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© 2000 American Society for Clinical Oncology Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer From the International Organization of Cancer Chronotherapy, Centre de Chronothérapie, Hôpital Paul Brousse, Villejuif, France; and Debiopharm S.A., Lausanne, Switzerland. Address reprint requests to Sylvie Giacchetti, MD, Centre de Chronothérapie, Hôpital Paul Brousse, 14 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cédex, France; email sylvie.giacchetti@ pbr.ap_hop_paris.fr.
PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)–leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m2/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m2, as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans.
RESULTS: Grade 3 to 4 toxicity from 5-FU–LV occurred in CONCLUSION: By chronomodulating 5-FU–LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.
FLUOROURACIL (5-FU), the reference drug used to treat colorectal cancer, has only achieved 10% of objective responses, when given as a single agent for first-line treatment of metastatic disease.1-3 The objective response rate was increased by combining 5-FU with leucovorin (LV) or methotrexate, as biochemical modulators of 5-FU cytotoxicity,4-6 or by administering 5-FU as a continuous venous infusion.7,8 Recently, bolus 5-FU–LV and continuous 5-FU were combined over 2 days. This alteration in the schedule significantly increased the objective response rate for the control 5-FU–LV from 14% to 33%.9 The acceptable tolerability of these regimens has further supported their widespread clinical use, despite a modest activity and no evidence of any clearcut survival advantage. Thus, the median survival time has usually ranged from 9 to 12 months in most trials, with less than 5% of the patients alive at 3 years.5-9 These results emphasize the need for new drugs and novel approaches in the treatment of metastatic colorectal cancer. Oxaliplatin (l-OHP) is a diaminocyclohexane platinum complex. Similar to cisplatin and carboplatin, the main mechanism of action is mediated by the formation of DNA adducts. Nevertheless l-OHP displays in vitro activity against cisplatin-resistant human tumor cells, including colorectal cells,10 and exhibited in vivo synergistic antitumor activity with 5-FU against transplantable tumor models.11,12 This third-generation platinum complex has not been associated with renal toxicity or with alopecia and has produced minimal hematotoxicity. Nausea, vomiting, and diarrhea are the main acute side effects. The dose-limiting toxicity consists of a cumulative sensory peripheral neuropathy exacerbated by exposure to cold.13,14 When used as a single agent, l-OHP achieved a 10% objective response rate in three phase II trials involving a total of 139 patients with metastatic colorectal cancer previously treated with 5-FU.15,16 In two recent phase II studies, objective response rates of 20% and 24% were reported in patients with previously untreated metastatic colorectal cancer.17,18 Chronotherapy consists of chemotherapy delivery according to biologic rhythms along the 24-hour scale.19 These genetically based rhythms modulate cellular metabolism and proliferation in normal tissues.20,21 As a result of chronotherapy, in laboratory rodents, the tolerability and antitumor efficacy of 5-FU and l-OHP, among 30 anticancer drugs, varied largely according to dosing time.19,22 The aim of transferring this concept to the clinic was primarily to increase dose-intensity through an adjustment of drug delivery to 24-hour rhythms in tolerability. A specific technology (programmable-in-time injectors) allowed the administration of chronotherapy to patients who were fully ambulatory.23 First, l-OHP was combined with 5-FU and LV, and for a long period, the combination was developed only as a chronomodulated infusion, in order to take advantage of an improved tolerability of all three agents. For this purpose, 5-FU and LV were administered from 2215 hours to 0945 hours, with peak delivery rate at 0400 hours; l-OHP was given from 1015 hours to 2145 hours, with peak delivery rate at 1600 hours. This three-drug chronomodulated regimen produced a 58% response rate in 93 patients with metastatic colorectal cancer. The median overall survival was 15 months.24 The activity of this three-drug combination was subsequently confirmed, using another infusion schedule consisting of a flat 2-day infusion of 5-FU–LV combined with a 2-hour infusion of l-OHP on day 1.25 The role of chronotherapy was then investigated in two consecutive European multicenter phase III studies. The chronomodulated administration of these three drugs was compared with their infusion at a constant rate in a total of 278 patients with previously untreated metastatic colorectal cancer. Chronotherapy reduced toxicity and nearly doubled the objective response rate, which was 51% with three-drug chronotherapy and 30% with flat infusion.26,27 We related the high antitumor efficacy of the three-drug chronotherapy regimen to both l-OHP activity and chronomodulated delivery, as this treatment method allows the safe delivery of high drug doses for prolonged treatment durations. We then investigated the contribution of l-OHP itself. l-OHP was given as a 6-hour flat infusion from 1000 to 1600 hours before the beginning of a 5-day chronomodulated infusion of 5-FU–LV. This infusion schedule was devised to remain close to the least toxic time of l-OHP.28
This multicenter, open, randomized, two-arm phase II/III study was approved by an internal review board and by the national biomedical ethics committees from three countries (France, Italy, and Belgium). From June 1994 to March 1996, 200 patients from 15 centers with previously untreated measurable metastases from colorectal cancer were randomly assigned to receive chronomodulated 5-FU and LV with or without l-OHP (Fig 1).
