Phase III Study of Weekly High-Dose Infusional Fluorouracil Plus Folinic Acid With or Without Irinotecan in Patients With Metastatic Colorec
http://www.100md.com
《临床肿瘤学》
the Department of Internal Medicine, University of Dresden, Dresden
Universit?tsklinik Tübingen, Tübingen
Medizinische Klinik, Saarbrücken
Charite Virchow Klinikum, Berlin
Medizinische Poliklinik der Universit?t, Würzburg
Dr.-Horst-Schmidt-Kliniken GmbH, Wiesbaden
St Antonius-Hospital, Eschweiler
Katharinhospital, Stuttgart
Kreiskrankenhaus, Aurich
University of Essen, Essen
Marienenhospital Ruhr University, Herne
Onkologische Schwerpunkpraxis, Leer, Germany
University Hospital, Gasthuisberg, Leuven
European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium
Laurentius Ziekenhuis, Roermond, the Netherlands
National Cancer Institute, Cairo, Egypt
Hopital Ambroise Paré, Boulogne, France
Deceased.
ABSTRACT
PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS).
PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m2 as a 2-hour infusion and FU 2.6 g/m2 by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m2 preceded by irinotecan 80 mg/m2 administered over 30 minutes (experimental group, n = 214).
RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001).
CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.
INTRODUCTION
Until recently, the preferred therapy for metastatic colorectal carcinoma was the thymidylate synthase inhibitor fluorouracil (FU).1 FU is normally administered in conjunction with leucovorin (folinic acid [FA]), which is thought to potentiate the action of FU by enhancing complex formation between thymidylate synthase and 5-fluorodeoxyuridylate produced from 5,10-methylenetetrahydrofolate generated from FA.2 Several studies have compared bolus with infusional administration of FU, and the infusional route has generally been found to improve safety and efficacy.3-5 The results of a study comparing the effect of high-dose, infusional FU, with or without FA, with the bolus Mayo Clinic FU/FA regimen in patients with advanced colorectal cancer have recently been reported. Compared with the Mayo Clinic regimen, FA with high-dose infusional FU significantly increased progression-free survival (PFS) but not overall survival (OS).6 Because FA significantly increases PFS, the Arbeitsgemeinschaft für Internistische Onkologie (AIO) regimen with FA was chosen as the reference arm for this study, with the primary end point being PFS.
Topoisomerase I is an enzyme involved in unwinding and rejoining DNA by single-chain cleavage during DNA replication. Irinotecan (7-ethyl-10-[4(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is a topoisomerase I inhibitor with antitumor properties. There are a number of reports of its use both as first-line7-12 and second-line monotherapy for the treatment of advanced colorectal cancer, including second-line treatment of FU-refractory tumors.13-20 This single-agent activity and the fact that the therapeutic target of irinotecan is distinct from that of FU provided the rationale for the use of irinotecan in combination with FU/FA for the first-line treatment of advanced and metastatic disease. Several studies have assessed the therapeutic value of irinotecan administered in combination with bolus or infusional FU/FA regimens, and irinotecan in combination with infusional FU/FA, in particular, is accepted as a reference regimen for the first-line treatment of patients with advanced or metastatic colorectal cancer.10,21-28 In addition to having improved therapeutic efficacy, infusional FU/FA in combination with irinotecan has the advantage of reduced toxicity compared with bolus FU/FA combination therapy.29,30
The AIO high-dose infusional FU/FA regimen (HDFU/FA) showed encouraging activity when compared with infusional FU alone and bolus FU/FA in the previous European Organisation for Research and Treatment of Cancer (EORTC) trial mentioned earlier.6 In a phase I study, encouraging activity was obtained when HDFU/FA was combined with irinotecan.31 The objective of the present randomized trial was to assess the potential additional therapeutic benefits of irinotecan combined with a weekly HDFU/FA regimen for the treatment of patients with metastatic colorectal cancer, with PFS as the primary end point.
PATIENTS AND METHODS
Patient Selection Criteria
All patients who were entered onto the study had to have histologically verified adenocarcinoma of the colon or rectum that had progressed to metastatic disease. Patients were at least 18 years of age and had a WHO performance status of 0, 1, or 2. Their disease was measurable or assessable and outside of the irradiation field in patients who had previously received radiotherapy. Previous adjuvant chemotherapy was allowed if it did not contain topoisomerase I inhibitor(s) and had been completed at least 6 months before entry onto the trial. No other therapeutic drugs were allowed within 4 weeks of entry onto the trial.
After clinical evaluation at 3 weeks or less before commencement of the trial, all patients had leukocytes at least 3,000/μL, platelets at least 100,000/μL, and adequate renal (creatinine 1.25x the upper limit of normal [ULN]) and hepatic function (total bilirubin 1.25x ULN, AST and ALT 3x ULN in absence of liver metastases; or total bilirubin 1.5x ULN, AST and ALT 5x ULN in presence of liver metastases). No patients had documented CNS metastases or severe cardiac disease, including uncontrolled angina pectoris or myocardial infarction, within the 6 months before entry onto the trial. Previous chemotherapy for metastatic disease and concurrent treatment with any other anticancer therapy were exclusion criteria. No patients had a second malignancy, except adequately treated in situ carcinoma of the cervix or nonmelanoma skin cancer. Patients were excluded if they had a bowel obstruction or subobstruction, Crohn's disease, ulcerative colitis, or history of chronic diarrhea. Pregnant or breast-feeding women and fertile patients (male or female) who did not have adequate contraception were not entered onto the study. Patients did not have any other severe uncontrolled medical condition.
Trial Design
This was a prospective, multicenter, randomized, nonblinded, phase III trial conducted between August 1999 and July 2001 at 56 institutions. Patients provided written informed consent and were centrally randomly assigned to two treatment groups by minimization (Fig 1). Patients were stratified by institution, prior adjuvant treatment, WHO performance status, and serum alkaline phosphatase.
The reference group (n = 216) received the standard AIO schedule of FA 500 mg/m2 administered by intravenous infusion over 2 hours, followed by FU 2.6 g/m2 administered by infusion over 24 hours. Both drugs were administered on days 1, 8, 15, 22, 29, and 36, followed by a 2-week rest. Each treatment cycle consisted of 49 days.
The experimental group (n = 214) received a similar schedule but with FU 2.3 g/m2, which was subsequently reduced to FU 2.0 g/m2 because of toxicity of therapy. Treatment was preceded on each occasion by irinotecan 80 mg/m2 administered intravenously over 30 minutes (Fig 1).
Patients were monitored throughout treatment for routine hematologic and biochemical parameters, and all measurable or assessable tumors were evaluated by chest x-ray, ultrasound, or computed tomography. Treatment was continued until disease progression, severe toxicity, treatment refusal (unrelated to toxicity), investigator decision, or death or until patient was lost to follow-up.
