1 Department of Medical Oncology, National Tumour Institute, Naples; 2 Chair of Medical Oncology, University Medical School, Cagliary; 3 Medical Oncology, City Hospital, Paola; 4 Chair of Medical Oncology, University Medical School, Palermo; 5 Medical Oncology, City Hospital, Penne; 6 Chair of Medical Oncology, University Medical School, Sassari; 7 Chair of Medical Oncology, Second University Medical School, Naples; 8 Medical Oncology, City Hospital, Terni; 9 Medical Oncology, City Hospital, Pozzuoli; 10 Medical Oncology, San Gennaro Hospital, Naples; 11 Medical Oncology, City Hospital, Campi Salentina; 12 Medical Oncology, IRCCS, Castellana Grotte; 13 Department of Medical Oncology, National Tumour Institute, Bari; 14 Medical Oncology, City Hospital, Caserta; 15 Department of Surgical Oncology, Tor Vergata University Medical School, Rome, Italy
* Correspondence to: Dr P. Comella, Division of Medical Oncology A, Department of Medical Oncology, National Tumour Institute, Via M. Semmola, 80 131 Naples, Italy. Tel. +39-081-5903-227; Fax: +39-081-5903821; Email: pasqualecomella{at}libero.it
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Abstract |
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Patients and methods:: Patients with measurable metastatic colorectal carcinoma were randomly allocated to receive: IRI 200 mg/m2 on day 1, l-FA 250 mg/m2 intravenously plus 5-FU 850 mg/m2 on day 2 (IRIFAFU); or OXA 100 mg/m2 on day 1, l-FA 250 mg/m2 plus 5-FU 1050 mg/m2 on day 2 [OXAFAFU high dose (hd)]. Cycles were given every 2 weeks. After a planned interim analysis, OXA was reduced to 85 mg/m2 and 5-FU to 850 mg/m2 [OXAFAFU low dose (ld)].
Results:: Two hundred and seventy-four patients (IRIFAFU, 135; OXAFAFUhd, 71; OXAFAFUld, 68) were treated. Forty-two confirmed responses were achieved with IRIFAFU, 29 with OXAFAFUhd and 32 with OXAFAFUld. The response rate with OXAFAFU [44%; 95% confidence interval (CI) 35% to 52%] was significantly higher (P=0.029) than that of IRIFAFU (31%; 95% CI 23% to 40%). Occurrence of grade 3 neutropenia with OXAFAFUld was similar to that for IRIFAFU (29% versus 31%), while severe diarrhoea was significantly lower (12% versus 24%). Median failure-free survival (7 versus 5.8 months; P=0.046) and overall survival of patients (18.9 versus 15.6 months; P=0.032) were significantly prolonged with OXAFAFU.
Conclusions:: OXAFAFU was more active and less toxic than IRIFAFU, and it should be preferred in the first-line treatment of advanced colorectal cancer patients.
Key words: 5-fluorouracil, irinotecan, metastatic colorectal carcinoma, oxaliplatin, randomized trial
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Introduction |
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During the last decade, new drugs have shown activity in this disease. First, irinotecan (IRI) has been proven to prolong survival and improve quality of life of 5-FU-refractory patients [8], and to have an activity comparable to FA/5-FU in the first-line setting [9
]. These findings suggested the lack of cross-resistance between IRI and FA/5-FU, supporting the commencement of trials testing their combination in front-line treatment. Saltz et al. [9
] reported on IRI plus FA/5-FU bolus given for four consecutive weeks every 6 weeks (IFL regimen). The response rate (RR) was significantly greater (39% versus 21%), and progression-free survival (PFS) (median 7 versus 4.3 months) and overall survival (OS) (median 14.8 versus 12.6 months) were significantly longer with the IFL in comparison with those obtained with the Mayo Clinic regimen. Douillard et al. [10
] administered the AIO or LV5FU2 regimen recycled either weekly or biweekly, alone or combined with IRI. RR (35% versus 22%), PFS (median 6.7 versus 4.4 months) and OS (median 17.4 versus 14.1 months) favoured the IRI-including treatment. In the Southern Italy Cooperative Oncology Group (SICOG) trial 9801, IRI was given biweekly on day 1, followed by levo-FA (l-FA) and 5-FU bolus on day 2. This IRIFAFU regimen produced a significantly greater RR (36% versus 20%) and longer PFS (median 7.2 versus 4.8 months) in comparison with a double modulation of 5-FU by means of MTX and l-FA [11
]. However, OS for the two arms was similar (14.7 versus 14.8 months, respectively).
