© 2006 European Society for Medical Oncology
Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer
1 Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen; 2 Comprehensive Cancer Centre North-Netherlands, Groningen; 3 Department of Medical Oncology, Leiden University Medical Center, Leiden; 4 Department of Medical Oncology, Laurentius Hospital, Roermond; 5 Department of Internal Medicine, Zaans Medical Center, Zaandam; 6 Department of Oncology, Martini Hospital, Groningen; 7 Department of Internal Medicine, Catharina Hospital, Eindhoven; 8 Department of Internal Medicine, Delfzicht Hospital, Delfzijl; 9 Department of Internal Medicine, Franciscus Hospital, Roosendaal; 10 Department of Oncology, Sint Antonius Hospital, Nieuwegein; 11 Department of Internal Medicine, Twente Hospital, Hengelo; 12 Department of Internal Medicine, Gelre Hospital, Apeldoorn, The Netherlands
* Correspondence to: Dr. G. A. P. Hospers, Department of Medical Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: g.a.p.hospers{at}int.umcg.nl
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Abstract |
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Background: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer.
Patients and methods: 302 patients were randomised and received bolus 5-FU 425 mg/m2 day 1–5, FA 20 mg/m2 day 1–5, q 4 wk or oxaliplatin 85 mg/m2, 2 h-infusion, FA 200 mg/m2, 1-h infusion. 5-FU 2600 mg/m2, 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR).
Results: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade 
toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%.
Conclusions: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.
Key words: advanced colorectal cancer, oxaliplatin, phase III study
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Fluorouracil (5FU) in combination with leucovorin (LV) was for many years the drug of choice for patients with advanced CRC, with a median survival of 11 to 14 months and, depending on administration via bolus or infusion, a response rate of 14–37% [1
]. In the last 5 years various new drugs (capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab) and combination regimens showed activity in phase III trials in patients with metastatic CRC. Median survival of 21 months and response rates of 50% were published [2, 3].
In 1999, a randomised multicentre trial started in The Netherlands comparing the standard regimen in The Netherlands, bolus 5FU/LV Mayo Clinic regimen (5 days per 28 days) with oxaliplatin in combination with 5FU/LV (biweekly; oxaliplatin in 2 h and 5FU/LV per 24 h). Oxaliplatin combined with 5FU showed activity with acceptable toxicity in two and three weekly regimens in patients with advanced CRC [4, 5]. The clinical toxicity profile of oxaliplatin differs from other platinum drugs. Oxaliplatin does not cause renal toxicity or minimal haematotoxicity; it causes both a reversible acute, cold-related dysesthesia and a dose limiting cumulative peripheral sensory neuropathy. In metastatic colorectal cancer oxaliplatin, as a single agent, induced responses in between 10% and 24% of the patients [6]. Oxaliplatin in combination with 5FU/LV resulted in randomised trials in response rates of 20 to 50% and median PFS of approximately 7.5–9.0 month [4, 5, 7]. In this study a modification of the biweekly regimen of oxaliplatin is given [4]. The biweekly oxaliplatin was combined with a 24-h infusion of high dose 5FU that had acceptable toxicity [8–10].
The objective of this trial was to assess the efficacy and toxicity of biweekly 24-h infusion of high dose 5FU/LV and oxaliplatin compared to the 5FU/LV based Mayo regimen. The primary objective was the response rate, the secondary endpoints were toxicity, quality of life, progression free and overall survival.
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patients and methods |
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eligibility and patient evaluation
Thirty Dutch hospitals participated in this study. All patients gave their written informed consent. Ethics committee approval was obtained at each site before study initiation. Patients had to have a histologically-proven colorectal adenocarcinoma, irresectable disease, at least one dimensionally measurable disease (
1 cm in diameter), age 18 years, WHO performance of 0, 1, 2 absolute granulocyte count > 1.5 x 109/L, bilirubin and creatinine < 1.5 x upper limit. Patients were excluded in case of previous chemotherapy except adjuvant completed >6 months prior to randomisation, second malignancy, previous radiation therapy unless measurable lesions are outside the radiation field, clinical signs of CNS metastasis, sensory neuropathy >NCI CTC grade 1.