Treatment Modification
Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria version 2.0. For any patient with diarrhea, stomatitis/mucositis, thrombocytopenia grade 1, leukopenia grade 2, or any other toxicity of more than grade 2 on the day of scheduled treatment, therapy had to be delayed until complete normalization, and the dose of FU and irinotecan had to be reduced to 80% of the previous dose for all further administrations. Treatment had to be stopped in case of grade 3 neurologic toxicity, any cardiac side effects, or grade 4 leukopenia or thrombocytopenia (< 25 x 109/L) at any time during the treatment. For patients with grade 3 thrombocytopenia, stomatitis/mucositis, constipation, or diarrhea or any other grade 3 toxicity, the doses of FU and irinotecan had to be reduced to 80% of the previous dose for all further administrations. For any patient experiencing hand-foot syndrome (palmar-plantar erythrodysesthesia) grade 3, the dose of FU only had to be reduced to 80% of the previous dose for all further administrations.
Concomitant Treatments
Patients experiencing cholinergic syndrome subsequently received atropine 0.25 mg subcutaneously, whereas patients experiencing delayed diarrhea were instructed to take two capsules (4 mg) of oral loperamide and then one capsule every 2 hours for at least 12 hours and up to 12 hours after symptoms ceased. This treatment was not to be administered for more than 48 hours, and oral rehydration was to be prescribed throughout the episode of diarrhea. If diarrhea persisted longer than 48 hours, a 7-day course of the broad-spectrum antibiotic fluoroquinolone was prescribed. In patients with severe diarrhea who failed to respond to loperamide, octreotide 100 μg was to be administered three times daily with rigorous oral fluid and electrolyte replacement, until diarrhea ceased. Preventive oral antibiotic therapy was to be administered to patients with severe leukopenia who were at risk from febrile infection. Patients with hand-foot syndrome were recommended to receive pyridoxine (vitamin B6) 100 to 150 mg/d. The choice of the prophylactic antiemetic treatment was left to the discretion of the responsible physician. A 5-hydroxytryptamine-3 antagonist was recommended in combination with dexamethasone in all patients receiving irinotecan.
End Points
Tumor responses were only assessed in patients with bidimensionally measurable lesions of at least 2 cm in diameter, according to WHO criteria. These measurements were performed on skin, lung, or liver metastases, lymph nodes, or soft tissue lesions by means of x-ray, ultrasound, magnetic resonance imaging, or computed tomography. Complete response was defined as complete disappearance of all known disease determined by two observations at least 4 weeks apart. Partial response was defined as a 50% or more decrease in total tumor size determined by two observations at least 4 weeks apart. Progressive disease was defined as a 25% or greater increase in size of one or more measurable lesions or the appearance of new lesions. No change was reported when there was neither a complete or partial response nor disease progression at least 7 weeks after the commencement of treatment.
For patients with measurable lesions only, progression was defined as an increase in size of existing lesions, appearance of new lesions, or deterioration of the patient's condition as a result of malignant disease. PFS was defined as the time interval from randomization to progression or death, whichever occurred first. Patients were censored at the date of last visit. OS was defined as the time interval between the date of randomization and the date of death. Performance status was scored using the WHO performance status scale.
Statistical Analysis
The original sample size for this study was determined to compare the PFS (primary end point of the study) in the two treatment arms. A total of 350 progressions or deaths (events) were required to provide an at least 80% power to be able to detect a shift in the median PFS from 7 months to 9.5 months. It was estimated that 430 patients (215 per arm) were needed for the study.
The duration of survival and PFS were estimated using the Kaplan-Meier method32 and compared using a two-sided log-rank test.33 For both end points, the study was assessed on an intent-to-treat basis. This patient set was derived from the set of all randomly assigned patients, and the analyses were carried out according to the treatment group assigned by randomization. Response to treatment was compared using a 2 test on all patients with measurable disease. The population used to evaluate the toxicity profile of the treatments included all eligible and ineligible patients who started the allocated treatment.
RESULTS
Four hundred thirty patients were entered onto the study (216 on the standard AIO HDFU/FA therapy regimen and 214 on the irinotecan and HDFU/FA regimen). One patient was ineligible because of a diagnosis of hepatocellular carcinoma. One patient allocated to irinotecan and HDFU/FA and two patients allocated to HDFU/FA alone died before receiving any chemotherapy. One patient allocated to HDFU/FA received irinotecan and HDFU/FA, leaving a total of 213 patients in each group for the safety assessment (Fig 2).
A total of 189 patients (87.5%) had measurable disease in the AIO HDFU/FA arm, and 180 patients (84.1%) had measurable disease in the experimental arm. There was no difference in the median age and in the percentage of patients older than the age of 70 years in both arms. Also, sex was equally distributed. Slightly more patients (55.1%) had a colon primary tumor in the experimental arm compared with the patients in the reference HDFU/FA regimen (46.8%). Approximately every fourth patient in both arms had received adjuvant therapy. Radiotherapy was administered to 5.6% and 8.4% of the patients in the reference and experimental arms, respectively. The risk groups that were defined by the four clinical parameters of performance status, initial WBC greater than or less than 10 x 109/L, level of serum alkaline phosphatase, and number of involved tumor sites34 were equally distributed among the treatment arms (Table 1).
Toxicity and Dose Amendment
Of the first 89 patients assigned to irinotecan and HDFU/FA with the FU dose of 2.3 g/m2, 18 serious adverse events (SAEs) possibly, probably, or definitely related to the drug were reported in 16 different patients. During the same time period, seven SAEs were reported in seven different patients in the standard arm. Examination of these SAEs revealed that the rate of gastrointestinal-associated SAEs was higher in the experimental group than in the control group. Moreover, during that period, three toxic deaths and one toxic death were observed in the irinotecan plus HDFU/FA and HDFU/FA arms, respectively. In compliance with a decision of the Independent Data Monitoring Committee, the dose was reduced to FU 2.0 g/m2. Compared with patients who received FU 2.0 g/m2, those who received the higher dose of FU experienced higher rates of leukopenia, diarrhea, alopecia, and cardiovascular symptoms. There seem to be no differences in the incidence of other side effects between the reference and experimental groups (Table 2).
Of all patients in the irinotecan plus HDFU/FA group during the first treatment cycle, 37% showed toxicity necessitating FU dose reduction, compared with 18% of patients from the reference group, who received FU 2.6 g/m2. In cycle 2, the rate of dose reductions was 17% and 14%, and in cycle 3, the rate was 6% and 7% for patients receiving HDFU/FA and HDFU/FA plus irinotecan, respectively. Thereafter, dose reductions occurred in no more than 2% of patients.
