1 Institut Paoli-Calmettes, University of the Mediterranean, Marseille; 2 Centre René Gauducheau, St Herblain; 3 CHU de Rouen, Rouen; 4 Centre Paul Papin, Angers; 5 Centre Antoine Lacassagne, Nice; 6 Center Alexis Vautrin, Vandoeuvre Les Nancy; 7 Centre Eugène Marquis, Rennes; 8 Institut Bergonié, Bordeaux; 9 Center René Huguenin, Saint Cloud; 10 Centre Val DAurelle Paul Lamarque, Montpellier; 11 Institut Jean Godinot, Reims, France; 12 AstraZeneca, Macclesfield, UK; 13 AstraZeneca, Rueil-Malmaison, France
Received 24 January 2002; accepted 18 February 2002
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Abstract |
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This multicenter, phase II, open-label study evaluated the antitumor efficacy and safety of oxaliplatin and raltitrexed (Tomudex) in non-pretreated advanced colorectal cancer patients.
Patients and methods:
Seventy-one patients received oxaliplatin 130 mg/m2 and raltitrexed 3 mg/m2 intravenously on an outpatient basis every 3 weeks. All patients had histologically proven metastatic colorectal adenocarcinoma, performance status 2 and good baseline organ function. Most (56%) had only one disease site. All patients were assessed for safety, and 66 of 69 eligible patients were assessed for response.
Results:
A total of 404 cycles were administered, with a median of six cycles per patient (range 112 cycles). Relative dose intensities were 0.98 and 0.98 for oxaliplatin and raltitrexed, respectively. The most common grade 34 toxicities (National Cancer Institute Common Toxicity Criteria) among treated patients were as follows: neutropenia (21 patients, 30%), asthenia (eight, 11%), diarrhea (12, 17%), liver function test abnormalities (24, 34%), nausea (nine, 13%) and vomiting (nine, 13%). Two treatment-related deaths occurred (hematotoxicity in one patient and gastrointestinal toxicity in the other) and two further deaths were possibly related to treatment (hepatic dysfunction in one patient and neuropathy in the other). Thirty-seven objective responses (one complete) were obtained [objective response rate 54%; 95% confidence interval (CI) 42% to 65%] in eligible patients. The median response duration was 8.5 months (95% CI 6.712.2 months), while median progression-free and overall survival among eligible patients were 6.2 (95% CI 5.16.9 months) and 14.6 months (95% CI 11.018.9 months), respectively.
Conclusions:
The present study confirms the feasibility of the raltitrexed plus oxaliplatin combination and its activity in non-pretreated advanced colorectal cancer patients.
Key words: colorectal cancer, first-line chemotherapy, metastatic disease, oxaliplatin, raltitrexed
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Introduction |
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In the search for effective, convenient and less toxic treatment options for this disease, raltitrexed (Tomudex; AstraZeneca, Rueil Malmaison, France) and oxaliplatin [trans-1-oxalato-diaminocyclohexane platinum (EloxatinTM); Sanofi-Synthelabo, Paris, France] have emerged as promising compounds with novel mechanisms of action and differential toxicity profiles.
Raltitrexed is a thymidylate synthase (TS) inhibitor, easily transported and concentrated in the cell, that blocks the production of thymidine monophosphate from deoxyuridine monophosphate in a reaction-specific manner. Oxaliplatin, a third-generation platinum analog, is a diaminocyclohexane (DACH) platinum that principally forms intra-strand DNA adducts [5], which differ from those formed by cisplatin or carboplatin in their capability to overcome resistance mechanisms [6]. An additive effect has been demonstrated in an in vitro and in vivo study of oxaliplatin and raltitrexed in human colonic cell lines and a murine tumor model [7].
In clinical studies, both these agents have been shown to be effective and well tolerated as single agents in the first-line treatment of metastatic colorectal cancer. In three randomized phase III studies, raltitrexed has shown response rates comparable to those achieved with standard modulated 5-FU bolus-based schedules (Mayo Clinic and Machover regimens) in non-pretreated patients, comparable overall survival in two of the three and a comparable toxicity profile [8]. Oxaliplatin has also shown promising efficacy as a first-line, single-agent treatment in a phase II study with a response rate of 24% and a median time to progression of 4.1+ months [9]; in a phase III trial oxaliplatin achieved a response rate of 51% and time to progression of 9.0 months in combination with 5-FU [3]. The combination of raltitrexed and oxaliplatin in a phase I trial yielded a favorable safety profile compared with any oxaliplatin/5-FU combination; a tumor control rate of 55% in advanced colorectal cancer patients who were 5-FU refractory and often pretreated with irinotecan and a noteworthy 35% response rate in cisplatin-pretreated malignant mesothelioma [10].
