Original article
Annals of Oncology 13: 1072–1079, 2002 DOI: 10.1093/annonc/mdf183
Multicenter non-randomized phase II study of raltitrexed (Tomudex) and oxaliplatin in non-pretreated metastatic colorectal cancer patients J.-F. Seitz1*, J. Bennouna2, B. Paillot3, E. Gamelin4, E. François5, T. Conroy6, J.-L. Raoul7, Y. Becouarn8, F. Bertheault-Cvitkovic9, M. Ychou10, S. Nasca 11, A. Fandi 12, P. Barthelemy 13 & J.-Y. Douillard 2 1
Institut Paoli-Calmettes, University of the Mediterranean, Marseille; 2Centre René Gauducheau, St Herblain; 3CHU de Rouen, Rouen; Centre Paul Papin, Angers; 5Centre Antoine Lacassagne, Nice; 6Center Alexis Vautrin, Vandoeuvre Les Nancy; 7Centre Eugène Marquis, Rennes; 8 Institut Bergonié, Bordeaux; 9 Center René Huguenin, Saint Cloud; 10Centre Val D’Aurelle Paul Lamarque, Montpellier; 11 Institut Jean Godinot, Reims, France; 12 AstraZeneca, Macclesfield, UK; 13AstraZeneca, Rueil-Malmaison, France 4
Received 24 January 2002; accepted 18 February 2002
Background: 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 1–12 cycles). Relative dose intensities were 0.98 and 0.98 for oxaliplatin and raltitrexed, respectively. The most common grade 3–4 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 6.7–12.2 months), while median progression-free and overall survival among eligible patients were 6.2 (95% CI 5.1–6.9 months) and 14.6 months (95% CI 11.0–18.9 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
Introduction Colorectal cancer is currently one of the most prevalent cancer types in Western countries, with >30% of cases diagnosed at an advanced stage. Approximately six of 10 colorectal cancer patients ultimately develop recurrent or metastatic disease and are therefore potential candidates for palliative chemotherapy.
*Correspondence to: Dr J.-F. Seitz, CHU Timone–Digestive Oncology Unit, 264 rue St Pierre, 13885 Marseille, Cedex 5, France. Tel: +33-4-91-38-60-23; Fax: +33-4-91-38-48-73; E-mail:
[email protected] © 2002 European Society for Medical Oncology
Although 5-fluorouracil (5-FU) remains the standard cytotoxic agent in the treatment of metastatic colorectal cancer, as a single agent it achieves objective responses in only 5–17% of patients. While modulation of 5-FU with folinic acid (FA) or methotrexate has led to greater efficacy and longer progressionfree survival, no such combination schedule has been proven to be clearly superior. More recently, combinations of 5-FU with oxaliplatin or irinotecan have been shown to be superior to modulated 5-FU in terms of time to progression and, for the latter, survival [1–4]. In the search for effective, convenient and less toxic treatment options for this disease, raltitrexed (Tomudex;
1073 AstraZeneca, Rueil Malmaison, France) and oxaliplatin [trans1-oxalato-diaminocyclohexane platinum (EloxatinTM); SanofiSynthelabo, 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 bolusbased 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.
Patients and methods Eligibility criteria All patients entering this single arm, multicenter, phase II, open-label study had histologically proven metastatic colorectal adenocarcinoma, with a maximum of one previous adjuvant treatment permitted. In patients having received such treatment, progression was to have occurred >6 months after the end of treatment. Patients were to have at least one bi-dimensionally measurable target lesion in a non-irradiated area with at least one diameter ≥2 cm, and to have given written informed consent before the start of study treatment. Other eligibility criteria included the
following: World Health Organization (WHO) performance status (PS) ≤2; life expectancy ≥3 months; adequate bone marrow function (polynuclear neutrophils ≥2000/mm3, platelets ≥100 000/mm3, hemoglobin ≥9 g/100 ml); liver function [alanine aminotransferase/aspartate aminotransferase ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN in cases of liver metastases, total bilirubin ≤1.25 × ULN, alkaline phosphatase ≤5 × ULN except in cases of bone metastases, lactate dehydrogenase ≤3.5 × ULN, prothrombin time ≥60% without anticoagulants]; and renal function (creatinine ≤1.25 × ULN and creatinine clearance ≥65 ml/min). Patients had not received previous chemotherapy for metastatic disease, were not receiving any concomitant anticancer or FA treatment (including vitamin supplements containing FA), and had no known brain metastases, infection, other tumors (except basal cell carcinoma or cervical cancer in situ with a disease-free interval >5 years), other uncontrolled conditions, sensitive peripheral neuropathy grade ≥1 [National Cancer Institute Common Toxicity Criteria (NCI-CTC)] or bone metastases as the only sign of metastatic disease. 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.