Baseline screening was performed within 15 days before study entry. Screening comprised of physical examination and laboratory studies, including blood count, serum liver function tests, serum creatinine, albumin, and CEA. Baseline evaluation of disease was performed 
30 days after randomisation. At the first day of each cycle physical examination, blood count, liver function tests and creatinine were assessed.
random assignment and stratification
Randomisation and registration were performed by the Comprehensive Cancer Centre North-Netherlands (CCCN) Data Centre. Patients were stratified by receipt of prior adjuvant chemotherapy (yes versus no).
response, progression criteria and duration of response
Lesions were defined measurable if at least one dimension (1 cm in diameter) could be serially evaluated. Evaluation of disease was performed every 8 weeks. Radiographic response was classified using the Response Evaluation Criteria in Solid Tumours [11]. Confirmed tumour response is defined as an objective tumour response of either CR or PR, which has been sustained for at least two consecutive evaluations taken at least 4 weeks apart.
The duration of response is defined as the interval from date of first documented response until the date of tumour progression. Progression free survival (PFS) is defined as the time between randomisation and the time of documented tumour progression or death due to colorectal cancer. Deaths due to malignancy occurring within the first 8 weeks after randomisation were measured as tumour progression. Survival was calculated as the period from the date of randomisation to the date of death or last contact. Without contradictory data, patients who died or were lost to follow-up were assumed to have progressed from the time they were last documented to be progression-free.
assessment of toxicity
Toxic effects were graded using the NCIC CTCAE (version 2.0) expanded common toxicity criteria (published: December 21, 1991).
treatment
The treatment (doses in mg/m2) was as follows:
- Arm A: bolus 5FU 425; day 1–5, LV 20; day 1–5, q 4 wk or
- Arm B: oxaliplatin 85; 2-h infusion, FA 200; 1h-infusion, 5FU 2600; 24h-infusion day 1, q 2 wk.
- Arm B: oxaliplatin 85; 2-h infusion, FA 200; 1h-infusion, 5FU 2600; 24h-infusion day 1, q 2 wk.
dose modifications
In case of grade III/IV toxicity, treatment was delayed until complete normalisation of gastrointestinal toxicity or, in case of other toxicity, toxicity was < grade 2 and ANC > 1.5 x 109/l and platelets > 100 x 109/l. If toxicity had not reached the described levels after two weeks of postponing treatment, the patient went off study due to toxicity. Any grade 3 or 4 toxic effects resulted in a 20% dose reduction of 5FU in all subsequent applications. The oxaliplatin dose was decreased to 65 mg/m2/cycle in subsequent cycles in case of recurrence of any of the above toxicity after 5FU dose modification.
quality-of-life assessment
Global QOL assessment was evaluated using a visual analogue scale (VASQOL) in which in a single 10-cm line anchored on the left with ‘worst’ and on the right with ‘best’ for QOL [12].
statistical analysis
The primary efficacy analysis was based on the cumulative response rate, the number of patients reaching PR or CR. If an increase in overall response rate of 15% to 30% was assumed, a total of 133 patients were needed per arm when tested one-sided with a type 1 error of 0.05 and a power of 90%. With an expected 10% non-evaluable patients 290 patients should be entered in the study.
The results of the study are based on an ‘intention to treat’ analysis. The intent to treat population included all patients who met the inclusion criteria and were randomised by the data centre. Patients who were annulled before the initiation of therapy were excluded from toxicity analysis. Fisher's exact test and the Pearson 
2 test for categorical data were used to compare toxicity and confirmed response rates. Progression free and overall survival were estimated by the product limit method, differences in distribution of survival time between the two treatment arms were assessed with the log-rank test and the Breslow test. A P-value less than 0.05 was considered statistically significant for the primary comparison of time to progression between the control and the experimental arm. All presented P-values are two-sided.
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results |
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patients and treatment
Between July 1999 and August 2002, 302 patients were enrolled. The patient demographic and pre-treatment characteristics were well balanced in both treatment arms (Table 1). [In all 39 patients who had prior adjuvant chemotherapy this consisted of 5FU/leucovorin.] The median follow-up was 31.8 months (range 6.0–62.8 months), 90.4% of the patients have died. At the time of analysis, all 29 patients who were alive at last contact had been followed for at least 6 months since the start of treatment.
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The median number of cycles was 6.0 (range 0–26) in the 5FU/LV arm and 9.0 (range 1–28) in the 5FU/LV/oxaliplatin arm, see Table 2. Median time on treatment (first day of first course until first day of last course) was 125 days in the 5FU/LV/oxaliplatin arm and 140 days in the 5FU/LV arm (P = 0.916). No dose adjustments were necessary in the 5FU/LV/oxaliplatin arm in 124 patients (82%) and in the 5FU/LV arm in 121 patients (80%). A dose reduction of 20% in any of the drugs in the 5FU/LV/oxaliplatin arm occurred in 25 patients (16.6%) and in 27 patients (17.9%) in the 5FU/LV arm. A delay of
1 week occurred in the 5FU/LV/oxaliplatin arm in 35 patients (23%) and in 26 patients (17.2%) in the 5FU/LV arm.
