Tumour Biology Centre at the
Albert-Ludwigs University Freiburg
Department of Medical Oncology
Colorectal cancer is the second most frequent cause of cancer-related death. Colorectal cancer is responsible for 1,023,000 new cases worldwide and 529,000 deaths each year.(1) In the last 10 years, new drugs and drug combinations have been launched on the market, with better response rates (RRs) and prolonged disease-free survival (DFS) for patients with advanced colorectal cancer.
Early chemotherapy improves survival. This was documented in 1992 in the first trials with fluorouracil (5-FU) versus best supportive care; median survival could be improved from approximately nine months (without treatment) to 14 months.(2) Combination with leucovorin could improve RR but not overall survival (OS). Multiple approaches have been investigated to optimise the effectiveness of chemotherapy with 5-FU and several biochemical modulators, such as combinations with leucovorin or interferon, application as bolus or continuous infusion of 5-FU. Continuous infusion improved RR, but improvements in OS were only marginal.(3)
The oral 5-FU prodrug capecitabin showed activity similar to that of bolus 5-FU and leucovorin. The toxicity profile of this drug, however, is more favourable for bone marrow suppression and stomatitis, although hand–foot syndrome occurs more frequently.(4–6)
Since new drugs, such as oxaliplatin and irinotecan, and monoclonal antibodies, such as bevacizumab and cetuximab, have been available, overall RR and OS have improved.
Oxaliplatin is a third-generation platinum derivative that forms bulky DNA adducts and induces cellular apoptosis.(7) The activity of oxaliplatin and that of 5-FU are highly synergistic; the mechanism of action of this drug seems to be the downregulation of thymidine synthase.(8) The most common toxicity is neuropathy with transient dysaesthesias, especially by exposure to cold temperatures.(9) Combination of oxaliplatin with bolus 5-FU and leucovorin, followed by a 46-hour infusion of 5-FU (a treatment schedule known as FOLFOX), achieves better RRs (50.7%) and median OS (16.2 months) than 5-FU and leucovorin alone.(9–12) A combination of oxaliplatin with fluorouracil and leucovorin chronomodulated resulted in an RR of 34% and a median survival of 19.9 months.(13)
Irinotecan is a semisynthetic derivate of the natural alkaloid camptothecin. Its cytotoxic mode of action occurs through its interaction with the enzyme topoisomerase I.(14) This enzyme is involved in the uncoiling of DNA for replication and transcription, and it causes single-stranded DNA breaks. Camptothecin stabilises these breaks and leads to DNA fragmentation with consecutive cell death through interaction with the replication fork. The most common toxicities are diarrhoea, bone marrow suppression, nausea, and vomiting, and alopecia. Special attention is needed for diarrhoea, which led to a higher than anticipated number of treatment-related deaths when it was first used with the combination of 5-FU and leucovorin.(15) Diarrhoea is caused by the active metabolite of irinotecan, SN-38, which, after first detoxification to an inactive, glucuronidated form, is split in the bowel by beta-glucuronidases, so that active SN-38 can exert its toxic effect again.
In one randomised trial, treatment with single-agent irinotecan showed RRs from 18% and median survivals from 12 months. Irinotecan in combination with fluorouracil and leucovorin (IFL) as first-line therapy in metastatic colorectal cancer (as bolus 5-FU and as continuous infusion over 46 hours) showed, in two randomised trials, RRs of 39% and 49% and median OS rates of 14.8 and 17.4 months.(16,17) Another study compared the effectiveness of using 5-FU according to the all-in-one (AIO) protocol (5-FU 2.3mg/m2 24-hour infusion and leucovorin 500mg/m(2) six times weekly with one week rest) versus FUFIRI 2.0 (irinotecan 80mg/m2, FA 500mg/m(2), 5-FU 2.0g/m(2) six times weekly with one week rest).(18) An RR of 31.5% was achieved with AIO, vs 54.2% for the irinotecan-containing regimen, resulting in an OS of 16.9 months for the AIO protocol and 20.1 months for FUFIRI 2.0.
The best combination: IFL, FOLFOX or IROX?
Recently, the results of the combinations IFL, FOLFOX and IROX (irinotecan and oxaliplatin) for the initial treatment of metastatic colorectal cancer have been reported from a multicentre trial with 795 patients in North America.(19) Treatment with FOLFOX showed an RR (45%), time to disease progression (9.3 months) and OS time (19.5 months) superior to those observed with either IFL or IROX.
