levoleucovorin and raltitrexed

To evaluate the efficiency and safety profile of raltitrexed-based chemotherapy in the treatment of advanced colorectal cancer.. An electronic search was undertaken to identify randomized controlled trials comparing raltitrexed-based regimen to 5-fluorouracil-based regimen in patients with advanced colorectal cancer. The outcomes included overall survival, overall response rate and toxicities.. This meta-analysis included 11 studies with 4622 patients. Overall, there were no significant differences between the two regimens in terms of overall survival (HR=1.06, 95% CI: 0.96-1.17, P=0.23) or overall response rate (RR=1.09, 95% CI: 0.86-1.38, P=0.47). In subgroup analysis, patients in raltitrexed/oxaliplatin group had significantly higher partial response (RR=1.53, 95% CI: 1.17-2.00, P=0.002), overall response rate (RR=1.42, 95% CI: 1.10-1.82, P=0.006), disease control rate (RR=1.16, 95% CI: 1.04-1.29, P=0.009) and lower progressive disease (RR=0.61, 95% CI: 0.45-0.84, P=0.002) when compared to 5-fluorouracil/leucovorin/oxaliplatin group. Occurrence of severe anemia (RR=2.23, 95% CI: 1.38-3.59, P=0.0001), asthenia (RR=2.29, 95% CI: 1.36-3.84, P=0.002), hepatic disorders (RR=7.51, 95% CI: 1.30-43.56, P=0.02), and nausea/vomit (RR=1.70, 95% CI: 1.03-2.81, P=0.04) were significantly higher with the raltitrexed arm treatment, while frequencies of grade 3/4 alopecia (RR=0.36, 95% CI: 0.26-0.50, P<0.00001) and stomatitis/mucositis (RR=0.14, 95% CI: 0.07-0.31, P<0.00001) were increased in the 5-fluorouracil group.. Raltitrexed-based chemotherapy regimen leads to an equivalent overall survival and response rates with acceptable toxicities compared to traditional 5-fluorouracil-based regimen in patients with advanced colorectal cancer. Raltitrexed can be a treatment option for these patients when 5-fluorouracil-based regimens are not tolerated or inappropriate.

Topics: Alopecia; Anemia; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mucositis; Nausea; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Randomized Controlled Trials as Topic; Stomatitis; Thiophenes; Vomiting

In 2002, the UK National Institute for Clinical Excellence (NICE) issued guidance on the use of irinotecan, oxaliplatin and raltitrexed in advanced colorectal cancer. This guidance recommended that UK patients with advanced colorectal cancer (CRC) receive 5-FU+folinic acid [leucovorin] as first line therapy, and were only eligible for irinotecan if their disease progressed. NICE guidance is adopted worldwide by more than 25 countries in addition to the British National Health Service. This guidance specifically recommended that, 'oxaliplatin could be used in first line treatment if in the opinion of an experienced liver surgeon, a patient might become potentially resectable'. Since 2002, the definition of hepatic resectability with curative intent for these patients has changed radically to encompass any patient in whom a 70% liver resection will achieve total macroscopic removal of all liver disease. Furthermore, compelling evidence has emerged over the last 2 years, which clearly demonstrates the therapeutic superiority of oxaliplatin and irinotecan based regimens over 5FU and leucovorin in the treatment of patients with advanced colorectal cancer. The original guidance was not due for review until 2007, presently NICE are reviewing this guidance prematurely, and new guidance will be issued by the summer of 2005, and clearly this review will have an impact in many countries. This paper summarises the present evidence for the use of these regimens. Most importantly, it is now a prerequisite for liver surgeons to work hand in hand with medical oncologists to obtain maximum survival benefit and increased chance of cure for these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Practice Guidelines as Topic; Quinazolines; Thiophenes; United Kingdom

The aim of this study is to perform a review of the literature on economic (or medico-economic) studies in the area of chemotherapy for colorectal cancer. French and international literature has been reviewed on this topic. Colorectal cancer represents a major public health problem due to high mortality, prevalence and costs. Up to now chemotherapy can be used at the adjuvant stage or at the palliative one. This work provides a synthesis of the main results of economic publications devoted to adjuvant and palliative chemotherapies, as well as a reflection on the limits frequently associated with such studies.

Topics: Antineoplastic Agents; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; France; Humans; Irinotecan; Leucovorin; Levamisole; Palliative Care; Quality-Adjusted Life Years; Quinazolines; Thiophenes

Metastatic colorectal cancer has a poor prognosis, and the majority of patients are left with palliative measures. The development seen using palliative chemotherapy is reviewed.. A systematic approach to the literature-based evidence was aimed at.. The continuous improvements during the past 13-15 years have been documented in several large conclusive trials. At the end of the 1980s, the evidence that chemotherapy should be used at all was very limited, whereas presently most patients can be offered two lines of chemotherapy based upon good scientific evidence. Median survival has gradually improved from below 6 months to above 18 months in some recent trials. Several important issues remain to be solved, such as the best sequence of treatments, what regimens to use in various situations, when to start and when to stop if a response is seen, and whether cure may be possible in a small subset of patients.. Progress has been rapid in advanced colorectal cancer. This is likely a result of well-designed trials in collaboration between academy and industry, showing a great interest in the disease. Future collaborations may hopefully introduce new treatment concepts, further improving outcome.

Topics: Antimetabolites, Antineoplastic; Camptothecin; Colorectal Neoplasms; Disease Progression; Enzyme Inhibitors; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Palliative Care; Quinazolines; Survival Analysis; Tegafur; Thiophenes; Thymidylate Synthase; Topoisomerase I Inhibitors; Treatment Outcome; Uracil

Colorectal Cancer (CRC) is the most frequent digestive cancer in France and a major public health problem. The benefits of adjuvant chemotherapy after curative resection of Stage III CRC has been clearly demonstrated. For metastatic CRC, palliative chemotherapy allows an improvement in survival duration and quality of life compared with symptomatic treatment. 5-FU/Leucovorin chemotherapy (Mayo Clinic protocol and LV5FU2) is the standard adjuvant therapy. The addition of irinotecan (FOLFIRI) or oxyplatin (FOLFOX) to this regimen may improve response in palliative situations. These two regimens have shown their superiority to 5FU/Leucovorin in both tumor response and survival. A good objective response to palliative chemotherapy may allow for a secondary resection of hepatic metastases as part of a multidisciplinary approach. Current studies aim to define: 1) optimal treatment strategies (which drug protocols? in what order?) as they apply to tumor spread, drug toxicity profiles, the general state of the patient, and the desired therapeutic effect; 2) evaluation of new drugs and novel therapeutic approaches. Despite notable progress, the prognosis still remains grim with a survival of only 40% at 5 years. Any improvement in results will require not only an improvement in chemotherapy but also an improvement in methods of early diagnosis (systematic mass screening) which would permit the diagnosis of CRC at earlier stages where curative resection is feasible.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Prognosis; Quality of Life; Quinazolines; Randomized Controlled Trials as Topic; Thiophenes; Time Factors

Phase I/II studies suggest that the combination of irinotecan with capecitabine is feasible and has promising activity. Diarrhea and neutropenia are dose limiting. Overall response rates (RRs) in the 40% to 60% range are seen from preliminary data. Work in progress is assessing the combination of irinotecan with UFT/leucovorin (LV). The use of irinotecan together with raltitrexed is also being investigated, as is its combination with oxaliplatin. Two phase II studies of irinotecan plus oxaliplatin in second-line patients report median survivals of 11-12 months. It seems possible to safely escalate the dose of single-agent irinotecan to 500 mg/m(2) in patients showing good tolerance of the drug. Irinotecan can be used in combination with LV5FU2 at doses up to 260 mg/m(2), especially if only one bolus of 5-fluorouracil (5-FU) is given. Control of tumor growth is achieved in 90% of patients. Preliminary data suggest that regimens based on 5-FU/LV and irinotecan can safely be combined with the anti-epidermal growth factor receptor (EGFR) antibody cetuximab. In patients with EGFR-positive tumors, this may prove an effective means of increasing response rate or combating treatment resistance. Following evidence that COX-2 inhibition can slow progression in familial adenomatous polyposis, celecoxib is to be studied in metastatic colorectal cancer (CRC). In vitro, the cyclin-dependent kinase inhibitor flavopiridol enhances the induction of apoptosis by chemotherapy. Clinically, it can safely be administered with irinotecan, and studies in CRC are planned.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; Cyclooxygenase 2; Deoxycytidine; Drug Administration Schedule; Enzyme Inhibitors; Flavonoids; Fluorouracil; Humans; Immunologic Factors; Irinotecan; Isoenzymes; Leucovorin; Membrane Proteins; Organoplatinum Compounds; Oxaliplatin; Piperidines; Prostaglandin-Endoperoxide Synthases; Quinazolines; Thiophenes; Treatment Outcome

THE SITUATION: With around 35.000 new cases per year and a 40% mortality rate, colorectal cancer is a real problem of health care in France. Chemotherapy for metastatic disease has completely changed during the ten last years with the emergence of promising new drugs such as oxaliplatin and irinotecan. Oral 5-FU prodrugs have also shown an interesting efficacy in this setting.. Showed increased response rate, progression free survival with both drugs, and overall survival, only with the irinotecan-based regimen. Moreover, after aggressive first-line chemotherapy, some patients can undergo surgical resection of the metastases, initially considered as unresectable. We still do not know if these aggressive first-line therapies should be proposed to all metastatic patients or only to a selected subgroup. The best strategies remain to be evaluated.. Of colorectal cancer, a 6-month 5-FU/folinic acid postoperative chemotherapy is actually the standard for the management of patients with positive lymph nodes (stage III). In stage II patients the benefit of such treatment remains controversial. The benefit of using oxaliplatin or irinotecan in association with 5-FU/folinic acid as adjuvant therapy is under investigation.. In this 21st century, chemotherapy has a major place in the therapeutic management of colorectal cancer patients.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Combined Modality Therapy; Deoxycytidine; Drug Therapy, Combination; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Postoperative Care; Prodrugs; Quinazolines; Randomized Controlled Trials as Topic; Thiophenes; Time Factors

In colorectal cancer, leucovorin-modulated 5-fluorouracil (5-FU) has been the mainstay of both adjuvant treatment and treatment of metastatic disease for many years. In advanced disease, response rates of 10-43% are reported; efforts to improve efficacy through schedule modification, including prolonged infusions, have led to limited success. New agents with improved efficacy, tolerability and ease of administration are required. Among the newer drugs, irinotecan and oxaliplatin are becoming established as first- and second-line treatment for advanced disease. Their novel mechanisms of action have proven to be of value in 5-FU-resistant patients. In tandem with these developments, thymidylate synthase inhibition has remained an important objective and oral fluoropyrimidines such as capecitabine and UFT (uracil plus tegafur)/leucovorin have been developed with this goal in mind. Two large, phase III studies of capecitabine in metastatic disease demonstrated objective response rates of 26.6 and 24.8%. UFT/leucovorin has also been evaluated in phase III trials, with an 11.7% response rate reported. Both agents are being evaluated in combination with oxaliplatin and irinotecan, and ultimately oral fluoropyrimidines as monotherapy or combination therapy may replace intravenous (i.v.) 5-FU as first-line treatment for metastatic colorectal cancer.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Pyrimidines; Quinazolines; Tegafur; Thiophenes; Uracil

