Dose Folinic Acid Research Articles

Folinic acid dose and addition of levamisole does not seem to improve survival or recurrence rates in people treated with adjuvant fluorouracil and folinic acid for colorectal cancer

Folinic acid dose and addition of levamisole does not seem to improve survival or recurrence rates in people treated with adjuvant fluorouracil and folinic acid for colorectal cancer

Sequential Trimetrexate, 5-Fluorouracil and Folinic Acid Are Effective and Well Tolerated in Metastatic Colorectal Carcinoma

Trimetrexate (TMTX) is a new antifolate which avoids competition for cellular uptake with folinic acid (FA). A regimen of sequential TMTX, FA and 5-fluorouracil (5-FU) has shown efficacy in patients with colorectal cancer. Therefore, we treated 34 previously untreated patients with metastatic colorectal cancer with a weekly chemotherapy regimen consisting of 110 mg/m² of TMTX intravenously, then 24 h later 200 mg/m² of FA (i.v.) and 500 mg/m² of 5-FU (i.v.). Thereafter, 7 doses of oral FA (15 mg) were given at 6-hourly intervals. A treatment cycle consisted of 6 weeks of treatment, then 2 weeks of rest. All patients were treated as outpatients unless complications arose. Thirty-three patients were assessable for tumor response, and all 34 patients were assessable for toxicity. Twelve patients (36%; 95% confidence interval: 25–49%) achieved a partial response. The median duration of response was 8.5 months, and median survival was 14 months. The most common toxicity was diarrhea of grade 3/4, observed in 22% of treatment cycles; this decreased to 8% with early loperamide treatment. Hematologic toxicity was mild. The sequential administration of TMTX, FA and 5-FU is an active regimen in the first-line treatment of metastatic colorectal cancer and warrants further studies.

Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial

Background Standard adjuvant chemotherapy for colorectal cancer consists of fluorouracil with folinic acid or levamisole. The large QUASAR randomised trial aimed to investigate (in a twoxtwo design) whether use of a higher dose of folinic acid or addition of levamisole to fluorouracil and folinic acid improved survival. Methods Patients with colorectal cancer, without evident residual disease, were randomly assigned fluorouracil (370 mg/m2) with high-dose (175 mg) or low-dose (25 mg) L-folinic acid and either active or placebo levamisole. The fluorouracil and folinic acid could be given either as six 5-day courses with 4 weeks between the start of the courses or as 30 once-weekly doses. Levamisole (50 mg) or placebo was given three times daily for 3 days repeated every 2 weeks for 12 courses. The primary endpoint was mortality from any cause. Analyses were by intention to treat. Findings Between 1994 and 1997, 4927 patients were enrolled. 1776 had recurrences and 1576 died. Survival was similar with high-dose and low-dose folinic acid (70·1% vs 71·0% at 3 years; p=0·43), as were 3-year recurrence rates (36·0% vs 35·8%; p=0·94). Survival was worse with levamisole than with placebo (69·4% vs 71·5% at 3 years; p=0·06), and there were more recurrences with the active drug (37·0% vs 34·9% at 3 years; p=0·16). Interpretation The inclusion of levamisole in chemotherapy regimens for colorectal cancer does not delay recurrence or improve survival. Higher-dose folinic acid produced no extra benefit in these regimens over that from low-dose folinic acid. Trials of chemotherapy versus no chemotherapy will show whether these four treatments are equally effective or equally ineffective.

Standard dose (Mayo regimen) 5-fluorouracil and low dose folinic acid: prohibitive toxicity?

