression-free survival improved in a superior fashion." Phase II studies tested capecitabine plus oxaliplatin (XELOX) in a every- 3-week schedule of capecitabine 1,000 mg/m2 twice daily for 14 days and oxaliplatin 130 mg/m2 day 1, or capecitabine 1,250 mg/m2 twice daily plus oxaliplatin 120 mg/m2. The objective response rate was 17% to 55%. Severe toxicities mainly occurred at higher doses that would generally not be used in practice. A phase II Swiss study enrolled 43 nontreated patients and 26 fluoropyrimidine- resistant patients. They received capecitabine 1,250 mg/m2 twice daily plus oxaliplatin 130 mg/m2. "Patients who did not receive prior therapy had a response rate of about 50%," Dr. Blanke reported. "Adding stable disease, about two-thirds of the patients had control of tumor. And median survival was also remarkable at 17 months. With those who had received previous therapy, tumor control was 50%. Median survival was 11.5%." Differing Results In an international phase II trial (Tabernero J, et al) using XELOX as first-line therapy in about 100 patients with metastatic colorectal cancer, capecitabine was started on the evening of day 1 of oxaliplatin, and given through the morning of day 15. "Again the combination was very effective," Dr. Blanke said. "Response rate was the primary objective, and it was 55%; tumor control was 86%; and progressionfree survival exceeded 7 months. Responses were seen in all groups regardless of prior treatment status, age, and performance status. The toxicity profile was fairly manageable." Interestingly, a US trial by Karmanos with untreated patients (not yet published) used dosing similar to the international study mentioned above. The only real difference in this study was that capecitabine was given at the same time as oxaliplatin- rather than being started later the same evening. "There was however, unexpected toxicity and lowered efficacy in this trial, " Dr. Blanke said. Then the capecitabine dose was reduced. "The objective response rate was lower than in other trials," he continued. "It was about 40%, but not the 50+% that was seen in the other trials. Interestingly, even with the lower dose, progression-free survival was very similar to what we've seen before-about 7 months. The toxicity profile was what we would expect once the diarrhea went away with the lowered dose." Why did the drug work with the European study, but not with the American study? The investigators speculated that perhaps because capecitabine was started before rather than after oxaliplatin, there may have been an unexpected direct interaction among the two drugs; or perhaps European colleagues were more rigorous in dose adjustments or patient monitoring. Ultimately the investigators agreed to use the 1,000 mg/m2 twice-daily dose instead of the 750 mg/m2 twice-daily dose, but strongly suggested that patients and hospitalizations be carefully monitored. Need to Incorporate Quality of Life Measures Commenting on the direction of future studies, Dr. Blanke said, "I think that capecitabine could theoretically replace infusional 5-FU in combination regimens with oxaliplatin. It is very likely that it will be a more convenient regimen than those incorporating infusional 5-FU because patients have to come in for treatment less frequently. There is no need for a central line or an infusion pump." "However, I would strongly argue at this point that we don't yet know the best dosing regimen, and we clearly need phase III trials for two reasons: we need to determine the best dose, and we need to see if capecitabine can really replace infusional 5-FU. And future trials should incorporate quality of life measures because that is an important benefit of the capecitabine/ oxaliplatin combination." Use in Liver Metastases About half of all patients who develop a recurrence after resection of the primary tumor in colorectal cancer go on to develop a recurrence in the liver. "This occurs in about 50,000 patients each year," noted Roy Smith, MD, of the National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh. "The 5-year survival after surgical resection of one of those hepatic metastases is about 37% if the patient had one metastasis, 34% if two metastases, and only 14% if there were three or more metastases. Once a metastasectomy is performed, about 40% of recurrences after resection are restricted to the liver. So it is important that adequate therapy be developed for patients who have isolated liver metastases because upon recurrence these patients may still be curable.' Systemic chemotherapy is presently of uncertain benefit. The rationale for using liver-directed chemotherapy with floxuridine (FUDR) is that it is 90% extracted by the liver on the first pass. The results of a series of well-designed clinical trials also justify the use of hepatic arterial infusion (HAI) of FUDR. "Newer combinations seem to have increased the response rate, both at non-liver sites as well as at the liver. These types of observations lead us to reconsider how best to treat patients with isolated liver metastases," Dr. Smith "Capecitabine may play a major role in the future treatment of patients with isolated liver metastases. The use of HAI for treatment of isolated hepatic metastases is based on the fact that liver metastases, if greater than 3 mm, are generally fed by the hepatic