Multicenter phase II trial evaluating a three-weekly schedule of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer

J. Aparicio1,+, J. M. Vicent2, I. Maestu3, S. Garcerá4, I. Busquier5, C. Bosch6, C. Llorca7, R. Díaz1, C. Fernández-Martos8 and A. Galán9

1 Medical Oncology, Hospital Universitario La Fe; 2 Medical Oncology, Hospital General Universitario, Valencia; 3 Medical Oncology, Hospital Virgen de los Lirios, Alcoy; 4 Medical Oncology, Hospital La Ribera, Alzira; 5 Medical Oncology, Hospital Provincial, Castellón; 6 Medical Oncology, Hospital Doctor Peset, Valencia; 7 Medical Oncology, Hospital General, Elda; 8 Medical Oncology, Instituto Valenciano de Oncología; 9 Hospital de Sagunto, Valencia, Spain

Received 13 November 2002; revised 16 January 2003; accepted 19 February 2003


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Irinotecan (CPT-11) and raltitrexed are active against advanced colorectal cancer (ACC), act through different mechanisms, and have only partially overlapping toxicity profiles. Phase I studies have shown that single-agent full doses of both drugs can be safely combined. The aim of this multicenter study was to assess the efficacy and toxicity of the combination in patients with 5-fluorouracil (5-FU)-refractory ACC.

Patients and methods:

Between October 1999 and December 2000, 52 patients (31 males, 21 females) with a median age of 62 years (range 39–75) were included and received CPT-11 (350 mg/m2 as a 60-min infusion) plus raltitrexed (3 mg/m2 as a 15-min infusion, 1 h after CPT-11), with courses repeated every 21 days. Objective response was assessed after every three courses, and treatment maintained until tumor progression or unacceptable toxicity.

Results:

A total of 313 cycles were administered, with a median of six cycles per patient (range 1–14). Seven patients (13.5%) achieved a partial response and one a complete response (1.9%), for an overall intention-to-treat response rate of 15.4% (95% confidence interval 6.1% to 27.2%). The incidence of grade 3/4 toxicity was 23.1% for diarrhea, 21.2% for asthenia, 17.3% for neutropenia, 13.4% for emesis and 7.7% for infection. There were no treatment-related deaths. With a median follow-up of 20 months, median survival was 11.9 months and median time to progression was 4.6 months.

Conclusions:

CPT-11 plus raltitrexed is active in patients with 5-FU-refractory ACC, at the expense of moderate toxicity.

Key words: irinotecan, metastatic colorectal cancer, phase II, raltitrexed, second line


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Irinotecan (CPT-11) is a semi-synthetic camptothecin derivative that acts as a DNA topoisomerase I inhibitor. In phase II trials, it has shown a consistent activity in patients with both chemonaïve and 5-fluorouracil (5-FU)-pretreated advanced colorectal cancer (ACC) (30% and 13% partial responses, respectively) [14]. The most frequent toxic effects are diarrhea, neutropenia and cholinergic syndrome. After the publication of the results of two large randomized trials [5, 6], CPT-11 monotherapy became the treatment of choice for patients with 5-FU-refractory disease. More recently, it has been demonstrated that the addition of CPT-11 to either bolus or infusional 5-FU-based first-line palliative chemotherapy improves both response rate and survival in ACC [7, 8].

Raltitrexed is a quinazoline folate-based specific thymidylate synthase inhibitor that has undergone extensive clinical evaluation in patients with untreated ACC [9, 10]. Its clinical activity in this setting is similar to that of modulated bolus 5-FU regimens (response rate of 20–25%), but with a better toxicity profile (mainly asthenia and increased serum transaminase levels) and patient convenience (single infusion every 21 days). In contrast, infused 5-FU regimens appear more active and less toxic than both bolus 5-FU regimens and raltitrexed. There seems to be, at most, incomplete cross-resistance between 5-FU and raltitrexed.

