Medical Oncology and Haematology Department, Istituto Clinico Humanitas, Milan, Italy
Received 16 November 2001; revised 13 February 2002; accepted 13 March 2002
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Abstract |
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Irinotecan and raltitrexed are active agents in metastatic colorectal cancer. Preclinical findings suggest a remarkable synergistic activity between the two drugs and the feasibility of this association has been shown in a recent phase I study. The aim of our phase II trial was to assess the efficacy and tolerability of the combination of irinotecan and raltitrexed in patients with metastatic colorectal cancer untreated with chemotherapy.
Patients and methods:
From June 1998 to February 2000, 46 patients were enrolled. Patients received irinotecan 350 mg/m2 on day 1 and raltitrexed 2.6 mg/m2 on day 2, every 3 weeks, for up to nine courses. Tumour assessment was performed every three cycles.
Results:
A total of 223 cycles of chemotherapy, with a median number of six (range 19) courses per patient, was administered. According to intention-to-treat analysis, the overall response rate was 46% (95% confidence interval 31% to 61%). The median duration of response was 21 weeks (range 11101), the median time to progression 27 weeks (range 1
116), and the median overall survival 57 weeks (range 1
130). The main toxicities were diarrhoea, with National Cancer Institute common toxicity criteria grade 3/4 in 26% of patients, grade 3/4 neutropenia in 20%, grade 3 nauseavomiting in 13%, grade 3 asthenia in 11% and grade 3/4 transaminase elevation in 4%.
Conclusions:
Results achieved with irinotecan and raltitrexed show that this regimen is active, despite not-negligible toxicity, and may represent a useful regimen for specific subgroups of colorectal cancer patients.
Key words: colorectal cancer, irinotecan, metastatic, phase II trial, raltitrexed
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Introduction |
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Irinotecan (CPT11), a topoisomerase I inhibitor, in two randomised phase III studies, was shown to significantly improve survival and quality of life in patients with 5-fluorouracil (5-FU)-resistant disease [2, 3]. Moreover, a substantial activity of irinotecan in chemotherapy-naïve colorectal patients, comparable to that of 5-FU, was observed in several phase II trials [4] and in a recent phase III study [5]. The toxicity of this drug is characterised by cholinergic syndrome, myelosuppression and delayed diarrhoea; the latter is unpredictable and may be life-threatening. Since irinotecan has a mechanism of action different from that of 5-FU, it was logical to combine these two drugs in an attempt to improve the results obtained with either as a single agent. Based on the promising results of phase I/II studies, two randomised phase III trials, one in Europe and one in North America, compared different schedules of 5-FU/folinic acid (FA) with the same 5-FU/FA schedule plus irinotecan. The findings of both of these trials showed a significant benefit of an irinotecan/5-FU/FA combination over 5-FU/FA alone, in terms of response rate, progression-free survival (PFS) and overall survival, as first-line treatment in advanced colorectal cancer [5, 6].
However, the use of 5-FU-based regimens has some limitations. The infusional administration requires the use of a venous catheter system and infusion pump, while the bolus schedule requires frequent hospital visits. Besides, 5-FU is contraindicated in cases of deficiency of dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme in the metabolism of 5-FU. The incidence of this pharmacogenetic syndrome in the general population is estimated to be as high as 3% and it results in severe toxicity following the administration of standard doses of fluoropyrimidine, with a mortality rate of up to 33% [7, 8]. Furthermore, the use of 5-FU could be contraindicated in patients with concomitant ischaemic heart disease [9, 10].
A potential substitute for 5-FU is raltitrexed, a pure thymidylate synthase inhibitor. Three randomised trials have been performed in advanced colorectal cancer patients, comparing raltitrexed with 5-FU/FA. The response rates in all three trials have been comparable and survival rates were comparable in two of the three; in the third trial, however, survival in the raltitrexed arm was inferior [11]. The main side-effects of raltitrexed are increased transaminase levels, asthenia, diarrhoea, nausea and vomiting, and neutropenia. Raltitrexed is administered as a short intravenous (i.v.) infusion once every 3 weeks, thus avoiding not only the implant of a venous catheter, but also the need for frequent hospital visits [11]. In addition, DPD is not involved in the metabolism of irinotecan and raltitrexed and it may be assumed that these agents could be used safely in patients with DPD deficiency [12]. Finally, some reports have shown that ischaemic heart disease is not a contraindication to the use of raltitrexed [13].
Irinotecan is a prodrug and its active metabolite, SN-38, has been studied in the laboratory in combination with raltitrexed. These studies have shown no cross-resistance; indeed, SN-38 has shown activity in raltitrexed-resistant cell lines. Synergism has been demonstrated when SN-38 is administered before raltitrexed. Moreover, a 24-h interval between exposure to SN-38 and raltitrexed significantly enhanced the magnitude of the synergy [14].
