No significant differences in the two treatments were found in the proportion of patients who achieved complete response, partial response, stable disease or progressive disease according to the combined analysis from four trials with 1151 participants. Test for heterogeneity of relative risk including all seven trials with 2095 patients was almost significant (P=0.06). However, using randomized effect model the relative risk was higher in the oxaliplatin group (P=0.01, Figure 1). We performed a sensitivity analysis to the comparison of relative risk. We noted that the gender ratios of the two treatments in the Tournig 2004 trial were significantly different: and because of poor comparability of data from two groups of this trial, we removed that data to conduct the sensitivity analysis for relative risk and the sensitivity analysis demonstrated the greater benefit of oxaliplatin group. There were no differences between the regimens in the duration of response or time to progression. A sensitivity analysis of weighted mean difference using random effect model showed that the survival of oxaliplatin group was longer than that of irinotecan group by 2 months (P=0.008, Figure 2, Table 3).
We only compared the incidence rate of grades 3 and 4 toxicities in this meta analysis (Table 4). The results of combined analysis showed that the incidences of nausea, emesis, diarrhoea and alopecia in irinotecan group were significantly higher than in oxaliplatin group. However, the incidence of neurotoxicity, neutropaenia and thrombocytopenia in irinotecan group were lower (P <0.05). No difference was found in the incidence of dehydration, anaemia or fatigue.
Methodological qualities of all seven trials were poor according to the Jadad scale 1996. There is still a lack of rigorously designed clinical trials of first-line treatment of advanced colorectal cancer by irinotecan or oxaliplatin in combination with fluorouracil/leucovorin. Poor quality was mainly ascribed to no mention of method of concealment of randomized allocation and double blinding. In the 7 series, although the dosages of oxaliplatin or irinotecan were not identical, the total usage amounts were similar. The combination regimens of irinotecan with fluorouracil/leucovorin included irinotecan/fluorouracil/leucovorin and two versions of folinic acid/fluorouracil/irinotecan. The dosages of irinotecan of all the trials were 70–275 mg/m2; however, the total usage amounts were 400–600 mg/m2 every 6 weeks. The combination regimens of oxaliplatin/fluorouracil/leucovorin included FOLFOX4 and FOLFOX6. The dosages of oxaliplatin of all the trials were 45–100 mg/m2; however, the total usage amounts were 255–300 mg/m2 every 6 weeks. No significant differences were found in patients’ characteristics such as age, gender or metastasis, indicating a favourable basis for the comparisons between regimens.
We thank all the friends who had supplied the information for the study, and professor LIU Gui-fen from Statistics Research Institute of Shanxi Medical University for her subservient suggestions and instructions, and BAI Li-xia from Shanxi Children's Hospital for her direction to the use of software.
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 77-108.
2. WAN DS. Clinical oncology. 2 ed. Science press: Beijing; 2005: 348.
3. Firvida JL, Irigoyen A, Vazquez-Estevez S, Diz P, Constenla M, Casal-Rubio J, et al. Phase II study of irinotecan
as first-line chemotherapy for patients with advanced colorectal carcinoma. Cancer 2001; 91: 704-711.
4. de Gramout A, Vignoud J, Tournigand C, Louvet C, Andre T, Varette C, et al. Oxaliplatin
with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 1997: 33: 214-219.
5. 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 randomized trial. Lancet 2000; 355: 1041-1047.
6. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan
plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan
Study Group. N Engl J Med 2000; 343: 905-914.
7. de Gramout 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: 2938-2947.
8. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin
, fluorouracil, and leucovorin as adjuvant treatment for colorectal cancer. N Engl J Med 2004; 350: 2344-2351.
9. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-214.
10. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Wiliamson SK, et al. Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan
or infused fluorouracil plus leucovorin and oxaliplatin
in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J Clin Oncol 2006; 24: 3347-3353.
11. Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 2005; 23: 4866-4875.
12. Comella1 P, Massidda B, Filippelli G, Palmeri S, Natale D, Farris A, et al. Oxaliplatin
plus high-dose folinic acid and 5-fluorouracil i.v. bolus (OXAFAFU) versus irinotecan
plus high-dose folinic acid and 5-fluorouracil i.v. bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial. Ann Oncol 2005; 16: 878-886.
13. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan
, and oxaliplatin
combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22: 23-30.
14. Kalofonos HP, Aravantinos G, Kosmidis P, Papakostas P, Econmopoulos T, Dimopoulos M, et al. Irinotecan
combined with leucovorin and 5-fluorouracil as first-line treatment in advanced colorectal cancer: a multicenter, randomized, phase II study. Ann Oncol 2005; 16: 869-877.
15. Delaunoit T, Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Findlay BP, et al. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan
. Cancer 2004; 101: 2170-2176.
16. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22: 229-237.
17. Misset JL. Oxaliplatin
in practice. Br J Cancer 1998; 77 (Suppl 4): 4-7.
18. Souglakos J, Syrigos K, Potamianou A, Polyzos A, Boukovinas I, Androulakis N, et al. Combination of irinotecan
(CPT-11) plus oxalplatin (L-OHP) as first-line treatment in locally advanced or metastatic gastric cancer: a multicentre phase II trail. Ann Oncol 2004; 15: 1204-1209.
19. Cassidy J, Misset JL. Oxaliplatin
-related side effects: characteristics and management. Semin Oncol 2002; 29 (5 suppl 15): 11-20.