1 Patras University Hospital,Patras; 2 Third Department of Medical Oncology, Agii Anargiri Cancer Hospital; 3 HYGEIA Medical Center, Athens; 4 Oncology Unit, Hippokratio General Hospital of Athens; 5 Attikon University Hospital, Athens; 6 Alexandra Hospital, Department of Clinical Therapeutics, University of Athens School of Medicine; 7 Oncology Department, Henry Dunan Hospital, Athens; 8 Oncology Department, University Hospital of Ionnina; 9 HeCOG Data Office, Athens; 10 Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
* Correspondence to: Dr H. P. Kalofonos, Division of Oncology, Department of Medicine, University Hospital, Patras Medical School, Rion 26500, Greece. Tel: +302610-999535; Fax: +302610-994645; Email: kalofon{at}med.upatras.gr
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Abstract |
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Materials and methods:: From January 1999 to February 2002, 295 patients were randomized to receive either IRI/LV/5-FU or OXA/LV/5-FU. The treatment schedules consisted of weekly IRI 70 mg/m2 or OXA 45 mg/m2 plus LV 200 mg/m2 followed immediately by intravenous bolus 5-FU 450 mg/m2 for 6 weeks, followed by a 2-week rest period. Treatment was continued for up to four cycles or until disease progression, unacceptable toxicity or patient refusal.
Results:: There were no significant differences between the study arms in the overall response rate (33% with IRI/LV/5-FU versus 32% with OXA/LV/5-FU based on responses demonstrated on a single evaluation; 23% with IRI/LV/5-FU versus 22.3% with OXA/LV/5-FU based on responses confirmed according to WHO criteria) median time to progression (8.9 versus 7.6 months), and median overall survival (17.6 versus 17.4 months). Toxicity profiles (grades 3 and 4) were similar in the IRI and OXA arms (diarrhea 12.3% and 9.8%, neutropenia 8.2% and 4.9%, and febrile neutropenia 1.4% and 1.4%, respectively), with the exception of grade 3 sensory neuropathy, which almost exclusively occurred in the OXA arm (0% versus 5.6%; P=0.003, Fisher's exact test).
Conclusion:: The IRI/LV/5-FU and OXA/LV/5-FU regimens demonstrated equally substantial efficacies and manageable toxicity profiles in the first-line treatment of patients with advanced CRC. However, IRI/LV/5-FU may be the preferable regimen to avoid significant neurotoxicity associated with OXA-LV/5-FU.
Key words: colorectal cancer, chemotherapy, irinotecan, oxaliplatin
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Introduction |
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The safety and efficacy of both IRI and OXA have been evaluated in several studies in patients with advanced CRC; these agents have demonstrated manageable toxicity and significant antitumor activity [8, 9
]. An even larger number of studies have been performed using the combination of IRI or OXA plus LV and bolus, or infusional 5-FU in patients with advanced CRC [10
12
]. Combination chemotherapy with LV-modulated 5-FU and IRI or OXA provides significant antitumor activity and a survival advantage over bolus and continuous-infusion 5-FU modulated with LV [7
]. These findings suggested no cross-resistance with 5-FU and IRI or OXA. Furthermore, the recorded toxicity of these regimens was acceptable and reversible, including patients with 5-FU-resistant disease. Newer agents have significantly increased the median overall survival in patients with advanced colorectal cancer and survival times of beyond 20 months have been reported in randomized trials with 5-FU, IRI and oxaliplatin [7
]. However, current clinical data have not properly addressed the question of whether all patients in the first-line setting should be treated with a combination regimen of IRI/LV/5-FU or OXA/LV/5-FU [7
]. Since there is no consensus regarding the optimum regimen for the treatment of advanced CRC, the challenge for the immediate future is to identify the most effective regimens and use them as the basis on which to add new promising antitumor agents.
A randomized, phase II clinical study was performed to compare directly IRI/LV/5-FU with OXA/LV/5-FU, in order to explore further the efficacy and safety profiles of these regimens in treating CRC. The primary objective of this randomized, multicenter trial was to compare the tumor response rate in non-pretreated patients with advanced CRC receiving IRI/LV/5-FU or OXA/LV/5-FU. Secondary objectives were to compare TTP, OS and toxicity profiles of the two regimens.
