Rescuing effect of folates on methotrexate cytotoxicity in human trophoblast cells.

OBJECTIVES: Methotrexate (MTX)is a folate antagonist that is administered in several conditions such as rheumatoid arthritis. Its use may associate with adverse effects presumably originating from folate deficiency. Although MTX side effects could be decreased by folate supplementation, the current guideline on folate administration is not precisely established, which could result in irreversible damage especially in high-risk groups like women in childbearing-age. Thus, this study aimed to investigate the in vitro rescuing effect of different folates including folic acid (FA), 5-methyltetrahydrofolate (MTHF) and folinic acid (5-Formyltetrahydrofolic acid, FTHF) on MTX-treated trophoblast cells. METHODS: HTR-8/SVneo cells were stressed with a minimum effective dose of MTX and simultaneously treated with different concentrations of FA, MTHF or FTHF. The rescuing effect was assessed by MTT viability assay. The evaluation was completed by microscopic monitoring, apoptosis assessment and measuring LINE-1 DNA methylation. RESULTS: The MTT viability assay showed no MTX-rescuing effect of FA, but a significant effect of FTHF or MTHF. Microscopic observations supported the results of the viability assay. Accordingly, apoptosis was reduced in MTHF or FTHF treatments, while FA has no effect on the apoptosis induced by MTX. The LINE-1 methylation was not affected by MTX treatment, and not significantly modified in folate supplemented cultures. CONCLUSIONS: Despite the general acceptance of administering FA to prevent adverse events of MTX therapy, our findings suggest that FA may not be optimal, and indicate FTHF or MTHF as a better choice. This study on trophoblast cells suggests that FTHF may be the optimal folate, particularly for women in childbearing-age.

Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model.

BACKGROUND & AIMS: Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy can have a significant impact on post-operative outcome following resection of colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described. The aim of this project was to establish a rodent model which could be utilised to investigate mechanisms underlying SOS to aid the development of therapeutic strategies. METHODS: C57Bl/6 mice, maintained on a purified diet, were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Sections of the liver and spleen were fixed in formalin and paraffin embedded for histological analysis. The role of oxidative stress on experimental-induced SOS was determined by dietary supplementation with butylated hydroxyanisole and N-acetylcysteine. RESULTS: FOLFOX treatment was associated with the development of sinusoidal dilatation and hepatocyte atrophy on H&E stained sections of the liver in keeping with SOS. Immunohistochemistry for p21 demonstrated the presence of replicative senescence within the sinusoidal endothelium. FOLFOX induced endothelial damage leads to a pro-thrombotic state within the liver associated with upregulation of PAI-1 (p<0.001), vWF (p<0.01) and Factor X (p<0.001), which may contribute to the propagation of liver injury. Dietary supplementation with the antioxidant BHA prevented the development of significant SOS. CONCLUSIONS: We have developed the first reproducible model of chemotherapy induced SOS that reflects the pathogenesis of this disease in patients. It appears that the use of antioxidants alongside oxaliplatin based chemotherapy may be of value in preventing the development of SOS in patients with colorectal liver metastases.

Efficacy and safety of irinotecan-based chemotherapy for advanced colorectal cancer outside clinical trials: an observational study.

BACKGROUND: This prospective observational study in typical community-based outpatient clinics evaluated the efficacy and toxicity of weekly and biweekly irinotecan-based chemotherapies and their compatibility depending on age. METHODS: 601 patients with advanced or metastatic colorectal cancer receiving first-, second-, or third-line irinotecan-based therapy were regularly analyzed for response and toxicity until the end of therapy. RESULTS: The median age was 65 (28-87) years, approximately one-third of the patients were ≥70 years old. Of all patients, 405 were treated weekly and 68 biweekly. Median overall survival (OS) for first-line therapy was 26.5 months for the <70-year-old patients and 19.4 months for the ≥70-year-old patients. Toxicities were moderate in all groups. Tumor growth control rates (TCR) and median time to progression (TTP) were marginally better for patients <70 years old. Median TTP was 9.9 months in first-line therapy, 9.8 months after adjuvant therapy, 7.7 months in second-line, and 6.4 months in third-line therapy. CONCLUSIONS: Toxicity and response data from this observational study clearly confirm the positive results from previous clinical studies and show a slight ad-vantage in efficacy for the <70-year-old patients.