Despite the perception that standard 5-fluorouracil/folinic acid (5-FU/FA) (425 mg/m2 per day and 20 mg/m2 per day intravenously once daily x 5 every 4 or 5 weeks) is well tolerated, we have been impressed by toxicity seen and frequent need for dose modification. We performed a retrospective analysis to quantitate the proportion of patients experiencing toxicity and attempted to identify associated clinical characteristics. One hundred thirty-four patients received 5-FU/FA at standard doses described by the Mayo regimen. Patient characteristics were as follows: female 35%, median age 66 years, Eastern Cooperative Oncology Group performance status less than or equal to 2, 96%. Sixty-eight percent received chemotherapy for metastatic disease. Forty-seven patients (35%+/-8%) experienced significant toxicity and were unable to receive the second cycle as scheduled: 76% required dose reduction, 11% discontinued therapy (including two toxic deaths), 11% discontinued therapy during the first cycle, and 2% required dose delay. Logistic regression was used to explore the following as predictors of toxicity: age, sex, performance status, adjuvant versus metastatic setting, prior chemotherapy, prior radiation, mean corpuscular volume, red blood cell distribution width, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin, and calculated creatinine clearance. No clinical characteristic was found to predict toxicity. Only high bilirubin approached statistical significance. We conclude that standard 5-FU/FA, when used in the general population, is associated with significant toxicity. Known clinical characteristics are not helpful in predicting toxicity. The lack of previous formal phase I evaluation of this regimen of 5-FU/FA raises concerns regarding its safety and generalizability in clinical practice.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

To assess the effects of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) and haematologic side effects of low-dose of Methotrexate (MTX) in patients with Rheumatoid Arthritis (RA) and to determine whether or not folate supplementation alters MTX efficacy. We searched the Cochrane Controlled Clinical Trial's Register (CCTR), the Cochrane Musculoskeletal Group Specialized Register and Medline up to and including June 1999, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). We also handsearched the following: (i) bibliographic references; (ii) current contents of the last 6 months; (iii) abstracts of the rheumatology meetings; and (iv) all issues of four journals; Journal of Rheumatology, Arthritis & Rheumatism, Clinical and Experimental Rheumatology, and British Journal of Rheumatology. All languages were included. Principal investigators were also contacted in order to look for unpublished literature. We selected all double-blind, randomized, placebo-controlled, clinical trials (RCTs), in which adult RA patients were treated with a low dose of MTX (<20 mg / week) concurrently with folate supplementation. Two observers extracted the data and assessed the quality of the trials. (BS, Z0) The overall treatment effect across trials was calculated using a fixed effect model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Results are presented with 95% Confidence Inervals (95% CI). Subgroup analyses were conducted evaluating different doses and sensitivity analysis looking at the quality of the trials. Publication bias was assessed with an inverted funnel plot technique. Heterogeneity of the trials was measured using a standard chi square test. Costs per month in different countries were compared. Of the 12 trials retrieved, 7 met the inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 80 patients with folinic acid and 67 patients with folic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but non-statistically significant reduction of 43% was found [OR = 0. 57 (95% CI 0.28 to 1.15)]. No major differences were observed between low and high doses of folic or folinic acid. Haematologic side effects could not be analyzed, since details of each haematologic side effect by patients were not provided. No consistent differences in disease activity parameters were observed when comparing placebo and folic or folinic acid at low or high doses, although patients on high dose folinic acid had an increase in the number of tender joints, but not swollen joints. Large differences in costs across countries were found, but folinic acid was more expensive in all. The results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.

Increasing doses of 5-fluorouracil and high-dose folinic acid in the treatment of metastatic colorectal cancer.

Combined 5-fluorouracil (5FU) and folinic acid (FA) is the first-line treatment of metastatic colorectal cancer. The aims of this study were to individualize the dose of 5FU in a weekly schedule in which the maximum tolerated dose of 5FU is administered to each patient, and to evaluate the impact of increasing 5FU doses on response and survival. Thirty-two patients (30 evaluable for response) with metastatic colorectal cancer were treated with weekly intravenous doses of FA 150 mg/m2 and a fast infusion of 5FU, at an initial dose of 600 mg/m2 which was increased by 60 mg/m2 every week until the appearance of a side effect, in order to determine the maximum tolerated dose for the patient. We obtained 11 objective responses (36.7%, median survival 22 months) and 15 disease stabilizations (50%, median survival 15 months); there were four cases of progressive disease (13.3%, median survival 4 months). The overall survival was 15 months. Twenty-eight patients (87.5%) tolerated 5FU doses of 720 mg/m2 or more. Weekly 5FU with high-dose FA modulation can be individualized by dose escalation. A 5FU dose of 720 mg/m2 per week seems to be critical, as higher doses are no more effective and lead to severe side effects. This schedule gives good results in terms of response, even though the complete response rate remains low.

