Randomized Multicenter Phase II Study Comparing a Combination of Fluorouracil and Folinic Acid and Alternating Irinotecan and Oxaliplatin With Oxaliplatin and Irinotecan in Fluorouracil-Pretreated Metastatic Colorectal Cancer Patients By Yves Be´couarn, Erick Gamelin, Bruno Coudert, Sylvie Ne´grier, Jean-Yves Pierga, Jean-Luc Raoul, Jocelyne Provenc¸al, Olivier Rixe, Claude Krisch, Caroline Germa, Mohamed Bekradda, Dominique Mignard, and Mireille Mousseau Purpose: To assess antitumor activity and safety of two regimens in advanced colorectal cancer (CRC) patients with proven fluorouracil (5-FU) resistance in a randomized phase II study: 5-FU/folinic acid (FA) combined with alternating irinotecan (also called CPT-11) and oxaliplatin (FC/FO tritherapy), and an oxaliplatin/ irinotecan (OC) combination. Patients and Methods: Sixty-two patients were treated: arm FC/FO (32 patients) received, every 4 weeks, FA 200 mg/m2 followed by a 400-mg/m2 5-FU bolus injection, then a 600-mg/m2 continuous infusion of 5-FU on days 1 and 2 every 2 weeks administered alternately with irinotecan (180 mg/m2 on day 1) and oxaliplatin (85 mg/m2 on day 15). Arm OC (30 patients) received oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 every 3 weeks. Results: In an intent-to-treat analysis, two partial responses lasting 10.7 and 16 months were observed

with the tritherapy regimen, and seven (median duration, 11 months; range, 10.6 to 11.4 months) were observed with the bitherapy regimen. Median progression-free and overall survival times were 8.2 and 9.8 months, respectively, in the FC/FO arm and 8.5 and 12.3 months, respectively, in the OC arm. Main grade 3/4 toxicities were, respectively, neutropenia, 53% and 47%; febrile neutropenia, 13% and 3%; diarrhea, 19% and 10%; vomiting, 6% and 13%; and neurosensory toxicity, 3% and 3%. No treatment-related deaths occurred. Conclusion: The every-3-weeks OC combination is safe and active in advanced 5-FU–resistant CRC patients. The lower activity data seen with the tritherapy regimen may be related to the lower dose intensities of irinotecan and oxaliplatin in this schedule. J Clin Oncol 19:4195-4201. © 2001 by American Society of Clinical Oncology.

OLORECTAL CANCER (CRC) is a major public health problem in Europe and in the United States. In France, CRC is the most commonly occurring cancer, with slightly more than 26,000 new cases per year.1 More than 50% of patients have or will have metastatic disease and are candidates for palliative chemotherapy.2 For over 40 years, the treatment of CRC has been based on fluorouracil (5-FU). The response rate to single-agent 5-FU in metastatic CRC is low, with pooled data showing a response rate of only approximately 11%.3 As 5-FU– based protocols play a major role in the treatment of advanced CRC,4 several modulations of 5-FU– based treatments have been tested, the most effective being 5-FU/folinic acid (FA). Metaanalysis of its prospective controlled assessment yields a response rate of 23%, with the median overall survival (OS) being 11 months.3 Chemotherapy can have an effect on symptoms with an improvement in quality of life and increased median survival in patients with metastatic disease.5-7 De Gramont et al’s8 LV5-FU2 schedule (biweekly combination of bolus and continuous-infusion 5-FU with highdose FA) was compared with the reference Mayo Clinic regimen (monthly 5-FU bolus with low-dose FA). The objective response rates were 32.6% and 14.4%, respec-

tively (P ⫽ .0004), with 11.1% of patients experiencing severe toxicities in the de Gramont scheme versus 23.9% in the 5-FU/low-dose FA arm (P ⫽ .0004), but there was no survival difference. This regimen has emerged in France and elsewhere as the new reference 5-FU/FA treatment in first-line palliative chemotherapy for CRC.8 Until recently, there have been limited therapeutic options for secondline treatment of patients with CRC who have failed 5-FU– based treatment. Two new cytotoxic agents, irino-