Treatment All patients received raltitrexed 3 mg/m2 as a 15-min intravenous (i.v.) infusion followed 45 min later by oxaliplatin130 mg/m2 as a 2-h i.v. infusion every 3 weeks. Prophylactic anti-emetic treatment with 5HT3 antagonists was systematically administered. In cases of decreased creatinine clearance, oxaliplatin administration was to remain unchanged while raltitrexed was to be administered every 4 weeks at 75% (55–65 ml/min) or 50% (25–54 ml/min) of the original dose. Treatment was discontinued if the creatinine clearance fell below 25 ml/min. In cases of paresthesia with pain or functional impairment, raltitrexed was to be administered at the original dose, and the oxaliplatin dose was to be reduced to 100 mg/m2 for first-time events lasting >7 days, to 80 mg/m2 for second-time events lasting >7 days or discontinued if paresthesia became persistent. Oxaliplatin was also reduced to 100 mg/m2 if paresthesia without associated symptoms became persistent. Doses for both drugs were also reduced if hematological toxicity grade ≥3 or digestive toxicity grade ≥2 occurred. If hematological toxicity or diarrhea grade ≥2 was present at day 21, treatment was delayed for a maximum of 2 weeks until symptoms were resolving or, in cases of diarrhea or mucositis, had resolved. Study treatment was discontinued if hematological toxicity or diarrhea persisted after the maximum 2-week delay; creatinine clearance fell below 25 ml/min in the event of grade 4 diarrhea or paresthesias with pain or functional impairment occurred. In the case of a complete or partial response, study treatment was continued until tumor progression or the onset of dose-limiting toxicity and, in the case of disease stabilization, further treatment was left to the discretion of the investigator. Analgesic radiotherapy to bone tumors was the only concomitant anticancer treatment permitted during the study.
Assessments Disease was assessed every three treatment cycles by clinical and/or iconographical evaluation [computed tomography (CT) scan, magnetic resonance imaging (MRI) or X-ray], employing the same method used to measure the initial targets. Tumor response was determined according to WHO criteria [11] and validated by an external radiological expert review.
1074 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.
Table 1. Patient characteristics No. of patients (%) No. of patients
71 (100)
Age (years)
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.
Median
63
Range
39–77
Sex
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 Kaplan–Meier product-limit method [13]. Patients who underwent post-study metastasectomy were not censored for progressionfree 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.
Male
48 (68)
Female
23 (32)
Performance status (WHO) 0
38 (54)
1
31 (44)
2
2 (3)
Primary tumor site Colon
48 (68)
Rectum
22 (31)
Rectosigmoid
1 (1)
Total no. disease sites 1
40 (56)
2
20 (28)
≥3
11 (15)
Sites of diseasea Intra-abdominal
Results
8 (11)
Liver
58 (82)
Patient characteristics
Lung
24 (34)
Seventy-one patients were treated in 12 French hospitals from June 1998 to June 1999. Two patients (3%) were ineligible: one patient had experienced rapid disease progression following adjuvant chemotherapy; the diagnosis of metastatic disease was not confirmed in the other. The demographic, pretreatment and disease history characteristics of treated patients are given in Table 1. The median age was 63 years (range 39–77 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.
Lymph nodes
13 (18)
Other
13 (18)
Extent of exposure A total of 404 cycles were administered, with 65 patients (92%) receiving at least three cycles (median six cycles per patient; range 1–12 cycles). The median cumulative dose was 18.0 mg/m2
Prior therapy Primary tumor resection
63 (89)
Metastasis resection
17 (24)
Chemotherapy
17 (24)
Immunotherapy
2 (3)
Radiotherapy No. patients symptomatic at baseline
14 (20) 30 (42)
Time from last adjuvant treatment to metastasis diagnosis (months) Median (n = 14) Range
11.5 0.3b–71
a
Patients may have had more than one site of disease. The interval of 0.3 months corresponds to an ineligible patient. WHO, World Health Organization.
