levoleucovorin and Neoplasms

High-dose methotrexate (HDMTX) is active against various malignancies; it possesses serious toxicities and is associated with patient characteristics, dosage regimens, comedications, and physiological status. There are many strategies to overcome HDMTX-induced toxicities, such as hydration, alkalization, leucovorin rescue, and haemodialysis. Leucovorin rescue is a cornerstone for toxicity prevention in HDMTX treatment. However, the leucovorin dose adjustment and the existence of leucovorin overrescue are still controversial. At present, various methods for calculating leucovorin doses in different tumour types have been proposed, including empirical calculations based on MTX plasma concentration, the Bleyer nomogram, and other methods. Nonetheless, leucovorin rescue protocols differ greatly across tumour types and medical institutions. Further studies are needed to investigate the optimal dosage regimen for leucovorin rescue in various tumours using HDMTX.

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Leucovorin; Methotrexate; Neoplasms; Renal Dialysis

FOLFIRINOX regimen is commonly used in colorectal and more recently pancreatic cancer. However, FOLFIRINOX induces significant and dose-limiting toxic effects leading to empirical dose reduction and sometimes treatment discontinuation. Model-based FOLFIRINOX regimen optimization might help improving patients' outcome. As a first step, the current review aims at bringing together all published population pharmacokinetics models for FOLFIRINOX anticancer drugs.. A literature search was conducted in the PubMed database from inception to February 2018, using the following terms: population pharmacokinetic(s), irinotecan, oxaliplatin, fluorouracil, FOLFIRI, FOLFOX, FOLFIRINOX. Only articles displaying nonlinear mixed effect models were included. Study description, pharmacokinetic parameter values and influential covariates are reported. For each model, the typical pharmacokinetic profile was simulated for the standard FOLFIRINOX protocol.. The FOLFIRINOX compounds have been studied only separately so far. A total of six articles were retained for 5-fluorouracil, 6 for oxaliplatin and 5 for irinotecan (also including metabolites). Either one- or two-compartment models have been described for 5-fluorouracil, while two- or three-compartment models were reported for oxaliplatin and irinotecan pharmacokinetics. Non-linear elimination was sometimes reported for 5-fluorouracil. Sex and body size were found as influential covariates for all molecules in some publications. Despite some differences in model structures and parameter values, the simulated profiles and subsequent exposure were consistent between studies.. The current review allows for a global understanding of FOLFIRINOX pharmacokinetics, and will provide a basis for further development of pharmacokinetics-pharmacodynamics-toxicity models for model-driven FOLFIRINOX protocol optimization to reach the best benefit-to-risk ratio.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasms; Oxaliplatin; Tissue Distribution

The unprecedented clinical activity of checkpoint blockade in several types of cancers has formally demonstrated that anti-tumor immune responses are crucial in cancer therapy. Durable responses seen in patients treated with immune checkpoint inhibitors (ICI) show that they can trigger the establishment of long-lasting immunologic memory. This beneficial outcome is however achieved for a limited number of patients. In addition, late relapses are emerging suggesting the development of acquired resistances that compromise the anticancer efficacy of ICI. How can this be prevented through combination therapies? We here review the functions of immune checkpoints, the successes of ICI in treating cancer and their therapeutic limits. We discuss how conventional cancer therapies can be properly selected to set up combinatorial approaches with ICI leading to treatment improvement. We finally summarize clinical data showing the ongoing progress in cancer treatment involving ICI and chemotherapy combination strategies.

Topics: Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Clinical Trials as Topic; CTLA-4 Antigen; Drug Resistance, Neoplasm; Drug Synergism; Fluorouracil; Humans; Immunomodulation; Ipilimumab; Leucovorin; Lymphocyte Activation; Lymphokines; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Organoplatinum Compounds; Programmed Cell Death 1 Receptor; T-Lymphocyte Subsets; Tumor Microenvironment

Since over 50 years, 5-fluorouracil (5-FU) is in use as backbone of chemotherapy treatment regimens for a wide range of cancers including colon, breast, and head and neck carcinomas. However, drug resistance and severe toxicities such as mucositis, diarrhea, neutropenia, and vomiting in up to 40% of treated patients often lead to dose limitation or treatment discontinuation. Because the oral bioavailability of 5-FU is unpredictable and highly variable, 5-FU is commonly administered intravenously. To overcome medical complications and inconvenience associated with intravenous administration, the oral prodrugs capecitabine and tegafur have been developed. Both fluoropyrimidines are metabolically converted intracellularly to 5-FU, which then needs metabolic activation to exert its damaging activity on RNA and DNA. The low response rates of 10-15% of 5-FU monotherapy can be improved by combination regimens of infusional 5-FU and leucovorin together with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), thereby increasing response rates to 30-40%. The impact of metabolizing enzymes in the development of fluoropyrimidine toxicity and resistance has been studied in great detail. In addition, membrane drug transporters, which are critical determinants of intracellular drug concentrations, may play a role in occurrence of toxicity and development of resistance against fluoropyrimidine-based therapy as well. This review therefore summarizes current knowledge on the role of drug transporters with particular focus on ATP-binding cassette transporters in fluoropyrimidine-based chemotherapy response.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; ATP-Binding Cassette Transporters; Biological Availability; Biological Transport; Camptothecin; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Humans; Leucovorin; Neoplasms; Organoplatinum Compounds; Tegafur

The use of adequate folinic acid rescue (in clinically relevant doses) after high dose methotrexate will prevent neurotoxicity without reducing treatment results.. A literature search was performed to test the hypothesis that no evidence for the existence of folinic acid over-rescue of high-dose methotrexate (MTX) in clinically relevant situations exists (evidence that too much folinic acid reduced cure rate).. Examples of folinic acid over-rescue after lower doses of MTX were found and has been cited as evidence of over rescue of high dose MTX. Mega doses of folinic acid, used when toxic levels of MTX occurred, also could neutralize the MTX effect. Data were found to support the contention that higher levels of MTX require disproportionally higher folinic acid doses for rescue. Careful examination of the available studies after HDMTX yielded more convincing alternative explanations for reduction in cure rate than over rescue. Little convincing evidence for the existence of over rescue after HDMTX was found.. The rescue of high-dose MTX with an appropriate dose of folinic acid that can prevent toxicity, especially neurotoxicity, was not shown to reduce the therapeutic effect. No evidence was found that higher doses of folinic acid after high dose MTX reduces the therapeutic effect.. Acceptance of the hypothesis can prevent harm being caused (especially brain damage) by reversing the trend of dose reduction in FA rescue. The recognition that the use of higher folinic acid doses is safe, can prevent neurotoxicity, and does not reduce prognosis has important implications for the development of effective non toxic treatment protocols.

Topics: Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Humans; Leucovorin; Methotrexate; Neoplasms

To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin.. A MEDLINE search was conducted for English-language human studies published between January 1980 and April 2012 using the terms l-LV, levoleucovorin, d,l-LV, leucovorin, folinic acid, folinate, 5-formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials.. Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed.. From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents.. The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice.

Topics: Antineoplastic Agents; Drug Interactions; Humans; Levoleucovorin; Neoplasms

The many virtues that made the yeast Saccharomyces cerevisiae a dominant model organism for genetics and molecular biology, are now establishing its role in chemical genetics. Its experimental tractability (i.e., rapid doubling time, simple culture conditions) and the availability of powerful tools for drug-target identification, make yeast an ideal organism for high-throughput phenotypic screening. It may be especially applicable for the discovery of chemical probes targeting highly conserved cellular processes, such as metabolism and bioenergetics, because these probes would likely inhibit the same processes in higher eukaryotes (including man). Importantly, changes in normal cellular metabolism are associated with a variety of diseased states (including neurological disorders and cancer), and exploiting these changes for therapeutic purposes has accordingly gained considerable attention. Here, we review progress and challenges associated with forward chemical genetic screening in yeast. We also discuss evidence supporting these screens as a useful strategy for discovery of new chemical probes and new druggable targets related to cellular metabolism.

Topics: Animals; Antimetabolites, Antineoplastic; Drug Screening Assays, Antitumor; Glycolysis; Humans; Leucovorin; Methotrexate; Molecular Targeted Therapy; Mutagenesis; Neoplasms; Phenotype; Saccharomyces cerevisiae

The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined.. We performed a literature review (1969 - 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases.. Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were < 750 mg/m(2)/day (36%), 751 - 999 (16%), 1,000 (26%), 1,001 - 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone previous or concomitant radiation therapy to the mediastinum. Of cardiac incidents that happened 69% were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% of patients whereas myocardial infarction was seen in 22%, arrhythmias in 23, acute pulmonary edema in 5, cardiac arrest and pericarditis in 1.4 and heart failure in 2. Electro-cardiographic evidence of ischemia or ST-T changes were recorded in 69% of patients, but abnormal cardiac enzymes were found in only 12%. The cardiac symptoms were reproducible in 47%, including in one patient subsequently treated with 5-FU p.o. Symptoms were also elicited when the same patients were treated with lower doses or different schedules. Of the patients 68% responded to conservative anti-anginal therapy, although prophylactic coronary vasodilators had limited efficacy. Overall, 8% of patients showing cardiotoxicity on 5-FU administration died. Furthermore, 13% reexposed to 5-FU died.. Our review suggests that 5-FU cardiotoxicity is an infrequent but real phenomenon that is independent of dose and may be related to a continuous infusion schedule. The presence of cardiac risk factors is not predictive. Patients should be observed closely and 5-FU administration discontinued if cardiac symptoms develop. A rechallenge with 5-FU should be reserved only for those patients in whom there is no reasonable alternative therapy and should be performed in the setting of aggressive prophylaxis and close monitoring.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Calcium Channel Blockers; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Fluorouracil; Heart Diseases; Humans; Leucovorin; Neoplasms; Risk Factors; Vasodilator Agents

After over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumours requires constant vascular growth and remodelling in order for solid tumours to grow beyond 1-2 mm3 in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which make them attractive therapeutic targets. A multitude of VEGF-targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Camptothecin; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Fluorouracil; Humans; Hypertension; Kidney Neoplasms; Leucovorin; Lung Neoplasms; Neoplasms; Neovascularization, Pathologic; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G(2) (CPDG(2)), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG(2) administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%-99.5%). The early administration of CPDG(2) in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations.

Topics: Antimetabolites, Antineoplastic; gamma-Glutamyl Hydrolase; Humans; Leucovorin; Methotrexate; Neoplasms; Renal Insufficiency

Capecitabine, an oral fluoropyrimidine carbamate, is adopted worldwide. As the treatment for metastatic colorectal cancer, capecitabine showed at least comparable efficacy with a favorable safety profile to bolus 5-FU/LV. In a large phase III trial (Xeloda Adjuvant Chemotherapy Trial: X-ACT), as the adjuvant treatment of patients with resected stage III colon cancer, capecitabine showed at least comparable disease-free survival, overall survival, and relapse-free survival with a favorable safety profile to bolus 5-FU/LV. Additionally, capecitabine-based combination regimens with oxaliplatin or irinotecan are now under evaluation. In phase II studies, capecitabine has shown the promising results in combination therapy. In Japan, capecitabine has been evaluated since 1994. In a recent phase II study, which evaluated the global dose as first-line treatment for metastatic colorectal cancer, the response rate was 35% (95% CI 23.1-48.4). The median time to disease progression was 169 days and the median overall survival was 617 days. Hand-foot syndrome (HFS), a characteristic adverse event of capecitabine, was observed in 73.3% of the patients, but the grade 3/4 was observed in 13.3% of the patients and only one patient discontinued the treatment due to HFS. An immediate approval of capecitabine in Japan is expected.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasms; Survival Rate

For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inh

Topics: Animals; Antineoplastic Agents; Apoptosis; Capecitabine; Cell Cycle; Cell Proliferation; Clinical Trials as Topic; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Leucovorin; Neoplasms; Oxonic Acid; Prodrugs; RNA, Messenger; Tegafur; Thymidylate Synthase

Cancer chronotherapy is attracting attention as a novel and logical therapy in which anti-cancer drugs are administered with optimal timing according to circadian rhythms of anti-cancer action and those of adverse effects on normal cells. Advances in chronobiology have identified the suprachiasmatic nucleus (SCN) as the center of biological rhythms and the area in which clock genes such as PER1, PER2, PER3, CLOCK, BMAL1, TIM, CRY1, CRY2, tau act to generate and coordinate biological rhythms. These findings have led to the development of chronotherapy. Clinically, patients with advanced gastrointestinal cancer have been treated by chronomodulated chemotherapy with good response. For colorectal cancer patients with unresectable liver metastases, chronotherapy with l-OHP + 5-FU + FA (folinic acid) has been reported to allow complete surgical resection of liver metastases, resulting in 39-50% 5-year survival. Many believe that chronotherapy will become accepted as a refined and advantageous therapeutic option for not only cancer but also for other diseases, due to its universally applicable principles.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chronotherapy; Fluorouracil; Humans; Leucovorin; Neoplasms; Organoplatinum Compounds; Oxaliplatin

5-fluorouracil (5-FU) has become the most commonly used drug in combination with radiation therapy. The recent availability of oral formulations of 5-FU in conjunction with the ability to modulate the anabolic and catabolic metabolism of 5-FU with leucovorin and dihydropyrimidine dehydrogenase (DPD) inhibitors, respectively, may provide a substantial improvement in the ease of administration and the efficacy of fluoropyrimidine therapy. Several oral fluoropyrimidines are under investigation. UFT (uracil:tegafur) plus oral leucovorin (Orzel) is the first oral DPD-inhibitory fluoropyrimidine. With daily administration, Orzel achieves similar concentrations of 5-FU obtained with continuous-infusion 5-FU. This paper summarizes the therapeutic rationale for Orzel and reviews the clinical experience with UFT and UFT/LV in combined modality therapy regimens.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Dihydrouracil Dehydrogenase (NADP); Female; Humans; Leucovorin; Male; Neoplasms; Oxidoreductases; Tegafur; 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

It has been determined that in the combination of Leucovorin (LV) and 5-fluorouracil (5-FU), LV potentiates the cytotoxic effect of 5-FU based on biochemical modulation. Many data suggest that LV/5-FU is a very effective combination, and most clinicians worldwide now regard it as the standard therapy for colorectal cancer. In Japan, clinical examinations of this combination using Levofolinate calcium (I-LV) have shown its effectiveness, and I-LV/5-FU for gastric and colorectal cancer was authorized by the Ministry of Public Welfare in Oct. 1999.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Drug Synergism; Fluorouracil; Humans; Leucovorin; Neoplasms

Protracted intravenous regimens of fluorouracil (5-FU) may be superior and better tolerated than intravenous bolus dosing. An effective oral regimen would allow a protracted course of 5-FU without the need for central venous lines and the associated increase in complications. Approximately 85% of 5-FU is degraded by dihydropyrimidine dehydrogenase (DPD); inhibition of this enzyme pathway can increase the amount of circulating 5-FU. Two oral fluoropyrimidines commonly referred to as DPD inhibitory fluoropyrimidines, or DIFs, UFT plus leucovorin (LV) and S-1 are reviewed herein. These agents represent an approach to more convenient, less toxic 5-FU therapy. In two multicenter, randomized, phase III trials in patients with advanced colorectal cancer, UFT/LV produced equivalent activity compared with intravenous 5-FU/LV but with significantly less major toxicity. The predominant side effect of UFT, diarrhea, is generally self-limited and easily managed. Myelosuppression and hand-foot syndrome were rarely noted in the schedules used in these trials. S-1 has demonstrated promising activity in phase II trials conducted in patients with gastric, colorectal, breast, and head and neck cancers. Ongoing trials are defining the roles of these agents in a variety of malignancies.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme Inhibitors; Humans; Leucovorin; Neoplasms; Oxidoreductases; Oxonic Acid; Pyridines; Radiation-Sensitizing Agents; Tegafur; Uracil

Topics: Antimetabolites, Antineoplastic; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Neoplasms; Randomized Controlled Trials as Topic; Safety

Fluorinated pyrimidines have long been used as radiosensitizers in combined-modality therapy for solid tumors. Nonetheless, the most commonly used drug, 5-fluorouracil (5-FU), is inconvenient to administer, particularly when given by continuous intravenous infusion. Continuous infusion 5-FU does offer a survival advantage over bolus in the treatment of large bowel tumors. This holds true regardless of whether radiation therapy is concomitantly given. UFT, a combination of uracil and tegafur (in a molar ratio of 4:1), is an attractive alternative. Trials to date suggest at least chemotherapeutic equivalence compared to 5-fluorouracil, and UFT is much simpler to administer. UFT is administered orally and can safely be combined with oral leucovorin. There is profound scientific rationale for using UFT with radiation therapy, and early trials in gastrointestinal malignancies demonstrate the safety and efficacy of the combination. Further studies will determine the optimal timing and uses for concomitant UFT and radiation therapy.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Neoplasms; Radiation-Sensitizing Agents; Tegafur; Uracil

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Colorectal Neoplasms; Combined Modality Therapy; Digestive System Neoplasms; Fluorouracil; Humans; Immunologic Factors; Interferon-alpha; Leucovorin; Lung Neoplasms; Neoplasm Staging; Neoplasms; Survival Analysis; Treatment Failure

UFT is an oral antineoplastic drug combining uracil and tegafur in a 4:1 molar ratio. Tegafur acts as a prodrug of 5-fluorouracil (5-FU), being slowly metabolized by cytochrome P450 to 5-FU. Uracil competitively inhibits the metabolism of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. At equimolar doses, higher peak plasma 5-FU concentrations are achieved with UFT plus oral leucovorin with similar systemic 5-FU exposure compared with low-dose continuous 5-FU infusions. The elimination half-life of 5-FU following UFT administration is approximately 7 h compared with 0.2 h with i.v. 5-FU. In phase II studies of UFT plus oral leucovorin for the treatment of advanced colorectal cancer, response rates ranged from 25 to 42%. UFT plus oral leucovorin is well tolerated, with manageable diarrhea being the only dose-limiting toxicity; the regimen is not associated with significant myelosuppression, mucositis, hand-foot syndrome or alopecia. UFT, with or without leucovorin, has also been evaluated alone or in combination with other cytotoxic agents for the treatment of advanced lung, breast and gastric cancers. UFT has also been evaluated as adjuvant therapy for colorectal, breast, gastric, head and neck, and superficial bladder cancers. UFT plus leucovorin offers patients an entirely oral cancer treatment, and appears to provide potential advantages over bolus 5-FU regimens with regard to toxicity and convenience of administration. These benefits should be advantageous in the adjuvant setting, as well as in advanced disease settings in which palliation is an important consideration. Ongoing clinical trials will further define the role of this promising oral treatment regimen.