Which sequence is best?
To evaluate the best sequence of therapy in metastastic disease, Tournigand and colleagues randomised 220 patients for either infusional 5-FU, leucovorin and irinotecan (FOLFIRI) followed by FOLFOX or FOLFOX followed by FOLFIRI.(20) RRs and OS times were similar in both treatment arms. Nonetheless, there seemed to be an advantage for FOLFOX first-line with regard to the resectability of liver metastases (22% in the FOLFOX group and 9% in the FOLFIRI group).
New targeted therapies have been developed after identifying molecular sites in tumour tissue. These therapeutic strategies aim to interrupt the cellular pathways essential for tumour growth, survival and metastasis. For clinical management, two promising classes of targeted compounds have been introduced: epidermal growth factor receptor (EGFR) antagonists and angiogenesis inhibitors.(21)
The target of this EGFR antagonist is a transmembrane glycoprotein that is involved in signalling pathways affecting cellular growth, differentiation, proliferation and programmed cell death.(22) In different tumours, this receptor is overexpressed, and it seems to be associated with a poorer prognosis in colorectal cancer.(23,24) The approval of cetuximab was based on a 2003 study from Cunningham and colleagues, the BOND study.(25) These authors randomly assigned 329 patients with advanced colorectal cancer refractory to irinotecan to receive either cetuximab with irinotecan or cetuximab alone. Patients given the combination had an RR of 23%, vs 11% for those who received only single-agent cetuximab. These results were seen especially in patients who were initially refractory to irinotecan and had afterwards a response to the combination therapy. Thus, there is a synergy between chemotherapy and cetuximab, and this synergy can occur in tumour cells already resistant to irinotecan. The most frequent side-effect of cetuximab is skin toxicity (acne-like rash).
In January 2005 the angiogenesis inhibitor bevacizumab was approved in Germany for the first-line treatment of advanced colorectal cancer in combination with 5-FU-based chemotherapy. The basis for this approval was a phase III study by Hurwitz and colleagues,(26) who assigned 815 patients to receive either IFL with bevacizumab or IFL with placebo. The combination with bevacizumab showed a statistically significant increase in the RR (45% with and 35% without bevacizumab), and an increase in median OS of 4.7 months (20.3 months, vs 15.6 months with IFL and placebo).
Progress in the treatment of advanced colorectal cancer has been achieved in recent years.
The addition of irinotecan or oxaliplatin to 5-FU-based chemotherapy could improve the RR and prolong DFS, and irinotecan could also prolong median OS. The optimal sequence is currently unclear.
Bevacizumab is a milestone for the first-line treatment of advanced colorectal cancer, and cetuximab is an EGFR antibody for second-line therapy. The randomised studies presented in Table 1 show a median survival of 20 months, but in these study periods at least one of the new drugs was not available. Using all currently available drugs in a perfect sequence should result in an OS of at least two years.
- Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002: cancer incidence, mortality and prevalence worldwide. IARC CancerBase no. 5, version 2.0. Lyon: IARC Press, 2004.
- J Clin Oncol 1992;10:904-11.
- J Clin Oncol 1998;16:301-8, 3537-41.
- J Clin Oncol 2001;19:4097-106.
- Proc Am Soc Clin Oncol 1999;18:265a.
- J Clin Oncol 2001;19:2282-92.
- Semin Oncol 1998;25:4-12.
- Mol Cancer Ther 2002;1:227-35.
- J Clin Oncol 2000;18:2938-47.
- J Clin Oncol 2003;21:2059-69.
- J Clin Oncol 2000;18:136-47.
- Proc Am Soc Clin Oncol 2002;Abstract 512.
- J Clin Oncol 2000;18:136-47.
- Cancer Chemother Pharmacol 1998;42:Suppl:S31-43.
- J Clin Oncol 2001;19:3801-7.
- N Engl J Med 2000;343:905-14.
- Lancet 2000;335:1372.
- Proc Am Soc Clin Oncol 2003;22:254.
- J Clin Oncol 2004;22:23-30.
- J Clin Oncol 2004;22:229-37.
- N Engl J Med 2005;352:476-87.
- Oncologist 2002;7 Suppl 4:2-8.
- Cancer 1993;71:2454-60.
- J Surg Oncol 1992;51:147-52.
- N Engl J Med 2004;351:337-45.
- N Engl J Med 2004;350:2335-42.