Preclinical evidence of a schedule-dependent synergism between raltitrexed and 5-fluorouracil (5-FU) has prompted clinical studies of this combination. We review the main preclinical and clinical results of raltitrexed/5-FU-based combination chemotherapy regimens in anticancer therapy. Promising results include: response rates of 25 and 23% with combinations of raltitrexed/5-FU/levofolinic acid (LFA) as first-line treatment and oxaliplatin/raltitrexed/5-FU/LFA as second-line treatment of metastatic colorectal cancer, respectively; and a 67% response rate in a phase I study of cisplatin/raltitrexed/5-FU/LFA as first-line treatment of advanced head and neck cancer, including a 100% response rate at the recommended dose. These combinations were well tolerated, with neutropenia as the main dose-limiting toxicity, allowing the drugs to be combined at the doses used in monotherapy. These results suggest a role for raltitrexed within combination regimens in colorectal cancer therapy, as well as other tumors such as head and neck cancer. A further potential application of raltitrexed in combination therapies is within multidisciplinary chemo-radiotherapy strategies, mainly in rectal cancer. Phase II studies are planned/ongoing to investigate these interesting possibilities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Rectal Neoplasms; Thiophenes

Chemotherapeutic options in the treatment of advanced colorectal cancer have markedly improved during the last years. This is partly due to the high-dose 5-FU regimen, but also to the development of new cytotoxic agents and drug combinations.. High-dose 5-FU, irinotecan, and oxaliplatin seem to be superior to low-dose 5-FU in terms of response rate and disease control. Combination of irinotecan with 5-FU/FA showed significant longer overall survival rates compared to 5-FU/FA alone in both published phase III trials. Today most patients are treated by a sequential therapeutic concept using the newer drugs mainly for second or third line therapy. However, there are reasons for the use of more intensive chemotherapy combinations in first line treatment. Combination of oxaliplatin with 5-FU/FA, that failed improvement of overall survival compared to 5-FU/FA alone, could downstage previously unresectable liver metastases for potentially curative surgery in some patients. Oral fluoropyrimidines mark another progress in the treatment of advanced colorectal cancer. They seem to be comparable to low-dose 5-FU/FA and could ease chemotherapy.. Prospective randomized phase III trials must confirm the best chemotherapy and the best strategy for the different subgroup of patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Carcinoma; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Tegafur; Thiophenes; Uracil

Oxaliplatin (Eloxatin) is a novel antineoplastic platinum derivative that may exert its cytotoxic effects by blocking DNA replication/transcription, thus resulting in cell death in proliferating cells, as well as apoptosis. Oxaliplatin is often more potent than other platinums such as cisplatin (Platinol) in vitro, and shows greater efficacy in preclinical studies against many tumor cell lines, including some that are resistant to cisplatin and carboplatin (Paraplatin). Oxaliplatin is approved for use with the fluoropyrimidines in the treatment of metastatic colorectal cancer in Asia, Latin America, and Europe. In light of the broad efficacy of oxaliplatin in several solid tumors and the encouraging preclinical data on combination therapy with novel agents (e.g., thymidylate synthase inhibitors, epidermal growth factor-receptor antagonists, microtubule interactive agents), this article will review the published literature on novel combinations that have been tested in the laboratory and/or the clinic.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Randomized Controlled Trials as Topic; Thiophenes

Since the publication of the results of phase I dose-finding studies, an extensive phase II and III clinical study programme has been undertaken to study the clinical efficacy and tolerability of the quinazoline folate analogue raltitrexed ('Tomudex'), a novel direct and specific inhibitor of thymidylate synthase. Two international phase III trials, studies 3 and 12, have compared raltitrexed 3 mg m(-2) with 5-fluorouracil (5-FU) plus low-dose leucovorin (LV) (Mayo regimen) or high-dose LV (Machover regimen) respectively. A North American study (study 10) was originally set up to compare two raltitrexed dosage arms (3.0 and 4.0 mg m[-2]) with 5-FU and low-dose LV, but the 4.0 mg m(-2) arm was discontinued prematurely because of excessive toxicity. Minimum follow-up times for studies 3, 10 and 12 were 15.5, 12 and 9 months, respectively (for data other than survival), with corresponding survival follow-up times of 26, 12 and 17 months. Objective response rates were similar for raltitrexed and 5-FU + LV, and palliative improvements were seen to a similar extent with both treatments in all phase III studies. Survival was statistically similar for raltitrexed and 5-FU + LV in both studies 3 and 12. Raltitrexed was, however, associated with inferior survival to 5-FU + low-dose LV in study 10, but there appears to be evidence that this was linked to an unconscious effect on investigator behaviour of early toxicity problems in this trial, in that patients appeared to be withdrawn from raltitrexed treatment without progression or protocolled toxicity. Moreover, it appeared that 5-FU + LV patients were continued on treatment after disease progression. 5-FU-based therapy was associated with a higher incidence of mucositis than raltitrexed in all studies, with the attainment of statistical significance in studies 3 and 12. Elevations in hepatic transaminase levels were seen with raltitrexed, but these are thought to be of no clinical significance. Overall, much greater levels of toxicity were seen with 5-FU + LV than with raltitrexed in early treatment cycles. In addition, retrospective UK audit data have shown the monthly cost of raltitrexed therapy to be similar to that of Mayo and continuous infusion 5-FU regimens, and appreciably lower than that of the de Gramont regimen of 5-FU (bolus + 22-h infusion) + high-dose LV. Thus, raltitrexed is an effective alternative to 5-FU-based therapy in patients with advanced colorectal cancer, with an acceptable and, unlike 5-

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Enzyme Inhibitors; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Quinazolines; Thiophenes; Thymidylate Synthase

Since its introduction in 1953, 5-fluorouracil based chemotherapy remained the standard treatment in advanced colorectal cancer. Continuous infusion or biochemical modulation by folinic acid enhanced the therapeutic efficacy of this agent. Quality of life is limited by the toxicity of these regimens as well as by the frequent visits to the hospital during each cycle. Raltitrexed, a thymidylate synthase inhibitor, offers similar antitumoral activity together with a tolerability in comparison to standard 5-fluorouracil based chemotherapy and its simple dosage schedule also contributes to better quality of life. New chemotherapeutic agents are currently in development for the treatment of patients refractory to 5-fluorouracil. Irinotecan and oxaliplatin demonstrate promising activity.

Topics: Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Colonic Neoplasms; Enzyme Inhibitors; Fluorouracil; Hospitalization; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Quality of Life; Quinazolines; Rectal Neoplasms; Thiophenes; Thymidylate Synthase; Topoisomerase I Inhibitors

Topics: Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Quinazolines; Thiophenes; Thymidylate Synthase

Since the late 1950s, 5-fluorouracil (5-FU) has remained the most effective chemotherapeutic agent in the treatment of advanced colorectal cancer, although response rates to 5-FU monotherapy are typically no more than 15%. However, efforts at improving the response to this agent have involved its administration with biochemical-modulating agents and in protracted infusion schedules. The combination of 5-FU with folinic acid has evinced the most promising results, with an approximate twofold increase in response rate compared with monotherapy (23% versus 11%). Preliminary evidence also suggests further benefits when this regimen is administered by continuous infusion. These results support the current clinical practice of using 5-FU plus folinic acid as first-line therapy in advanced colorectal cancer. However, for those patients refractory to a 5-FU-based chemotherapy, there is no established effective treatment option. Current approaches to enhance second-line therapy involve biochemical modulation of 5-FU and prolongation of its administration schedule or the use of new antitumor agents such as CPT-11 (irinotecan) and oxaliplatin. Among the new agents in development, CPT-11 has demonstrated promising antitumor activity in phase II studies of patients with advanced colorectal cancer, achieving response rates of 15% to 32% and 17% to 25% in chemotherapy-naive and pretreated patients, respectively. Prior disease progression on 5-FU does not affect the response to CPT-11, indicating no cross-resistance between the two agents. This suggests that CPT-11 is a promising new second-line agent for this difficult-to-treat disease. Additional studies will address the benefit of CPT-11 alone in second-line treatment and determine the role of CPT-11 in combination with thymidylate synthase inhibitors in first-line treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Thiophenes

Chemotherapy for advanced colorectal cancer is reviewed stressing the historical development of combination chemotherapy and the application of a new idea called biochemical modulation based upon a preclinical biochemical and molecular pharmacological rationale. While 5-fluorouracil (5-FU) is a key drug for more than three decades, many a combination chemotherapy with 5-FU and other drugs such as methyl-CCNU, vincristine, streptozocin, mitomycin C and so on has been studied extensively only to show no significant improvement compared with monotherapy with 5-FU. Recently, the mechanisms of 5-FU action have been recognized more in detail biochemically, and it enabled us to try the drug in a more optimal way. For example, bolus i.v. infusion of 5-FU can produce a response rate of around 10% to 15% at most for advanced colorectal cancer. On the other hand, a more continuous mode of i.v. infusion, typically known as protracted i.v. infusion lasting up to 6 weeks or more, can produce the response rate of up to 40%. The difference underlying the mechanisms of action in these typical two administrative methods is that the main target can be RNA-directed cytotoxicity in the bolus type infusion and it can be shifted toward DNA-directed cytotoxicity in the continuous type infusion through the inhibition of thymidylate synthase (TS) enzyme activity which is relevant to DNA de novo synthesis. More importantly, investigations using clinical materials imply that DNA-directed cytotoxicity may be more relevant in a clinical setting, showing consistent findings between bench-top experiments and the clinical outcome. Given a precise knowledge about the mechanisms of 5-FU action, we could have developed a new type combination chemotherapy called biochemical modulation which manipulates non-cytotoxic agents or cytotoxic agents in non-cytotoxic level as modulators enhancing cytotoxicity of 5-FU biochemically. Among modulators, leucovorin (LV) has been shown to have a pivotal role in this field. Although no optimal combination dose schedule of LV is well known, randomized studies have shown improved activity of 5-FU modulation by LV over 5-FU alone for advanced colorectal cancer doubled the response rate by monotherapy (20-25%) vs 10-15%). New drugs are also promising with the response rate of 25% approximately obtained with a new camptothecin derivative CPT-11, and a pure TS inhibitor, Tomudex in phase II trials. It is also necessary to explore the clinical activity of the com

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Quinazolines; Remission Induction; Thiophenes; Thymidylate Synthase

Topics: Antidotes; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Quinazolines; Thiophenes; Thymidylate Synthase

A third-line chemotherapy regimen for metastatic colorectal cancer (mCRC) is not available in China. Studies have shown that raltitrexed or S-1 has no complete cross-resistance with fluorouracil (5-FU). In this phase II study, we prospectively analyzed the efficacy and safety of raltitrexed combined with S-1 (RS regimen) in the treatment of mCRC after the failure of conventional chemotherapy.. A total of 105 patients with mCRC with progression following treatment with 5-FU, oxaliplatin, and irinotecan were enrolled between November 2015 and May 2019. Patients received intravenous infusion of raltitrexed (3 mg/m. In the intention-to-treat patients, the objective response and disease control rates were 7.62% and 48.57%, respectively. The median progression-free survival and median overall survival were 2.5 and 8.0 months, respectively. Common adverse events included neutropenia, anemia, thrombocytopenia, and nausea, while neutropenia, anemia, thrombocytopenia nausea, diarrhea, skin eruption, and oral ulceration had grade 3 or higher adverse events. Subgroup analysis revealed that primary site or gene mutation status had little influence on the RS regimen efficacy, while the baseline albumin level, 5-FU administration in second-line therapy, and number of previous treatment regimens affected the efficacy.. The RS regimen demonstrated favorable effects in patients with mCRC following failure of standard chemotherapy, and could be a new choice for third-line treatment, and must be verified in future randomized clinical trials (Clinical trial: NCT02618356).