As these two drugs have different mechanisms of action with additive activity, encouraging efficacy and safety profiles as single agents and promising results as outpatient therapy in the phase I combination trial, a phase II trial was undertaken to determine the activity and safety of their combination as first-line treatment in metastatic colorectal cancer patients, the results of which are reported here.
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Patients and methods |
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The protocol was approved on 8 January 1998 by the Ethics Review Committee (CCPPRB) of Cochin-Port Royal Hospital in Paris, France, and the trial was conducted in accordance with good clinical practice standards.
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Treatment |
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Assessments |
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Safety was evaluated before every cycle for all patients who had received at least one treatment cycle, according to NCI-CTC criteria [12]. Clinical examinations and blood chemistry analyses, including renal and liver function measurements, were performed every 3 weeks; blood counts were performed weekly and before each new cycle.
After discontinuation of study treatment, all patients were followed up every 3 months until death. Patients who discontinued treatment for reasons other than progression were evaluated every 3 months for tumor response until progression occurred.
Statistical design and analysis
The primary endpoint of this trial was the evaluation of the rate of objective response of the raltitrexed/oxaliplatin combination in non-pretreated metastatic colorectal cancer. Secondary endpoints investigated were progression-free survival, overall survival, duration of response and tolerance of the combination. The null hypothesis tested was that the objective response rate was 10%, rejected with a power of 90% at a significance level of 5% assuming that the true objective response rate is 30%. Progression-free survival was defined as the time that elapsed between the start of study treatment and disease progression or death, while overall survival was calculated from the start of study treatment until death, both being determined by the KaplanMeier product-limit method [13]. Patients who underwent post-study metastasectomy were not censored for progression-free survival. Response duration was calculated from the date of response documentation for complete responders, or treatment initiation for partial responders, to the date of progression or death.
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Results |
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The demographic, pretreatment and disease history characteristics of treated patients are given in Table 1. The median age was 63 years (range 3977 years), with 48 men (68%) and 23 (32%) women. At inclusion 97% of patients had a WHO PS of 0 or 1. For 68% of patients the primary disease site was the colon, with all other patients having rectal disease, except for one patient with a rectosigmoidal tumor. All eligible patients had metastatic disease at inclusion: 45 (63%) presenting with synchronous metastasis; 31 (43%) had two or more disease sites. Fifty-eight patients (82%) had liver involvement at inclusion; 24 patients (34%) had lung disease; 13 (18%) had lymph-node involvement; and intra-abdominal involvement was present in eight patients (11%). Seventeen patients (24%) had received adjuvant chemotherapy, principally with 5-FU.
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Disease response
As determined by external review, 37 of 69 eligible patients experienced a confirmed disease response to raltitrexed/oxaliplatin therapy, including one complete response, yielding a response rate of 54% [95% confidence interval (CI) 42% to 65%] (Table 2). Median response duration was 8.5 months (95% CI 6.712.2), with nine ongoing responses. Stable disease was observed in 22 patients (32%), so a total of 59 patients (86% of eligible patients) benefited from disease control. Three eligible patients were not assessable for disease response; they died before the first disease assessment for reasons other than disease progression, in two cases as a result of treatment toxicity.
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Survival
With a median follow-up of 14.3 months (range 0.423.1 months), the median progression-free survival for eligible patients was 6.2 months (95% CI 5.16.9 months). Eleven patients (16%) had not experienced disease progression, the follow-up being 9.9 months for one patient and 16.720.7 months for the other 10 patients. Twenty-six of the 69 eligible patients (38%) were still alive at the last follow-up contact, with a median overall survival of 14.6 months (95% CI 11.018.9 months). The estimated 1-year survival rate was 59%.