Of the 89 irinotecan plus HDFU/FA patients exposed to the initial dose of FU, 40.4% needed a dose reduction during the first chemotherapy cycle. In contrast, only 33.9% of the 124 irinotecan plus HDFU/FA patients exposed to the amended dose of FU needed a dose reduction during the first chemotherapy cycle. Quantitative information related to the treatments received are listed in Table 3. The median number of cycles per patient in both groups was three cycles (range, one to nine cycles; Table 3). Overall, the relative dose intensities for FU and FA were similar in both groups, with a median of approximately 80% of the intended dose being administered.
Response to Treatment
The median duration of follow-up was 2.3 years (95% CI, 2.1 to 2.4 years). Median PFS in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) versus 6.4 months (95% CI, 5.3 to 7.2 months) in the reference group (P < .0001; hazard ratio = 0.65; 95% CI, 0.53 to 0.79; Fig 3) When considering only those patients entered after the FU dose reductions, the hazard ratio was 0.71 (95% CI, 0.55 to 0.91). At 1 year, 27.6% (95% CI, 21.5% to 33.7%) and 14.8% (95% CI, 10.0% to 19.5%) of the patients were free from progression in the experimental and reference arms, respectively.
The improvement in PFS was not associated with a significantly enhanced OS (Fig 4). The median OS was 20.1 months (95% CI, 18.0 to 21.9 months) in patients treated with irinotecan plus HDFU/FA compared with 16.9 months (95% CI, 15.3 to 19.0 months) in the reference group. A transient benefit of irinotecan was observed in the short term (Wilcoxon, P = .0509), with a 1-year survival rate of 75.4% (95% CI, 69.6% to 81.3%) in the experimental group compared with 66.4% (95% CI, 60.0% to 72.8%) in the reference group. The survival curves cross around month 24 of the trial, reflecting the greater benefit of salvage treatment in the reference arm. Overall, the trial shows no statistically significant benefit of immediate intensive treatment in terms of OS (P = .2779, log-rank test). However, this observed survival difference corresponded to a hazard rate of 0.88 (95% CI, 0.70 to 1.11) for the whole cohort. The hazard ratio for patients entered onto the study after the FU dose reduction was 0.87 (95% CI, 0.63 to 1.20).
The response to treatment in patients with measurable disease was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the reference group (Table 4). The difference was significant (P < .0001). The median duration of response in the irinotecan plus HDFU/FA group was 10.1 months (95% CI, 8.7 to 11.2 months) compared with 9.2 months (95% CI, 8.2 to 10.4 months; P = .11, log-rank test) in the reference group. Secondary resection of metastases was possible in six and 14 patients in the irinotecan plus HDFU/FA and HDFU/FA groups, respectively.
Treatment Discontinuation and Second-Line Treatment
A higher proportion of patients in the HDFU/FA group than in the irinotecan plus HDFU/FA group discontinued treatment because of disease progression or relapse (61.5% v 43.7%, respectively). When comparing the reasons for discontinuation in patients who received FU 2.3 g/m2 with those who received FU 2.0 g/m2 plus irinotecan (data not shown), major differences were not observed. A lower proportion of patients in the irinotecan plus HDFU/FA group (55.6%) received additional second-line treatment than in the AIO HDFU/FA group (65.3%; Table 5). Also, second-line therapy for the HDFU/FA group included irinotecan in a higher proportion of the patients than in the experimental irinotecan plus HDFU/FA group. Conversely, a higher proportion of the experimental group patients received oxaliplatin as second-line therapy compared with reference group patients (34% v 52%, respectively; Table 5).
DISCUSSION
This study demonstrates a clear benefit in terms of response rate and PFS of adding irinotecan to high-dose infusional therapy with FU/FA for patients with advanced colorectal cancer. This benefit was reflected in the enhanced median PFS and PFS rate at 1 year. However, because the duration of response was not significantly different, it may be speculated that the improvement in the response rate is quantitative rather than qualitative (ie, irrespective of which regimen is used, if response is achieved the duration, or quality, is similar). Thus, the longer PFS in the experimental combination arm may be mainly a result of the increased number of patients who achieved a response.
All the responses in this trial were confirmed at least 4 weeks after their first occurrence. The response rate of 62% observed in the experimental arm corresponds well to the 64% (16 of 25 patients) response rate that was observed for the regimen of irinotecan plus HDFU/FA in the previous phase I study in previously untreated colorectal cancer patients.21
The median OS was also increased for the irinotecan plus HDFU/FA, but this difference was not statistically significant (P = .2779; hazard ratio = 0.88; 95% CI, 0.70 to 1.11). The trial is underpowered to detect a survival difference of that magnitude. It is noteworthy, however, that this is one of the longest median survival times achieved in a randomized multicenter trial both using this combination and for first-line therapy in general. In our previous study,6 patients receiving only AIO HDFU/FA therapy had a median survival of 13.7 months, whereas in the present study, patients receiving the same AIO HDFU/FA therapy had a median survival of 16.9 months. This is presumably a consequence of more intensive second-line therapy, and this hypothesis is supported by the similar median PFS times for patients receiving AIO therapy in the two studies.6 Also, median survival is improved by more intensive first-line treatment; this is clearly demonstrated by comparison of the arms of the present study with the arm of the previous EORTC 40952 study6 presented in Figure 5. Although comparisons over time and studies may be problematic, the EORTC 40952 and 40986 studies are consecutive trials by the same group of investigators with identical patient selection criteria. In addition, these data (Fig 5) strongly suggest that all patients should receive all available active drugs during the course of their disease.
The findings of the present study are consistent with those previously reported for the addition of irinotecan to other FU/FA regimens and are broadly similar to those of Douillard et al,26 who studied approximately the same number of patients but used two different treatment schedules, using either weekly (AIO) or biweekly (de Gramont) FU/FA treatment cycles. The majority of the patients in the study by Douillard et al26 underwent the biweekly protocol, in which slightly higher overall doses of irinotecan but lower doses of FU were administered. Only one third of their patients underwent a treatment regimen similar to that of the present study, except that the FU dose in the AIO combination arm in their study was 2.3 g/m2. Hence, the two studies may not be directly comparable. Also, Douillard et al26 only followed OS to a median of 23.3 months compared with 28 months of median follow-up in this study. This was the point at which the survival curves for the patient groups with and without irinotecan were beginning to converge, as was the case in our study. It may be speculated that, although more patients receiving irinotecan plus HDFU/FA initially show a more rapid and sustained response (partial response instead of no change), resulting in a longer PFS, than patients on HDFU/FA alone, relapse proceeds at a similar rate in both groups. By 2 years, only a small proportion of patients remain alive, so any statistical comparisons at this point are less reliable. Also, the trial was not powered for survival; thus, the number of patients and events was too low to draw final conclusions. To demonstrate an increase in survival from 17 to 20 months (HR = 1.18) with 80% power, approximately 1,200 events would be needed (approximately 2,000 patients).