C

From the Institut Bergonie´, Bordeaux; Centre Paul Papin, Angers; Centre Georges-Franc¸ois Leclerc, Dijon; Centre Le´on Be´rard, Lyon; Institut Curie and Aventis, Paris; Centre Euge`ne Marquis, Rennes; Centre Hospitalo-Universitaire, Grenoble; Clinique C. Bernard, Metz; Centre Hospitalo-Universitaire, Amiens; and Cvitkovic et Associe´s Consultants, Kremlin-Biceˆtre, France. Submitted December 14, 2000; accepted June 26, 2001. Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 19-23, 2000. Address reprint requests to Yves Be´couarn, MD, Department of Digestive Oncology, Institut Bergonie´, Regional Cancer Center, 229, cours de l’Argonne, 33076 Bordeaux Cedex, France; email: [email protected]. © 2001 by American Society of Clinical Oncology. 0732-183X/01/1922-4195/$20.00

Journal of Clinical Oncology, Vol 19, No 22 (November 15), 2001: pp 4195-4201

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tecan (also called CPT-11) and oxaliplatin, have proven efficacy in this indication. Irinotecan, a topoisomerase I inhibitor, has become the treatment of reference in second-line metastatic CRC. This is based on several phase II9-12 and phase III13,14 studies that investigated irinotecan activity that demonstrated significantly improved survival and a better quality of life compared with best supportive care or continuous-infusion 5-FU in second-line treatment of metastatic CRC. Recently, the combination of irinotecan with 5-FU/FA has been proven to be more active and efficacious, with a survival benefit, than 5-FU/FA regimens in first-line treatment for metastatic CRC patients, which led to its registration both in Europe and the United States for this indication.15 Oxaliplatin, a new third-generation analog in the 1,2diaminocyclohexane family of platinum compounds, has been approved in Europe for the treatment of advanced metastatic CRC when combined with 5-FU/FA, on the basis of the results of a phase III study that showed a benefit in progression-free survival (PFS) when oxaliplatin/5-FU was compared with 5-FU alone.16 An objective response rate of 10% has been reported for its use as a single agent in advanced CRC patients with proven resistance to fluoropyrimidines, although in previously untreated patients, an objective response rate of 12% to 20% has been reported.17-20 Several experimental and clinical studies have shown that oxaliplatin elicits a supra-additive effect or a high potentiation of efficacy when combined with 5-FU, even after the initial failure of 5-FU– based treatment.21,22 Combinations of both biweekly schedules of LV5-FU2/ oxaliplatin22,23 and of LV5-FU2/irinotecan24-26 have already been tested and have proven effective in patients resistant to a 5-FU– based treatment. Experimental data showed synergistic activity of the SN38 (active metabolite of irinotecan)/oxaliplatin combination,27 and excellent preliminary results using irinotecan/oxaliplatin combinations in CRC patients refractory to 5-FU have been obtained.28-33 Weekly, every-2-weeks and every-3-weeks combination regimens have been tested. However, only the results from the every-3-weeks regimen feasibility trials were available at the conception of the present study. To further evaluate the combination of both new agents and to simultaneously explore the alternatives of their respective combinations with the LV5-FU2 regimen, we designed a randomized phase II study in CRC patients with documented evidence of resistance to 5-FU. PATIENTS AND METHODS

Patients Between July 1997 and April 1999, 64 patients were enrolled onto this study by nine French centers. The protocol was approved by the