b
(range 3.0–33.0 mg/m2) and 780 mg/m2 (range 130–1383 mg/m2) for raltitrexed and oxaliplatin, respectively. Median absolute dose intensity was 0.98 mg/m2/week (range 0.56–1.05 mg/m2/ week) and 42.5 mg/m2/week (range 25.0–46.0 mg/m2/week) for raltitrexed and oxaliplatin, respectively, close to the planned dose intensities of 1.0 and 43.3 mg/m2/week, the
1075
Survival
Table 2. Efficacy in eligible patients No. of patients (%) No. of eligible patients
69 (100)
Response (WHO criteria) Complete response
1 (1)
Partial response
36 (52)
Stable disease
22 (32)
Progressive disease Non-assessable Objective response rate, % (95% CI)
7 (10) 3 (4) 54 (42–65)
Duration of response, months (95% CI)
8.5 (6.7–12.2)
Median progression-free survival, months (95% CI)
6.2 (5.1–6.9)
Median overall survival, months (95% CI)
14.6 (11.0–18.9)
CI, confidence interval; WHO, World Health Organization.
relative dose intensity being 0.98 for both agents. Seventyfive cycles were delayed (23% of cycle intervals) for a median of 5 days (range 1–19), but only 26 cycles (8% of cycle intervals) were delayed due to toxicity. Hematotoxicity (mostly neutropenia) was the principal cause of cycle delays for toxicity (18 cycles, 5% of cycle intervals), while gastrointestinal and hepatic toxicity forced treatment delay in three and five cycles, respectively. Dose reductions were undertaken in 17 patients (26% of patients receiving at least two cycles). The raltitrexed dose was reduced in 15 patients, accompanied by an oxaliplatin dose reduction in nine of them, for reasons of hematological toxicity (six patients), gastrointestinal toxicity (five patients), hepatic toxicity (three patients) or for reasons unknown (one patient). Oxaliplatin alone was reduced in two patients due to neurotoxicity, following five and seven cycles.
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 6.7–12.2), 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. Thirty-eight patients (54%) received second-line chemotherapy, containing 5-FU in all cases and combined with irinotecan in 25 cases. Only one response to salvage therapy was observed; 14 patients experienced disease stabilization.
With a median follow-up of 14.3 months (range 0.4–23.1 months), the median progression-free survival for eligible patients was 6.2 months (95% CI 5.1–6.9 months). Eleven patients (16%) had not experienced disease progression, the follow-up being 9.9 months for one patient and 16.7–20.7 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 11.0– 18.9 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 17.4–23.2 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 3–4 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%. Nineteen patients (27%) discontinued therapy due to toxicity: six patients because of peripheral sensory neuropathy, principally mild to moderate paresthesias, after a median of 8.5 cycles (range 8–12 cycles); two patients each because of
1076 Table 3. Toxicities related to study treatment, per patient NCI-CTC grade (%) (n = 71) 1
2
3
4
Anemia
21 (30)
12 (17)
2 (3)
1 (1)
Leukopenia
15 (21)
14 (20)
7 (10)
5 (7)
Neutropenia
14 (20)
10 (14)
9 (13)
12 (17)
Thrombocytopenia
29 (41)
6 (8)
2 (3)
3 (4)
Nausea
31 (44)
12 (17)
9 (13)
Vomiting
18 (25)
12 (17)
6 (8)
3 (4)
Diarrhea
13 (18)
15 (21)
7 (10)
5 (7)
Mucositis
4 (6)
Constipation
4 (6)
Hematological
Gastrointestinal
4 (6) –
2 (3) –
–
– –
Neurological Neurosensory
39 (55)
19 (27)
Neuromotor
4 (6)
1 (1)
–
Taste alteration
7 (10)
1 (1)
–
–
Visual
4 (6)
–
–
–
–
–
–
–
6 (8)
– 1 (1)
Other Allergy
2 (3)
Alopecia
5 (7)
2 (3) –
Anorexia
8 (11)
6 (8)
3 (4)
Asthenia
17 (24)
13 (18)
8 (11)
Condition aggravated
–
2 (3)
1 (1) –
3 (4)
2 (3)
Cutaneous
2 (3)
3 (4)
–
–
Fever
2 (3)
4 (6)
–
–
Infection
3 (4)
2 (3)
– –
1 (1)
LDH increased
18 (25)
2 (3)
Liver function tests
21 (30)
17 (24)
23 (32)
–
Pain
12 (17)
7 (10)
1 (1)
Pulmonary
1 (1)
1 (1)
1 (1)
Weight decrease
5 (7)
6 (8)
2 (3)
1 (1) – 1 (1) –
LDH, lactate dehydrogenase; NCI-CTC, National Cancer Institute Common Toxicity Criteria.