[Obliterative bronchiolitis with organising pneumonia following FOLFOX 4 chemotherapy]. / Bronchiolite oblitérante avec pneumonie organisée après chimiothérapie de type FOLFOX 4.

INTRODUCTION: FOLFOX 4 chemotherapy (5-fluorouracil, leucovorin and oxaliplatin) is the standard adjuvant treatment for stage III colon cancer. The principal secondary effects described are haematological, gastro-intestinal or neurological. A single case of obliterative bronchiolitis with organising pneumonia has been described recently. CASE REPORT: We report the case of a female patient aged 74 years who, after 12 courses of FOLFOX 4 chemotherapy, developed acute onset of severe shortness of breath and a dry cough but remained afebrile. A thoracic CT-scan showed symmetrical bilateral interstitial infiltration that was reticular in appearance, and predominantly basal and peripheral in distribution. Broncho-alveolar lavage revealed an alveolitis with 9% eosinophils and 4% neutrophils. Transbronchial biopsies showed the appearances of obliterative bronchiolitis with organising pneumonia. Systemic corticosteroid treatment led to a remarkable clinical and functional improvement. CONCLUSION: To our knowledge, this is the second case of obliterative bronchiolitis with organising pneumonia that has been described following adjuvant treatment based on FOLFOX 4.

[Reduction of oxaliplatin-related neurotoxicity by Gosha-jinki-gan].

PURPOSE: Oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin (FOLFOX) has emerged as the treatment of choice for advanced-stage colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity. We decided to use Gosha-jinki-gan for prevention of oxaliplatin-related neurotoxicity following the report of Fushiki et al. METHODS: The subjects were 14 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m(2)) was given intravenously as a FOLFOX4 regimen. All 14 patients received Gosha-jinki-gan every day after first oxaliplatin infusion. RESULT: 7 patients had grade 3 toxicity(neutropenia 6, thrombocytopenia 1). Sensory neuropathy occurred in 10 patients (71.4%). There was no neurotoxicity with functional impairment in this study. CONCLUSIONS: Gosha-jinki-gan seems to prevent acute oxaliplatin-induced neurotoxicity.

[Systemic treatment of peritoneal metastases]. / Systemische Behandlungsmöglichkeiten der Peritonealkarzinose.

Peritoneal metastases are common in metastatic disease of many tumour types and thus are determinant for prognosis and development of tumour-related symptoms that jeopardise quality of life. Systemic chemotherapy has proven efficacious in improving both prognosis and quality of life in numerous tumour types and should therefore be considered as part of the treatment strategy--although there is no large body of data from predefined cohorts with"only peritoneal" manifestation. In further clinical trials therefore, improvement of systemic chemotherapy by integration of novel agents should be implemented in multimodal treatment approaches combining systemic treatment, cytoreductive surgery, and intraperitoneal treatment strategies.

Avaliação da qualidade de vida e toxicidades em pacientes com câncer colorretal tratados com quimioterapia adjuvante baseada em fluoropirimidinas / Evaluation of the toxicity and quality of life in patients with colorectal cancer treated with chemotherapy

