Irinotecan and High-Dose Fluorouracil/Leucovorin for Metastatic Colorectal Cancer
Irinotecan and High-Dose Fluorouracil/Leucovorin for Metastatic Colorectal Cancer
Colorectal cancer is common in the western world. Surgery is usually the first treatment option for patients presenting with early colorectal cancer, but it is frequently ineffective; many patients develop metastatic disease following potentially curative surgery. Treatment with fluorouracil (5-FU), usually modulated with leucovorin, has been considered standard treatment for these patients.[1-3] Until recently, there has been no standard treatment available for patients whose disease has progressed after first-line treatment. The prognosis for such patients has been poor, with a short survival time and poor quality of life.[1,4-5] Continuous infusion of 5-FU might be provided to these patients using either the de Gramont, the Lokich, or the AIO (Arbeitsgruppe Internistische Onkologie [of the German Cancer Society]) regimen.[6-8]
Superiority of one regimen over the other, however, has not been shown. In the past, many patients with 5-FU-resistant colorectal cancer have received best supportive care because of the low response rates and toxicity characteristic of older cytotoxic agents. Newer cytotoxic agents have been developed in the hope of improving treatment options for colorectal cancer. Irinotecan (CPT-11, Camptosar) is among these newer agents and has indeed provided encouraging results.
Irinotecan, administered at a dose of 350 mg/m2 once every 3 weeks in Europe and at a dose of 100 to 125 mg/m2 every week for 4 to 6 weeks in the United States, has been shown to be an effective and manageable second-line regimen for patients with colorectal cancer. Based on the encouraging phase II activity observed with irinotecan in the treatment of second-line metastatic colorectal cancer, two randomized phase III trials were conducted. The phase III trial data demonstrated that the new topoisomerase I inhibitor irinotecan is superior to both best supportive care alone and high-dose infusion of 5-FU in second-line therapy for metastatic colorectal cancer.[11,12]
Taken together, these studies justified considering irinotecan as the reference therapy for patients with metastatic colorectal cancer for whom 5-FU has failed. However, a question remained: might earlier use of irinotecan in combination with 5-FU further extend the survival of patients with metastatic colorectal cancer?
High-dose infusional regimens of 5-FU modulated with leucovorin are commonly used in Europe, and randomized trials have demonstrated that this approach is superior to bolus 5-FU in terms of response rate, time to progression of disease, and safety.[3,13,14]
Irinotecan and 5-FU have different mechanisms of action, and there appears to be a lack of clinical cross resistance between them. This observation is supported by a series of phase II studies, largely with 5-FU-resistant disease.[10,15-18]
Rationale for the Study
Because both infusional 5-FU and irinotecan have proven activity in metastatic colorectal cancer, the logical next step was to determine whether their use in combination would be of additional benefit. Schedule-dependent synergistic activity when the two drugs were delivered in combination had already been demonstrated both in vitro and in vivo.[19-21]
Several clinical trials have been undertaken with the 5-FU and irinotecan combination, and various schedules have been evaluated.[22-25] Vanhoefer and colleagues recommended for further study an 80 mg/m2 dose of irinotecan in combination with 2,600 mg/m2 5-FU administered over 24 hours plus 500 mg/m² leucovorin given on a weekly ´ 6 schedule. These investigators concluded that the combination improved the efficacy of the treatment, with a manageable safety profile.
Similarly, Ducreux and colleagues conducted a dose-finding study with irinotecan in combination with 5-FU/leucovorin. Their recommended dose for further phase II studies was 180 to 200 mg/m2 of irinotecan in combination with 5-FU/leucovorin (leucovorin at 200 mg/m2 via 2-hour infusion, followed by a 10-minute infusion of 5-FU at 400 mg/m2, followed by a 22-hour continuous infusion of 5-FU at 600 mg/m2) administered every 2 weeks.
Based on the available data, a phase III trial with the irinotecan/5-FU/leucovorin combination was conducted to confirm its efficacy and safety in the first-line treatment of metastatic colorectal cancer.