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Materials and methods |
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The study was approved by the Hellenic Cooperative Oncology Group (HeCOG) Protocol Review Committee and the institutional review boards of the participating institutions. Before randomization, all patients gave written informed consent according to institutional guidelines and eligibility was confirmed by a protocol-specific checklist.
All eligible patients had to provide complete medical history and had to undergo a physical examination that included assessment of weight, height and WHO PS. In addition, assessment of tumor size, carcino-embryonic antigen (CEA) and carbohydrate antigen 199 level, abdominal pelvic computed tomographic scan, chest X-ray, complete blood cell count, biochemistry profile and electrocardiography were also performed. Patients were stratified according to WHO PS (0 versus 1/2), presence of hepatic metastases and previous adjuvant chemotherapy. Patients were then randomly assigned to one of the two treatment regimens by the HeCOG central office in Athens, Greece.
During treatment, clinical examination, body weight, WHO PS, subjective symptoms and all adverse reactions were recorded before each treatment. Biochemistry profile and complete blood cell count were repeated every 2 weeks, and target lesions were re-assessed every two cycles of chemotherapy by computed tomographic scan, X-ray and/or magnetic resonance imaging, enabling retrospective and independent evaluation. An independent review of response was performed in all patients.
Chemotherapy regimens
In treatment arm A, IRI was administered at a dose of 70 mg/m2 in normal saline solution 250 ml as a 90-min i.v. infusion, followed by LV 200 mg/m2 in normal saline solution 500 ml as a 2-h i.v. infusion and 5-FU 450 mg/m2 as an i.v. bolus at the end of LV infusion. In treatment arm B, OXA was administered at a dose of 45 mg/m2 in dextrose 5% solution 250 ml as a 90-min i.v. infusion, followed by LV 200 mg/m2 in normal saline solution 500 ml as a 2-h i.v. infusion and 5-FU 450 mg/m2 as an i.v. bolus at the end of LV infusion. Treatment was administered weekly for 6 weeks, followed by a 2-week rest period [11, 14
]. A single cycle represented six weekly infusions over 8 weeks. In both treatment arms, chemotherapy was administered for up to four cycles or until disease progression, unacceptable toxicity or patient refusal. Concomitant medication routinely given before chemotherapy included ondansetron 8 mg, according to the conventional anti-emetic protocol.
Dose modification
Dose adjustments of the study drugs or treatment delays were calculated according to toxicity grade. Dose modification was determined according to the system showing the greatest degree of toxicity. Toxicities were graded using the National Cancer Institute common criteria. For diarrhea, patients were to receive supportive care, as well as intensive treatment with loperamide. The doses of IRI and 5-FU were to be reduced by 20%, 30% and 40% during a cycle for grades 2, 3 and 4 diarrhea, respectively. The OXA dose was to be reduced by 30% for persistent or temporary (714 days) painful paresthesia, dysesthesia or functional impairment. For persistent grade 3 neurotoxicity, despite the 30% dose reduction, or for grade 4 neurotoxicity, OXA was to be omitted in subsequent cycles. For grade 2/3 hematologic toxicity, treatment was to be delayed for 1 week or until hematologic recovery. If recovery was not achieved, the dose levels of IRI, OXA and 5-FU would be reduced by 20%. Subcutaneous administration of granulocyte colony-stimulating factor 5 µg/kg/day on 5 consecutive days was permitted at the investigator's discretion. For severe toxicity (grade 3/4), the dose levels of IRI, OXA and 5-FU were to be reduced by 20% soon after the toxicity had cleared up. For handfoot syndrome (grade 3/4), the dose of 5-FU only was to be reduced by 20%. For angina or myocardial infarction, treatment was to be ceased. For grade 3 mucositis, after 1 week delay, the dose of 5-FU was to be reduced by 25%. For any grade 4 toxicity, except gastrointestinal or hematologic toxicity, patients were to be withdrawn from the study. Any patient who required >2 weeks of recovery for adverse events would be excluded from the study.
No prophylactic treatment was permitted for diarrhea. Specific guidelines for curative treatment of delayed diarrhea were provided, which recommended loperamide 2 mg (1 capsule) every 2 h for 12 h after the last loose stool for a maximum of 48 consecutive hours.
