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Originally published as JCO Early Release 10.1200/JCO.2004.11.974 on December 9 2003 © 2004 American Society of Clinical Oncology.
Scheduling of Fluorouracil: A Forget-Me-Not in the Jungle of DoubletsOspedale San Martino, Genoa, Italy The ultimate goal of randomized phase III clinical trials is to help clinicians choose the best treatment for their patients. The large study reported in this issue of the Journal of Clinical Oncology by Goldberg et al [1] achieves this goal. It conveys the message that the FOLFOX regimen (fluorouracil [FU], leucovorin [LV], and oxaliplatin) is more active in response rate and time to progression, more efficacious in overall survival, and less toxic than the IFL regimen (irinotecan, FU, and LV). The IROX regimen (irinotecan and oxaliplatin) is better than IFL as well, but only in terms of overall survival (OS); IROX's activity is the same and its toxicity is worse with regard to vomiting and paresthesias. The authors conclude that FOLFOX should be an additional first-line standard treatment for advanced colorectal cancer. The findings certainly support this conclusion for the US, where the first-line treatment of advanced colorectal cancer is likely to change. However, the impact of these data will be more limited on the other side of the Atlantic, as few oncologists in continental Europe use IFL because use of oxaliplatin or irinotecan plus infusional FU has been common practice since the year 2000. The background for this difference in practice is illustrated in Figure 1, which summarizes the advancements in the first-line treatment of this disease through randomized trials during the last 20 years. Every vertical arrow indicates a new regimen, with superior efficacy compared with a prior regimen, whereas the horizontal arrows indicate regimens producing longer time to progression (TTP) and response rate, but without significant survival improvement. In addition, the plus or minus symbols refer to the toxicity of the new therapy compared with the previous one. Every regimen reported in the Figure therefore represents a "full" step ahead (vertical) or a "half" step ahead (horizontal) in the treatment of this disease. It is easy to understand that FU was superior to best supportive care, and that FU plus LV was in turn superior to FU, though with more toxicity. IFL [2] was subsequently more efficacious than FU plus LV, again, at the cost of additional toxicity. It is with great enthusiasm that the enhanced efficacy of FOLFOX observed in this trial is finally accompanied by the minus sign as far as toxicity is concerned. The IROX regimen is not included because of its toxicity profile, whereas IFL plus bevacizumab [3], with its very significant prolongation of OS afforded by the angiogenesis inhibitor compared with IFL alone, opens a new avenue of combined chemotherapy and targeted therapy. Protracted systemic FU infusions, with or without LV (here referred to as "infusional FU"), have never produced significantly longer OS compared with bolus FU plus LV in randomized trials. In addition, the inconvenience of prolonged infusions explains in part the prior reluctance of US oncologists to use this mode of administration. Branching out from the infusional FU baseline, only FOLFIRI (FU, LV, and irinotecan) produces significantly longer OS at the cost of increased toxicity [4]. This regimen may thus be interpreted as two steps ahead relative to bolus FU and LV (or, if one wishes, one and a half steps ahead). The same FOLFOX at the top of the US vertical series [1] failed to show a survival advantage in the European trial by de Gramont using infusional FU as the control arm, despite a superior response rate and time to tumor progression—perhaps because of smaller sample sizes and more liberal crossover treatments [5]. In addition, the FUFOX (FU and oxilaplatin) [6] and the Arbeitsgemeinschaft Internistische Onkologie (AIO) FU plus irinotecan [7] regimens appear on the horizontal axis, despite OS values of approximately 20 months, indicating benefit limited to TTP and response rate compared with infusional FU. The extensive use of second- and third-line therapies, known to affect the overall survival of patients, may explain these results. In fact, these trials were conducted in continental Europe, where both oxaliplatin and irinotecan were available on the market for the last several years. The concept that "the more agents employed, the longer the OS," is strengthened by the short OS value (11 months) reported in 2003 by a British trial based on infusional FU alone [8].