RACIONAL: O câncer colorretal é a quarta causa de câncer no Brasil e o 5-fluourouracil uma das principais drogas usadas no tratamento adjuvante e paliativo dessa doença. A toxicidade da quimioterapia e as alterações de qualidade de vida, causadas pela própria doença e pelo tratamento, são motivo de muitos estudos. OBJETIVO: Avaliar nos doentes com câncer colorretal em tratamento quimioterápico, a toxicidade e possíveis alterações da qualidade de vida. MÉTODOS: Durante o período de março de 2001 a maio de 2003 no Ambulatório de Oncologia da Disciplina de Gastroenterologia Clínica da Universidade Federal de São Paulo, foram acompanhados 45 pacientes com câncer colorretal em tratamento quimioterápico adjuvante ou paliativo com 5-fluourouracil e ácido folínico durante seis ciclos. A toxicidade gastrointestinal e hematológica foi analisada utilizando-se as Recomendações para a Graduação da Toxicidade Aguda e Subaguda. Após o término de cada ciclo quimioterápico, os resultados foram anotados de acordo com os respectivos graus que variaram entre 0 e 4. A qualidade de vida foi pesquisada pelo questionário WHOQOL bref (World Health Organization Quality of Life) que consta de 26 questões e é composto por 4 domínios: físico, psicológico, relações sociais e meio ambiente, no início, no 3° e no 6° ciclo de tratamento. RESULTADOS: Entre os 45 pacientes, 28 eram do sexo masculino, a média de idade foi de 58,4 anos (34 a 79 anos). Segundo a classificação da União Internacional Contra o Câncer, 34 (75,6 por cento) eram estádio II ou III e 11 estádio IV (24,4 por cento). Quanto à localização, 64,4 por cento eram de cólon. Em 57,7 por cento a quimioterapia foi adjuvante e nos demais paliativa. As toxicidades mais comumente encontradas foram náuseas (42 por cento), diarréia (38 por cento) e neutropenia (15,7 por cento). Não houve diferença significante entre os graus de toxicidade nos diferentes ciclos, assim como entre os doentes em tratamento adjuvante ou paliativo. Quanto à qualidade de vida foram observadas alterações significantes nos domínios físico e psicológico quando comparadas a primeira com a segunda ou a primeira com a terceira aplicação do questionário. Não foi encontrada alteração da qualidade de vida entre os doentes em quimioterapia adjuvante quando comparada aos em tratamento paliativo. Independente da indicação terapêutica, a média dos escores de qualidade de vida diminuiu em relação aos domínios físico e social na terceira aplicação do teste. CONCLUSÃO: As toxicidades gastrointestinais foram mais freqüentes que as hematológicas com o esquema utilizado. A qualidade de vida diminuiu após o início da quimioterapia em relação à atividade física e psicológica. No estudo da média dos escores observou-se queda dos mesmos nos domínios físico e social. A análise do questionário não mostrou alteração de qualidade vida quando comparados os doentes em tratamento paliativo com os em adjuvância.

BACKGROUND: The colorectal cancer is the fourth cause of cancer in Brazil and 5-fluorouracil is the drug most commonly used in the adjuvant or palliative treatment of this disease. AIM - Evaluating in patients with colorectal cancer and chemotherapy, the toxicity and the quality of life. PATIENTS AND METHODS: From March 2001 and May 2003, 45 patients treated with colorectal cancer treated with 5-fluourouracil and folinic acid were followed closely during six cycles. The gastrointestinal and hematologic toxicity was analysed making use of the chart "Recommendations for the Graduation of Acute and Subacute Toxicity". After the end of each cycle of chemotherapy, the results were registered according to the respectives degrees that vary from 0 to 4. The quality of life was researched through the WHOQOL bref (World Health Organization Quality of Life) questionary that consists of 26 questions and 4 domains: physical, psychological, social relations and environmental, in the beginning, on the 3rd and 6th cycles of treatment. RESULTS: Among the 45 patients, 28 were male, the average age was 58.4 years old (from 34 to 79 years old). According to the International Union Against Cancer classification, 34 patients (75.6 percent) had tumors stage II or III and 11 had tumors stage IV (24.4 percent), 64.4 percent were in the colon. In 57.7 percent the chemotherapy was adjuvant and in the others palliative. The toxicities more commonly found were nauseas (42 percent), diarrhea (38 percent), and neutropenia (15.7 percent). There was no significant difference among the degrees of toxicity in the different cycles as well as among the patients in adjuvant or palliative treatment. Significant alterations was found among the quality of life in the physical and psychological domains when the 1st and the 2nd or the 1st and the 3rd application of the test were done. Alterations of the quality of life were also found in the social domain when the first evaluation was compared with the last one. There was no difference between the quality of life and the treatment.

Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro.

Gemcitabine, oxaliplatin, leucovorin, and 5-fluorouracil (GOLF) is a novel multidrug regimen inducing high levels of necrosis and apoptosis in colon carcinoma cells. This regimen is also able to promote a process of Ag remodeling including up-regulation of immunotherapy targets like carcinoembryonic Ag (CEA), thymidylate synthase (TS). We have conducted a preclinical study aimed to investigate whether these drug-induced modifications would also enhance colon cancer cell immunogenicity. Several CTL lines were thus generated by in vitro stimulating human HLA-A(*)02.01(+) PBMCs, from normal donors and colon cancer patients, with autologous dendritic cells cross-primed with cell lysates of colon cancer cells untreated, irradiated, or previously exposed to different drug treatments including the GOLF regimen. Class I HLA-restricted cytolytic activity of these CTL lines was tested against colon cancer cells and CEA and TS gene transfected target cells. These experiments revealed that CTLs sensitized with GOLF-treated cancer cells were much more effective than those sensitized with the untreated colon carcinoma cells or those exposed to the other treatments. CTL lines sensitized against the GOLF-treated colon cancer cells, also expressed a greater percentage of T-lymphocyte precursors able to recognize TS- and CEA-derived peptides. These results suggest that GOLF regimen is a powerful antitumor and immunomodulating regimen that can make the tumor cells a suitable means to induce an Ag-specific CTL response. These results suggest that a rationale combination of GOLF chemotherapy with cytokine-based immunotherapy could generate a chemotherapy-modulated Ag-specific T-lymphocyte response in cancer patients able to destroy the residual disease survived to the cytotoxic drugs.