CPT-11 and raltitrexed have only partially overlapping toxicity profiles and different modes of action. Both drugs are active as single agents and may be given as a short 3-weekly infusion, thus obviating complex schedules or the need for implantable venous access devices. Preclinical studies have demonstrated a pronounced sequence-dependent synergy between SN-38 (the active metabolite of CPT-11) and raltitrexed [11]. Three recent phase I studies have shown that single-agent full-dose CPT-11 and raltitrexed can be safely given in patients with ACC [1214]. All these considerations prompted us to conduct a multicenter phase II trial.

The aims of this study were to assess the efficacy of this combination in patients with 5-FU-refractory ACC, and to evaluate treatment-related toxicity in this setting. The primary end points were the analysis of tumor response and toxicity. Secondary end points were time to disease progression and overall survival.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Inclusion criteria for this study were: histological confirmation of ACC, not amenable to surgical resection (i.e. metastatectomy); disease progression while on first-line palliative 5-FU-based chemotherapy or relapse within 6 months after adjuvant 5-FU-based chemotherapy (prior oxaliplatin was allowed); WHO performance status 0–2 and life expectancy of at least 3 months; age 18–75 years; satisfactory renal, hepatic and bone marrow function; wash-out time of 4 weeks after the last chemotherapy infusion; and written informed consent.

Exclusion criteria were: more than two prior chemotherapy schedules (including one adjuvant and one palliative); prior exposure to CPT-11 or raltitrexed; chronic enteropathy on unresolved bowel obstruction; pregnancy; previous malignant disease other than carcinoma in situ of the cervix or basal cell carcinoma of the skin; cerebral metastases or leptomeningeal carcinomatosis; and severe or uncompensated concomitant medical conditions.

Pretreatment patient evaluation included clinical history and physical examination, full blood count, renal and liver function tests, serum carcinoembryonic antigen and CA 19-9 levels, ECG and computed tomography (CT) scan of the thorax, abdomen and pelvis. CPT-11 350 mg/m2 was administered as a 60-min infusion followed 1 h later by raltitrexed 3 mg/m2 administered as a 15-min infusion, both in a 3-weekly schedule. Atropine prophylaxis and antiemetics (dexamethasone plus antiserotoninergic) were routinely prescribed. Chemotherapy was maintained until tumor progression or unacceptable toxicity.

Patients were assessed before each cycle for medical history, blood cell counts and serum creatinine. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria [15]. Delayed-onset diarrhea was managed with the conventional high-dose loperamide schedule [16]. Patients with severe or refractory diarrhea, or with diarrhea and concomitant fever or dehydration, and those with febrile neutropenia, were hospitalized for parenteral therapy. Treatment was delayed up to a maximum of 2 weeks if hematological recovery was not complete (absolute neutrophil count >1.5 x 109/l and platelet count >100 x 109/l) on day 21. Doses of CPT-11 were reduced by 25% in case of grade 3/4 neutropenia, thrombocytopenia, diarrhea or mucositis; if any of these toxicities recurred thereafter, raltitrexed was reduced by 25% (except for diarrhea, in which case CPT-11 was further reduced by 50%). If an abnormal serum creatinine level was detected, creatinine clearance was calculated and the raltitrexed dose modified accordingly, as it appears in the drug prescribing information.