Topics: Administration, Oral; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Drug Combinations; Humans; Leucovorin; Lung Neoplasms; Neoplasms; Stomach Neoplasms; Tegafur; Uracil

Topics: Administration, Oral; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Combined Modality Therapy; Deoxycytidine; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Recurrence, Local; Neoplasms; Tegafur; Time Factors; Uracil

The results from preclinical studies using murine tumor models show that the combination of docetaxel (Taxotere) and fluorouracil (5-FU) is highly synergistic. Phase I studies in patients with advanced solid tumors indicate that 60 mg/m2 of docetaxel administered as a 1-hour intravenous infusion followed by a daily intravenous bolus of 300 mg/m2 of 5-FU on days 1 through 5 is the recommended dose for phase II studies. Preliminary results from another phase I study using a continuous infusion regimen for 5-FU suggest that 85 mg/m2 of docetaxel administered as a 1-hour intravenous infusion followed by continuous infusion of 750 mg/m2 per day of 5-FU on days 1 through 5 may be the recommended dose for phase II studies. As expected, dose-limiting toxicities included neutropenia and mucositis. Ongoing phase I/II and II studies are investigating the combination of docetaxel with continuous infusion of 5-FU in patients with metastatic breast cancer and with cisplatin (Platinol) and continuous infusion of 5-FU, with and without leucovorin, in patients with head and neck cancer. Preliminary results are encouraging and warrant further study.

Topics: Adult; Aged; Animals; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Models, Animal; Docetaxel; Dose-Response Relationship, Drug; Drug Synergism; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Mice; Middle Aged; Mucous Membrane; Neoplasms; Neutropenia; Paclitaxel; Taxoids

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasms; Treatment Outcome

This paper chronicles developments in the laboratory of Dr. Bruce Chabner during the period 1978-1981. Initial work demonstrated that methotrexate is taken up by human breast cancer cells by a high affinity, carrier-mediated energy-dependent transport system similar to that described in murine leukemia cells. Conversion of methotrexate to a high molecular weight polyglutamate metabolite was also demonstrated to occur in human breast cancer cells. Polyglutamates became the predominant form of intracellular drug, both free in the cytosol and bound to dihydrofolate reductase, during a 24 h exposure to clinically achievable methotrexate concentrations. Intracellular retention of polyglutamates led to prolonged suppression of thymidine synthesis and loss of cell viability after removal of extracellular drug. This work identified methotrexate polyglutamates as biologically active enzyme inhibitors in human tumor cells and launched a series of investigations on the interaction of these derivatives with folate-requiring enzymes.

Topics: Animals; Antimetabolites, Antineoplastic; Fluorouracil; Humans; Leucovorin; Methotrexate; Mice; Neoplasms; Polyglutamic Acid

An antifolate first introduced into the clinic about half decades ago, Methotrexate is effective against a variety of human cancers, when administered alone or in combination with leucovorin rescue at wide-ranging doses and by many different schedules. We know much more about MTX and its molecular and cellular pharmacology and mechanisms of anti-cancer action in light of current knowledge of the biochemistry of folate. This understanding has stimulated novel approaches to the clinical application of the drug and has greatly enhanced its therapeutic efficacy.

Topics: Antidotes; Antimetabolites, Antineoplastic; Bone Neoplasms; Drug Synergism; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Methotrexate; Neoplasms; Osteosarcoma

Topics: Animals; Antimetabolites, Antineoplastic; Fluorodeoxyuridylate; Fluorouracil; Folic Acid; Folic Acid Antagonists; Glycine Hydroxymethyltransferase; Humans; Leucovorin; Neoplasms

Thymidylate synthase forms the target for anticancer therapy with fluoropyrimidines. Anticancer activity can be increased by the use of different modulators of fluoropyrimidine metabolism, which lead to an enhanced inhibition of thymidylate synthase. In vitro and in vivo studies with fluoropyrimidines and two of these modulators, folinic acid (leucovorin) and interferon, are summarized. The promise of these preclinical results is reflected by the response data of several clinical trials. The biochemical effects of these modulators are described and illustrated by the fluoropyrimidine-mediated inhibition of thymidylate synthase in tumour samples, which is clearly enhanced by folinic acid. The regulation of thymidylate synthase synthesis may also be crucial for total blockade of thymidylate synthase activity. This regulation may be influenced by interferon-gamma. Although the addition of modulators increases the activity of fluoropyrimidines at the level of thymidylate synthase, most solid tumours, especially colorectal carcinomas, are resistant to these combinations. For this reason, new, more potent inhibitors of thymidylate synthase have been developed, the antifolates. Preclinical data show that some of these compounds have good antitumour activity, but they still have to prove their value in the clinic. These two approaches, the use of modulators and new compounds, have shown activity preclinically and the extension of these findings to clinical studies stresses the importance of thymidylate synthase as a target in fluoropyrimidine therapy of solid tumours.

Topics: Animals; Antimetabolites, Antineoplastic; Fluorouracil; Folic Acid Antagonists; Humans; Interferons; Leucovorin; Neoplasms; Thymidylate Synthase

Topics: Aspartic Acid; Drug Interactions; Fluorouracil; Humans; Leucovorin; Methotrexate; Neoplasms; Phosphonoacetic Acid; Trimetrexate

In the past few years it has become clear that the individual stereoisomers, especially the enantiomers, of a biologically active chiral molecule may differ in potency, pharmacological action, metabolism, toxicity, plasma disposition and urine excretion kinetics. The situation exists in all classes of therapeutically active agents including chiral agents used in clinical oncology. Chiral anticancer agents which exist as a pair of enantiomers are commonly administered as racemic (50:50) mixtures of the two isomers. The possibility exists that only one of the enantiomers possesses the desired pharmacological activity while the other is responsible for part or all of the observed toxicity. The toxicity due to the non-efficacious isomer may be the difference between a clinically useful anticancer drug and one which is too toxic to use.. The chiral compounds used in standard and experimental cancer chemotherapy include leucovorin, ifosfamide and verapamil. Only one stereoisomer of leucovorin, (6S)-leucovorin is active and data suggests that the administration of just the single isomer may enhance the activity of the agent as well as improve therapeutic monitoring. Both enantiomers of verapamil, (R)-verapamil and (S)-verapamil, are active in reversing adriamycin resistance in some tumor lines. The standard clinical formulation of verapamil is a mixture of the two isomers and cannot be used in clinical treatment of resistant disease due to the cardiotoxicity of the (S)-isomer. (S)-verapamil is the active calcium channel blocking agent while (R)-verapamil has no effect in this area. Thus, an effective anticancer drug would be (R)-verapamil. Data also exists which suggests that the use of a single isomer of ifosfamide may reduce dose limiting CNS toxicity.. The existence of stereoisomeric forms of a chemical has been a recognized fact for almost 150 years. However, the clinical consequences of symmetry and asymmetry are only just beginning to be considered. Within the three-dimensional structures of the human body lie tremendous potentials for differential drug actions and, perhaps, new keys to the treatment of cancer and other diseases. The next few years should see the end to the two-dimensional clinical pharmacology we are accustomed to and the growth of stereochemical clinical pharmacology; where we always know what the right and left hands are doing.

Topics: Antineoplastic Agents; Humans; Ifosfamide; Leucovorin; Neoplasms; Stereoisomerism; Verapamil

Fluorouracil remains the single most active chemotherapy agent in colorectal cancer. One of its principal mechanisms of action is inhibition of the enzyme thymidylate synthase (TS), a central enzymatic step in de novo pyrimidine synthesis. Leucovorin, which is metabolized intracellularly to polyglutamated 5,10-methylenetetrahydrofolate, modulates the cellular cytotoxicity of fluorouracil by increasing TS inhibition in vitro and in vivo. Leucovorin modulation of fluorouracil has been studied in preclinical systems and in a large number of clinical trials using various doses and schedules of both drugs. The collective data support the use of continuous infusion or repetitive low-dose schedules of leucovorin. Furthermore, these schedules appear to be less dependent on the leucovorin dose to achieve maximal clinical efficacy than does intermittent single bolus therapy. These schedules appear to be the most effective in the generation of the higher polyglutamates of 5,10-methylenetetrahydrofolate, the most efficient intracellular folate metabolite for ternary complex formation and TS inhibition.

Topics: Drug Synergism; Fluorouracil; Humans; Leucovorin; Neoplasms

The influence of folate and antifolate on the cytostatic activity of fluoropyrimidines has been examined extensively. From all of present work, it is apparent that methotrexate can be synergistic or antagonistic in its interaction with 5-fluorouracil, depending on the sequence used and the metabolic machinery present in the target cell. The interaction between commonly administered 5-fluorouracil and leucovorin may enhance carcinostatic efficacy of 5-fluorouracil in patients with colon carcinoma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Interactions; Fluorouracil; Humans; In Vitro Techniques; Leucovorin; Methotrexate; Mice; Neoplasms; Neoplasms, Experimental

Maximal dosing of cytotoxic chemotherapy drugs is often limited by the development of severe nonmyelosuppressive toxicities. Numerous studies have demonstrated that sulfur-containing nucleophiles can antagonize the dose-limiting effects of alkylating agents on the genitourinary tract. Examples include the use of sodium thiosulfate to prevent cisplatin-induced renal tubular necrosis and the use of sulfhydryl-containing compounds like N-acetylcysteine and 2-mercaptoethanesulfonate (mesna) to block oxazophosphorine-induced bladder toxicity. Mesna does not block the antitumor action of oxazophosphorines due to its rapid formation of the inactive dimer dimesna in the bloodstream. The active monomer is selectively reduced from dimesna in renal tubule cells, thereby limiting the inactivation of toxins like acrolein to the genitourinary tract. Recent clinical trials suggest that oral mesna has adequate bioavailability (roughly 50% by urinary thiol measurements) to prevent urotoxicity in high-dose ifosfamide regimens. In addition, mesna is stable in aqueous oral formulations. This may facilitate more convenient oral mesna dosing in protocols using high-dose cyclophosphamide or ifosfamide. Whereas agents like mesna and sodium thiosulfate complex directly with activated (electrophilic) alkylator species, chemoprotectants for the anthracyclines appear to complex with metal cofactors like iron, which are required for the production of cardiotoxicity. Several ethylenediaminetetraacetic-like agents have been evaluated, and a water-soluble piperazinyl derivative, ICRF-187, is currently undergoing clinical evaluation in patients receiving large cumulative doxorubicin doses. An initial clinical trial suggests that ICRF-187 can prevent doxorubicin-induced cardiomyopathy. As with mesna, ICRF-187 does not block the myelosuppressive or the antitumor effects of doxorubicin. Overall, these studies show that site-selective chemoprotection is now feasible for at least two major classes of anticancer agents.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Asparaginase; Cisplatin; Cyclophosphamide; Fluorouracil; Humans; Ifosfamide; Leucovorin; Mesna; Methotrexate; Neoplasms; Razoxane; Sulfhydryl Compounds; Uridine

5-fluorouracil (5-FU) administered by protracted intravenous infusion has been shown to have clinical utility against colorectal cancer and several other advanced tumors. However, additional therapeutic strategies are needed to further improve treatment results. Although the addition of low-dose cisplatin appeared to improve the clinical activity of 5-FU infusion in early phase II studies, subsequent evaluation has failed to substantiate these early reports. In addition, toxicity has been significantly increased. Combinations of cisplatin and other drugs with 5-FU infusion are currently being evaluated. Phase I studies demonstrate that only low doses of concomitant leucovorin are necessary to potentiate 5-FU infusion; phase II studies to evaluate efficacy are underway. Although combinations of 5-FU and biological therapies such as alpha 2a-interferon appear to be very promising, they will require extensive phase II and III testing to define their clinical utility and toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Evaluation; Fluorouracil; Humans; Leucovorin; Methotrexate; Neoplasms

Exposure of tumor cells to reduced folates before or with the fluoropyrimidines, 5-fluorouracil or 5-fluoro-2'deoxyuridine, results in a substantial increase in the activity of these drugs. Available evidence suggests that the mechanism of this synergism is a kinetic stabilization of complex formed between thymidylate synthase and fluorodeoxyuridylate that also involves a mole of the cofactor for the thymidylate synthase reaction, 5,10-methylenetetrahydrofolate. This effect results in an extended time of depletion of thymidine nucleotides with a resultant increased level of cell death. The biochemical aspects of this interaction are discussed and related to the therapeutics of this combination.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Floxuridine; Fluorodeoxyuridylate; Fluorouracil; Humans; Leucovorin; Neoplasms; Thymidylate Synthase

With a resurgence of interest in leucovorin calcium (LV), many questions about its role in cancer chemotherapy are being asked again. How does it modulate 5-fluorouracil (5-FU) therapy? Can it potentiate the cytotoxicity of 5-FU more in malignant than in normal cells? Does it rescue tumor cells from high-dose methotrexate (MTX) more than it does normal cells? How should LV rescue be individualized to maximize the therapeutic index? When can LV be administered orally, and how can LV rescue be conducted at home? When is LV rescue necessary, and what toxicities occur when it is inadequate? Some answers to these questions are provided in this review.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Fluorouracil; Humans; Leucovorin; Methotrexate; Neoplasms

The biochemical modulation of 5-fluorouracil (FU) by using it in combination with leucovorin (LV) is reviewed. One of the mechanisms of action of FU is inhibition of thymidylate synthase (TS), a critical enzyme in the de novo synthesis of thymidylate required for DNA repair and synthesis. In the presence of 5, 10-methylene tetrahydrofolate, 5-fluoro-deoxyuridine monophosphate (FdUMP), which is an active nucleotide of FU, forms a ternary complex with TS, resulting in enzyme inhibition. The rationale for the use of LV with FU is to increase of formation and stability of catalytically inactive ternary complexes. In clinical trials, the dose schedules of 500 mg/m2 iv bolus or 500 mg/m2 continuously iv infusion is frequently used in order to obtain an ideal plasma concentration of active LV metabolites. Preliminary clinical trials using the combination of FU and LV appear to be capable of increasing of the clinical activity of FU for colorectal and breast cancers. Several randomized studies have supported the increase in response rates seen in the uncontrolled trials but additional studies are required to demonstrate a positive impact on the survival of treated patients.

Topics: Chemical Phenomena; Chemistry; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Neoplasms; Stomach Neoplasms

Recent studies have clarified the critical role that polyglutamylation plays in methotrexate (MTX) action. Polyglutamate derivatives of MTX bind to dihydrofolate reductase (DHFR) with affinities comparable to the monoglutamate, but their retention in cells results in a sustained block in tetrahydrofolate (FH4) synthesis. One important element in the selectivity of MTX action is the preferential buildup and retention of these polyglutamyl forms in susceptible tumor cells as compared to host cells of the bone marrow or gastrointestinal mucosa. This selectivity in the accumulation of MTX polyglutamyl forms has now been further shown to play an important role in the selectivity of leucovorin rescue and may provide a unique new approach to nucleoside protection as well. This paper reviews the current understanding of the biochemical basis for leucovorin rescue and its selectivity. Important elements in leucovorin rescue are reactivation of DHFR with depression of cellular dihydrofolate (FH2) and provision of folate substrate to circumvent the block in FH4 synthesis. Selectivity of leucovorin rescue may be attributed to direct inhibition by MTX polyglutamyl forms, as well as FH2 polyglutamates that accumulate in their presence, at the levels of thymidylate synthase and transformylation during purine nucleotide biosynthesis. The presence of cellular MTX polyglutamates impairs reactivation of endogenous DHFR activity by leucovorin metabolites, and the resultant maintenance of high cellular levels of cellular FH2 and the polyglutamyl derivations of MTX impair the utilization of added FH4 in susceptible tumor cells. This paper also develops the concept of "early" nucleoside protection in antifolate therapy. In this approach, nucleosides are administered simultaneously with a pulse of MTX to provide early host protection from the cytotoxic effects of modest doses of MTX. Cessation of protection occurs at a time when extracellular and intracellular monoglutamate has fallen to low levels, and the polyglutamyl forms of the drug are present in susceptible tumors but not in host tissues of the gut and bone marrow. Data are presented to demonstrate that increased doses of MTX can be administered in normal and tumor-bearing animal systems as well as in humans by this technique.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Transport; Drug Administration Schedule; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Neoplasms; Nucleosides; Polyglutamic Acid; Tetrahydrofolate Dehydrogenase

Three cooperative groups are currently accruing patients to randomized Phase III studies of 5-FU plus leucovorin. These studies should provide data allowing more definitive conclusions regarding the therapeutic utility of this combination. Until results of these studies are available, 5-FU plus leucovorin (CF) remains an investigational treatment, not suitable for routine use.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoplasms; Randomized Controlled Trials as Topic

Topics: Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Neoplasms

High-dose methotrexate (HDMTX) with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology for more than a decade. Administration of HDMTX results in tumoricidal plasma concentrations of the drug without significant host toxicity, provided that plasma MTX levels are monitored and LV rescue is properly administered. The original premise of LV rescue was that the provision of reduced folate to normal cells would circumvent the metabolic block produced by MTX and allow resumption of DNA synthesis, although the presumed therapeutic selectivity of leucovorin has not yet been adequately explained. Despite a strong pharmacologic rationale and a vast clinical experience, HDMTX with leucovorin rescue has not been shown to be unequivocally superior to conventional doses of MTX in any clinical situation except, perhaps, for treatment of osteogenic sarcoma and childhood acute leukemia. While HDMTX is an important component of effective treatment regimens for these diseases, its precise contribution to the success of these regimens remains undefined. Although HDMTX can theoretically overcome all known mechanisms of MTX resistance, no data exist to suggest that this can be accomplished in the clinic. Thus, this well-known but poorly understood treatment regimen must remain a subject of clinical investigation rather than a part of routine clinical practice.