Oxaliplatin (OXA) has shown activity in vitro against 5-FU-resistant colon cancer cell lines [12], and it is effective in both chemonaïve and 5-FU-pretreated patients [13
15
]. Interestingly, preclinical studies have shown the greatest cell kill when OXA was followed by a short rather than prolonged 5-FU exposure [16
]. However, in early clinical trials OXA was usually combined with chronomodulated or flat infusional 5-FU [17
20
]. In front-line, the FOLFOX4 regimen obtained a significantly greater RR (51% versus 23%) and longer PFS (median 9 versus 6.2 months) in comparison with LV5FU2. OS was also longer (median 16.2 versus 14.7 months) [20
]. Conversely, there are still few clinical data about efficacy of OXA and FA/5-FU given as bolus. Some investigators have explored the addition of OXA to FA/5-FU delivered daily for 5 days (i.e. Machover or Mayo Clinic regimen). Activity was reported in 40% to 45% of patients [21
, 22
], but toxicity was substantial. More recently, Hochster et al. [23
] administered OXA 85 mg/m2 on day 1 and 15, and FA 20 mg/m2 plus 5-FU 500 mg/m2 on days 1, 8 and 15, recycling every 28 days, achieving a 63% RR and a 15.9 month median OS in 41 patients. The Nordic Group explored the addition of OXA 85 mg/m2 to a combination of FA 60 mg/m2 and 5-FU 500 mg/m2 given for two consecutive days, administered biweekly, obtaining a 62% RR and a median OS of 16.1 months [24
].
Therefore, the combination of OXA and FA/5-FU bolus showed promising activity in metastatic patients. For these reasons, we carried out a phase I study to find the recommended doses for an OXA plus FA/5-FU bolus biweekly regimen (OXAFAFU). Although the maximum tolerated doses were not reached up to 130 mg/m2 for OXA and 1050 mg/m2 for 5-FU, some concern about the occurrence of cumulative neurotoxicity suggested OXA 100 mg/m2 was not exceeded in further evaluation. Therefore, we set up a multicentre randomised phase III trial to assess the activity and toxicity of OXAFAFU, and to compare this new regimen with the IRIFAFU in metastatic colorectal cancer patients [25].
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Patients and methods |
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Patients evaluation
Medical history and physical examination were taken at study entry. Biochemistry profile, blood cell count with white cell count and differential, and carcinoembryonic antigen (CEA) serum level assessment, were routinely performed. Target lesions were measured by computed tomography (CT) or magnetic resonance imaging (MRI) scans no more than 4 weeks before initial therapy. During treatment, white cell count with differential was performed weekly. Biochemistry, symptoms, body weight and non-haematological toxicity were checked before each cycle. Toxicity was scored according to WHO criteria [26]. Neuropathy was defined according to the Lévi scale [27
]. For the study purpose, the worst toxicity suffered by each patient during the whole treatment was recorded.
CT or MRI scans were repeated after every four cycles, and at the end of treatment. Response was defined according to WHO criteria [26]. Responses were reassessed 8 weeks after their first documentation, and only confirmed responses were computed in the activity analysis. Duration of response was calculated from initial therapy up to documented progression of disease (PD), or last follow-up. Failure-free survival (FFS) was calculated from registration to the time of treatment discontinuation for any reason (occurrence of progression or unacceptable toxicity, because of patient's refusal or when it was deemed in the patient' best interest by the attending physician). OS was calculated from registration to death for any cause, or patient's last follow-up.
Treatment
Patients were stratified according to centre, previous adjuvant chemotherapy and PS, and randomly allocated to receive: IRI 200 mg/m2 i.v. (90 min) on day 1, l-FA 250 mg/m2 i.v (2 h), 5-FU 850 mg/m2 i.v. bolus on day 2 (IRIFAFU regimen); or OXA 100 mg/m2 i.v. (2 h) on day 1, l-FA 250 mg/m2 i.v. (2 h), 5-FU 1 050 mg/m2 i.v. bolus on day 2 [OXAFAFU high dose (hd)]. In both arms, cycles were repeated every 2 weeks. A planned interim analysis on toxicity was carried out when half of the target population had been treated, to assess whether frequency of febrile neutropenia exceeded 10% of patients, which was the predefined restraint for dosage amendment. At that time the actual occurrence of febrile neutropenia among patients treated with OXAFAFUhd was 13%, and therefore the study regimen was amended: OXA and 5-FU were reduced to 85 mg/m2 and 850 mg/m2, respectively [OXAFAFU low dose, (ld)] for the subsequent patients.
