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Colorectal cancer (CRC) is the third most common cancer in the USA, with approximately 145,000 new cases expected in 2005.(1) Estimated five-year survival rates range from 90% for patients with stage I disease to <10% for patients with advanced colorectal cancer.(1) Until recently, 5-fluorouracil (5-FU)-based therapy was the only treatment commonly used for palliative care in patients with metastatic CRC (mCRC); however, this treatment has a limited impact on survival.(2-5) Compared with bolus FU/leucovorin (LV), prolonged infusion of 5-FU in combination with the biomodulator LV improves safety and efficacy profiles.(6,7) The introduction of irinotecan led to an effective second-line treatment for those patients who progressed after 5-FU-based regimens.(8) The addition of irinotecan to 5-FU plus leucovorin (IFL) also improved the survival of previously untreated patients with advanced disease.(9,10) Oxaliplatin (1-OHP), a diaminocyclohexane platinum complex, demonstrated activity as a single agent(11) and in combination with fluoropyrimidines.(12-14) including the oral fluoropyrimidine capecitabine, in a convenient and safety-chronomodulated regimen.(15-18) There have been dramatic changes in the medical treatment of CRC during the past five years, making such treatment considerably more complex than previously and with much more to offer mCRC patients. The development of “targeted” drugs for the treatment of CRC is in progress and so far the monoclonal antibodies bevacizumab (BV) and cetuximab (CX) are clearly in the lead, with justified use in some clinical situations. Recent progress in CRC treatment stems from the new “targeted” and the “old” cytotoxic drugs individually and their combined use to produce optimal activity. Bevacizumab and cetuximab provide clinically relevant yet marginal patient benefit at high costs, making their routine use in the large populations of mCRC patients difficult.
Bevacizumab in mCRC
Randomised studies have investigated the effects of bevacizumab in combination with 5-FU/LV and IFL as first-line therapy and in combination with FOLFOX and cetuximab/irinotecan as second-line therapy.
In a phase II study, 104 patients were randomised to bolus 5-FU/LV alone or 5-FU/LV in combination with low- (5mg/kg every two weeks) or high-dose (10mg/kg every two weeks) bevacizumab.(19) Compared with 5-FU/LV alone, addition of low-dose bevacizumab improved the efficacy (see Table 1). High-dose bevacizumab produced intermediate results. Crossover from 5-FU/LV to high-dose bevacizumab alone produced partial response (PR) in two out of 22 patients. Increased and potentially severe toxicity (hypertension and thrombosis) was observed with addition of bevacizumab, and epistaxis was seen in approximately half of the patients on bevacizumab.
In another phase II study, 209 patients not considered optimal candidates for first-line irinotecan-containing therapy were randomised to bolus 5-FU/LV alone or 5-FU/LV combined with low-dose bevacizumab.(20) Thirty-eight percent of the patients in the bevacizumab group and 46% in the placebo group received oxaliplatin and/or irinotecan following first-line 5-FU/LV. Addition of bevacizumab significantly prolonged progression-free survival (PFS) but not tumour response rate or overall survival (OS) (see Table 1). Ten percent of the bevacizumab patients had a grade 3–4 arterial thrombotic event.
In a pivotal trial, 813 patients were randomised to IFL or IFL in combination with low-dose bevacizumab.(21) Initially, the trial also included a third arm, in which patients were treated with 5-FU/LV/bevacizumab but this arm was terminated after a safety analysis. Mean patient age for the study was only 59 years and approximately 55% of the patients had ECOG performance status 0 (see Table 1). Although approximately 55% of patients in both treatment groups had postprogression chemotherapy,(22) second-line therapy OS was significantly prolonged for all patients (20.3 months vs 15.6 months). Survival improvements were also observed in the subgroup receiving oxaliplatin as second-line treatment (25 months vs 22 months) and in patients who did not receive second-line oxaliplatin (20 months vs 16 months). The combination arm was significantly more toxic, with grade 3/4 adverse events in 85% vs 74% of patients. However, there was no difference with respect to fatal adverse events. Outstanding and potentially serious adverse effects in the bevacizumab arm were hypertension in 22% (grade 3 in 11%) and gastrointestinal perforation in 1.5%. There was no clear difference in thromboï¿½’embolic events, serious bleeding or proteinuria, in contrast with the few cases of severe bleeding observed in nonsmall-cell lung cancer patients treated with bevacizumab in combination with chemotherapy.(23) Data from this trial have been further analysed, showing prolonged survival in multiple subgroups.(24) There was no increased risk of bleeding in patients in the bevacizumab arm who were on full-dose anticoagulation due to thrombosis emerging during the trial.(25) Compromised wound healing or increased bleeding were observed for primary bevacizumab compared with the IFL-alone arm.(26) An increase in wound healing/bleeding complications, from 0/25 patients in the IFL arm to 4/40 patients in the bevacizumab arm, was observed when surgery was performed closely to bevacizumab/IFL treatment.(27) Bevacizumab did not increase venous thromboï¿½’embolism whereas arterial thromboembolism was increased, from 1% to 3% in the pivotal trial and from 5% to 10% in the trial on less fit patients receiving 5-FU/LV alone or 5-FU/LV/bevacizumab.(28)
Chen et al studied the efficacy of the combination of bolus or infused 5-FU/LV and low-dose bevacizumab in patients progressing after irinotecan- and oxaliplatin-based regimens.(29) The response rate of approximately 2% and median TTP of 3.7 months indicate very limited activity of this combination in this setting.