Topics: Humans; Leucovorin; Methotrexate; Neoplasms

Topics: Animals; Anions; Binding, Competitive; Biological Transport, Active; Carrier Proteins; Cell Line; Cell Membrane; Computers; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance; Folic Acid Antagonists; Humans; In Vitro Techniques; Leucovorin; Membrane Proteins; Methotrexate; Models, Biological; Neoplasms; Polyglutamic Acid; Structure-Activity Relationship; Tetrahydrofolates

Topics: Administration, Oral; Animals; Biological Transport; Central Nervous System; Drug Resistance; Folic Acid; Folic Acid Antagonists; Gene Amplification; Head and Neck Neoplasms; Humans; Kinetics; Leucovorin; Leukemia, Lymphoid; Lung Neoplasms; Methotrexate; Neoplasms; Osteoma, Osteoid; Thymidylate Synthase; Tissue Distribution

Therapeutic drug monitoring procedures after moderate and high-dose methotrexate (MTX) therapy are reviewed. Serum levels of MTX along with creatinine clearance and weight loss can serve to identify patients at risk of serious hematological toxicity. Preventive measures to avert or reduce MTX toxicity include increased citrovorum factor rescue treatment, hydration, and alkalinization of the urine in order to increase the urinary clearance of MTX and prevent its precipitation in acidic urine. The toxicity of MTX is associated with a prolonged retention of the drug in the body. Since the initial clearance of MTX correlates well with endogenous creatinine clearance, only patients with normal renal functions are eligible for high-dose MTX therapy; however, MTX-induced renal toxicity may impair renal function during the course of therapy. Therefore, careful drug monitoring techniques are essential and have contributed to the effective use of high-dose MTX, although the potential of serious toxicity cannot be completely prevented. Further studies are needed to understand the complex mechanisms by which MTX exerts its toxic and therapeutic effects in cancer patients.

Topics: Dose-Response Relationship, Drug; Humans; Kinetics; Leucovorin; Methotrexate; Neoplasms

Topics: Humans; Kinetics; Leucovorin; Methotrexate; Neoplasms; Protein Binding

Methotrexate is now used widely for the treatment of acute leukemia, non-Hodgkin's lymphoma, osteogenic sarcoma, choriocarcinoma, breast carcinoma, pulmonary and epidermoid carcinoma, and intrathecal chemotherapy. It is also useful in bone marrow transplantation, severe psoriasis, rheumatoid arthritis, dermatomyositis, Wegener's granulomatosis and sarcoidosis. The recent dramatic intensification of methotrexate therapy can be attributed in part to advances in our understanding of the clinical pharmacology of the folate antagonists, as well as to the combination of positive results and their effective dissemination to medical oncologists. The review summarizes the pharmacologic findings and illustrates how they are currently being applied to the treatment of malignant disease.

Topics: Absorption; Bone Marrow; Cell Cycle; Drug Interactions; Drug Resistance; Folic Acid Antagonists; History, 20th Century; Humans; Injections, Intravenous; Injections, Spinal; Leucovorin; Methotrexate; Neoplasms; Nervous System; Research Design; Tissue Distribution; United States

Topics: Aminopterin; Animals; Folic Acid; History, 20th Century; Humans; Leucovorin; Leukemia, Experimental; Methotrexate; Mice; Neoplasms; Time Factors

Patients with malignant lymphoma, diffuse type, have an unfavorable prognosis when compared to those patients with modular patterns. Prior to the introduction of combination chemotherapy, 50% survival rates for MC-D or PDL-D were about 2 years, HL-D about 1 year. Aggressive combination chemotherapy for advanced MC-D or PDL-D results in complete remission rates of 22-82%, with median survivals of 1-2 years. Patients with localized HL-D are probably curable with radiotherapy alone in 75% of cases. Patients with advanced disease are best treated with intensive combination chemotherapy, achieving a long-lasting complete remission in over one-half of cases, with median survivals now at 1-3 years. Many of these patients are probably cured, central nervous system relapse may now be a concern. The results of treatment of advanced histiocytic lymphoma are now approaching the results reported for advanced Hodgkin disease.

Topics: Antineoplastic Agents; Central Nervous System Diseases; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Humans; Leucovorin; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Neoplasms; Prednisone; Remission, Spontaneous; Vincristine

In combination chemotherapy, the type of drug interactions can be divided into three broad categories: 1) combinations based on cooperative effects of active drugs; 2) combinations in which the effectiveness of an active drug is increased by the concurrent administration of an inactive agent; and 3) combination of an active drug with an agent capable of selectively reversing the toxicity of the first drug. Many concepts have been proposed to explain the synergistic interaction between two active drugs at the level of the target cell. These include multiple inhibition of a single enzyme, enhanced activation, decreased inactivation, increased drug uptake, sequential blockade, concurrent inhibition, complimentary inhibition, and concerted inhibition. The therapeutic advantage of combination chemotherapy may reside in the whole organism, reflecting increased bioavailability of drug, reduced dose-limiting toxicity or reduced impairment of host defenses; it may reside in the tumor cells, reflecting the multiple molecular mechanisms of interaction mentioned above. Examples discussed include among others methotrexate plus citrovorum factor, thymidine or allopurinol, araC plus tetrahydrouridine and 3-deazauridine plus testosterone.

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Antagonism; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Humans; Leucovorin; Mercaptopurine; Methotrexate; Neoplasms; Neoplasms, Experimental; Uridine

Topics: Antineoplastic Agents; Drug Interactions; Drug Therapy, Combination; Folic Acid Antagonists; Half-Life; Humans; Leucovorin; Leukoencephalopathy, Progressive Multifocal; Liver; Methotrexate; Neoplasms

A brief review of the pharmacology of methotrexate is presented, and the rationale for the administration of high-dose methotrexate and the necessity of a folinic acid rescue to prevent methotrexate toxicity are discussed. Critical factors concenrning the use of this therapy, as well as unusual toxicities associated with the use of high-dose methotrexate, are presented. Several drug-and patient-related variables which may affect the toxicity of this dual drug administration are discussed to better enable pharmacists to monitor patients receiving this form of therapy. High-dose methotrexate with folinic acid rescue has improved the therapeutic index of methotrexate. The optimal dosage and duration of the two agents are yet to be determined.

Topics: Absorption; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Monitoring, Physiologic; Neoplasms; Time Factors

Topics: Adult; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Child; Cyclophosphamide; Doxorubicin; Drug Combinations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunotherapy; Leucovorin; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasms; Osteosarcoma; Prednisone; Rhabdomyosarcoma; Testicular Neoplasms; Thiotepa; Vinblastine; Vincristine

Topics: Animals; Antineoplastic Agents; Binding Sites; Chickens; Cyclophosphamide; Cytarabine; Fluorouracil; Guinea Pigs; Humans; Immunity; Immunity, Cellular; Immunosuppressive Agents; Leucovorin; Male; Mercaptopurine; Methotrexate; Mice; Neoplasms; Piperazines; Rats; Stimulation, Chemical

This paper presents an overview of studies of therapy of head and neck squamous cell carcinoma in which chemotherapy was combined with other modalities. The rationale for using chemotherapy with surgery is discussed, but ststematic studies of this combination of modalities have not been reported. Systemic chemotherapy plus radiation therapy has been studied using hydrozyurea, t-fluorouracil (5-FU), and methotrexate (MTX). Uncontrolled studies with hydroxyurea report favorable results, but a well-controlled study gave negative results. Controlled studies with 5-FU have given favorable results in certain tumor stages and sites of origin. MTX plus radiation in a small series produced slightly better survival than radiation alone. Intra-arterial chemotherapy plus radiation therapy has been the subject of exploratory studies but no firm conclusions can be drawn from these studies. Chemotherapy plus immunotherapy has been explored and merits further study. Based on the studies reported to date one can suggest the need for large-scale randomized control studies of long-term chemotherapy combined with other modalities.

Topics: Bleomycin; Carcinoma, Squamous Cell; Cyclophosphamide; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Hydroxyurea; Immunotherapy; Laryngeal Neoplasms; Leucovorin; Methotrexate; Neoplasm Metastasis; Neoplasms; Radiotherapy; Vinblastine

Topics: Alkaloids; Alkylating Agents; Antibiotics, Antineoplastic; Antimetabolites; Antineoplastic Agents; Cell Survival; Child; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Humans; Immunotherapy; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Neoplasms; Plants, Medicinal; Vincristine

5-Fluorouracil (5-FU) is administered with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible due to their chemical incompatibility, so conditions for the maximum possible beneficial interaction cannot be met. To overcome this, we developed a novel all-in-one, pH neutral stable solution of 5-FU plus LV with β-cyclodextrin (termed Deflexifol) and assessed its safety and tolerability in a first-in-human phase I trial.. Patients with advanced solid malignancy received Deflexifol as weekly bolus (375-575 mg/m²) or two-weekly 46 h infusion (1200-3600 mg/m²) for six cycles in a 3+3 dose escalation design. Adverse events, pharmacokinetics and tumor response rates were assessed by standard methods.. Deflexifol is safer and effective in bolus and infusion schedules at higher doses than that permitted by separate infusion of 5-FU and LV. A phase II study evaluating Deflexifol is planned.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms

Lenalidomide has synergistic anticancer effects when used with chemotherapy. We conducted a phase I study of lenalidomide in combination with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) in patients with advanced cancer.. A "3 + 3" study design was used. Lenalidomide was given orally on days 1-14, oxaliplatin and leucovorin were given intravenously on day 1, and 5-fluorouracil was given as a continuous infusion on days 1-2. The dose escalation phase of the study was followed by an expansion phase. We assessed the maximum tolerated dose, dose-limiting toxicities, and response.. Thirty-eight patients were treated [median age 53 years (range 31-76); male/female 20:18]. The most common diagnosis was colorectal cancer (CRC) (n= 30, 79%). Overall, 132 cycles (median 2/patient) were administered. No dose-limiting toxicities were observed. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3/4 treatment-related toxicities (all reversible) were seen in 14 (37%) patients and included neutropenia (n = 11), thrombocytopenia (n = 2), and fatigue (n = 2). There were no thrombotic events. Response was evaluable in 32 patients: 19 (59%) had stable disease (SD), including SD ≥ 6 months in 4 (13%) patients. Tumor types with SD ≥ 6 months were CRC (n = 2; progression-free survival [PFS] 11.3 and 7.1 months, respectively), gastric (n = 1; PFS 8.5 months), and pancreatic (n = 1; PFS 6.4 months) cancer. The median PFS and overall survival durations were 2.2 months (range <1.3-23) and 5.5 months (range <1.6-23), respectively.. Lenalidomide in combination with FOLFOX was well tolerated. Four patients had prolonged stable disease. This combination merits further investigation for selected patient populations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Lenalidomide; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Survival Rate; Thalidomide; Treatment Outcome

The granisetron transdermal system (GTS) showed non-inferior efficacy to oral granisetron to control chemotherapy-induced nausea and vomiting (CINV) during multiday chemotherapy. We compared the efficacy and safety of GTS with that of intravenous and oral granisetron in Korean patients receiving moderately emetogenic chemotherapy (MEC).. A total of 276 patients were randomized into GTS (n = 139, one patch on days 1-4) or control group (n = 137, intravenous on day 1 and oral on days 2-4). The primary endpoint was the percentage of patients achieving complete response (CR) from chemotherapy initiation until 24 h after the final administration.. Out of 234 patients (112 in GTS and 122 in control group) included in the per protocol analysis, 97.9 % had gastrointestinal cancer and 76.9 % received 3-day chemotherapy. The GTS showed non-inferior efficacy achieving CR in 75.0 % of the patients; 74.6 % of the patients in the control group achieved CR (95 % confidence interval -10.73 to 11.55 %). The CR rate did not change after subgroup analyses by sex, age, and chemotherapy naivety and analysis per day and overall days of treatment. The GTS group showed sustained CR from day 1 to day 4. Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), showed no difference. Both treatments were well tolerated and safe.. The GTS showed non-inferior efficacy to intravenous and oral granisetron. The safety, tolerability, and FLI-E scores of the GTS were comparable to those of control group. The GTS offers a convenient alternative option for relieving CINV in patients receiving MEC.

Topics: Administration, Cutaneous; Adult; Aged; Antiemetics; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Female; Fluorouracil; Granisetron; Humans; Leucovorin; Male; Middle Aged; Nausea; Neoplasms; Organoplatinum Compounds; Prospective Studies; Remission Induction; Republic of Korea; Safety; Vomiting

The oral PI3K inhibitor BKM120 has been reported as safe and well tolerated in early phase clinical trials of advanced cancer patients. We performed a phase I trial of BKM120 plus mFOLFOX6 (5-FU/LV + oxaliplatin), a common chemotherapeutic backbone in GI malignancies, to establish the maximum tolerated dose (MTD) and characterize the safety and tolerability of the combination.. Patients with advanced solid tumors received oral BKM120 daily combined with standard doses of mFOLFOX6 every 2 weeks of a 28 day cycle. The study utilized a standard 3 + 3 dose escalation schema.. A total of 17 patients received treatment with BKM120, 13 of which were evaluate for dose limited toxicity (DLT). The most common tumor types were colorectal cancer, cholangiocarcinoma, pancreatic cancer and hepatocellular carcinoma. DLT included grade 3 hyperglycemia, grade 3 AST/ALT elevation, grade 4 neutropenia and grade 4 thrombocytopenia. A total of 76 % of patients experienced treatment related grade 3/4 adverse events (AEs), the most common of which were neutropenia, fatigue, leukopenia, hyperglycemia and thrombocytopenia. One patient demonstrated an unconfirmed partial response and three patients had stable disease.. The MTD of BKM120 in combination with standard doses of mFOLFOX6 was 40 mg daily, which is well below the 100 mg daily dose proven effective and tolerable both as a single agent and in combination with other chemotherapeutics. In addition, the regimen of BKM120 with mFOLFOX6 in patients with refractory solid tumors resulted in increased toxicity than would be expected from either the PI3K inhibitor or the chemotherapy backbone alone.

Topics: Administration, Oral; Adult; Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Organoplatinum Compounds; Phosphoinositide-3 Kinase Inhibitors

This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.. Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.. Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.. While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Monitoring; Early Termination of Clinical Trials; Everolimus; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Protein Kinase Inhibitors; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases

To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2).. In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks.. Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg.. Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Young Adult

Platinum agents have been used for a variety of cancers, including pivotal use in pediatric tumors for many years. Oxaliplatin, a third generation platinum, has a different side effect profile and may provide improved activity in pediatric cancers.. Patients 21 years or younger with progressive or refractory malignant solid tumors, including tumors of the central nervous system were enrolled on this multi-center open label, non-randomized Phase 1 dose escalation study. The study used a standard 3 + 3 dose escalation design with 2 dose levels (85 and 100 mg/m(2) ) with an expansion cohort of 15 additional patients at the recommended dose. Patients received oxaliplatin at the assigned dose level and 5-fluorouracil (5-FU) bolus 400 mg/m(2) followed by a 46-hour 5-FU infusion of 2,400 mg/m(2) every 14 days. The leucovorin dose was fixed at 400 mg/m(2) for all cohorts.. Thirty-one evaluable patients were enrolled, 8 at 85 mg/m(2) and 23 at 100 mg/m(2) for a total of 121 courses. The median age was 12 years (range 2-19 years). The main toxicities were hematologic, primarily neutrophils and platelets. The most common non-hematologic toxicities were gastrointestinal. Stable disease was noted in 11 patients (54% of evaluable patients) and 1 confirmed partial response in a patient with osteosarcoma.. The maximum planned dose of oxaliplatin at 100 mg/m(2) per dose in combination with 5-FU and leucovorin was safe and well tolerated and in this patient population. This combination demonstrated modest activity in patients with refractory or relapsed solid tumor and warrants further study. Pediatr Blood Cancer 2013;60:230-236. © 2012 Wiley Periodicals, Inc.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Neoplasms; Organoplatinum Compounds; Oxaliplatin

Following the dose-escalation stage, this double-blind expansion stage of the phase I study evaluated the safety, pharmacodynamics, pharmacokinetics, anti-vascular effects and antitumour activity of aflibercept 4 mg/kg with irinotecan, 5-fluorouracil and leucovorin (LV5FU2).. Patients with advanced solid tumours were randomised at cycle-1 to placebo or aflibercept (4 mg/kg) on day 1 then irinotecan-LV5FU2 on days 1 and 2. Subsequently, all patients received aflibercept with irinotecan-LV5FU2 every 2 weeks. Anti-vascular effects were assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).. Twenty-seven patients were treated; 14 received placebo in cycle-1 followed by aflibercept in later cycles and 13 received aflibercept 4 mg/kg upfront. The median number of aflibercept cycles was 16 (range 1-44), 12 patients received ≥20 cycles. Most frequent grade 3/4 adverse events were neutropenia (37%), fatigue (33%) and hypertension (30%). No anti-aflibercept antibodies were detected. Four patients achieved partial responses and 17 had stable disease, lasting >3 months in 14 patients. Plasma levels of free over vascular endothelial growth factor-bound aflibercept were adequate, with steady-state achieved from cycle-3. Exploratory DCE-MRI showed no significant perfusion changes with aflibercept.. Aflibercept 4 mg/kg plus irinotecan-LV5FU2 every 2 weeks had acceptable toxicity and pharmacokinetics, and showed promising antitumour activity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prognosis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Tissue Distribution

The goal of this study was to assess the effect of oral cryotherapy on the development of oral mucositis related to infusion of 5-fluorouracil (5-FU) with leucovorin.. This study, a randomized controlled trial with random assignments to the experimental and control groups, was conducted with cancer patients. The study included 60 patients; 30 patients in the study group were instructed to hold ice cubes in their mouth shortly before, during, and shortly after infusion of 5-FU with leucovorin, the 30 patients in the control group received routine care. Oral mucositis in the patients was evaluated at 7, 14, and 21 days after chemotherapy. For analysis of data, chi-square, Fisher's tests were used; p < 0.05 was accepted as statistically significant.. In the majority of patients receiving cryotherapy, oral mucositis was not observed (Grade 0) at 7 and 14 days. Similarly, incidence of Grades 1, 2, and 3 oral mucositis in the experimental group was quite a bit lower when compared to the control group (p < 0.05). On day 21, no statistically significant difference between the experimental and control groups was determined based on the development of oral mucositis (p > 0.05).. We found that oral cryotherapy has a significant contribution to the protection of oral health by reducing mucositis score according to the WHO mucositis scale, especially on the 7th and 14th days. Nurses' awareness of how cryotherapy can affect patients and options for resolving problems will enable them to provide a higher standard of individualized care.