Two strategies of development converge to result in some common conclusions. First, doublets, FOLFOX or FOLFIRI, are the most efficacious combinations available today. Second, the same doublets are more toxic than infusional FU, which predicts that the triplet, FU-oxaliplatin-irinotecan [9], is unlikely to become widely used due to toxicity. Third, FU is still the basic component of the most efficacious regimens, and attempts to delete it as with IROX in the present study, have not been successful so far. Fourth, infusional FU is the best partner in combination with oxaliplatin or irinotecan; the toxicity of IFL, in which FU is given as a weekly bolus, is, in fact, unacceptable [1,10], and irinotecan given with a 5-day bolus FU plus LV regimen was one of the original arms of this protocol that was terminated because of excessive toxicity. The story is similar for bolus FU and oxaliplatin combinations. Two recently published phase II trials indirectly suggest increased toxicity when oxaliplatin is combined with either weekly bolus FU plus leucovorin, as in the FLOX regimen (FU, LV, and oxilaplatin) [11], or with a 5-day monthly bolus FU plus LV regimen [12]. All of these data lead to the conclusion that we must not forget the relevance of appropriate FU scheduling when using a doublet, and this notion is going to last even in the next era of trials of doublets, with or without targeted therapies. Can we agree with the conclusion of Dr Goldberg et al that FOLFOX should be a standard first-line therapy for advanced colorectal cancer? Yes, we can. But we should also agree with the older conclusion that FOLFIRI should also be considered as a standard first-line treatment for this disease [4]. Therefore, US oncologists should adjust to using more infusional FU than they have done so far, unless oral fluoropyrimidines are demonstrated to be as effective as infusional FU in doublets. No randomized study is available supporting the routine substitution of oral fluoropyrimidines for infusional FU, though the phase II data with these combinations are very promising [13,14], and the direct comparison of capecitabine with oxaliplatin to capecitabine with irinotecan seems to demonstrate rough equivalence, and with the same toxicity profile observed with infusional FU [15]. Which one is best: FOLFOX or FOLFIRI? There is a head-to-head comparison, published in abstract form, suggesting equivalence [16]. In addition, the Tournigand trial [17] investigating the best sequence of administration in first- and second-line treatment (FOLFOX to FOLFIRI compared with the opposite sequence) indicates equivalence as well. The difference between the regimens lies in the spectrum of toxicity: more peripheral neuropathy with FOLFOX, more diarrhea and asthenia with FOLFIRI. Considering these toxicities and the palliative nature of most interventions in stage IV patients (with the exception being potentially surgically resectable metastases), should doublets always be used as first-line therapy, or could we start with less toxic chemotherapy (infusional FU or oral fluoropyrimidines alone) and then reserve doublets as second- or third-line treatments? Neither the Goldberg et al study nor any other study adequately addresses this issue of sequential therapy. Marketing studies in the Western hemisphere suggest that up to 40% of patients receive single-agent fluoropyrimidine as first-line therapy. Toxicity and increased costs probably account for this attitude. An ongoing British trial comparing infusional FU followed by an oxaliplatin-containing or an irinotecan-containing doublet to such doublets upfront will hopefully answer this question. A final word about the implications of this study on the adjuvant treatment of colon cancer: The positive implication is that the recently reported data from the adjuvant MOSAIC study [18] gain further clinical plausibility; this trial showed an additional 23% relative risk reduction in 3-year relapse-free survival with the FOLFOX regimen, compared with infusional FU alone. Along the same line of reasoning, cautious optimism seems justified relative to the outcome of the Pan European Trial on Adjuvant Colon Cancer adjuvant trial comparing FOLFIRI to infusional FU alone. On the other hand, the potential negative implication is the possibility that adjuvant studies already completed, employing doublets with the bolus FU plus LV schedule, such as IFL and the FLOX regimen, may not show the same benefit. The improvements in colorectal cancer treatment have been so fast and so substantial in the last 5 years that the choice of the experimental or the control arm in the studies discussed herein might not seem optimal now. The original selection of the study arms in this trial (Fig 1) is a measure of these rapid changes. But the fact remains that today fewer stage III colorectal cancer patients relapse and more and more stage IV patients are alive at 2 or 3 years on both sides of the Atlantic, likely as a result of using these new regimens. So far, infusional FU remains a central component of the success. There are two immediate challenges—to see if we can substitute mechanical infusion with oral fluoropyrimidines without losing efficacy, and to evaluate how much further we can go with the combined use of chemotherapy and targeted agents, such as the anti–epidermal growth factor receptor or vascular endothelial growth factor antibodies and small molecules. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Alberto F. Sobrero, Sanofi, Aventis, Merck. Received more than $2,000 a year from a company for either of the last 2 years: Alberto F. Sobrero, Sanofi, Aventis, Merck.
