|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2004.05.113 on December 2 2003 © 2004 American Society of Clinical Oncology. FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR StudyFrom the GERCOR; Hôpital Saint-Antoine; Hôpital Tenon; Hôpital Georges Pompidou; Aventis; International Drug Development Institute, Paris; Clinique de l'Orangerie, Strasbourg; Clinique Saint-Jean, Lyon; Clinique Drevon, Dijon; Centre Jean Bernard, Le Mans; Clinique Courlancy, Reims, France; International Drug Development Institute, Brussels, Belgium Address reprint requests to A. de Gramont, MD, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris, Cedex 12, France; e-mail: aimery.de-gramont{at}sat.ap-hop-paris.fr.
PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m2 or dl-LV 400 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 to 3,000 mg/m2 every 46 hours every 2 weeks, either with irinotecan 180 mg/m2 or with oxaliplatin 100 mg/m2 as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULTS: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P = .99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P = .64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P = .26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.
Colorectal cancer accounts for 10% to 15% of all cancers and is the second leading cause of cancer deaths in western countries. Approximately half of all patients develop metastatic disease [1]. Palliative chemotherapy is more effective than the best supportive care at prolonging survival and improving quality of life [2]. Until recently, the antimetabolite fluorouracil (FU), which has been available for over 40 years, and leucovorin (LV) modulation were the standard of care, despite having no major impact on survival [3]. We showed that a fortnightly (every 2 weeks) regimen (LVFU2) which combined LV + FU bolus and infusion was safer and more active than LV + FU as a bolus [4]. We further developed a simplified fortnightly LVFU2 regimen which combined LV + FU bolus on day 1 only with a high-dose FU infusion [5]. This regimen achieved promising activity without increasing toxicity [6]. Two new drugs, irinotecan and oxaliplatin, have demonstrated survival improvement, when given either alone or in combination with LV + FU, in first- or second-line therapy [7-12]. Irinotecan inactivates topoisomerase I via its active metabolite SN38. Phase III studies of patients whose disease had progressed after first-line FU have shown that irinotecan as a single agent increased survival compared with best supportive care or LV + FU infusion [7,8]. In two first-line phase III studies, a significant survival advantage was demonstrated for irinotecan combined with LV + FU, compared with LV + FU alone [9,10]. Oxaliplatin, a cytotoxic agent from the diaminocyclohexane family, has a mechanism of action similar to that of other platinum derivatives, but its spectrum of antitumor activity against tumor models differs from those of cisplatin and carboplatin. Its activity against cisplatin-resistant carcinoma and colon carcinoma cell lines has been demonstrated in vitro. In addition, experimental data showed synergistic activity for the oxaliplatin/FU combination [13]. Phase II studies of the combination of FU + LV and oxaliplatin have demonstrated activity in patients previously treated with FU [14-17]. A randomized study has shown that the combination of the LVFU2 schedule with oxaliplatin (FOLFOX4) prolonged progression-free survival (PFS) [11]. Another recent phase III study has shown improved survival for FOLFOX4 over irinotecan in combination with LV + FU as a bolus [12]. The simplified LVFU2 regimen has been combined with irinotecan (FOLFIRI regimen) and with oxaliplatin (FOLFOX6 regimen) and evaluated in second-line therapy [16,18,19]. The present randomized study was designed to evaluate these two improved regimens and to determine the best sequence to treat patients with metastatic colorectal cancer.
The eligibility criteria for inclusion onto the study were: adenocarcinoma of the colon or rectum; unresectable metastases; at least one bidimensionally measurable lesion of  2 cm or a residual nonmeasurable lesion; adequate bone marrow, liver (alkaline phosphatases < 3 upper limits of normal [UNL], total bilirubin < 1.5 UNL, AST and ALT  3 UNL) and renal function (creatinine 135 µmol/L); WHO performance status (PS) of 0 to 2; age 18 to 75 years. Previous adjuvant chemotherapy, if given, must have been completed at least 6 months before inclusion. Patients with CNS metastases, second malignancies, bowel obstruction, current diarrhea grade 2, symptomatic angina pectoris, or disease confined to previous radiation fields were excluded. Written informed consent was required and the Ethical Committee approved the study.
