1University Hospital Gasthuisberg, Leuven, Belgium; 2Institute of Cancer Research, Royal Marsden Hospital, London, UK; 3Department of Medical Oncology, Ottawa Regional Cancer Centre, Ontario, Canada; 4Servicio de Oncologiá/Hematologiá, Valencia, Spain; 5Department of Oncology, Akademiska Sjkhuset, Uppsala, Sweden
Received 22 February 2001; revised 31 August 2001; accepted 20 September 2001.
Abstract
Raltitrexed (Tomudex) monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC), and has single-agent activity in a variety of advanced solid tumours. Although both raltitrexed and 5-FU are thymidylate synthase inhibitors, raltitrexed has a specific mode of action and a toxicity profile distinct from 5-FU. The mechanism of action of raltitrexed is also completely different from that of oxaliplatin, irinotecan and other drugs with which it has been combined. These properties, together with preclinical data, suggested that combinations of raltitrexed with 5-FU, other chemotherapeutic agents, or radiotherapy could result in improved therapies for a variety of advanced solid tumours, including advanced CRC.
This review outlines the appropriate management of patients treated with raltitrexed, whether as monotherapy or in combination, and discusses the preliminary results of combination studies with raltitrexed in a range of tumour types including advanced CRC, malignant mesothelioma, gastric, pancreatic, head and neck, and non-small-cell lung cancers. Of particular interest is the combination of raltitrexed and oxaliplatin, which has shown promising antitumour effects in first-line treatment of advanced CRC and malignant mesothelioma, a disease that is refractory to chemotherapy.
Key words: colorectal cancer, 5-fluorouracil, mesothelioma, oxaliplatin, raltitrexed
Introduction
Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase (TS). It predominantly enters the cell via the reduced folate carrier and then undergoes polyglutamation. The polyglutamated form is more potent than the parent compound. It is retained in the cell and prevents TS from binding to its folate cofactor. 5-fluorouracil (5-FU) is also an inhibitor of TS. However, it is metabolised into several active agents, including the TS inhibitor fluorodeoxyuridine monophosphate, which binds to the pyrimidine binding site of the enzyme [1]. Other 5-FU metabolites have multiple effects such as nonspecific disruption of RNA and DNA synthesis [2].
Although 5-FU has been the basis of standard treatment for advanced colorectal cancer (CRC), tumour responses are often disappointing. In addition, the optimum treatment regimen remains unclear despite extensive investigation of i.v.- and bolus-dosing schedules, and combination with a variety of modulating agents, particularly leucovorin (LV) [3]. Bolus and infusional 5-FULV regimens are still used as standard in many areas, but the current standard therapy for advanced CRC is generally a combination of 5-FULV with either oxaliplatin or irinotecan [47]. However, toxicity continues to be problematic in some 5-FU treatment schedules and alternative agents are needed for use in monotherapy and combination regimens.
Raltitrexed is an alternative to standard 5-FULV-based regimens for the first-line treatment of advanced CRC. In three out of four phase III randomised studies, median survival with raltitrexed (9.710.9 months) was comparable to that of bolus or infusional 5-FULV (10.012.7 months) [811]. Response rates with raltitrexed were equivalent to those of either bolus or infusional 5-FU-based regimens in all four studies. However, in two of the four trials the additional protocol end point, of time to progression, was significantly shorter in the group of patients receiving raltitrexed than the group treated with 5-FULV [9, 10]. The tolerability of raltitrexed has also been well defined in trials in more than 1000 patients with advanced CRC. While it has an acceptable and manageable toxicity profile if administered appropriately, like other cytotoxic agents, such as 5-FU, it is associated with systemic, gastrointestinal and haematological side effects [12]. However, there is a significantly lower incidence of both severe leucopenia and mucositis with raltitrexed compared with bolus 5-FULV regimens. Although raltitrexed is associated with a statistically significant higher incidence of severe increases in liver transaminases than bolus 5-FULV regimens, such changes are usually asymptomatic and self-limiting when not associated with disease progression. Also, reduced incidences of diarrhoea have been recorded during treatment with raltitrexed compared with 5-FU regimens [9, 10].