Topics: Antineoplastic Agents; Cryotherapy; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasms; Stomatitis; Treatment Outcome

This dose escalation, uncontrolled phase I study evaluated the tolerability, pharmacokinetics (PK), and antitumor activity of oral sorafenib 100, 200, or 400 mg twice daily (bid, continuous regimen) in combination with 5-fluorouracil/leucovorin (5-FU/LCV, intravenous infusion or bolus) in patients with advanced, solid tumors. A total of 47 patients (median age 57 years; colon cancer, 55%; pancreatic cancer, 21%; prior systemic therapy, 96%) received treatment; 24 were included in the PK analyses, and 38 were evaluable for tumor response. Treatment-emergent adverse events were observed in 98% of patients (≥grade 3, 55%); the most frequently reported were fatigue (51%), stomatitis/pharyngitis (47%), and hand-foot skin reaction (45%). Concomitant 5-FU/LCV resulted in no clinically relevant changes in the area under the plasma concentration-time curve in the dosing interval (AUC(0-12)) and maximum plasma concentration (C(max)) of sorafenib (100-400 mg bid) at steady state. Although the start of infusion until the last quantifiable plasma concentration (AUC(0-tn)) and C(max) of 5-FU were increased by concomitant sorafenib 100 to 200 mg, no consistent effect was observed with 400 mg sorafenib. Two (5%) patients with colon cancer achieved partial response; 16 (42%) patients (the majority with colon and pancreatic cancer) had stable disease. Sorafenib plus 5-FU/LCV was generally well tolerated with encouraging antitumor activity and no clinically relevant drug-drug interactions in patients with advanced solid tumors.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Benzenesulfonates; Drug Administration Schedule; Drug Interactions; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Israel; Leucovorin; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Sorafenib; Treatment Outcome; Vitamin B Complex

This phase I study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor effects of sunitinib combined with modified FOLFOX6 (mFOLFOX6).. Patients with advanced solid malignancies received mFOLFOX6 in 2-week cycles with escalating sunitinib doses (25, 37.5, and 50 mg/day) on three schedules: 2 weeks on, 2 weeks off (2/2); 4 weeks on, 2 weeks off (4/2); or continuous daily dosing (CDD). Patients received up to 8 treatment cycles (Schedule 2/2 and CDD schedule) or 6 cycles (Schedule 4/2). An expansion cohort enrolled patients with metastatic colorectal cancer at the Schedule 2/2 MTD.. Overall, 53 patients were enrolled, with 43 evaluable for dose-limiting toxicity (DLT). On Schedule 2/2 (n = 18), DLTs occurred in three patients at 50 mg/day (grade 4 neutropenia [n = 1]; grades 3 and 4 thrombocytopenia [n = 2]) and two patients achieved partial responses (PRs). On Schedule 4/2 (n = 13), 37.5 mg/day exceeded the MTD with two DLTs (febrile neutropenia and grade 4 hypokalemia, respectively). On the CDD schedule (n = 12), the MTD was 25 mg/day; one DLT (grade 3 stomatitis) was reported and two patients achieved PRs. The most common adverse events were neutropenia, fatigue, and thrombocytopenia. No clinically significant drug-drug interactions were apparent between sunitinib, its metabolite SU12662, and mFOLFOX6.. Sunitinib combined with mFOLFOX6 had acceptable tolerability. The MTDs were sunitinib 50 mg/day on Schedule 2/2 and 25 mg/day on the CDD schedule. A MTD for Schedule 4/2 was not established.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Fluorouracil; Humans; Indoles; Leucovorin; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pyrroles; Sunitinib; Thrombocytopenia; Treatment Outcome

Axitinib and bevacizumab are targeted therapies against the vascular endothelial growth factor pathway.. Patients with previously treated solid tumors received axitinib (starting dose 5 mg twice daily) combined with FOLFOX plus bevacizumab (1, 2, or 5 mg/kg, cohorts 1-3, respectively), FOLFIRI (cohort 4), or FOLFOX (cohort 5). Safety and pharmacokinetics were assessed.. Thirty patients were enrolled (n = 16, 8, and 6 for cohorts 1-3, 4, and 5, respectively). Plasma concentrations and pharmacokinetic (PK) parameters were similar when drugs were administered alone and in various combinations. Most treatment-emergent adverse events (AEs) were mild to moderate and clinically manageable (most common: nausea, fatigue, diarrhea, anorexia, hypertension). Two of the four patients receiving axitinib with FOLFOX plus 5 mg/kg bevacizumab experienced dose-limiting toxicity (DLT) of inability to resume treatment for 14 days following treatment interruption (associated AE: hypertension); the maximum tolerated dose of bevacizumab in this combination was 2 mg/kg. No DLTs occurred with axitinib plus FOLFIRI or FOLFOX. Ten patients had RECIST-confirmed partial tumor responses (objective response rate: 33.3%).. Axitinib is well tolerated in combination with FOLFOX, FOLFIRI, or FOLFOX plus 2 mg/kg bevacizumab. PK interactions appear to be absent.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Imidazoles; Indazoles; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Treatment Outcome

Edotecarin (J-107088), a novel inhibitor of topoisomerase I has an additive effect on colon cell lines (HCT-116) when combined with 5-fluorouracil (5-FU). We conducted a phase I study to determine the maximum tolerated dose and recommended a phase II dose of edotecarin in combination with infusional 5-FU/leucovorin (LV) in patients with advanced solid tumors. Patients and cohorts of three to six patients were sequentially enrolled at progressively higher dose levels of edotecarin administered as a 1-h intravenous (IV) infusion every 2 weeks. The edotecarin starting dose was 6 mg/m, followed by 200 mg/m LV IV infusion administered over 2 h, then 400 mg/m bolus dose of 5-FU before the start of 2400 mg/m 5-FU continuous infusion for a further 46 h. Patients were evaluated for safety, pharmacokinetics, and tumor response according to the Response Evaluation Criteria in Solid Tumors criteria. Fourteen patients (10 male; four female) received a total of 90 cycles (range 3-18). Dose-limiting toxicities were observed in five of the 14 patients treated in the study. All dose-limiting toxicities were related to neutropenia. Only the 6 and 8 mg/m edotecarin dose levels were explored; however, no maximum tolerated dose was declared. One confirmed complete response in a patient with hepatocellular carcinoma and seven stable disease responses were achieved in the 14 treated patients. Pharmacokinetic analysis showed that edotecarin achieved and maintained apparent steady-state plasma concentrations during the IV administration in both the cycles. The administration of edotecarin in combination with infusional 5-FU/LV once every 14 days, even without the 5-FU bolus, did not permit adequate time for recovery from neutropenia.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Topoisomerase I Inhibitors

The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors.. FOLFIRI + flavopiridol were administered every 2 weeks. Based on sequence-dependent inhibition, flavopiridol was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses were determined, one with flavopiridol administered over 1 h, and one with flavopiridol split as a 30-min bolus followed by a 4-h infusion.. A total of 74 patients were enrolled and 63 were evaluable. The MTD with FOLFIRI was flavopiridol 80 mg/m(2) over 1 h or 35 mg/m(2) bolus + 35 mg/m(2) over 4 h. Dose-limiting toxicities were diarrhea, fatigue, neutropenia, and neuropathy. Clinical activity included 2 partial responses in small bowel cancer and bladder cancer and 1 complete response in mucosal melanoma. Stable disease was seen in 22 patients. Pharmacokinetic studies showed increasing C(max) with increasing flavopiridol dose. Clinical benefit was correlated with the presence of wild-type p53. Of 25 patients with colorectal cancer, 11 had as best response SD for >3 m (median 6 m, range 4.2-15.4 m), despite failing ≥1 irinotecan-containing regimen.. Treatment with flavopiridol and FOLFIRI is a safe and effective regimen. Concentrations of flavopiridol that enhance the effects of FOLFIRI can be achieved. Clinical activity is encouraging and includes prolonged stable disease in patients with irinotecan-refractory colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Flavonoids; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Endostar is a proteolytic fragment of collagen XVIII that has been shown to have antitumor activity, with a favorable toxicological profile. We conducted this study to investigate its efficacy and safety when combined with chemotherapy in patients with advanced solid tumors.. From July 2006 to September 2008, 45 patients with histologically or cytologically confirmed solid tumors were enrolled into this study. All received Endostar at a dose of 7.5 mg/m2 /day as an intravenous infusion for more than 7 days, in combination with chemotherapy. Patients were treated until tumor progression or unacceptable toxicity.. No treatment related death occurred in this study. Main reported toxicities included: myelosuppression (82.2%), hepatic impairment (42.2%), anorexia (20.0%), nausea (24.4%), vomiting (22.2%), diarrhea (20.0%), febrile (20.0%) and fatigue (24.4%). No complete response was observed. Two patients (2/42) had partial response, twenty-one (21/42) remained stable, and nineteen (19/42) had progressive disease. Median time to tumor progression was 3.0 months (range, 0.5-12.0). Median overall survival was 30.0 months (95% confidence interval: 20.0-40.0) and 1 year survival rate was 81.0%.. Our study revealed that toxicity of Endostar combined with chemotherapy in the treatment of solid tumors was tolerable with moderate efficacy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carboplatin; Cisplatin; Deoxycytidine; Docetaxel; Endostatins; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Recombinant Proteins; Survival Rate; Taxoids; Treatment Outcome

A phase I study of high-dose capecitabine given over 2 days, along with oxaliplatin, bolus 5FU and leucovorin (LV), was designed to simulate FOLFOX6 without the need for infusional 5FU.. Schedule A included oxaliplatin 100 mg/m(2), 5FU 400 mg/m(2), and LV 20 mg/m(2) (all given IV on days 1 and 15, 28 day cycle). Capecitabine was administered orally every 8 h x 6 doses, days 1 and 15. Schedule B excluded 5FU and LV, maintaining oxaliplatin and capecitabine. Pharmacokinetics were performed for capecitabine for 6 patients on each schedule.. 36 patients were treated. The dose-limiting toxicities seen included nausea, dehydration, fatigue, hypotension and confusion. Minimal palmar-plantar erythrodysesthesia was seen. Myelosuppression was common, but not a dose limiting toxicity. The pharmacokinetic parameters for capecitabine were unaltered.. Using capecitabine to mimic FOLFOX6 is feasible and well tolerated with a toxicity profile that differs from standard 14-day capecitabine dosing, with less palmar-plantar erythrodysesthesia. The phase II dose for capecitabine in combination with oxaliplatin, 5FU, and LV is 1,500 mg/m(2)/dose or 2,250 mg/m(2)/dose in the absence of bolus 5FU/LV.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Deoxycytidine; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Organoplatinum Compounds; Prognosis; Tissue Distribution; Treatment Outcome

The purpose of this study was to evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted.. This was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3.. Forty-five subjects were enrolled. No difference in dose-normalized AUC(0-last) for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected.. Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bevacizumab; Camptothecin; Drug Interactions; Female; Fluorouracil; Gastrointestinal Tract; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Leukopenia; Male; Middle Aged; Neoplasms; Pharmacogenetics; Polymorphism, Genetic; Prodrugs

Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner.. We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated.. Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m(2)) and 5FU (2,400 mg/m(2)), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m(2) flavopiridol, 85 mg/m(2) oxaliplatin, and 1,800 mg/m(2) 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders.. Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cyclin-Dependent Kinases; Female; Flavonoids; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Piperidines; Tumor Suppressor Protein p53

We evaluated the advantages and disadvantages of Huber Plus through three outpatients treated with central venous (CV) port chemotherapy (FOLFOX). One of the three outpatients first received chemotherapy with safety huber (Huber Plus) in this study, and the huber needle was changed from non-safety to a safety huber (Huber Plus) in two of the three outpatients. All three outpatients were taught about needle removal methods and port care. In patients? education, 1) we used a skin model and training CV port, and 2) dressing materials were used as film dressing plus three-point fixation by Fixomull stretch. As a result, the safety system assured zero incidents. Moreover, the evaluation revealed that operability and pain of Huber Plus were not clinical problems. We suggest that Huber Plus is applicable in outpatient chemotherapy and that our care plan with patients? education might become a standard treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Infusion Pumps, Implantable; Leucovorin; Neoplasms; Organoplatinum Compounds; Outpatients; Patient Education as Topic; Surveys and Questionnaires

Systemic chemotherapy may damage gastrointestinal epithelium. Mucositis is associated with increased intestinal permeability (IP). It is known that IP test with chromium 51-ethylene diaminetetra-acetate (51Cr-EDTA) is a useful tool to assess the mucositis. Oral glutamine supplements (OGS) may have a role in the prevention of chemotherapy-induced mucositis/stomatitis. The aim of this study was to characterize the relationship between the urinary excretion of 51Cr-EDTA and the severity of mucositis, and the effect of OGS on 5-fluorouracil/leucovorin (FU/LV)-induced mucositis/stomatitis.. Fifty-one patients with advanced or metastatic cancer received FU/LV chemotherapy. The control group included 18 healthy volunteers. IP was assessed via the measurement of 51Cr-EDTA urinary excretion after oral challenge, on days 7 after the discontinuation of chemotherapy. Of the 51 patients, 22 patients received OGS (30 g/day) and 29 received only best supportive care (BSC). Glutamine supplementation continued for 15 days. It was initiated at least 3 days before the beginning of chemotherapy. Mucositis/stomatitis was graded according to version 3.0 of the Common Terminology Criteria for Adverse Events.. In the chemotherapy group, the median (25 percentile, 75 percentile) IP test score was significantly higher than those of the control group [6.78% (4.63, 10.66) vs. 2.17% (1.38, 2.40), P<0.001]. The severity of stomatitis was significantly correlated with IP test scores (r=0.898, P<0.001). In the OGS group, the median IP test score was significantly lower than that of the BSC group [4.69% (3.10, 6.48) vs. 8.54% (6.48, 15.31), P<0.001]. A mucositis/stomatitis of grade 2-4 was observed in two patients of the OGS group (9%), and in 11 patients (38%) in the BSC group (P<0.001).. The IP test may be a useful tool in the evaluation of mucositis/stomatitis. OGS may exert a protective effect on FU/LV-induced mucositis/stomatitis. Further studies, however, will be necessary to define the role of glutamine supplementation in FU/LV-induced mucositis/stomatitis.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chromium Radioisotopes; Edetic Acid; Female; Fluorouracil; Glutamine; Humans; Intestinal Absorption; Leucovorin; Male; Middle Aged; Mucositis; Neoplasms; Permeability; Severity of Illness Index; Stomatitis; Treatment Outcome

Erlotinib (Tarceva) is a potent epidermal growth factor receptor (HER1) inhibitor. Infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) is a standard therapy for colorectal cancer. This trial assessed the maximum tolerated dose (MTD), safety, preliminary efficacy, and pharmacokinetics of erlotinib combined with FOLFOX.. Patients with advanced solid tumors were sequentially enrolled into three cohorts (cohort 1: 100 mg/d erlotinib, 65 mg/m(2) oxaliplatin, 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 400 mg/m(2) continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m(2) and 5-FU infusion increased to 600 mg/m(2); and cohort 3: erlotinib increased to 150 mg/d).. Thirty-two patients were enrolled (23 with colorectal cancer): no dose-limiting toxicities (DLT) were observed in cohort 1. In cohort 2, two of nine patients experienced a DLT (both diarrhea). In cohort 3, two of nine patients had a DLT (diarrhea and staphylococcal septicemia). Cohort 3 determined the MTD cohort and expanded to 17 patients in total. The most common adverse events were diarrhea, nausea, stomatitis, and rash (primarily mild/moderate). No pharmacokinetics interactions were observed. One patient (colorectal cancer) had a complete response, seven patients had a partial response, and nine had stable disease.. The MTD was defined as follows: 150 mg/d erlotinib, 85 mg/m(2) oxaliplatin; 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 600 mg/m(2) infusion 5-FU. At the MTD, the combination was well tolerated and showed antitumor activity, warranting further investigation in patients with advanced colorectal cancer and other solid tumors.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Erlotinib Hydrochloride; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Quinazolines