[Chemotherapy of advanced colorectal carcinoma: treatment options for elderly patients]. / Chemotherapie des fortgeschrittenen kolorektalen Karzinoms: Behandlungsoptionen für ältere Patienten.

At present, approximately 70% of patients with colorectal cancer are older than 65 years at the time of diagnosis. This cancer population needs to be thoroughly assessed for the benefits of adjuvant or palliative chemotherapy. A comprehensive geriatric assessment may allow subdividing the population of elderly cancer patients into three groups thus helping to guide treatment decisions. It has been demonstrated that the use of 5-fluorouracil (5-FU) based adjuvant chemotherapy in elderly patients effectively reduces mortality and can be applied with acceptable toxicity. Systemic chemotherapy for patients with metastatic disease will have palliative effects and lead to prolongation of survival. While several data exist for the combination of 5-FU and folinic acid in elderly patients, data about combination chemotherapy with 5-FU and new drugs such as irinotecan or oxaliplatin is still limited. There appears to be an age-associated increase in drug-specific toxicity when these agents are used. However, for carefully selected elderly patients receiving adequate monitoring throughout therapy these new treatment approaches can be made available. Clinical studies also indicate that treatment effectiveness in selected elderly patients is comparable to that observed in the younger patient population. Future trials need to further redefine treatment strategies in elderly patients with colorectal cancer.

Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer.

PURPOSE: To study tolerability and efficacy of an intensified chronomodulated schedule of fluorouracil (5-FU) and l-folinic acid (l-FA) as first-line treatment of metastatic colorectal cancer, 5-FU was given near individually determined dose-limiting toxicity in a multicenter phase II trial. PATIENTS AND METHODS: One hundred patients (68 men and 32 women, median age 62 years, World Health Organization performance status less-than-or-equal 2) with previously untreated and inoperable metastases received chronomodulated daily infusion of 5-FU/l-FA (from 10:00 PM to 10:00 AM with peak at 4:00 AM). 5-FU dose was escalated from 900 to 1,100 mg/m(2)/d with fixed dose of l-FA at 150 mg/m(2)/d for 4 days every 14 days. RESULTS: 5-FU dose escalation was achieved in 66% of the patients. Grade 3 to 4 toxicities mainly consisted of nausea or vomiting (14% of patients and 1.5% of courses), hand-foot syndrome (38% of patients and 8% of courses), mucositis (26% of patients and 4% of courses), and diarrhea (21% of patients and 2.3% of courses). Objective response rate (ORR) was 41% (95% confidence interval, 31.5% to 50.5%). Twenty patients underwent metastases surgery; among these, 12 had a complete resection. Median progression-free survival was 7 months. Median survival was 17 months; 28% of the patients were alive at 2 years and 18.6% at 3 years. CONCLUSION: The ORR achieved with intensified chronomodulated delivery of 5-FU/l-FA was nearly twice as high as that earlier obtained by our cooperative group using less intensive 5-FU/FA chronotherapy.

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD).

Prior studies have suggested that pre-irradiation methotrexate (MTX)-based chemotherapy improves duration of response and survival in primary central nervous system lymphoma (PCNSL). To circumvent the potential emergence of drug resistance, we combined high-dose MTX with agents highly active against systemic lymphoma. Patients received three week cycles of CHOD (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [2 mg maximum] on day 1; dexamethasone 10 mg/m2 days 1-5), and MTX (3.5 gm/m2) with leucovorin rescue on day 8 (or on recovery from the CHOD nadir). Whole brain irradiation (WBRT) was planned after at least three cycles. Eighteen patients were treated. Complete responses were seen in eleven patients, and partial responses in three. Four progressed during therapy, three succumbing to progressive disease and one subsequently responding to WBRT. Response duration was 37.5 months in those responding to therapy. The time to progression for all eighteen patients was 19.5 months. Medial survival was 25.5 months. Disease-free survival was 50% at 38 months in MCHOD responders. Grade 3 or 4 myelotoxicity was seen in 19 of 50 cycles. There were three instances of neutropenic fever, three of azotemia, two of deep vein thrombosis, and one each of community-acquired pneumonia, intracranial hemorrhage, superior vena cava syndrome, and hepatotoxicity. Late radiation-related toxicities were seen in two patients. Pre-irradiation MCHOD has activity against PCNSL, but appears to be no better than MTX monotherapy and has greater toxicity.