Cytotoxic drugs in each doublet were reduced by 25% after occurrence of grade 4 haematological toxicity, or grade 3 non-haematological toxicity, on previous cycle. Chemotherapy was administered until the confirmed achievement of a complete response (CR) (minimum of eight cycles), or up to 12 cycles. Treatment was discontinued earlier in the case of documented PD, unacceptable toxicity, patient's refusal or when it was believed in the best patient's interest by the attending physician. After PD, a cross-over policy, i.e. IRIFAFU in second-line after OXAFAFU in first-line and vice versa, was advised but not mandatory.
Statistical considerations
We assumed that the OXAFAFU regimen might increase by 50% (from 5 to 7.5 months) the median FFS in comparison with the IRIFAFU regimen. With 257 events on the whole series of patients there is an 80% power to demonstrate this difference with a 0.05 alpha error [28]. Therefore, a recruitment of 280 patients has been planned for the comparative analysis. This number of patients may also give an 80% power to detect a 15% difference in RR between the OXAFAFU and IRIFAFU [29].
The occurrence of responses and toxicities was compared using the 2-test or Fisher's exact test where appropriate [30
], and a P value <0.05 was considered significant. Univariate and multivariate analyses were performed for identifying factors associated with RR. Actuarial median [with 95% confidence interval (CI)] of FFS and OS times were obtained using the KaplanMeier method [31
], and compared using the log-rank test [32
].
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Results |
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A similar trend was seen for OXAFAFUhd: DI4 was 41 mg/m2/week for OXA, and 426 mg/m2/week for 5-FU, while DI8 was 37 mg/m2/week and 374 mg/m2/week, and DI12 was 39 mg/m2/week and 354 mg/m2/week, respectively. DI was quite similar for OXAFAFUld: DI4 was 39 mg/m2/week for OXA and 417 mg/m2/week for 5-FU; DI8 was 34 mg/m2/week and 344 mg/m2/week, and DI12 was 35 mg/m2/week and 327 mg/m2/week, respectively. Cumulative OXA dosage was 705 mg/m2 (range 1001200) with OXAFAFUhd, and 780 mg/m2 (range 821114) with OXAFAFUld.
Activity
There were 42 confirmed responses (16 CRs and 26 PRs) among patients treated with IRIFAFU, 29 (seven CRs and 22 PRs) among patients treated with OXAFAFUhd and 32 (13 CRs and 19 PRs) among patients treated with OXAFAFUld. CRs were usually achieved in patients with a limited spread of disease. In detail, 12 of 16 CRs in IRIFAFU group were achieved in patients with only one involved organ (which was the liver in eight cases); in OXAFAFUhd group, six of seven CRs had only one site of disease (liver in four cases), while in OXAFAFUld group, eight of 13 CRs had a single metastatic site (liver in five cases).
In all, OXAFAFU yielded a significantly higher RR (44%; 95% CI 35% to 52%) than IRIFAFU (31%; 95% CI 23% to 40%) (P=0.029). The proportion of patients achieving a PR was also greater among patients treated with OXAFAFU (29% versus 19%; P=0.002), while no difference was seen in occurrence of CRs (14% versus 12%), although a non-significant trend towards a higher achievement of CRs was observed among patients treated with OXAFAFUld. The difference in RR between IRIFAFU and OXAFAFUld was also significant (P=0.032). Moreover, the rate of disease control (response or stabilisation) was greater with OXA (66%) than with IRI (58%) (Table 3).
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Time to response achievement was 2.9 months (range 1.69) for IRIFAFU, and 3.2 months (range 1.79.3) for OXAFAFU. Median duration of CRs was 5.2 months (range 219) in the IRIFAFU group, 17.2 months (range 2.425.3) in the OXAFAFUhd group and 8.5 months (range 216.4) in the OXAFAFUld group. Median duration of all responses was 7.9 months (range 1.920.8) for patients treated with IRI, and 8.5 months (range 1.522.1) for patients treated with oxaliplatin (OXAFAFUhd, 10.5 months; OXAFAFUld, 7.9 months).