However, there is continuing debate about whether to treat all patients upfront with combination FU/FA therapy or whether to give the same drugs sequentially to have a second-line treatment available for the patients when and if required. The survival curves for this study show that, until approximately 28 months, patients who received the combination therapy had a better survival time than patients who received the AIO HDFU/FA regimen. This was true for approximately 80% of patients because only approximately 20% of patients were alive at 28 months in both arms. For these 20% of patients, the survival curves converged, and presumably, for these 20% of patients who represent the long-term survivors in each arm, the first-line AIO HDFU/FA therapy followed by second- or even third-line treatment gave similar results. However, the survival was not inferior for those patients who received the irinotecan plus HDFU/FA combination first-line treatment and who may not have had the chance to receive irinotecan as a second- or third-line treatment. Thus, all patients should receive the combination therapy as first-line treatment, and monotherapy should be the exception for those patients who are not suitable for irinotecan or oxaliplatin combination because of other comorbidities.
As previously reported,24-26 side effects, mainly comprising diarrhea and neutropenia, are associated with the FU/FA and irinotecan treatment combination. The side effects were generally manageable, with grade 3 and 4 diarrhea reported in 21% and 24% of patients and febrile neutropenia reported in 1% and 2% of patients receiving the AIO HDFU/FA and reduced FU AIO HDFU/FA plus irinotecan combinations, respectively. All side effects were substantially reduced after the first cycle of treatment. The reduction in FU dose from 2.3 to 2.0 g/m2, which was prompted by a high incidence of side effects, did not seem to alter treatment efficacy in this study. This is supported by the similar hazard ratio in patients receiving the reduced dose relative to the whole cohort. The lower dose of FU 2.0 g/m2 is the recommended dose for future protocols because this dose was associated with less gastrointestinal toxicity and fewer instances of patient hospitalizations than reported in previous studies, particularly those using bolus FU regimens.29 Nevertheless, even with the lower FU dose, approximately one third of patients required an FU dose reduction in the first cycle of treatment, which was not very different from the 40% of patients receiving the higher dose. This regimen has the advantage that dose adjustments can be performed on a weekly basis according to the individual toxicity. Compared with other infusional FU/FA and irinotecan regimens, our schedule has a remarkable low incidence of alopecia, presumably because of the low weekly dose of irinotecan. This regimen may be an alternative for those patients who are concerned about alopecia, which may occur more frequently with the biweekly regimens.
Our study supports the idea that infusional FU may be the optimal way to administer FU when combined with irinotecan or oxaliplatin because toxicity seems to be lower and efficacy seems quite high.30 Because of the rather low overall toxicity, our regimen seems suitable to be combined with new targeted agents, such as cetuximab or bevacizumab. In fact, irinotecan, FU, and FA plus bevacizumab was superior to irinotecan, FU, and FA alone.35 Bevacizumab is approved in the United States and Europe for combination with FU and irinotecan. We would speculate that our regimen may also be further improved by bevacizumab or cetuximab. Phase I data indicate feasibility and promising activity when cetuximab is added to our HDFU/FA plus irinotecan regimen.36
Appendix
The following clinicians contributed patients to the trial: Prof H. Bleiberg, (Brussels); Dr M. Peeters (Gent); Dr A. Vandebroek, (Antwerp); Prof E. Van Cutsem, (Leuven); Dr J. Janssens (Turnhout); Dr H. Schmidt (Berlin); Dr J.-Y. Douillard (Nantes); Prof D. Jaecke (Strasbourg); Prof N.L. Balleisen (Hamm); Dr H.-G. Hoeffkes (Fulda); Prof H.J. Schmoll (Halle);Dr M. Sandman (Wuppertal); Dr W. Abenhardt, Prof R. Fuchs (Eschweiler); Dr F. Lordick (Muenchen); Dr U. Vanhoefer (Essen); Dr K.-T. Steurer (Nurnberg); Dr H. Scherubl (Berlin); Prof R. Voigtmann (Bochum); Dr P. Schoeffski (Hannover); Prof C. Bokemeyer, Dr J. Hartmann (Tübingen); Prof C. Aul (Duisburg); Prof M. Lorenz (Frankfurt); Prof N. Haim, (Haifa); Prof G. Doelken (Greifswald); Dr R. Souchon (Hagen); Prof P. Caenepeel (Genk); Prof B. Nordlinger, Prof P. Rougier, (Boulogne); Dr P. Reichardt (Berlin); Prof M.P. Lutz, (Ulm); Dr H.-G. Mergenthaler (Stuttgart); Dr H. Knipp (Essen); Dr K. Huntenburg (Neustadt); Dr C. Haag (Dresden); Prof C.-H. K?hne (Rostock/Dresden); Prof H. Rückle-Lanz (Würzburg); Dr T. Langenbuch (Aurich); Dr C. Klinkenstein (Frankfurt); Dr H. Eimermacher, Dr N.W. Lindeman (Hagen); Dr J. Papke (Neustadt-in-Sachsen); Dr R. Pasold (Potsdam); Dr E. Kettner (Magdeburg); Prof H.J. Wilke (Essen); Dr G. Hartung (Rostock); Dr N. Frickhofen (Wiesbaden); Prof J.T. Fischer (Karlsruhe); Dr R. Albrecht (Aue); Dr A. Rennert (Plauen); Prof H. Gerhartz (Meissen); Dr K. Becker (Hamburg); Dr U. Gerecke (Stralsund); and Dr J. Wils (Roermond).
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank data manager Nathalie Garzon Vanacker for her valuable contribution to the study.
NOTES
Supported by an educational grant from Aventis Pharma, Antony, France.