Response criteria
Response was assessed in accordance with WHO criteria. Measurements were obtained at baseline, week 16, and after completion of treatment until disease progression. Measurement of bone metastases was not used as a parameter of tumor response. Patients with tumors not meeting the criteria for response or progressive disease (PD) were considered stable (SD). All patients entered in the study were analyzed on an intent-to-treat basis.
Statistical analysis
This was an open-label, randomized, parallel-group study. The primary end point for sample size determination was tumor response rate. A total of 304 eligible patients ensured 80% power (at the 5% level of significance) for a two-sided test of the hypothesis of ±15% difference in response rate relative to a baseline response rate of 25%. An interim analysis, according to the O'Brien Fleming boundary based on the Lan-DeMets -spending function, was performed when 50% of patients had been evaluated for response to investigate the premature end of the study. An efficacy analysis was performed on the evaluable population. The TTP was calculated from the randomization date to the first occurrence of PD. However, patients who died due to disease-related factors without documentation of PD were considered to have an event at the estimation of TTP. Survival time was calculated from the date of randomization to the date of death or last follow-up. Pearson chi-square test and Fisher's exact test [15
] were used to compare patient characteristics, response, and toxicity. The KaplanMeier method was used to calculate TTP, median follow-up and OS curves, whereas the log-rank test was used to compare time-to-event distributions. Prognostic factor analyses were performed with Cox proportional hazards model [16
]. A backward selection procedure identified the subclass of significant variables among the following: age (<65 versus
65 years), WHO PS (0 versus 1/2), sex (men versus women), treatment group (A versus B), primary site (right versus left colon), hemoglobin level (<12 versus
12 g/dl), serum glutamic-oxaloacetic transaminase (normal versus abnormal), serum glutamic-pyruvic transferase (normal versus abnormal), CEA (<10 versus
10), number of metastatic sites (single versus multiple), adjuvant chemotherapy (no versus yes), and weight loss (no versus yes). The significant factors were kept in the model if the maximum likelihood ratio criterion had a P value <0.05. Exact confidence intervals (CIs) were used to determine the 95% upper and lower confidence limits of a response rate [17
]. The analysis was made on an intent-to-treat basis.
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Results |
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The median relative dose intensity for 5-FU was 0.76 (range 0.011.00) in arm A and 0.74 (0.071.00) in arm B. The relative dose intensities for IRI in arm A and OXA in arm B were 0.76 (range 0.051.00) and 0.71 (0.041.00), respectively. The median numbers of treatment cycles were 4 (range 18) in arm A and 3 (17) in arm B (Table 2).
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Discussion |
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The efficacy results reported here are consistent with the study by Tournigand et al. [18], which showed no significant differences in overall response rate, TTP, and OS between two groups of patients treated with either LV-modulated infusional 5-FU plus IRI, followed by LV/5-FU plus OXA, or with the same schedule with OXA replacing IRI. The present results are also in agreement with those of Grothey et al. [19
], who found no differences in overall response rate and progression-free survival between patients treated with either capecitabine plus IRI or capecitabine plus OXA. In contrast, a large randomized trial (N=795) by the US Intergroup [20
], demonstrated that OXA plus infusional 5-FU with LV (FOLFOX4) was more active than IRI with bolus-administered 5-FU plus LV (IFL). In the latter study, FOLFOX4 had a response rate of 45% versus 31% with IFL (P=0.002), a median TTP of 8.7 versus 6.9 months (P =0.0014), and an OS of 19.5 versus 15.0 months (P=0.0001). The US Intergroup Study, however, offered IRI as second-line treatment for the FOLFOX4 arm, whereas OXA was not available as a second-line treatment in the IFL arm. Therefore, the survival difference favoring OXA as first-line treatment may have been skewed because of the availability of an effective second-line treatment in the FOLFOX4 arm. Furthermore, it is also important to note the different routes of 5-FU administration in the US Intergroups Study (bolus 5-FU in IFL versus infusional 5-FU in FOLFOX4); as the investigators noted, this difference made it unfeasible to compare directly the relative efficacies of IRI and OXA. Taken together with the results of Tournigand et al. [18
] and Grothey et al. [19
], the present findings support the possibility that the survival difference noted in the Intergroup Trial [20
] is explained by differences in the availability of second-line treatments, and in the routes of 5-FU administration.
