Department of Medical Oncology
Radboud University Nijmegen
Chemotherapy prolongs the median survival for patients with advanced colorectal cancer.(1) For decades, the standard treatment for patients with advanced colorectal cancer consisted of the intravenous (IV) infusion of 5-fluorouracil (5FU) and leucovorin (LV).(2) Schedules of 5FU/LV were given either as bolus or as continuous infusion. Although this may have had an impact on toxicity, no preference for a particular schedule was established in terms of prognosis, with median overall survival of approximately 11–12 months. In the past decade, significant advances have been made, with the development of new cytotoxic agents (irinotecan and oxaliplatin), oral fluoropyrimidines (capecitabine and uracil-ftorafur [UFT]) and signal transduction inhibitors (inhibitors of vascular endothelial growth factor [VEGF] and epidermal growth factor receptor [EGFR]).(3)
Irinotecan and oxaliplatin
The value of irinotecan as second-line treatment for 5FU-refractory patients has been established for several years,(4) and data from a randomised study have been published recently for oxaliplatin.(5) The obvious next step was to investigate their use in first-line combinations with 5FU/LV. Two studies with irinotecan plus bolus or infusional 5FU/LV compared with 5FU/LV alone showed a significant benefit in median overall survival (2.2 and 3.3 months, respectively).(6,7) However, these studies have been criticised because effective second-line treatment with irinotecan in the control arm was not a prospective part of the study design.(8) Therefore, although irinotecan combination was widely accepted as the new standard in first-line treatment at that time, the question of whether to give these drugs concomitantly or sequentially remained unanswered. Previous studies in which the addition of oxaliplatin to 5FU/LV was compared with 5FU/LV alone showed a benefit only in response rate and progression-free survival for the combination, but not in overall survival, for which endpoint these studies were not designed. A combination of infusional 5FU/LV and oxaliplatin (FOLFOX) was recently shown to prolong overall survival significantly compared with a bolus 5FU/LV/irinotecan regimen (IFL).(9) In many countries, these results have shifted the preference for first-line regimen to FOLFOX. The same criticism as that raised for irinotecan combination applies to this study, since 60% of patients received second-line irinotecan after failure on FOLFOX; however, due to its limited availability at the time of the study, only 24% of patients failing IFL received oxaliplatin. The finding that the difference in median overall survival (4.5 months) was much larger than the difference in median time to progression (1.8 months) also suggests that subsequent treatment had a significant impact on survival outcome. Furthermore, the different modes of 5FU administration between the two treatment arms (continuous versus bolus infusion) may have been responsible for the higher incidence of severe toxicities as well as the decreased efficacy in the IFL arm. This view is supported by the results of another study in which FOLFOX and infusional 5FU/LV plus irinotecan (FOLFIRI) had comparable results, although this study was not designed to assess survival as primary endpoint.(10)
Two important studies will provide a better insight into this ongoing debate. In the UK, the FOCUS study compares sequential versus concomitant treatment for irinotecan or oxaliplatin with 5FU/LV (modified de Gramont schedule) in separate treatment arms. The first results of this study do not show an advantage for combination therapy over sequential therapy.(11) The only study that prospectively evaluates the sequential versus concomitant use of all three effective agents (ie, a fluoropyrimidine, irinotecan and oxaliplatin) is the CAIRO study of the Dutch Colorectal Cancer Group (DCCG). In this study, the treatment with first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin is compared with first-line capecitabine + irinotecan and second-line capecitabine + oxaliplatin. Until the results of these two studies are available, the sequential use of these agents remains a valid option.
Studies on the combination 5FU/LV + irinotecan + oxaliplatin have been published.(12) No data are currently available to demonstrate a clear synergistic effect of this combination. The possible disadvantage of such a combination may be that the combined use of these drugs will not allow their administration at full dose and, therefore, will limit their dose intensity. It may be better for patients to be exposed to these drugs at any time during their treatment than for these drugs to be given concomitantly. This view is supported by a retrospective analysis showing that the median overall survival is increased in patients who have been exposed to 5FU/LV, irinotecan and oxaliplatin.(13)
Regarding the sequence of irinotecan and oxaliplatin, since approximately 30–40% of patients are not eligible for second-line treatment, one may argue that the best regimen (ie, most effective and/or least toxic) should be given first (if one wishes to give these agents in first-line at all; see above). The few patients who experience severe toxicity by irinotecan are likely to be hospitalised, whereas the majority of patients experiencing dose-limiting toxicity by oxaliplatin remain outpatients in most cases. In a recent study, patients were randomised between FOLFOX and FOLFIRI with a crossover upon progression.(10) The incidence of serious adverse events was higher in patients treated with FOLFIRI (14% versus 5%), but overall incidence of grade 3–4 toxicities and percentage of patients that had to discontinue treatment for toxicity reasons was greater upon treatment with FOLFOX (74% versus 53%, and 11% versus 6%, respectively). This study did not demonstrate any difference in progression-free, overall survival or first-line response rates. A small difference in favour of FOLFOX was noted in second-line response rate, but this could be because second-line FOLFIRI after failure on FOLFOX may be inferior to irinotecan monotherapy. Since there is no rationale to combine irinotecan with 5FU/LV after previous exposure to 5FU/LV, irinotecan monotherapy may be preferred, as it allows a higher irinotecan dose-intensity compared with FOLFIRI. Current data suggest that the choice of either irinotecan or oxaliplatin for first-line therapy can be made on individual patients preferences.