Is Continuous 24-Hour Infusion of 5-Fluorouracil plus High-Dose Folinic Acid Effective in Patients with Progressive or Recurrent Colorectal Cancer?

Background: To evaluate the therapeutic activity of 24-hour continuously infused 5-fluorouracil (5-FU) modulated by high-dose folinic acid in patients with metastatic colorectal cancer who had recurred or progressed following mainly bolus 5-FU/folinic acid chemotherapy. Patients and Methods: Forty-two patients with a median age of 59 years (45–76) were enrolled. Karnosfky status was 90% (80–100), previous chemotherapy regimen bolus 5-FU/folinic acid (n = 33, 79%) or 24-hour continuous 5-FU ± interferon α₂ (n = 9, 21%). Chemotherapy was given as a weekly infusion of 500 mg/m² folinic acid over 2 h followed by a 24-hour continuous infusion of 2,600 mg/m² 5-FU for 6 consecutive weeks followed by a 2-week rest period. Results: No complete but 6 partial responses were observed (ORR: 14%, CI_95%: 3.5–25.1%) with a median response duration of 7.3 months (range: 1.4–10.6). The median survival from the start of continuous infusion of 5-FU was 11.6 months (range: 2–27, CI_95%: 9.4–13.8) and the 1-year survival rate was 46%. Disease stabilization and minor responses were achieved in another 25 patients (61%). WHO grade III/IV diarrhea occurred in 26% of patients, mucositis, nausea/vomiting and hand-foot syndrome in 5% each. Two cases of WHO grade III anemia and leukocytopenia were observed (5% each). Dose reductions had to be performed in 11 patients because of unacceptable diarrhea with subsequent stop of treatment in 2 patients. Progressive disease while receiving previous bolus 5-FU chemotherapy was associated with a lower response rate, shorter progression-free interval and overall survival compared to response and survival of patients who had achieved temporary disease stabilization during previous bolus 5-FU therapy. Conclusions: Continuous infusion of 5-FU/folinic acid displays activity in pretreated and refractory colorectal cancer with acceptable toxicity. Patients who had achieved disease stabilization or objective remission with previous 5-FU bolus therapy appear to be more likely to benefit from second-line treatment. Questions remaining to be addressed include the optimal starting dose of continuously infused 5-FU and whether the dose of folinic acid can be reduced or completely eliminated with respect to toxicity and health economics.

Successful Rescue in a Patient with High Dose Methotrexate-Induced Nephrotoxicity and Acute Renal Failure

We describe the case of a 35-year old male who developed acute renal failure following high dose methotrexate therapy for Burkitt's non Hodgkin lymphoma. Serum methotrexate levels reached 37 μmol/l, and remained higher than 1 μmol/l for more than a week. Folinic acid rescue was intensified to 200–400 mg intravenously every 4 hours. As methotrexate binds markedly to proteins, plasma exchange was initially chosen, 4 sessions being performed from day 2 to day 4. The methotrexate pharmacokinetic profile was not significantly modified during plasma exchange, and serum drug level was 3 μmol/l. Continuous veno-venous hemodiafiltration was therefore performed from day 5 to day 10. This procedure also seemed ineffective, with evidence of low ultrafiltrate clearance. No extrarenal toxicity was observed in our patient. Thus, conventional extrarenal procedures appear to have a limited role in the setting of overexposure to methotrexate. The use of very high doses of folinic acid in our case probably played a major role in the eventual favorable outcome.

Methotrexate in Rheumatoid Arthritis

Methotrexate is now the disease-modifying antirheumatic drug prescribed most frequently for the treatment of rheumatoid arthritis. Methotrexate is an antifolate that inhibits methylation reactions and reactions of amino acid, purine and pyrimidine metabolism. Toxic manifestations of methotrexate administration for rheumatoid arthritis (at relatively low doses compared with those used in cancer chemotherapy) include cytopenias, gastrointestinal intolerance, liver disease, pulmonary injury, central nervous system dysfunction, skin rashes and nodulosis. Delayed wound healing and increased risk for infections with opportunistic organisms also occur. Some of these toxic manifestations respond to supplementation with folates [folic acid or folinic acid (calcium folinate)]. The folate status of patients has been shown to be impaired after prolonged treatment with methotrexate, and poor baseline folate status is an independent risk factor for subsequent toxicity. Numerous studies have now documented that folic acid, even in high doses, and moderate doses of folinic acid are beneficial in preventing methotrexate toxicity without affecting efficacy. In this article we present guidelines and rationale for monitoring methotrexate therapy, and guidelines for folate supplementation during methotrexate therapy for rheumatoid arthritis. It is our recommendation that folic acid should be empirically supplemented in all patients at the initiation of methotrexate therapy. This regimen is associated with a high benefit : risk ratio and is likely to be cost effective.