Off-study treatments
Soon after the discontinuation of front-line treatment, nine patients with PR (three in the IRIFAFU group and six in the OXAFAFU group) were rendered disease-free by surgical resection of liver metastases.
At progression after first-line IRIFAFU, 77 (57%) patients received second-line treatments. Among these, 62 patients received OXA associated with 5-FU or capecitabine. Local treatment of liver metastases (radiofrequency ablation or intra-arterial chemotherapy) was performed in five patients. Eighteen (13%) patients received a third-line treatment (oral fluoropyrimidines). Among patients receiving OXAFAFU in front-line, salvage treatments were delivered in 78 (56%) patients: IRI, alone or combined with 5-FU or mitomycin C, was administered in 52 patients. Six patients underwent local management for liver metastases. Twenty (14%) patients received third-line treatment with oral fluoropyrimidines.
Toxicity
At interim analysis, neutropenia was more pronounced with OXAFAFUhd than with IRIFAFU (grade 3, 55% versus 39%; P=0.029), and febrile neutropenia was more frequent (19% versus 9%; P=0.041) After dosage amendment, despite a greater occurrence of thrombocytopenia of any grade with OXAFAFUld, no difference in severe haematological toxicity was seen between this regimen and the reference treatment (Table 4). As for non-haematological toxicity, occurrence of diarrhoea was significantly lower among patients treated with OXAFAFUld, and grade
3 was less frequent (12% versus 28%; P=0.005). The proportion of patients complaining of severe emesis was more than halved (4% versus 10%; P=0.113). Hair loss was also less pronounced with OXA-based treatment. Grade 3 neuropathy was recorded in 14% of patients treated with OXAFAFUhd, and in 3% of patients treated with OXAFAFUld, despite similar OXA cumulative dosages. This finding might be explained by the reduced amount of OXA, and consequently by its decrease serum peak concentration after each administration. Overall, 44% of patients treated with OXAFAFUld and 53% treated with IRIFAFU suffered from at least one episode of grade
3 toxicity (except for alopecia). Early deaths (within 60 days from initial therapy) were 4% in both the IRIFAFU and OXAFAFU groups. Five patients died because of severe adverse events possibly or probably related to the received treatment: three patients (two in the IRIFAFU group and one in the OXAFAFUhd group) died as a consequence of severe diarrhoea; one patient died of myocardial infarction after the first course of IRIFAFU, and another patient had a gastric haemorrhage after the first course of OXAFAFUld.
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PS was the baseline clinical feature mostly affecting the outcome of patients. Indeed, FFS was 8.3 months and OS 20.5 months, for patients with PS 0, as opposed to 3.4 months and 11.1 months, respectively, for patients with PS 1. The difference of FFS for patients treated with IRI and those treated with OXA was statistically significant (P=0.046) when adjusted for PS (Figure 1). Comparison of OS between IRI- and OXA-treated patients, which was of borderline significance (P=0.058), reached a significant level (P=0.032) when adjusted for PS. It is noteworthy that OS curves of the two groups of patients progressively diverged after the first year of follow-up: indeed, survival probability was 60% versus 65% at 12 months, 42% versus 52% at 18 months, and 23% versus 39% at 24 months, respectively (Figure 2). Moreover, we noted that OS of patients sequentially treated with all three active drugs, i.e. 5-FU, IRI and OXA, was significantly longer in comparison with that of patients not receiving all three drugs (median 16.6 versus 13 months, respectively) (P=0.009).
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Discussion |
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With these premises in mind, we believe that the present trial provided evidence that OXAFAFU is more active than IRIFAFU. Indeed, the greater RR was obtained using stringent criteria (i.e. including only confirmed responses). Moreover, this greater activity was independent of PS and CEA baseline value, which were the only pretreatment variables affecting RR in the multivariate analysis, and it was obtained despite the dose reduction implemented after the interim analysis on toxicity. Therefore, RR of OXAFAFU was not related to the dosage, provided that a similar number of cycles, duration of treatment and DI were administered in the two groups of patients treated with this regimen.