Ethics Review Committee of Bordeaux before the enrollment of any patient. All patients were informed of the investigational nature of this study, and each patient provided written informed consent before registration onto the study. Inclusion criteria included: histologically proven adenocarcinoma of the colon or rectum; documented progressive disease after no more than one regimen of optimal 5-FU ⫾ FA-based chemotherapy for metastatic disease and/or no more than one line of 5-FU– containing treatment after prior adjuvant chemotherapy if discontinued less than 6 months before study entry; World Health Organization (WHO) performance status ⱕ 2; age between 18 and 75 years; measurable metastatic disease (bidimensionally measurable lesion according to WHO criteria); absence of resectable liver metastasis; written informed consent; adequate hematologic function (hemoglobin ⱖ 10 g/dL, absolute neutrophil count ⱖ 2 ⫻ 109/L, platelets ⱖ 100 ⫻ 109/L); adequate renal and hepatic functions (creatinine ⱕ 1.25 times the upper limit of normal [ULN], total bilirubin ⱕ 1.25 times the ULN, AST and ALT ⱕ 3 times the ULN [in cases of liver metastasis, total bilirubin ⱕ 1.5 times the ULN, AST and ALT ⱕ 5 times the ULN]); intervals since the last antitumor treatment and randomization of 4 weeks for chemotherapy (6 weeks after mitomycin or nitrosourea) and surgery and 6 weeks for radiotherapy; and the ability to comply with scheduled follow-up and management of toxicity. Exclusion criteria included more than one regimen of palliative ⫾ adjuvant chemotherapy; prior chemotherapy with topoisomerase I inhibitors or oxaliplatin; unresolved bowel obstruction or partial bowel obstruction; prior or current history of chronic diarrhea; severe gastrointestinal toxicity while receiving 5-FU; current uncontrolled infection; other serious illness or medical condition, including contraindication to 5-FU; past or current history of cancer other than colorectal carcinoma, except curatively treated nonmelanoma skin cancer or in situ cervical cancer; concomitant treatment with any other investigational drug; concurrent treatment with any other anticancer therapy; and pregnancy.

Methods The primary end point of this study was response rate, which was evaluated according to WHO criteria and reviewed in cases of objective response or sustained disease stabilization (ⱖ 3 months) by a committee of independent experts. Patients were considered assessable for response if they had received at least two cycles of the tritherapy treatment or three cycles of the bitherapy treatment. Serosal effusions and CEA levels were not considered measurable disease. Before chemotherapy. All patients were checked for eligibility before admittance onto the study. An initial radiologic assessment (chest radiography and computed tomography scan of abdominal and/or thoracic measurable lesions) was conducted within 2 weeks before inclusion. A clinical evaluation and biologic assessment were conducted within 1 week before inclusion. The first treatment administration occurred within 8 days of the randomization date. During treatment. Clinical and biologic assessments were conducted on day 1 of each cycle. Blood analysis was conducted each week. Radiologic assessment was performed every other cycle in the FC/FO arm (every 8 weeks) and every three cycles (9 weeks) in the OC arm. Treatment toxicity was evaluated before each cycle according to the National Cancer Institute (NCI) common toxicity criteria. Neurologic toxicity was graded according to the oxaliplatin-specific scale.34 Treatment discontinuation. Treatment was discontinued in cases of disease progression, unacceptable toxicity, or patient refusal. Patients were followed up every 2 months after treatment discontinuation.

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IRINOTECAN AND OXALIPLATIN ⫾ 5-FU IN CRC