The protocol was approved by the investigator’s hospital ethics committee. A two-staged Simon accrual optimal design was adopted. The minimum target activity level was 10%, and early discontinuation was planned in the case of no response in the first 21 patients. Alternatively, a sample size of 50 evaluable patients was chosen for an expected maximum of 25% response rate, with alpha and beta errors of 0.10. Responses were evaluated every three courses with standard WHO criteria [17] by means of CT scans. Ninety-five per cent confidence intervals (CIs) were calculated for response rates. Relative dose intensity (per cent of intended dose in mg/m2/week) was calculated for each patient. Kaplan–Meier actuarial survival estimates were performed for overall survival and time to progression [18].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between October 1999 and December 2000, 52 patients were enrolled in this study. Their main clinical features are summarized in Table 1. All patients had been previously treated with (and shown refractory to) 5-FU-based chemotherapy. The most commonly used regimens were 5-FU plus low-dose leucovorin (Mayo scheme; 14 patients in the adjuvant setting, 21 in first-line palliative chemotherapy), 5-FU plus levamisole (Moertel’s schedule; two cases in the adjuvant setting), tegafur/uracil (UFT) plus leucovorin (adjuvant, one case; palliative, five cases), continuous-infusion 5-FU (two patients in the adjuvant setting, three as palliative treatment), and the combination of UFT, leucovorin and oxaliplatin (palliative, eight cases). Eight patients had been previously irradiated (pelvic fields).


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Table 1. Patient characteristics
 
Overall, 313 treatment courses of raltitrexed plus CPT-11 were delivered (median six per patient; range 1–14). Ten patients (19.2%) needed dose reductions (six due to diarrhea, two due to myelotoxicity and two due to both toxicities). Twenty cycles (6.4%) were delayed due to persistent toxicity (11 cases) and administrative causes (nine cases). Median overall relative dose-intensity delivered was 0.962 for CPT-11 and 0.963 for raltitrexed.

Table 2 shows the distribution of main adverse effects of treatment according to the number of patients and cycles delivered. Myelotoxicity was mild and generally uncomplicated. Eighty-two episodes of delayed diarrhea (26.2% of cycles) were seen in 38 patients (73.1%), but only 31 of them (9.9% of cycles) required specific therapy with high-dose loperamide (n = 21), plus oral quinolones (n = 10) and hospital admission (n = 8). Other reported toxicities included one case each of dizziness, skin rash, dyspnea and auricular dysrhythmia. No treatment-related deaths were noted.


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Table 2. Treatment toxicity (expressed as percentage of 52 patients/percentage of 313 cycles)
 
Response was assessed in 48 patients with measurable disease who received at least two treatment cycles. One complete response (2.1%) and seven partial responses (14.6%) were observed, for an overall response rate of 16.7%. Furthermore, 24 patients (50%) showed stabilization of their previous progressive disease, while 16 (33.3%) did not respond at all. In the intention-to-treat analysis, eight of 52 patients were deemed responders, and thus actual antitumor efficacy was 15.4% (95% CI 6.1% to 27.2%). Responses among patients pretreated with oxaliplatin were seen in one of eight cases (12.5%). At September 2002, all patients have progressed and 44 (84.6%) have died. With a median follow-up of 20 months (range 5–28 months), median time to disease progression was 4.6 months and median overall survival was 11.9 months (Figures 1 and 2).



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Figure 1. Overall survival curve (n = 52).

 


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Figure 2. Time to disease progression curve (n = 52).

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Colorectal cancer is one of the leading causes of cancer death in the Western world. The main form of treatment is surgical resection, but nearly two-thirds of patients will have metastatic disease in the course of the disease and thus are candidates for chemotherapy. These patients share a poor prognosis and, with the exception of cases in which a complete surgical resection of liver metastases is possible, are incurable today. However, systemic chemotherapy has been shown to improve both survival and quality of life in comparison with best supportive care [19]. Modern chemotherapy schedules are based on combinations of 5-FU (by bolus injection or as a continuous infusion) with either CPT-11, oxaliplatin or both. These first-line regimens offer a response rate of ~50% and median survival times exceeding 15 months [7, 8, 20]. In second-line treatment, the benefit of chemotherapy is more limited, but significantly improved over best supportive care [5, 6]. However, almost only CPT-11 monotherapy has been properly explored in this context. Thus CPT-11 has an established role in the treatment of ACC, in both the first- and second-line [21, 22].