Chemotherapy
Patients randomly assigned to arm A received first FOLFIRI until progression or unacceptable toxicity and then FOLFOX6. The opposite sequence was administered in patients randomly assigned to arm B. In case of toxicity imputed to oxaliplatin or irinotecan during first-line therapy and no progressive disease, patients could receive LV and FU alone until progression, and then the other regimen. Treatment was continued until disease progression, unacceptable toxicity, or patient choice. Toxicity was assessed before starting each 2-week cycle using the National Cancer Institute-Common Toxicity Criteria [20]. A specific scale was used for sensory neurotoxicity: grade 1 is short-lasting paresthesia with complete regression before the next cycle, grade 2 is persistent paresthesia or dysesthesia without functional impairment, and grade 3 is persistent functional impairment.
Chemotherapy was delayed until recovery if neutrophils < 1.5 x 109/L, platelets < 100 x 109/L, or for significant persisting nonhematologic toxicity. FU infusion dose was reduced to the previous level or 2,000 mg/m2 if related
Evaluation Criteria The primary objective of the study was the second PFS; time duration from randomization until progression after the second-line of chemotherapy. If the patient could not receive the second-line for medical reason or refusal, the PFS on first-line therapy was used. Secondary objectives of the study were PFS, overall survival (OS), response rates (RRs), and safety.
Statistical Considerations
Patient Characteristics From December 1997 to September 1999, 226 patients were randomly assigned at 42 institutions, 113 in each arm. Six patients were not analyzed as a result of being ineligible and not treated (four in arm A and two in arm B). Characteristics of 220 eligible patients are reported in Table 1. Characteristics of the patients were well-balanced between arms, except for sex-ratio, where the percentage of males was higher in arm B, and age > 65 years, where the percentage was slightly greater in arm B.
The cutoff dates were March 31, 2001 for PFS, when the number of events required for analysis was reached, and August 30, 2002 for OS, with a median potential follow-up time for the entire cohort of 43.9 months.
Progression-Free Survival
Second-line therapy. According to the external review, median PFS was 4.2 months (95% CI, 3.7 to 5.2) for arm A (FOLFOX6) versus 2.5 months (95% CI, 2.1 to 3.3) for arm B (FOLFIRI; P = .003; Fig 2). According to the investigators' assessments, these values were 4.9 months (95% CI, 3.8 to 5.7) for arm A versus 2.3 months (95% CI, 2.1 to 3.5) for arm B. The median delay between progression on first-line therapy and the first cycle of second-line therapy was 21 days in arm A and 15 days in arm B (P = .27). As of March 31, 2001, 81 patients (74%) had received per protocol FOLFOX6, second-line therapy in arm A and 69 patients (62%) FOLFIRI second-line therapy in arm B, including one patient who received FOLFOX6 instead of FOLFIRI. Eight patients in both arms received a second line of treatment out of study. Three patients in arm A and five in arm B received the second line after the cut-off date. Five patients in arm A and eight in arm B had no tumor progression after first-line therapy. Twelve patients (11%) in arm A and 17 (15%) in arm B could not receive a second-line therapy as a consequence of death, poor PS, or refusal. Second progression-free survival. According to the external review, median second PFS was 14.2 months (95% CI, 12.0 to 16.9) for arm A versus 10.9 months for arm B (95% CI, 9.0 to 14.6; P = .64; Fig 3). According to the investigators' assessments, median second PFS was 14.2 months (95% CI, 12.2 to 15.4) for arm A versus 11.8 months (95% CI, 9.2 to 14.6) for arm B. At 15 months, PFS was 47.2% in arm A versus 37.3% in arm B.
Independent prognostic factors for improved second PFS were: good PS (P = .001), no prior adjuvant chemotherapy (P = .001), low lactate dehydrogenase (P = .011), and female sex (P = .043).
