Fluorouracil (5-FU) has been the mainstay of treatment for colorectal cancer in the US for the past 40 years, primarily because no other agents with significant activity in colorectal cancer have been available. As a result, researchers focused on optimizing 5-FU therapy with two main strategies. The first was to add agents to 5-FU in a logical, biologically-based fashion that generates an enhanced anticancer response. Agents tested include leucovorin, methotrexate(Drug information on methotrexate) (Folex, Mexate),[2,3] trimetrexate(Drug information on trimetrexate) (Neutrexin), PALA (Sparfosate sodium), IUdR, AZT, interferon, and many others. This strategy of biochemical modulation succeeded in generating improvements in response rates over single-agent 5-FU.
The second major avenue of research altered the treatment schedule for 5-FU. Traditionally, 5-FU was administered as a bolus infusion and, consequently, was associated with a distinctive efficacy and side effect profile. However, when 5-FU is infused over a prolonged period, an alternate efficacy and toxicity profile emerges. An extreme example of this strategy is the use of chronomodulated infusional 5-FU in an attempt to take advantage of diurnal variations in the metabolism of this agent.
Multiple studies, including meta-analyses, have been performed comparing bolus schedules of 5-FU with prolonged infusion schedules in colon cancer patients.[12,13] The evidence suggests that infusional schedules are less toxic, have higher response rates, and improve survival, compared with bolus schedules (Table 1). Major reasons for the lack of widespread use of continuous infusion 5-FU center around the inconvenience of prolonged infusion therapies and enhanced physician and patient care demands. The development of an orally bioavailable compound may circumvent these problems and lead to superior therapy for patients with colon cancer.
Because it is rapidly and inconsistently metabolized by dihydropyrimidine dehydrogenase (DPD), it is not feasible to use 5-FU orally. Several approaches have been pursued in an attempt to bypass DPD metabolism and create an orally bioavailable compound. One approach involves the use of agents that inhibit or compete directly with DPD and, in a sense, "level the playing field" so that 5-FU becomes orally bioavailable.[14,15]
The agent capecitabine(Drug information on capecitabine) (Xeloda) approaches this problem in a different way. This compound was designed to be resistant to DPD metabolism in its native form. However, through a series of enzymatic steps within the body and a final step within tumor cells, capecitabine is metabolized to become 5-FU. Essentially, it is selectively activated within tumors as 5-FU, resulting in reduced systemic exposure and toxicity while maintaining high concentrations of intratumoral 5-FU.
There is considerable interest and debate surrounding the history of these oral 5-FU agents, and in this article, I will review the development and clinical experience of capecitabine in colorectal cancer. The successful evolution of these compounds has resulted in a more convenient method of administering 5-FU, a lower toxicity profile, and a significantly higher response rate in patients with metastatic colon cancer when compared to IV 5-FU.
Three phase I trials of single-agent capecitabine using three different treatment schedules were performed in patients with a variety of malignant tumors. One involved prolonged continuous exposure using twice-daily dosing without interruptions. A second used capecitabine alone in a 2-week-on and 1-week-off schedule. The third used a similar intermittent schedule, but with the addition of leucovorin. These studies found that the intermittent schedules allowed administration of higher doses of capecitabine but resulted in greater hand-foot syndrome. Diarrhea was reported as the dose-limiting toxicity in all treatment schedules.
An early clinical trial was performed in patients with colon cancer to prove that (1) the key activating enzyme, thymidine phosphorylase (TP), is indeed overexpressed within tumors as compared to normal tissues, and (2) that capecitabine is selectively activated within tumors resulting in higher 5-FU concentrations. The study was designed to treat patients who were scheduled to undergo resection of either their primary colon cancer or a metastasis with a preoperative course of capecitabine 2500 mg/m2 split into two daily doses for 5 to 7 days. Resections were performed within 12 hours after administration of the last dose.
Phase I Results
The resected specimens were then analyzed for levels of TP and 5-FU. Comparisons were made between tumor, and surrounding normal tissue, and plasma. The results strongly support the theory that capecitabine is selectively activated within tumors. First, tumor tissues markedly overexpress TP when compared to normal tissues (with the exception of normal liver, which also express high levels of TP). In an exact parallel, 5-FU levels were markedly higher in tumors compared to surrounding tissue and plasma, and again, the liver was the exception with fairly high levels of 5-FU. In fact, when the concentrations of 5-FU in tumor were compared to those within the plasma, a twenty-fold increase in 5-FU was found within tumors (Figure 1).
These data have been compared to similar analyses of IV 5-FU, which demonstrated that, following intravenous administration of 5-FU in colon cancer patients, there are higher concentrations of 5-FU in circulating plasma than in the tumor. Therefore, this study strongly supported the importance of mechanisms of selective activation and increased delivery of 5-FU to the tumor.
As reviewed above, several schedules emerged from the phase I trials, each having advantages and disadvantages. In order to define the optimum schedule to carry forward into more definitive phase III trials, a randomized phase II trial was performed comparing the three leading schedules of capecitabine in colorectal cancer. A summary of the trial design is shown in Figure 2. This trial was performed in patients with metastatic colon cancer who had received no previous therapy. Patients were randomized to one of three schedules of capecitabine. The end points of the trial were response rates and toxicity, and an analysis for dose intensity was also performed.
Results demonstrated no difference in survival among the three treatment arms. However, there was significant improvement in time to disease progression in the patients who received capecitabine alone on an intermittent schedule as seen in Table 2. As predicted, the higher dose, intermittent schedules resulted in greater toxicity, particularly diarrhea and hand-foot syndrome, when compared with the lower-dose continuous infusion schedule. The intermittent schedule without leucovorin was selected for the phase III randomized trials based on the improved time to disease progression, the higher dose intensity, and the better therapeutic index associated with that regimen.
Two phase III trials were conducted comparing capecitabine to intravenously administered 5-FU and leucovorin in patients with previously untreated metastatic colorectal cancer. One trial was performed primarily in Europe and the other, primarily in North America. The design of the trials was identical and each was powered to show equivalence in overall response rate between capecitabine and IV 5-FU/leucovorin. Secondary objectives included a comparison of the toxicity, time to disease progression, overall survival, time to response, quality of life, and duration of response.
At the time the trials were designed, the standard of care for front-line treatment of metastatic colon cancer was the Mayo Clinic schedule of 5-FU and leucovorin5-FU 425 mg/m2 plus leucovorin 20 mg/m2 administered intravenously for 5 days every 28 days. This regimen was therefore selected as the control arm for both of these studies. The standard criteria for phase III randomized trials in this disease population established eligibility for these studies. Tumor responses were analyzed by the investigators and by an independent group of radiologists, who were blinded. Tumor assessment was based on WHO criteria.