A recent phase I study by Ford et al. [15] showed that this combination had manageable toxicity and was active in advanced gastrointestinal tract adenocarcinoma at the recommended doses of irinotecan 350 mg/m2 and raltitrexed 3 mg/m2. It is worth noting that in this study the two drugs were administered on the same day, without taking advantage of the synergism observed in the preclinical studies where a 24-h interval between the administration of the two agents was employed [14]. In a preliminary assessment in pretreated patients, we administered the two drugs in the sequence suggested by the preclinical data and observed an unexpectedly high rate of gastrointestinal toxicity.
Based on these data, we designed a phase II study using the same sequence but reducing the dose of raltitrexed according to the last but one dose level of the phase I trial published by Ford et al. [15]. Our aim was to evaluate the efficacy and the tolerability of irinotecan and raltitrexed as first-line treatment in patients with advanced or metastatic colorectal cancer, in order to identify an active combination to overcome the limitations related to the use of 5-FU-based regimens detailed above.
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Patients and methods |
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Patients were excluded from the study if they had brain metastases, prior malignancy (except adequately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix), concomitant severe uncontrolled diseases (e.g. active infections, diabetes mellitus, heart diseases). Exclusion criteria also included pregnancy, breast-feeding and inadequate contraceptive precautions.
All eligible patients were required to give written informed consent before entry to the study. The trial was approved by the local ethics committee.
Treatment schedule
Eligible patients were treated with irinotecan 350 mg/m2 as a 90-min infusion on day 1, and raltitrexed 2.6 mg/m2 as a 30-min infusion on day 2. Both drugs were administered as i.v. infusions in 0.9% saline. A combination of i.v. 5-hydroxytryptamine type 3 receptor antagonists and dexamethasone were given on days 1 and 2, 15 min before starting chemotherapy to reduce the incidence of nausea and vomiting. Atropine 0.25 mg (subcutaneously) was given on day 1 before irinotecan infusion to prevent cholinergic syndrome. High-dose loperamide was given in cases of delayed diarrhoea. The regimen was repeated every 3 weeks for a maximum of nine cycles or until there was evidence of either unacceptable side-effects or progressive disease (PD). Post-study second-line chemotherapy with 5-FU/FA and oxaliplatin was allowed.
Dose adjustments for both study drugs were made according to the greatest degree of toxicity. Treatment was delayed if the neutrophil count was not 1.5 x 109/l and/or if the platelets count was not
100 x 109/l. If recovery was not evident within a further 2 weeks (5 weeks after commencement of the course), the patient was withdrawn from the study. If recovery was evident by day 35, the dose of both drugs was decreased by 50%. If the patient had greater than grade 3 National Cancer Institute common toxicity criteria (NCI-CTC) non-haematological toxicity (except for alopecia), the treatment was withheld until recovery to grade 2 had occurred and a dose reduction of 25% was made for subsequent cycles of treatment.
Treatment evaluation
Pretreatment evaluations consisted of complete medical history and physical examination with the assessment of performance status score, haematological and biochemical profiles, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) assessment, chest X-rays in anteriorposterior and lateral view and/or computed tomography (CT) scan of the chest, sonography or CT scan of the abdomen, ECG and cardiac evaluation. Brain CT scan and radionuclide bone scans were performed only if clinically indicated. All pretreatment imaging procedures were performed within 6 weeks of study entry. The physical examination, the assessment of toxicity, complete blood cell count (with differential count) and biochemistry profile were performed at the beginning of each cycle. Imaging studies, CEA and CA 19-9 assessment were repeated every three treatment cycles to assess objective response and, in the event of response or stable disease, 4 weeks later to confirm the response/stable disease. Toxicity was evaluated according to NCI-CTC.
Tumour response was assessed after three cycles of chemotherapy according to South Western Oncology Group criteria. Where the tumour had progressed at the time of the assessment, the treatment was deemed to have failed. The same applied where the patient was lost to follow-up or had died. Response rate, survival and toxicity were assessed for all enrolled patients on an intention-to-treat basis. The duration of complete response (CR) was defined as the time between the first documentation of the CR and the first documented observation of PD. The duration of partial response (PR) was defined as the time between the initiation of treatment and the time of PD. TTP was defined as the interval between the initiation of treatment and the occurrence of PD. Survival was measured from the initiation of treatment to the date of death or to the last follow-up assessment. Median PFS was calculated from the start of treatment to the first documented disease progression or death.