Eight patients (12%), seven of whom were responding, discontinued trial therapy without experiencing disease progression in order to undergo metastasis resection and/or surgery of the residual initial tumor. All but one of these patients were alive at 17.423.2 months after start of treatment, two having resumed raltitrexed/oxaliplatin treatment post-surgery and three having received other post-study chemotherapy.
Toxicity
All 71 patients were assessed for toxicity, and the incidences according to the worst grade toxicity per patient are presented in Table 3. Four patient deaths (6% of treated patients) were possibly related to the trial treatment: two of these cases, one due to hematotoxicity and the other to gastrointestinal toxicity, were definitely related to treatment, whereas the two other deaths, one due to hepatic dysfunction and the other to neuropathy, were classified as possibly related to treatment (see Discussion). Hematological toxicity was frequent, with anemia, neutropenia, leukopenia and thrombocytopenia each occurring in >50% of patients. A third of the patients experienced grade 3 or 4 neutropenia, reaching grade 4 in 17% of patients. Three patients experienced an episode of febrile neutropenia. Severe thrombocytopenia and anemia were less frequently observed, with grade 4 toxicity seen in 4 and 1% of patients, respectively. Oxaliplatin-induced peripheral neurosensory toxicity was ubiquitous, with 82% of patients experiencing mild to moderate neuropathy and 8% of patients having some degree of function impairment. Infrequent mild or moderate neuromotor toxicity or visual abnormalities were also observed. Despite systematic anti-emetic prophylaxis, gastrointestinal toxicities frequently accompanied raltitrexed/oxaliplatin treatment. Thirteen per cent of patients experienced severe nausea and vomiting, with 4% of patients experiencing grade 4 vomiting, while grade 34 diarrhea was seen in 17% of patients. Asthenia, a characteristic side effect of raltitrexed treatment, was present in >50% of patients, 11% of patients experiencing severe fatigue. The investigators determined that treatment-related hepatic toxicity resulted in abnormal liver function tests in 87% of patients, attaining grade 3 in 32%.
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Discussion |
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Current development efforts in the treatment of first-line metastatic colorectal cancer patients have two main aims. First, to achieve improved efficacy over the standard modulated 5-FU therapies, particularly in patients with poor prognosis, via the introduction of agents with novel mechanisms of action, such as oxaliplatin and irinotecan. Secondly, to ameliorate treatment conditions for patients via the use of new TS inhibitors with more convenient administration modalities. The combination therapies evaluated in this context in phase II/III studies are raltitrexed/irinotecan (preliminary results of phase II trials) [1416]; oxaliplatin/raltitrexed (phase II) [1719]; irinotecan/5-FU (phase III) [1, 20]; and oxaliplatin/5-FU (phase III) [3, 4, 20, 21]. Data from this raltitrexed/oxaliplatin phase II study are encouraging in that the 54% objective response rate reported here is similar to the objective response rate reported in other phase II and III trials of oxaliplatin/5-FU [3, 4, 20] or irinotecan/5-FU combinations [2, 20] as well as raltitrexed combined with irinotecan [1416], especially in light of recent evidence from the Meta-Analysis Group in Cancer for the validity of response as a surrogate endpoint for survival [22]. In terms of tumor control (response or disease stabilization), the rate of 86% achieved compares favorably with the rate achieved with all other combinations, with only seven patients experiencing disease progression as best response to treatment. The median progression-free survival of 6.2 months was comparable to the 6.77.0 months obtained in phase III trials with irinotecan/5-FU [1, 2], but lower than the 8.79 months obtained with oxaliplatin/5-FU [3, 4]. The median overall survival of 14.6 months was close to the range of values observed for first-line therapy with other new combinations of 5-FU with oxaliplatin (flat or chronomodulated infusion) or irinotecan (14.719.4 months). The efficacy observed in this trial is corroborated by a recently completed phase III trial using the same regimen [17]. Also, promising activity (41% objective response rate) and a good safety profile were observed in a preliminary study with a regimen employing oxaliplatin at 100 rather than 130 mg/m2 [23].
The activity of the raltitrexed/oxaliplatin combination allowed some patients with initially unresectable disease to become candidates for disease resection, the proportion of patients undergoing resection being similar to that reported in other studies using combination regimens [20, 24]. Patients undergoing post-chemotherapy disease resection seemed to experience significant benefit, with all except one remaining alive at 1.52 years.
