Floxuridine

It can improve quality of care and offer modest increases in survival

Colorectal cancer is the second most common cause of death from cancer in industrialised countries. Despite intensive investigations over the past decade, there has been no improvement in the long term prognosis of most patients with advanced disease. These patients have an estimated five year survival rate of 5% (excluding the comparatively small number of patients who have disease limited to the liver, which is suitable for surgical resection or ablative techniques).[1] Outcomes depend on a variety of factors, such as physical functioning and the tumour burden. Until recently, the role of chemotherapy as palliative treatment in advanced colorectal cancer has been questioned. However, the report from the Colorectal Cancer Collaborative Group in this week's journal (p 531) essentially confirms the role of chemotherapy in improving both the survival and the quality of life of patients with advanced colorectal cancer.[2]

The group's report looks at the results of a systematic review and meta-analysis of randomised trials that compared chemotherapy with best supportive care in patients with advanced colorectal cancer. The analysis was based on data from individual patients, and if these were not available published summary statistics were used.[2] The main end points were survival, disease progression, quality of life, drug toxicity, and cost effectiveness. These are all relevant, especially since the study was evaluating a non-curative therapy. Data were obtained from 13 trials: allocation to the treatment group was truly random only in 10 trials, and there was a marked heterogeneity of the regimens used.

Regardless of these shortcomings, the meta-analysis of data from individual patients found that there was a 35% reduction in the risk of death and a median survival of 11.7 months in patients treated with chemotherapy compared with a median survival of 8.0 months in patients who received the best supportive care.[2]

Because chemotherapy extends the median survival time by only a small but significant amount, its palliative benefit must be clarified. The most relevant end points for evaluating palliation are quality of life and alleviation of disease related symptoms, both of which are important to patients with this disease.[3] In this analysis, data on quality of life were available in six of 13 trials, although the instruments used were not always validated or specific for cancer.[2] Data on toxicity in these studies could not be summarised: only one study compared toxicity in both arms of the trial. Nevertheless, the palliative benefit of chemotherapy was clear in two specific groups of patients: those who previously had not been treated but were asymptomatic and those who were symptomatic and for whom first line therapy had failed.

The first group was addressed by the Nordic Gastrointestinal Tumour Adjuvant Trial Group, which randomly allocated 183 asymptomatic patients with metastatic colorectal cancer to early chemotherapy or expectant therapy as soon as patients had symptoms related to the disease.[4] Patients allocated to early chemotherapy not only survived 14 months (compared with 9 months for patients in the expectant therapy group) but the onset of their symptoms was significantly delayed. A parallel assessment of quality of life in a subset of patients confirmed that quality of life was not reduced in asymptomatic patients who received chemotherapy.[5] The National Cancer Institute of Canada and the Australasian Gastrointestinal Trials Group have recently completed two similar randomised trials, although the results have yet to be reported.

The second group of patients was addressed by a British study which randomly allocated patients with advanced colorectal cancer for whom initial therapy with 5-fluorouracil had failed to best supportive care or treatment with irinotecan.[6] Patients treated with irinotecan had a one year survival rate of 36.2% compared with 13.8% for those treated with best supportive care (P = 0.0001); those in the irinotecan group had a median survival advantage of two months.[6] Quality of life was measured using a validated scale developed by the European Organisation for Research and Treatment of Cancer, one that is specific for patients with cancer.[7] All scores favoured treatment with irinotecan, in particular the global quality of life score (P [is less than] 0.001), the pain score (P = 0.008), and appetite (P = 0.002).[6]

Economic rationalists would expect that the cost effectiveness of such palliative therapy would be added to the equation. Is palliative chemotherapy cheaper than the best supportive care? Retrospective studies in advanced prostate cancer,[8] lung cancer,[9] and colorectal cancer[10] clearly show that compared with less active regimens or best supportive care, systemic chemotherapy is cost effective by virtue of the increased response rate of tumours, its impact on survival, and the reduction in hospitalisations. Only prospective economic analyses will ultimately confirm or refute these observations.

It might be expected that response to treatment might influence survival. In a meta-analysis comparing the efficacy of intravenous 5-fluorouracil given by continuous infusion or by bolus, the overall response rates were 22% and 14% respectively (P = 0.0002); there was a survival advantage of 0.8 months for patients treated by infusion (12.1 months v 11.3 months, P = 0.04).[11] More recently, the same group explored the relation between response rates to various 5-fluorouracil regimens and survival.[12] This analysis evaluated data from 3791 patients enrolled in 25 randomised trials of standard bolus, single agent 5-fluorouracil, and experimental treatments (5-fluorouracil combined with folinic acid or methotrexate or infusions of 5-fluorouracil or floxuridine (5-fluoro-2'-deoxyuridine) through hepatic arterial infusion). The experimental regimens were associated with a 10.5% higher tumour response rate (P [is less than] 0.001), with an improvement in overall survival of about two months (P = 0.002). The overall survival benefit was a true function of the higher response rates obtained with the experimental therapy.[12] The more active the regimen (measured using tumour response as a surrogate) the greater the prolongation of overall survival.

Chemotherapy prolongs the time to tumour progression and the overall survival of patients with advanced colorectal cancer. These survival gains are accompanied by palliative benefits despite the potential toxicity of chemotherapy. Thus, there is now strong evidence to suggest that chemotherapy should be offered to all patients with advanced colorectal cancer, depending on their physical functioning. Patients should be allowed to make an informed decision, because only they can balance the modest gains in survival and improvements in quality of life from chemotherapy against the potential adverse effects of treatment.

M Michael consultant medical oncologist J R Zalcberg director

Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag No 1A, Beckett Street, Victoria 8002, Australia (zalcberg@petermac.unimelb.edu.au)

[1] Parkin DM, Pisani P, Ferlay J. Cancer statistics. CA Cancer J Clin 1999;49:33-64.

[2] Colorectal Cancer Collaborative Group. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. BMJ 2000;321:531-5.

[3] Guyatt GH, Feeney DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med 1993;118:622-9.

[4] Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Expectant or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. J Clin Oncol 1992;10:904-11.

[5] Glimelius B, Graf W, Hoffman K, Pahlman L, Sjoden PO, Wenberg A. General condition of asymptomatic patients with advanced colorectal cancer receiving palliative chemotherapy. A longitudinal study. Acta Oncol 1992;31:645-51.

[6] Cunningham D, Pryhonen S, James RD, Punt CJA, Hickish TF, Heikkila R, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1999;352:1413-8.

[7] Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international trials in oncology. J Natl Cancer Inst 1993;85:365-76.

[8] Bloomfield DJ, Krahn MD, Neogi T, Panzarella T, Smith TJ, Warde P, et al. Economic evaluation of chemotherapy with mitoxantrone plus prednisone for symptomatic hormone-resistant prostate cancer: based on a Canadian randomized trial with palliative end points. J Clin Oncol 1998;16:2272-9.

[9] Coukell AJ, Noble S, Faulds D. Vinorelbine in advanced non-small cell cancer. A pharmacoeconomic review. Pharmacoeconomics 1999;15:405-17.

[10] Cunningham D, Falk S, Jackson D. Irinotecan and infusional 5-fluorouracil as first line treatment of metastatic colorectal cancer: improved survival and cost-effective compared with infusional 5-FU [abstract]. Proc Am Soc Clin Oncol 2000;19:981A.

[11] Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301-8.

[12] Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P, et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Lancet 2000;356:373-8.

BMJ 2000;321:521-2

COPYRIGHT 2000 British Medical Association
COPYRIGHT 2000 Gale Group