Correspondence
Irinotecan plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer
N Engl J Med 2001; 344:305-307January 25, 2001
- Article
To the Editor:
The study by Saltz et al. (Sept. 28 issue)1 leaves unanswered questions regarding the toxicity and dose intensity of the combination of irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. The authors indicate that “the median relative intensity of the dose of irinotecan . . . was similar in the group given irinotecan alone and the group given irinotecan, fluorouracil, and leucovorin.” However, the median relative intensity of the dose of fluorouracil was lower in the triple-drug combination than in the two-drug combination.
These points lead us to ask the following: During cycle 1 of therapy, what proportion of patients in the triple-drug group received all four weekly treatments? What proportion of patients receiving the triple-drug combination had a reduction in the dose during cycle 1 — that is, how many received treatment during all four weeks but at reduced doses? What percentage of patients who received the triple-drug combination during cycle 2 had dose reductions as a result of dose-limiting toxicity during cycle 1? What proportion of patients had dose reductions in cycle 3 because of dose-limiting toxicity in cycle 2?
1 ReferencesCharles Erlichman, M.D.
Richard M. Goldberg, M.D.
Michael J. O'Connell, M.D.
Mayo Clinic, Rochester, MN 559051
Saltz LB ,Cox JV ,Blanke C , et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905-914
Full Text | Web of Science | Medline
To the Editor:
We recently determined the cost-effectiveness ratio of adding irinotecan to the regimen of fluorouracil and leucovorin in patients with advanced colorectal cancer1 and found an unfavorable pharmacoeconomic index (about 50,000 euros [$47,578] per year of life gained) using the clinical results reported by Douillard et al.2 The study by Saltz et al. provides further data on this combination of three drugs, necessitating a reassessment of the cost effectiveness of this treatment.
We analyzed the survival data given in Figure 2 of the article by Saltz et al. to estimate the overall increase in survival per patient (or the incremental effectiveness) derived from the three-drug regimen as compared with the two-drug regimen. For this purpose, we used a standard Gompertz analysis3,4 in which survival rates were extrapolated after 39 months. The cost of irinotecan was based on current prices in Italy (1.7 euros [$1.62] per milligram of drug) and the United Kingdom (£1.30 [$1.95] per milligram). The incremental cost per patient was estimated on the basis of an average cumulative dose of irinotecan of 4277 mg per patient. In this calculation, a dose of 125 mg per square meter of body-surface area per week for 4 weeks every 6 weeks was approximated as 629 mg per patient per month, given a body-surface area of 1.73 m2 and a mean lifetime duration of treatment of 6.8 months; because the median duration of treatment and not the mean lifetime duration of treatment was reported in the study by Saltz et al., we estimated this information by analyzing the area under the curve for progression-free survival in Figure 1 of the article, since progression-free survival represents the duration of treatment according to the study's protocol. In terms of effectiveness, our analysis showed that the overall increase in survival was 2.0 months per patient (mean survival, 16.5 and 14.5 months per patient in the triple-drug group and the two-drug group, respectively). In the economic comparison of the two treatments, the irinotecan group had an incremental cost of £5,560 ($8,341) per patient. These data indicate that the use of irinotecan as an adjunctive therapy for this condition has a cost per year of life gained (the incremental cost divided by the increase in survival) of £32,706 ($49,066). These figures remained virtually unchanged by the addition of a 3 percent annual discount for both costs and survival.
Analyses of the results of Saltz et al. confirm that the cost-effectiveness ratio of irinotecan for advanced colorectal cancer is in the range we reported previously and is quite unfavorable.
4 ReferencesMonica Vaiani, Pharm.D.
Sabrina Trippoli, Pharm.D.
Andrea Messori, Pharm.D.