Treatment Patients were randomly assigned to receive either FC/FO or OC, with entry stratified according to center. The first sequence of FC/FO treatment started with a 90-minute intravenous (IV) infusion of irinotecan (180 mg/m2) on day 1, followed by a 2-hour rest period and then the LV5-FU2 regimen (FA 200 mg/m2 as a 2-hour infusion and 5-FU 400 mg/m2 bolus and 600 mg/m2 as a 22-hour continuous infusion on days 1 and 2). On day 15, patients received a 2-hour IV infusion of oxaliplatin (85 mg/m2) followed, after a 1-hour rest period, by the same LV5-FU2 regimen (days 15 and 16). Treatment was repeated every 4 weeks. In the OC arm, a 2-hour IV infusion of oxaliplatin (85 mg/m2) on day 1 was followed, after a 1-hour rest, by a 30-minute IV infusion of irinotecan (200 mg/m2), with treatment repeated every 3 weeks.29 Corticosteroids and setrons were delivered before each treatment arm to prevent emesis. LV5-FU2, irinotecan, and oxaliplatin doses and schedules were adjusted in the event of certain NCI toxicities, according to the following guidelines. Hematologic toxicity was evaluated during every cycle beginning at day 15 for FC/FO and day 21 for OC. In the event of myelosuppression (absolute neutrophil count ⬍ 1.5 ⫻ 109/L and/or platelets ⬍ 75 ⫻ 109/L) at the planned date for the next sequence of FC/FO or the next cycle of OC, treatment was postponed for 1 or 2 weeks until recovery. After a 2-week delay with no recovery, the patient went off the study. In cases of recovery in the FC/FO arm, the irinotecan dose was reduced by 20% (twice if necessary, eg, to 150 mg/m2 then to 120 mg/m2) and by 25% for oxaliplatin (60 mg/m2), 5-FU bolus (300 mg/m2), and infusion (450 mg/m2). In the OC arm, irinotecan dose reductions were identical to those in the FC/FO arm (20% decrease, twice if necessary, eg, to 150 mg/m2 then to 120 mg/m2), but oxaliplatin dose intensity was not reduced. The same dose reductions were implemented in cases of grade 4 neutropenia or thrombocytopenia or grade 3 neutropenia associated with fever. Patients went off the study after two dose reductions. For patients who experienced grade 3 or 4 diarrhea that required IV rehydration in the FC/FO arm, the irinotecan dose was reduced by 20%, twice in cases of persistence (150 mg/m2 then to 120 mg/m2). If diarrhea occurred during the second sequence (FO), the oxaliplatin dose was reduced by 25% (60 mg/m2), and if diarrhea persisted in the next cycle, the 5-FU dose was reduced by 25% (bolus, 300 mg/m2; infusion, 450 mg/m2). In the OC arm, the first dose reduction implemented was for irinotecan (150 mg/m2), and in the case of persistence of diarrhea at the next cycle, the oxaliplatin dose was reduced (60 mg/m2). When grade 4 peripheral neuropathy occurred, study treatment was discontinued. For grade 3 neuropathy, oxaliplatin doses were decreased initially to 60 mg/m2 and then, in cases of persistence, to 50 mg/m2. If, after these delays and dose reductions, there was no recovery, treatment was to be terminated.

Statistical Considerations Response rate was the primary end point in this trial. Secondary end points were PFS, duration of response, and OS. PFS was calculated from the time of the first infusion to disease progression or death, the duration of complete response from the date of documentation to the progression date, and the duration of partial response from first infusion to the progression date. The Simon two-stage optimal design35 was used to determine the number of patients to be included in this phase II study. With a 5% alpha risk and a 10% beta risk, we determined a first-stage response probability of 10% (which, if true, implied discontinuing the trial) and

a minimal rate of efficacy of 30% (which, if true, implied moving on to the second stage of the trial). The number of patients to be included in each arm was calculated to be 18 for the first stage and an additional 17 for the second stage. After the inclusion of 35 patients in each arm, the observation of six or fewer patients with objective responses allowed a conclusion of insufficient treatment efficacy, with a maximum of 70 patients (35 per arm) to be included in this study. Statistical analysis was performed using SPSS, version 9 (SPSS, Inc, Chicago, IL).

RESULTS

Patient Characteristics Between July 1997 and April 1999, 64 patients were enrolled, of whom 62 (32 in the FC/FO arm and 30 in the OC arm) received at least one cycle and were therefore assessable for toxicity. Two patients, both randomized in the OC arm, did not receive any treatment after moving to a nonparticipating study site in one case and rapid worsening of liver function and general status in the other. Four patients did not meet the inclusion criteria regarding delay since last chemotherapy. They were kept in the statistical analysis because results were given on an intent-to-treat basis. Two (one in each arm) presented delays longer than 6 months. For the two others (one in each arm also), washout occurred in less than 1 month. In first-line metastatic chemotherapy, these latter patients had received weekly and bi-weekly regimens, which could explain the good safety profile under study treatment because none presented any grade 3/4 toxicity. Therefore, no delay in neither administration nor dose reduction was required. Fifty-seven patients were assessable for efficacy, according to the expert review committee (27 of 32 in the FC/FO arm and 30 of 30 in the OC arm). Five patients in the FC/FO arm were considered not assessable by the expert panel and the investigators. Three died before the first tumor assessment from causes unrelated to tumor progression or to treatment (two pulmonary embolisms, one pulmonary edema), one patient was withdrawn from the study because of toxicity, and the other could not be evaluated because of missing imaging evidence. Patient, tumor, and previous treatment characteristics are presented in Table 1. Efficacy and Survival At the cutoff date, median follow-up time was 14.4 months (range, 3.8 to 24.5 months), and four patients were still on treatment (one in the FC/FO arm with nine cycles and three in the OC arm, one patient with six cycles and two patients with nine cycles). Efficacy could be evaluated in 57 of 62 patients (five excluded by the expert panel committee). Results are, therefore, given in intent-to-treat. The efficacy results according to the expert panel are indicated in Table 2.

