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Background: The De Gramont regimen (or high-dose LV5FU2, HD-LV5FU2) is considered a standard treatment for metastatic colorectal cancer. The aim of the study was to evaluate the efficacy and the costs of three regimens as compared to HD-LV5FU2: raltitrexed (R), LV5FU2 with a lower dose of folinic acid (LD-LV5FU2), and weekly infusional 5FU (WI-FU). Methods: An economic analysis was performed prospectively as part of a randomized trial comparing first-line chemotherapy regimens in 294 patients with unresectable metastatic colorectal cancer. The primary endpoint was event-free survival (EFS). Direct medical costs were computed from the health system viewpoint using 2001 unit costs. Results: None of the three regimens improved EFS as compared to HD-LV5FU2. R was less effective and more toxic. The mean total cost per patient was € 15,970 for HD-LV5FU2. The cost of R (€ 10,687) was lower than that of HD-LV5FU2 (p = 0.008). The cost of LD-LV5FU2 (€ 14,888) and of WI-FU (€ 13,760) was not significantly different from that of HD-LV5FU2. Conclusion: The lower efficacy and increased toxicity of R made it a clinically inferior regimen despite its easy administration and lower cost. The HD-LV5FU2 protocol remains a better treatment. LD-LV5FU2 appeared a good alternative regimen because it reduced costs without jeopardizing its efficacy. The WI-FU regimen did not show a significant difference in terms of efficacy, but suggested toxicity to be slightly increased. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

LV5FU2 with high-dose leucovorin (LV), weekly infusional 5-fluorouracil (5FU) (AIO schedule) and raltitrexed have been demonstrated to be active agents in first-line treatment of colorectal cancer. We performed a 4-arm randomised trial to compare (1) a low-dose intravenous bolus of LV (20 mg/m2), followed by an intravenous bolus of 5FU (400 mg/m2), followed by a 22-hour continuous infusion of 5FU (600 mg/m2) on day 1 and day 2/2 weeks (ldLV5FU2 arm), (2) a weekly continuous infusion of high-dose 5FU (2.6 g/m2/week) for 6 weeks followed by a rest week (HD-FU arm) and (3) raltitrexed (Tomudex® arm; 3 mg/m2/3 weeks) to standard LV5FU2. From 1997 to 2001, 294 patients were included. The 4 arms were well balanced for sex ratio, age, WHO performance status, the primary tumour site and prior adjuvant chemotherapy. Treatment was stopped due to low accrual. Two toxicity-related deaths were observed in the Tomudex arm. The treatments gave rise to different rates of grade 3–4 neutropenia (3, 4, 11 and 14% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively, p = 0.028), leucopenia and vomiting. At least one episode of grade 3–4 toxicity was observed in 27, 25, 38 and 47% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.016). An objective response was observed in 28, 21, 22 and 10% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.04). Progression-free survival (PFS) of the patients in the Tomudex arm was statistically lower compared to that of patients treated with LV5FU2 or ldLV5FU2 (combined group; p = 0.013, log rank test). In conclusion, Tomudex is more toxic and yields shorter PFS than infusional 5FU. Despite the early closure of the study and the lack of power of the comparison, it seems that ldLV5FU2 could be considered as an active, easier and less expensive option for the treatment of metastatic colorectal cancer compared to classic LV5FU2 or weekly HD-FU. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of raltitrexed (Tomudex®) on the quality of life in a multicenter, phase II study in advanced pancreatic and biliary carcinomas. Patients and Methods: Forty-six patients with advanced, histologically proven pancreatic (n = 37, 80.4%) or biliary (n = 9, 19.6%) carcinoma received 3 mg/m2 raltitrexed intravenously once every 3 weeks. For the quality of life assessments, EORTC QLQ-C30 was used, and the evaluation of the clinical benefit was performed according to the 4 criteria of the clinical benefit response. All patients were assessed for safety, and 41 patients were evaluable for objective response. Results: Patients (63% male/37% female) had a mean age of 61.2 years, 71.7% had a PS of 0–1, 78.3% had metastatic disease, and 63% had at least 2 tumoral sites. A total of 176 cycles were administered with a mean of 4 cycles per patient (range 1–12). Three out of 43 patients evaluable for EORTC QLQ-C30 (7.0%; CI95% 