Azienda Ospedaliera Careggi, 50134 Florence, Italy1
Trippoli S ,Vaiani M ,Cattel F ,Messori A . Cost-effectiveness of irinotecan in advanced colorectal cancer. Ann Oncol 2000;11:899-900
CrossRef | Web of Science | Medline2
Douillard JY ,Cunningham D ,Roth AD , et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-1047
CrossRef | Web of Science | Medline3
Messori A ,Becagli P ,Trippoli S ,Tendi E . A retrospective cost-effectiveness analysis of interferon as adjuvant therapy in high-risk resected cutaneous melanoma. Eur J Cancer 1997;33:1373-1379
CrossRef | Web of Science | Medline4
Messori A ,Trippoli S ,Becagli P ,Tendi E . Pharmacoeconomic profile of paclitaxel as a first-line treatment for patients with advanced ovarian carcinoma: a lifetime cost-effectiveness analysis. Cancer 1996;78:2366-2373
CrossRef | Web of Science | Medline
To the Editor:
In the study by Saltz et al., roughly 40 percent of the patients were asymptomatic at the time of randomization (as indicated by an Eastern Cooperative Oncology Group [ECOG] performance status of 0). It is therefore surprising to find an increase in the overall quality of life after the initiation of treatment (as indicated by the scores on the Global Health Status Subscale of the Quality of Life Questionnaire), because diarrhea is an important side effect of this regimen. It would have been appropriate to provide quality-of-life data specific for diarrhea and not just on a global basis. The initial increase in the global score might simply reflect a placebo effect resulting from the initiation of treatment. Since irinotecan leads to alopecia (as well as to cholinergic symptoms and diarrhea) and the combination of fluorouracil and leucovorin does not, none of the data on quality of life should be considered to have been obtained in a blinded fashion.
Bernhard C. Pestalozzi, M.D.
University Hospital, 8091 Zurich, SwitzerlandTo the Editor:
The randomized trial conducted by Saltz et al. had three groups: irinotecan plus fluorouracil and leucovorin, fluorouracil and leucovorin (a standard treatment), and irinotecan alone. The statistical analysis was, however, limited to the first two groups. The results with irinotecan alone should have been fully presented, and the P values should have been corrected to take into account the multiple tests. Doing so, for instance, will change the P value corresponding to the log-rank test for overall survival from 0.04 to 0.08, if the Bonferroni method is used.
It would be useful to know the duration of follow-up and the number of deaths in each group. Information on the amount of missing data on quality of life and the methods used to handle these missing data in the analysis should be given. Clinically relevant results such as the proportion of patients who received second-line therapy and the quality of life in the irinotecan group should be reported.
We think that the authors' conclusion is overoptimistic, because their analysis focuses on the largest observed difference.
Jean-Pierre Pignon, M.D., Ph.D.
Michel Ducreux, M.D.
Institut Gustave-Roussy, 94805 Villejuif CEDEX, FranceAuthor/Editor Response
The authors reply:
To the Editor: The respective percentages of patients in the study group who received the full dose of irinotecan (125 mg per square meter) plus fluorouracil (500 mg per square meter) were as follows: for day 1 of cycle 1, 100 percent and 100 percent; for day 8 of cycle 1, 89 percent and 88 percent; for day 15 of cycle 1, 64 percent and 64 percent; for day 22 of cycle 1, 45 percent and 45 percent; for day 1 of cycle 2, 47 percent and 48 percent; and for day 1 of cycle 3, 42 percent and 41 percent. In the control group, the percentages of patients who received the full dose of fluorouracil (425 mg per square meter) was 95 percent on days 1 through 5 of cycle 1, 56 percent on days 1 through 5 of cycle 2, and 48 percent on days 1 through 5 of cycle 3. Thus, the likelihood that a dose reduction would be required was similar with the two regimens. Dose reductions in both groups were primarily the result of neutropenia and gastrointestinal toxicity. Discontinuations because of adverse events and treatment-related deaths were as infrequent with the triple-drug therapy (7.6 percent and 0.9 percent, respectively) as with the two-drug therapy (6.4 percent and 1.4 percent, respectively).