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Prospective Studies; Quinazolines; Salvage Therapy; Thiophenes; Treatment Outcome

Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer.. In patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, S-1 plus raltitrexed showed a good objective response rate (ORR) and significant survival benefit in our previous study. In the present study, we assessed the activity and safety of bevacizumab combined with S-1 and raltitrexed.. This investigator-initiated, open-label, single-arm, phase II trial was performed at West China Hospital in China. Patients with mCRC who had disease progression after fluoropyrimidine, irinotecan, and oxaliplatin and had at least one measurable lesion were eligible for this trial. Anti-epidermal growth factor receptor (EGFR) (for tumors with wild-type RAS) and anti-vascular endothelial growth factor (VEGF) therapy in the first or second line was allowed, but patients who had been treated with bevacizumab across two consecutive chemotherapy regimens were excluded. Patients received bevacizumab (7.5 mg/kg on day 1), oral S-1 (80-120 mg per day for 14 days), and raltitrexed (3 mg/m. From September 2015 to November 2019, 44 patients were enrolled. Tumor response evaluation was available in 44 patients at the time of the analysis. There were no complete responses; the ORR was 15.9%, and the disease control rate was 54.5%. Median PFS and OS were 110 days (95% confidence interval [CI], 65.0-155.0) and 367 days (95% CI, 310.4-423.6), respectively. The combination was well tolerated.. Bevacizumab combined with S-1 and raltitrexed showed promising antitumor activity and safety in refractory mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Quinazolines; Thiophenes

We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy.. This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate.. The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade ≥ 3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%-89%) and 85% (95%CI, 69%-93%), respectively, for the sequential-schedule.. These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemoradiotherapy, Adjuvant; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Early Termination of Clinical Trials; Female; Fluorouracil; Humans; Italy; Kaplan-Meier Estimate; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Predictive Value of Tests; Quinazolines; Rectal Neoplasms; Risk Factors; Thiophenes; Time Factors; Treatment Outcome

There was conducted an assessment of the effectiveness of a combination of systemic and regional modes of chemotherapy versus systemic chemoinfusion in treatment of 70 patients with unresectable metastases of colorectal cancer in the liver after extrahepatic progression of a disease. The use of combined therapy statistically significantly increased overall survival more than doubled as compared to a group of systemic chemotherapy (median 10 vs. 4.5 months, p = 0.002) as well as the time before intrahepatic progression (median 5.9 vs. 3.5 months, p = 0.01). In addition, there was a trend toward a greater frequency of objective responses in the combination therapy group 18% in comparison with 9.7% in the systemic chemotherapy group (p = 0.49) but the difference was not statistically significant and it needed further study on more clinical material.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Disease Progression; Doxorubicin; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Organoplatinum Compounds; Quinazolines; Thiophenes; Treatment Outcome

The aim of this study was to compare TOMOX versus FOLFOX4 as first-line treatment of advanced colorectal cancer (CRC).. 191 chemotherapy-naïve patients were randomized to receive TOMOX or FOLFOX4. Patients were evaluated every 3 months and chemotherapy was continued until disease progression or unacceptable toxicity. Overall response rate was the primary endpoint.. 183 patients were included in the intent-to-treat analysis (92 TOMOX and 91 FOLFOX4). Overall response rate was 45.6 and 36.3 % (p = 0.003) for TOMOX and FOLFOX4, respectively. No statistically significant differences were observed in overall survival (15.6 and 17.2 months; p = 0.475); progression-free survival (7.7 and 8.7 months; p = 0.292), and response duration (6.4 and 7.6 months; p = 0.372) for TOMOX and FOLFOX4, respectively. Grades 3 and 4 neutropenia (p < 0.0001) and leukopenia (p = 0.028) were more common with the FOLFOX4 regimen, while hepatic disorders and asthenia were higher in TOMOX group (p = ns). There were two treatment-related deaths in the FOLFOX4 arm and one in the TOMOX arm. Quality of life analysis based on the SF-36 revealed differences between the two regimens for physical and mental composite scores after 6 weeks, and for body pain and emotional role functioning after 6 and 12 weeks; all of these favored the FOLFOX4 arm (p ≤ 0.05).. TOMOX and FOLFOX4 seem to have similar efficacy and are well tolerated in the first-line treatment for advanced CRC with different profiles of toxicity. The convenient TOMOX regimen may offer an alternative to fluoropyrimidine-based regimens.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Thiophenes

PETACC-1 assessed if raltitrexed is non-inferior to 5-fluorouracil and leucovorin for relapse-free survival (RFS) and overall survival (OS) in adjuvant stage III colon cancer.. Non-inferiority required both HR for RFS and OS<1.25 at 1-sided alpha=0.05. Patients (1921) were randomised to six cycles of 5-FU/LV (n=969) or eight cycles of raltitrexed (n=952). We report the final results in 993 eligible patients who started and completed the allocated treatment (489 5-FU/LV and n=504 Raltitrexed) of whom respectively 146 and 148 died, respectively.. The trial closed prematurely when 17 (1.9%) raltitrexed-related deaths were reported. Haematological and gastrointestinal toxicities were more frequent with 5-FU/LV, liver toxicities with raltitrexed. Raltitrexed was stopped for toxicity in 13.2% and 5-FU/LV in 8.5%. Sixty-day mortality was 9% versus 7%. With 4.1 years median follow-up, the HR for RFS was 1.16 (90% CI 0.99-1.37) and that for OS was 1.01 (90% CI 0.84-1.23).. The trial failed to demonstrate non-inferiority of raltitrexed.. Free drugs and financial support from AstraZeneca.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Quinazolines; Survival Analysis; Thiophenes; Treatment Outcome; Young Adult

Oxaliplatin (OXA), raltitrexed (RTX), 5-fluorouracil (FU) and folinic acid (FA) have shown activity in metastatic colorectal cancer, radioenhancing effect and synergism when combined. We evaluated a chemotherapy (CT) combination of OXA, RTX and FU/FA during preoperative radiotherapy (RT) in locally advanced rectal cancer (LARC) patients. Fifty-one patients with LARC at high risk of recurrence (T4, N+ or T3N0 < or =5 cm from anal verge and/or circumferential resection margin < or =5 mm) received three biweekly courses of CT during pelvic RT (45 Gy). Surgery was planned 8 weeks after CT-RT. Recommended doses (RDs) determined during phase I were utilised in the subsequent phase II trial, where the rate of tumour regression grade (TRG) 1 or 2 was the main end point. No toxic deaths occurred, and severe toxicity was easily managed. In phase II, RDs delivered in 31 patients were OXA 100 mg m(-2) and RTX 2.5 mg m(-2) on day 1, and FU 900 mg m(-2) and LFA 250 mg m(-2) on day 2. Main severe toxicities by patients were grade 4 neutropenia (23%) and grade 3 diarrhoea (19%). In 71% (95% confidence limits, 52-86%) of patients, TRG1 (13) or TRG2 (9) was obtained. All patients are alive and recurrence-free after a median follow-up of 29 months. Combination of OXA, RTX and FU/FA with pelvic RT has an acceptable toxicity and a high clinical activity in LARC and should be studied further in patients at high risk of recurrence.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Digestive System Surgical Procedures; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Preoperative Care; Quinazolines; Thiophenes

The aim of the study was to evaluate the safety and efficacy of the raltitrexed/5-fluorouracil/levofolinic acid combination regimen as first-line chemotherapy for elderly patients with advanced/metastatic colorectal cancer.. Previously untreated patients with metastatic colorectal cancer received raltitrexed 2 mg/m(2) i.v. plus levofolinic acid and 5-fluorouracil according to the De Gramont' schedule given every 2 weeks as first-line chemotherapy. Patients were re-evaluated after six cycles and chemotherapy was continued up to tolerance or disease progression.. Seventy patients aged >/=65 years were accrued from 11 centers between September 2001 and July 2002. According to the intention-to-treat analysis, the overall response rate was 35% (95% CI 29.5% to 40.5%) including one complete response (1%) and 24 partial responses (34%). Twenty patients (31%) showed a stabilization of disease for a tumor growth control rate of 64% (95% CI 57% to 71%). The median overall survival was 12.5 months and the median time to disease progression was 6.5 months. No toxic deaths or allergic reaction were recorded. Grade 4 toxicities were non-existent. The main hematological toxicity was grade 3 neutropenia, which occurred in 9% of patients, and grade 3 anemia in only one case, while no case of graded 3 thrombocytopenia was observed. Grade 3 non-hematological toxicities were asthenia (11%), transient increase of transaminases (10%) and diarrhea (4%).. The results of this study suggest that the raltitrexed/5-fluorouracil/levolofinic acid combination is an effective and well tolerated regimen for the treatment of elderly patients with advanced colorectal cancer. Its ease of administration and patient's tolerance warrant further investigation over 5-fluorouracil/folinic acid regimens.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Quinazolines; Thiophenes

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).. 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.. 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 euro 15,970 for HD-LV5FU2. The cost of R (10,687 euro) was lower than that of HD-LV5FU2 (p = 0.008). The cost of LD-LV5FU2 (14,888 euro) and of WI-FU (13,760 euro) was not significantly different from that of HD-LV5FU2.. 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.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Cost of Illness; Cost-Benefit Analysis; Disease-Free Survival; Female; Fluorouracil; France; Health Care Costs; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Quinazolines; Survival Rate; Thiophenes; Treatment Outcome

Policies of UK clinicians regarding the duration of chemotherapy for patients with advanced colorectal cancer are not consistent. We aimed to compare effectiveness of continuous and intermittent chemotherapy in such patients.. Patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich, or raltitrexed chemotherapy, were randomised to either intermittent (a break in chemotherapy, re-starting on the same drug on progression), or continuous chemotherapy until progression.. 354 patients (178 intermittent, 176 continuous) were enrolled from 42 UK centres. At randomisation, 41% of participants had part or complete response; 59% were stable. Only 66 (37%) patients allocated to intermittent treatment restarted as planned, after a median of 130 days. Median time on treatment after restarting was 84 days. Patients in the continuous group remained on treatment for a median of a further 92 days. Similar proportions of patients in both groups received second-line therapy. Patients on intermittent chemotherapy had significantly fewer toxic effects and serious adverse events than those in the continuous group. There was no clear evidence of a difference in overall survival (hazard ratio 0.87 favouring intermittent, 95% CI 0.69-1.09, p=0.23).. Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression. They showed that it is safe to stop chemotherapy after 12 weeks and re-start the same treatment on progression in patients with chemosensitive advanced colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusion Pumps; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Staging; Palliative Care; Quinazolines; Survival Analysis; Thiophenes