Ratio of 2'-deoxyadenosine-5'-triphosphate/thymidine-5'-triphosphate influences the commitment of human colon carcinoma cells to thymineless death.

In colon cancers induction of a thymineless state following inhibition of thymidylate synthase (TS) by 5-fluorouracil combined with leucovorin can initiate a cytotoxic response. Using a 5-fluorouracil-leucovorin-treated human colon carcinoma cell line (GC3/cl) and a clonally derived TS- mutant, initiation events that dictate the onset of and commitment to thymineless death have been examined. Initial events related to a temporally associated decrease in dTTP and elevation in the dATP pools; no depletion of dGTP or elevation in dCTP was detected. Nucleosomal degradation of DNA commenced at 24 h in TS- and 49 h in GC3/c1, and was associated with the more rapid development of an imbalance in the dATP and dTTP pools and a higher dATP:dTTP ratio in TS- cells. The contribution of elevated dATP or depleted dTTP pools to thymineless death was subsequently determined by treatment of GC3/cl or TS- cells with deoxyadenosine to elevate the dATP pool either under thymidine-replete or thymineless conditions. Thus, deoxyadenosine supplementation under dTTP-replete conditions elevated the dATP pool for 16 h and was cytotoxic to cells. During dTTP depletion elevated dATP was maintained, and cytotoxicity was significantly and rapidly enhanced by deoxyadenosine but could be reversed by thymidine. Data suggest that maintenance of elevated dATP and the dATP:dTTP ratio are essential initiation events in the commitment of colon carcinoma cells to thymineless death.

Clonogenic survival studies of human colon tumor cell lines in vitro: combined hyperthermia, 5-fluorouracil/leucovorin, carboplatin and tumor necrosis factor.

The responses of DLD-1 and HCT-15 human colon adenocarcinoma cells to hyperthermia, 5-fluorouracil (5-FU)/leucovorin, carboplatin and tumor necrosis factor-alpha, singly and in multiple combinations, were evaluated in clonogenic assays. The combination of hyperthermia with the lower dose combination resulted in a survival fraction of about 0.005 to 0.001 for both cell types, whereas estimated additive interactions alone would have resulted in a survival fraction of about 0.5 (DLD-1) or 0.05 (HCT-15). A survival fraction of 0.00001 or greater was observed when the higher dose levels were combined with hyperthermia, whereas additive interactions alone would have achieved a decrease of only 0.001 or 0.0001 in the surviving fraction. The combination of the three other modalities at either dose level under conditions of hyperthermia or normothermia achieved statistically significant apparently supra-additive losses of clonogenicity in HCT-15 cells; similar results were obtained with the lower dose level in DLD-1 cells. Our results suggest that human colon tumor cells are markedly sensitive to this combination of modalities when used at clinically achievable dose levels.

Preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for rectal cancer.