Combinations of raltitrexed with other active antitumour agents, with different mechanisms of action and distinct tolerability profiles, may be expected to offer improved efficacy whilst maintaining acceptable toxicity. Based on these properties, possible combinations with raltitrexed include 5-FU, irinotecan, platinum-based agents (e.g. cisplatin and oxaliplatin) and radiotherapy. This review summarises raltitrexed combination therapy studies in advanced CRC and other solid tumour types for which treatment prospects are emerging. Furthermore, recommendations are provided for the appropriate management of patients receiving raltitrexed treatment, whether as monotherapy or in combination, based on extensive clinical experience.
Safety and patient management
As expected with cytotoxic therapy, life-threatening toxicity has been reported with raltitrexed in all of the large phase III studies. Most of the treatment-related deaths (3.8% raltitrexed compared with 2.6% 5-FULV) appeared to be due to a combination of gastrointestinal toxicity (mainly diarrhoea) and myelosuppression, usually with infection or sepsis [12]. Many occurred in the absence of appropriate dose reductions as specified in the prescribing information. When patients were excluded who did not receive appropriate dose reductions or delays, or who were not treated according to the prescribing information, the incidence of treatment-related deaths was 1.3% during treatment with raltitrexed, compared with 1.7% during treatment with bolus 5-FULV [12]. Qualitatively similar events were observed in a large multicentre trial, designed to compare raltitrexed in the adjuvant setting with the standard regimen of 5-FU plus folinic acid. The trial was ended when the number of drug-related deaths in the raltitrexed group (1.9%) was double that in the control group (0.8%). However, the majority of deaths in the raltitrexed group (65%) were due to serious deviations from the trial protocol, including failure to modify the dose of raltitrexed based on creatinine clearance calculations [13].
Since renal excretion (extrapolated to infinity) accounts for 4050% of the total raltitrexed dose in patients with normal renal function [14], impaired renal function (creatinine clearance <65 ml/min) may result in plasma accumulation, leading to increased toxicity [15]. Indeed, poor toxicity outcomes have been associated with impaired renal function without appropriate dose modification. To ensure that patients receive a dose suitable for their renal status, serum creatinine measurements must be made prior to the start of treatment and before each subsequent treatment. If an abnormal serum creatinine level is detected, creatinine clearance should be calculated or measured and the raltitrexed dose modified accordingly (Table 1). In addition, serum creatinine may not correlate well with creatinine clearance, for example, if the patient is elderly or has undergone a sudden weight loss. In this case, creatinine clearance should also be calculated or measured and the dose of raltitrexed modified if appropriate.
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Raltitrexed combination studies
Advanced colorectal cancer
The recent introduction of new drugs with single-agent activity against advanced CRC but with distinct mechanisms of action has enabled the investigation of combination regimens. In two phase III studies of oxaliplatin in combination with infusional 5-FU and calcium folinate, the response rate and progression-free survival were better than with just 5-FU and calcium folinate [4, 5]. However, these studies did not show survival benefits. Another phase III study, primarily conducted in Europe, compared irinotecan combined with 5-FULV, and 5-FULV alone, as first-line therapy for metastatic CRC [6]. The results showed that progression-free survival (median 6.7 compared with 4.4 months, P <0.001) and objective response rate (35% compared with 22%, P <0.005) were significantly improved with the triple-drug therapy compared with the two-drug therapy. These results were complemented by an American phase III study, which compared the combination irinotecan5-FULV with bolus doses of 5-FULV [7]. The irinotecan5-FULV combination consistently provided significantly higher response rates (33% compared with 18%, P <0.001) and median time to treatment failure (5.0 compared with 3.8 months, P <0.05). Moreover, irinotecan 5-FULV is the only treatment to show a survival advantage in metastatic CRC over high-dose continuous infusion 5-FULV.
The results of these studies into combination chemotherapy as first-line treatment for CRC have clearly shown that it is more active than monotherapy. However, there are still opportunities for improvement and this provides the rationale for investigations into combination therapy with raltitrexed.