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Michael M, Hedley D, Oza A, et al: The palliative benefit of irinotecan in 5-fluorouracil-refractory colorectal cancer: Its prospective evaluation by a Multicenter Canadian Trial. Clin Colorectal Cancer 2: 93-101, 2002
Tsavaris NB, Polyzos A, Gennatas K, et al: Irinotecan (CPT-11) in patients with advanced colon carcinoma relapsing after 5-fluorouracil-leucovorin combination. Chemotherapy 48: 94-99, 2002
Vieitez JM, Carrasco J, Esteban E, et al: Irinotecan in the treatment of advanced colorectal cancer in patients pretreated with fluorouracil-based chemotherapy: A study to determine recommendable therapeutic dosage. Am J Clin Oncol 26: 107-111, 2003
Cassinello J, Lopez-Alvarez P, Martinez-Guisado A, et al: Phase II study of weekly irinotecan (CPT-11) as second-line treatment of patients with advanced colorectal cancer. Med Oncol 20: 37-43, 2003
Fuchs CS, Moore MR, Harker G, et al: Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21: 807-814, 2003
Vanhoefer U, Harstrick A, Achterrath W, et al: Irinotecan in the treatment of colorectal cancer: Clinical overview. J Clin Oncol 19: 1501-1518, 2001
Cunningham D, Maroun J, Vanhoefer U, et al: Optimizing the use of irinotecan in colorectal cancer. Oncologist 6:17-23, 2001 (suppl 4)
Rougier P, Mitry E: Review of the role of CPT-11 in the treatment of colorectal cancer. Clin Colorectal Cancer 1: 87-94, 2001
Benson AB, Goldberg RM: Optimal use of the combination of irinotecan and 5-fluorouracil. Semin Oncol 30:68-77, 2003 (suppl 6)
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
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
Glimelius B, Risatmaki R, Kjaer M, et al: Irinotecan combined with bolus 5-fluorouracil and folinic acid Nordic schedule as first-line therapy in advanced colorectal cancer. Ann Oncol 13: 1868-1873, 2002
Bouzid K, Khalfallah S, Tujakowski J, et al: A randomized phase II trial of irinotecan in combination with infusional or two different bolus 5-fluorouracil and folinic acid regimens as first-line therapy for advanced colorectal cancer. Ann Oncol 14: 1106-1114, 2003
Sargent DJ, Niedzwiecki D, O'Connell MJ, et al: Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 345: 144-145, 2001
Van Cutsem E, Douillard JY, K?hne C-H: Toxicity of irinotecan in patients with colorectal cancer. N Engl J Med 345: 1351-1352, 2001
Vanhoefer U, Harstrick A, K?hne C-H, 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
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958
Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966
K?hne C-H, Cunningham D, Di Costanzo CF, et al: Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic cancer: Results of a multivariate analysis of 3825 patients. Ann Oncol 13: 308-317, 2002
Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335-2342, 2004
Sch?ffski P, Lutz MP, Folprecht G, et al: Cetuximab (C225) plus irinotecan (CPT-11) plus infusional 5FU-folinic acid (FA) is safe and active in metastatic colorectal cancer (MCRC), that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 21: 159a, 2002 (abstr 633)(C.-H. K?hne, E. van Cutse)
Universit?tsklinik Tübingen, Tübingen
Medizinische Klinik, Saarbrücken
Charite Virchow Klinikum, Berlin
Medizinische Poliklinik der Universit?t, Würzburg
Dr.-Horst-Schmidt-Kliniken GmbH, Wiesbaden
St Antonius-Hospital, Eschweiler
Katharinhospital, Stuttgart
Kreiskrankenhaus, Aurich
University of Essen, Essen
Marienenhospital Ruhr University, Herne
Onkologische Schwerpunkpraxis, Leer, Germany
University Hospital, Gasthuisberg, Leuven
European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium
Laurentius Ziekenhuis, Roermond, the Netherlands
National Cancer Institute, Cairo, Egypt
Hopital Ambroise Paré, Boulogne, France
Deceased.
ABSTRACT
PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS).
PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m2 as a 2-hour infusion and FU 2.6 g/m2 by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m2 preceded by irinotecan 80 mg/m2 administered over 30 minutes (experimental group, n = 214).
RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001).
CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.
INTRODUCTION
Until recently, the preferred therapy for metastatic colorectal carcinoma was the thymidylate synthase inhibitor fluorouracil (FU).1 FU is normally administered in conjunction with leucovorin (folinic acid [FA]), which is thought to potentiate the action of FU by enhancing complex formation between thymidylate synthase and 5-fluorodeoxyuridylate produced from 5,10-methylenetetrahydrofolate generated from FA.2 Several studies have compared bolus with infusional administration of FU, and the infusional route has generally been found to improve safety and efficacy.3-5 The results of a study comparing the effect of high-dose, infusional FU, with or without FA, with the bolus Mayo Clinic FU/FA regimen in patients with advanced colorectal cancer have recently been reported. Compared with the Mayo Clinic regimen, FA with high-dose infusional FU significantly increased progression-free survival (PFS) but not overall survival (OS).6 Because FA significantly increases PFS, the Arbeitsgemeinschaft für Internistische Onkologie (AIO) regimen with FA was chosen as the reference arm for this study, with the primary end point being PFS.
Topoisomerase I is an enzyme involved in unwinding and rejoining DNA by single-chain cleavage during DNA replication. Irinotecan (7-ethyl-10-[4(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is a topoisomerase I inhibitor with antitumor properties. There are a number of reports of its use both as first-line7-12 and second-line monotherapy for the treatment of advanced colorectal cancer, including second-line treatment of FU-refractory tumors.13-20 This single-agent activity and the fact that the therapeutic target of irinotecan is distinct from that of FU provided the rationale for the use of irinotecan in combination with FU/FA for the first-line treatment of advanced and metastatic disease. Several studies have assessed the therapeutic value of irinotecan administered in combination with bolus or infusional FU/FA regimens, and irinotecan in combination with infusional FU/FA, in particular, is accepted as a reference regimen for the first-line treatment of patients with advanced or metastatic colorectal cancer.10,21-28 In addition to having improved therapeutic efficacy, infusional FU/FA in combination with irinotecan has the advantage of reduced toxicity compared with bolus FU/FA combination therapy.29,30
The AIO high-dose infusional FU/FA regimen (HDFU/FA) showed encouraging activity when compared with infusional FU alone and bolus FU/FA in the previous European Organisation for Research and Treatment of Cancer (EORTC) trial mentioned earlier.6 In a phase I study, encouraging activity was obtained when HDFU/FA was combined with irinotecan.31 The objective of the present randomized trial was to assess the potential additional therapeutic benefits of irinotecan combined with a weekly HDFU/FA regimen for the treatment of patients with metastatic colorectal cancer, with PFS as the primary end point.
PATIENTS AND METHODS
Patient Selection Criteria
All patients who were entered onto the study had to have histologically verified adenocarcinoma of the colon or rectum that had progressed to metastatic disease. Patients were at least 18 years of age and had a WHO performance status of 0, 1, or 2. Their disease was measurable or assessable and outside of the irradiation field in patients who had previously received radiotherapy. Previous adjuvant chemotherapy was allowed if it did not contain topoisomerase I inhibitor(s) and had been completed at least 6 months before entry onto the trial. No other therapeutic drugs were allowed within 4 weeks of entry onto the trial.
After clinical evaluation at 3 weeks or less before commencement of the trial, all patients had leukocytes at least 3,000/μL, platelets at least 100,000/μL, and adequate renal (creatinine 1.25x the upper limit of normal [ULN]) and hepatic function (total bilirubin 1.25x ULN, AST and ALT 3x ULN in absence of liver metastases; or total bilirubin 1.5x ULN, AST and ALT 5x ULN in presence of liver metastases). No patients had documented CNS metastases or severe cardiac disease, including uncontrolled angina pectoris or myocardial infarction, within the 6 months before entry onto the trial. Previous chemotherapy for metastatic disease and concurrent treatment with any other anticancer therapy were exclusion criteria. No patients had a second malignancy, except adequately treated in situ carcinoma of the cervix or nonmelanoma skin cancer. Patients were excluded if they had a bowel obstruction or subobstruction, Crohn's disease, ulcerative colitis, or history of chronic diarrhea. Pregnant or breast-feeding women and fertile patients (male or female) who did not have adequate contraception were not entered onto the study. Patients did not have any other severe uncontrolled medical condition.