Inclusion and Noninclusion Criteria Patients had to have histologically proven colorectal carcinoma, bidimensionally measurable metastatic lesions with one diameter of at least 20 mm, and World Health Organization (WHO) performance status  2. If prior adjuvant chemotherapy had been given, it had to be completed for at least 6 months. Adequate bone marrow, renal, and hepatic function was required, and clinical, biologic, and radiologic assessments had to be performed within 30 days before the start of treatment. Patients also had to give signed written informed consent to participate. Noninclusion criteria were as follows: brain metastases, age greater than 76 years, previous chemotherapy or radiotherapy for metastatic disease, second malignancy (except in situ carcinoma of the cervix or basal cell skin cancer), and peripheral sensory neuropathy. Baseline symptoms were recorded and a physical examination was performed; complete blood cell counts and carcinoembryonic antigen (CEA) and CA19-9 serum levels were obtained initially and immediately before each treatment course. Computed tomography (CT) scans of the abdomen, pelvis, and thorax and an abdominopelvic ultrasonogram were obtained within 1 month before the onset of therapy and after every third course.
Randomization Procedure
Chemotherapeutic Regimen and Dose Modifications The toxicities of each course were recorded before the next course was started and were graded according to the WHO criteria for hematology, hand-foot syndrome, and alopecia.29 Nausea, vomiting, diarrhea, and mucositis were graded according to a WHO-modified grading system.26 Peripheral sensory neuropathy was graded according to a specific scale that we developed for the initial assessment of l-OHP neuropathy; it takes into account the severity and duration of paresthesias as follows: grade 1-a, peripheral paresthesias of moderate intensity lasting 7 or fewer days; grade 1-b, peripheral paresthesias of moderate intensity lasting 8 to 14 days; grade 1-c, incomplete recovery between courses or mild hypoesthesias of the fingertips or soles of the feet; and grade 2, early functional impairment.26 In cases of acute grade 2 toxicity other than neuropathy or alopecia, the doses remained unchanged for next course. In cases of grade 3 or 4 toxicity, except for alopecia or neuropathy, the doses per course were reduced by 100 mg/m2 for 5-FU and by 25 mg/m2 for l-OHP. In cases of grade 1-c sensory neuropathy, the l-OHP dose was decreased by 25 mg/m2 down to 100 mg/m2; if grade 1-c neurotoxicity persisted, the l-OHP dose was further reduced by 25 mg/m2 down to 85 mg/m2. In cases of persistent grade 1-c neuropathy despite two dose reductions or grade 2 neurotoxicity, l-OHP was withdrawn.
Primary and Secondary Objectives Target lesions were considered measurable if they were not located in any previous radiation therapy field or in the bones. Measurements of target lesions were obtained by CT scan, with additional ultrasonography and magnetic resonance imaging if necessary. Response was assessed after every third treatment course and was defined according to the following WHO criteria: (1) complete response, complete disappearance of all symptoms and signs of disease for a minimum of 4 weeks; (2) partial response, a 50% reduction (or more) in the sum of the products of the perpendicular diameters of measurable disease and the appearance of no new malignant lesion for a minimum of 4 weeks; (3) stable disease, no appearance of new areas of disease or less than 50% decrease or less than 25% increase in the described measurements; and (4) progressive disease, more than 25% increase in the measurements and/or appearance of new lesions.29 In the present study, response was confirmed radiologically 9 weeks after its first documentation. Nevertheless, it could not be obtained in all the responding patients, since surgery of residual metastases was encouraged usually soon after a good response had been obtained. Secondary objectives included toxicity, progression-free survival (PFS), and overall survival.