hematological and gastrointestinal toxicity and three patients because of both hematological and gastrointestinal toxicities. The remaining six patients were withdrawn after suffering depression, weight loss, pulmonary fibrosis or deterioration of general status.
Discussion This single-arm multicenter phase II study was designed to assess the efficacy of raltitrexed combined with oxaliplatin in patients with non-pretreated metastatic colorectal cancer.
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) [14–16]; oxaliplatin/raltitrexed (phase II) [17–19];
1077 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 [14–16], 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 6.7–7.0 months obtained in phase III trials with irinotecan/5-FU [1, 2], but lower than the 8.7–9 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 (14.7–19.4 months). The efficacy observed in this trial is corroborated by a recently completed phase I–II 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 1.5–2 years. A high percentage (63%) of patients were metastatic at diagnosis, compared with 15–25% 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 0–1 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 treatmentrelated 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, 17–19, 26–28]. 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 3–4 neutropenia in the present study (17 versus 6%) and slightly less frequent grade 3–4 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 8–12 cycles) following neurotoxicity and five cycles (range 1–8 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
1078 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.
Acknowledgements The authors wish to thank the following physicians who treated patients in the present cohort: Dr Brunet (Institut Bergonié, Bordeaux), Dr Boucher (Centre Eugène Marquis, Rennes), Drs Capodano and Giovannini (Institut Paoli-Calmettes, Marseille), Dr Jacob (Centre François Baclesse, Caen), Dr Michel (CHU de Rouen, Rouen), Dr Nguyen (Institut Jean Godinot, Reims). The authors also wish to thank Gregoire Edorh for monitoring the centers and Muriel Licour for analysis of the data. Preliminary results of this study have been presented at the following conferences: Thirty-fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, USA, May 15–18, 1999; European Organisation for Research and Treatment of Cancer—Fondation Française de Cancérologie Digestive Joint Meeting; Liver and Gastro-Intestinal Tract Cancers, Paris, France, June 23–26, 1999; ECCO 10: The European Cancer Conference, Vienna, Austria, 12–16 September, 1999; Thirty-sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, USA, May 20–23, 2000. The present work was sponsored by the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) and supported by Astra Zeneca, France. Tomudex is a trade mark of the AstraZeneca group of companies.
References 1. Saltz L, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 905–914. 2. Douillard JY, Cunningham D, Roth A et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 1041–1047. 3. De Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947. 4. Giacchetti S, Zidani R, Perpoint B et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracilleucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18: 136–147. 5. Raymond E, Faivre S, Woynarowski J et al. Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 1998; 25: 4–12. 6. Fink D, Nebel S, Aebi S et al. Effect of loss of DNA mismatch repair on cisplatin, oxaliplatin, and JM 216 sensitivity. Proc Am Assoc Cancer Res 1997; 38: 523 (Abstr).