Gemcitabine and uracil-ftorfar (UFT) are nucleotide analogs with overlapping clinical activity and complementary mechanisms of action. The primary objective of this study was to determine the maximum tolerated dose of UFT/leucovorin and gemcitabine.. The major eligibility criteria included a diagnosis of nonhematologic cancer with no conventional effective therapy, normal organ function, and Eastern Cooperative Oncology Group performance status of 0-2. The starting doses were 600 mg/m2 gemcitabine weekly for 3 of 4 weeks and 150 mg/m2 UFT daily and 30 mg leucovorin 3 times a day, both for 21 days. Cycles were repeated every 28 days.. Twenty-eight patients (male:female 13:15) were treated. The median number of cycles per patient was 3 (range, 0-17). Two of 3 patients on dose level 4 (250 mg/m2 UFT, 800 mg/m2 gemcitabine) developed dose-limiting toxicities consisting of hand-foot syndrome and infection.. The recommended doses for phase II trials are 800 mg/m2 gemcitabine days 1, 8, and 15 and 200 mg/m2 UFT per day and 90 mg leucovorin per day on days 1 through 21.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Tegafur; Uracil

This phase I study was designed to determine the optimally tolerated regimen (OTR), safety, and clinical activity of lapatinib in combination with FOLFOX4 [oxaliplatin/leucovorin/5-fluorouracil (5-FU)] in patients with solid tumors. Furthermore, the pharmacokinetics of lapatinib, oxaliplatin, and 5-FU when given alone and in combination were evaluated.. This study was conducted in two parts. Part 1 was designed to determine the OTR and part 2 was the pharmacokinetic part of the study. Lapatinib was administered once daily for the entire duration of the study. Leucovorin and oxaliplatin were given concurrently over 2 h as an i.v. infusion, after which 5-FU was given as a bolus followed by continuous infusion over 22 h on day 1. 5-FU and leucovorin administration were repeated in an identical manner on day 2. Cycles were repeated every 2 weeks. Once the OTR was determined, it was to become the dose level for patients included in the pharmacokinetic part of the study.. A total of 34 patients was treated in this study. No dose-limiting toxicities were observed and the OTR was established at 1,500 mg/d lapatinib in combination with the standard FOLFOX4 regimen. Nonhematologic toxicities consisted mainly of nausea, diarrhea, vomiting, fatigue, neuropathy, and mucositis. The most important hematologic toxicity was neutropenia. No drug-drug interactions between lapatinib and the FOLFOX4 regimen were observed.. Lapatinib can be safely administered in combination with the standard FOLFOX4 regimen. Further studies are warranted to explore the potential additive antitumor effect of lapatinib in combination with the FOLFOX4 regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Lapatinib; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Quinazolines

This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination.. Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination.. The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease.. The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Lapatinib; Leucovorin; Male; Middle Aged; Neoplasms; Quinazolines; Tandem Mass Spectrometry

Pre-clinically, hyaluronan (HA) has been demonstrated to systemically target chemotherapeutic drugs to tumours while ameliorating treatment toxicities. This study is a preliminary clinical investigation to determine if HA could be safely used in combination with 5-fluorouracil (5-FU) and doxorubicin (DOX).. Thirty patients with metastatic cancer were intravenously administered 500 mg/m2 HA in combination with escalating doses of DOX (30-60 mg/m2) or 5-FU (cumulative dose of 1,350-2,250 mg/m2 per cycle). The effect of pre-administration of 20 mg/m2 of folinic acid on HA/5-FU chemotherapy was also investigated. Patients were randomized to receive either HA/chemotherapy or chemotherapy alone in their first treatment cycle and vice versa for the second cycle. Patients received HA and chemotherapy in all subsequent cycles.. Treatment was well tolerated, tumour responses were observed and the co-administration of HA did not alter the pharmacokinetics of clinically relevant doses of 5-FU or DOX.. High doses of intravenous high-molecular-weight HA can be safely co-administered with clinical doses of chemotherapy without significantly altering the toxicity or pharmacokinetics of the drugs or HA.

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Hyaluronic Acid; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasms

In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions.. CPT-11 was first given at four levels (70-140 mg/m(2)/24 hours), followed by leucovorin 500 mg/m(2)/0.5 hours and 5-FU 2,000 mg/m(2)/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m(2)/48 hours.. Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 micromol/L at 3,900 mg/m(2)/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m(2)/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with >/=1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype.. Doses (mg/m(2)) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Camptothecin; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Infusion Pumps; Irinotecan; Leucovorin; Male; Neoplasms; Neutropenia; Pharmacogenetics; Promoter Regions, Genetic; Thymidylate Synthase; Treatment Outcome

To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTD) of L-OHP plus 5-FU and LV in patients with advanced solid malignancies.. Patients received escalated doses of L-OHP (starting dose 50 mg/m2) as a 2-hour IV infusion on Days 1 and 15, and LV (500 mg/m2 as a 2-hour IV infusion) followed by escalated doses of 5FU (starting dose 1,800 mg/m2) as a 22-hour continuous IV infusion on Days 1, 8, 15, 21 every 6 weeks. DLTs were evaluated in the first cycle.. Fifty-two patients [median age: 66 years; PS (ECOG) 0-1 in 90 percent] were treated on 12 dose-levels. Five (10 percent) patients had received 2 prior chemotherapy regimens, 24 (46 percent) one, and 23 (44 percent) were chemo-naïve. The DLT was reached at the dose of LOHP 100 mg/m2 and 5FU 2,200 mg/m2. Dose-limiting events were G3 diarrhea, G3 asthenia, G4 neutropenia, and G4 thrombocytopenia. Grade 3 diarrhea was observed in 6 (12 percent) patients and Grade 3 fatigue in 6 (12 percent). One (2 percent) patient developed Grade 4 neutropenia and another (2 percent) Grade 4 thrombocytopenia.. The MTD were L-OHP 95 mg/m2 on d1 and d15 and 5FU 2,200 mg/m2/week for 4 consecutive weeks every 6 weeks.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Female; Genotype; Hematologic Diseases; Humans; Irinotecan; Leucovorin; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Middle Aged; Neoplasms; Polymorphism, Genetic; Tablets; Tegafur; Treatment Outcome; Uracil

The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of irinotecan and oxaliplatin with a fixed 5-fluorouracil (5-FU)/leucovorin (LV) regimen in patients with metastatic solid tumors.. The trial was designed to evaluate escalating doses of oxaliplatin and irinotecan, starting at 60 mg/m2 and 90 mg/m2, respectively, given at day 1 with the full-dose LV5FU2 regimen, given on days 1 and 2 as follows: folinic acid 200 mg/m2 followed by 5-FU 400 mg/m2 bolus and 600 mg/m2 22 h continuous infusion, every 2 weeks. The second cohort of patients was treated at the recommended dose for oxaliplatin and irinotecan with the simplified LV5FU regimen: on day 1, a 2-h infusion of folinic acid (400 mg/m2), followed by a 10-min intravenous bolus of 5-FU (400 mg/m2), followed by a continuous infusion of 5-FU (2400 mg/m2) over 46 h.. Thirty-four patients were treated at the following dose levels (oxaliplatin/irinotecan mg/m2): 60/90, 60/120, 85/120, 85/150, 85/180, 85/200 and 85/220 and seven patients were treated at the recommended dose with the simplified LV5FU scheme. The MTD was reached at dose level 85/220 mg/m2 but the recommended dose chosen for the second step was 85/180 mg/m2 to keep a better compliance with the biweekly schedule. Main grade 3/4 toxicities per patient included the following: neutropenia in 78% (febrile episodes in 12%), diarrhea in 27%, nausea/vomiting in 24% and peripheral neuropathy in 37% (Lévi's scale). Antitumor activity was observed at almost all dose levels. Most objective responses were observed in digestive malignancies, since 10 out of 11 were obtained in five colorectal cancers, two pancreatic cancers, two cholangiocarcinoma and one gastric cancer.. The recommended dose for the triple association is 85/180 mg/m2 of oxaliplatin and irinotecan, respectively, with LV5FU2 or simplified LV5FU. The antitumor activity in gastrointestinal malignancies should be evaluated in phase II studies in different tumor types.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin

To determine the toxicities and pharmacokinetic effects of eniluracil (EU) given on two weekly dosing schedules with 5-fluorouracil (5-FU) and leucovorin (LV).. A group of 26 patients received a single 24-h i.v. infusion of 5-FU 2300 mg/m(2) to provide a pharmacokinetic reference. After 2 weeks, patients received oral EU 20 mg plus LV 30 mg on days 1-3 with a single dose of 5-FU 15-29 mg/m(2) on day 2, or LV 30 mg on days 1-2 with a single dose of EU at least 1 h prior to 5-FU 29 mg/m(2) on day 2 weekly for 3 of 4 weeks.. Diarrhea was the most common dose-limiting toxicity. The recommended dose of 5-FU is 29 mg/m(2) per day. EU on either schedule decreased 5-FU plasma clearance by 48 to 52-fold, prolonged the half-life to >5 h, and increased the percentage of 5-FU excreted in the urine from 2% to 64-66%. With EU, plasma fluoro-beta-alanine was not detected while urinary excretion was reduced to <1% of that seen with i.v. 5-FU alone. Marked increases in both plasma and urinary uracil were seen. Thymidylate synthase ternary complex formation was demonstrated in bone marrow mononuclear cells isolated 24 h after the first oral 5-FU dose; the average was 66.5% bound.. Either a single 20-mg dose of EU given prior to or for 3 days around the oral 5-FU dose led to comparable effects on 5-FU pharmacokinetic parameters, and inhibition of dihydropyrimidine dehydrogenase and thymidylate synthase.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Area Under Curve; Enzyme Inhibitors; Female; Fluorouracil; Half-Life; Humans; Infusions, Intravenous; Leucovorin; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Uracil

CCI-779 is a novel ester of the immunosuppressive agent sirolimus that exerts cytostatic effects by the inhibition of the translation of cell-cycle regulatory proteins. We investigated the maximum tolerated dose (MTD) and pharmacokinetics (PK) of CCI-779 in combination with leucovorin (LV) and 5-fluorouracil (5-FU) in patients with advanced solid tumors.. Patients were treated with LV at 200 mg/m(2) as a 1-h i.v. infusion directly followed by continuous 24-h i.v. infusion of 5-FU, in the first patient at 2000 mg/m(2) and in subsequent patients at 2600 mg/m(2). CCI-779 was administered directly prior to LV as a 30-min i.v. infusion at a starting dose of 15 mg/m(2) beginning at day 8 and escalated in subsequent cohorts of patients. One cycle consisted of six weekly administrations followed by 1 week of rest. Blood samples were drawn to assess PK of CCI-779 as well as its effect on steady-state 5-FU exposures.. Twenty-eight patients entered the study, the majority having tumor types for which 5-FU is used as a treatment. CCI-779 doses of 15, 25, 45 and 75 mg/m(2) were investigated. Skin toxicity (rash) was prominent at all dose levels examined. Stomatitis was the dose-limiting toxicity (DLT) for 75 mg/m(2) doses of CCI-779. Subsequently the cohort at 45 mg/m(2) was expanded to a total of 15 patients, and at this dose level two treatment-related deaths occurred due to mucositis with bowel perforation. Based on the toxicities observed, it was decided to discontinue the study. Partial responses were observed in three patients with gastrointestinal tumors. No pharmacokinetic interaction between CCI-779 and 5-FU was observed.. The safety profiles of CCI-779 and 5-FU/LV suggest an overlap of drug-related toxicities, and the administration of these drugs at these doses and schedule resulted in unacceptable toxicity and therefore cannot be recommended. If CCI-779 is to be used in combination with 5-FU/LV, other doses or schedules of administration will need to be explored.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Sirolimus

Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice.. Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but < or =3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin > or =5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m(2). 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m(2), and plasma concentrations were measured every 3 h during the first two infusions for each patient.. Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m(2) produced dose-limiting toxicity (DLT) in six of 20 evaluable patients. These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance.. Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m(2) with leucovorin 500 mg/m(2) as a 24-h continuous infusion.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Bilirubin; Creatinine; Dose-Response Relationship, Drug; Fatigue; Female; Fluorouracil; Humans; Infusions, Intravenous; Kidney Diseases; Leucovorin; Liver Diseases; Male; Middle Aged; Neoplasms; Neutropenia; Thrombocytopenia

A number of recent clinical trials testing the combination of 5-fluorouracil (5-FU) and gemcitabine in patients with advanced pancreatic adenocarcinoma have shown a significant clinical response rate, but also significant toxicity. As the two antimetabolites may interact at several biochemical levels along their pathways of activation, we investigated whether gemcitabine (GEM) affects 5-FU pharmacokinetics in cancer patients. Thus, we compared 5-FU pharmacokinetics in two groups of patients with various cancers who received the same schedule of 5-FU and folinic acid (FUFA), with or without GEM. There was a significant increase in systemic (5-FU) exposure and toxicity in the FUFA plus GEM group. Our finding may be useful in designing future studies of the combination in order to reduce the occurrence of side-effects and to maximise the antitumour activity.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Drug Interactions; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms

Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2'-deoxyuridine (FUDR), we studied this combination in a phase I trial.. Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity.. During cycle 1, six of eight patients who received 150 or 100 mg/m2 over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m2 over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m2 over 1 h, 7 did not complete cycle 1 due to thrombocytopenia (n=6) or diarrhea (n=1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5-19.5 mg/m2 over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 micro M (24 h), 16.3 micro M (2 h), and 31.9 micro M (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion.. Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Administration Schedule; Female; Floxuridine; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Ribonucleotide Reductases; Thrombocytopenia

We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics.. Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD.. Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P =.048), but objective neurotoxicity was not seen.. The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases

Irinotecan (CPT-11) and 5-fluorouracil (5-FU)/leucovorin are active agents in colorectal cancer. A sequence-dependent synergism of SN-38 followed by 5-FU/leucovorin in vitro led us to conduct a phase I trial of CPT-11 followed by 5-FU/leucovorin to determine the maximum tolerated dose (MTD) and toxicities of this regimen and to obtain preliminary indications of its activity in patients with advanced solid tumors.. Fifty-six patients were enrolled in sequential cohorts to receive escalating doses of CPT-11 (90 min infusion) on day 1, followed by leucovorin 20 mg/m(2) (intravenous push) and 5-FU (90 min infusion) on days 2-5 of each 21-day cycle.. A total of 347 treatment cycles (median 4, range 1-25) were administered. Dose-limiting toxicities were diarrhea, neutropenia and fatigue. Nine patients with colorectal cancer and one with gastric cancer had partial or minor responses. Eight of the 10 had prior chemotherapy.. CPT-11 and 5-FU/leucovorin, as constituents of this novel mechanism-based schedule, have promising activity in patients who have received prior chemotherapy. The recommended phase II/III starting doses are CPT-11 275 mg/m(2) over 90 min on day 1, and 5-FU 400 mg/m(2) plus leucovorin 20 mg/m(2) on days 2-5 every 21 days. This combination can be administered safely to this schedule if there is strict adherence to the 90 min infusion time for both CPT-11 and 5-FU.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms; Neutropenia

The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the protein kinase C-alpha antisense oligonucleotide ISIS 3521 (ISIS Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients with refractory solid tumors received ISIS 3521 as a 21-day continuous infusion administered simultaneously with 5-FU and LV given daily for 5 days repeated every 4-5 weeks (one cycle). 5-FU and ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received 5-FU (425 mg/m(2)/day) and LV (20 mg/m(2)/day) for 5 consecutive days. Grade 1-2 toxicities included alopecia, fatigue, mucositis, diarrhea, anorexia, nausea/vomiting, and tumor pain. One patient had grade 3 chest pain considered to be related to 5-FU therapy, another patient had dose-limiting grade 3 mucositis resolving in <7 days, and one patient with a history of gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4 neutropenia, which resolved without colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD. ISIS 3521 PKs in the presence of 5-FU was consistent with those reported previously. 5-FU PK parameters were also similar in the presence or absence of ISIS 3521. Six of 14 patients ( approximately 43%) across all dose cohorts had an improvement in measurable tumor response ranging from minor reduction in tumor size (4 patients) to objective partial response (>50% reduction in tumor size, 2 patients). ISIS 3521 is tolerable at its recommended single-agent dose when given with 5-FU and LV. There is no apparent PK interaction between ISIS 3521 and 5-FU and LV. Antitumor activity was observed with the combination; however, it is uncertain whether clinical activity is a result of enhanced drug interaction. Our study warrants further exploration of efficacy in a Phase II and/or Phase III cl

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Diarrhea; DNA, Antisense; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fatigue; Female; Fluorouracil; Humans; Isoenzymes; Leucovorin; Male; Middle Aged; Nausea; Neoplasms; Neutropenia; Oligonucleotides; Protein Kinase C; Protein Kinase C-alpha; Thionucleotides; Thrombocytopenia; Treatment Outcome; Vomiting

This study determined the effect of different weekly dosing schedules of 5-fluorouracil (5-FU)/leucovorin (LV)/eniluracil on dihydropyrimidine dehydrogenase (DPD) activity and plasma uracil levels.. Plasma and mononuclear cells were isolated from peripheral blood samples obtained before, during, and at various times after 5-FU/LV/eniluracil therapy. Two schedules were studied: 20 mg of eniluracil p.o. plus 30 mg of LV p.o. on days 1-3 with a single dose of 5-FU given day 2, or 30 mg of LV p.o. on days 1-2 with a single dose of eniluracil and 5-FU on day 2. DPD activity was determined with a radioisotopic enzyme assay; the reaction products were separated by high-performance liquid chromatography. Plasma uracil levels were determined by gas chromatography-mass spectroscopy.. During oral therapy, DPD activity was profoundly depressed, and uracil levels were strikingly elevated with both schedules. With the daily-for-3-days schedule, DPD activity was similar to baseline values by 3 weeks after the earlier eniluracil dose, whereas it appeared to recover earlier in patients receiving the single-dose schedule, reaching baseline values by 2 weeks. Although baseline uracil values did not predict DPD activity accurately, plasma uracil levels >0.95 microM were associated with significantly lower DPD activity (median, 18.4 versus 287.6 pmol/min/mg).. When eniluracil is given with 5-FU/LV, DPD inhibition appears to be influenced by schedule, and the time to recovery is much longer than has been observed with eniluracil given alone.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dihydrouracil Dehydrogenase (NADP); Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Leukocytes, Mononuclear; Male; Middle Aged; Neoplasms; Oxidoreductases; Time Factors; Uracil