Trial Design
This was a prospective, multicenter, randomized, nonblinded, phase III trial conducted between August 1999 and July 2001 at 56 institutions. Patients provided written informed consent and were centrally randomly assigned to two treatment groups by minimization (Fig 1). Patients were stratified by institution, prior adjuvant treatment, WHO performance status, and serum alkaline phosphatase.
The reference group (n = 216) received the standard AIO schedule of FA 500 mg/m2 administered by intravenous infusion over 2 hours, followed by FU 2.6 g/m2 administered by infusion over 24 hours. Both drugs were administered on days 1, 8, 15, 22, 29, and 36, followed by a 2-week rest. Each treatment cycle consisted of 49 days.
The experimental group (n = 214) received a similar schedule but with FU 2.3 g/m2, which was subsequently reduced to FU 2.0 g/m2 because of toxicity of therapy. Treatment was preceded on each occasion by irinotecan 80 mg/m2 administered intravenously over 30 minutes (Fig 1).
Patients were monitored throughout treatment for routine hematologic and biochemical parameters, and all measurable or assessable tumors were evaluated by chest x-ray, ultrasound, or computed tomography. Treatment was continued until disease progression, severe toxicity, treatment refusal (unrelated to toxicity), investigator decision, or death or until patient was lost to follow-up.
Treatment Modification
Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria version 2.0. For any patient with diarrhea, stomatitis/mucositis, thrombocytopenia grade 1, leukopenia grade 2, or any other toxicity of more than grade 2 on the day of scheduled treatment, therapy had to be delayed until complete normalization, and the dose of FU and irinotecan had to be reduced to 80% of the previous dose for all further administrations. Treatment had to be stopped in case of grade 3 neurologic toxicity, any cardiac side effects, or grade 4 leukopenia or thrombocytopenia (< 25 x 109/L) at any time during the treatment. For patients with grade 3 thrombocytopenia, stomatitis/mucositis, constipation, or diarrhea or any other grade 3 toxicity, the doses of FU and irinotecan had to be reduced to 80% of the previous dose for all further administrations. For any patient experiencing hand-foot syndrome (palmar-plantar erythrodysesthesia) grade 3, the dose of FU only had to be reduced to 80% of the previous dose for all further administrations.
Concomitant Treatments
Patients experiencing cholinergic syndrome subsequently received atropine 0.25 mg subcutaneously, whereas patients experiencing delayed diarrhea were instructed to take two capsules (4 mg) of oral loperamide and then one capsule every 2 hours for at least 12 hours and up to 12 hours after symptoms ceased. This treatment was not to be administered for more than 48 hours, and oral rehydration was to be prescribed throughout the episode of diarrhea. If diarrhea persisted longer than 48 hours, a 7-day course of the broad-spectrum antibiotic fluoroquinolone was prescribed. In patients with severe diarrhea who failed to respond to loperamide, octreotide 100 μg was to be administered three times daily with rigorous oral fluid and electrolyte replacement, until diarrhea ceased. Preventive oral antibiotic therapy was to be administered to patients with severe leukopenia who were at risk from febrile infection. Patients with hand-foot syndrome were recommended to receive pyridoxine (vitamin B6) 100 to 150 mg/d. The choice of the prophylactic antiemetic treatment was left to the discretion of the responsible physician. A 5-hydroxytryptamine-3 antagonist was recommended in combination with dexamethasone in all patients receiving irinotecan.
End Points
Tumor responses were only assessed in patients with bidimensionally measurable lesions of at least 2 cm in diameter, according to WHO criteria. These measurements were performed on skin, lung, or liver metastases, lymph nodes, or soft tissue lesions by means of x-ray, ultrasound, magnetic resonance imaging, or computed tomography. Complete response was defined as complete disappearance of all known disease determined by two observations at least 4 weeks apart. Partial response was defined as a 50% or more decrease in total tumor size determined by two observations at least 4 weeks apart. Progressive disease was defined as a 25% or greater increase in size of one or more measurable lesions or the appearance of new lesions. No change was reported when there was neither a complete or partial response nor disease progression at least 7 weeks after the commencement of treatment.
For patients with measurable lesions only, progression was defined as an increase in size of existing lesions, appearance of new lesions, or deterioration of the patient's condition as a result of malignant disease. PFS was defined as the time interval from randomization to progression or death, whichever occurred first. Patients were censored at the date of last visit. OS was defined as the time interval between the date of randomization and the date of death. Performance status was scored using the WHO performance status scale.
Statistical Analysis
The original sample size for this study was determined to compare the PFS (primary end point of the study) in the two treatment arms. A total of 350 progressions or deaths (events) were required to provide an at least 80% power to be able to detect a shift in the median PFS from 7 months to 9.5 months. It was estimated that 430 patients (215 per arm) were needed for the study.
The duration of survival and PFS were estimated using the Kaplan-Meier method32 and compared using a two-sided log-rank test.33 For both end points, the study was assessed on an intent-to-treat basis. This patient set was derived from the set of all randomly assigned patients, and the analyses were carried out according to the treatment group assigned by randomization. Response to treatment was compared using a 2 test on all patients with measurable disease. The population used to evaluate the toxicity profile of the treatments included all eligible and ineligible patients who started the allocated treatment.
RESULTS
Four hundred thirty patients were entered onto the study (216 on the standard AIO HDFU/FA therapy regimen and 214 on the irinotecan and HDFU/FA regimen). One patient was ineligible because of a diagnosis of hepatocellular carcinoma. One patient allocated to irinotecan and HDFU/FA and two patients allocated to HDFU/FA alone died before receiving any chemotherapy. One patient allocated to HDFU/FA received irinotecan and HDFU/FA, leaving a total of 213 patients in each group for the safety assessment (Fig 2).
A total of 189 patients (87.5%) had measurable disease in the AIO HDFU/FA arm, and 180 patients (84.1%) had measurable disease in the experimental arm. There was no difference in the median age and in the percentage of patients older than the age of 70 years in both arms. Also, sex was equally distributed. Slightly more patients (55.1%) had a colon primary tumor in the experimental arm compared with the patients in the reference HDFU/FA regimen (46.8%). Approximately every fourth patient in both arms had received adjuvant therapy. Radiotherapy was administered to 5.6% and 8.4% of the patients in the reference and experimental arms, respectively. The risk groups that were defined by the four clinical parameters of performance status, initial WBC greater than or less than 10 x 109/L, level of serum alkaline phosphatase, and number of involved tumor sites34 were equally distributed among the treatment arms (Table 1).