Overall Survival
Independent prognostic factors for improved OS were: good PS (P < .0001), low lactate dehydrogenase (P < .001), no prior adjuvant chemotherapy (P = .001), low alkaline phosphatase (P = .012), metastasis confined to the liver (P = .016), carcinoembryonic antigen (P = .016), and female sex (P = .048).
Objective Tumor Responses
Only two independent prognostic factors were found to be significant for first-line response: good PS (P = .001) and liver-only metastases (P = .004). Secondary surgery to remove metastases was performed in 10 patients (9%) in arm A versus 24 patients (22%) in arm B (P = .02). All patients undergoing secondary surgery had liver metastases except one who had a lumbar aortic lymph node metastasis. Thirty patients had a single metastatic site, three had two sites, and one had three sites. The mean number of cycles given before surgery was 12 cycles of FOLFIRI and 10 cycles of FOLFOX6. According to expert review, eight patients (7%) had a R0 resection in arm A versus 14 in arm B (13%; P = .26). In addition, two patients underwent a second or third surgical resection. Median OS in patients who had surgery was 47 months in the FOLFIRI first-line arm, and was not reached in the FOLFOX6 arm (P = .96). Second-line therapy. The RRs were 15% with FOLFOX6 second-line (95% CI, 7% to 23%) versus 4% with FOLFIRI second-line (95% CI, 0% to 9%; P = .05; Table 3). In second-line therapy, the investigators' assessments of objective response for FOLFOX6 and FOLFIRI were 21% and 6%, respectively.
Secondary surgery to remove metastases after second-line therapy could be performed in two patients in arm A and one in arm B.
Toxicity Elderly patients (> 65 years; n = 90) did not experience increased toxicity in first-line therapy as compared with younger subjects. Second-line therapy. During second-line therapy, arm A patients received a median of eight cycles (range, 2 to 23) of FOLFOX6, and those in arm B received a median of six cycles (range, 1 to 33) of FOLFIRI. There were no therapy-related deaths. The toxicity profile in each regimen showed minor differences compared with first-line therapy (Table 3). Grade 3/4 neutropenia and thrombocytopenia and neurotoxicity were less frequent with FOLFOX6, while gastrointestinal toxicities were less frequent with FOLFIRI. Of note, only 19% of the patients who developed grade 3 neurotoxictiy on first-line oxaliplatin still had a grade 3 neurotoxicity when they began second-line FOLFIRI. Overall, 49% of the patients experienced grade 3/4 toxicities with FOLFOX6 second-line versus 44% with FOLFIRI (P was not significant). Serious related adverse events occurred in 6% of the patients with FOLFIRI and in 4% of patients with FOLFOX6. Ten (12%) of the patients with FOLFOX6 second-line and one patient (1%) with FOLFIRI had to stop for toxicity. Elderly patients (> 65 years; n = 59) did not experience increased toxicity, as compared with younger subjects. During the first 60 days in second-line therapy, six patients died (three in each arm; arm A, 4%; arm B, 3%). Vascular events were reported in three cases: pulmonary embolism in one FOLFIRI first-line patient and one FOLFOX6 second-line patient, and a third patient who developed congestive heart failure on first-line FOLFOX6.
Dose-Intensity
Weight and Performance Status A weight increase of at least 5% was recorded for four patients receiving second-line therapy FOLFIRI (6%) versus seven patients on FOLFOX6 (9%; P = .55). PS improved in 12 patients among 34 assessable patients with PS > 0 (35%) on FOLFIRI, versus nine among 35 assessable patients (26%) on FOLFOX6 (P = .44).
Our study is the first randomized study of two sequential regimens incorporating oxaliplatin and irinotecan in the treatment of advanced colorectal cancer. The first and most impressive result of this study is an OS in excess of 20 months in both arms, which has not been previously reached in any randomized study of metastatic colorectal cancer therapy. We could not identify better prognostic factors in our population compared with other studies (Table 4).