Statistical analysis
In accordance with the Simons optimal two-stage design, the study was planned to compare a response probability of 20% under the null hypothesis with a response probability of 40% under the alternative, with an alpha level of 5% and a power of 80% [16]. The study had to be stopped and the treatment judged ineffective if the number of responses was three or less in the first 13 patients, or 12 or less in the total sample of 43 subjects. Response rate, survival and toxicity were assessed for all enrolled patients on an intention-to-treat basis. The KaplanMeier method was used to analyse median survival and median PFS. Dose intensity was calculated according to Hryniuk et al. [17]. The confidence limits for the response probability actually observed were computed as described by Atkinson and Brown [18].
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Results |
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Response and survival
Response data are provided in Table 2. According to intention-to-treat analysis, we observed four CRs (9%) and 17 PRs (37%), accounting for an overall response rate of 46% [95% confidence interval (CI) 31% to 61%]. Fourteen patients (30%) had stable disease. Eleven patients (24%) had treatment failure: six (13%) progressed during treatment, two (4%) had early death and three (7%) were lost to follow-up. Median time to response was 13 weeks (range 923) and median duration of response was 21 weeks (range 11101). Median TTP was 27 weeks (range 1
116). Median overall survival was 57 weeks (range 1
130), and the 1-year survival rate was 63% (95% CI 47% to 75%).
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Discussion |
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We designed the current trial to assess the efficacy of the combination of irinotecan and raltitrexed in previously untreated metastatic colorectal cancer patients in order to identify an active combination overcoming the limitations related to the use of the 5-FU-based regimen. The use of this combination was justified by the entirely different mechanisms of action of the two drugs. Preclinical data documented that the exposure of colon carcinoma cells to the irinotecan active metabolite SN-38 24 h before exposure to raltitrexed consistently resulted in a synergistic cell kill [14]. A recent phase I study showed that this combination had manageable toxicity and was active in advanced gastrointestinal cancer [15]. As we stated in the Introduction, in our phase II trial we employed a different schedule with respect to the phase I by Ford et al. [15], in order to take advantage of the synergism observed in the preclinical studies [14]. Because of the high toxicity observed with this schedule in a preliminary experience, we decided to use a reduced dose of raltitrexed.
The main purpose of our study was to assess the efficacy of the combination in terms of overall response rate, and eventually to promote the subsequent development of the regimen in phase III trials. The patients enrolled in this study were representative of a metastatic colorectal cancer population in the first-line setting in terms of number of metastatic sites, proportion of patients (63%) with synchronous metastases and liver involvement. It is noteworthy that all of the patients had a good performance status, because patients with poor health status were assigned to a concomitant specific trial.
The high overall response rate observed (46% with 95% CI 31% to 61%) confirms the synergism between the two drugs. The response rate and the median TTP of 27 weeks (range 1116) are similar to results reported recently with the most active regimens with 5-FU/FA, and irinotecan or oxaliplatin [5, 6, 19]. However, the median overall survival of 57 weeks (range 1
130) was slightly inferior to that of the other studies. Since we could not identify any prognostic factor associated with treatment failure, we hypothesise that these data could be influenced by the limited use of salvage protocols and by the treatment duration. Indeed, in our study, patients received a maximum of nine courses of treatment, whereas in the other studies treatment was given until disease progression. Nevertheless the hypothesis that this regimen has diminished activity compared with 5-FU/FA and irinotecan or oxaliplatin combinations cannot be excluded.
The second goal of this study was to assess the toxicity profile of the combination used. As expected, gastrointestinal and haematological toxicity were the main toxicities. One must be cautious in evaluating the results of different studies, but, comparing our results with the series of irinotecan, FA and infusional 5-FU, the incidence of haematological toxicity and mucositis does seem to be lower. On the other hand, diarrhoea, nausea and vomiting, and transaminitis were somewhat higher. The prophylactic use of atropine reduced the incidence of severe cholinergic syndrome. In our study we observed two unexpected early deaths (4%), both occurring after the first cycle of chemotherapy as a result of gastrointestinal syndrome, including diarrhoea, vomiting, abdominal cramping, severe dehydration, neutropenia, fever and electrolyte imbalance.
It is worth noting that the combination of irinotecan, FA and bolus 5-FU has recently been reported to be associated with a similar high rate of early death related to gastrointestinal syndrome and ischaemic events in two clinical trials [20]. A panel of experts has suggested that an increased awareness is needed among health care providers regarding the gastrointestinal syndrome associated with irinotecan-based regimens, especially in the first few weeks of treatment when most severe treatment-related toxicities occur [21].
In conclusion, the results we achieved with irinotecan and raltitrexed show that this regimen is active, despite not-negligible toxicity, and may represent a useful regimen for specific subgroups of colorectal cancer patients, in which the use of 5-FU is contraindicated due to DPD deficiency, cardiac disease or contraindication/refusal to allow the implantation of a central venous catheter.
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Footnotes |
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References |
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