Ftorafur is an orally available prodrug of 5-fluorouracil (5-FU). Its combination with uracil in a molar ratio of 1:4 (UFT) increases the 5-FU concentration in tumor cells compared with ftorafur alone. Paclitaxel has a broad spectrum of activity against solid tumors and synergic effects with UFT have been demonstrated in vitro. A phase I study was performed to determine the maximum tolerated dose of the combination of UFT and paclitaxel in patients with advanced solid tumors.. UFT and folinic acid were applied at 300 mg/m2/day and 90 mg/day, respectively, on days 1-28, repeated on day 36. Paclitaxel was applied on days 1, 8, 15 and 22 of each cycle. The starting dose of paclitaxel was 50 mg/m2 and escalation in 10 mg/m2 steps was performed up to 100 mg/m2 weekly.. Forty-seven consecutive patients with various solid tumors have been included in six different dose levels. One hundred and thirty cycles have been applied. The treatment was well tolerated overall. Most frequently encountered adverse effects were gastrointestinal and hematological toxicity (diarrhea CTC 3/4 in 6% of patients, anemia in 11%, leukocytopenia in 9%, polyneuropathy in 9%, fatigue in 11%, other in 6%). Partial remissions were observed in 28% of patients.. Owing to the lack of overlapping toxicities, UFT/folinic acid plus paclitaxel can be combined at doses of proven single agent activity. Side effects are mainly attributable to the gastrointestinal toxicity of UFT and to the neuro- and hematotoxicity of paclitaxel. The recommended doses for phase II studies are 300 mg/m2 of UFT plus 90 mg of folinic acid on days 1-28, and 90 mg/m2 of paclitaxel weekly.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Paclitaxel; Survival Analysis; Tegafur; Treatment Outcome

Tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) is inhibited by the recombinant humanized (rhu) monoclonal antibody (MAb) rhuMAbVEGF, which has synergy with chemotherapy in animal models. The present study was designed to assess the safety and pharmacokinetics of weekly intravenous (IV) rhuMAbVEGF with one of three standard chemotherapy regimens.. Twelve adult patients were enrolled four on each combination. rhuMAbVEGF, 3 mg/kg IV, was administered weekly for 8 weeks with (1) doxorubicin 50 mg/m(2) every 4 weeks; (2) carboplatin at area under the curve of 6 plus paclitaxel 175 mg/m(2) every 4 weeks; and (3) fluorouracil (5-FU) 500 mg/m(2) with leucovorin 20 mg/m(2) weekly, weeks 1 to 6 every 8 weeks.. The median number of rhuMAbVEGF doses delivered was eight (range, four to eight doses). Grade 3 toxicities were diarrhea (one 5-FU patient), thrombocytopenia (two patients on carboplatin plus paclitaxel), and leukopenia (one patient on carboplatin plus paclitaxel). These toxicities were likely attributable to the chemotherapy component of the regimen. The mean (+/- SD) peak serum level of rhuMAbVEGF was 167 +/- 46 microg/mL, and the mean terminal half-life was 13 days. Total (free plus bound) serum VEGF levels increased from 51 +/- 39 pg/mL (day 0) to 211 +/- 112 (day 49) pg/mL. Three responding patients continued treatment with rhuMAbVEGF and chemotherapy, receiving the equivalent of 36, 20, and 40 total rhuMAbVEGF doses with no cumulative or late toxicities.. rhuMAbVEGF can be safely combined with chemotherapy at doses associated with VEGF blockade and without apparent synergistic toxicity. Its contribution to the treatment of advanced solid tumors should be evaluated in randomized treatment trials.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Drug Interactions; Endothelial Growth Factors; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Lymphokines; Male; Middle Aged; Neoplasms; Paclitaxel; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

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

Six patients with incurable malignancies were originally treated with vitamin E, 3200 IU/day for fourteen days, followed by the same dose of vitamin E daily plus LCV (20 mg/m2 i.v. bolus daily x 5) with 5FU (425 mg/m2 i.v. bolus immediately following LCV). The same schedule of LCV and 5FU was repeated 4 weeks later, then every 5 weeks indefinitely. When 3 of the first 6 had grade 3/4 toxicity, six more patients were treated on the identical drugs and schedule. Seven of twelve total patients had one or more grade 3/4 toxicities. Neutropenia, abdominal pain, and diarrhea were most common. No patient had a documented response, though seven patients did have stable disease. Though the combination of vitamin E and chemotherapy was toxic, this trial demonstrated maximal therapeutic doses of vitamin E can be combined with standard 5FU and LCV, without significantly increasing the side effects of the chemotherapy itself.

Topics: Abdominal Pain; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Dinoprost; Dose-Response Relationship, Drug; F2-Isoprostanes; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Neutropenia; Vitamin E

Preclinical data suggests that the action of fluoropyrimidines may be enhanced by the addition of hydroxyurea. We developed a phase I trial to determine the maximum tolerated dose and pharmacokinetics of i.v. hydroxyurea (HU) in combination with i.p. 5-fluoro-2'-deoxyuridine (FUdR) and leucovorin (LV). Eligible patients had metastatic carcinoma confined mostly to the peritoneal cavity, and adequate hepatic, renal and bone marrow function. Patients were treated with a fixed dose of FUdR (3 g) and LV (640 mg) administered on days 1--3. HU was administered as a 72-h infusion starting simultaneously with i.p. therapy on day 1. The following dose levels were studied: 2.0, 2.5, 3.0 and 3.6 g/m(2)/day. Pharmacokinetics were studied in blood and peritoneal fluid. Twenty-eight patients were accrued. Steady-state plasma and peritoneal fluid HU levels increased with increasing dose, and steady state was achieved within 12 h of continuous dosing. The steady-state HU plasma:peritoneal fluid concentration ratio ranged from 1.06 x 10(3) to 1.25 x 10(3) and the plasma HU clearance ranged from 4.63 to 5.81 l/h/m(2). Peritoneal fluid AUC = 137,639 +/- 43,914 microg/ml x min, t(1/2) = 100.9 +/- 56.4 min and Cl = 25.29 +/- 10.88 ml/min. Neutropenia represented the dose-limiting toxicity. We conclude that i.p. FUdR and LV in combination with i.v. HU is well tolerated. The addition of systemic HU increased the incidence of myelosuppression.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Female; Floxuridine; Humans; Hydroxyurea; Injections, Intraperitoneal; Injections, Intravenous; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Time Factors

This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors.. Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m(2) over 1 hour and a 5-FU 450 mg/m(2) IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m(2)/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest.. The MTD of gemcitabine was established at 900 mg/m(2) given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m(2). One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months.. The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Neutropenia

The palliation of symptoms and improvement of quality of life are important aspects of therapy in patients with incurable metastatic cancer. This article describes the preliminary results of a phase I study of uracil and tegafur, an orally available fluorouracil (5-FU) derivative combined with oral leucovorin plus weekly intravenous paclitaxel. While the daily oral dose of UFT is fixed at 300 mg/m2 plus 90 mg leucovorin on days 1 to 28, paclitaxel is escalated in 10 mg/m2 steps starting with 50 mg/m2 weekly as a 1-hour infusion. To date, 26 patients with a median age of 57 years have been entered into the protocol and have received a median 2.2 cycles of therapy. Dose level 4 (paclitaxel 80 mg/m2) has been recently completed. Major dose-limiting toxicities were fatigue syndrome (two patients) and diarrhea (five patients). Preliminary responses have been observed in three of 14 currently evaluable patients. This protocol is taking the development of protracted 5-FU administration--given orally as UFT--in combination with paclitaxel one step further, using paclitaxel in a dose-dense, weekly schedule. It is hoped that an active regimen for the outpatient treatment of solid tumors will be developed.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Fatigue; Female; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Paclitaxel; Tegafur; Uracil

This phase I study examines the dose escalation of UFT given in combination with fixed doses of oral leucovorin and weekly doses of paclitaxel in patients with metastatic solid tumor malignancies (excluding colorectal cancer). There are two main objectives for this study. The first is to determine both the maximum tolerated dose and the dose-limiting toxicities of UFT when administered with leucovorin in combination with weekly paclitaxel (1-hour infusions of 80 mg/m2 for 4 weeks every 6 weeks). The second is to define the appropriate dose for phase II studies. Both UFT and leucovorin combinations, as well as paclitaxel, are known to be effective as single agents in heavily pretreated patients with a variety of solid tumor malignancies. UFT plus leucovorin provide activity comparable to that of intravenously administered 5-fluorouracil plus leucovorin, and weekly schedules of paclitaxel offer high dose intensity with limited hematologic toxicity. This combination is advantageous in its ease of administration and could be a tolerated outpatient regimen in patients with metastatic solid tumor malignancies.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Paclitaxel; Tegafur; Uracil

The combination of irinotecan and fluorouracil (5-FU) is synergistic when applied to human colon cancer cell lines in vitro and appears to be schedule-dependent: maximal activity occurs when irinotecan is administered prior to 5-FU. In this phase I study, irinotecan is administered in combination with UFT and leucovorin in patients with advanced solid tumors. Irinotecan is given as a 90-minute intravenous infusion on day 1 followed by twice-daily UFT plus oral leucovorin on days 2 through 15. Cycles are repeated every 21 days. Five patients have been treated to date; four are evaluable for toxicity. Starting doses were irinotecan 200 mg/m2/day, UFT 200 mg/m2/day, and leucovorin 60 mg/day. Preliminary results indicate that irinotecan in combination with UFT plus leucovorin is well tolerated at the initial doses (described in this article).

Topics: Administration, Oral; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms; Tegafur; Uracil

Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule.. Patients received a single 24-hour infusion of 5-FU (2,300 mg/m(2) on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m(2) PO bid on day 2).. Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m(2) PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m(2) PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19.. The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Dihydrouracil Dehydrogenase (NADP); Drug Administration Schedule; Enzyme Inhibitors; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Oxidoreductases; Uracil

To determine the feasibility, maximal tolerated doses, and response rates for a combined regimen of the platinum and 5-fluorouracil oral analogues bis-acetato-ammine-dichloro-cyclohexyl-amine platinum(IV) (JM-216) and uracil/ftorafur (UFT) coadministered as a 14 consecutive-day every 28-day schedule.. Of 20 patients enrolled in this investigation, 17 on the following dose escalation scheme were evaluable for toxicity and/or response: I UFT 300 mg/day, JM-216 5 mg/day (three patients), II UFT 300 mg/day, JM-216 10 mg/day (four patients), III UFT 300 mg/day, JM-216 20 mg/day (ten patients).. All 17 evaluable patients were evaluable for toxicity. At dose level III dose-limiting nausea and emesis were observed in one patient despite maximal antiemetic support. Importantly, neurotoxicity and nephrotoxicity were not observed at the JM-216 dose levels examined in this study. This observation is consistent with results seen with single agent JM-216.. For JM-216 and UFT administered at 20 mg/day and 300 mg/day over 14 days, nausea and emesis were observed as the principal dose-limiting toxicities. These doses are considerably below the maximally tolerated doses of single agent JM-216 and UFT. Shorter administration schedules should be explored in an attempt to increase the dose intensity and minimize the toxicity of this combination oral regimen.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Combinations; Humans; Leucovorin; Neoplasms; Organoplatinum Compounds; Tegafur; Treatment Outcome; Uracil; Vomiting

Since cancer is incurable in many patients, palliation of symptoms and quality-of-life issues are important aspects of therapy. Uracil and tegafur (UFT) plus calcium folinate are the components of the oral agent known as Orzel, which offers activity comparable to intravenously administered 5-fluorouracil (5-FU) combined with calcium folinate. Paclitaxel (Taxol), administered intravenously on a weekly schedule, offers high dose intensity and high response rates with limited hematologic toxicity. It is the aim of this phase I study to define the dose-limiting toxicity, possible antitumor activity, and appropriate phase II study dose for the combination of UFT plus calcium folinate administered orally for 4 weeks plus weekly doses of paclitaxel. The daily dose will be fixed at UFT 300 mg/m2 plus calcium folinate 90 mg, both divided into three doses per day; paclitaxel will be escalated in each cohort of patients in 10-mg/m2 steps, starting with 50 mg/m2 weekly. This protocol will take the success of protracted 5-FU infusion--here achieved orally with UFT plus calcium folinate--in combination with paclitaxel one step further by using paclitaxel in a dose-dense, less toxic weekly schedule. It may be anticipated that an active outpatient therapy for a variety of solid tumors will result.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Routes; Female; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Neoplasms; Paclitaxel; Tegafur; Treatment Outcome; Uracil

Gemcitabine (Gemzar) is a nucleoside analog increasingly used in the treatment of a variety of solid tumors. DNA synthesis is inhibited by gemcitabine by masked chain termination and via inhibition of ribonucleotide reductase. Synergy may exist between gemcitabine and other antimetabolites, including 5-fluorouracil. The varying patterns of dose-limiting toxicities to gemcitabine and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) permit their use in combination. The primary aim of this phase I study is to determine the maximum tolerated doses of gemcitabine and UFT plus oral calcium folinate in patients with a variety of solid tumors. Only eight patients have been recruited to date, with myelosuppression being the main toxicity observed.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; DNA, Neoplasm; Drug Administration Routes; Female; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Ribonucleotide Reductases; Tegafur; Treatment Outcome; Uracil

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU). The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0-2, and signed informed consent. Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m2, 5FU 255 mg/m2 and gemcitabine 600 mg/m2. 5FU and gemcitabine were escalated in tandem to 340 mg/m2 and 800 mg/m2 and thereafter to 425 mg/m2 and 1000 mg/m2, respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1-32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses. The maximum tolerated dose is leucovorin 20 mg/m2, 5FU 340 mg/m2, and gemcitabine 800 mg/m2. The impact of drug sequence remains undetermined.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Time Factors; Treatment Outcome

Diarrhea is dose-limiting with weekly 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been associated with a decrease in chemotherapy-associated mucosal toxicity. This study was conducted to determine the maximum tolerated dose (MTD) of weekly 5-FU when administered with GM-CSF and high-dose LV. Patients were treated with intravenous LV 500 mg/m2 plus 5-FU weekly for six doses followed by a 2-week rest. GM-CSF 250 mg/m2 was administered subcutaneously 5 days each week. Cohorts were treated with 5-FU at 600, 700, and 800 mg/m2 weekly. Twenty-nine patients were treated. The MTD of 5-FU in this schedule was 700 mg/m2/week, with diarrhea dose-limiting. 5-FU delivered dose intensity at the MTD was 424 +/- 23.7 mg/m2/week, including rest periods. 5-FU and LV pharmacokinetics were not altered by concurrent treatment with GM-CSF. In a weekly schedule with high-dose LV and GM-CSF, the MTD of 5-FU and 5-FU delivered dose intensity were higher than previously reported with 5-FU and LV administered without GM-CSF.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Bone Marrow Diseases; Cohort Studies; Diarrhea; Drug Administration Schedule; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infusions, Intravenous; Injections, Intravenous; Injections, Subcutaneous; Intestinal Mucosa; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Peripheral Nervous System Diseases; Severity of Illness Index; Stomatitis; Treatment Outcome; Venous Thrombosis

To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85.. Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin.. Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d.. 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Dihydrouracil Dehydrogenase (NADP); Drug Interactions; Enzyme Inhibitors; Female; Fluorouracil; Gas Chromatography-Mass Spectrometry; Half-Life; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Oxidoreductases; Uracil

Aminopterin (AMT) is a potent folate analog that is no longer in routine clinical use. Because of laboratory data that suggests improved metabolism of AMT versus methotrexate (MTX) in lymphoblasts, we developed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of AMT.. Twenty patients with refractory malignancies were treated. The starting dose of AMT was 2.5 mg/m2 every 12 hours for two doses weekly: the dose of AMT was decreased and leucovorin (LV) rescue was added after the DLT was observed. Pharmacokinetics were performed after both intravenous (i.v.) and oral AMT administration.. Mucosal toxicity was dose-limiting and resulted in the need for a dose reduction (dose level 2: AMT 2 mg/m2 every 12 hours for two doses weekly) and, subsequently, the addition of scheduled LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two doses followed by LV 5 mg/m2 orally every 12 hours for two doses, starting 24 hours after the second dose of AMT). The mean areas under the curve (AUC) for the i.v. (n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14 micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the oral bioavailability in 12 matched subjects was 83.5% +/- 8.3%. One patient with endometrial adenocarcinoma achieved a complete response (CR) and remains on therapy at 11+ months. Seven patients had stable disease (SD) for 8 weeks or greater, which included one patient with a metastatic nerve sheath tumor who was stable for 9 months.. We conclude that AMT has good oral bioavailability and that, when given on a q12 hour x two weekly schedule, the MTD is 2 mg/m2 with delayed LV rescue.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aminopterin; Area Under Curve; Biological Availability; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Folic Acid Antagonists; Humans; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Treatment Outcome

Capecitabine (Xeloda) is a novel rationally designed fluoropyrimidine carbamate. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes resulting in preferential release of 5-fluorouracil (5-FU) at the tumor site. Preclinical studies indicated an enhancement of the therapeutic index when capecitabine was combined with leucovorin. This Phase I trial was designed to determine the safety profile, maximal tolerated dose, and pharmacokinetic profile of the combination of capecitabine plus a fixed dose of p.o. leucovorin (60 mg/day) during administration to patients with refractory advanced cancers. The intention was to administer both drugs continuously, but the starting dose of capecitabine was also the maximum tolerated dose (1004 mg/m2/day) in six patients treated with this regimen. A cycle of treatment was then redefined as leucovorin and capecitabine given p.o., twice daily for 2 consecutive weeks followed by a 1-week rest period. Capecitabine doses from 1004 mg/m2/day to 2510 mg/m2/day were evaluated with the intermittent schedule over approximately 80 courses in an additional 25 patients. The dose-limiting toxicities that defined the maximum tolerated dose at 2000 mg/m2/day were diarrhea, nausea, vomiting, and palmar plantar erythrodysesthesia. The recommended Phase II dose using this schedule was 1650 mg/m2/day of capecitabine plus leucovorin 60 mg/day. Plasma concentrations of capecitabine, intermediate metabolites, and 5-FU were measured in 26 patients on days 1 and 14 of therapy. The pharmacokinetics of capecitabine were characterized by rapid GI absorption, with Cmax at 1 h, followed by conversion to active drug. The coadministration of leucovorin had no effect on the pharmacokinetics of capecitabine. Two patients with colorectal cancer, both previously treated with 5-FU, had partial responses. Phase II studies have confirmed the promising antitumor activity of this drug, and capecitabine is currently in Phase III evaluation.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Treatment Outcome

Our objective was to find the minimum dose of leucovorin (LV; 5-formyltetrahydrofolate) needed to potentially provide selective protection of normal tissue in patients with tumors resistant to methotrexate (MTX) by virtue of transport during prolonged therapy with high-dose trimetrexate (TMTX). Based upon the known daily requirement for folate, that tumors are often resistant to methotrexate via a transport-based mechanism, and that large doses of trimetrexate can be given with large doses of leucovorin for the treatment of patients with Pneumocystis carinii, a protocol was designed to find the minimum LV dose required to allow the administration of large doses of TMTX. Patients were treated in 28-day cycles consisting of 14 consecutive days of oral TMTX (45 mg/m2 every 12 h), followed by 14 days of rest. The dose of concurrent LV was started at 5 mg/m2 twice daily. Cohorts of patients received successive half doses of LV so long as three consecutive patients had less than or equal to grade 3 toxicity. Ten patients received 29 courses of therapy. The most common toxicities encountered were thrombocytopenia (38%), mucositis (14%), and neutropenia (10%). At a LV dose of 2.5 mg/m2, toxicities were consistently limited to less than or equal to grade 3 and only one episode of grade 4 hematological toxicity. Although there was marked interpatient variability, the minimally effective LV dose for selective protection seems to be 2.5 mg/m2. If tumors are resistant to methotrexate because of decreased transport of drug (and also folate), then the same pharmacological principle used to develop TMTX/LV for the treatment of P. carinii may be applied to treatment of some patients with cancer.