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BE´COUARN ET AL Table 1.

Patient and Tumor Characteristics at Baseline FC/FO Arm

No. of patients treated Age, years Median Range Sex Male Female WHO performance status 0 1 2 Patients with ⱖ 1 symptom Primary tumor location Colon Rectum No. of organs involved 1 2 ⱖ3 Site of disease Liver Lung Intra-abdominal lymph nodes Extra-abdominal lymph nodes Peritoneum Other Type of previous chemotherapy Adjuvant only Palliative only Adjuvant and palliative Time between last chemotherapy and first infusion, months Median Range

Table 2.

No.

%

No.

%

32

100

30

100

64 44-75

Response Rate (external review committee)

OC Arm

FC/FO Arm (n ⫽ 32) No.

Overall response Complete response Partial response Stable disease Progressive disease Not assessable Objective response rate, 95% CI, % Duration of responses, months Median Range

63 43-75.5

20 12

20 10

13 17 2 23

72

21 8 1 17

57

23 9

72 28

23 7

77 23

13 8 11

41 25 34

12 14 4

40 47 13

26 14 7 3 4 11

81 44 22 9 13 34

26 16 4 – 3 5

87 53 13 – 10 16

2 25 5

6 78 16

5 19 6

17 63 20

2 17 8 5

OC Arm (n ⫽ 30)

%

No.

– 6 53 25 16 0.8-20.8

%

– 23 47 30 – 9.9-42.3

7 14 9

–* 10.7/16

11 10.6-11.4

*Because there were only two responders in the FC/FO arm, the median value could not be calculated.

delays [26 of 36] were between 3 to 7 days and 28% [10 of 36] lasted more than 8 days). The main reason for these delays in both treatment arms was hematologic toxicity (54% for FC/FO and 50% for OC), although up to 40% in FC/FO and 47% in OC were because of patient requests. Fewer patients in the OC arm had their dose reduced for two cycles or more compared with patients in the FC/FO arm (23% v 36%). Toxicity

1.3 0.4-42.5

1.2 0.2-9.9

Sixty-two patients were assessable for toxicity. No toxic deaths were reported. Chemotherapy had to be stopped for six patients (three in each arm) as a result of adverse events. The incidence of main toxic effects according to the NCI common toxicity criteria scale are listed in Table 4 as the

Table 3.

The median OS was 9.8 months (95% confidence interval [CI], 6.4% to 13.2%), and median PFS was 8.2 months (95% CI, 6.4% to 13.2%), in the FC/FO arm. In the OC arm, median OS was 12.3 months (95% CI, 9.8% to 14.8%), and median PFS was 8.5 months (95% CI, 4.0% to 12.9%). One-year survival seemed to be slightly longer in the OC arm than in the FC/FO arm (54% v 40%). Extent of Exposure and Cycle Delays The extent of exposure is presented in Table 3. Cycle delays (eg, delay in scheduled treatment of more than 3 days) were more frequent in the FC/FO arm (71% of patients and 31.5% of cycles) than in the OC arm (50% of patients and 19% of cycles). The duration of delays was also longer in the FC/FO arm (40% of cycle delays [14 of 35] were between 3 and 7 days, and 60% [21 of 35] lasted more than 8 days), compared with the OC arm (72% of cycle

Extent of Exposure FC/FO Arm

Dose

No. of cycles Total Median Range Median cumulative doses Irinotecan, mg/m2 Oxaliplatin, mg/m2 5-FU, g/m2 Median dose intensities Irinotecan, mg/m2/wk Oxaliplatin, mg/m2/wk 5-FU, mg/m2/wk Relative dose intensity, % Irinotecan Oxaliplatin 5-FU

Range

OC Arm Dose

Range

FC, 143; FO, 131 4 1-11 720 340 16 42.8 19.7 843.1

180-1,980 85-935 2-44 27.3-51.6 14.6-21.4 482.8-1,000 ⱖ 93 ⱖ 93 84

216 6 2-17 1.2* 510

64.2 27.6

0.4-3.3* 170-1,445

37.8-67.7 21.2-28.7

ⱖ 93 ⱖ 93

*Dose and range for irinotecan in the OC arm is measured in g/m2.

