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Department of Medical Oncology
Hospital Universitario La Fe
Colorectal cancer (CRC) is the third most common malignant disease and the second most frequent cause of cancer-related death in Western countries. Worldwide, it causes 1,023,000 new cases and 529,000 deaths each year.(1) Although only approximately 30% of patients present with distant metastases, around 50% of patients with early-stage CRC will ultimately succumb to metastatic disease. The benefits of systemic chemotherapy in this context were established in the 1980s, when several phase III studies showed improvement in quality of life, time to disease progression and overall survival with the use of leucovorin (LV)-modulated 5-fluorouracil (5-FU) regimens.(2) Nonetheless, metastatic CRC (mCRC) remains largely an incurable disease, with the notable exception of cases in which complete resection of limited liver metastases can be carried out.(3)
For more than three decades, therapeutic options for patients with advanced CRC have been based almost exclusively on 5-FU, which still constitutes the backbone of the new combination regimens. However, in the past five years, four new drugs (two chemotherapeutic agents, irinotecan and oxaliplatin, and two targeted monoclonal antibodies, bevacizumab and cetuximab) have been incorporated into first- and second-line treatment strategies that are improving clinical outcome for this patient population. This review discusses the results of recent studies and the design of ongoing clinical trials with these new agents in the treatment of mCRC.
Irinotecan monotherapy was the first drug showing improved overall survival in second-line therapy after 5-FU failure.(4,5) Three subsequent randomised trials assessed the addition of irinotecan to 5-FU/LV regimens in the first-line therapy of advanced CRC (see Table 1).(6–8) A significant improvement in the response rate, progression-free survival and overall survival was demonstrated. Oxaliplatin was also shown to be active in refractory CRC and synergistic with 5-FU. Then, four phase III trials compared 5-FU/LV schemes with the same regimens plus oxaliplatin in the first-line setting (see Table 2).(9–12) Again, response rate and progression-free survival were significantly enhanced. However, overall survival was not affected, probably due to patient crossover and effective second-line therapies.
The relative merits of irinotecan and oxaliplatin in first line have been directly compared in five randomised trials (see Table 3).(13–17) Efficacy results were roughly equivalent in three of them. The studies of Goldberg(13) and Comella,(17) however, compared different 5-FU regimens and do not answer the question of whether oxaliplatin is better than irinotecan in first-line combinations. Furthermore, bolus IFL (irinotecan, fluorouracil and leucovorin) was shown to be a rather toxic combination.(18) The question as to whether 5-FU can be safely substituted by oral fluoropyrimidines such as capecitabine has not been definitively answered, and results from randomised trials are awaited.(19) Today, infusional 5-FU/LV plus either irinotecan or oxaliplatin represents the standard initial chemotherapy, with FOLFIRI and FOLFOX4 among the most active and widely extended regimens.
The sequential administration of both schedules offers the best published results in a phase III trial, with median survival times exceeding 20 months.(14) In fact, patient outcome is significantly improved with exposure to all active drugs in the course of disease, and the order in which it is done does not seem to matter.(20) However, the consistency of first-line survival benefit with irinotecan, the dose-limiting cumulative neurotoxicity with oxaliplatin, and a better response rate with FOLFOX in second line, suggest that FOLFIRI offers some clinical advantages as initial treatment.
Integration of biological agents
Bevacizumab is a humanised monoclonal antibody directed against vascular endothelial growth factor-A that has been recently approved for mCRC in first-line therapy. Table 4 summarises the results of two randomised phase II trials and the pivotal phase III trial, showing that the addition of bevacizumab to IFL significantly improves the response rate, progression-free survival and overall survival over IFL alone.(21–23) While mild arterial hypertension is the commonest side-effect associated with this drug, occasional life-threatening complications (arterial thromboembolic events and gastrointestinal perforations) have been described. Nowadays, the combination of FOLFIRI or FOLFOX plus bevacizumab represents the preferred front-line treatment for advanced CRC in Europe and the USA.
Cetuximab is a chimeric human–murine monoclonal antibody against the epidermal growth factor receptor (EGFR). It is currently approved for use in patients who have failed prior irinotecan-based therapy in advanced CRC based on phase II experience.(24,25) Its main adverse events are an acne-like skin rash, hypomagnesaemia and hypersensitivity reactions. In contrast with initial recommendations, EGFR expression by immunohistochemistry is of little help in the selection of patients more likely to benefit from cetuximab therapy.(26)
Current clinical randomised trials are comparing FOLFIRI or FOLFOX (at the oncologist’s choice) plus bevacizumab (control arm) with the same chemotherapy plus either cetuximab or both antibodies (CALGB/SWOG Intergroup 80405), or plus bevacizumab in combination with another monoclonal antibody against the EGFR, panitumumab (PACCE, Panitumumab Advanced Colorectal Cancer Evaluation). Other ongoing studies are evaluating the value of adding cetuximab to oxaliplatin-(OPUS phase II randomised trial) or irinotecan-based combinations (CRYSTAL phase III study) in the first-line setting.
Conclusions and future directions
The availability of five drugs (5-FU, irinotecan, oxaliplatin, bevacizumab and cetuximab) active against advanced CRC has significantly improved patient outlook. However, these new agents (mainly the monoclonal antibodies) are associated with increased economic costs and treatment complexity. FOLFIRI or FOLFOX plus bevacizumab represents the standard first-line therapy, with chemotherapy crossover plus cetuximab reserved for the second-line. Future clinical trials will address the question of which is the best combination of cytotoxics and cytostatics, the preferred treatment sequence and the optimal duration of therapy.
Other relevant issues remain unsolved, as is the development of useful predictive markers, probably derived from pharmacogenomic studies.(27) They would allow the design of more individually tailored treatments in order to improve response rates and decrease toxicity in CRC patients.