artery, whereas normal hepatic sites are fed by the portal venous system. Therefore, giving HAI can achieve high concentrations of cytotoxic agents at the tumor site, while theoretically sparing normal liver tissue. In addition, being selective in the type of drug used can achieve high concentrations due to the first-pass mechanism, and with total body clearance protecting other sites of the body from cytotoxicity. explained." Systemic Therapy A number of phase II trials have looked at systemic therapy vs alternatives such as HAI with FUDR, 5-FU, or other drugs. "Looking at about 10 studies in total, there does seem to be an improvement over systemic therapy, and there also seems to be an improvement with HAI in median survival," Dr Smith said. "However, there have been two metaanalyses and they draw into question whether there has really been any improvement at all, and whether the findings significance. In terms of hepatic progression- free survival, initially there was an impressive difference for HAI, but after 5 years of follow-up that advantage has largely disappeared. The benefit is transient, and needs to be improved upon." The necessity for an hepatic artery catheter is also a disadvantage of HAI and another reason to look for newer agents. "Two agents that may play an important role in treatment of this disease are oxaliplatin and capecitabine," said Dr. Smith. "Oxaliplatin may play a role for obvious reasons, and capecitabine because it can mimic continuous infusion 5-FU; furthermore, evidence that thymidine phosphorylase (TP) has increased activity in normal liver tissue as well as in colorectal malignant tissue is an added reason for considering this combination. By using capecitabine, theoretically we should have a concentration effect in the liver and in the metastatic disease located within the liver." Twocurrent trials share basic premises. "The first premise is that there is a modest advantage with HAI, and alternating HAI with another therapy offers a small additional advantage. Right now it is FUDR and 5-FU, but it could be something else in the future," Dr. Smith said. The second premise is the demonstrated efficacy of tolerability of combinations of oxaliplatin and capecitabine in the treatment of metastatic disease at other sites, as well as in the liver. Increased TP levels in the liver and in metastases may offer an advantage due to increased concentrations of 5-FU when patients are exposed to capecitabine. "Third, it may be possible to eliminate HAI from the treatment template," Dr. Smith said. "There is very little evidence that it prolongs survival. Finally, the identification and introduction of an innovative systemic therapy might bring additional benefit to what little benefit exists with intrahepatic FUDR." Other Trials Proceeding The North Central Cancer Treatment Group (NCCTG) is conducting two trials, a phase II trial and a randomized phase III trial, to evaluate these suppositions. Patients with resected-liver-only metastases from colorectal cancer are evaluated for safety, 2-year survival, 2-year recurrence rate, and time to recurrence. The treatment paradigm is FUDR at 0.2 mg/kg/d on days 1 to 14, 1 week rest, then capecitabine/ oxaliplatin over the next 14 days (see Figure 1). Over the course of the trial, patients developed significant gastrointestinal toxicity and for this reason the dose of capecitabine has been reduced from 1,000 mg/m2 to 850 mg/m2 twice daily. A NSABP trial with an accrual goal of 400 patients will treat patients with either surgical resection or some type of ablation, then randomize patients to either a treatment arm that received capecitabine plus oxaliplatin systemically, or an arm that receives capecitabine plus oxaliplatin plus FUDR by HAI. This trial will compare progression-free interval, overall survival, liver disease-free interval, and treatment toxicity, and examine molecular markers. "We believe that the use of systemic chemotherapy with capecitabine plus oxaliplatin will improve overall survival and both hepatic and systemic disease-free survivals," Dr. Smith said. "It is also likely that the addition of regional therapy with FUDR by HAI techniques will further improve hepatic disease control, diseasefree survival, and overall survival. Should we find that both arms of the trial have similar benefits and adverse event profiles, we can then select the more convenient or cost-effective arm as a template for future trials that investigate the treatment of patients with isolated hepatic metastases." In summarizing, Dr. Smith remarked, "Patients with resected liver metastases from colorectal cancer have poor survival and high recurrence rates. HAI with FUDR is marginally better than systemic 5-FU, and even that advantage is debatable. Alternating HAI with 5-FU and FUDR seems to be better than 5-FU alone, but this conclusion is derived from a trial that is sorely underpowered. "TP is active in normal liver and liver metastases, capecitabine is activated in colorectal cancer tissue, and a capecitabine/ oxaliplatin combination appears to be effective in colorectal cancer, and fairly well tolerated. Based on these data, the NCCTG and NSABP have undertaken these two combined projects to try to change the paradigm in the treatment of patients with isolated hepatic metastases that have been resected," Dr. Smith concluded.