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efficacy end points
tumour response.
Whereas in the 5FU/LV group 28 patients (18.5%; 95%CI 12.3–24.7) achieved a confirmed PR or CR, in the 5FU/LV/oxaliplatin group a confirmed response was noted in 51 patients (33.8%; 95%CI 26.2–41.4) (Table 3a). The unconfirmed response is presented in Table 3b. The median time until confirmation of response in our study was 9 weeks. A total of 15 patients were not evaluable, because one or more tumour measurements were missing. Of these patients nine went off study within 14 days after starting the study treatment due to refusal or toxicity and no formal response evaluation could be performed. For the remaining six patients, the response was not documented on a confirmatory scan, therefore these patients were qualified for SD.
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progression free survival.
A total of 144 patients in the 5FU/LV arm and 142 patients in the 5FU/LV/oxaliplatin arm had progressed at the time of analysis, see Figure 1. The median PFS was 5.6 months (95%CI 4.8–6.3 months) in the 5FU/LV arm and 6.7 months (95%CI 5.7–7.7 months) in the 5FU/LV/oxaliplatin arm (deleted) (P = 0.016, two-sided).
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survival.
With a median follow-up of 31.8 months 273 (90.4%) patients had died. The median overall survival (Figure 2) for the 5FU/LV and the 5FU/LV/oxaliplatin arm were 13.3 months (95%CI 11.2–15.4 months) and 13.8 months (95%CI 11.7–15.9 months), respectively. In univariate analysis survival there was no statistically significant difference (P = 0.619).
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quality of life
Seventy percent of the patients were assessable for QOL measurements. There was no significant difference in QOL between both arms.
toxicity
Grade 3 or higher toxicity is presented in Table 4. 5FU/LV/oxaliplatin was associated with less grade 3/4 stomatitis or diarrhoea compared with 5FU/LV, but sensory neuropathy occurred only in the 5FU/LV/oxaliplatin arm. Idiosyncratic reactions occurred only in the 5FU/LV/oxaliplatin arm; two classical anaphylaxis, five atypical with haemolysis, thrombocytopenia, renal and pulmonary dysfunction, with one toxic death. During the whole period of the first-line treatment with the 5FU/LV/oxaliplatin arm fever (>38°C) without leucopenia or infection occurred significantly more often than in the control arm (Odds ratio 3.048). In the control arm there was one toxic death due to neutropenic septicaemia and in the 5FU/LV/oxaliplatin arm one toxic death due to an idiosyncratic reaction. This patient experienced haemolysis, thrombocytopenia, renal and a pulmonary dysfunction. Within the first 8 weeks of treatment eight patients died in the 5FU/LV arm (six due to tumour progression, one due to toxic death, 1 unknown) and seven patients died in the 5FU/LV/oxaliplatin arm (five due to tumour progression, one due to bowl perforation, one due to an external cause).
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salvage treatments
Salvage treatment was not specified in the protocol. A total of 188 (62.3%) patients received salvage treatment. The proportion of patients was 64.2% (n = 97) in the 5FU/LV arm and 60.3% (n = 91) in the 5FU/LV/oxaliplatin arm (P =0.553). Crossover of the 5FU/LV arm to the 5FU/LV/oxaliplatin arm occurred in 19.9%. Irinotecan was given as salvage therapy to 62 (41.1%) patients in the control and 70 (46.4%) patients in the experimental arm (Table 5).
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discussion |
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Oxaliplatin in a biweekly schedule, combined with continuous infusion 5FU results in a higher response rate, and a longer PFS, when compared with the classical five-day bolus 5FU regimen. The higher response rate (33.8% versus 18.5%) might be clinically relevant if salvage surgery is considered in patients with metastatic disease. Such surgery has been demonstrated to be potentially curative [13
]. In this respect the response rate of 33.8% in our regimen is probably underestimated due to the definition of ‘confirmed response rate’, as the time to confirmation in this study is a median of 9 weeks, and the unconfirmed response rate is 45%. This advantage in activity does not incriminate the quality of life, mainly because the neurotoxicity of the regimen does not interfere with daily activities in the vast majority of patients. The increase in PFS, although significant, did not translate in a significant OS advantage of the oxaliplatin regimen.
The fact that addition of oxaliplatin did not result in an increase in OS is in agreement with other phase III trials comparing 5-FU/LV with oxaliplatin [4, 14]. Despite an increase in PFS, the lack of significant survival differs in the studies of Gramont [4], Giachetti [14] and our study, and is explained by the fact that none of these studies were designed for OS as primary endpoint and thus lacked the optimum number of patients [15]. Also these studies had a high percentage of cross over rates. In our study however the cross over rate was only 19.9%.