Study Objectives and Treatment Protocols
The primary end point of the study was response rate, with secondary end points including time to progression of disease, time to treatment failure, overall survival, safety, and quality of life.
A total of 188 patients received a 5-FU/leucovorin regimen alone and 199 patients received a 5-FU/leucovorin regimen plus irinotecan. The 5-FU/leucovorin regimen used was decided by the lead investigator in each participating center prior to the start of the trial; the alternatives were either the de Gramont schedule administered every 2 weeks or the weekly AIO schedule.
In the case of centers using the AIO regimen, 54 control patients received leucovorin at 500 mg/m2 IV over 2 hours followed by 5-FU at 2,600 mg/m2 IV over 24 hours. In the investigational arm of the study, 43 patients received the same weekly leucovorin/5-FU regimen (with 2,300 mg/m2 of 5-FU) preceded by 80 mg/m2 of irinotecan given as a 90-minute IV infusion. In both arms of the study, patients received six infusions spaced a week apart, with the six infusions constituting one cycle.
A larger number of patients (288 in total) were randomized to receive either the standard de Gramont protocol (200 mg/m2 of leucovorin IV over 2 hours followed by a 400 mg/m2 bolus of 5-FU then 600 mg/m2 of 5-FU infused over 22 hours) or the de Gramont protocol preceded by 180 mg/m2 of irinotecan. In both arms of the study, 5-FU and leucovorin were administered on days 1 and 2, whereas irinotecan was given on day 1 only. A single cycle consisted of three treatments 2 weeks apart.
To be eligible for the study, patients had to have one or more bidimensionally measurable, unresectable lesions. Patients were between 18 and 75 years of age, and had a WHO (World Health Organization) performance status of 2 or less. Trial entrants had not received prior chemotherapy for advanced disease. However, patients who had been given adjuvant chemotherapy were not excluded provided that treatment had ended 6 or more months before the study.
Randomization resulted in a good balance of patient characteristics and prognostic factors across the two arms of the study (Table 1). The exceptions were a statistically significant excess of patients with cancer of the rectum in the irinotecan plus 5-FU arm of the study (40% vs 32% of controls, P = .04 by chi square test), and a greater proportion of female patients in the control arm of the study (47% vs 33%, P = .006).
The median duration of treatment among patients receiving the combination of irinotecan and 5-FU/leucovorin was 24 weeks with the AIO regimen and 25 weeks with the de Gramont protocol. The corresponding figures for the control arm of the study were somewhat shorter (21 and 18 weeks, respectively). A median of three cycles of treatment was delivered to control patients and to those receiving irinotecan plus the AIO 5-FU/leucovorin regimen. In the combination group treated with the de Gramont 5-FU protocol, the median number of cycles was 4.
In the control arm of the study, the relative dose intensity of 5-FU administered was 0.9 with the AIO regimen and 0.96 with the de Gramont protocol. The relative dose intensity for 5-FU was somewhat less in groups receiving combination therapy (0.81 for AIO and 0.92 for de Gramont). In the latter groups, the relative dose intensities for irinotecan were 0.82 and 0.93.
The proportions of patients experiencing grade 3/4 hematologic toxicities and selected grade 3/4 nonhematologic toxicities on the every-2-week and weekly schedules are shown in Table 2 and Table 3, respectively. The incidence of grade 3/4 neutropenia was increased with the combination of irinotecan with 5-FU/leucovorin. However, the number of patients in whom febrile neutropenia developed remained low (5%), and infection accompanied the neutropenia in only 2% of patients. There was one septic death.
Of the nonhematologic toxic effects, diarrhea was the most frequent. Grade 3/4 diarrhea affected 22% of patients receiving irinotecan plus 5-FU/leucovorin and 10% of those treated with 5-FU/leucovorin alone. However, this problem was manageable. The incidence of nausea and vomiting, asthenia, and mucositis was low in all groups. Grade 1/2 alopecia was experienced by 51% of patients in the combination arm of the study and by 17% of controls.