Toxicity and Dose Amendment
Of the first 89 patients assigned to irinotecan and HDFU/FA with the FU dose of 2.3 g/m2, 18 serious adverse events (SAEs) possibly, probably, or definitely related to the drug were reported in 16 different patients. During the same time period, seven SAEs were reported in seven different patients in the standard arm. Examination of these SAEs revealed that the rate of gastrointestinal-associated SAEs was higher in the experimental group than in the control group. Moreover, during that period, three toxic deaths and one toxic death were observed in the irinotecan plus HDFU/FA and HDFU/FA arms, respectively. In compliance with a decision of the Independent Data Monitoring Committee, the dose was reduced to FU 2.0 g/m2. Compared with patients who received FU 2.0 g/m2, those who received the higher dose of FU experienced higher rates of leukopenia, diarrhea, alopecia, and cardiovascular symptoms. There seem to be no differences in the incidence of other side effects between the reference and experimental groups (Table 2).
Of all patients in the irinotecan plus HDFU/FA group during the first treatment cycle, 37% showed toxicity necessitating FU dose reduction, compared with 18% of patients from the reference group, who received FU 2.6 g/m2. In cycle 2, the rate of dose reductions was 17% and 14%, and in cycle 3, the rate was 6% and 7% for patients receiving HDFU/FA and HDFU/FA plus irinotecan, respectively. Thereafter, dose reductions occurred in no more than 2% of patients.
Of the 89 irinotecan plus HDFU/FA patients exposed to the initial dose of FU, 40.4% needed a dose reduction during the first chemotherapy cycle. In contrast, only 33.9% of the 124 irinotecan plus HDFU/FA patients exposed to the amended dose of FU needed a dose reduction during the first chemotherapy cycle. Quantitative information related to the treatments received are listed in Table 3. The median number of cycles per patient in both groups was three cycles (range, one to nine cycles; Table 3). Overall, the relative dose intensities for FU and FA were similar in both groups, with a median of approximately 80% of the intended dose being administered.
Response to Treatment
The median duration of follow-up was 2.3 years (95% CI, 2.1 to 2.4 years). Median PFS in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) versus 6.4 months (95% CI, 5.3 to 7.2 months) in the reference group (P < .0001; hazard ratio = 0.65; 95% CI, 0.53 to 0.79; Fig 3) When considering only those patients entered after the FU dose reductions, the hazard ratio was 0.71 (95% CI, 0.55 to 0.91). At 1 year, 27.6% (95% CI, 21.5% to 33.7%) and 14.8% (95% CI, 10.0% to 19.5%) of the patients were free from progression in the experimental and reference arms, respectively.
The improvement in PFS was not associated with a significantly enhanced OS (Fig 4). The median OS was 20.1 months (95% CI, 18.0 to 21.9 months) in patients treated with irinotecan plus HDFU/FA compared with 16.9 months (95% CI, 15.3 to 19.0 months) in the reference group. A transient benefit of irinotecan was observed in the short term (Wilcoxon, P = .0509), with a 1-year survival rate of 75.4% (95% CI, 69.6% to 81.3%) in the experimental group compared with 66.4% (95% CI, 60.0% to 72.8%) in the reference group. The survival curves cross around month 24 of the trial, reflecting the greater benefit of salvage treatment in the reference arm. Overall, the trial shows no statistically significant benefit of immediate intensive treatment in terms of OS (P = .2779, log-rank test). However, this observed survival difference corresponded to a hazard rate of 0.88 (95% CI, 0.70 to 1.11) for the whole cohort. The hazard ratio for patients entered onto the study after the FU dose reduction was 0.87 (95% CI, 0.63 to 1.20).
The response to treatment in patients with measurable disease was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the reference group (Table 4). The difference was significant (P < .0001). The median duration of response in the irinotecan plus HDFU/FA group was 10.1 months (95% CI, 8.7 to 11.2 months) compared with 9.2 months (95% CI, 8.2 to 10.4 months; P = .11, log-rank test) in the reference group. Secondary resection of metastases was possible in six and 14 patients in the irinotecan plus HDFU/FA and HDFU/FA groups, respectively.
Treatment Discontinuation and Second-Line Treatment
A higher proportion of patients in the HDFU/FA group than in the irinotecan plus HDFU/FA group discontinued treatment because of disease progression or relapse (61.5% v 43.7%, respectively). When comparing the reasons for discontinuation in patients who received FU 2.3 g/m2 with those who received FU 2.0 g/m2 plus irinotecan (data not shown), major differences were not observed. A lower proportion of patients in the irinotecan plus HDFU/FA group (55.6%) received additional second-line treatment than in the AIO HDFU/FA group (65.3%; Table 5). Also, second-line therapy for the HDFU/FA group included irinotecan in a higher proportion of the patients than in the experimental irinotecan plus HDFU/FA group. Conversely, a higher proportion of the experimental group patients received oxaliplatin as second-line therapy compared with reference group patients (34% v 52%, respectively; Table 5).
DISCUSSION
This study demonstrates a clear benefit in terms of response rate and PFS of adding irinotecan to high-dose infusional therapy with FU/FA for patients with advanced colorectal cancer. This benefit was reflected in the enhanced median PFS and PFS rate at 1 year. However, because the duration of response was not significantly different, it may be speculated that the improvement in the response rate is quantitative rather than qualitative (ie, irrespective of which regimen is used, if response is achieved the duration, or quality, is similar). Thus, the longer PFS in the experimental combination arm may be mainly a result of the increased number of patients who achieved a response.
All the responses in this trial were confirmed at least 4 weeks after their first occurrence. The response rate of 62% observed in the experimental arm corresponds well to the 64% (16 of 25 patients) response rate that was observed for the regimen of irinotecan plus HDFU/FA in the previous phase I study in previously untreated colorectal cancer patients.21
The median OS was also increased for the irinotecan plus HDFU/FA, but this difference was not statistically significant (P = .2779; hazard ratio = 0.88; 95% CI, 0.70 to 1.11). The trial is underpowered to detect a survival difference of that magnitude. It is noteworthy, however, that this is one of the longest median survival times achieved in a randomized multicenter trial both using this combination and for first-line therapy in general. In our previous study,6 patients receiving only AIO HDFU/FA therapy had a median survival of 13.7 months, whereas in the present study, patients receiving the same AIO HDFU/FA therapy had a median survival of 16.9 months. This is presumably a consequence of more intensive second-line therapy, and this hypothesis is supported by the similar median PFS times for patients receiving AIO therapy in the two studies.6 Also, median survival is improved by more intensive first-line treatment; this is clearly demonstrated by comparison of the arms of the present study with the arm of the previous EORTC 40952 study6 presented in Figure 5. Although comparisons over time and studies may be problematic, the EORTC 40952 and 40986 studies are consecutive trials by the same group of investigators with identical patient selection criteria. In addition, these data (Fig 5) strongly suggest that all patients should receive all available active drugs during the course of their disease.