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IRINOTECAN AND OXALIPLATIN ⫾ 5-FU IN CRC Table 4.

Drug-Related Toxicity Per Patient

NCI-CTC Grade 1/2 FC/FO Arm

Neutropenia Febrile neutropenia Anemia Thrombocytopenia Nausea Vomiting Diarrhea Neurosensory* Asthenia

NCI-CTC Grade 3/4 OC Arm

FC/FO Arm

OC Arm

No.

%

No.

%

No.

%

No.

%

9 – 20 8 19 14 23 19 24

28 – 63 25 59 44 72 59 75

12 – 16 10 24 19 21 25 15

40 – 53 33 80 63 70 83 50

17 4 1 1 – 2 6 1 3

53 13 3 3 – 6 19 3 9

14 1 1 1 1 4 3 1 4

47 3 3 3 3 13 10 3 13

*See text for oxaliplatin-specific scale.

maximum grade seen per patient. In the FC/FO arm, 17 patients (53%) presented grade 3/4 neutropenia, and four (13%) experienced severe febrile neutropenia, although in the OC arm, 14 patients (47%) presented with grade 3/4 neutropenia, and one (3%) experienced severe febrile neutropenia. Six patients (19%) in the FC/FO arm experienced severe diarrhea for one cycle each (three with grade 3, and three with grade 4) as did three patients (10%) in the OC arm (two with grade 3, and one with grade 4). Severe vomiting was reported in two patients (6%) in the FC/FO arm (grade 3 and grade 4, each for one cycle) and in four patients (13%) in the OC arm (three with grade 3 for one cycle and one with grade 4 for one cycle). Grade 1 to 4 asthenia occurred in 84% of patients in the FC/FO arm and 63% in the OC arm. All neurotoxicities were classified as neurosensory and none as neuromotor. One patient (3%) in each arm experienced grade 3 neurosensory toxicity. The patient in the OC arm experienced toxicity after 10 cycles that ultimately resulted in study discontinuation after a total oxaliplatin dose of 850 mg/m2. The patient in the FC/FO arm presented with grade 3 toxicity after eight cycles and a total oxaliplatin dose of 510 mg/m2. A total of six patients discontinued treatment due to toxicity (three in each arm). In the FC/FO arm, these discontinuations were the consequence of grade 4 diarrhea, prolonged grade 2 thrombocytopenia, and transient elevation of bilirubin. The latter case was initially deemed to be study treatment–related because of periodic and transient bilirubin increase after administration of irinotecan. However, retrospective analysis showed that this patient had an increased baseline level of unconjugated bilirubin, probably related to previously undiagnosed Gilbert’s syndrome. Irinotecan administration has been shown to be associated with transient rises in bilirubin in patients with this otherwise benign condition.36 It is of note that conjugated bilirubin and alkaline phosphatase levels increased continuously in this patient after several cycles, irre-

spective of irinotecan administration and concomitant with hepatic tumor progression. In the OC arm, treatment was discontinued for grade 2 transaminitis, for febrile neutropenia associated with grade 4 diarrhea, vomiting, and gastric dilatation, and for grade 3 peripheral neuropathy reported after 10 treatment cycles. Retrospective analysis linked two of these cases (bilirubin increase in the FC/FO arm and transaminase increase in the OC arm) to concomitant tumor progression. DISCUSSION

Colorectal cancer is a serious public health concern. Although the prognosis for CRC patients improved with the development of 5-FU/FA treatment, the median response duration and survival for patients with this cancer remains limited. To improve prospects for patients with colorectal cancer, further research into alternative treatments should be conducted. Oxaliplatin and irinotecan have mechanisms of action that are independent of thymidylate synthase inhibition. A recent report of a phase I study that explored the combination of oxaliplatin and irinotecan administered every 3 weeks29 offered an interesting chemotherapeutic possibility for patients who had not responded to 5-FU– based first-line therapy. The same regimen was used in the first arm of the present randomized phase II study. The perceived activity of this regimen has since been confirmed in several other studies using different schedules and regimens.28-33 For the second arm of our study, we decided to assess a combination of a previously tested infusion of 5-FU/FA regimen with irinotecan alternating with oxaliplatin. Modulation of 5-FU in second-line treatment may offer some clinical benefit,37 and combinations of both biweekly schedules of LV5-FU2/oxaliplatin22,23 and LV5-FU2/irinotecan24,26 have proven effective in patients resistant to 5-FU. Thus, the present study (started in 1997) represents the first