Topics: Adolescent; Adult; Antidotes; Antimetabolites, Antineoplastic; Child; Child, Preschool; Drug Interactions; Feasibility Studies; Humans; Infant; Leucovorin; Liver Function Tests; Mucous Membrane; Neoplasms; Thrombocytopenia; Treatment Outcome; Trimetrexate

A combination of oral 13-cis-retinoic acid (cis-RA) and subcutaneous interferon alfa-2a (IFN) has been reported to yield high response rates in patients with squamous cell carcinomas (SCCAs) of the cervix and skin. Cisplatin and 5-fluorouracil with leucovorin (5-FU/LV) are chemotherapeutic agents commonly used for SCCAs.. To determine the maximum tolerated doses (MTDs) of cisplatin and 5-FU/LV when combined with IFN and cis-RA, and to define a recommended phase II regimen for testing in cervical cancer and other appropriate tumor types.. Phase I cohort design. Cisplatin was administered every 3 weeks. 5-FU and LV were administered together as a weekly 24-h infusion. Cis-RA was given orally twice daily. IFN was initially given subcutaneously at a dose of 3 million units (MU) daily.. A total of 31 patients were treated. The IFN dose was reduced to 3 MU three times weekly because of patient intolerance. Cytopenias prevented the administration of weekly 5-FU/LV. Single-agent cisplatin with three times weekly IFN and twice daily cis-RA was tolerable. Four partial responses were observed, in patients with adrenal cancer, bladder cancer, gastric cancer, and adenocarcinoma of unknown primary.. The recommended phase II regimen is cisplatin 100 mg/m2 every 3 weeks, IFN 3 MU three times weekly, and cis-RA 1 mg/kg daily. This appears to be more toxic than single-agent cisplatin, but the preliminary activity observed warrants further testing.

Topics: Administration, Oral; Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Synergism; Female; Fluorouracil; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Isotretinoin; Leucovorin; Leukopenia; Male; Middle Aged; Neoplasms; Recombinant Proteins; Remission Induction

The phase I development program of tegafur and uracil (UFT) in the United States has included evaluation of the drug as a single agent and subsequent studies of its biochemical modulation by oral leucovorin. Phase I trials of single-agent UFT examined both a 5-day schedule repeated every 21 days and a 28-day schedule repeated every 35 days. In all of the trials the total dose was divided by three and administered three times daily at 8-hour intervals. Like intravenous schedules of fluorouracil (5-FU), UFT has schedule-dependent toxicity, with granulocytopenia being the dose-limiting toxicity for the 5-day regimen and diarrhea being the dose-limiting toxicity for the 28-day regimen. The suggested phase II doses for UFT administered without leucovorin were 800 mg/m2/day for the 5-day schedule and 360 mg/m2/day for the 28-day schedule. Subsequent phase I studies combining UFT with oral leucovorin used a 28-day schedule repeated every 35 days. Diarrhea was the dose-limiting toxicity, and the recommended phase II dose was UFT, 300 mg/m2/day, plus leucovorin, 90 mg/day. Pharmacokinetic evaluation showed that single-dose UFT results in maximum plasma levels and an area under the concentration-time curve that increased with escalating UFT doses. In addition, 5-FU levels were detectable throughout the 28-day dosing period; however, there was no evidence of significant accumulation of uracil, tegafur, or 5-FU. The administration of leucovorin in this trial provided continuous exposure of d,l-leucovorin and 5-methyltetrahydrofolate with little variation between doses or days.

Topics: Administration, Oral; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Drug Combinations; Fluorouracil; Humans; Leucovorin; Neoplasms; Tegafur; Tetrahydrofolates; Uracil

The combination of IFN-alpha-2a (IFN-alpha) and IFN-gamma-1b (IFN-gamma) has been found to produce more than additive cytotoxicity with fluorouracil (5-FU) in HT 29 colon cancer cells due to enhanced DNA-directed effects. We therefore studied the combination of IFN-gamma with IFN-alpha, 5-FU, and leucovorin (LV) in a clinical trial. Fifty-three patients received an initial cycle of 5 million units (MU)/m2 IFN-alpha s.c. on days 1-7 with 500 mg/m2 LV and 370 mg/m2 5-FU i.v. on days 2-6. IFN-gamma was then added once tolerable doses of 5-FU and IFN-alpha were established for each patient. IFN-gamma was administered at one of six dose levels between 0.3-4.8 MU/m2 s.c. on days 1-7. This design permitted comparison of the clinical toxicity and pharmacokinetics of 5-FU in two consecutive cycles in an individual treated with the same doses of 5-FU/LV/IFN-alpha in the absence and presence of IFN-gamma. In 43 matched patient cycles, the addition of IFN-gamma did not seem to worsen gastrointestinal toxicity, and skin toxicity tended to be milder. 5-FU clearance was higher in 14 cycles with IFN-gamma compared to the patient's prior cycle with the same doses of 5-FU/LV/IFN-alpha: 798 +/- 309 versus 601 +/- 250 ml/min/m2 (mean +/- SD; P = 0.04). In these 28 cycles, the median 5-FU clearance was significantly lower in 11 cycles that were complicated by more severe diarrhea: 524 versus 798 ml/min/m2 (grade 2 versus 0-1; P = 0. 0032). Overall, 38% and 26% of patients had grade 3-4 diarrhea and mucositis. Dose reductions of IFN-gamma for chronic fatigue, malaise, or anorexia were ultimately required more frequently with >/=2.4 MU/m2 (P = 0.018), and the maximum tolerated dose of IFN-gamma was considered to be 1.2 MU/m2/ day. Objective responses were seen in 41% of 29 measurable colorectal cancer patients. Compared to our previous experience with 5-FU/LV/IFN-alpha, IFN-gamma and IFN-alpha appeared to have opposite effects on 5-FU clearance. These results suggest that any potential benefit of adding IFN-alpha to 5-FU/LV on this schedule may not depend solely on alterations in 5-FU clearance.

Topics: Adult; Aged; Antineoplastic Agents; Clinical Protocols; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Interferon-gamma; Leucovorin; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Pilot Projects; Recombinant Proteins

In a pilot trial, we treated patients with solid tumors with 5-FU (5-fluorouracil), leucovorin (LV), and cisplatin (FLP) with Adriamycin in selected patients (FLAP). 5-FU/LV were administered weekly for 6 weeks, with cisplatin at two dose levels (and Adriamycin in some patients) at weeks 1 and 4. Nine patients received FLP; 11 received FLAP.FLP was able to be administered with a cisplatin dose of 75 mg/m2; the maximum-tolerated dose of FLAP included a cisplatin dose of 60 mg/m2. Significant toxicities included granulocytopenia, thrombocytopenia, and diarrhea. Preliminary activity was demonstrated with FLAP in patients with adenocarcinomas of the stomach and gastroesophageal (GE) junction. Ongoing trials of FLAP are underway in patients with gastric and GE junction carcinomas in the neoadjuvant and advanced disease settings.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Pilot Projects

A priming dose of 5-fluorouracil can decrease the toxicity and retain the efficacy of high-dose methotrexate in laboratory models. This Phase I study determined the maximum tolerated dose of methotrexate that can be administered after a dose of 5-fluorouracil without leucovorin rescue. Forty-two patients received 5-fluorouracil (500 mg/m2) by bolus injection followed in 2 h by methotrexate infused over 1 h; treatment was repeated every 3 weeks. Patients received five doses of leucovorin (10 mg/m2 every 6 h); this was reduced to two doses and then to zero doses (no rescue) if less than grade 2 toxicity occurred in prior treatments. If safe, at least two patients received no leucovorin rescue with their first treatment. The dose of methotrexate was escalated in cohorts of patients, starting with a methotrexate dose of 200 mg/m2. Previously untreated patients maximally tolerated 1600 mg/m2 of methotrexate with 5-fluorouracil pretreatment. Leukopenia combined with stomatitis prevented deescalation of leucovorin doses. Fourteen percent of total courses and 15% of courses without leucovorin rescue resulted in dose limiting toxicity. MTX levels exceeded levels that require leucovorin rescue. Four of the 33 (12%) advanced head and neck cancer patients had objective responses to therapy; median survival was 10 months. Previously treated patients were less tolerant; oral and hematological toxicities were troublesome; 400 mg/m2 of methotrexate was the approximate maximum tolerated dose. Forty-seven percent of total courses and 60% of courses without leucovorin rescue resulted in dose limiting toxicity. There were no responses. Although the antineoplastic activity is poor, prior 5-fluorouracil exposure does protect tissues susceptible to methotrexate toxicity.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Survival Rate

Dose intensification of 5-fluorouracil (5-FU) is complicated by increased toxicity. 5-FU is a fluorine-substituted pyrimidine analog of uracil. In preclinical studies, administration of oral uridine (Ur) has been shown to allow for dose intensification of 5-FU with enhancement of its antitumor activity. Therefore, a Phase I trial was designed aimed at dose intensification of 5-FU as a component of a modified 5-FU-doxorubicin-methotrexate (FAMTX) regimen using oral Ur rescue.. Methotrexate (MTX) was administered to all patients at a fixed dose of 1.5 g/m2. MTX was followed 24 hours later by escalating doses of 5-FU starting at 800 mg/m2 with leucovorin rescue. Cycles of 5-FU and MTX were repeated every 15 days. Every other cycle, patients received doxorubicin. "Adria cycles") at a dose of 30 mg/m2. Oral Ur was administered at a dose of 8 gm/m2 every 6 hours for 12 doses. In the first phase of the study, patients received Ur only if they developed Grade 3 or 4 hematologic toxicity. In the second phase, all patients received Ur 24 hours after 5-FU on all cycles.. Without Ur rescue, the maximum tolerated dose (MTD) of 5-FU was 900 mg/m2 on the Adria cycles and 1.1 gm/m2 on the non-Adria cycles. With Ur, the MTD of 5-FU increased to 1.2 gm/m2 on the Adria cycles and to 1.6 gm/m2 on the non-Adria cycles.. In this modified FAMTX regimen, oral Ur administration allowed for dose-intensification of 5-FU, with a 33% increase in the MTD of 5-FU on the Adria cycles and a 45% increase in the MTD of 5-FU dose on the non-Adria cycles.

Topics: Administration, Oral; Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Methotrexate; Middle Aged; Neoplasms; Neutropenia; Uridine

To determine the maximum-tolerable dose (MTD) of fluorouracil (5FU) when given with fixed doses of leucovorin and irinotecan (CPT-11), to define the dose-limiting toxicities of this combination, and to evaluate the effect of 5FU on the pharmacokinetics of CPT-11.. CPT-11, leucovorin, and 5FU were administered in repeated 6-week cycles that consisted of weekly treatment with all three drugs for 4 consecutive weeks followed by a 2-week break. On day 1 of treatment, CPT-11 alone was given by 90-minute infusion, and pharmacokinetic sampling was performed over 24 hours. Leucovorin and 5FU were administered by brief intravenous injection on day 2. On days 8, 15, and 22, CPT-11 infusion was immediately followed by leucovorin and then 5FU. A second 24-hour pharmacokinetic sampling was performed on day 8, which permitted comparison of the pharmacokinetics of CPT-11 with and without 5FU. For the second 6-week cycle, leucovorin was administered first, followed by 5FU and then CPT-11, and a third pharmacokinetic sampling was performed.. Forty-two patients were entered onto this trial. The CPT-11 dose was initially fixed at 100 mg/m2. Leucovorin was fixed at 20 mg/m2. 5FU doses of 210, 265, 340, 425, and 500 mg/m2 were studied. When the 500-mg/m2 dose of 5FU was found to be tolerable, this was then maintained and CPT-11 was escalated to 125 and then 150 mg/m2. This final CPT-11 dose exceeded the MTD. Neutropenia was the major dose-limiting toxicity. Diarrhea was common, but was rarely dose-limiting. Coadministration of 5FU had no substantial effect on the pharmacokinetics of CPT-11 or SN-38. Among the 38 patients with colorectal cancer, six partial responses (PRs) were seen in this predominantly 5FU-refractory patient population.. 5FU does not substantially affect the metabolism of CPT-11 to its active metabolite, SN-38. The combination of CPT-11125 mg/m2, 5FU 500 mg/m2, and leucovorin 20 mg/m2 is feasible and tolerable on this schedule.

Topics: Adult; Aged; Antidotes; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Diarrhea; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.

Topics: Administration, Oral; Adult; Aged; Aminopterin; Antineoplastic Agents; Drug Interactions; Drug Monitoring; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasms

Lometrexol (5,10-dideazatetrahydrofolic acid) is a new antifolate that is highly selective in inhibiting the key enzyme of purine synthesis glycinamide ribonucleotide formyltransferase. The most promising preclinical features of lometrexol in animal models were its significant activity against a broad panel of solid tumors, the schedule dependency of its antitumor activity, and the availability of a rescue regimen with folinic or folic acid. In the present study, lometrexol was first given daily for 3 consecutive days, repeated every 4 weeks (part I). The occurrence of delayed myelotoxicity prompted the development of a rescue regimen with lometrexol given in a single dose on day 1, followed by oral folinic acid, 15 mg four times a day, from day 3 to day 5 (part II). Longer time intervals between administration of lometrexol and start of rescue were then evaluated (part III), and in the last part of the study (part IV), the maximum tolerated dose of single intermittent doses of lometrexol with folinic acid given from day 7 to day 9 was established. Sixty adult patients entered the study. In part I, the highest daily dose that could be safely given was 4 mg/m2, for a total dose of 12 mg/m2. Cumulative early stomatitis and delayed thrombocytopenia were dose limiting. The use of oral folinic acid made it possible to escalate the dose up to 60 mg/m2, and the maximum tolerated dose was reached at this dose when folinic was given from day 7 to day 9, with anemia being the dose-limiting toxicity. A shorter time interval between lometrexol and folinic acid administrations (from day 5 to day 7) is recommended for Phase II evaluations to optimize the antitumor effect. Anemia was normochromic and macrocytic, possibly due to a deficiency of folic acid. One partial response of 8 months' duration was reported in a patient with epithelial cancer of the ovary, relapsing after cisplatin and alkylating agents. The use of folic acid as rescue, proposed on the basis of experimental data and pharmacological considerations, has also allowed the repeated administration of lometrexol at doses higher than in the previous studies. The advantages of rescue with folinic acid over supplementation with folic acid, however, are difficult to define.