REFERENCES
1. Goldberg RM, Sargent DJ, Morton RF, 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 22:23-30, 2004
2. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000 3. Hurwitz H, Fehrenbacher L, Cartwright T, et al: Bevacizumab prolongs survival in first line colorectal patients: Results of a phase III trial of bevacizumab in combination with bolus IFL as first line therapy in subjects with metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:253, 2003 (abstr 1013) 4. Douillard JY, Cunningham D, Roth AD: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicenter randomised trial. Lancet 15:1372-1379, 2000
5. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment of advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 6. Grothey A, Deschler B, Kroening H, et al: Phase III study of bolus 5-fluorouracil (5-FU) /folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusional/ FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 21:129, 2002 (abstr 512) 7. Koehne CH, Van Cutsem E, Wils J: Irinotecan improves the activity of the AIO regimen in metastatic colorectal cancer: Results of EORTC GI group study 40986. Proc Am Soc Clin Oncol 22:254, 2003 (abstr 1018) 8. Maughan TS, James RD, Kerr DJ: Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: A multicentre randomised trial. Lancet 36:457-464, 2003
9. Falcone A, et al: Biweekly chemotherapy with oxaliplatin, irinotecan, infusional fluorouracil, and leucovorin: A pilot study in patients with metastatic colorectal cancer. J Clin Oncol 20:4006-4014, 2002
10. Rothenberg ML, Meropol NJ, Poplin E: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19:3801-3807, 2001
11. Hochster H, Chachoua A, Speyer J, et al: Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer. J Clin Oncol 21:2703-2707, 2003 12. Ravaioli A, Marangolo M, Pasquini E, et al: Bolus fluorouracil and leucovorin with oxaliplatin as first-line treatment in metastatic colorectal cancer. J Clin Oncol 20:2545-2550, 2003 13. Van Cutsem E, Twelves C, Tabernero J, et al: XELOX: Mature results of a multinational, phase II trial of capecitabine plus oxaliplatin, an effective 1st line option for patients with metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol 22:1023, 2003 14. Patt YZ, Lin E, Leibman J, et al: Capecitabine plus irinotecan for chemotherapy naive patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:281, 2003 (abstr 1130) 15. Grothey A, Jordan K, Keliner O, et al: Randomized phase II trial of capecitabine plus irinotecan vs capecitabine plus oxaliplatin as first line therapy of metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:255, 2003 (abstr 1022) 16. Colucci G, Maiello E, Gebbia V, et al: Preliminary results of a randomized multicenter study of the Gruppo Oncologico Italia Meridionale, comparing FOLFIRI vs FOLFOX in advanced colorectal cancer. Proc Am Soc Clin Oncol 22:255, 2003 (abstr 1021) 17. Tournigand C, Louvet C, Quinax E, et al: Folinic acid, fluorouracil, and irinotecan followed by folinic acid, fluorouracil, and oxaliplatin or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22: 10.1200/JCO.2004.05.113 18. De Gramont A, Banzi M, Navarro M, et al: Oxaliplatin/FU/LV in adjuvant colon cancer: Results of the international randomized mosaic trial. Proc Am Soc Clin Oncol 22:253, 2003 (abstr 1015)
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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