Targeting advanced colorectal cancer

teaser

Andrew E Hendifar
Resident, Internal Medicine

Anthony B El-Khoueiry
MD

Heinz J Lenz
MD
Division of Medical Oncology
Kenneth Norris Comprehensive Cancer Center
University of Southern California
Keck School of Medicine
Los Angeles, CA
USA
E:[email protected]

Colorectal cancer is the third most frequently diagnosed cancer in the USA, with an estimated 147,000 new cases in 2004.(1) Even with advances in screening and early detection, nearly half of all patients present with advanced disease.(2) Until recently patients with metastatic colorectal cancer (MCRC) could expect an average survival of 12 months with the standard treatment of 5-fluorouracil (5-FU) in combination with leucovorin (LV).(3) In 2000, the US Food and Drug Administration (FDA) approved IFL (irinotecan/
5-FU/leucovorin) after it was shown to improve overall survival to 14.8 months in a report by Saltz et al.(4) Since then, new agents such as oxaliplatin, capecitabine, bevacizumab and cetuximab have been approved for the treatment of MCRC. These therapies have brought new hope to patients, with a clear improvement in overall survival (OS) that has surpassed 20 months.(5) The explosion of successful treatment options has also fundamentally changed the approach to treating advanced colon cancer. No longer a “one size fits all” proposition, treating advanced colorectal cancer requires an understanding of the drugs, their side-effects and their targets (see Table 1 and Box 1).

[[HPE20_table1_51]]

[[HPE20_box1_52]]

Fluoropyrimidines

5-FU plus leucovorin
5-FU exerts its antineoplastic activity by inhibiting thymidylate synthase, an enzyme crucial for DNA synthesis. The combination of 5-FU and LV was considered the standard of care until 2000. This combination has a superior response rate (RR) and median survival (11.7 months vs 10.5 months, p=0.004) compared with monotherapy.(3) Several attempts have been made to improve the therapeutic effect by altering the mode of administration. Recent evidence indicates that continuous infusion (CI) 5-FU CI/LV has a longer progression-free survival (PFS) (p=0.003) compared with bolus regimen (Mayo) but no clinically significant difference in OS.(6) Neutropenia and stomatitis were more frequent in those receiving the Mayo regimen, but those receiving the CI regimen had a higher incidence of hand–foot syndrome and diarrhoea.

Capecitabine
Capecitabine, an oral fluoropyrimidine, is a prodrug of 5-FU and is converted by the enzyme thymidine phosphorylase (TP), which is highly expressed in tumour tissue.(7) Capecitabine has been shown to be equivalent to 5FU/LV as first-line therapy for MCRC in two phase III randomised trials.(8,9) In both studies, capecitabine had a superior toxicity profile, with significantly lower incidence of diarrhoea, stomatitis, nausea and alopecia (p<0.05). Capecitabine is often used palliatively when treatment with a fluoropyrimidine alone is preferred.

Irinotecan as first-line therapy in advanced colorectal cancer
Irinotecan, a prodrug of SN 38, achieves its antitumour effects through the inhibition of topoisomerase I.(10) It is now approved in the USA as a first-line therapy in combination with 5-FU/LV for advanced MCRC and as monotherapy in fluoropyrimidine-refractory patients. Irinotecan, in combination with 5FU/LV, was superior to 5-FU/LV alone as first-line therapy in two phase III randomised trials. The significant difference between the two trials was the 5-FU schedule. Saltz et al compared the Mayo clinic regimen with irinotecan in combination with 5FU/LV bolus (IFL), whereas Douillard et al compared infusional 5FU/LV (De Gramont or AIO) with irinotecan (FOLFIRI).(11,12) Both regimens demonstrated a  statistically and clinically significant improvement in response and overall survival. In these two studies, the addition of irinotecan to 5-FU/LV also increased the rate of grade 3 and 4 diarrhoea.

Oxaliplatin as first-line therapy in advanced colorectal cancer
Oxaliplatin, a platinum analogue with a diaminocyclohexane moiety, inhibits DNA synthesis through the formation of intrastrand DNA adducts. Clinical toxicities differ from other platinum agents as there is no renal toxicity and minimal haematotoxicity.(13) Already approved in Europe as a second-line treatment for MCRC, several trials evaluated oxaliplatin with varying doses and modes of administration of 5-FU in first-line treatment.(14) There was an increase in the response rate (49–53%, p<0.001) and disease-free survival (7.8–8.7 months, p<0.05) in patients receiving oxaliplatin in combination with 5-FU.(15–17)

In the USA, oxaliplatin has been recently approved in combination with 5-FU/LV for the first-line treatment of advanced colorectal cancer.