Treatment Withdrawal Discontinuation of initial treatment, irrespective of cause, was classified as treatment failure. After treatment failure, patients in arm 1 could receive l-OHP and patients in both arms could be treated with a three-drug schedule different from that tested in this study.
Statistical Methods A phase II trial was first conducted to detect an efficacy of at least 30% according to the Gehan method.31 If no response was registered in the first 18 patients (nine in each arm) in one modality, the trial had to be stopped, because estimated efficacy would be less than 30%. Otherwise, the trial was continued as a phase III trial, according to O’Brien and Fleming,30 with two intermediate analyses and a final analysis. All statistical tests were two-tailed. All data were analyzed with the intention-to-treat method, using SAS software (version 6.11; SAS, Inc, Cary, NC). For all variables, except the primary efficacy variable, the level of significance was .05. PFS and overall survival were counted from the date of randomization to the date of disease progression, as assessed by the investigators, or to the date of death. Thus, patients who dropped out for reasons other than disease progression were censored at the dropout date. Patients for whom response was not evaluated were considered to have progressed on day 1. Kaplan-Meier curves were drawn for PFS and overall survival and compared between both arms with the log-rank test.32
Regression or Cox univariate analyses were performed for 16 parameters: treatment arm, sex, performance status, age (continuous variable), institution, primary tumor site (colon, rectum), Dukes’ stage, number of organs involved (continuous variable), organs involved (liver only v other organs ± liver), degree of liver involvement ( The analysis of prognostic factors for binary variable was performed using logistic regression. The significance of differences in outcome was first tested with univariate analysis for each clinical characteristics. We selected those factors with P < .2 for the multivariate analysis. All patients’ data were included in the analysis of response, PFS, and overall survival, in the group corresponding to the random assignment. For toxic effects, the population consisted of all the patients who had received at least one infusion of study drug according to the allocated treatment arm. The main analysis was performed in February 1997. Survival was updated in October 1997 and in January 1999.
Two hundred patients were enrolled onto the trial (Fig 2). Two patients in arm 1 and one patient in arm 2 were ineligible. One patient in arm 2 did not receive l-OHP and thus was not treated according to the allocated schedule. Despite randomization, a few imbalances were found with regard to patient characteristics. The incidence of primary rectal cancer was greater in arm 2 than in arm 1. Twice as many patients from arm 1 had received 5-FU–based adjuvant chemotherapy as compared with arm 2 patients. Half as many patients in arm 1 had normal CEA levels as compared with patients in arm 2. The last two differences were statistically significant (Table 1).
A total of 728 courses were given to the patients in arm 1 and 776 to those in arm 2. The median number of courses per patient was six in arm 1 and eight in arm 2 (range, one to 15 in each treatment arm). Follow-up ranged from 35 to 67 months (median follow-up, 47 months).
Toxicity There were no other treatment-related withdrawals for severe toxicity in arm 1. Twelve patients in arm 2 withdrew from therapy because of toxicity, which consisted of peripheral sensory neuropathy in 10 of them (grade 2, six patients; iterative grade 1-c, four patients). In these latter patients, the cumulative l-OHP dose ranged from 675 to 1,650 mg/m2 (median, 1,075 mg/m2). Other causes of withdrawal were grade 4 diarrhea and vomiting (one patient) and nonspecific vasculitis compatible with a toxic cutaneous reaction (one patient).