759 - Phase II study of 24 hours-infusion of 5-fluorouracil and high dose folinic acid in patients with progressive or recurrent colorectal cancer (CRC)

759 - Phase II study of 24 hours-infusion of 5-fluorouracil and high dose folinic acid in patients with progressive or recurrent colorectal cancer (CRC)

Retrospective Comparative Analysis of 5FU + Low-Dose Folinic Acid vs. 5FU + High-Dose Folinic Acid in the Treatment of Metastatic Colorectal Cancer

Two regimens of 5FU and folinic acid in the treatment of metastatic colorectal cancer were retrospectively analyzed. 33 patients received the high dose (HD) schedule (5FU 370 mg/m2 and Folinic Acid 200 mg/m2 i.v. on D1-5, every 4 weeks), 61 patients received the low dose (LD) schedule (5FU 400 mg/m2 and Folinic Acid 20 mg/m2 i.v. on D1-5, every 4 weeks). One patient in each group achieved a complete response, the overall response rate was 28% and 11% for the HD and LD groups, respectively. The median response duration was 183 days for the HD and 112 days for the LD group. The median survival duration was 387 days for the HD and 405 days for the LD group. The response rate and duration of response were higher in the HD group though this did not reach statistical significance. There was no difference in overall survival between the two patient groups. Neutropenia and gastro-intestinal symptoms were the most common toxicities, they were equal in both groups. One patient (3%) in the HD and 5 patients (9%) in LD group discontinued treatment due to toxicity. There were no treatment related deaths. It is concluded that low dose folinic acid in combination with 5FU is effective and produces similar toxicities as high dose folinic acid. It is concluded that low dose folinic acid in combination with 5FU is an effective alternative to high dose regimen in the palliative management of patients with metastatic colorectal cancer. However though it did not reach statistical significance the high dose regimen was associated with a higher response rate. This could have a significant effect when the combination is used in the adjuvant treatment of high risk patients.

Noninvasive evaluation of cardiotoxicity of 5-fluorouracil and low doses of folinic acid: A one-year follow-up study

To conduct a serial evaluation of the cardiac effects of antineoplastic therapy with 5-fluorouracil (5-FU) and low-dose folinic acid. Sixteen patients with colon-rectal carcinoma, without cardiac disease, treated with 400 mg/ m2/die of 5-FU and 20 mg/m2/die of folinic acid for five days, once a month, for six months. Parameters evaluated: blood pressure, ECG, two-dimensional and digitized M-mode echocardiograms before and after the first and fifth drug administrations of the first cycle, after the fifth drug administration of the sixth cycle and six months after the treatment. Blood pressure, heart rate, left ventricular (LV) diameter and LV mass index did not change; all of the patients showed a decrease in the peak shortening rate of the LV diameter index of systolic function, and of the peak lengthening rate of the LV diameter and peak thinning rate of LV posterior wall, indexes of diastolic function, with abnormal values in 11 patients at the end of treatment LV wall motion remained normal in all; two patients developed transient T wave inversion without chest pain and with normal cardiac enzymes and myocardial scintigraphy during dypiridamole stress test. Six months after the treatment all indexes of LV systolic and diastolic function had returned within the normal limits and were similar to pre-treatment values. 5-FU and low-dose folinic acid treatment induced a decrease of LV systolic function and an impairment of diastolic function, that developed without symptoms and were transient and reversible.