7. Raymond E, Djelloul S, Buquet-Fagot C et al. Oxaliplatin (LOHP) and cisplatin (CDDP) in combination with 5FU, specific thymidine synthase (TS) inhibitors (AG337, ZD169), and topoisomerase I (Topo-I) inhibitors (SN38, CPT-11) in human colorectal, ovarian and breast cancer. Proc Am Assoc Cancer Res 1996; 37: 291 (Abstr). 8. Cunningham D. Mature results from three large controlled studies with raltitrexed (Tomudex). Br J Cancer 1998; 77: 15–21. 9. Becouarn Y, Ychou M, Ducreux M et al. Phase II trial of oxaliplatin as first line chemotherapy in metastatic colorectal cancer patients. J Clin Oncol 1998; 16: 2739–2744. 10. Fizazi K, Ducreux M, Ruffie P et al. Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer. J Clin Oncol 2000; 18: 2293–2300. 11. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207–214. 12. Macdonald J, Haller D, Mayer R. Grading of toxicity. In Macdonald J, Haller D, Mayer R (eds): Manual of Oncologic Therapeutics. Philadelphia, PA: Lippincott 1995; 519–523. 13. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 14. Carnaghi C, Zucali PA, Rimassa L et al. Promising activity of irrinotecan (CPT-11) and raltitrexed (ZD1694) as first line chemotherapy in metastatic colorectal cancer (MCC). Proc Am Soc Clin Oncol 2000; 19: 307a (Abstr 1211). 15. Nobile M, Gozza A, Heouaine A et al. Irinotecan (CPT-11) and raltitrexed (Tomudex) in advanced colorectal cancer: a phase II study. Proc Am Soc Clin Oncol 2000; 19: 309a (Abstr 1220). 16. Escudero P, Espinosa J, Milla A et al. An ongoing phase II study of raltitrexed (Tomudex) plus irinotecan in advanced colorectal cancer. Proc Am Soc Clin Oncol 2001; 20: 120b (Abstr 2230). 17. Scheithauer W, Kornek G, Ulrich-Pur H et al. Oxaliplatin plus raltitrexed in patients with advanced colorectal carcinoma.Cancer 2001; 91: 1264–1271. 18. Garcia-Arroyo F-R, Constenla M, Lorenzo I et al. Raltitrexed combined with oxaliplatin as first-line treatment in patients (p) with advanced colorectal cancer (aCRC). Preliminary data of a phase II study. Proc Am Soc Clin Oncol 2001; 20: 116b (Abstr 2216). 19. Pinto C, Mini E, Gentile A et al. Oxaliplatin (OHP) and raltitrexed (RTX) in advanced colorectal cancer (ACRC) patients: a phase II study. Proc Am Soc Clin Oncol 2001; 20: 113b (Abstr 2204). 20. Tournigand C, Louvet C, Quinaux E et al. FOLFIRI followed by FOLFOX versus FOLFOX followed by FOLFIRI in metastatic colorectal cancer (MCRC): final results of a phase III study. Proc Am Soc Clin Oncol 2001; 20: 124a (Abstr 494). 21. Grothey A, Deschler B, Kroening H et al. Bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) versus weekly high-dose 24 h 5-FU infusion/FA + oxaliplatin (OXA) in advanced colorectal cancer (CRC). Results of a phase III study. Proc Am Soc Clin Oncol 2001; 20: 125a (Abstr 496). 22. Buyse M, Thirion P, Carlson R et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 2000; 356: 373–378. 23. Catalano V, Ferrau F, Massacesi C et al. Raltitrexed (TOM) may replace the de Gramont regimen in combination with oxaliplatin (L-OHP) for the treatment of advanced colorectal cancer. Proc Am Soc Clin Oncol 2001; 20: 145a (Abstr 576). 24. Giacchetti S, Itzhaki M, Gruia G et al. Long term survival of patients with unresectable colorectal cancer liver metastases following infu-
1079 sional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 1999; 10: 663–669. 25. Skibber JM, Minsky B, Hoff PM. Cancer of the colon. In DeVita VT, Hellman S, Rosenberg S (eds): Cancer: Principles and Practice of Oncology, 6th edition. Philadelphia, PA: Lippincott Williams & Wilkins 2001: 1216–1271. 26. Scheithauer W, Kornek G, Schuell B et al. Second-line treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy. Ann Oncol 2001; 12: 709–714. 27. Fizazi K, Doubre H, Viala J et al. The combination of raltitrexed (Tomudex) and oxaliplatin is an active regimen in malignant mesothelioma: results of a phase II study. Proc Am Soc Clin Oncol 2000; 19: 578a (Abstr 2276).
28. Maisano R, Caristi N, Toscano G et al. Raltitrexed and oxaliplatin as first-line treatment of advanced pleural mesothelioma. Preliminary data of a phase II study. Ann Oncol 2000; 11 (Suppl 4): 110 (Abstr 498P). 29. Cunningham D, Zalcberg J, Rath U et al. Final results of a randomized trial comparing Tomudex (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann Oncol 1996; 7: 961–965. 30. Cocconi G, Cunningham D, Van Cutsem E et al. Open, randomized multicenter trial of raltirexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. J Clin Oncol 1998; 16: 2943–2952.