Raltitrexed5-FU combination
Although raltitrexed and 5-FU are both inhibitors of TS, they act via different mechanisms, occupy different binding sites and have different specificities for the enzyme. A metabolite of 5-FU, F-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), binds to the pyrimidine binding site of TS, leading to depletion of dTTP and reducing the rate of DNA synthesis.
Preclinical observations using in vitro human carcinoma cell lines consistently showed sequence-specific additive or synergistic cytotoxicity [19]. In the case of the HCT-8 cell line, raltitrexed leads to an increase of intracellular phosphoribosyl pyrophosphate (PRPD), which suggests that the cytotoxic effects of raltitrexed combined with 5-FU may be due to the increased formation of 5-FU nucleotides. This in turn leads to enhanced incorporation of 5-FU nucleotides into RNA and increased cell killing. Whether this factor is responsible for the synergistic activity in this cell line, or if this observation extends to other cell lines, is unknown. Because of their different cellular pharmacology, raltitrexed and 5-FU present several different sites for interaction that may be very complex.
A summary of phase I and II trials in which a combination of raltitrexed and 5-FU (bolus, infusion or oral fluoropyrimidines) has been used as first- or second-line therapy is given in Table 3. It was observed that the two agents can be combined almost at their respective recommended doses as single agents. Manageable tolerability and favourable response rates have resulted from such combinations. Further promising response rates have been obtained with triple combinations that include these two agents [20].
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A phase I study first demonstrated promising activity for this combination, with stable disease lasting for at least 3 months in six out of 11 heavily pretreated patients, with progressive advanced CRC before inclusion [24]. The recommended dose was determined as raltitrexed 3.0 mg/m2 with oxaliplatin 130 mg/m2, and dose-limiting toxicities (DLTs) were asthenia, nausea and vomiting. The efficacy of this combination as a first-line treatment for advanced CRC was subsequently confirmed in two phase II studies (Table 4) with objective response rates of 46% [25] and 60% [26] and disease progression in only 4% and 8% of patients, respectively (Figure 1).
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The promising phase I and preliminary phase II data with the raltitrexedoxaliplatin combination as a first-line treatment, prompted the initiation of a phase II study of this combination as a second-line therapy in patients with advanced CRC. This showed a promising activity; the reported response rate was 16% [27].
Raltitrexedirinotecan combination
Irinotecan is a DNA topoisomerase I inhibitor that inhibits cell division. It is approved as a single agent for the treatment of 5-FU-refractory CRC. Furthermore, the addition of irinotecan to 5-FULV, as first-line treatment for metastatic CRC, significantly increased median survival compared with just 5-FULV [6, 7]. In vitro studies have demonstrated synergistic cytotoxicity with a short-term exposure to SN38, the active metabolite of irinotecan, followed by raltitrexed [28]. It was observed, however, that the reverse sequence, longer exposure or co-exposure had an antagonistic effect, which led to the hypothesis that raltitrexed reduces the rate of DNA synthesis. This, in turn, reduces the rate at which the topoisomerase ISN38 cleavable complex is converted into DNA strand breaks.
A phase I study has demonstrated that the combination of raltitrexed and irinotecan has activity, with manageable toxicity, in 5-FU pretreated patients with advanced gastrointestinal cancer [29]. Of 30 evaluable patients, six (20%) had a partial response. The recommended dose was irinotecan 350 mg/m2 (30 min infusion), followed after 30 min with raltitrexed 3 mg/m2 (15 min infusion), on a 3-weekly schedule. DLTs were lethargy and diarrhoea. A further phase I study is ongoing to determine the recommended dose of a triple combination of raltitrexed, irinotecan and 5-FU (Maroun, Canada).
Raltitrexedradiotherapy combination
A number of studies have demonstrated benefits of combining preoperative or postoperative 5-FU with radiotherapy, compared with radiotherapy alone, in patients with rectal cancer [30]. Like 5-FU, raltitrexed has radiosensitising effects and has been shown in preclinical studies to be at least equivalent to 5-FU in inhibiting tumour cell survival and tumour xenograft growth in irradiation studies [31]. Therefore, a series of trials have been initiated to investigate combinations of raltitrexed with radiotherapy.