The incidence of grade 3 to 4 toxicity per patient was
Grade 3 to 4 mucositis occurred in 4% of the patients in arm 1 as compared with 10% in arm 2; the difference was not statistically significant. Severe hand-foot syndrome was found in one patient in arm 1 and in none of the patients in arm 2. Grade 3 or 4 neutropenia was a rare event in both arms (1% in arm 1 and 2% in arm 2). Nevertheless, the incidence of neutropenia irrespective of grade was four-fold higher in arm 2 than in arm 1 (32% v 8%, P < .001). The incidence of thrombocytopenia of all grades was 1% in arm 1 and 21% in arm 2 (P = .02). One case of grade 3 thrombocytopenia was encountered in arm 2. Initial hemoglobin grade worsened for more patients in arm 2 (six of 23, or 26%) than in arm 1 (three of 26, or 12%). Grade 3 anemia was encountered in one patient in arm 2 and two patients in arm 1; all three of these patients had baseline hemoglobin grade 1. No renal toxicity was encountered, as assessed by serum creatinine concentration. A mild to moderate increase in serum transaminase (AST) level (grade 1 or 2) was encountered in 60% of the patients in arm 2 as compared with 24% of the patients in arm 1 (P = .001). Grade 2 toxicity was observed in 17 patients in arm 2 and in five patients in arm 1 (P = .06). Two patients in each arm displayed a grade 3 to 4 liver enzyme increase. Peripheral sensory neuropathy consisted of long-lasting paresthesias in the finger tips and/or the soles of the feet (specifically, grades 1-c and 2). It occurred in 45 patients and in 100 (13%) of 753 courses exclusively in arm 2. Thirteen of these 45 patients subsequently displayed difficulties in fine manual activities, such as writing and buttoning (grade 2). The median cumulative l-OHP dose that led to onset of grade 1-c neuropathy was 716 mg/m2 (range, 250 to 1,625 mg/m2). The median cumulative l-OHP dose that led to onset of grade 2 neuropathy was 1,100 mg/m2 (750 to 1,650 mg/m2). One patient displayed masseter contractions for 4 days during the second course; the contractions disappeared spontaneously without sequelae and did not reappear during the next courses. One acute spasm was observed in this study. Alopecia of mild or moderate severity (grade 1 or 2) was reported for five patients in arm 1 and four patients in arm 2.
5-FU and l-OHP Dose-Intensities
Antitumor Efficacy An independent radiology assessment was performed for 182 charts (91% of all registered patients). Fifteen patient charts (eight in arm 1 and seven in arm 2) did not undergo extramural review because CT scans were unavailable for 13 cases (six in arm 1 and seven in arm 2) and only ultrasonograms were available for two cases (arm 1). Three patients in arm 2 died or withdrew before any tumoral assessment and thus could not be evaluated for response (Fig 2); they were considered to have progressed on day 1. Sixteen patients in arm 1 and 53 patients in arm 2 achieved an objective response as assessed by extramural review (Table 4). As a result, the objective response rate was 16% (95% confidence interval [CI], 9% to 24%) in arm 1 and 53% (95% CI, 42% to 63%) in arm 2. The difference was highly statistically significant (P < .0001). According to the investigators’ assessments, the objective response rates were 23% (96% CI, 15% to 32%) in arm 1 and 59% (95% CI, 48% to 68%) in arm 2 (P < .001).
Responses were further confirmed at 9 weeks in 12 patients in arm 1 and 34 patients in arm 2, as assessed by the extramural review committee. Lack of confirmation at 9 weeks was caused by toxicity (arm 2, two patients), progressive disease (arm 1, three patients; arm 2, 12 patients), an unavailable CT scan (arm 2, one patient), and complete surgical removal of metastases (arm 1, one patient; arm 2, four patients). Thus, the rate of objective responses that were confirmed at 9 weeks, as per extramural review committees, was 12% (95% CI, 6% to 20%) in arm 1 and 34% (95% CI, 24% to 44%) in arm 2 (P < .001). The median time to best response was similar in both arms, ie, 6 months (range, 4.3 to 7.4 months) in arm 1 and 5 months (range, 4.3 to 5.5 months) in arm 2.
Metastases Surgery
PFS and Overall Survival
The median overall survival time was 19.9 months (range, 14 to 25.7 months) in arm 1 and 19.4 months (range, 15.4 to 23.4) in arm 2. The difference was not statistically significant (Fig 4). The estimated survival rates at 2 and 3 years were 45% and 30%, respectively, in arm 1, and 37% and 23.5%, respectively, in arm 2.