Giantonio et al randomised 579 patients previously treated with 5-FU/LV and irinotecan to FOLFOX (FU/LV/oxaliplatin) alone or in combination with high-dose bevacizumab.(30) OS was significantly improved (12.5 months vs 10.7 months) in the bevacizumab arm. Grade 3 nausea (10% vs 5%), sensory neuropathy (15% vs 9%), vomiting (8% vs 3%) and hypertension (5% vs 2%) were significantly more frequent in patients receiving FOLFOX. Bowel perforation was only observed in the bevacizumab arm in 1% of the patients.
Saltz et al recently presented the first data from the BOND II trial, in which 74 irinotecan-resistant patients mostly treated with oxaliplatin were randomised to receive irinotecan (same schedule as given prior to entry) in combination with cetuximab and low-dose bevacizumab or bevacizumab and cetuximab without irinotecan.(31) It was concluded that concurrent administration of cetuximab and bevacizumab was feasible and that toxicity was as would be predicted from the individual agents, without clear indication of synergistic toxicity. Addition of bevacizumab seemed to add efficacy in terms of response rate and TTP in both regimens compared with historical controls. However, the use of historical data for comparison does not allow the question of improved efficacy to be answered.
A further phase III study will assess the FOLFOX regimen with or without bevacizumab in the second-line setting for patients who have failed previous irinotecan plus 5-FU treatment.(32) These results will help to define the extent to which antivascular endothelial growth factor (VEGF) therapy can be used in the treatment of colorectal cancer.
Cetuximab in mCRC
No reliable data are currently available on the efficacy of cetuximab in the first-line setting. Preliminarily data from phase II trials in first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing tumours has shown high tumour response rates (70-80%) from cetuximab in combination with irinotecan/5-FU/LV or oxaliplatin/5-FU/LV.(33,34)
Saltz et al observed a 9% tumour response rate of cetuximab alone in 57 patients progressing on irinotecan and with EGFR-expressing tumours in a phase II trial, with a median survival of 6.4 months.(35) In another phase II study, the response rate was 23% when cetuximab and irinotecan were combined in 121 irinotecan-resistant patients.(36)
These results were confirmed and expanded in the pivotal BOND I study, reported by Cunningham et al,(37) which compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in mCRC refractory to treatment with irinotecan. A total of 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen were randomly assigned to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). The response rate in the combination-therapy group was significantly higher than that in the monotherapy group (22.9% vs 10.8%) and the median time to progression was significantly greater in the combination-therapy group (4.1 months vs 1.5 months).
Lenz et al observed a tumour response rate of 12% from cetuximab alone in 346 patients with EGFR-expressing tumours resistant to both irinotecan and oxaliplatin.(38) Out of nine erroneously enrolled EGFR-negative patients, two had PR. A recent retrospective study by Chung et al confirmed activity of cetuximab/irinotecan or cetuximab alone in EGFR-negative mCRC patients.(39) PR was observed in four of 14 patients. The recommended practice of testing EGFR status by immunohistochemistry to select for cetuximab therapy is clearly inappropriate and other predictive tests are needed.(40)
Vincenzi et al evaluated the efficacy of cetuximab in weekly combination with irinotecan in mCRC patients refractory to previous treatments based on oxaliplatin or irinotecan.(41) Fifty-five heavily pretreated patients were followed for tumour response and were also evaluated for the time to tumour progression and safety of treatment. The median time to progression was 4.7 months and the median survival time was 9.8 months.
Gebbia et al evaluated the efficacy and safety of irinotecan/cetuximab administered as third- or fourth-line therapy in a retrospective series of patients with mCRC refractory to oxaliplatin and irinotecan.(42) The median PFS was 3.1 months, whereas median OS was six months.
There have been dramatic changes in the medical treatment of CRC during the past five years, making such treatments considerably more complex but with more options offered to mCRC patients. The development of “targeted” drugs is in progress in CRC and so far the monoclonal antibodies bevacizumab and cetuximab are clearly in the lead, with justified use in some clinical situations. Although the contribution from these antibodies cannot be denied, therapeutic improvement is still minimum in absolute terms and comes at a price that will be difficult to handle in tax-funded healthcare systems.