IRI and OXA have been evaluated in combination with 5-FU using several alternative administration schedules including weekly bolus 5-FU, short- and long-term 5-FU, and substitution for 5-FU with capecitabine. The use of continuous i.v. infusion of 5-FU in a number of studies has demonstrated reduced toxicity and increased survival compared with bolus 5-FU, although there are significant limitations to this administration method, including the need for implantable access devices, portable infusion pumps and patient education for handling these devices, as well as the risk of infection and thrombosis. In the present study, the combination of IRI or OXA with bolus-administered 5-FU was used, since this schedule was previously implemented by our group in phase II studies [11, 14
], and because of the proven efficacy, acceptable toxicities, convenience and cost effectiveness of the regimen.
Recently, there have been concerns raised regarding use of the bolus regimen of 5-FU/LV plus weekly IRI, i.e. IFL [13]. A higher incidence of treatment-related deaths has been reported with IFL compared with 5-FU/LV [21
]; however, this increased incidence was not observed with the bolus 5-FU regimen in the present study, possibly due to the dose level of IRI [14
]. One approach to optimizing 5-FU-based therapy further and to overcoming the drawbacks of continuous i.v. infusion has been the development of oral fluoropyrimidine derivatives designed to generate 5-FU predominately within tumor cells [22
, 23
]. Oral administration of capecitabine avoids the technical barriers of infusional administration, thus allowing significant flexibility. Capecitabine plus IRI or OXA has been evaluated in a number of clinical studies [24
, 25
] and may be an important alternative in the management of patients with advanced CRC.
With regard to treatment tolerance, no unexpected adverse events or toxic deaths were observed in this study (Table 3). Treatment-related grade 3/4 toxicities were acceptable and corresponded to the known toxicities of IRI/LV/5-FU and OXA/LV/5-FU, as recorded in previous trials [1014
]. The incidence of severe (grade 3/4) toxicity was similar between treatment regimens, except for neurotoxicity, which was higher in the OXA/LV/5-FU regimen, presumably due to the cumulative toxicity from OXA [26
]. Grade 1 and 2 neurotoxicity was significantly higher in Group B [33 (23.2%) patients experienced grade 1 neurotoxicity and 14 (9.9%) patients experienced grade 2 neurotoxicity) as opposed to Group A where only two cases (1.4%) of grade 1 neurotoxicity were reported]. Nausea and vomiting were observed in only 0.7% of patients treated with IRI/LV/5-FU versus 3.5% with OXA/LV/5-FU. Diarrhea was recorded in 12.6% of patients treated with IRI/LV/5-FU versus 9.8% with OXA/LV/5-FU, but it was not as serious as in previous studies, probably due to the dose level of IRI, as well as to patient susceptibility. Myelotoxicity was also acceptable, with severe neutropenia affecting 8.2% and 4.9% of patients treated with IRI/LV/5-FU and OXA/LV/5-FU, respectively. Severe adverse events requiring early discontinuation of study treatment occurred in 3% and 8% of patients treated with IRI/LV/5-FU and OXA/LV/5-FU, respectively.
In accordance with multivariate analysis, WHO PS, presence of liver metastases with increased levels of transaminases, increased CEA, anemia and number of metastatic sites had an impact on survival. In contrast, history of adjuvant chemotherapy did not have an effect. However, because the percentage of patients with adjuvant treatment was low (20%), these findings should be interpreted with caution.
This study showed that the weekly schedules of IRI/LV/5-FU and OXA/LV/5-FU were equally efficacious regimens in the first-line management of previously untreated patients with advanced CRC. Although both treatments demonstrated generally manageable toxicity profiles, the IRI regimen may be the preferable choice due to the significantly greater incidence of grade 3 peripheral neuropathy observed with OXA. Further studies are needed to compare the efficacy and tolerability of IRI or OXA combined with infusional 5-FU plus LV or capecitabine in advanced CRC, keeping in mind the superior convenience of oral fluoropyrimidines with similar efficacy and toxicity profiles.
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Acknowledgements |
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Received for publication December 20, 2004. Revision received February 1, 2005. Accepted for publication February 14, 2005.
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