Prognostic Factors for Response and Survival The number of organs involved was the only factor that influenced both response and survival, according to multivariate analysis. Treatment arm and age were joint prognostic factors for response, and performance status and percentage of liver involvement were jointly predictive for survival (Table 5).
This randomized multicenter study assessed the effect of adding l-OHP to chronomodulated 5-FU and LV in 200 patients with previously untreated metastatic colorectal cancer. The three-drug treatment increased the objective best response rate three-fold as compared with 5-FU–LV alone. Objective response documentation was based on extramural review of all available CT scans. The results confirmed that this three-drug combination achieves 50% or more objective responses as first-line treatment of metastatic colorectal cancer, as previously reported.24,26,27,33,34 Despite randomization, statistically significant imbalances in patient characteristics were found with regard to adjuvant chemotherapy and abnormal CEA plasma level. Nevertheless, these factors were not predictive for response or survival in the univariate analysis (P > .2) and therefore were not included in the multivariate analysis. Chronomodulated 5-FU–LV produced severe toxicity in 5% of the patients and in 2% of the courses. This incidence seems to be much lower than that achieved with most current 5-FU–LV regimens. Thus, grade 3 or 4 diarrhea, mucositis, and neutropenia were reported in 15% to 40% of the patients, according to the 5-FU–LV regimen that was given9,38-54 (Table 6).
The good tolerability of chronomodulated 5-FU–LV allowed the effective administration of the planned dose-intensity of both drugs throughout the whole treatment span. Nevertheless, this well-tolerated regimen achieved a modest antitumor activity. The objective response rate was 16%, and 12% of objective responses were maintained at 9 weeks. These figures are consistent with the antitumor activity of 5-FU–LV produced by much more toxic regimens. From 1987 to 1998, to the best of our knowledge, 22 reported multicenter, randomized trials have involved first-line 5-FU–LV as one of the treatment arms in patients with metastatic colorectal cancer. Although the objective response rate to 5-FU–LV has ranged from 11% to 43%, the method used for documenting it has varied widely among the trials. CT scans were mandatory in only two trials,46,50 responses were reviewed by an extramural panel of radiologists in four trials (41%),44,47,49,52 and responses were confirmed in nine trials (41%).36-38,40-42,46,49,52 The use of the intent-to-treat method was not systematically reported. We could not identify any published phase III trial involving one 5-FU–LV treatment arm where all three of these conditions were fulfilled. One phase III trial comparing bolus 5-FU to 5-FU–LV involved an extramural review of responders, intent-to-treat analysis, and confirmation of response at 8 weeks, but CT scan documentation was not required.47 In this study, the objective response rate to 5-FU–LV was 18%, which was close to the rate obtained with 5-FU–LV in the present trial (Table 6). Combined l-OHP and chronomodulated 5-FU–LV displayed acceptable tolerability. Severe diarrhea was the most frequent acute side effect. It occurred in 43% of the patients. Eight patients were hospitalized and required rehydration to treat this toxic symptom. One patient was withdrawn from treatment because gastrointestinal intolerance. Severe diarrhea was usually well managed with loperamide treatment, since it occurred in only 10% of the courses despite minimal, if any, reduction of the 5-FU or l-OHP dose. In our previous multicenter experience with the three-drug combination as first-line treatment, severe diarrhea occurred in 35% of the patients receiving a 5-day constant-rate infusion of all three agents and in 29% of the patients receiving chronomodulated delivery of all three drugs.26 Nausea and vomiting required preventive antiemetics with anti–5-hydroxytryptamine-3. The incidence of severe hematologic or grade 2 or higher liver enzyme toxicity was minimal with either treatment modality. No renal toxicity was reported. Alopecia was minimal. Peripheral sensory neuropathy was the cumulative dose-limiting toxicity of the three-drug combination and was not encountered in the patients who received 5-FU–LV only. Thus l-OHP–related toxicity led to treatment withdrawal in 10 patients. It consisted of moderate functional impairment in 13 patients who had received a median cumulative l-OHP dose