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BE´ COUARN ET AL

sequential tritherapy approach to the treatment of pretreated CRC patients using these drugs. In the absence of phase I data concerning the recommended dose of the triple association, we chose to alternate the previously explored combinations of irinotecan or oxaliplatin with LV5-FU2.22-26 However, alternating regimens favors safety (no overlap of toxicity) at the expense of dose-intensity. Hence in the FC/FO arm, with the addition of a third drug to irinotecan and oxaliplatin, the planned dose-intensity of the thymidylate synthase inhibition–independent drugs was decreased with respect to the bitherapy arm, although LV5-FU2 was given at the full dose. The planned dose intensities of irinotecan and oxaliplatin were 45 mg/m2/wk and 21.25 mg/m2/wk, respectively, in the FC/FO arm and 66.7 mg/m2/wk and 28.3 mg/m2/wk in the OC arm, respectively, which are similar to the dose intensities actually administered. The fact that these two compounds, which are thought to be the most active in the setting of 5-FU resistance, were not administered at optimal doses may explain the observed difference in efficacy. The objective response rate in intent-to-treat defined as the primary end point was 6.2% (two partial responses) in the FC/FO arm (LV5-FU2/irinotecan/oxaliplatin), which was somewhat lower than expected.22-26 In the OC arm, patients treated every 3 weeks with irinotecan and oxaliplatin had a response rate of 23.3%, with seven partial responses. This response rate compares favorably with other reported bitherapy regimens26,28,31,38-40 for second-line treatment of 5-FU–pretreated, resistant, metastatic CRC. However, it is lower than the response rate reported by Scheithauer et al31 with an intensified irinotecan/oxaliplatin regimen. The treatment consisted of oxaliplatin 85 mg/m2 on days 1 and 15 and irinotecan 80 mg/m2 on days 1, 8, and 15 every 4 weeks. The rate of tumor control (partial response and stable disease) and the PFS are remarkably similar in the two arms. The median duration of response

was 8.5 months in the OC arm but could not be calculated in the FC/FO arm because there were only two responders. PFS was approximately equal in both arms (8.2 months in the FC/FO arm and 8.5 months in the OC arm), with a longer median survival time in the OC arm (12.3 months) compared with the FC/FO arm (9.8 months). These results compare favorably with other reported bitherapy studies evaluating regimens associating 5-FU with either oxaliplatin22,23,28,38-40 or irinotecan.24-26,28 OS in the present study is comparable with that reported by Scheithauer et al,31 which did nonetheless show a better response rate. As expected, severe toxicities were mostly hematologic and less frequently gastrointestinal, but in both cases these were easily dealt with. Neutropenia and gastrointestinal toxicities were present in both arms, although severe febrile neutropenia and severe diarrhea were more prevalent in the FC/FO arm than the OC arm. Despite a similar incidence of grade 3 peripheral neuropathy in both arms, a total of 26 patients (87%) developed peripheral neurotoxicity in the OC arm, compared with 20 patients (63%) in the FC/FO arm. This event could be explained by the higher cumulative dose of oxaliplatin administered in arm OC compared with the FC/FO arm, although this neurotoxicity is comparable to that seen after different regimens of 5-FU and oxaliplatin with identical median cumulative doses of oxaliplatin.39,40 The response rate observed with the FC/FO regimen does not encourage us to explore this schedule any further in second-line patients. However, the alternating regimen may eventually deserve further consideration in first-line treatment when patients may receive the maximum benefit from their tumor sensitivity to 5-FU. The OC regimen seems safe and active in a phase II setting in a population of CRC patients previously treated with and resistant to 5-FU ⫾ FA. Other studies in previously treated 5-FU–resistant patients involving the OC combination ⫾ FA confirm the promising nature of this combination.28,31-33,41-43

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