Previous studies have shown that in first-line therapy, the addition of irinotecan or oxaliplatin to the LVFU2 fortnightly regimen has an impact on survival of patients with metastatic colorectal cancer [9-11]. However, survival in the trials with the combination of LV + FU, and irinotecan or oxaliplatin was in the range of 15 to 17 months, a benefit of 1.5 to 3.5 months over LV + FU alone, although crossovers from LV + FU alone to the more active treatment tended to decrease the relative size of the benefit. Second-line studies have also shown an impact on survival. In the two randomized second-line studies using irinotecan as single agent, the benefit on survival ranged between 1.5 to 3 months [7,8]. Oxaliplatin alone has a limited efficacy as single-agent in second-line therapy, but FOLFOX regimens have given 20% to more than 40% RRs and median survivals between 10 and 17 months [14-17]. Of note, in the present study, 82% of the patients in one arm and 74% in the other arm received second-line chemotherapy. However, the low RR of FOLFIRI in second-line suggests that FU may not be necessary in this setting. The new simplified LVFU2 fortnightly regimen could also have an impact on survival. Three phase III studies combined the first LVFU2 regimen with irinotecan (LVFU2/irinotecan) and oxaliplatin (LVFU2/oxaliplatin or FOLFOX4) [10-12]. In our study, the new simplified LVFU2 regimen was combined with irinotecan at the same dose as the previous study (FOLFIRI) and oxaliplatin at higher dose (FOLFOX6). The results of FOLFIRI first-line compared favorably to LVFU2/irinotecan. However, the results of FOLFOX6 and FOLFOX4 first-line were similar despite the higher dose of oxaliplatin in FOLFOX6 (Table 4). In second line therapy, after irinotecan based-chemotherapy, FOLFOX6 and FOLFOX4 also achieved similar results [27]. Our study failed to demonstrate that a sequence of first-line irinotecan followed by second-line oxaliplatin, or the reverse sequence beginning with first-line oxaliplatin, was better than the other. RRs, PFS first-line, second PFS, and OS did not differ between the two arms with statistical significance. However, our first objective, second PFS, did not provide a good evaluation of two lines of treatment. The effect of chemotherapy could not be properly evaluated in patients having surgery, a therapeutic break, or delayed second-line therapy. Furthermore, in our study there was an imbalance between the numbers of patients in the two study arms who had received the second-line therapy at the time of analysis. For future trials using a multiline strategy, we will use the concept of time of disease control (TDC) which could be a new tool to assess the duration of the therapeutic effect [28]. To perform TDC, PFS for each line is added. But, in case of progression at the first tumor assessment on any therapy line, PFS for this line is null. Intervals between the therapeutic lines are also not considered in the TDC. The Kaplan-Meier method is then used to perform TDC curves. In this study, median TDC was 10.5 months in arm A and 8.7 months in arm B (P = .64), 3.7 months and 2.2 months less than the median second PFS, respectively. Over 15% of the patients underwent curative surgery in our study—22% with FOLFOX6 first-line and 9% with FOLFIRI. However, inoperability criteria were not provided, which could explain in part this high resection rate and the difference between two regimens that achieved the same RR. Surgery of metastases after chemotherapy could be another breakthrough in the therapy of patients with advanced colorectal cancer. As expected, the toxicity profile of both regimens showed some differences. Gastrointestinal toxicities, except diarrhea, were more frequent with FOLFIRI and hematologic toxicity was more frequent with FOLFOX6 in first-line therapy. Alopecia and fatigue were more frequent with FOLFIRI. We observed an unexpectedly high rate of oxaliplatin neurotoxicity, with 34% of first-line patients developing grade 3 toxicity. This could be because of the higher dose of oxaliplatin in the FOLFOX6 regimen than in the FOLFOX4. However, it may also reflect the difficulty of assessing sensory neurotoxicity. The specific scale which rates grade 3 as a persistent functional impairment could overestimate the incidence of severe neurotoxicity when cycles are repeated at short intervals. This is supported by the observation that only 19% of the patients remained with grade 3 neuropathy at the beginning of FOLFIRI after FOLFOX6, despite a median time between the regimens of less than 1 month. The final conclusion of the study is that both sequences are similar and achieve an impressive survival. However, the fact that a substantial proportion of patients did not get second-line therapy makes the choice in first-line therapy particularly important. Future developments should focus on the two limitations shown in this study, namely neurotoxicity that forces many patients to stop oxaliplatin before tumor resistance develops, and the relatively poor efficacy of FOLFIRI as second-line therapy. The ongoing GERCOR studies are designed to overcome these limitations. These are OPTIMOX [29], which evaluates a limited number of cycles of the new FOLFOX7 regimen with reintroduction of oxaliplatin after LV/FU maintenance therapy, and the FOLFIRI3 study [30] which evaluates a new second-line regimen. Preliminary results of this study have been presented previously by others based on earlier data, and with different conclusions about the results [31]. With the full data, we believe our conclusions about the roles of oxaliplatin and irinotecan in first- and second-line therapy are correct.
