Developing therapies for colorectal cancer

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D Alan Anthoney
MRCP PhD
Oncology and Haematology Department
University of Leeds
UK
E:[email protected]

The past five years have seen a significant change in the management of advanced colorectal cancer, with the establishment of 5-fluorouracil (5FU), oxaliplatin and irinotecan combinations as standard for primary and salvage therapy. Internationally, different approaches as to which agents should be used in first-line and salvage therapy have been developed and have become standards of care. A number of large randomised trials have recently been reported that will help in determining optimal treatment strategies. In addition, the role of these combinations in the adjuvant setting after resection of colonic adenocarcinoma is becoming clearer.

The introduction of targeted therapies into the treatment of colorectal cancer is now upon us, adding further complexity but with the potential for significant additional improvements in survival. However, such developments come at a cost and, increasingly, healthcare systems are asking who is going to pay for this progress.

Which cytotoxics and what sequence?
Until recently, the standard first-line therapy for colonic adenocarcinoma in the USA was the IFL regimen (irinotecan 125mg/m(2), 5FU bolus 500mg/m(2), leucovorin [LV] 20mg/m(2) weekly for four weeks out of six), whereas in much of continental Europe combined infusion and bolus 5FU with oxaliplatin (FOLFOX regimens or variants) was favoured. Recommendations in the UK were for first-line 5FU/LV, with irinotecan being used as salvage therapy.

The Intergroup study (INT 09741), a randomised comparison of FOLFOX, IFL and an irinotecan and oxaliplatin combination (IROX), aimed to determine optimal first-line therapy for metastatic colonic cancer.(1) Response rates in the FOLFOX arm were significantly improved compared with IFL or IROX (45% vs 31% [p=0.002] and 35% [p=0.03], respectively), with no significant difference between the latter two arms. Median time to progression (8.7 months, 6.9 months and 6.5 months, respectively) and overall survival (OS; 19.5 months vs 15 months, p=0.0001) were also superior for the FOLFOX arm compared with IFL and IROX. With the exception of peripheral neuropathy, toxicity was better in the FOLFOX arm.(1) The apparent benefits of first-line oxaliplatin over irinotecan observed in this trial are confounded by the fact that it was also a comparison of infusional versus bolus 5FU regimens. In addition, patients receiving IFL as initial therapy had limited access to second-line oxaliplatin at the time of the study, thus resulting in a lack of equivalence in salvage therapies between the arms. However, on the strength of this study, the FDA recently approved oxaliplatin in combination with infusional 5FU regimens as first-line therapy for advanced colon cancer.

Three studies have helped clarify optimal sequencing of agents in the advanced colon cancer setting. Two hundred and twenty patients with assessable, untreated metastatic colorectal cancer (mCRC) were randomised between initial treatment with the FOLFOX6 or the FOLFIRI regimen (LV 200mg/m(2); bolus 5FU 400mg/m(2); 46-hour infusion 5FU 2.4�3.0g/m(2), plus oxaliplatin 100mg/m(2) or irinotecan 180mg/m(2) on day 1, every 14 days) and the opposite regimen upon disease progression. Responses to first-line therapy were not significantly different between the two arms (FOLFIRI: 56%; FOLFOX: 54%) and, although responses to FOLFOX as second-line therapy were greater than with FOLFIRI, median OS was not significantly different between the arms (FOLFOX:FOLFIRI 20.6:21.5 months).(2)

The MRC CR08 (FOCUS) trial studied differences in response and survival between treatment arms in which 5FU/LV/ oxaliplatin/irinotecan were used as single agents or in combination as first-, then second- and even third-line therapy (see Figure 1). The results of this trial (the largest ever conducted in mCRC, with over 2,000 patients randomised) confirmed that combination chemotherapy (5FU/LV + oxaliplatin or irinotecan) as first-line therapy was associated with improved response.(3) However, OS did not differ significantly between arms in which 5FU/LV was used alone as first-line therapy, with oxaliplatin and irinotecan combinations used for salvage therapy, and those using upfront 5FU/LV and oxaliplatin or irinotecan combinations. A significant minority of patients who received 5FU/LV alone as first-line therapy did not receive salvage therapy, presumably due to rapid disease progression. This has been one argument used to support combination therapy as first-line treatment.