Raltitrexed and the treatment of advanced colorectal cancer

Objective. Colorectal cancer is the second largest cause of death from malignant disease in Western countries. Although surgical resection is the preferred treatment in early disease, chemotherapy has an important role to play both as an adjunct to surgery and in the palliation of advanced disease. For many years 5-fluorouracil (5-FU) has been the only cyto toxic drug with significant activity in this condition and, recently, considerable effort has been directed toward enhancing its activity and finding better, alternative agents. Recently, raltitrexed (Tomudex; Zeneca Pharmaceuticals), the first of a new class of cytotoxic drugs, the selective, direct, thymidylate synthase inhibitors, received its first regulatory ap proval for the first-line treatment of advanced colo rectal cancer. The purpose of this review is to con sider the efficacy, toxicity, and resource implications of using this new antineoplastic agent, alongside developments that have been made in the more effective use of fluoropyrimidines, and the place of drug treatment in the management of colorectal cancer. Data Sources. A variety of sources were used, including manual and on-line (Medline and Pharm- line) literature searching. Approved and other drug names were used as primary search terms, linked with colorectal cancer where limitation was required. The medical information department of Zeneca Pharma ceuticals also was used where appropriate. Study Selection. Particular attention was di rected to randomized clinical trials, but nonrandom ized and preclinical studies were considered where appropriate. Conclusions. Although colorectal cancer is in herently resistant to cytotoxic chemotherapy, such treatment now has an established role as an adjunct to surgery and in the palliation of advanced disease. The optimum 5-FU- based regimen has yet to be estab lished with certainty, although in advanced disease a four-times-weekly, 5-day regimen of 5-FU and low- dose folinic acid is probably the best of those fully evaluated to date. Raltitrexed seems to be as effective as this combination while having definite advantages in terms of toxicity and the resources required for its preparation and administration, although it remains to be seen to what extent these and other resource benefits will be offset by its higher cost and how its efficacy and tolerability will compare with other 5-FU- based regimens in ongoing clinical trials.

An analysis of drug costs for the management of chemotherapy-related side effects in advanced colorectal cancer

Purpose. To assess whether there is a difference in associated drug costs for the management of chemo therapy-related side effects for patients with advanced colorectal cancer treated with raltitrexed (Tomudex, Zeneca Limited) or 5-FU plus folinic acid (Mayo regimen). Data Sources. The drugs used for the manage ment of side effects were determined using a UK cohort (n = 62) taken from a large phase III ralti trexed clinical study. This study compared the toler ability and efficacy of raltitrexed vs 5-FU plus low- dose folinic acid and reported a significantly lower incidence of WHO grade 3/4 mucositis and leucope nia with raltitrexed. Drug costs were sourced using the British National Formulary, the Monthly Index of Medical Specialities and the Chemist and Druggist. Drug costs for the management of individual chemo therapy-related side-effects were calculated for both treatment groups and the total mean cost was com pared using the Student t test. Costs associated with the use of drugs for the management of clinically similar side effects, for example, nausea and vomiting were also investigated. Results. There was a significant reduction in the mean total drug cost per patient for the management of chemotherapy-related side effects in the raltitrexed group compared to the 5-FU/folinic acid treatment group (£,64.27 vs £139.14; P = .0016). Infection was the most costly individual side effect for both treat ment groups but was lower in the raltitrexed cohort (£25.46 vs £59.93). Drug costs for the management of nausea and vomiting, pain and abdominal pain, and mucositis side effects were also considerably lower in the raltitrexed cohort. Conclusion. The significantly lower drug cost for the management of chemotherapy-related side effects for the raltitrexed patients in the UK cohort suggests that the lower WHO grade 3/4 toxicity observed with raltitrexed in the phase III study would also be associated with a reduction in drug costs for the management of chemotherapy-related side ef fects.