Vaiani et al. made certain assumptions in calculating their cost-effectiveness ratios. Cunningham et al.1 and Schmitt et al.2 also calculated cost-effectiveness ratios for the addition of irinotecan to first-line therapy with fluorouracil and leucovorin, using clinical-trial data (and including the cost of health care resources), and arrived at substantially lower estimates of £14,794 ($22,194) in the United Kingdom and 214,098 francs ($31,061) in France. Vaiani et al. did not account for the lifetime costs of drugs and treatments associated with treatment with fluorouracil and leucovorin followed by second-line irinotecan, the prior standard of care.
Sixty-one percent of patients who received irinotecan, fluorouracil, and leucovorin had symptoms of cancer at base line (as indicated by an ECOG performance status of 1 or 2). Thus, most of these patients had the potential for therapy-mediated improvements in the global quality of life. We focused on the global scale because it presumably reflects each patient's weighting of the various aspects of the quality of life. Patients who received triple-drug therapy had better tumor control (with improved role-functioning, fatigue, and pain scores) and a lower incidence of mucositis (with improved anorexia scores),3 advantages that may have offset decreases in the quality of life associated with the occurrence of diarrhea. The 39 percent of patients in the triple-drug group who were asymptomatic at base line (as indicated by an ECOG performance status of 0) had a particularly prominent difference in median survival of 5.8 months, as compared with that in the two-drug group (median survival, 21.8 months vs. 16.0 months).
In response to Pignon and Ducreux: no adjustment in the level of significance was necessary or appropriate, because the only protocol-designated hypothesis testing we did concerned a comparison of the triple-drug group with the two-drug group. The group given irinotecan alone was to be analyzed with the use of descriptive statistics alone. Data on the numbers of patients at risk in all groups are shown in the figures. The duration of follow-up after the end of the accrual period was the same in all groups (19 months). Further details regarding post-study therapy are available elsewhere.4 We used standard techniques5 to account for missing data on the quality of life.
5 ReferencesLeonard B. Saltz, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021Langdon L. Miller, M.D.
Pharmacia, Peapack, NJ 079771
Cunningham D ,Falk S ,Jackson DL . Irinotecan in first line treatment of metastatic colorectal cancer: improved survival and cost-effective compared with infusional 5-FU. Eur J Cancer 2000;36:Suppl 3:S18-S18 abstract.
CrossRef | Web of Science | Medline2
Schmitt C ,Levy-Piedbois C ,Frappe M ,Durand-Zaleski I . Cost-effectiveness analysis of irinotecan as first-line therapy in advanced colorectal cancer. Eur J Cancer 2000;36:Suppl 3:S24-S24 abstract.3
Locker PK ,Miller LL ,Pirotta N ,Elfring GL ,Leonard SB . Weekly irinotecan (C) combined with 5-fluorouracil (F) and leucovorin (L) in patients with untreated metastatic colorectal cancer (MCRC): impact on quality of life. Prog Proc Am Soc Clin Oncol 2000;19:620a-620a abstract.4
See http://www.fda.gov/ohrms/dockets/ac/00/slides/3592s1e/sld057.htm.
5
Zwinderman AH . Statistical analysis of longitudinal quality of life data with missing measurements. Qual Life Res 1992;1:219-224
CrossRef | Medline
- Citing Articles (4)
Citing Articles
1
Michael Jefford, John Zalcberg. (2005) Recent Advances in the Systemic Therapy of Metastatic Colorectal Cancer. American Journal of Cancer 4:1, 15-34
CrossRef2
Lucy C Scott, Chris Twelves. (2003) Cost-Effective Strategies in the Management of Advanced Colorectal Cancer. American Journal of Cancer 2:2, 111-124
CrossRef3
R. M. Goldberg. (2002) A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin. Annals of Oncology 13:10, 1674-1680
CrossRef4
Axel Grothey, Hans-Joachim Schmoll. (2001) New chemotherapy approaches in colorectal cancer. Current Opinion in Oncology 13:4, 275-286
CrossRef