Investigators: Dr E. Achille, Strasbourg; Dr T. Andre, Paris; Dr D. Avenin, Paris; Dr C. Bachmeyer, Creil; Dr M. Benchalal, Mulhouse; Dr Ch. Berger, Avignon; Dr C. Boaziz, Sarcelles; Dr A. Boutan-laroze, Argenteuil; Dr C. Bressac, Marscille; Dr R. Brunet, Bordeaux; Dr E. Carola, Senlis; Dr S. Cattan, Paris; Dr L. Chauvenet, Paris; Dr P. Colin, Reims; Pr A. de Gramont, Paris; Dr J. Doll, Le Chesnay; Dr P.L. Etienne, St Brieue; Dr P.L. Etienne, St Brieuc; Dr J.P. Fauchart, Charleville-Mézières; Dr M.H. Filippi, Ferolles-Attilly; Dr M. Flesch, Dijon; Dr G. Ganem, Le Mans; Dr J.L. Gaudin, Lyon; Pr M. Hebbar, Lille; Dr C. Hennequin, Paris; Dr J.H. Jacob, Caen; Dr B. Landi, Paris; Dr F. Lipinski, Bayonne; Dr G. Lledo, Lyon; Dr J.P. Lotz, Paris; Pr C. Louvet, Paris; Dr F. Maindrault, Paris; Dr P. Marti, Pau; Dr F. Morvan, Pontoise; Dr E. Noirclerc, Mulhouse; Dr P. Nouyrigat, Hyères; Dr C. Tournigand, Paris, France. GERCOR: F. Devillards, C. Gobin, V. Lotz, M. Rouyer, L. Renaud; IDDI: M. Buyse, E. Quinaux, G. Fesneau; AVENTIS: D. Mery-Mignard, C. Couteau, M.L. Risse, J.C. Pouget, S. Automne, I. Ploton, R. Madueno, C. Bovancheau.
The following authors 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: Aimery de Gramont, Aventis, Sanofi; Gerard Lledo, Aventis, Sanofi; Christophe Louvet, Aventis, Sanofi. Performed contract work within the last 2 years: Emmanuel Quinaux, Aventis; Marc Buyse, Aventis. Served as an officer or member of the Board of a company: Dominique Mery-Mignard, Aventis; Corinne Couteau, Aventis; Gerard Lledo, Sanofi. Received more than $2,000 a year from a company for either of the last 2 years: Aimery de Gramont, Aventis, Sanofi; Dominique Mery-Mignard, Aventis; Corinne Couteau, Aventis; Christophe Louvet, Sanofi.
We are indebted to the physicians and all who contributed to this study.