Cisplatin, 5-Fluorouracil, and High-Dose Folinic Acid in Patients with Advanced Unresectable Head and Neck Cancer

For patients with advanced, unresectable head and neck (HN) cancer, surgery and/or radiotherapy are the standard treatments but have poor results. A phase II trial of a continuous infusion of cisplatin, 5-FU, and high dose folinic acid (PFL) as induction chemotherapy in patients with previously untreated, locally advanced HN cancer was performed in an attempt to confirm the encouraging results reported by Dana Farber investigators using an identical regimen. Forty-five consecutive patients with unresectable HN cancer were treated every 28 days with a continuous infusion of cisplatin 25 mg/m(2)/day (days 1-5), 5-FU 800 mg/m(2)/day (days 2-6), and folinic acid 500 mg/m(2)/day (days 1-6). After three courses of chemotherapy, patients were treated with surgery and/or radiotherapy. Objective responses were observed in 26 of 38(69%) evaluable patients with 14(37%) clinical complete responses. Grade III-IV toxicity was important and consisted mainly of mucositis and neutropenia that were found in 47 and 18%, respectively , of patients after the first course. There was one toxic death. PFL is an active, toxic induction regimen for far-advanced HN cancer, yielding a response rate in the range of the widely used cisplatin and 5-FU (PF) schedule; a comparative trial is warranted before concluding that PFL is superior to the latter combination.

A Phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma.

A Phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma.

Critical factors for optimizing the 5-fluorouracil-folinic acid association in cancer chemotherapy

The 5-fluorouracil (FU)-folinic acid (FA) association has demonstrated clinical efficacy in colorectal cancer, both in adjuvant and metastatic situations. However, there is no clear consensus about the optimal FU-FA schedule and dose. In addition, it would be of interest to identify FU-FA-responsive tumors. Our purpose was to review preclinical and clinical data dealing with prediction of FU-FA sensitivity and optimization of FU-FA schedules. Preclinical studies have highlighted the importance of thymidylate synthase (TS), the cellular target of the FU-FA mechanism of action, for predicting FU sensitivity. It appears that the more sensitive cell lines express the lowest TS activity. Interestingly, the cell lines sensitive to FA supplementation are those more sensitive to FU. The role of TS in FU-FA responsiveness has been clearly demonstrated in patients with colorectal and gastric cancers. Preliminary in vitro and clinical data have shown that the folylpolyglutamate synthetase (FPGS), the enzyme responsible for folate polyglutamylation, is another promising tool for identifying FU-FA-responsive tumors. So far, results of clinical trials do not form a clear consensus regarding the need to administer high FA doses for improving FU-FA treatment. Experimental studies on human cancer cell lines have demonstrated the wide variability among cell lines, ranging from 0.05 to 200 microns, of 1 FA concentrations required for maximal FU potentiation. In addition, pharmacokinetic studies have reported a significant variability of active folates in plasma after administration of standard-dose FA. Altogether, these observations favour high-dose FA administration to achieve high folate concentrations in plasma and thus to counteract the variability of the 1 FA concentrations required. With respect to the choice of FU-FA schedule, it appears from experimental data that increasing the duration of exposure to FA enhances FU-FA cytotoxicity, probably through an increased formation of reduced folate polyglutamate forms. Considering the S-phase specificity of FU cytotoxicity as well as its rapid elimination from plasma, a schedule of prolonged exposure to both FU and FA should be considered preferable. Results of the new FU-FA administration schedules such as the one consisting of a 2-hour FA administration followed by a combination of FU bolus and FU infusion, or the chronomodulated FU-FA infusion, open up promising approaches for improving the therapeutic index of FU-FA chemotherapy. Finally, future clinical studies should investigate tumoral parameters pharmacologically linked to FU-FA sensitivity such as pre-treatment TS and FPGS activities. Such tumoral investigations along with FU and FA pharmacokinetic investigations should provide a better understanding of inter-patient variability in response to FU-FA therapy and an optimal management of this chemotherapy regimen.

Palliative treatment for advanced gastrointestinal cancer: is response a suitable end-point?