Phase I studies have defined the recommended doses of raltitrexed in combination with preoperative [32] and postoperative [33] radiotherapy, and in patients with advanced inoperable/recurrent rectal cancer [34] (Table 5). An encouraging response rate of 73% (eight of 11 patients, including three complete responses, assessed according to WHO criteria) was observed in the preoperative study. An ongoing phase II study will further evaluate this combination in the preoperative setting and two ongoing phase II trials are assessing the efficacy of raltitrexed and radiotherapy in patients with advanced in-operable or recurrent rectal cancer.
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In general, results from trials in advanced CRC have been encouraging and support the continued investigation of all the combinations investigated to date. Preliminary data also indicate that such combinations may be beneficial in patients with other solid tumours.
Malignant mesothelioma
Patients with malignant mesothelioma, a tumour of the pleura or peritoneum, have a poor prognosis, with median survival generally ranging from 4 months for extensive malignant disease to 18 months for malignant local pleural disease [36]. Malignant mesothelioma is relatively refractory to chemotherapy and, as there is no standard therapy, patients with malignant mesothelioma are routinely proposed for entry into trials assessing new drugs and combinations.
Encouraging initial results using a combination of raltitrexedoxaliplatin in patients with malignant mesothelioma prompted the enrolment of such patients, with a range of advanced solid tumours, into a phase I/II trial. Ultimately, interesting antitumour activity was observed, with six objective partial responses among 17 assessable patients (35%, 95% confidence interval 14% to 59%). These included four patients who were considered to be cisplatin-refractory as defined by disease progression (Table 6). This result supported the initiation of a phase II trial [37]. Preliminary results are again promising, with a response rate of 25% among 56 evaluable patients (Figure 2), indicating that this combination warrants further investigation in phase III studies in patients with malignant mesothelioma.
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Non-small-cell lung cancer
NSCLC is the most commonly occurring form of lung cancer. Although no standard chemotherapy regimen exists for the treatment of metastatic NSCLC, cisplatin-based combination chemotherapy is commonly used [38]. A phase I trial of raltitrexed with cisplatin in metastatic NSCLC established the maximum tolerated doses of the 3-weekly combination to be raltitrexed 3.5 mg/m2 and cisplatin 80 mg/m2, and determined that the recommended dose for further study was raltitrexed 3.0 mg/m2 and cisplatin 80 mg/m2. The toxicity was predictable and manageable, and was similar to that frequently observed with cisplatin alone or in combination. Toxicity solely related to raltitrexed included diarrhoea [39].
Advanced gastric cancer
The prognosis for patients with advanced gastric cancer is poor. However, combination chemotherapy has resulted in significant survival advantages compared with best supportive care alone. At present, many of the active regimens in advanced gastric cancer include 5-FU infusion in combination with cisplatin, and often also a third agent, such as an anthracycline. High response rates have been obtained, in particular with the use of protracted venous infusional 5-FU, cisplatin and epirubicin (ECF regimen) [40]. However, this regimen uses an indwelling central venous catheter, with significant morbidity. The option of replacing the infusional 5-FU with raltitrexed has therefore been investigated.
Promising efficacy results were obtained in the phase I dose-finding study, in patients with inoperable advanced gastro-oesophogeal cancer who received a regimen including raltitrexed, cisplatin and epirubicin (Table 6). Of 20 evaluable patients, nine (45%) responded to therapy [41], prompting a phase II study. Initial results showed a response rate of 29%. However, concerns resulting from treatment-related deaths during the trial due to neutropenic sepsis (one patient) and cardiorespiratory complications of chemotherapy-induced enteritis (one patient), and one death considered to be possibly treatment-related due to myocardial infarction, led to premature termination of this trial [42]. A phase I study has also determined the recommended doses for a combination of raltitrexed and the anthracycline doxorubicin as treatment for advanced or metastatic gastric cancer (Table 6).