There are several limitations of the use of 5-FU-based regimens. The infusional administration requires the use of a central venous catheter system and infusion pump, while the bolus schedule requires frequent hospital visits. Moreover, these combinations are not devoid of clinically significant toxicity. Besides, 5-FU should be used with caution in patients with concomitant ischemic heart disease, and is contraindicated in cases of deficiency of dihydropyrimidine dehydrogenase (DPD), a pharmacogenetic syndrome associated with life-threatening toxicity due to fluoropyrimidines and an estimated prevalence of 3% in the general population. The development of potentially less-toxic schedules of administration, alternative combinations and markers that may identify suitable candidates for each therapy is therefore of interest.

Raltitrexed is a comfortable alternative to 5-FU whose convenient schedule seems attractive for combinations [23, 24] and for elderly patients [25]. It is also indicated in patients with ischemic heart disease and 5-FU intolerance. The combination of CPT-11 and raltitrexed is feasible, with asthenia and diarrhea as the dose-limiting toxicities [1214]. The recommended doses for phase II trials were CPT-11 350 mg/m2 and raltitrexed 3 mg/m2, with minor schedule variations (both drugs given either on the same day or on two consecutive days). Objective responses were seen in 20% of 30 patients [12] and 17% of 12 patients [14] with pretreated ACC in phase I studies. The present paper shows a 15.4% (by intention-to-treat analysis) response rate in a formally planned phase II trial for 5-FU-refractory ACC. In an indirect comparison with data from phase II and III trials of second-line CPT-11 monotherapy, a moderate improvement in response rate, median time to progression and median survival is suggested with the addition of raltitrexed [16, 21, 22]. Moreover, this schedule is convenient for patients, thus obviating complex infusion programs or the need for implantable venous access devices. Severe toxicities (mainly asthenia and diarrhea) appear more frequent than with single-agent CPT, but seem tolerable. In fact, side-effects of chemotherapy did not limit long-term administration to patients who were benefiting from therapy. Furthermore, in our experience, the activity of the combination does not significantly decrease with prior exposure to oxaliplatin. Given the demonstrated synergism between modulated 5-FU and oxaliplatin [20] and its increasing use in both first-line and adjuvant treatment, we now have at our disposal two active combinations, with theoretically no cross-resistance, which can be employed either alternating or sequentially for ACC patients. A recent paper has shown a response rate of 46% with this combination (using reduced doses of raltitrexed) in first-line therapy at the expense of ‘not-negligible’ toxicity [26].

Infused 5-FU regimens have been shown to have better toxicity profiles and provide improved response rate and quality of life in single-agent comparisons against bolus 5-FU [27] and raltitrexed [28]. Moreover, the newer oral fluoropyrimidines (mainly capecitabine) compared favorably with the Mayo Clinic regimen in terms of efficacy and safety profile, and are currently undergoing evaluation in combination therapy [29]. Thus, phase III trials of CPT-11 plus raltitrexed versus the more standard CPT-11 plus infused 5-FU-based combinations (such as FOLFIRI) or the new CPT-11 plus capecitabine schedules are needed to compare efficacy, safety, quality of life aspects and economic costs in both first- and second-line treatment of ACC. Meanwhile, this novel schedule can be useful for specific groups of patients such as those with DPD deficiency, ischemic heart disease, contraindications or refusal to central catheter implantation, previous treatment with oxaliplatin plus fluoropyrimidines, or when the need for convenient scheduling is a factor.


    Acknowledgements
 
This study was supported in part by a grant from Prasfarma, SA, Barcelona, Spain. Preliminary results were presented at the 25th European Society for Medical Oncology Congress, Hamburg, 13–17 October 2000.


    Footnotes
 
+ Correspondence to: Dr J. Aparicio, Servicio de Oncología Médica, Hospital Universitario La Fe, Avda. Campanar 21, E-46009 Valencia, Spain. Tel: +34-6-197-3138; Fax: +34-6-197-3138; E-mail: aparicio_josurt{at}gva.es Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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