Treatment results of standard chemotherapy in advanced gastrointestinal tract cancer are disappointing. 5-Fluorouracil (FU) is the therapeutic mainstay since its discovery more than 35 years ago. Response rates of single agent FU treatment range between 5 and 20% dependent on dose and schedule. The efforts of the last two decades have been focused on the improvement of objective response rates using several combinations of chemotherapy regimens including doxorubicin, cisplatin, mitomycin and etoposide. Most of the phase l/II studies have reported encouraging treatment results initially with respect to response rates. Subsequent randomized trials, however, revealed a high rate of World Health Organization (WHO) grade III/IV toxicity of these combination regimens, which was not compatible with the palliative treatment intention (1). Another approach to improve the therapeutic effects of standard FU treatment was to combine it with modulating agents such as cl-interferon, folinic acid, Nphosphon-acetyl-L-aspartate (PALA) and methotrexate. Biomodulation of FU with folinic acid has become the standard treatment for advanced colorectal cancer, with response rates being superior to those with single agent FU and low treatment-related toxicity. Double modulation of FU with folinic acid and cl-interferon has achieved respectable response rates in advanced gastric and pancreatic carcinoma. Moderate toxicity and effective control of tumour-related symptoms, notably tumour-related pain, have emerged as the crucial parameters supporting a high palliative quality of this treatment, rather than high objective response rates. Over the past few years, the authors have conducted phase II trials in advanced pancreatic and gastric carcinoma and two randomized multicentre trials in advanced colorectal cancer. End-points of all trials were toxicity profile, objective responses, duration of response, progression-free intervals, median survival time and quality of life under treatment. Evaluation of the randomized trial in colorectal cancer with weekly high dose (A) vs low dose (B) folinic acid/ FU revealed objective response rates of 28% (A) and 23% (B), respectively. Toxicity was mild with a rate of WHO grade III/IV toxicity ~15% in both arms. Median survival was 12.5 months in both arms. Quality of life under treatment was high due to the outpatient treatment setting, low toxicity and effective

A phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma

To evaluate the toxicities of a Phase I study of radiation therapy with concurrent 5-fluorouracil (5FU) and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma. Twenty-seven patients with locally advanced carcinoma of the pancreas (n = 19), bile duct (n = 7), and gall bladder (n = 1) were entered into a Phase I study of combined radiation therapy, 5FU, and folinic acid. Radiation was given as a split course of 40 Gy in 20 daily fractions with a gap of 2 weeks after 20 Gy. 5-Fluorouracil, 300 to 375 mg/m2/day and folinic acid, 20 mg/m2/day were given as an i.v. bolus daily for 5 days beginning on day 1 and again on day 29. Eight patients developed Grade 3 or 4 toxicities (National Cancer Institute common toxicity criteria) including nausea and vomiting (n = 4), oral mucositis (n = 4), myelosuppression (n = 2), infection (n = 2), and diarrhea (n = 1). Four patients did not complete the planned protocol due to treatment toxicities. There were two treatment deaths secondary to septic neutropenia. Treatment toxicity appeared to be related to age (> 70), performance status (ECOG = 2), and 5FU dose (> 350 mg/m2/day). This protocol is poorly tolerated by elderly patients or those with poor performance status, and 350 mg/m2/day is our recommended dose for 5FU as given in this protocol.

734 Tissue levels of 5,10 methylenetetrahydrofolate and tetrahydrofolate in pts with colorectal carcinoma with or without pretreatment with folinic acid or 5-methyltetrahydrofolate

The modulation of 5-fluorouracil (5-FU) with folinic acid (FA) has been established in vitro and in various clinical studies for the treatment of colorectal carcinomas. Although pharmacokinetics and metabolism of FA in serum are well established the dose of folinic acid is still debated. As only few data about tissue levels of the modulating metabolite of FA, 5,10-methylentetrahydrofolate (mTHF), in humans are available, we used the “tritium-release-assay”, for evaluation of reduced tissue folate pools in mucosa, primary tumor, liver and liver metastases from pts with colon carcinoma with and without pretreatment with various doses of FA or 5-mTHF. Drugs were given i. v. as short term infusion just before surgery. So far, analysis has been completed in 68 pts (23 mucosa, 22 tumor, 11 liver and 12 metastases) without pretreatment as well as 22 pts after pretreatment with 200 mg/m 2 FA and 20 pts with 5-mTHF, respectively. In both treatment groups reduced folate pools in mucosa and primary tumor were expanded, 5-mTHF however was somewhat less effective than FA. Furthermore, mucosa and tumor tissue was obtained after pretreatment with low dose (20 mg/m 2 ) and high dose (500 mg/m 2 ) FA from 10 pts. each treatment group. These specimen are currently under investigation regarding combined pools of mTHF and THF, and data will be presented at the meeting. Supported by DFG grant Ku 753-1/2and MEDAC GmbH.