The tolerance and efficacy of oxaliplatin and irinotecan for metastatic colorectal cancer are unknown in elderly patients. Methods. All consecutive patients over 74 years treated with oxaliplatin or irinotecan for metastatic colorectal cancer were enrolled. The tumour response was assessed every 2-3 months and toxicity was collected at each cycle according to World Health Organisation criteria. A total of 66 patients were enrolled from 12 centres. The median age was 78 years (range, 75-88 years); 39 patients had no severe comorbidity according to the Charlson score. In total, 44 and 22 patients received oxaliplatin or irinotecan, respectively, in combination with 5-fluororuracil+/-folinic acid or raltitrexed in 64 patients. A total of 545 chemotherapy cycles were administered in first (41%), second (51%) or third line (8%). A dose reduction occurred in 190 cycles (35%). Complete response, partial response and stabilisation occurred in 1.5, 20 and 47% of patients, respectively. The median time to progression and overall survival were 6.8 and 11.2 months in first line and 6.3 and 11.6 months in second line, respectively. Grade 3 and 4 toxicity occurred in 42% of patients: neutropenia 17%, diarrhoea 15%, neuropathy 11%, nausea and vomiting 8% and thrombopenia 6%. There was no treatment-related death. In selected elderly patients, chemotherapy with oxaliplatin or irinotecan is feasible with manageable toxicity.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Survival Analysis; Thiophenes; Treatment Outcome

Raltitrexed (Tomudex) is proven effective in metastatic colorectal cancer. Between 1998-2000, 25 patients were included in a randomized phase II study comparing raltitrexed (13 patients) and the Nordic FLv regimen (12 patients). 23 patients were evaluable for response. The overall response rate was 2/12 (1 CR, 1 PR) in the raltitrexed arm and 1/11 (1 CR) in the Nordic FLv arm, respectively. There was no difference in overall survival (raltitrexed--14.7 months, Nordic FLv--15.4 months). 23 patients were evaluable for Quality of Life (QoL) analysis. 23/25 and 17/21 questionnaires (EORTC QLQ C-30) were returned at baseline and first evaluation. Raltitrexed tended to be the most toxic regimen, when looking at nausea and vomiting, appetite loss, diarrhea and global QoL. However, most patients (65%) recommended the raltitrexed treatment schedule. The total treatment cost was equal in both arms (about 6,800 EURO/patient) and the hospital/hospital hotel stay costs accounted for more than half of it.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Health Care Costs; Humans; Length of Stay; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Norway; Quality of Life; Quinazolines; Surveys and Questionnaires; Survival Analysis; Thiophenes; Treatment Outcome

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.. Patients with inoperable locally advanced or metastatic SCCHN, not pretreated with chemo- or radiotherapy were randomized to receive either CDDP 60 mg/m2 and raltitrexed 2.5 mg/m2 on day 1 and LFA 250 mg/m2 and 5-FU 900 mg/m2 on day 2 (arm A) or CDDP 65 mg/m2 and methotrexate 500 mg/m2 on day 1, and LFA 250 mg/m2 and 5-FU 800 mg/m2 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.. 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).. 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.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Dose-Response Relationship, Drug; Female; Fluorouracil; Head and Neck Neoplasms; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neutropenia; Quinazolines; Thiophenes; Treatment Outcome

The present study aimed at evaluating the efficacy of Raltitrexed, a specific thymidilate synthase inhibitor, in patients with advanced colorectal cancer (ACC) in relapse (>8 weeks) after a prior response or disease stabilization to first-line chemotherapy combination with lrinotecan+5-Fluorouracil (5-FU)+Leucovorin (LV).. Twenty-five patients with metastatic ACC entered; 17 males/8 females, median age 61 (range: 47-70), median Karnovsky PS: 80 (70-90), and sites of metastases; liver: 21, lung: 4, lymph nodes: 7, peritoneal: 5 and a life expectancy of at least 3 months, were entered in the present pilot study. All patients had progressed after prior chemotherapy with lrinotecan+5-FU+LV. Raltitrexed was administered at a dose of 3 mg/m2 i.v. every 21 days.. Three patients (12%) achieved a partial response (PR), 8 (32%) had stable disease (SD), and the remaining 14 (56%) developed progressive disease (PD). Median time-to-progression (TTP) was 5.5 months (range, 2-8.5), and median overall survival (OS) 8 months (range, 4.0-12.5). Toxicity was generally mild; it consisted mainly of myelosuppression; neutropenia grade 1-2: 52%-grade 3: 28%, and anemia grade 1-2 only: 36%. Mild mucositis grade 1-2 occurred in 13.5% of patients and was the principal non-hematologic toxicity.. Response to treatment with Raltitrexed is limited in patients with ACC failing after an initial response or non-progression to the weekly lrinotecan+5-FU+LV combination. However, it appears that a limited number of patients with PR/SD may derive clinical benefit, but final proof would require a randomized study.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Peritoneal Neoplasms; Quinazolines; Salvage Therapy; Secondary Prevention; Thiophenes; Treatment Outcome

The aim of the present study was to define the activity and tolerability of a triplet regimen including oxaliplatin 130 mg x m(-2) (2 h i.v. infusion) and raltitrexed 3.0 mg x m(-2) (15 min i.v. infusion) given on day 1, followed by levo-folinic acid 250 mg x m(-2) (2 h i.v. infusion) and 5-fluorouracil 1050 mg x m(-2) i.v. bolus on day 2, every 2 weeks, in pretreated colorectal cancer patients. From April 1999 to December 2000, 50 patients were enrolled: 26 were males and 24 females, their median age was 63 (range, 43-79) years; ECOG performance status was 0 in 26 patients, > or =1 in 24 patients; 26 patients had received previous adjuvant chemotherapy, 40 patients had been exposed to one or two lines of palliative chemotherapy (including irinotecan in 31 cases); 18 patients were considered chemo-refractory. A total of 288 cycles were administered, with a median number of 6 (range 1-12) courses per patient. A complete response was obtained in three patients, and a partial response in nine patients, giving a major response rate of 24% (95% confidence interval, 13-38%), while 15 further patients showed a stable disease, for an overall control of tumour growth in 60% of patients. Three complete responses and three partial responses were obtained in patients pretreated with irinotecan (response rate, 19%); among refractory patients, three achieved partial responses (response rate, 13%). After a median follow-up of 18 (range, 10-30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was > or =1.33 (showing a significant delay of tumour growth) in 16 (40%) patients. Actuarial median progression-free survival time was 7.6 months, and median survival time was 13.6 months: estimated probability of survival was 55% at 1 year. Main severe toxicity was neutropenia: World Health Organisation grade 4 affected 32% of patients; non-haematological toxicity was mild: World Health Organisation grade 3 diarrhoea was complained of by 8%, and grade 3 stomatitis by 4% of patients; neurotoxicity (according to Lévi scale) was scored as grade 3 in 8% of patients. In conclusion, this regimen was manageable and active as salvage treatment of advanced colorectal cancer patients; it showed incomplete cross-resistance with irinotecan-based treatments, and proved to delay the progression of disease in a relevant proportion of treated patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Salvage Therapy; Thiophenes; Treatment Outcome

We have recently evaluated the combination of raltitrexed, levofolinic acid (LFA) and 5-fluorouracil (5-FU) in advanced head and neck and colorectal cancer, and we have shown that this combination is well tolerated and has clinical activity. Clinical combination studies have shown that raltitrexed and anthracyclines can be combined at full doses without unexpected toxicities. Based on these observations, we started a phase I study of mitoxantrone plus raltitrexed administered on day 1, followed by LFA and 5-FU on day 2 in patients with advanced solid tumors.. Mitoxantrone was given at a starting dose of 6 mg/m2, raltitrexed at a fixed dose of 3 mg/m2, LFA at a fixed dose of 250 mg/m2, and 5-FU at a starting dose of 750 mg/m2. Mitoxantrone and 5-FU doses were subsequently escalated alternately up to dose-limiting toxicity. Treatment was repeated every 14 days.. Four dose levels were tested in 18 patients. All three patients treated at the fourth dose level had grade 4 neutropenia after the first cycle. Therefore, this level was defined as the maximum tolerated dose and the dose level immediately below (mitoxantrone 7 mg/m2 and 5-FU 900 mg/m2) was selected for further evaluation. Neutropenia was the main toxic effect. Nonhaematologic side effects were mild. One complete response and five partial responses (all but one in patients with head and neck cancer) were observed, for an overall response rate of 33% (95% confidence interval, 13% to 59%).. Mitoxantrone, raltitrexed and 5-FU can be combined at doses which are close to those used in monotherapy. The observed activity is encouraging, especially in the subset of patients with head and neck cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Mitoxantrone; Neoplasms; Quinazolines; Thiophenes

To evaluate the efficacy and tolerance of combined raltitrexed and oxaliplatin in patients with advanced colorectal cancer pretreated with fluoropyrimidine leucovorin-based chemotherapy.. Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding palliative chemotherapy with fluoropyrimidines leucovorin +/- irinotecan, participated in this study. Treatment consisted of oxaliplatin 130 mg/m2 and raltitrexed 3.0 mg/m2 both given on day 1 every three weeks for a total of eight courses unless prior evidence of progressive disease.. The overall objective response rate was 33.3% for all 36 evaluable patients (95% confidence interval (CI): 18.6%-51%). Seventeen additional patients (47.2%) had stable disease, and only seven (19.5%) progressed. The median progression-free survival was 6.5 months (range 1.2-14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8 of 36 patients (22%) experiencing grade 3 or 4 neutropenia. Grade 3 non-haematological adverse reactions included peripheral sensory neuropathy in three, asthenia in one, diarrhea in two, and clinically insignificant increase in serum transaminases in two patients, respectively.. Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine leucovorin + irinotecan pretreated colorectal cancer. Because of its favorable toxicity profile and convenient three-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Salvage Therapy; Thiophenes; Treatment Outcome

To determine the maximum tolerated dose of oxaliplatin (L-OHP) given as a two-hour infusion followed by raltitrexed (Tomudex [TOM]) administered as a 15-min infusion on day 1, and bolus 5-fluorouracil (5-FU) modulated by a fixed dose of levo-folinic acid (LFA) 250 mg/m2 on day 2, recycling every two weeks, and to have preliminary evidence of activity of this combination in pretreated advanced colorectal cancer patients.. Fifty-two patients with advanced colorectal carcinoma previously treated with one (25 cases) or two or more lines of chemotherapy, including irinotecan (26 cases), and/or modulated 5-FU (40 cases) entered this study. Starting doses of L-OHP, TOM, and 5-FU were 85, 2.5 and 750 mg/m2, respectively.. Seven dose levels were tested. Neutropenia was the main dose limiting toxicity of the dose escalation (8 of 13 cases). The recommended doses were 130 mg/m2 of L-OHP, and 3.0 mg/m2 of TOM on day 1, followed by 250 mg/m2 of LFA, and 1050 mg/m2 of 5-FU on day 2, every two weeks. Severe diarrhoea and stomatitis were rarely reported. Most patients complained of mild peripheral sensitive aeurotoxicity, which was related to the cumulative dose of L-OHP. Twelve patients were considered as having a major responses (one complete), and an additional eight patients showed a minor response; the median time to treatment failure was twenty-four weeks.. With this regimen it is possible to give full doses of all three cytotoxic drugs every two weeks. Its activity and its manageable toxicity profile deserve further evaluation in pretreated advanced colorectal cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Rectal Neoplasms; Thiophenes; Treatment Outcome