[[HPE25_fig1_34]]

A meta-analysis of seven randomised trials of combination chemotherapy in colorectal cancer has suggested, in confirmation of the above trials, that patients receiving all three active cytotoxics in the course of their treatment have the greatest chance of prolonged survival.(4)

Targeted therapies in mCRC
Significant advances in our understanding of cancer biology have identified specific molecular processes that have strong associations with the cancer phenotype (eg, loss of growth control and metastasis), and these have been investigated as potential targets for anticancer drug development.

Angiogenesis is the process by which tumours establish their own blood supply by formation of new blood vessels from the surrounding tissue. Overexpression by colonic cancer cells of factors that stimulate angiogenesis (eg, vascular endothelial growth factor [VEGF]) has been shown to be associated with poor prognosis. Bevacizumab is a recombinant humanised monoclonal IgG1 antibody that binds to VEGF, inhibiting several of its actions, including endothelial cell growth, vascular permeability and angiogenesis. A number of clinical trials have been carried out in which bevacizumab has been used in combination with 5FU/LV, IFL or FOLFOX as first-line or salvage chemotherapy for mCRC. The combination of �bevacizumab (5mg/kg IV twice weekly) plus IFL has been shown to give significantly better response rates (44.8% vs 34.8%) and progression-free survival (10.6 vs 6.2 months) compared with IFL plus placebo.(5) Bevacizumab combined with FOLFOX as salvage therapy has shown significant improvements in progression-free (7.4 vs 5.5 vs 3.5 months) and overall survival (12.5 vs 10.7 vs 10.2 months) compared with the FOLFOX regimen or bevacizumab alone (ECOG 3200 trial).(6) Further studies determining the role of bevacizumab as salvage therapy are ongoing.

The epidermal growth factor (EGF) and its receptor (EGFR) have been identified as important mediators of cell growth and replication. Increased EGFR-mediated signalling has been associated with many features of the cancer cell phenotype, such as cell differentiation, proliferation, migration, angiogenesis and apoptosis, processes that are crucial in facilitating tumour progression and metastasis. Increased activity of the EGF/EGFR signalling pathway has been associated with advanced disease, metastatic phenotype and poor prognosis in colorectal cancer.

Cetuximab, a chimeric IgG1 monoclonal antibody against the extracellular ligand binding region of EGFR, inhibits downstream signalling and subsequent internalisation and destruction of EGFR upon binding. The initial clinical development of cetuximab has focused on its role as salvage therapy (either alone or in combination) after failure of irinotecan-based chemotherapy. A randomised phase II trial has compared cetuximab as a single agent versus cetuximab plus the previously used irinotecan chemotherapy regimen in patients progressing on or within three months of completion of irinotecan-based chemotherapy. Patients in this study all had EGFR-positive advanced colorectal cancer (as determined by immunohistochemistry of tumour samples). Around 80% of patients had received two or more lines of chemotherapy (>60% of them having received oxaliplatin) before entering the study. Results showed that adding �cetuximab to the chemotherapy regimen that the patient had previously failed brought about responses in 23%, whereas cetuximab on its own had an 11% response rate. The median time to progression for the cetuximab/ chemotherapy patients was 4.1 months, compared with 1.5 for cetuximab alone. OS was not statistically different between the groups, although about half of the single- agent cetuximab group had irinotecan chemotherapy added in upon failure, with clinical benefit seen in over 35%.(7) Numerous studies looking at the effect of cetuximab (alone or in combination with irinotecan +/- oxaliplatin +/- bevacizumab) as first-line or salvage therapy are likely to be reported in 2006.

The toxicity profile of the novel targeted agents is different from that observed with standard cytotoxics. Bevacizumab causes elevation of blood pressure, which is normally mild and controlled by medication. Grade 3/4 hypertension occurs in around 10% of cases. Cases of delayed wound healing and gastrointestinal perforation have also been reported in one study (in around 3�5% of cases).