1.4–19.0%) had a quality of life improvement. Thirty-two patients fulfilled the 4 criteria required to evaluate the clinical benefit response; 5 were responders (15.6%; CI95% 5.3–32.8%); 1 patient was a good responder based on both the EORTC questionnaire and the clinical benefit response. Forty-one patients were assessable for response, 3 responded to treatment (response rate: 6.5 %; CI95% 1.3–17.9%). Median survival was 4.6 months (CI95% 2.9–8.2 months), the 1-year survival rate was 21.8%. The most common grade 3–4 toxicities were neutropenia (8%), leukopenia (8%), thrombopenia (6%), anemia (6%), liver enzyme elevations (11%), asthenia (9%), vomiting (9%), abdominal pain (7%), and phlebitis (6%). One treatment-related death occurred (neutropenic sepsis). Conclusion: Raltitrexed appeared to be generally well tolerated and showed a clinical benefit response and/or quality of life improvement in a limited number of patients. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: The combination of irinotecan and raltitrexed is safe and active in 5-fluorouracil-refractory, metastatic colorectal cancer (CRC), with the advantage of its convenient three-weekly schedule. The aim of this multicenter phase II study was to assess its efficacy and toxicity in first-line treatment. Methods: Between May 2000 and March 2001, 62 previously untreated patients received irinotecan (350 mg/m2) plus raltitrexed (3 mg/m2), with courses repeated every 21 days. Objective response was assessed every three courses, and treatment maintained until tumor progression or unacceptable toxicity. Results: A total of 331 cycles were administered, with a median of five cycles per patient (range, 1–16). Seventeen patients achieved a partial response and 2 a complete response, for an overall intention-to-treat response rate of 30% (95% confidence interval, 18–44%). The incidence of grade 3–4 toxicity per patient was diarrhea (27%), emesis (13%), anemia (12%), neutropenia (9%), and asthenia (7%). Three patients (5%) died from treatment-related adverse events (diarrhea plus neutropenia). The median potential follow-up is now 37 months. Median survival was 12.2 months, and median time to progression was 6.3 months. Conclusions: The combination of irinotecan plus raltitrexed is an easy comfortable schedule for patients with metastatic CRC, but both efficacy and toxicity results seem suboptimal for first-line treatment. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: This multicenter phase II study was designed to determine the activity and tolerance of gemcitabine and raltitrexed in advanced pancreatic adenocarcinoma. Patients andMethods: Thirty-three chemonaive patients with measurable disease received the TOMGEM regimen consisting of Raltitrexed 3 mg/m2 in 15 min followed by Gemcitabine 1,000 mg/m2 in 30 min on day 1, Gemcitabine alone 1,000 mg/m2 on day 8 and repeated on day 21. Results: Thirty-three patients (median age: 62; locally advanced/metastatic disease: 5/28) were enrolled; the total number of cycles administered was 173 (median: 4). There were 10 partial response (confirmed), 2 stable disease (SD) ≥24 weeks, 7 SD <24 weeks, and 14 progressive disease for a response rate of 30.3% (95% CI: 14–46%); a clinical benefit was observed in 8/30 patients assessed (30%); median duration of response was 9.1 months. National Cancer Institute Common Toxicity Criteria grade III or IV neutropenia/thrombocytopenia were observed in 42 and 12% of the patients, respectively. Relevant nonhematological toxicities (grade III–IV) were rare although one toxic death was observed. Median time to progression was 2.8 months; one-year survival was 21%; median survival was 4.7 months. Conclusion: Our data suggest that the combination of raltitrexed/gemcitabine is a very convenient regimen with an acceptable toxicity, and is active in advanced pancreatic cancer. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Cisplatin (CDDP) is among the most active single agents against squamous cell carcinoma of the head and neck (SCCHN), and it is still the reference drug in the induction chemotherapy setting, when used in combination with infusional 5-fluorouracil (5-FU). Raltitrexed has been shown to be devoid of clinical activity against SCCHN when used alone; however, both preclinical and early clinical data regarding the combination raltitrexed-CDDP hold promise. Thymidylate synthase is the target enzyme of both raltitrexed and 5-FU; however, the two drugs have distinct sites of action on the enzyme and the combination of the two agents may be synergistic. We have previously shown that the combination of raltitrexed, levofolinic acid (LFA) and 5-FU has clinical activity against SCCHN; in a subsequent phase I study, cisplatin was added, and the combination of CDDP plus raltitrexed on day 1, followed by LFA and 5-FU on day 2, was judged feasible and active, since a 67% response rate was shown across all dose levels, with a 100% response rate at the recommended dose for phase II. Methods: Patients with inoperable locally advanced or metastatic SCCHN, not pretreated with chemo- or radiotherapy were randomized to receive either CDDP 60 mg/m[sup 2] and raltitrexed 2.5 mg/m[sup 2] on day 1 and LFA 250 mg/m[sup 2] and 5-FU 900 mg/m[sup 2] on day 2 (arm A) or CDDP 65 mg/m[sup 2] and methotrexate 500 mg/m[sup 2] on day 1, and LFA 250 mg/m[sup 2] and 5-FU 800 mg/m[sup 2] on day 2 (arm B). Both treatments were repeated every 2 weeks. Evaluation for tumor response was performed after four cycles. According to Simon two-stage design, with a target complete response (CR) rate (p1) of 35%, at least 7 CR among the first 31 treated patients and 16 CR among the final sample size of 52 patients were required. Results: An interim analysis was performed when 36 patients were evaluable in each arm. In arm A, 10 CR (28%) and 19 partial responses (PR) (53%) were observed, for an overall response rate of 81%. In arm B, 3 CR (8%) and 12 PR (34%) were observed, for an overall response rate of 42%. The difference in both CR and overall response rate between the two arms was statistically significant (p = 0.03 and <0.001, respectively). Therefore, the accrual was stopped in arm B and continued only in arm A. Overall, 13 CR (21%) and 34 PR (56%) were observed among the 61 patients who were accrued in arm A, for an overall response rate of 77% (95% confidence interval 64–87%). Neutropenia was the main side effect in both arms (grade 3–4 in 45 and 23 patients in arm A and B, respectively). Extrahematologic toxicity was mild in both arms; however, 2 patients in arm B died due to toxicity (grade 4 mucositis in one case, grade 4 renal toxicity in the other). Conclusions: Although response data for our experimental treatment look encouraging, the hypothesis of a 35% activity, expressed as capability to induce a CR, cannot be accepted. The results obtained in this study are not substantially different from those of other trials of CDDP-5-FU-based regimens, and our combination is unlikely to represent a major breakthrough when used in this setting.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250–350 mg/m[sup 2] as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m[sup 2] as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3–4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m[sup 2] ) and raltitrexed (3 mg/m[sup 2] ) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to define the maximum tolerated dose (MTD) of the combination of raltitrexed plus carmofur, and to evaluate the tolerability and efficacy of this combination in metastatic colorectal cancer. Methods: Twenty-eight patients (23 receiving first-line therapy, 5 receiving second-line therapy) entered the study; 16 were chemonaive. Raltitrexed (Tomudex) 1.5–3.0 mg/m[sup 2] was given as a 15- to 30-min intravenous infusion on day 1 of a 21-day cycle followed by carmofur 300–400 mg/m[sup 2] orally 3 times daily on days 2–14. Therapy was given until disease progression or dose-limiting toxicity (DLT) occurred. Results: A total of 170 cycles of therapy were administered. The MTD was reached at the raltitrexed dose of 3.0 mg/m[sup 2] and the carmofur dose of 400 mg/m[sup 2] . DLTs included grade 3–4 diarrhea, fatigue, anorexia, mucositis, anemia, thrombocytopenia, neutropenia, neurological symptoms and febrile neutropenia. Eleven of the 22 evaluable first-line patients achieved a partial response (response rate 50%, 95% confidence interval 29–71%), 8 had stable disease and 3 had disease progression. One of the 5 patients who received second-line therapy responded. Conclusions: The recommended dose of this combination therapy for further evaluation is raltitrexed 3.0 mg/m[sup 2] plus carmofur 300 mg/m[sup 2] . This combination has unique but manageable toxicity and promising efficacy in metastatic colorectal cancer.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]