The higher RR was obtained at the price of similar occurrence of haematological toxicity (with amended dosages), and lower non-haematological toxicity in comparison with IRIFAFU. The better tolerability was also confirmed by a longer FFS time. Since FFS is also affected by factors other than PD, we believe it provided a clinically important measurement of the treatment on study in comparison with the reference regimen. Patients compliance was favoured by our policy of delivering a maximum of 12 cycles, so that chronic toxicities, namely OXA-induced peripheral neuropathy, rarely occurred. This is in contrast with other trials, in which neuropathy with functional impairment was reported in higher proportions of patients [20, 21
, 33
, 34
].
Recently, two trials randomly compared OXA and IRI associated with FA/5-FU in advanced colorectal cancer patients (Table 5). In the GERCOR study, patients were treated biweekly with l-FA 200 mg/m2 infusion, plus 5-FU 400 mg/m2 bolus and 24003000 mg/m2 infusional over 46 h, preceded by either OXA 100 mg/m2 (FOLFOX6) or IRI 180 mg/m2 (FOLFIRI) [33]. After PD, patients received the alternative regimen in a cross-over design. In this study, no differences in RR, PFS or OS were observed. The conclusions were that the two regimens used sequentially provided an outstanding long survival, and that any efforts should be made in the future for increasing the proportion of patients who will receive both treatments.
|
Therefore, our study was the first one directly comparing OXA and IRI, both associated with FA/5-FU i.v. bolus. The results of this trial demonstrated that OXAFAFU was more active than IRIFAFU. Moreover, patients treated with OXAFAFU had a significantly longer FFS and OS. At this point, it is important to remember that our trial was not powered to reach a level of significance with an actual 3-month difference in median OS. However, it has recently been stressed that the lack of a statistically significant survival prolongation in trials assessing combination regimens in metastatic colorectal cancer patients should not be interpreted as an evidence of no survival benefit at all [36].
Our findings were obtained despite the fact that similar proportions of patients in both arms were given second- and third-line treatment, and received sequentially all three active drugs. It may be extrapolated from the GERCOR trial that FOLFOX6 was more active after failure of FOLFIRI regimen than vice versa (RR 15% versus 4%, and PFS 4.2 versus 2.5 months, respectively). If we apply this observation to our patients, we could argue that an OXA-based regimen in second-line, although more active, did not compensate for a less active IRI-based treatment in first-line. In fact, we observed that median OS for patients sequentially receiving all three cytotoxic agents differed according to front-line treatment: it was 18.6 months for patients in OXAFAFU arm, and 15.9 months for patients in IRIFAFU arm. For these reasons, we believe that OXAFAFU should be used first in the treatment of metastatic colorectal cancer patients. Moreover, it should be taken into account that not all patients will receive second-line treatment. In our experience, the proportion of these patients is progressively increasing, from 40% of our previous study to >50% in the present one. However, many patients still do not receive salvage treatment for several reasons. For these patients, survival expectancy is affected only by the front-line treatment. Therefore, it is crucial for them to receive the most tolerable and effective regimen, because a significant correlation between RR and survival has already been established for these patients [37
].
In conclusion, the OXAFAFU regimen showed activity and toxicity comparable with those reported with the FOLFOX4. In our opinion, the OXAFAFU is preferable because it does not require central venous catheter and infusional devices, being more comfortable for outpatient treatment and less costly. For these reasons, the OXAFAFU regimen is from now on the reference regimen for SICOG investigators, to be challenged in future trials.
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Acknowledgements |
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Other SICOG investigators (and Institutions) taking part in this trial were: Rossana Casaretti, Antonio Avallone (National Tumour Institute, Naples); Maria Teresa Ionta (University Medical School, Cagliari); Antonio Gambardella (Second University Medical School, Naples); Giuseppe De Cataldis (Da Procida Hospital, Salerno); Anna Russo (University Medical School, Palermo); Salvatore Del Prete (City Hospital, Frattamaggiore); Annunziato Iannelli (City Hospital, Siderno); Maria di Grazia (City Hospital, Caserta); Teresa Bellelli (Clinic Malzoni, Agropoli); Enrico Barbato (City Hospital Aversa); Maddalena Bianco (City Hospital, Castellammare); Liberato Di Lullo (City Hospital, Isernia); Ettore Greco (City Hospital, Lametia); Filomena Del Gaizo (City Hospital, Avellino); and Sergio Catanzani (City Hospital, Terni, Italy).
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Notes |
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Received for publication December 22, 2004. Revision received January 11, 2005. Accepted for publication January 12, 2005.
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