Sponsored by Aventis, Paris, France. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49:8-31, 1999 2. Glimelius B, Hoffman K, Graf W, et al: Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer 73:556-562, 1994[CrossRef][Medline] 3. 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[Abstract]
4. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 15:808-815, 1997 5. de Gramont A, Louvet C, André T, et al: A simplified bimonthly regimen with leucovorin and 5-fluorouracil for metastatic colorectal cancer. Proc Am Soc Clin Oncol 16:287a, 1997 (abstr 1019) 6. de Gramont A, Louvet C, André T, et al: Infusional 5-fluorouracil: the bimonthly approach. In Bleiberg H. et al (ed): Colorectal Cancer, a clinical guide to therapy. London, Dunitz, 2002, pp 463-466 7. Cunningham D, Pyrh"nen 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[CrossRef][Medline] 8. Rougier P, Van Custem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998[CrossRef][Medline]
9. 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 10. 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 355:1041-1047, 2000[CrossRef][Medline]
11. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 12. Goldberg RM, Morton RF, Sargent DJ, et al: N9741: oxaliplatin or CPT-11 plus 5-fluorouracil/leucovorin or oxaliplatin plus CPT-11 in advanced colorectal cancer. Updated efficacy and quality of life data from an intergroup study. Proc Am Soc Clin Oncol 22:252, 2003 (abstr 1009) 13. Raymond E, Buquet-Fagot C, Djelloul S, et al: Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast, and ovarian cancers. Anticancer Drugs 8:876-885, 1997[Medline] 14. de Gramont A, Vignoud J, Tournigand C, et al: Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33:214-219, 1997
15. André T, Bensmaine M, Louvet C, et al: Multicentrer phase II study of bimonthly high dose leucovorin, fluorouracil infusion and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 17:3560-3568, 1999 16. Maindrault-Goebel F, Louvet C, André T, et al: Oxaliplatin added to the simplified bimonthly leucovorin and 5FU regimen as second line therapy for metastatic colorectal cancer. Eur J Cancer 35:1338-1342, 1999 17. Maindrault-Goebel F, Louvet C, André T, et al: High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouacil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX7). Eur J Cancer 37:1000-1005, 2001
18. Maindrault-Goebel F, de Gramont A, Louvet C, et al: Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48h 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Ann Oncol 11:1477-1483, 2000 19. André T, Louvet C, Maindrault-Goebel F, et al: CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer 35:1343-1347, 1999 20. MacDonald J, Haller D, Mayer R: Grading of toxicity, in MacDonald J, Haller D, Mayer R (eds): Manual of Oncologic Therapeutics. Philadelphia, PA, Lippincott, 1995, pp 519-523 21. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 22. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trials. Biometrics 31:103-115, 1975[CrossRef][Medline] 23. Freedman LS: Tables of the number of patients required in clinical trials using the logrank test. Stat Med 1:121-129, 1982[Medline] 24. Kaplan EL, Meier P: Non parametric estimation from incomplete observations: J Am Stat Assoc 53:457-481, 1958[CrossRef] 25. Mantel N, Haenzel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719-748, 1959 26. Cox DR: Regression models and life-tables. J R Stat Soc 34B:187-220, 1972 27. Rothenberg ML, Oza AM, Burger B, et al: Final results of a phase III trial of 5-FU/leucovorin versus oxaliplatin versus the combination in patients with metastatic colorectal cancer following irinotecan, 5FU, and leucovorin. Proc Am Soc Clin Oncol 22:253, 2003 (abstr 1011) 28. Maindrault F, Louvet C, André T, et al: Time of disease control to evaluate the impact on survival of three chemotherapy lines in metastatic colorectal cancer based on 5-flourouracil, oxaliplatin and irinotecan. Proc Am Soc Clin Oncol 20:146a, 2001 (abstr 581) 29. André T, Figer A, Cervantes A, et al: FOLFOX7 compared to FOLFOX4. Preliminary results of the randomized Optimox study. Proc Am Soc Clin Oncol 22:253, 2003 (abstr 1016) 30. Mabro M, Artru P, Flesch M, et al: Irinotecan, 5-fluorouracil infusion and leucovorin (FOLFIRI-3) in pretreated patients with metastatic colorectal cancer: results of a multicenter phase II study. Proc Am Soc Clin Oncol 22:280, 2003 (abstr 1125) 31. Douillard JY, Sobrero A, Carnaghi C, et al: Metastatic colorectal cancer: Integrating irinotecan into combination and sequential chemotherapy. Ann Oncol 14:7-12, 2003 (suppl 2) Submitted May 16, 2003; accepted October 8, 2003. This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