Oral agents, such as capecitabine and UFT/LV, are an important development in the treatment with fluoropyrimidines. Both agents have shown comparable results in overall and progression-free survival, but with improved tolerability to bolus 5FU/LV.(14–19) The two studies involving capecitabine showed a significantly superior overall response rate for capecitabine.(19) With capecitabine, significantly lower incidence rates of stomatitis, diarrhoea, nausea, alopecia, neutropenic fever/sepsis and treatment-related hospitalisation rate were observed compared with bolus 5FU/LV. Capecitabine treatment was associated with a higher incidence of hand–foot syndrome and uncomplicated hyperbilirubinaemia. Compared with 5FU/LV, UFT/LV was associated with less stomatitis, diarrhoea, nausea/vomiting, myelosuppression including neutropenic fever and documented infection. Similarly to capecitabine, uncomplicated hyperbilirubinaemia was observed with UFT/LV. Given its earlier availability and its easier dosing schedule (twice versus three times daily), capecitabine is currently being used more frequently in colorectal cancer than UFT/LV. As is the case with any oral agent, when compared with IV administration, patient compliance is more of an issue, and this aspect should receive appropriate attention in patient education. Combination studies of capecitabine with irinotecan or oxaliplatin have shown promising response rates,(20,21) but data from randomised studies have not yet been released. Finally, preliminary results of a randomised phase II study of capecitabine administered in combination with either irinotecan or oxaliplatin do not suggest superiority in terms of feasibility or response rate for either regimen.(22)
Signal transduction inhibitors
Two agents of this class of drugs have recently been approved: cetuximab, an antibody against EGFR, and bevacizumab, an antibody against VEGF. Although conflicting data have been published regarding the prognostic significance of the expression of EGFR and VEGF on colorectal cancer cells, efficacy data from their respective inhibitors have been presented.
Cetuximab blocks the binding of EGF to its receptor and enhances the effects of chemotherapy by inhibiting cell proliferation, tumour neoangiogenesis and metastatic potential, as well as promoting apoptosis. Although some activity has been demonstrated when given as a single agent,(23) pivotal data were derived from a trial in which cetuximab alone was randomised versus cetuximab + irinotecan in 329 irinotecan-refractory patients.(24) Time to progression and response rates were significantly better for the combination (4.1 versus 1.5 months, and 23% versus 11%, respectively). Overall survival did not differ between the two treatment arms, probably due to a design that allowed crossover.
Bevacizumab inhibits tumour neoangiogenesis by blocking VEGF. It was tested versus placebo in combination with the bolus 5FU/LV/irinotecan (IFL) regimen in 815 previously untreated patients.(25) Median overall survival was significantly improved by almost five months (from 15.6 to 20.3 months), as were progression-free survival (from 6.2 to 10.6 months) and response rate (from 35% to 45%).
Several obvious questions can be raised. Is one positive trial sufficient for a definite proof of efficacy? How does the efficacy of these agents relate to the expression of their respective targets on the tumour? Will they have comparable efficacy in combination with other chemotherapy regimens? Are we currently employing their most effective doses and schedules? Could these agents have a role as maintenance treatment in responding patients? Why should colorectal cancer be a good target for bevacizumab? What is the correlation between EGFR expression on (primary or metastatic) tumour tissue and response to cetuximab?
Confirmatory data on the efficacy of bevacizumab and cetuximab should be available soon. Based on current (limited) data, it is impossible to give any recommendation on their use outside the setting in which they have been developed.
New agents have significantly increased the median overall survival in patients with advanced colorectal cancer, and survival times of 21 months have been reported in randomised trials with 5FU, irinotecan and oxaliplatin.(10) With more data available on the use of oxaliplatin and irinotecan, more options are open for systemic treatment. Further results from ongoing studies are needed before any regimen or schedule can be regarded as optimal in a given situation. Individual preferences or the medical condition of the patient may play an important role in the choice of a particular treatment. Oral fluoropyrimidines are likely to replace IV 5FU/LV schedules in combination therapy and, currently, they are the best alternative to 5FU/LV monotherapy. Pharmacogenomics may prove a valuable tool in the selection of patients with the best chance for response or with a high likelihood of toxicity from a probably ineffective treatment.(26) Very promising data have been published for anti-VEGF and anti-EGFR therapy. These data, however, need further confirmation before these agents can be largely accepted. Better patient selection criteria should also become available for these classes of agents. Promising preliminary data have been published on the combined use of these drugs.(27) The availability of several effective but expensive new drugs in such a common tumour type as colorectal cancer will have an enormous impact on healthcare budgets.(28)
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