The findings of the present study are consistent with those previously reported for the addition of irinotecan to other FU/FA regimens and are broadly similar to those of Douillard et al,26 who studied approximately the same number of patients but used two different treatment schedules, using either weekly (AIO) or biweekly (de Gramont) FU/FA treatment cycles. The majority of the patients in the study by Douillard et al26 underwent the biweekly protocol, in which slightly higher overall doses of irinotecan but lower doses of FU were administered. Only one third of their patients underwent a treatment regimen similar to that of the present study, except that the FU dose in the AIO combination arm in their study was 2.3 g/m2. Hence, the two studies may not be directly comparable. Also, Douillard et al26 only followed OS to a median of 23.3 months compared with 28 months of median follow-up in this study. This was the point at which the survival curves for the patient groups with and without irinotecan were beginning to converge, as was the case in our study. It may be speculated that, although more patients receiving irinotecan plus HDFU/FA initially show a more rapid and sustained response (partial response instead of no change), resulting in a longer PFS, than patients on HDFU/FA alone, relapse proceeds at a similar rate in both groups. By 2 years, only a small proportion of patients remain alive, so any statistical comparisons at this point are less reliable. Also, the trial was not powered for survival; thus, the number of patients and events was too low to draw final conclusions. To demonstrate an increase in survival from 17 to 20 months (HR = 1.18) with 80% power, approximately 1,200 events would be needed (approximately 2,000 patients).
However, there is continuing debate about whether to treat all patients upfront with combination FU/FA therapy or whether to give the same drugs sequentially to have a second-line treatment available for the patients when and if required. The survival curves for this study show that, until approximately 28 months, patients who received the combination therapy had a better survival time than patients who received the AIO HDFU/FA regimen. This was true for approximately 80% of patients because only approximately 20% of patients were alive at 28 months in both arms. For these 20% of patients, the survival curves converged, and presumably, for these 20% of patients who represent the long-term survivors in each arm, the first-line AIO HDFU/FA therapy followed by second- or even third-line treatment gave similar results. However, the survival was not inferior for those patients who received the irinotecan plus HDFU/FA combination first-line treatment and who may not have had the chance to receive irinotecan as a second- or third-line treatment. Thus, all patients should receive the combination therapy as first-line treatment, and monotherapy should be the exception for those patients who are not suitable for irinotecan or oxaliplatin combination because of other comorbidities.
As previously reported,24-26 side effects, mainly comprising diarrhea and neutropenia, are associated with the FU/FA and irinotecan treatment combination. The side effects were generally manageable, with grade 3 and 4 diarrhea reported in 21% and 24% of patients and febrile neutropenia reported in 1% and 2% of patients receiving the AIO HDFU/FA and reduced FU AIO HDFU/FA plus irinotecan combinations, respectively. All side effects were substantially reduced after the first cycle of treatment. The reduction in FU dose from 2.3 to 2.0 g/m2, which was prompted by a high incidence of side effects, did not seem to alter treatment efficacy in this study. This is supported by the similar hazard ratio in patients receiving the reduced dose relative to the whole cohort. The lower dose of FU 2.0 g/m2 is the recommended dose for future protocols because this dose was associated with less gastrointestinal toxicity and fewer instances of patient hospitalizations than reported in previous studies, particularly those using bolus FU regimens.29 Nevertheless, even with the lower FU dose, approximately one third of patients required an FU dose reduction in the first cycle of treatment, which was not very different from the 40% of patients receiving the higher dose. This regimen has the advantage that dose adjustments can be performed on a weekly basis according to the individual toxicity. Compared with other infusional FU/FA and irinotecan regimens, our schedule has a remarkable low incidence of alopecia, presumably because of the low weekly dose of irinotecan. This regimen may be an alternative for those patients who are concerned about alopecia, which may occur more frequently with the biweekly regimens.
Our study supports the idea that infusional FU may be the optimal way to administer FU when combined with irinotecan or oxaliplatin because toxicity seems to be lower and efficacy seems quite high.30 Because of the rather low overall toxicity, our regimen seems suitable to be combined with new targeted agents, such as cetuximab or bevacizumab. In fact, irinotecan, FU, and FA plus bevacizumab was superior to irinotecan, FU, and FA alone.35 Bevacizumab is approved in the United States and Europe for combination with FU and irinotecan. We would speculate that our regimen may also be further improved by bevacizumab or cetuximab. Phase I data indicate feasibility and promising activity when cetuximab is added to our HDFU/FA plus irinotecan regimen.36
Appendix
The following clinicians contributed patients to the trial: Prof H. Bleiberg, (Brussels); Dr M. Peeters (Gent); Dr A. Vandebroek, (Antwerp); Prof E. Van Cutsem, (Leuven); Dr J. Janssens (Turnhout); Dr H. Schmidt (Berlin); Dr J.-Y. Douillard (Nantes); Prof D. Jaecke (Strasbourg); Prof N.L. Balleisen (Hamm); Dr H.-G. Hoeffkes (Fulda); Prof H.J. Schmoll (Halle);Dr M. Sandman (Wuppertal); Dr W. Abenhardt, Prof R. Fuchs (Eschweiler); Dr F. Lordick (Muenchen); Dr U. Vanhoefer (Essen); Dr K.-T. Steurer (Nurnberg); Dr H. Scherubl (Berlin); Prof R. Voigtmann (Bochum); Dr P. Schoeffski (Hannover); Prof C. Bokemeyer, Dr J. Hartmann (Tübingen); Prof C. Aul (Duisburg); Prof M. Lorenz (Frankfurt); Prof N. Haim, (Haifa); Prof G. Doelken (Greifswald); Dr R. Souchon (Hagen); Prof P. Caenepeel (Genk); Prof B. Nordlinger, Prof P. Rougier, (Boulogne); Dr P. Reichardt (Berlin); Prof M.P. Lutz, (Ulm); Dr H.-G. Mergenthaler (Stuttgart); Dr H. Knipp (Essen); Dr K. Huntenburg (Neustadt); Dr C. Haag (Dresden); Prof C.-H. K?hne (Rostock/Dresden); Prof H. Rückle-Lanz (Würzburg); Dr T. Langenbuch (Aurich); Dr C. Klinkenstein (Frankfurt); Dr H. Eimermacher, Dr N.W. Lindeman (Hagen); Dr J. Papke (Neustadt-in-Sachsen); Dr R. Pasold (Potsdam); Dr E. Kettner (Magdeburg); Prof H.J. Wilke (Essen); Dr G. Hartung (Rostock); Dr N. Frickhofen (Wiesbaden); Prof J.T. Fischer (Karlsruhe); Dr R. Albrecht (Aue); Dr A. Rennert (Plauen); Prof H. Gerhartz (Meissen); Dr K. Becker (Hamburg); Dr U. Gerecke (Stralsund); and Dr J. Wils (Roermond).
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank data manager Nathalie Garzon Vanacker for her valuable contribution to the study.
NOTES
Supported by an educational grant from Aventis Pharma, Antony, France.
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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