of 1,100 mg/m2. This dose was administered over approximately 6 months. Thus, peripheral sensory neuropathy usually occurred after the maximum response to therapy had been obtained. Indeed, the median time to maximum response was 5 months. Late occurrence of this dose-limiting toxicity also explains why it did not affect dose-intensity for up to nine courses. In the present trial, l-OHP was infused at a constant rate for 6 hours, from 1000 to 1600. This schedule was devised to avoid the stressful acute laryngospasm or other pharyngolaryngeal dysesthesias and/or muscular spasms observed with the 2-hour infusion of this drug16-18 and to take advantage of improved tolerability when l-OHP is given in the middle of the day, as a result of circadian rhythms.22,26,27 Indeed, a single acute spasm was reported in the present trial, and the incidence of functional impairment from peripheral sensory neuropathy was similar to that previously reported by us using chronomodulated delivery for 5 days. Nevertheless, these rates were markedly lower than those which resulted from continuous flat infusion for 5 days (31%)27 and those which were reported after a 2-hour infusion on a single day (33%).25 The difference between both treatment arms was highly statistically significant, irrespective of whether objective responses had been defined by the investigators, defined by an extramural review committee, or further documented 9 weeks later. Indeed, five patients (5-FU–LV, one patient; l-OHP/5-FU–LV, four patients) underwent surgical removal of metastases with curative intent within 1 month after the first documentation of an objective response and were not considered as responders in the confirmed response assessment.
Median PFS was one of the secondary end points of the trial and was statistically increased by nearly 3 months in the l-OHP arm. The median survival time was similar in both groups, yet it exceeded by nearly 6 months that usually achieved in similar populations of patients registered in multicenter randomized trials. The survival in the 5-FU–LV/l-OHP arm was comparable to that previously achieved by us as first-line treatment.26,27 It is surprising, however, that the large and statistically significant differences in rates of objective responses between both treatments groups did not translate into survival differences. This held true even if stable disease was considered as a treatment success (arm 1, 61%; arm 2, 77%; P < .02, In conclusion, l-OHP added significant activity to chronomodulated 5-FU–LV as first-line chemotherapy for metastatic colorectal cancer and displayed acceptable toxicity. No difference in survival was found between the two treatment arms, but the trial was not designed to answer this question, as the number of patients planned in this study was inadequate to validate survival differences and second-line treatment with l-OHP was allowed after chronomodulated 5-FU–LV treatment failed. Our current aim is to evaluate the effect on survival of chronomodulation of the three-drug combination in patients with metastatic colorectal cancer in a multicenter randomized trial of the European Organization for Research and Treatment of Cancer.
Supported by contracts from Debiopharm S.A.–Université Paris Sud and Association Internationale Pour la Recherche sur le Temps Biologiques et la Chronotherapie International, Hôpital Paul Brousse, Villejuif, France. We thank M. Bayssas, M.C. Pinel, S. Brienza, and A. Metouri from Debiopharm, S.A.; H. Sancho-Garnier, H. Bleiberg, J.P. Droz, and J.J. Lokich for their advice and comments while on the policy board; M. Buyse and L. Ritter for the final statistical analysis; M. Itzhaki for the intermediate analyses; F. Kunstlinger for the radiologic review at Paul Brousse Hospital; H. Caillet, A. Sibert, and C. Patriarche for reviewing all of the radiology charts; our colleagues H. Curé, C. Farabos, F. Kreutz, D. Mille, and L. Dogliotti from collaborative institutions; our colleagues from Paul Brousse Hospital, C. Brezault-Bonnet, F. Goldwasser, C. Jasmin, D. Machover, M. Musset, J.M. Tigaud, and H. Bismuth, for their contributions to the care and referral of patients; E. Bailly and G. Debotte for technical help, and M. Lévi for editing the manuscript.
 Deceased.  Presented in part at the Thirty-Third Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 17-20, 1997 (abstr 805).
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ABSTRACT
INTRODUCTION
2 test). Indeed, the survival in the 5-FU–LV arm was much longer than that achieved with conventional 5-FU–LV in phase III trials.