A high percentage (63%) of patients were metastatic at diagnosis, compared with 1525% of colorectal cancer patients diagnosed with metastases in the general population [25], and 82% of patients had hepatic involvement. However, in terms of patient condition and tumor burden at inclusion, the cohort was representative of the population selected for first-line phase II trials in colorectal cancer, with 97% of patients having a PS of 01 and 84% having less than three disease sites. A relatively low proportion of patients had received prior adjuvant chemotherapy (24%).
An unusual rate of deaths possibly due to toxicity occurred in this study. Two definite cases (3%) of toxic death occurred and two other deaths were possibly related to the treatment. Of the former, one patient experienced medullar aplasia and septic shock following the seventh treatment cycle; this may have been avoidable as treatment was given at full dose despite severe neutropenia in the two preceding cycles. The second patient died during the third cycle of severe treatment-related diarrhea, with concomitant vomiting and abdominal pain. This patient had undergone a total colectomy 15 years earlier for familial adenomatous polyposis; therefore, there is some doubt as to whether his treatment with two agents that induce diarrhea was advisable. As for the two deaths considered to have possibly been related to treatment, one patient experienced respiratory failure with laryngeal diplegia. Stupor, without evidence of cerebral abnormalities, occurred during the second cycle; the patient recovered, but then experienced a recurrence starting on day 10 of the third cycle. While rapid-onset pharyngeo-laryngeal dysesthesia is known to occur during or immediately after oxaliplatin infusions, laryngeal paralysis has not been observed with this agent. The possibility of a central nervous system accident unrelated to treatment cannot be eliminated. In the second case, a patient with massive liver involvement died during the first cycle of acute liver dysfunction. The post-mortem finding of acute liver ischemia without inflammation is consistent with chemotherapy-induced toxicity. The rate of mortality that is possibly treatment-related is superior to that previously reported for the raltitrexed/oxaliplatin regimen under study, with only one possible toxic death observed in 244 patients (0.4%) treated in phase I or II trials [10, 1719, 2628]. Nevertheless, a 2.6% rate of toxic death was observed in the 469 patients in two phase III trials of raltitrexed monotherapy [29, 30]. In any case, the events observed in this trial serve to underline the necessity of strict adherence to guidelines for patient surveillance and dose adjustment, despite the less onerous, ambulatory administration scheme permitted by this combination.
The incidence and severity of toxicities observed, apart from these four fatal events, was as would be expected based on the single-agent toxicity profiles and the phase I combination experience [10]. The only differences from the toxicity profile at the recommended dose in the phase I trial are the observations of more frequent grade 34 neutropenia in the present study (17 versus 6%) and slightly less frequent grade 34 vomiting (13 versus 19%) and asthenia (11 versus 19%). The toxicity profile in the present study is also concordant with that reported by Scheithauer et al. [17] for the same raltitrexed/oxaliplatin combination [17]. Nevertheless, lower rates of severe diarrhea (7% of patients), asthenia (2%) and liver function abnormalities (14%) were observed in that trial.
An elevated rate of treatment discontinuation due to toxicity was observed in this study, with 27% of patients discontinuing because of neurotoxicity, hematotoxicity, gastrointestinal toxicity or other toxicities. However, these treatment discontinuations generally took place only after the patient had received a significant number of cycles, the median being 8.5 cycles (range 812 cycles) following neurotoxicity and five cycles (range 18 cycles) for other toxicity types, and had experienced benefit from therapy, 14 of 19 patients having responded.
In conclusion, the raltitrexed/oxaliplatin combination achieved noteworthy activity in first-line therapy of metastatic colorectal cancer patients, which appears similar to data for other new combination regimens currently being explored. While displaying significant rates of severe hematological and gastrointestinal toxicities, these did not interfere with patients ability to benefit from treatment. However, the occurrence of four deaths possibly related to treatment is of concern in this population of patients who are early on in the therapeutic pathway for metastatic disease. Further investigation of this active association in second-line therapy [26], in management strategy trials and in comparison with other combinations, such as 5-FU/oxaliplatin, are warranted.
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Acknowledgements |
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Footnotes |
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References |
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