BMJ  2004;329:124-126 (17 July), doi:10.1136/bmj.329.7458.124

Editorial

New treatments for colon cancer

Though experimental, they may herald a new era of cancer therapy

Until the early 1990s the medical treatment of colorectal cancer represented a therapeutic desert with little or no progress. Since then we have witnessed the establishment of effective adjuvant chemotherapy and the treatment of advanced disease has improved substantially. In the past year colorectal cancer has been at the cutting edge of new developments in medical oncology. Although some of these new treatments are still experimental and not yet standard practice, they are worth flagging up at this preliminary stage because the proof of principle they have established may herald a change in the way all cancer is treated in future.

Fluorouracil has represented the cornerstone of medical treatment of colorectal cancer for nearly 40 years, but it took until 1990 to show that adjuvant chemotherapy with fluorouracil with levamisole improved disease free and overall survival in Dukes's C (stage III) colon cancer.^{1 w1} Subsequent studies have shown that fluorouracil with folinic acid confers similar benefit but is less toxic and takes six months of treatment rather than a year.^{2 3 w2} This treatment improves absolute survival by an average of 5-10% at five years, which represents a 25-35% reduction in mortality and has now become standard practice. The data on the role of adjuvant chemotherapy for patients with Dukes's B (stage II) disease have been inconsistent, but a recent UK randomised trial in nearly 3000 patients with Dukes's B colorectal cancer has now convincingly shown a small (3%) but significant (P = 0.02) absolute survival benefit in this group of patients..^{2 3 w2}

Until recently the treatment of advanced disease was disappointing, with fluorouracil and folinic acid yielding response rates of 10-25% with little effect on survival. Several phase III trials have now shown that adding irinotecan or oxaliplatin doubles the response rates to around 50% and increases progression free survival.^{4 5} Irinotecan also increases median overall survival by about three months,⁶ which, although modest, is often of interest to patients with advanced cancer.⁷ A similar survival benefit for oxaliplatin is likely to emerge from current phase III trials.^w3

Oxaliplatin has also been shown to downsize liver metastases, to enable potentially curative resection to be performed in several patients whose tumour would previously have been considered inoperable.⁸ The survival rates of 34% at five years and 20% at 10 years of patients undergoing resection after neoadjuvant (given before surgery) chemotherapy with fluorouracil, folinic acid, and oxaliplatin for liver metastases that were originally considered inoperable are similar to those of patients undergoing primary resection.⁸

Thirty years ago Folkman proposed that new blood vessel formation (angiogenesis) was important for cancer growth,⁹ but until now inhibition of angiogenesis has not been shown to be of clinical benefit in solid tumours. A large phase III trial in patients with untreated metastatic colorectal cancer looking at the addition of an anti-VEGF (vascular endothelial growth factor) monoclonal antibody—bevacizumab—to fluorouracil, folinic acid, and irinotecan has recently shown an increase in response rate and progression-free survival.¹⁰ Most importantly it also showed a five month median prolongation of overall survival. As a result of this study bevacizumab has recently been licensed by the US Food and Drug Administration for first line treatment of metastatic colon cancer. This heralds a new era in cancer treatment, not just for colorectal cancer. Median survivals of over 20 months in patients with metastatic colorectal cancer were unheard of just a few years ago and are now within our grasp.

Cituximab, a new antibody to the epidermal growth factor receptor (EGFR) expressed in around 80% of colorectal cancers, has activity and little toxicity in colon cancers that are resistant to chemotherapy, both as a single agent and in combination with chemotherapy.¹¹ This is of modest but real benefit in about 20% of patients with advanced colorectal cancer. Cituximab has been licensed in Switzerland and the US and been recommended for approval by the scientific advisory body of the European Union.

New treatments in advanced disease will often have a much greater effect on survival if used as adjuvant treatment for earlier stages of disease.^w4 The adjuvant trials looking at the addition of oxaliplatin or irinotecan to fluorouracil and folinic acid have therefore been awaited with great interest.

The Mosaic adjuvant chemotherapy trial has recently been published.¹² This large, international, phase III study recruited 2246 patients with Dukes's B (stage II) and Dukes's C (stage III) colon cancer. The trial looked at the addition of oxaliplatin to standard postoperative adjuvant chemotherapy with fluorouracil and folinic acid and showed that adding oxaliplatin resulted in a reduction in relapse rates of 23% (P = 0.0002). The increase in disease-free survival was also significant (P = 0.002) With only three years' follow up it is too early for this to have been translated into a survival advantage, but three year, disease free survival has been shown to be a good predictor of five year overall survival in trials of adjuvant treatment of colon cancer.¹³ If the outcome is confirmed this regimen offers the opportunity of nearly doubling the benefit of adjuvant fluorouracil and folinic acid in colon cancer and will save many thousands of lives.

Several phase III trials are currently ongoing to assess the potential benefit of combining irinotecan with fluorouracil and folinic acid in the adjuvant setting. The use of anti-vascular endothelial growth factor antibodies and of cituximab in combination with adjuvant chemotherapy will now be explored in the adjuvant setting and holds out the promise of further incremental benefits. This has been a remarkable year for colorectal cancer, with new treatments likely to be available for patients with early disease as well as those with advanced disease in the near future. The problem the NHS will have to face is how to pay for them, as undoubtedly they will not be cheap.

Barts and the London NHS Trust, London EC1A 7BE (maurice{at}slevin.uk.com)

Barts and the London NHS Trust, London EC1A 7BE

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See also p 133

Additional references w1-w4 are on bmj.com

Competing interests: MS has received research funding, and both MS and SP have been funded to attend cancer conferences, by companies producing drugs mentioned in this editorial.

References

1. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322: 352-8.[Abstract]
2. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) Investigators. Lancet 1995;345: 939-44.[CrossRef][ISI][Medline]
3. Gray RG, Barnwell J, Hills R, McConkey C, Williams N, Kerr D, for the QUASAR Collaborative Group. QUASAR: a randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. Proc Am Soc Clin Oncol 2004;23 (Abstr 3501). www.asco.org/ac/1,1003,_12-002643-00_18-0026-00_19-003857,00.asp (accessed 14 Jun 2004).
4. De Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first line treatment in advanced colorectal cancer. J Clin Oncol 2000;18: 2938-47.[Abstract/Free Full Text]
5. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, et al. Phase III multicentre randomised trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18: 136-47.[Abstract/Free Full Text]
6. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355: 1041-7.[CrossRef][ISI][Medline]
7. Slevin ML, Stubbs L, Plant HJ, Wilson P, Gregory WM, Armes PJ, et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public. BMJ 1990;300: 1458-60
8. Adam R. Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases. Ann Oncol 2003;ii(suppl 2): 13-6.
9. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285: 1182-6.
10. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350: 2335-42.[Abstract/Free Full Text]
11. Cunningham D, Humblet Y, Siena, Khayat D, Bleiberg H., Santoro A, et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol 2003;22:252. (Abstr 1012.) www.asco.org/ac/1,1003,_12-002640-00_18-0023-00_19-00101988-00_28-002,00.asp (accessed 28 Feb 2004).
12. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. The Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. N Engl J Med 2004;350: 2343-51.[Abstract/Free Full Text]
13. Sargent D, Wieand S, Goldberg R, O'Connel M, Benson A, Catalano P, et al. 3 year DFS vs. 5 year OS as an endpoint for adjuvant colon cancer studies: data from randomized trials. Rockville, MD: Food and Drug Administration, 2003. www.fda.gov/cder/drug/cancer_endpoints/Sargent/index.htm (accessed 12 Jun, 2004).

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