Response and Survival Rates
The combination of irinotecan with 5-FU/leucovorin resulted in a significantly higher response rate, longer time to progression of disease, and improved 1-year survival than 5-FU/leucovorin alone (Table 4). The confirmed overall response rate (the primary end point of the study) was significantly higher among patients receiving irinotecan plus 5-FU/leucovorin than among those treated with 5-FU/leucovorin alone (40.8% vs 23.1%, P < .001). In the former group, there was also a confirmed complete response rate of 3.6%, whereas no complete responses were experienced in the control group.
At 1 year, 69% of patients treated with irinotecan plus 5-FU/leucovorin were alive, compared with 59% of controls (P = .03). The median survival time was also significantly longer in the combination arm (17.4 vs 14.1 months, P = .03).
Multivariate analysis identified treatment with irinotecan plus 5-FU/leucovorin as an independent predictor of response (odds ratio 2.6, P < .001). Weight loss (5% or less at baseline) was also significant (odds ratio 2.5, P = .004), as was shorter time (< 12 months) between first diagnosis and first detection of metastases. Risk of progression of disease was predicted by treatment without irinotecan (odds ratio 1.6, P < .001). Patient age and liver involvement were also identified as having prognostic significance.
Of the patients randomized to receive the combination of irinotecan and 5-FU/leucovorin, 40% subsequently received second-line chemotherapy for metastatic disease. In 16%, such treatment involved an oxaliplatin-containing regimen; in 15%, 5-FU alone; and in 6%, a further irinotecan combination. A larger proportion of patients who did not initially receive irinotecan (58%) were given second-line therapy. In 31%, this treatment involved an irinotecan-containing regimen; in 13%, it involved an oxaliplatin combination regimen.
Results from the two randomized phase III trials with irinotecan in patients for whom 5-FU had failed confirmed the efficacy of irinotecan as second-line treatment of colorectal cancer. These results were particularly encouraging in this difficult-to-treat patient population. Irinotecan is now used as standard treatment of such patients.
In the context of first-line treatment of metastatic colorectal cancer, the response and survival benefits that follow the addition of irinotecan to continuous infusion of 5-FU/leucovorin regimens are striking. Patients treated with 5-FU/leucovorin alone were 1.6 times more likely to experience progression of disease than those treated with irinotecan plus 5-FU/leucovorin. Patients treated with the combination were 2.6 times more likely to respond than those receiving 5-FU/leucovorin alone.
This study demonstrates that first-line combination therapy significantly extends overall survival compared with the infusional 5-FU/leucovorin treatment. The finding is all the more encouraging since the effect of first-line therapy is likely to have been diluted by subsequent second-line chemotherapy, and particularly by the second-line use of an irinotecan-containing regimen in 31% of patients initially randomized to the control group. Another randomized study, reported by Saltz, confirmed the benefit of irinotecan combined with 5-FU/leucovorin in terms of efficacy and survival benefit, except in the subgroup of patients with a performance status of 1 or 2 or an elevated lactate dehydrogenase level at baseline.
Given these data, the combination of irinotecan with 5-FU/leucovorin should be considered the first-line treatment of choice for metastatic colorectal cancer. Adjuvant studies with this combination are ongoing.
1. Cohen AM, Minsky BD, Schilsky RL: Cancer of the colon, in De Vita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5th ed, pp 1144-1196. Philadelphia, Lippincott-Raven, 1997.
2. Cunningham D, Findlay M: The chemotherapy of colon cancer can no longer be ignored. Eur J Cancer 29A: 2077-2079, 1993.
3. The Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992.
4. Fages B, Cote C, Gruia G, et al: Tumor response and stabilization rates are worthwhile surrogate efficacy endpoints in metastatic colorectal cancer: Analysis of data in 455 5-FU resistant patients treated with CPT-11 (abstract). Proc Am Soc Clin Oncol 16:288, 1997.