Pancreatic cancer
The prognosis is extremely poor for patients with pancreatic cancer, due to difficulties in diagnosis, the aggressiveness of pancreatic cancers and the lack of effective systemic therapies. Patients with locally advanced disease and a reasonable performance status are commonly treated with 5-FU-based chemoradiotherapy. However, the limited therapeutic options and modest impact of such treatment on survival warrants the investigation of new therapies in patients with locally ad-vanced disease. A phase II trial of raltitrexed with radiotherapy is ongoing in patients with locally advanced, inoperable but non-metastatic pancreatic cancer (Price, UK).
Similarly, most studies of single-agent or combination chemotherapy in patients with advanced pancreatic cancer have resulted in low response rates and little reproducible effect on survival or quality of life. 5-FU remains the most extensively studied agent for pancreatic cancer; however, in a randomised comparison, gemcitabine treatment resulted in a significantly higher clinical benefit response (24% compared with 5%) and median survival, although this was still only 6 months [43]. Raltitrexed monotherapy also has modest activity in patients with advanced pancreatic cancer: a response rate of 5% was obtained in a phase II study. However, the majority of these patients had been pretreated [44].
A combination of raltitrexed and gemcitabine is currently being investigated in phase II trials in patients with advanced or metastatic pancreatic cancer (Sleeboom, Holland; Borner, Switzerland) and advanced pancreatic and biliary tract cancer (van Laethem, Belgium). The recommended dose for these studies was determined in a phase I study in patients with a range of tumour types in which two patients with pancreatic cancer had disease stabilisation (Table 6) [45].
Head and neck cancer
The median survival for patients with locally advanced or metastatic head and neck cancer is 6 months, a figure that has not been improved by chemotherapy. Therefore, such patients are candidates for trials of new agents and combinations [46]. The most active single agents include methotrexate, cisplatin and 5-FU. Standard treatment is a combination chemotherapy regimen, most commonly cisplatin with infusional 5-FU.
A phase I study of raltitrexed5-FU with levofolinic acid (LFA) has demonstrated an encouraging response rate (35%) in patients with locally advanced or metastatic head and neck cancer [47]. However, rather than continue with this regimen in phase II studies, the investigators decided to add cisplatin, the most active single-agent in head and neck cancer, to the combination. The ensuing phase I/II study demonstrated that it is possible to combine cisplatin, raltitrexed and 5-FU at doses close to their single-agent doses with an encouraging response rate (67%) in patients receiving first-line therapy for the treatment of locally advanced or metastatic squamous cell carcinoma of the head and neck. Furthermore, all of the 15 patients treated at the recommended dose achieved an objective response. A randomised phase II trial comparing cisplatinraltitrexed5-FULFA with cisplatinmethotrexate5-FULFA is ongoing. A phase I/II trial has also defined the recommended dose for the combination of raltitrexed and cisplatin [48].
Summary and future perspectives
Raltitrexed is established in the first-line treatment of advanced CRC. It has a convenient administration schedule, and an acceptable and manageable toxicity if given appropriately. However, as with other cytotoxic agents, careful management of patients is required to avoid serious toxicity. Combinations of raltitrexed with a broad range of cytotoxic agents have been shown to be feasible in colorectal, lung, gastric, and head and neck cancers. Schedules have been established for combination with 5-FU, oxaliplatin, irinotecan, cisplatin, doxorubicin, gemcitabine and radiotherapy. Promising results have been obtained with combination chemotherapy in patients with advanced CRC (with first-line response rates ranging from 39 to 60%) and other advanced solid tumours, especially malignant mesothelioma. Ongoing studies should further establish a role for raltitrexed as a component of combination therapies in a variety of advanced solid tumours.
Acknowledgements
Tomudex is a trade mark of the AstraZeneca group of companies.
Footnotes
+ Correspondence to: Dr E. Van Cutsem, Department of Internal Medicine, University Hospital Gasthuisberg, 3000 Leuven, Belgium. Tel: +32-16-344-218; Fax: +32-16-344-419; E-mail: eric.vancutsem@uz.kuleuven.ac.be
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