Oxaliplatin vs irinotecan: is one regimen superior?
The results from phase III trials clearly support the use of irinotecan or oxaliplatin as first-line therapy; however, there have been relatively few studies evaluating these regimens head to head. A recent trial conducted by the North Central Cancer Treatment group (N9741) compared FOLFOX-4 vs IFL vs IROX in 796 patients.(18) FOLFOX-4 was significantly superior to IFL in all measured endpoints. Both oxaliplatin-containing arms resulted in a statistically significant survival advantage over IFL. It is unclear whether the superiority of FOLFOX-4 should be attributed solely to the addition of oxaliplatin or to the mode of 5-FU administration.

There is no significant difference between oxaliplatin- and irinotecan-based combinations when the mode of fluoropyrimidine administration is comparable. Tournigand et al randomised 226 patients to FOLFOX-6 followed by FOLFIRI at the time of progression vs FOLFIRI followed by FOLFOX-6.(19) The choice of the frontline regimen did not lead to any difference in RR (54% vs 56%, respectively), progression-free survival (8.0 vs 8.5) or overall survival (20.6 vs 21.5). Similarly, CapIri and CapOx were compared in a randomised phase II trial of 161 patients.(20) There was no significant difference in median progression-free survival (mPFS of 8.2 and 6.6+ months respectively) and median OS (15.8+ months). In both trials, the sequence of the regimens did not affect OS.

In a review of seven recently published phase III trials, Grothey and colleagues examined the importance of all three active cytotoxic agents, 5-FU, irinotecan and oxaliplatin, on OS. They found that median OS was significantly correlated with the percentage of patients receiving all three agents (p=0.0008) and not those receiving any particular second-line therapy.(21) These findings suggest that maximising OS involves the use of all three agents, irrespective of sequence.

Monoclonal antibodies: targeted therapies

Bevacizumab
Bevacizumab (BV) is a recombinant, humanised monoclonal antibody directed against the vascular endothelial growth factor, which is highly expressed in colon cancer.(22) After several promising clinical and preclinical studies, a randomised phase II trial with 104 untreated metastatic colorectal cancer patients compared two regimens of BV (5mg/kg or 10mg/kg) plus 5-FU/LV with 5-FU/LV alone.(23) The arm with BV at 5mg/kg had a significantly improved RR (40% vs 17%, p=0.029) and PFS (9.0 months vs 5.2, p=0.005) as compared to the arm with 5-FU/LV alone. In this study, BV was well tolerated but was associated with higher incidence of thrombosis, epistaxis and hypertension. A pivotal phase III trial was then developed to compare bevacizumab plus IFL vs IFL alone.(24) The median duration of survival was 20.3 months for the group with bevacizumab vs 15.6 months in the group given IFL alone (p<0.001). BV in combination with IFL was associated with gastrointestinal perforation (1.5%). These two trials formed the basis for the FDA approval of BV in combination with 5FU-based chemotherapy as first-line treatment in metastatic colorectal cancer.

Cetuximab
Cetuximab is an IgG1 monoclonal antibody that blocks epidermal growth factor (EGF) and transforms growth factor-alpha binding to the EGF receptor by competing with ligand binding and receptor tyrosine kinase activation. Objective responses to cetuximab were first described in combination with irinotecan, and as a single agent (RR=17% and 10.5%, respectively) in a phase II trial of patients with irinotecan-refractory metastatic colorectal cancer that expressed EGF receptors.(25,26) Following these results, a randomised phase II trial showed that cetuximab in combination therapy was superior to single therapy in this patient population.(27) Cetuximab has also recently shown efficacy and safety in metastatic colorectal cancer refractory to oxaliplatin and as a first-line agent in combination with FOLFORI.(28,29) It is now approved for use in irinotecan- refractory MCRC in combination with irinotecan or alone in patients intolerant of irinotecan.

Conclusion
FOLFIRI and FOLFOX are two cytotoxic first-line chemotherapeutic regimens that are equivalent in treating advanced colorectal cancer. Promising results of trials with the monoclonal antibodies bevacizumab and cetuximab have led to their approval as agents for MCRC. The evidence supports using a targeted agent in combination with a cytotoxic regimen to extend survival. The challenge ahead is to identify interindividual genetic variations that will predict response and toxicity to these agents. These genetic differences can be used to tailor regimens, including both cytotoxic and targeted therapies, which will improve efficacy and reduce toxicity.

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