In contrast to these three studies [this study, 4, 14] the median OS in the study of Goldberg et al. [5], Grothey et al. [20], and Comella et al. [23] did show a significant improvement for the oxaliplatin/5FU regimen in the first-line (see Table 6). The studies of Goldberg [5] and Comella [23], however, compare two different combination regimens and do not answer the question of whether addition of oxaliplatin to 5FU in the first-line will result in a survival benefit. In the study of Grothey et al. addition of oxaliplatin to 5FU/LV compared with 5FU/LV in the first-line did result in a 3.6 months increase in median OS. However, based on the available data [2, 20] there is an imbalance in second line treatment (see Table 6). Second line treatment certainly also contributes significantly to OS and it has been stated that survival increases as more patients receive all three available active chemotherapeutic agents [2]. In our study the salvage treatment is relatively well balanced with a cross over of only 19.9% and in both arms over 60% of patients received some form of salvage treatment consisting of single agent irinotecan in approximately 45% of the patients in both arms.
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The lack of effect of the oxaliplatin/5FU regimen on median OS in our patients is probably not due to excessive toxicity of this regimen. In the oxaliplatin arm of this study, compared to the 5FU/LV arm, there was a significant decrease in mucositis and diarrhoea, complications that are especially compromising in the day-to-day performance of patients. The low incidence of these complications occurs despite the higher 5FU dose in the 24h regimen described here compared to the Gramont regimen. Also over a period of approximately one year the quality of life as measured with the visual analogue scale, in both patient groups, does not change significantly.
An inadequate dose per cycle or cumulative dose of oxaliplatin in our study to explain the lack of the oxaliplatin/5FU regimen on median OS in our patients is unlikely due to the achieved RR and PFS and the similarities of our regimen with other regimens (see Table 6).
Patient characteristics that might influence survival as explanation for our median OS data, might also be detected in the control arm. The median survival of 
13.5 months in both arms in our study seems relatively short. However, given the overlap of the confidence intervals of the OS the same results were found in other recently published comparable phase III trials (three chemotherapeutic drugs available) in metastatic colorectal cancer where the median OS of the treatment arms (without biologicals) varied between 12 and 20 months [2, 3, 8, 16]. In these studies also a comparable percentage of more than 50% of the patients received second line treatment. No meaningful differences in performance status, number of affected sites, and percentage of liver involvement could be detected in our study compared with other published studies [3–5, 14, 16].
One last variable to potentially explain a variation in median OS is the percentage of patients that undergo salvage surgery, an often not well-documented variable. For instance in the study of Giacchetti [14] the OS of 19 months might be influenced by salvage surgery as it could be performed in no less then 25% of the patients. In our study no patients underwent such surgery.
In this study the occurrence of the toxic idiosyncratic reactions is limited to the experimental arm. In two patients classical platinum anaphylaxis occurred and in five patients (3.3%) an atypical acute presentation was seen with haemolysis, thrombocytopenia, and renal and pulmonary dysfunction. The event reported here has been described earlier in which this reaction was accompanied by a strong positive Coombs test and increased TNF-
and IL10 serum levels [17]. Of the seven described patients in this report two patients died. This syndrome leads to one toxic death in our study. Fever without leucopenia or infection was detected significantly more often during the treatment period in the experimental arm compared to the control arm. In two overviews [18, 19] the classical anaphylaxis and fever are described after treatment with oxaliplatin. The incidence of this reaction seems to be dependent on the chemotherapy schedules given and the number of cycles [19]. A 6-h infusion compared to a 2-h infusion and fewer expositions to oxaliplatin seems to decrease the risk of hypersensitivity reactions [19].
In conclusion, our study shows a benefit in terms of response rate and PFS for treatment with oxaliplatin added to an infusional schedule of 5FU/LV compared to bolus 5FU/L. Although the study was not designed to detect a benefit in OS, the survival rates in both study arms were quite comparable despite a low crossover rate. Given the overlap of the confidence intervals of PFS and OS of our study with previously published results, it may well be that our results represent by chance the lower range of the expected outcome with oxaliplatin/5FU/LV in metastatic colorectal cancer. We conclude that it still remains to be unequivocally demonstrated that the addition of oxaliplatin to 5FU (or analogue) significantly prolongs survival in patients treated for advanced CRC with at least two lines of treatment.
Received for publication July 26, 2005. Revision received September 26, 2005. Revision received October 31, 2005. Accepted for publication November 10, 2005.
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