The combination of cisplatin (CDDP) and 5-fluorouracil (5-FU) can be regarded as a reference regimen in squamous cell carcinoma of the head and neck (SCCHN). Raltitrexed (Tomudex) is a direct and specific thymidilate synthase (TS) inhibitor, which has shown clinical activity against SCCHN in a previous phase I study, when combined with 5-FU and levo-folinic acid (LFA). Preclinical data support the combination of CDDP and raltitrexed. The aim of the present study was to evaluate the combination of cisplatin, raltitrexed. LFA and 5-FU in a phase I-II study.. Patients with locally advanced or metastatic SCCHN were treated with a combination of cisplatin at the starting dose of 40 mg/m2. followed by raltitrexed at the starting dose of 2.5 mg/m2 on day 1; levo-folinic acid at fixed dose of 250 mg/m2, followed by 5-fluorouracil at the starting dose of 750 mg/m2 on day 2. Doses of the three cytotoxic agents were alternately escalated up to dose-limiting toxicity (DLT). Treatment was recycled every two weeks and given up to a maximum of eight courses; after chemotherapy, patients with locally advanced disease received a locoregional treatment.. Forty-five patients were entered into the study. Six dose levels were tested. At CDDP 50 mg/m2, raltitrexed 3 mg/m2, 5-FU 900 mg/m2, four out of six patients showed DLT, which was in all cases grade 4 neutropenia. Therefore, this dose level was defined as maximum tolerated dose (MTD). CDDP 60 mg/m2, raltitrexed 2.5 mg/m2, LFA 250 mg/m2, 5-FU 900 mg/m2 was the dose level recommended for phase II. CDDP, Raltitrexed and 5-FU mean actually delivered dose intensities at the selected dose level were 26, 1.05, and 378 mg/m2/week, respectively. Neutropenia was the main side effect and was observed even at the lowest dose levels. Nonhematologic side effects were mild. Nine complete responses (20%) and twenty-one partial responses (47%) were observed, for an overall response rate of 67% (95% confidence interval (95% CI): 51%-80%), according to intention to treat analysis. Fifteen of fifteen patients (100%) treated at the dose level selected for phase II had an objective response (5 complete responses, 10 partial responses).. The results of our dose escalation clearly demonstrate that it is possible to combine CDDP, raltitrexed, and modulated 5-FU at effective doses, without unexpected toxicities. The response data point to an impressive clinical activity, which will be better defined by an ongoing large phase II study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Dose-Response Relationship, Drug; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neutropenia; Quinazolines; Thiophenes; Treatment Outcome

To assess the cost effectiveness of healthcare interventions from a societal perspective, it is necessary to include costs such as patients' travel costs and the opportunity cost of patients' time spent consuming healthcare.. To analyse patients' travel and time costs associated with 2 alternative drug therapies for advanced colorectal cancer: raltitrexed and fluorouracil plus folinic acid (leucovorin) [5FU + FA].. The analysis is based on a prospective substudy within a multinational randomised controlled trial of raltitrexed versus 5FU + FA.. 495 patients with advanced colorectal cancer were enrolled in the trial, 270 of whom completed the questionnaire on costs.. Data were collected within the trial to estimate the numbers of journeys made to and from hospital by patients and the time lost from usual activities over the period of therapy. A subset of patients were asked to complete a questionnaire to provide the information necessary to value time and travel costs in monetary terms. These data, together with UK transport costs and forgone time values, were used to value the transport and opportunity costs of time of all patients in the trial.. The total travel cost per patient was statistically significantly higher in the 5FU + FA group (p < 0.001; median of 31.50 Pounds with raltitrexed, 96.00 Pounds with 5FU + FA; 1997 prices). Overall time cost per patient was also higher in the 5FU + FA group (p = 0.005; median of 168.80 Pounds with raltitrexed, 224.04 Pounds with 5FU + FA). Adding the two gives a median total cost per patient of 206.08 Pounds [interquartile range (IQR) 108 Pounds to 482 Pounds] among patients randomised to raltitrexed and 342.25 Pounds (IQR 214 Pounds to 555 Pounds) for those in the 5FU + FA group (p < 0.001). The sensitivity analysis showed that, even under extreme assumptions, raltitrexed imposed fewer time and travel costs on patients. These cost differences are likely, in part, to reflect the longer treatment times for 5FU + FA patients (median 16.9 vs 12.7 weeks).. Different chemotherapy regimens for advanced colorectal cancer can impose different travel and time costs on patients. Over the period of treatment in a randomised controlled trial of 495 patients, those randomised to 5FU + FA were found to have a median travel plus time cost 136 Pounds per patient higher than those randomised to raltitrexed.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Cost of Illness; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Prospective Studies; Quinazolines; Surveys and Questionnaires; Thiophenes; Time Factors; Travel; United Kingdom

The aim of this randomised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil (LFA-5-FU), combined with either irinotecan (CPT-11 + LFA 5-FU) or raltitrexed (Tomudex) (TOM + LFA-5-FU), in advanced colorectal cancer patients, and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate (MTX + LFA-5-FU).. One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease (34 of them previously exposed to adjuvant 5-FU) were randomly allocated to receive: CPT-11, 200 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 850 mg/m2 s i.v. bolus (arm A); TOM, 3 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 1050 mg/m2 i.v. bolus (arm B); or MTX, 750 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 800 mg/m2 i.v. bolus (arm C). Courses were repeated every two weeks in all arms of the trial. Response rate (RR) was evaluated after every four courses. The sample size was defined to have an 80% power to detect a 35% RR for each experimental treatment, and to show a difference of at least 4% in RR with the standard treatment if the true difference is 15% or more.. The RRs were: 34% (95% confidence interval (95%, CI): 21%-48%) in arm A, including 3 complete responses (CRs) and 15 partial responses (PRs), 24% (95% CI: 14%-38%) in arm B, including 2 CRs and 11 PRs, and 24% (95% CI: 14%-38%), with 2 CRs and 11 PRs, in arm C. After a median follow-up time of 62 (range 18-108) weeks, the median time to progression was 38, 25, and 27 weeks for arm A, B, and C, respectively. With 94 patients still alive, the one-year probability of survival was 61%, 54%, and 59%, respectively. WHO grade 3 or 4 neutropenia and diarrhoea affected 46% and 16%, respectively, of patients treated with CPT-11 + LFA 5-FU. Median relative dose intensity over eight cycles (DI8) was 78% for CPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA-5-FU were neutropenia (16%) and diarrhoea (16%), but median relative DI8 was 93% for TOM, and 82% for 5-FU.. CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU. The hypothesis of a RR 15% higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis. The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA 5-FU combination, and dose not deserve further evaluation in advanced colorectal cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Quality of Life; Quinazolines; Thiophenes; Treatment Failure

Our objective was to establish the balance between costs and effects of treatment with Tomudex (raltitrexed) as an alternative to treatment with 5-fluorouracil (5-FU) plus leucovorin (LV) in patients with advanced colorectal cancer. Data were used from an international, open label randomized clinical trial. Costs were calculated by multiplying resource utilization data with Dutch estimates of unit costs. Effects have been expressed in terms of 6 months and 1 year survival, and in terms of the number of patients without severe adverse events including WHO grade 3 and 4 leucopenia, mucositis, anemia and severe asthenia. Cost effectiveness is expressed in terms of costs per additional day of survival and costs per additional patient without any severe adverse event. The clinical results did not show significant survival differences implying great uncertainty about the cost-effectiveness of raltitrexed in terms of additional costs per additional life-year gained. However, 80% of the initially higher cost of raltitrexed ($3132 per patient) is compensated by savings due to a more convenient administration scheme leading to a net cost of $626 per patient treated. Weighed against the decrease in adverse events, a cost-effectiveness ratio results of $3936 per additional patient free of any severe adverse event. More favorable estimates result when the convenience of the administration scheme is valued in positive monetary terms.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Cost-Benefit Analysis; Costs and Cost Analysis; Fluorouracil; Health Care Costs; Humans; Leucovorin; Netherlands; Quinazolines; Randomized Controlled Trials as Topic; Survival Analysis; Thiophenes

This multicenter phase II study was designed to assess the efficacy of the alternating schedule of tomudex with methotrexate (MTX)/5-fluorouracil (5-FU)/leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer.. Patients with histologically proven metastatic colorectal cancer and at least one bidimensionally measurable lesion, aged 18-70, with performance status < or = 2, normal baseline biological values, and no prior chemotherapy, were selected. Treatment was tomudex 3 mg/m2 and, after two weeks, MTX, 200 mg/m2 by 30' infusion after hydration with 1500 ml saline solution, followed on day 2 by 5-FU, 600 mg/m2 and leucovorin, orally, 15 mg for six times every 6 hours, beginning 24 hours after MTX. Cycles were repeated every four weeks. Tumor response assessment was performed after three cycles.. Thirty-four patients were enrolled in this study, of whom twenty-four had liver metastases, nine local relapse, five lymph node involvement, four lung metastases, and three peritoneal carcinomatosis. Four patients achieved objective responses (one complete and three partial), for an overall response rate of 12% (95% CI: 0%-22%). Twelve patients had stable disease and 18 progressed on therapy. Median survival for all patients was 13 months. Two patients experienced grade 3 WHO neutropenia while hepatotoxicity was reported in 13 patients (6 grade 1, 3 grade 2, 3 grade 3, 1 grade 4), suggesting that this combination could increase hepatic toxicity in comparison to tomudex or MTX/5-FU alone.. Our results suggest that this regimen does not warrant further investigation in advanced colorectal cancer patients, at least not with this schedule and doses.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Prognosis; Quinazolines; Survival Rate; Thiophenes; Treatment Outcome

In vitro studies have shown a schedule-dependent synergism between Tomudex and 5-fluorouracil (5-FU). Incubation of different types of head and neck and colorectal cancer cells with levofolinic acid (LFA) plus 5-FU for 4 or 24 h, after 24-h incubation with Tomudex, produces a clear synergism. The purpose of this study was to evaluate the tolerability and activity of a combination of Tomudex, LFA, and 5-FU in advanced head and neck and colorectal cancer. Furthermore, the potential for 5-FU pharmacomodulation by Tomudex was also evaluated through an intrapatient assessment of dihydropyrimidine dehydrogenase (DPD) activity and 5-FU AUC with and without pretreatment with Tomudex. Eligible patients were treated with Tomudex at the starting dose of 1.5 mg/m2 on day 1, LFA at a fixed dose of 250 mg/m2 on day 2, immediately followed by bolus 5-FU at the starting dose of 600 mg/m2. Tomudex and 5-FU doses were alternately escalated. Courses were repeated every 2 weeks. In the second course, LFA and 5-FU were administered on day 1 and Tomudex on day 2; further treatment was given according to the sequence used in the first course. Plasma 5-FU concentrations were analyzed on courses 1 and 2 using a high-performance liquid chromatography assay with UV detection. DPD activity was measured in peripheral blood mononuclear cells on courses 1 and 2 using incubation of cytosol with [14C]FU and quantitation of metabolite formation. Fifty-eight patients were enrolled in the study. Dose escalation was stopped at step 8, because of the occurrence of dose-limiting toxicity in two of three patients. The dose level immediately before (3 mg/m2 Tomudex, 1050 mg/m2 5-FU) was selected for further evaluation. Tomudex and 5-FU mean dose intensities actually delivered at the seventh step were 1.32 and 462 mg/m2/week, respectively. Six of 40 patients with metastatic colorectal cancer obtained an objective response (15%; 95% confidence interval, 6-30%). In particular, three complete responses and three partial responses were observed. Six of 17 patients with locally advanced or metastatic head and neck cancer obtained an objective response (1 complete response + 5 partial responses; 35%; 95% confidence interval, 14-62%). Median duration of response in colorectal cancer patients was 12 months. 5-FU AUC was not significantly different between the two courses (median intrapatient difference, 9.3%; P = 0.28). DPD activity in course 1 was significantly higher than course 2 (P = 0.041) in the 16

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Quinazolines; Thiophenes

When assessing the value of a particular treatment, it is important to consider the impact it may have on the quality of life of those being treated. This is particularly so for cancer patients, whose life expectancy may be short. Patients with advanced colorectal cancer who participated in two international comparative studies of raltitrexed ('Tomudex') vs standard 5-fluorouracil (5-FU) plus leucovorin (LV) completed previously validated quality-of-life questionnaires (EORTC questionnaire, EuroQol and Rotterdam Symptom Check List) at various times during the studies. Early statistically significant advantages of raltitrexed vs 5-FU plus LV on quality of life were observed at week 2 in five of eight of the EuroQol and three of four of the Rotterdam Symptom Check List dimensions. Such advantages were not observed using the EORTC questionnaire, which was not completed until week 12. The necessary dose delays and different dose schedules made it difficult in these studies to compare the impact on quality of life of the two treatments. It may be that performance status, effect on disease-related symptoms and the incidence of toxicity are the most important indications of a patient's quality of life.