5. Glimelius B, Hoffman K, Graf W, et al: Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. Cancer 73:556-562, 1994.
6. de Gramont A, Bosset J-F, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997.
7. Hansen R, Quebbeman E, Ausman R, et al: Continuous systemic 5-fluorouracil infusion in advanced colorectal cancer: Results in 91 patients. J Surg Oncol 40:177-181, 1989.
8. Weh MJ, Wilke HJ, Dierlamm J, et al: Weekly therapy with folinic acid (FA) and high-dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal cancer. Ann Oncol 5:233-237, 1994.
9. Van Halteren HK, Wagener DJ, Vreugdenhil G, et al: Advanced colorectal cancer, refractory to infusional fluorouracil treatment: Efficacy of second line fluorouracil in combination with a different biochemical modulation. Anticancer Res 17:2715-2719, 1997.
10. Cunningham D: Setting a new standard Irinotecan (Campto) in the second-line therapy of colorectal cancer: Final results of two phase III studies and implications in clinical practice. Semin Oncol 26(suppl 5):1-5, 1999.
11. Cunningham D, Pyrhönen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998.
12. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lance. 352:1407-1412, 1998.
13. Köhne CH, Schöffski P, Wilke H, et al: Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: Results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 16:418-426, 1998.
14. Aranda E, Cervantes A, Anton A, et al: A phase III multicenter randomized study in advanced colorectal cancer (CRC): Fluorouracil (FU) high-dose continuous infusion (CI) weekly versus fluorouracil + leucovorin (LV) (abstract): Preliminary results. Proc Am Soc Clin Oncol 16:281, 1997.
15. Van Cutsem E, Rougier P, Droz JP, et al: Clinical benefit of irinotecan (CPT-11) in metastatic colorectal cancer (CRC) resistant to 5-FU (abstract). Proc Am Soc Clin Oncol 16:268, 1997.
16. Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14:1128-1135, 1996.
17. Creemers GJ, Lund B, Verweij J: Topoisomerase I inhibitors: Topotecan and irinotecan. Cancer Treatment Rev 20:73-96, 1994.
18. Pitot HC, Wender DB, O’Connell MJ, et al: Phase II trial of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 15:2910-2919, 1997.
19. Mans DR, da Rocha AB, Vargas Schwartzbold C, et al: Assessment of the efficacy of the irinotecan (Campto)/5-fluorouracil (5-FU) combination in a panel of human colon carcinoma cell lines. Proc Am Assoc Cancer Res 37:291, 1996.
20. Guichard MJ, Caliaro G, Houlin R, et al: Sequential exposure to CPT-11 and 5-FU is synergistic in human colon carcinoma HT-29 cell line. Proc Am Assoc Cancer Res 37:292, 1996.
21. Grivivich I, Mans DRA, da Rocha AB, et al: The cytotoxicity of irinotecan (CPT-11)-5-FU combination in human colon carcinoma cell lines is related to the sequence-dependent introduction of DNA lesions (abstract). Proc Am Assoc Cancer Res 38:2133, 1997.
22. Goldberg R, Erlichman C: Irinotecan plus 5-FU and leucovorin in advanced colorectal cancer: North American trials. Oncology 12(8 suppl 6):64-71, 1998.
23. Khayat D, Gil-Delgado M, Antoine EC, et al: European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. Oncology 12(8 suppl 6):59-63, 1998.
24. Vanhoefer U, Harstrick A, Köhne CH, et al: Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer. J Clin Oncol 17:907-913, 1999.
25. Ducreux M, Ychou M, Seitz J-F, et al: Irinotecan combined with bolus fluorouracil, continuous infusion fluorouracil, and high-dose leucovorin every two weeks (LV5FU2 regimen): A clinical dose-finding and pharmacokinetic study in patients with pretreated metastatic colorectal cancer. J Clin Oncol 17:2901-2908, 1999.
26. 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 randomized trial. Lancet 355:1041-1047, 2000.
27. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343: 905-914, 2000.