Cetuximab has diarrhoea and skin rash as dose-limiting toxicities. The skin rash is an acneiform rash observed in many EGFR-targeted agents. Of interest is the association between the severity of the rash and response to treatment. It has been postulated that rash should be used as a surrogate marker of response.

Adjuvant treatment of resected colon cancer
The benefits observed with irinotecan, oxaliplatin, bevacizumab and cetuximab in the advanced disease setting have naturally resulted in studies to determine their effect on preventing relapse post‑resection of primary disease. Two randomised phase III studies (one with mature published data(8) and the other presented in an abstract(9)) of more than 4,600 patients with stage II and III resected colon cancer have shown that addition of oxaliplatin to 5FU/LV reduces the relative risk of relapse by around 20%. The benefit was only significant for node-positive disease (although the debate rages as to its use in stage II disease, where many patients with other poor prognosis features have a greater risk of relapse than some stage III patients).

Oxaliplatin-induced peripheral �neuropathy appears to resolve in the vast majority of patients within a year of completion of treatment. Oxaliplatin-based adjuvant chemotherapy is rapidly becoming standard therapy for stage III colon cancer. Interestingly, similar studies of irinotecan/5FU/LV as adjuvant therapy have shown less significant reductions in disease-free survival. The role of bevacizumab and cetuximab in the adjuvant setting is currently under investigation.

Cost issues
Although relatively ineffective, 5FU (even in combination with LV) is fairly cheap. The addition of oxaliplatin or irinotecan, and then possibly cetuximab or bevacizumab (or ultimately cocktails of three or more agents), has resulted in an exponential growth of the drug costs of treating advanced colon cancer. Recent journal and media articles(10) have focused on this issue and, at the American Society of Clinical Oncology meeting in 2005, the costs of different adjuvant regimens for the potential at-risk population in the USA were compared and shown to be possibly too great for even one of the wealthiest healthcare systems (ASCO 2005; Educational session). The issue of who pays for state-of-the-art colon cancer treatment (whether in a private or public healthcare system) is likely to remain a hot topic for years to come.

Summary
The rapid expansion in the number of active agents in the treatment of colorectal cancer has led to considerable confusion as to strategies for optimal treatment.

Although becoming clearer through the results of large trials, treatment options are likely to be affected by access to newer agents, in many healthcare systems, at least in the short term.

References

1. Goldberg RM, Sargent DJ, Morton RF, et al. J Clin Oncol 2004;22:23-30.
2. Tournigand C, Andre T, Achille E, et al. J Clin Oncol 2004;22:229-37.
3. Seymour M, et al. ASCO 2005: Abstract 3518.
4. Grothey A, Sargent D, Goldberg RM, Schmoll HJ. J Clin Oncol 2004;22:1209-14.
5. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med 2004;350:2335-42.
6. Giantonio BJ, Catalano PJ, Meropol NJ, et al. ASCO 2005: Abstract 2.
7. Cunningham D, Humblet Y, Siena S, et al. N Engl J Med 2004;351:337-45.
8. Andre T, Boni C, Mounedji-Boudiaf L, et al. N Engl J Med 2004;350:2343-51.
9. Arkenau H, Schmoll H, Kubicka S, et al. ASCO 2005: Abstract 3500.
10. Berenson A. Costly cancer drugs bring hard decisions. International Herald Tribune, 13 July 2005.

Resources
American Society of Clinical Oncology. Audio/visual
presentations on sessions from 2005 meeting: Can society afford state of the art cancer treatment?
W:www.asco.org/ac/1,1003,_12-002514-00_18-0034-00_19-0094-00_21-00108,00.asp
Adjuvant oxaliplatin in colorectal cancer
W:www.asco.org/ac/1,1003,_12-002511-00_18-0034-00_19-003050,00.asp
www.asco.org/ac/1,1003,_12-002511-00_18-0034-00_19-002418-00_21-00108,00.asp
FOCUS trial
W:www.asco.org/ac/1,1003,_12-002511-00_18-0034-00_19-001999,00.asp
Bevacizumab plus oxaliplatin
W:www.asco.org/ac/1,1003,_12-002511-00_18-0034-00_19-004925,00.asp