Topics: Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Enzyme Inhibitors; Fluorouracil; Humans; Leucovorin; Quality of Life; Quinazolines; Surveys and Questionnaires; Thiophenes; Thymidylate Synthase

To compare raltitrexed (Tomudex; Zeneca Pharmaceuticals Ltd, Macclesfield, United Kingdom) a direct, specific thymidylate synthase (TS) inhibitor with fluorouracil (5-FU) plus high-dose leucovorin (LV) as first-line treatment for advanced colorectal cancer (ACC).. A total of 495 patients were randomized to raltitrexed (3 mg/m2) once every 3 weeks or 5-FU (400 mg/m2) plus LV (200 mg/m2) daily for 5 days every 4 weeks.. The randomized groups were well balanced demographically. With a minimum 17-month follow-up, median survival was comparable between groups (10.9 months raltitrexed v 12.3 months 5-FU/LV; hazards ratio, 1.15; 95% confidence interval [CI], 0.93 to 1.42; P=.197), although time to progression was statistically significantly shorter in the raltitrexed group. Overall objective responses were comparable (19% raltitrexed v 18% 5-FU/LV), with more than 50% of patients in each group having stable disease. Significantly less World Health Organization (WHO) grade 3 and 4 stomatitis (2% v 16%, P < .001) and a reduced incidence of leukopenia (6% v 13%) and diarrhea (10% v 19%) occurred in the raltitrexed group (particularly at cycle 1 ). This resulted in fewer dose reductions at cycle 2 (4% raltitrexed v 28% 5-FU/LV) and early quality-of-life (QoL) benefits for raltitrexed patients. Reversible, clinically insignificant increases in transaminases were reported in 13% of raltitrexed patients. Palliative benefits of weight gain, improved performance status, and reduced disease-related symptoms were evident in both groups.. Raltitrexed is confirmed as an effective option in the first-line palliative management of ACC, with comparable efficacy to and tolerability advantages (in terms of reduced incidence of stomatitis, diarrhea, and leukopenia) over 5-FU/LV. Raltitrexed has the added convenience of an every 3 weeks dosing schedule.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Quality of Life; Quinazolines; Survival Analysis; Thiophenes

5-Fluorouracil (5-FU) has been widely used for over 30 years. Recently, investigators have described interactions between toxicity with 5-FU and age and gender. Pharmacokinetics of infusional 5-FU are known to be gender dependent, with drug clearance being lower in females. The full impact of age and gender on both toxicity and response has not been fully explored and is worthy of further investigation. 439 patients were entered into a phase III trial comparing a novel thymidylate synthase (TS) inhibitor Tomudex (raltitrexed, formerly ZD1694) with 5-FU and leucovorin (LV) for the treatment of advanced colorectal cancer. Approximately 20-24% of patients in each treatment group were aged 70 years or older and 41% of the patients were female. In a multiple regression analysis, female patients receiving 5-FU + LV experienced significantly more grade 3/4 leucopenia, whilst those receiving raltitrexed had more rises in transaminase levels. Grade 3/4 leucopenia and mucositis were significantly correlated with age (especially > 70 years) only in patients receiving 5-FU + LV. Patients receiving 5-FU + LV were significantly more at risk of experiencing grade 3/4 haematological and non-haematological toxicity in the first three cycles than patients receiving raltitrexed. Female gender and increased age predict for increased grade 3/4 toxicity in patients receiving modulated 5-FU. Further studies with modulated 5-FU which utilise a modified dose reduction schema for female patients, or patients aged 70 years or over, may be appropriate.

Topics: Adult; Age Factors; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Quinazolines; Sex Factors; Thiophenes

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Longitudinal Studies; Male; Middle Aged; Quinazolines; Thiophenes

'Tomudex' (ZD1694), a direct and specific thymidylate synthase (TS) inhibitor entered phase III studies in November 1993. We present here the first analysis of a randomised multicentre, international phase III study. 439 patients with previously untreated advanced colorectal cancer were randomised to Tomudex 3.0 mg/m2 given once every 3 weeks or 5-fluorouracil (5-FU) 425 mg/m2 and leucovorin (LV) 20 mg/m2 for 5 days (the Mayo regimen), given every 4-5 weeks. Patients were evaluated weekly for toxicity and every 12 weeks for objective response. The two groups were well matched in terms of demographic characteristics. The mean age of the patients was 61 years and most had either liver (78%) or lung (25-29%) metastases. Ninety seven per cent of patients allocated to Tomudex and 94% of those allocated to 5-FU plus LV had measurable disease. Response was assessed using WHO/UICC criteria; all response data were source validated; 19.8% of patients who received Tomudex and 12.7% of patients who received 5-FU plus LV had complete or partial responses (P = 0.059, odds ratio 1.7, 95% confidence limits 0.98-2.81). There were no statistically significant differences in time to progression or survival between the two groups. Patients who received Tomudex spent a substantially shorter time in hospital for dosing and had significantly lower rates of grade 3 and 4 toxicities such as leucopenia and mucositis. Patients who received Tomudex had a significantly higher incidence of reversible grade 3 or 4 increase in transaminases, which appear to be of limited clinical significance. Improvement in quality of life, weight gain and performance status was seen in both groups. Tomudex has benefits in terms of higher response rates, reduced toxicity and more frequent palliative benefits when compared with 5-FU plus LV in the management of advanced colorectal cancer, and has a more convenient administration schedule.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Length of Stay; Leucovorin; Leukopenia; Male; Middle Aged; Quality of Life; Quinazolines; Stomatitis; Survival Rate; Thiophenes

To assess the safety and efficacy of oxaliplatin (OXA) plus dual inhibition of thymidilate synthase during preoperative pelvic radiotherapy (RT) in patients with poor prognosis for rectal carcinoma.. Sixty-three patients with the following characteristics, a clinical (c) stage T4, cN1-2, or cT3N0 of ≤5 cm from the anal verge and/or with a circumferential resection margin (CRM) of ≤5 mm (by magnetic resonance imaging), received three biweekly courses of chemotherapy with OXA, 100 mg/m2; raltitrexed (RTX), 2.5 mg/m2 on day 1, and 5-fluorouracil (5-FU), 900 mg/m2 (31 patients) or 800 mg/m2 (32 patients); levo-folinic acid (LFA), 250 mg/m2 on day 2, during pelvic RT (45 Gy). Pathologic response was defined as complete pathological response (ypCR), major (tumor regression grade(TRG) 2 to 3, with ypCRM-ve and ypN-ve) or minor or no response (TRG4 to -5, or ypCRM+ve, or ypN+ve). Adjuvant 5-FU/LFA regimen was given in cases of cT4, ypN+ve, or ypCRM+ve.. Overall, neutropenia (40%) and diarrhea (13%) were the most common grade≥3 toxicities, and tolerability was better with a 5-FU dose reduction. No significant difference in pathologic response was seen according 5-FU dosage: overall, a ypCR was obtained in 24 (39%) patients, and a major response in 20 (32%) patients. The 5-year probability of freedom from recurrence was 80% (95% confidence interval, 68%-92%); it was 56% for the minor/no response group, while it was around 90% for both the ypCR and the major response group.. OXA, RTX, and 5-FU/LFA administered during pelvic RT produced promising early and long-term results in rectal carcinoma patients with poor prognosis. The postoperative treatment strategy applied in our study supports the risk-adapted approach in postoperative management.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Proteins; Neoplasm Staging; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Postoperative Complications; Preoperative Care; Prognosis; Quinazolines; Radiotherapy Dosage; Rectal Neoplasms; Remission Induction; Thiophenes; Thymidylate Synthase; Treatment Outcome; Vitamin B Complex

Despite the introduction of several novel anticancer agents almost 50% of colorectal cancer (CRC) patients die for cancer suggesting the necessity of new therapeutical approaches. In this study we demonstrated that the HDAC inhibitor vorinostat exerted potent antiproliferative effect in a panel of mut- and wt-p53 human CRC cell lines. Moreover, in combination with 5-fluorouracil modulated by folinic acid (5FU-FA) or with Raltitrexed (RTX), both commonly used in the treatment of this disease, it showed a clear schedule-dependent synergistic antiproliferative interaction as demonstrated by calculating combination indexes. Only simultaneous, or 24 h pretreatment with vorinostat followed by either agent, produced synergistic effect paralleled by evident cell cycle perturbations with major S-phase arrest. Moreover, we provided for the first time evidences that vorinostat can overcome resistance to both 5FU and RTX. Downmodulation of Thymidilate synthase (TS) protein induced by vorinostat within 24 h, represented a key factor in enhancing the effects of both drugs in sensitive as well as resistant tumor cells. Furthermore, p53, whose wild-type expression is critical for sensitivity to 5FU and RTX, was upregulated by vorinostat in wt- and downregulated in mut-p53 cells, suggesting an additional mechanism of the antiproliferative synergistic interactions observed. Overall these data add new insights in the mechanism of vorinostat antitumor effect and suggested that the association of vorinostat plus 5FU-FA and/or RTX should be clinically explored.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Growth Processes; Cell Line, Tumor; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Fluorouracil; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; HT29 Cells; Humans; Hydroxamic Acids; Leucovorin; Quinazolines; Thiophenes; Thymidylate Synthase; Tumor Suppressor Protein p53; Vorinostat

5-Fluorouracil (5-FU) is considered to be the backbone of colorectal cancer (CRC) systemic therapy since the great majority of recommended regimens include its administration. A clinical picture consisting of chest pain, sometimes cardiac enzyme elevation, electrocardiogram abnormalities consistent with myocardial ischemia, and normal coronary angiogram associated with 5-FU administration have been infrequently reported. The clinical dilemma is: which chemotherapy regimen should we use in CRC patients with a previous acute coronary syndrome (ACS) associated with 5-FU?. We describe the case of a 55-year-old otherwise healthy woman with metastatic colon adenocarcinoma who presented an ACS probably secondary to arterial vasospasm while receiving continuous intravenous 5-FU infusion (mFOLFOX6 regimen). After the ACS, the patient was treated with raltitrexate plus oxaliplatin (TOMOX) and subsequently with irinotecan plus cetuximab with no other cardiac event.. The risk of cardiotoxicity associated with 5-FU is low but real. The probable mechanism is arterial vasospasm, as suggested by our case report. Both the use of the TOMOX regimen and irinotecan plus cetuximab seems to be safe regimens to be considered in this clinical scenario.

