Eric Van Cutsem
Digestive Oncology Unit
University Hospital Gasthuisberg
In recent years, many important new treatment options have been developed that changed the outcome for patients with colorectal cancer (CRC). Therapeutic milestones have included:
- Improved use of 5-fluorouracil (5-FU).
- Introduction of the new cytotoxic agents irinotecan and oxaliplatin, initially as second-line therapies, then as part of first-line combinations, and more recently in the adjuvant setting.
- The development of oral fluoropyrimidines and of several novel targeted agents.
Infusional 5-FU regimens
Intravenous (IV) 5-FU, which has been in clinical use for at least 40 years, has antitumour activity in a range of malignancies, including CRC. Its activity can be enhanced via modulation with folinic acid (FA). A number of IV 5-FU schedules have been developed. Infusional regimens are generally a better way of administering 5-FU; they appear to be less toxic, induce a higher response rate (RR) and show a longer time to progression (TTP) than bolus schedules. However, infusional regimens do not seem to have a significant survival advantage and have more technical requirements than bolus administration. In Europe, infusional 5-FU regimens are now widely used.(1–3)
New cytotoxic agents:new second-line treatment
The late 1990s saw the emergence of two important new cytotoxic agents in the treatment of metastatic CRC (mCRC), the topoisomerase-1 inhibitor irinotecan and the third-generation platinum oxaliplatin. It has been shown that irinotecan increases the overall survival and improves the quality of life of patients with mCRC resistant to 5-FU.(4–7) Several studies also showed the activity of oxaliplatin in 5-FU- or irinotecan-refractory CRC.(8–10)
New cytotoxic agents: first-line combinations
The next step was to combine irinotecan or oxaliplatin with 5-FU/FA. Several large studies have shown that the combination of irinotecan plus 5-FU/FA,(11–13) and of oxaliplatin plus 5-FU/FA,(14–16) was more active than 5-FU/FA alone. The RR is higher and the time to tumour progression, progression-free survival and overall survival are longer when patients with mCRC are treated with one of these combinations, compared with 5-FU/FA alone. Although the number of adverse events is higher, the toxicity is acceptable and the tolerance is good in experienced hands.
Oral fluoropyrimidines are likely to have an increasing role in the treatment of mCRC. Although several of these agents are now entering clinical use, most of the available data so far are for capecitabine. A precursor of 5-FU, capecitabine undergoes two enzymatic conversions in the liver, then a third and final conversion to 5-FU at the tumour site by thymidine phosphorylase (TP). This enzyme is present at high levels in tumour tissue, which explains why much higher 5-FU levels are reached in tumour tissue than in normal tissue after treatment with capecitabine.(17)
Two large studies in mCRC(18,19) showed that RR was higher with oral capecitabine than with IV 5-FU/FA, and that TTP and survival rates were identical.(20) The activity of tegafur/uracil (UFT) in combination with FA is comparable to that of IV 5-FU/FA. Phase II studies have shown a promising activity of the combination of oral fluoropyrimidines with irinotecan and oxaliplatin.(21–25) Phase III studies will demonstrate whether IV 5-FU/FA can be completely replaced by oral fluoropyrimidines in combination regimens with irinotecan and oxaliplatin.
Novel targeted agents
The epidermal growth factor receptor (EGFR) is an important therapeutic target to which several classes of agents are being directed. These include monoclonal antibodies (MAbs), such as cetuximab and panitumumab, and small-molecule EGFR tyrosine kinase inhibitors, such as gefitinib, erlotinib and EKB-569. Studies showed encouraging results for cetuximab in combination with irinotecan in patients with irinotecan-refractory, EGFR-positive mCRC, which led to the registration of cetuximab in patients with EGFR-expressing irinotecan-refractory CRC. An objective RR of 23% has been demonstrated in this setting.(26–28) Cetuximab monotherapy was also active in this setting, although to a lesser extent.(29–31) Phase II studies have now shown the promising activity of cetuximab with irinotecan/5-FU/FA or with oxaliplatin/5-FU/FA in patients with previously untreated mCRC.
Several classes of angiogenesis inhibitors are under development, many of which target the vascular endothelial growth factor receptor (VEGF). Drugs being studied include bevacizumab, the recombinant human MAb against VEGF. It has been shown that the addition of bevacizumab to a standard regimen of irinotecan/5FU/FA increases RR, TTP and survival rates in patients with mCRC, compared with a regimen of irinotecan/5-FU/FA alone. Several phase II studies also suggest that bevacizumab increases the activity of 5-FU. Results of the studies of oxaliplatin/5-FU/FA in combination with bevacizumab are eagerly awaited.(32,33) Randomised studies are also ongoing with the oral small-molecule VEGFR tyrosine kinase inhibitor vatalanib (PTK787) in combination with cytotoxic treatment.
Another potential therapeutic target is the cyclooxygenase-2 (cox-2) enzyme. Several cox-2 inhibitors have been developed, with celecoxib being the most widely investigated. Although most of the relevant research has been preclinical, a placebo-controlled study in 77 patients with familial adenomatous polyposis showed that high-dose celecoxib significantly reduced the number and size of residual adenomatous polyps in the rectum after partial colectomy.(34) Celecoxib has also demonstrated a dose-dependent inhibition of lung metastases in the HT29 human colon carcinoma model. There is also some evidence that the cox-2 enzyme may have a prognostic role in the adjuvant setting. A randomised phase III trial in mCRC using a 2 x 2 factorial design is being carried out by the European Organisation for Research and Treatment of Cancer (EORTC) to compare the efficacy of infusional 5-FU/FA versus oral capecitabine, each in combination with irinotecan with or without celecoxib.
There are now ample data showing that chemotherapy significantly prolongs median survival and improves quality of life compared with best supportive care alone in CRC. Available evidence suggests that infusional 5-FU regimens have a better benefit/risk ratio than bolus schedules. Integration of the new agents irinotecan and oxaliplatin into treatment has led to further improvement in TTP, survival and quality of life. Irinotecan and oxaliplatin are now regarded as essential therapeutic agents in CRC, and both are active as first- and second-line treatment of mCRC. With appropriate selection, a median survival of approximately 18 months can now be reached in mCRC.
To investigate whether this benefit can be extended to patients with earlier disease, a series of multicentre trials are randomising stage II/III colon cancer patients to adjuvant 5-FU/FA regimens with and without irinotecan or oxaliplatin.
The activity of oral fluoropyrimidines (the most active of which is currently capecitabine) in mCRC is comparable to that of IV 5-FU regimens. Combinations of oral fluoropyrimidines with irinotecan or oxaliplatin are feasible, and early data show promising activity.
Novel targets, including EGFR, VEGF and the cox-2 enzyme, are presently under investigation in CRC. It has already been shown that cetuximab, panitumumab and bevacizumab impact on the outcome for patients with metastatic disease. Molecular markers may also prove to be important for response prediction and as prognostic markers. Further investigations are clearly needed with regard to appropriate patient selection to optimise efficacy and, hopefully, to minimise toxicity with the combination therapies now available, as well as to determine the optimal treatment strategy.
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