BACKGROUND: A Phase I trial was performed to determine the maximum tolerated dose of concurrent preoperative radiation therapy (5040 cGy) and 2 cycles (bolus daily times 5) of 5-fluorouracil (5-FU) and low-dose leucovorin (LV) (20 mg/m2), followed by surgery and 10 cycles of postoperative 5-FU/LV in patients with primary or recurrent rectal cancer. METHODS: Twenty-four patients were entered into the study. Preoperatively, the initial dose of 5-FU was 325 mg/m2. 5-FU was escalated 50 mg/m2, while the dose of LV and radiation therapy remained constant. Chemotherapy and radiation began concurrently on day 1. The postoperative chemotherapy was not dose escalated; 5-FU, 425 mg/m2, and LV, 20 mg/m2. The median follow-up was 10 months (range, 4-19 months). RESULTS: The resectability rate with negative margins in the 23 patients who underwent surgery was 100%. One patient refused surgery. The pathologic complete response rate was 13% (3 of 23). An additional four patients had negative nodes and a microscopic foci of tumor in the bowel wall. Therefore, the total clinical complete response rate was 30% (7 of 23). The maximum tolerated dose of 5-FU for the preoperative combined modality segment was 375 mg/m2; therefore, the recommended Phase II dose level is 325 mg/m2. The incidence of Grade 3+ toxicity for the 22 patients treated at the recommended 5-FU dose level (325 mg/m2) during the preoperative combined modality segment was as follows: diarrhea, 14%; erythema, 5%; hematologic, 10%; and total, 18%. The median nadir counts were leukocyte count, 3.7 (range, 1.5-5.9); hemoglobin count, 12.2 (range, 10.2-14.3); and platelet count (times 1000), 165 (range, 92-237). CONCLUSIONS: With this regimen, the recommended doses of chemotherapy in the combined modality segment are slightly higher than those recommended in arm 2 of the Intergroup postoperative adjuvant rectal trial 0114. This regimen will serve both as the preoperative arm of the Intergroup randomized trial of preoperative versus postoperative combined modality therapy for resectable rectal cancer (INT R9401) as well as the basis for the combined modality segment of NSABP RO-3.

Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: a report from the Children's Cancer Study Group.

Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.

Administration of folinic acid after low dose methotrexate in patients with rheumatoid arthritis.

Folinic acid (leucovorin) supplementation has been suggested as a possible means of treating the short term side effects that occur with low dose methotrexate (MTX). However, it has not been established whether leucovorin will abrogate the antiarthritic effect of MTX. We entered 20 patients with rheumatoid arthritis treated with MTX into a 48 week randomized, double blind, crossover trial of folinic acid vs placebo. The dose of folinic acid was equal to the dose of MTX and it was given orally 4 h following the single, weekly MTX administration. Under these conditions, leucovorin did not decrease the therapeutic effect of MTX. While the incidence of stomatitis and gastrointestinal toxicity were lower during leucovorin treatment, our study lacked sufficient power to establish a statistically significant difference.

5-Fluorouracil and high-dose folinic acid as second-line chemotherapy in head and neck cancer.

Experimental and clinical data support the concomitant use of 5-fluorouracil (5-FU) and high-dose folinic acid (HDFA). To verify the role of such a combination in far advanced head and neck cancer, we performed a phase II study employing weekly HDFA, 500 mg/m2 in 2-h infusions, and 5-FU, 600 mg/m2 bolus injection. Twenty-seven evaluable patients with recurrent disease entered the study. One complete response, seven partial responses, 10 stable disease, and nine progressions were observed: the overall response rate was 29.6%. Oral mucositis and diarrhea were major side effects; five patients discontinued the treatment due to toxicity; no deaths correlated to the treatment were detected. Considering the characteristics of our patients, the 5-FU/HDFA combination has shown a satisfactory antitumoral activity, but toxicity was similar to other chemotherapy regimens.

Biologic modulation of 5-fluorouracil with high-dose leucovorin and combination chemotherapy of 5-fluorouracil and cisplatin in metastatic colorectal adenocarcinoma.

The data from an ongoing 3-arm prospective study of 72 patients with advanced colorectal carcinoma is presented. The 3 regimens are as follows: Regime 1 (every 4 weeks)--5-fluorouracil (FUra) (450 mg/m2 iv bolus daily for 5 days, then 200 mg/m2 iv bolus every other day for 6 doses); regime 2 (every week for 4 weeks, then every other week)--methotrexate (MTX) (50 mg/m2 in a 4-hour infusion) followed by FUra (600 mg/m2 iv bolus); regime 3 (weekly for 6 weeks followed by a 2-week rest period)--D,L-leucovorin (D,L-CF) (500 mg/m2 in a 2-hour infusion) with FUra (600 mg/m2 iv bolus) 1 hour after the D,L-CF infusion began. All monitoring lesions except lung were documented by tissue biopsy. Thirteen of 18 patients in the FUra + D,L-CF arm were evaluable for response. Six of the 13 patients (46%) have had a partial response. The duration of the 6 responses has been 11, 8, 7, 4, 3 and 3 months. In patients with liver metastases as the monitoring lesion, a dramatic improvement in liver function tests has been seen during the first 2 courses (12 weeks) of treatment, but this was not sustained. The toxicity of FUra + D,L-CF was predominantly gastrointestinal; unlike with FUra alone, myelosuppression was not predominant.