Topics: Acute Coronary Syndrome; Adenocarcinoma; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Thiophenes

A 71-year-old woman was referred to a surgical oncology clinic after CT raised suspicion for a bladder neoplasm. She had previously undergone right hemicolectomy and received adjuvant chemotherapy for pT3N1MX cancer of the cecum. A retroperitoneal recurrence had been deemed unsuitable for surgical resection, and had instead been treated with chemoradiation therapy. Follow-up CT raised suspicion for a possible bladder neoplasm.. CT, physical examination, urinalysis, cystoscopy with biopsy, pathological analysis and immunohistochemical analysis.. Adenocarcinoma of the cecum metastatic to the bladder.. The patient underwent open bladder resection with total excision of the neoplasm and was administered adjuvant chemotherapy consisting of irinotecan and cetuximab. Subsequent recurrences at the same site were treated with transurethral resection, while chemotherapy was still in progress. At 7 months' follow-up, the patient remained alive, with no evidence of further recurrence.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cecal Neoplasms; Cetuximab; Chemotherapy, Adjuvant; Colectomy; Female; Fluorouracil; Humans; Immunohistochemistry; Irinotecan; Leucovorin; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Organoplatinum Compounds; Quinazolines; Retroperitoneal Neoplasms; Sacrum; Thiophenes; Tomography, X-Ray Computed; Urinary Bladder Neoplasms

Solid tumors may occur in 3% of the patients with chronic myeloid leukemia (CML). Philadelphia (Ph)-positive CML was diagnosed in a 66-year-old man upon a white blood cell count of 58.1 x 10(9)/L. He had no symptoms and physical findings 3 years after treatment for rectal adenocarcinoma. Imatinib mesylate 400 mg/day was started and white blood cell count was lowered to 5.7 x 10(9)/L in 1 month. The patient had received several chemotherapeutic agents such as 5-fluorouracil, irinotecan, raltitrexed, capecitabine, and oxaliplatin. In the literature, there are two reports on CML after the treatment of colorectal carcinoma. The possibility of a relationship between oxaliplatin and/or irinotecan and CML may not be fully excluded. In conclusion, hematological disorders such as CML may emerge in colorectal carcinoma and whole blood counts should be carefully checked. The possibility of a relationship between CML and the chemotherapeutic agents in colorectal carcinoma should be further evaluated.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Deoxycytidine; Fluorouracil; Fusion Proteins, bcr-abl; Humans; In Situ Hybridization, Fluorescence; Irinotecan; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Liver Neoplasms; Male; Neoplasms, Second Primary; Organoplatinum Compounds; Oxaliplatin; Philadelphia Chromosome; Quinazolines; Rectal Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Thiophenes

5-Fluorouracil, usually in combination with folinic acid, is widely used in the treatment of both colorectal and head and neck squamous cell cancer patients. Since 5-fluorouracil plus folinic acid and the antifolate thymidylate synthase inhibitor; raltitrexed have distinct mechanisms of action and toxicity profiles, we have evaluated the potential synergistic antitumor interaction between these two agents combined with a sequential schedule of administration in KB (wt-p53) and Cal27 (mut-p53) head and neck squamous cell carcinomas, and LoVo (wt-p53) and HT29 (mut-p53) colorectal cell lines. The combination between a 24-h exposure to raltitrexed followed by a 4-h exposure to 5-fluorouracil plus folinic acid was globally synergistic, as assessed by the median effect principle and combination index. A specific contribution of folinic acid to the cytotoxic effect of the raltitrexed/5-fluorouracil combination was clearly demonstrated by the evaluation of the potentiation factor. In all cell lines, a 1.5- up to 17-fold reduction in the IC50 of both raltitrexed and 5-fluorouracil plus folinic acid was observed in the combination setting compared with the concentrations of the each drug used alone. Moreover, we demonstrated that raltitrexed/5-fluorouracil plus folinic acid induced a distinct S-phase block of the cell cycle, as well as a potentiation of the apoptotic cell death, compared with 5-fluorouracil plus folinic acid or raltitrexed/5-fluorouracil combination. This preclinical work represents, at least to our knowledge, the first demonstration of a synergistic interaction between raltitrexed and 5-fluorouracil modulated by folinic acid, and could represent a rationale for further clinical investigation of raltitrexed/5-fluorouracil plus folinic acid combination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Fluorouracil; Head and Neck Neoplasms; Humans; Inhibitory Concentration 50; Leucovorin; Quinazolines; Thiophenes

Pemetrexed, a new generation antifolate recently approved for the treatment of mesothelioma and non-small cell lung cancer, is an excellent substrate for the reduced folate carrier (RFC). To explore the carrier's effect on pemetrexed activity, RFC was inactivated in HCT-15 colon cancer cells by mutagenesis and PT632 selective pressure. A clone (PT1) was obtained with a glycine to arginine substitution at amino acid 401, resulting in the loss of RFC function. PT1 cells were resistant to PT632 (178-fold), methotrexate (4-fold), and ZD1694 (Tomudex, raltitrexed; 20-fold), but were 3-fold collaterally sensitive to pemetrexed when grown in 25 nmol/L of 5-formyltetrahydrofolate. PT1 cells transfected with wild-type RFC had antifolate sensitivities comparable to that of wild-type HCT-15 cells, indicating that the RFC mutation was the sole basis for resistance. Folate pools were contracted in PT1 cells by 32% or 60%, as measured by radiolabeling intracellular folates or by an enzyme binding assay, respectively. This was reflected in marked (6.5-fold) collateral sensitivity to trimetrexate. The initial uptake of pemetrexed in PT1 cells was markedly reduced ( approximately 85%) but intracellular pemetrexed levels increased to approximately 60% and approximately 70% to that of wild-type cells after 2 hours and 6 days, respectively. There was increased pemetrexed inhibition of glycinamide ribonucleotide transformylase and, to a lesser extent, thymidylate synthase in PT1 cells growing in 5-formyltetrahydrofolate based on nucleoside protection analyses. Hence, loss of RFC function leads to collateral sensitivity to pemetrexed in HCT-15 cells, likely due to cellular folate pool contraction resulting in partial preservation of pemetrexed polyglutamylation and increased target enzyme inhibition. micro

Topics: Amino Acid Substitution; Antineoplastic Agents; Arginine; Carrier Proteins; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Neoplasm; Folate Receptors, GPI-Anchored; Folic Acid Antagonists; Glutamates; Glycine; Guanine; Humans; Leucovorin; Methotrexate; Mutation; Pemetrexed; Phosphoribosylglycinamide Formyltransferase; Purines; Pyrimidines; Quinazolines; Receptors, Cell Surface; Thiophenes; Thymidylate Synthase

Raltitrexed (Tomudex), a classical folate antagonist, is a selective inhibitor of thymidylate synthase (TS). It has significant single-agent activity in metastatic colorectal cancer. Severe life-threatening toxicity related to the administration of 5-fluorouracil and leucovorin is described in two patients, both of whom were not deficient in dihydropyrimidine dehydrogenase. Raltitrexed was administered to both patients with clinically acceptable side effects and allowed a TS inhibitor to be administered as part of an adjuvant program.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Aged; Antimetabolites, Antineoplastic; Colonic Diseases; Drug Hypersensitivity; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Middle Aged; Quinazolines; Thiophenes; Thymidylate Synthase

Plasma levels of folates and thymidine in mice are about 10-fold higher than in humans and may influence the therapeutic efficacy of thymidylate synthase (TS) inhibitors, such as 5-fluorouracil (5FU) and the antifolates pemetrexed (MTA) and raltitrexed (RTX). Therefore, we tested their therapeutic efficacy in various murine tumor models, grown in mice on a normal and a folate-depleted diet, with high and low thymidine kinase (TK) levels. MTA and RTX were inactive against Colon-26-10 [doubling times gained by treatment; growth delay factor (GDF), 0.5 and 0.3, respectively], whereas 5FU was very active (GDF, >10; complete cures). Colon-26-10/F, grown in mice on a folate-depleted diet, was more sensitive to RTX and MTA (GDF, 2.1 and 1.3, respectively) but not to 5FU (GDF, 1.2); however, leucovorin reversed the effect leading to cures. Folate depletion did not reverse resistance of Colon-26A and Colon-26G (low TK) to MTA and RTX, whereas leucovorin only enhanced the 5FU effect in Colon-26A and Colon-26A/F. Folic acid at 15 mg/kg did not improve the therapeutic efficacy of MTA in folate-deficient mice. The folate-depleted diet decreased the reduced folates in Colon-26A/F and Colon-26-G/F tumors less (4-5-fold; P < 0.01) than in Colon-26-10/F tumors (8-fold; P < 0.001). Folate depletion increased TS levels 2-3-fold in all of the models and TK levels 6-fold (P < 0.01) in Colon-26G/F, explaining the lack of activity of MTA and RTX in Colon-26G/F. In contrast, TK-deficient FM3A/TK tumors were much more sensitive to RTX, MTA, and 5FU than parent FM3A tumors, which have comparable TS levels. The rate of thymidine phosphorylysis varied considerably in all of the tumors without a clear relation to antitumor activity. In conclusion, tumor folates may potentiate (5FU) or protect (antifolates). Murine tumor models should combine low folates and low thymidine rescue to optimize preclinical testing of antifolates.

Topics: Animals; Antimetabolites, Antineoplastic; Cell Division; Colonic Neoplasms; Diet; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Female; Fluorouracil; Folic Acid; Folic Acid Antagonists; Glutamates; Guanine; Leucovorin; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Pemetrexed; Quinazolines; Thiophenes; Thymidine; Thymidine Kinase; Thymidylate Synthase

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor that is effective for the treatment of advanced colorectal cancer and other solid tumors. However, a small minority of patients receiving RTX monotherapy will experience grade III/IV gastrointestinal toxicity that can be life-threatening, particularly if copresenting with neutropenia. Lack of vigilance in recognition and treatment of symptoms of toxicity or violations of protocol have led to treatment-related deaths in some hospitals. The safety of RTX could be improved if an effective rescue agent was available. Leucovorin (LV) is a reduced folate cofactor that competes with RTX for transport and polyglutamation in both tumor and normal tissues and thus has potential as a rescue agent. In vitro cell studies are presented suggesting that the growth-inhibitory, and potentially cytotoxic, effects of RTX on populations of viable cells can be reversed by the delayed administration of LV. The mechanisms involved are inhibition of further drug uptake and polyglutamation and a redistribution and/or reduction in the concentration of preformed raltitrexed polyglutamates. A more clinically relevant in vivo mouse model was used to test the hypothesis further. BALB/c mice treated with 100 mg/kg/day x 4 days of RTX were used as a model for gastrointestinal and bone marrow toxicity. LV (200 mg/kg), which was given after the onset of severe weight loss and diarrhea (twice daily, days 5-7), prevented further weight loss and induced earlier recovery. This was accompanied by improvement in the histological appearance of the intestine (day 7) and the concentration of neutrophils and platelets in the blood (day 9). BALB/c mice could not tolerate 100 mg/kg daily x 5 days unless LV (200 mg/kg twice daily) was given on days 6-8. Measurement of RTX (polyglutamates) by RIA after 100 mg/kg RTX daily (days 1-4) showed less drug in plasma (3-4-fold), liver (8-11-fold), kidney (3-4-fold), and small intestinal epithelium (3-4-fold) on day 7 in LV-treated mice (100 or 200 mg/kg twice daily) compared with controls. A single injection of 100 mg/kg RTX (day 1) gave plasma levels of 3-4 pmol/ml on day 4 that are more clinically relevant. Administration of LV (100 or 200 mg/kg; twice daily on days 4-6) reduced the RTX concentration in the liver 2-4-fold on days 7, 9, and 11 compared with controls. A model is proposed where LV and/or its anabolic products can compete with RTX uptake into tissues and interfere with the hom

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Cell Division; Cell Line; Drug Interactions; Humans; Intestinal Mucosa; Intestine, Small; Leucovorin; Leukemia L1210; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Neutropenia; Polyglutamic Acid; Quinazolines; Thiophenes; Thrombocytopenia

Topics: Advisory Committees; Antidotes; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Colonic Neoplasms; Control Groups; Drug Industry; Europe; Fluorouracil; Humans; Leucovorin; Multicenter Studies as Topic; Quinazolines; Research Subjects; Thiophenes

The surgical treatment of colorectal cancer (CRC) in elderly patients (age 70 years or older) has improved, but data on adjuvant and palliative chemotherapy tolerability and benefits in this growing population remain scarce. Elderly patients are underrepresented in clinical trials, and results for older patients are seldom reported separately.. Using a prospective database, we analyzed demographics, chemotherapy toxicity, response rates, failure-free survival (FFS), and overall survival (OS) of CRC patients receiving chemotherapy at the Royal Marsden Hospital. The cutoff age was 70 years.. A total of 844 patients received first-line chemotherapy with various fluorouracil (5-FU)-containing regimens or raltitrexed for advanced disease, and 543 patients were administered adjuvant, protracted venous infusion 5-FU or bolus 5-FU/folinic acid (FA) chemotherapy. Of the 1,387 patients, 310 were 70 years or older. There was no difference in overall or severe (Common Toxicity Criteria III to IV) toxicity between the two age groups, with the exception of more frequent severe mucositis in older patients receiving adjuvant bolus 5-FU/FA. For patients receiving palliative chemotherapy, no difference in response rates (24% v 29%, P =.19) and median FFS (164 v 168 days) were detected when the elderly were compared with younger patients. Median OS was 292 days for the elderly group and 350 days for the younger patients (P =.04), and 1-year survival was 44% and 48%, respectively. The length of inpatient hospital stay was identical.. Elderly patients with good performance status tolerated adjuvant and palliative chemotherapy for CRC as well as did younger patients and had similar benefits from palliative chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Databases, Factual; Female; Fluorouracil; Geriatrics; Humans; Leucovorin; Male; Middle Aged; Palliative Care; Prospective Studies; Quality of Life; Quinazolines; Survival Analysis; Thiophenes

The resistance to folate-based antifolates is associated with impaired function of the reduced folate carrier (RFC), one of the major routes of folate transport into cancer cells. To clarify the importance of RFC functions in the antifolate resistance, we have examined the expression of RFC1 and its phenotype as a folate transporter in human leukemia cell lines resistant to various antifolates. MOLT-3 cells resistant to ZD9331 (a thymidylate synthase (TS) inhibitor that utilizes the RFC for cell entry) (MOLT-3/ZD9331) showed decreased expression of RFC1 concomitant with diminished cellular uptake of [3H]methotrexate (MTX). K562 cells resistant to raltitrexed (ZD1694, another TS inhibitor that utilizes the RFC for cell entry) (K562/ ZD1694 x C) scarcely expressed RFC1, which is in accordance with the impaired uptake of folate analogs and the high degree of resistance to ZD1694 and MTX. On the other hand, no apparent decrease of RFCI1 expression was found in transport-deficient MTX-resistant MOLT-3 cells (MOLT-3/MTX10000) though its phenotype showed defective transport of MTX or ZD1694. In these cell lines with impaired RFC function, [3H]leucovorin (LV) uptake was only moderately decreased as compared to [3H]MTX or [3H]ZD1694 uptake. These cells grew with a minimal retardation in folate-free medium supplemented with 10 nM LV, suggesting that these cell lines with impaired RFC function had enough folate transporters to transport LV. In contrast to downregulation of RFC, the much greater uptake of [3H]MTX was observed in the MOLT-3/trimetrexate (TMQ)800-MTX10000 in parallel with increased RFC1 expression. These cell lines with the altered expression of RFC1 may serve as models useful for investigating the regulation of RFC1 expression and for understanding the molecular mechanism(s) behind the transport-mediated antifolate resistance.

Topics: Antimetabolites, Antineoplastic; Biological Transport; Carrier Proteins; Drug Resistance, Neoplasm; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Membrane Proteins; Membrane Transport Proteins; Methotrexate; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quinazolines; Tetrahydrofolate Dehydrogenase; Thiophenes; Tumor Cells, Cultured

The role of a membrane-associated folate binding protein (mFBP) in transport of folate analogues was investigated in three epithelial cell lines that were grown in high folate medium and folate-conditioned medium and express different levels of mFBP: human nasopharyngeal KB cells, monkey kidney MA104 cells, and IGROV-I ovarian carcinoma cells. Folate analogues were selected for which mFBP exhibits a low affinity, i.e., methotrexate (MTX) and 10-ethyl-10-deazaaminopterin (10-EdAM) or a (moderately) high affinity as compared to folic acid, i.e., N-(5[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl(-N-m ethylamino]-2-theonyl)-L-glutamic acid (ZD1694), N10-propargyl-5,8-dideazafolic acid (CB3717), and 5,10-dideazatetrahydrofolic acid. Regardless of the medium folate status, growth inhibition studies with IGROV-I and MA104 cells demonstrated a lack of correlation between the affinity of mFBP for the antifolate drugs and their sensitivity profile; both cell lines were highly sensitive to growth inhibition by MTX, 10-EdAM, ZD1694 and 5,10-dideazatetrahydrofolic acid, but were insensitive for CB3717. The same drug sensitivity profile was observed for KB cells, with the exception that these cells were also sensitive to growth inhibition by CB3717 but only in folate-conditioned medium. This overall drug sensitivity profile appeared to correlate with the differential efficiency of drug transport via the "classical" reduced folate/MTX carrier (RFC), rather than by mFBP. Characteristics that further supported functional RFC activity in KB, IGROV-I, and MA104 cells included: (a) the growth inhibitory effects of the drugs could be prevented by the reduced folate leucovorin rather than by folic acid; (b) rates for uptake of [3H]10-EdAM were 2-4-fold higher than for [3H]MTX at 1 microM extracellular concentrations and coincided with the affinity of the RFC for these drugs, rather than those of the mFBP; (c) uptake of [3H]10-EdAM and [3H]leucovorin was markedly inhibited by leucovorin and 10-EdAM, respectively, or by an N-hydroxysuccinimide ester of MTX (irreversibly labeling RFC) but only to a minor extent by folic acid or an N-hydroxysuccinimide ester of folic acid (irreversibly labeling mFBP); and, finally, (d) labeling with an N-hydroxysuccinimide ester of [3H]MTX identified a protein with a molecular weight within the range of that reported for the RFC in human leukemic cells. Altogether, these results indicate that both RFC and mFBP are coexpressed in three epithe

Topics: Aminopterin; Animals; Carrier Proteins; Cell Division; Female; Folate Receptors, GPI-Anchored; Folic Acid; Folic Acid Antagonists; Glutamates; Haplorhini; Humans; Kidney; Leucovorin; Methotrexate; Nasopharyngeal Neoplasms; Ovarian Neoplasms; Quinazolines; Receptors, Cell Surface; Tetrahydrofolates; Thiophenes; Tumor Cells, Cultured

The cytotoxicity and molecular effects of antifolate thymidylate synthase inhibitor, ICI-D1694, against human ileocecal carcinoma, were evaluated. The drug concentration for 50% inhibition of cell growth by ICI-D1694 is 73 nM and 3 nM following 2 hr and 72 hr exposure, respectively. The drug induces high level of DNA single strand breaks in a time dependent manner, but subsequent to maximum inhibition of thymidylate synthase. Drug effects can be reversed by thymidine and leucovorin at > 1 microM concentrations. Leucovorin action is primarily at the cell membrane level, competing with the transport and activation of ICI-D1694. Thymidine, however, exerts its competitive effect primarily at the level of thymidylate synthase.

Topics: Antimetabolites, Antineoplastic; Carcinoma; Dose-Response Relationship, Drug; Drug Interactions; Evaluation Studies as Topic; Humans; Intestinal Neoplasms; Leucovorin; Quinazolines; Thiophenes; Thymidine; Thymidylate Synthase; Tumor Cells, Cultured

CCRF-CEM human leukemia sublines resistant to short-term methotrexate (MTX) exposure as a result of decreased folylpolyglutamate synthetase (FPGS) activity were examined for their response to other cytotoxic agents. The R3/7 and R30dm sublines display 25 and 1%, respectively, of the FPGS activity of CCRF-CEM cells as measured with MTX in vitro. Response to agents in outgrowth experiments was examined under both continuous exposure (120 h, where MTX resistance is not observed) and short-term (6-14.5 h) exposure. During continuous exposure to various classes of agents, cross-resistance of R3/7 and R30dm that correlated with FPGS level was not observed, although some minor (< or = 3-fold) stochastic variations in sensitivity were noted. These agents included actinomycin D, Adriamycin, etoposide, vincristine, cisplatin, cytosine arabinoside, 5-fluorouracil, and some other antifolates. Cross-resistance during continuous exposure that did correlate with FPGS level was noted, however, to glutamate-containing thymidylate synthase inhibitors (including ICI D1694) and, to a minor extent, to 6-mercaptopurine and 5-fluorodeoxyuridine. Slight collateral sensitivity during continuous exposure that apparently correlated with FPGS level was noted to the lipid-soluble antifolate trimetrexate and to 5,8-dideazapteroyl-L-ornithine, an FPGS-specific inhibitor. In short-term exposures (where MTX resistance of the sublines is observed), the resistant sublines displayed sensitivity or cross-resistance to each agent that was qualitatively similar to that observed for the same agent in continuous exposure. Because of the requirement for reduced folates in the anti-DNA mechanism of action of fluoropyrimidines and the current clinical use of leucovorin (LV) to enhance their effects, the interaction of LV and fluoropyrimidines was examined. The results suggest that even highly FPGS-deficient cells are as sensitive to the effects of LV modulation as are wild-type cells even at fluoropyrimidine exposure times as short as 4 h.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Cell Division; Drug Resistance; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Peptide Synthases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Quinazolines; Tetrahydrofolates; Thiophenes; Tumor Cells, Cultured