Topics: Adult; Bone Marrow; Folic Acid Antagonists; Humans; Leucovorin; Neoplasms; Tetrahydrofolates

Cisplatin (CDDP) administration by the intra-arterial hepatic route (i.a.h.) in patients with primary or metastatic liver malignancies could enhance the anti-tumor activity of the drug and reduce its systemic toxicity. The aim of the present study was to compare Pt pharmacokinetics and the toxicity of the circulating drug after i.a.h. versus intravenous (i.v.) administration. CDDP pharmacokinetics was followed-up in 11 i.a.h. courses given to 7 patients with liver malignancies and compared with 19 i.v. courses in 15 patients with cancer of different origins. The Pt level in blood was monitored by sensitive atomic absorption spectrometry. The dose given was in the range of 25-80 mg/m2/treatment. For analysis and for comparison purposes, the data from both CDDP treatments were normalized to a standard dose of 35 mg/m2. The mean peak Pt level for i.a.h. treatment was found to be about half of the mean peak value for i.v. administration with a similar dose-independent bi-exponential rate of elimination i.a.h. CDDP treatment was relatively well tolerated with no symptoms of either nephro- or neurotoxicity. For in vitro evaluation of peripheral CDDP toxicity, a sensitive ovarian carcinoma cell line, OV-1063, was used. A cytotoxic effect was recorded only within 2 hr following high-dose i.v. CDDP treatment. A substantial fraction of the drug given by the i.a.h. route was found to be extracted by the liver in the first passage, with reduced drug level in the peripheral blood plasma relative to the dose given. This may explain the apparent diminution of side-effects following i.a.h. CDDP treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Kidney Diseases; Leucovorin; Liver; Liver Neoplasms; Methotrexate; Neoplasms; Nervous System Diseases; Ovarian Neoplasms; Remission Induction; Spectrophotometry, Atomic; Tumor Cells, Cultured; Vinblastine

Topics: Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasms; Palliative Care; Randomized Controlled Trials as Topic

This phase I trial evaluated a high-dose, short-term infusion of zidovudine (AZT) following oral leucovorin (LV) and bolus 5-fluorouracil (FUra). Thirteen patients with metastatic cancer received 30 cycles of therapy. Plasma monitoring demonstrated a dose-dependent increase in peak plasma levels of AZT through the range of dose levels, from 104.3 +/- 8.7 microM at the 1.5 g/m2 dose of AZT to 1312.6 +/- 165.9 microM at the 11.0 g/m2 dose. While AZT did not potentiate the usual clinical toxicities of LV plus FUra, an unexpected finding of symptomatic hypotension during the AZT infusion was the dose-limiting toxicity in this trial. One partial response was observed in a previously untreated patient with metastatic colorectal cancer. The maximal tolerated dose of AZT, 7.0 g/m2 over 2 hr, is recommended for future phase II evaluation of this novel combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Zidovudine

Bayesian methods for the analysis of clinical trials data have received increasing attention recently as they offer an approach for dealing with difficult problems that arise in practice. A major criticism of the Bayesian approach, however, has focused on the need to specify a single, often subjective, prior distribution for the parameters of interest. In an attempt to address this criticism, we describe methods for assessing the robustness of the posterior distribution to the specification of the prior. The robust Bayesian approach to data analysis replaces the prior distribution with a class of prior distributions and investigates how the inferences might change as the prior varies over this class. The purpose of this paper is to illustrate the application of robust Bayesian methods to the analysis of clinical trials data. Using two examples of clinical trials taken from the literature, we illustrate how to use these methods to help a data monitoring committee decide whether or not to stop a trial early.

Topics: Bayes Theorem; Clinical Trials as Topic; Data Collection; Data Interpretation, Statistical; Extracorporeal Membrane Oxygenation; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Infant, Newborn; Leucovorin; Leukopenia; Likelihood Functions; Neoplasms; Persistent Fetal Circulation Syndrome; Stomatitis; Survival Rate; Treatment Outcome

Circadian (about 24 h) changes modulate cellular metabolism and proliferation in healthy tissues. As a result, the extent of toxicity of cancer chemotherapy varies by 50% or more according to dosing time in mice or rats. These experimental data led to test the principle of adapting chemotherapy delivery to circadian rhythms--so-called "chronotherapy"--in cancer patients. Clinical trials first aimed to assess toxicities and maximal tolerated dose of chronotherapy schedules. Programmable-in-time pumps became the indispensable tool for reliably testing this principle in a large enough patient population and without any need for hospitalization. Results from randomized clinical trials have indicated that chronotherapy allowed to increase dose intensity (DI, a secondary criterion in these trials) by 13 to 45% as compared to injecting the drug at another time (doxorubicin, cisplatin) or according to a flat rate (5-fluorouracil, floxuridine, oxaliplatin). A non-randomized trial further suggested this principle would also apply to cytokine delivery (interferon alpha). Two consecutive randomized trials have revealed that chronotherapy-related increase in 5-FU DI was further associated with a 20% increase in response rate of patients with metastatic colorectal cancer to the 3-drug association that was used (5-FU, folinic acid and oxaliplatin). In a subsequent phase II trial 5-FU daily dose and 3-drug treatment frequency were increased in 50 patients with this disease. Such intrapatient dose escalation protocol also disclosed a positive correlation between DI of 5-FU and response. New anticancer drugs should benefit from this approach so that both their clinical safety and patient's quality of life are improved, through ambulatory administration.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chronobiology Phenomena; Circadian Rhythm; Cisplatin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Humans; Infusion Pumps; Interferon-alpha; Leucovorin; Male; Mice; Neoplasms; Neoplasms, Experimental; Organoplatinum Compounds; Ovarian Neoplasms; Oxaliplatin; Rats

Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Diarrhea; Digestive System; Drug Synergism; Female; Fluorouracil; Folic Acid; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Neutropenia; Phosphonoacetic Acid; Proportional Hazards Models; Pyrimidines; Remission Induction; Risk Factors; Thymidylate Synthase

The best schedule for administering floxuridine (FUDR) has not yet been established. Duration of infusion, need (and dosage) of leucovorin (folinic acid, FA), and circadian timing need to be further specified. Nevertheless, FUDR delivery according to circadian rhythms has allowed increase of dose intensity without enhancing the side effects. A 5-day infusional schedule combining FUDR and L-FA was devised as an attempt to increase dose intensity and to provide therapy every 3 weeks to patients with advanced cancer. An ambulatory programmable-in-time pump was used for this purpose. Fourteen patients entered this trial. Two dose levels (mg/kg x 5 days) were evaluated: 0.5 mg/kg/day in six patients and 0.525 mg/kg/day in eight patients. Both patient groups received a concurrent infusion of L-FA 10 mg/m2/day i.v. The delivery patterns of both FUDR and L-FA varied sinusoidally during the 24 hours with a maximum at 18.00 hours. Courses were repeated every 3 weeks. Of 35 courses, treatment produced mucosites greater than grade 2 in only two of them. No severe diarrhea, the dose-limiting toxicity of FUDR when infused over 14 days, was encountered at the dose levels tested. This 5-day chronotherapy schedule allowed delivery of a larger amount of FUDR than the flat delivery described in a previous report. A daily dose of 0.525 mg/kg FUDR, combined with 10 mg/mg2 L-FA, with intraindividual dose escalation according to tolerance, is recommended for future investigations of the activity of this chronotherapy schedule.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Carcinoma, Renal Cell; Chronobiology Phenomena; Colorectal Neoplasms; Drug Administration Schedule; Feasibility Studies; Female; Floxuridine; Humans; Infusions, Intravenous; Kidney Neoplasms; Leucovorin; Male; Middle Aged; Neoplasms; Stomach Neoplasms

Topics: Aspartic Acid; Drug Interactions; Fluorouracil; Humans; Leucovorin; Methotrexate; Neoplasms; Phosphonoacetic Acid; Trimetrexate

5-Fluorouracil (5-FU) activity for various carcinomas of adults has been enhanced through the synergistic effect of leucovorin. Few pediatric studies of 5-FU in pediatric patients have been previously reported.. Fifty-eight patients were treated with a 4-hour infusion of leucovorin, 400 mg/m2, administered daily for 5 days every 3-4 weeks. 5-Fluorouracil was administered by bolus injection 1 hour into each leucovorin infusion. Eleven adolescent patients with colorectal carcinoma, Stage 3 or 4, were treated with therapeutic intent, and other patients with a variety of drug-resistant pediatric solid neoplasms received similar treatment.. Patients with measurable disease of colorectal carcinoma responded favorably to 5-FU/leucovorin. Stable disease activity was seen with other tumor types. Specifically, there were no objective responses in 12 patients with Ewing's Sarcoma or 11 with osteosarcoma. There were 4 deaths in this study from causes related to toxicity. Nonfatal grade 3/4 toxicities included mucositis, rash, myelosuppression, nausea, vomiting, diarrhea, and infection.. The authors do not plan further evaluation of 5-FU/leucovorin in additional pediatric patients with colon cancer or other heavily pretreated malignant solid tumors and are presently treating their patients with colon carcinoma with 5-FU/leucovorin/interferon-alpha 2a.

Topics: Adolescent; Carcinoma; Child; Child, Preschool; Colorectal Neoplasms; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Infant; Leucovorin; Male; Neoplasms; Osteosarcoma; Sarcoma, Ewing; Treatment Outcome

A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly x 6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with a t1/2 beta of approximately 2 h. Plasma clearance was high (> 200 1 h-1). No correlation between pharmacokinetic parameters and toxicity could be identified.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Floxuridine; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Treatment Outcome

Thirteen patients with intra-abdominal malignancies entered a phase I study of fluorouracil (5-FU) given by continuous infusion (96 h) iv and ip, simultaneously, and modulated by high-dose folinic acid-iv. Severe but reversible stomatitis was the only dose-limiting toxicity at a dose of 5-FU of 550 mg/m2/day. Local toxicity (5-FU-induced abdominal pain) was a significant side effect in patients receiving more than 1 cycle. The pharmacokinetic advantage of 5-FU-ip was confirmed in our study (ratio AUC peritoneum/plasma between 160 and 328). The systemic exposure to 5-FU (plasmatic AUC ranging from 73.4 to 173.21 microM) and to AF were found in efficacious ranges. The recommended dose of 5-FU iv and ip is 500 mg/m2/day. This regimen is feasible and may potentially have application for adjuvant chemotherapeutic programs after surgery for colorectal cancer.

Topics: Abdominal Neoplasms; Drug Synergism; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intraperitoneal; Leucovorin; Male; Middle Aged; Neoplasms

Cancer chemotherapy with folate antimetabolites has been traditionally targeted at the enzyme dihydrofolate reductase and is based on the requirement of dividing tumor cells for a supply of thymidylate and purines. However, a new compound, 5,10-dideazatetrahydrofolate (DDATHF, whose 6R diastereomer is also known as Lometrexol), has become available that prevents tumor cell growth by inhibiting the first of the folate-dependent enzymes involved in de novo purine synthesis, glycinamide ribonucleotide formyltransferase.. We investigated the toxicity and therapeutic activity of DDATHF in a phase I clinical trial.. DDATHF was given at one of the following dose levels to 33 patients (16 females and 17 males) with malignant solid tumors: 3.0 mg/m2 per week (level A) to 10 patients, 4.5 mg/m2 per week (level B) to 13 patients, or 6.0 mg/m2 per week (level C) to 10 patients. Each drug cycle consisted of three weekly injections of DDATHF followed by a 2-week rest prior to redosing in the next cycle.. Of 33 patients, 27 received at least one full cycle of DDATHF. Thrombocytopenia was the major dose-limiting toxicity, and it was severe in one of 10 patients during the first cycle and in two of four patients during the second cycle. Because of cumulative toxicity at 6.0 mg/m2, second or later cycles were abbreviated to two weekly doses. Stomatitis was generally mild, but it was dose-limiting in one patient. Neutropenia was infrequent and mild, and normocytic anemia requiring blood transfusion was common with repeat dosing. Leucovorin was given for grade 2 or greater thrombocytopenia and resulted in hematologic recovery within 1 week in all eight patients so treated. Without leucovorin, the thrombocytopenia lasted from 7 to 49 days in three patients. A partial response was noted in one patient with non-small-cell lung cancer and a minor response in one patient with breast cancer. Three patients with colorectal cancer achieved stable disease for greater than 3 months with improvement in carcinoembryonic antigen levels in one patient.. DDATHF has an unusual pattern of toxicity with repetitive dosing, and humans with advanced cancer are considerably more sensitive than would be predicted from previous animal studies. Although doses of 6.0 mg/m2 per week on our schedule have been determined to be safe, repeated cycles require careful monitoring because of cumulative toxic effects.. Additional phase I studies of DDATHF that relate toxicity to folate intake and tissue folate pools appear warranted.

Topics: Adult; Aged; Drug Administration Schedule; Female; Folic Acid Antagonists; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Purines; Tetrahydrofolates; Treatment Outcome

In a previous phase I study we identified the maximally tolerated dose (MTD) of a continuous intravenous infusion of fluorodeoxyuridine (FUdR) to be 0.3 mg/kg daily for 5 days when combined with oral leucovorin (LV) given at 100 mg q4h. In an attempt to modulate FUdR further, we added escalating doses of interferon alpha-2b (IFN) to FUdR/LV in a phase I cohort study. A total of 36 patients with refractory solid tumor were treated at two dose levels of FUdR and five dose levels of IFN. Although the initial patient cohort was treated with a dose of FUdR lower than that previously identified as the MTD [FUdR at 0.2 mg/kg daily with LV at 100 mg q4h and IFN at 2 million units (MU)/m2 daily], three of six patients developed grade 3 mucositis, indicating that the toxicity of FUdR/LV was increased in the presence of low doses of IFN. After decreasing the FUdR dose to 0.1 mg/kg daily, we could increase the dose of IFN from 2 to 30 MU/m2 daily in five additional cohorts of patients. With increasing IFN doses, no increase in mucositis or dermatitis was observed, indicating no further potentiation of FUdR/LV toxicity with higher IFN doses. However, known toxicities of IFN, including transient myelosuppression and hepatic transaminase elevation, were observed more frequently at IFN doses of 15 and 30 MU/m2 daily, where they became dose-limiting. We conclude that IFN modulates FUdR/LV at low doses, resulting in increased FUdR toxicity. When the dose of IFN is increased, this FUdR/LV toxicity does not appear to be potentiated further and IFN-related toxicities become dose-limiting.

Topics: Administration, Oral; Adult; Aged; Cohort Studies; Drug Administration Schedule; Female; Floxuridine; Humans; Infusions, Intravenous; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Mouth Mucosa; Neoplasms; Recombinant Proteins; Stomatitis

This phase I study of 36 patients was performed to identify the maximal tolerated dose of oral calcium leucovorin (CLV) that could be concomitantly administered with protracted 5-fluorouracil (5-FU) infusion (greater than 30 days). Administration of CLV in very small doses (5 mg p.o. q8h) with 5-FU, 200-300 mg/m2/day, resulted in excessive toxicity requiring treatment interruption in all patients. Subsequent reduction in the dose of 5-FU to 100 mg/m2/day with simultaneous administration of CLV, 5 mg p.o. q8h, decreased the toxicity and allowed for protracted administration of the combination. In subsequent patients the dose of oral CLV was increased to 22.5 mg p.o. q8h, which resulted in treatment-limiting toxicity in the majority of patients. Toxicity consisted almost exclusively of mucositis. No myelosuppression or significant organ toxicity was observed. We conclude that even low doses of oral CLV potentiate the biological effect of infusion 5-FU. If the combination is to be given on a protracted basis, 5-FU must be administered at a much smaller dosage than has been traditionally utilized.

Topics: Aged; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms

A Phase I study was conducted to determine whether the addition of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to a combined 5-fluorouracil (5-FU) and folinic acid (FA) regimen would allow an escalated starting dose of 5-FU. FA (500 mg/m2) was administered as a 2-hour infusion on days 1 through 5, with 5-FU administered as a bolus injection 1 hour after the initiation of FA. Fifteen patients were enrolled in the trial; six were entered at a dose level of 375 mg/m2 of 5-FU, six at 450 mg/m2, and three at 540 mg/m2. rhGM-CSF was administered subcutaneously on days 6 through 15. A course of therapy was repeated every 28 days. Serious toxicity was observed at 450 mg/m2, with two patients developing grade 3 mucositis and one, grade 4 mucositis. Dose-limiting toxicity occurred at 540 mg/m2, at which point three patients developed grade 4 mucositis. One patient with metastatic colon cancer who received 5-FU at 540 mg/m2 achieved a partial response. Because of this persistent mucositis, the addition of rhGM-CSF used in this schedule would not allow an increased starting dose of 5-FU.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Pancreatic Neoplasms; Recombinant Proteins

The inhibition of pyrimidine metabolism by 5-fluorouracil (5-FU) enhances the anti-cancer effects of zidovudine (formerly called AZT) in in vitro and in vivo model systems without additive toxicity. Zidovudine-induced DNA damage correlates with cytotoxicity.. A Phase I trial of high-dose continuous-infusion intravenous zidovudine therapy in combination with 5-FU and leucovorin therapy was performed. Eighteen patients with advanced malignant tumors were treated with 43 courses of oral leucovorin (50 mg every 4 hours); continuous-infusion 5-FU (800 mg/M2/day) for 72 hours (3 days); and zidovudine, begun 24 hours after the start of 5-FU and leucovorin, for 48 hours, and terminating with the end of the 5-FU infusion. Zidovudine plasma levels and zidovudine-induced DNA damage were assessed.. Zidovudine administered in doses of 2-20 g/M2/day, added no obvious toxicity to the basic chemotherapeutic treatment with 5-FU and leucovorin but resulted in a dose-dependent biologic effect manifested by an increase in DNA strand breaks in peripheral blood cells. At doses greater than 15 g/M2/day, altered plasma kinetics of zidovudine were observed; plasma zidovudine levels increased dramatically in relation to the dose of zidovudine. Limitations in drug administration restricted administration of higher intravenous doses without achieving a maximally tolerated dose. No responses were seen in this heavily pretreated population.. Based on the results of preclinical studies, plasma zidovudine levels greater than those achieved at the maximal dose (133 microns) are required for increased anti-cancer activity with 5-FU. Additional studies using a bolus or rapid infusion as a method of achieving higher peak levels are indicated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; DNA Damage; DNA, Neoplasm; Dose-Response Relationship, Drug; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Middle Aged; Neoplasms; Zidovudine

We conducted a phase I trial of fluorouracil (5-FU), leucovorin, (LCV), and recombinant interferon-alpha-2b (rIFN-alpha-2b). The doses of each of the three agents were escalated sequentially. 5-FU and LCV were administered by IV bolus, weekly for 6 weeks and rIFN-alpha-2b was administered by subcutaneous injection, three times weekly for 6 weeks. Twenty-nine patients with advanced cancer (75% colon or pancreatic cancer) were treated. Partial remissions were observed in three patients (10%) with previously untreated colon cancer, colon cancer refractory to 5-FU plus LCV and previously untreated pancreatic cancer, respectively. An additional three patients with pancreatic, prostate, and rectal cancer had a 50% reduction in tumor markers but no change in objective tumor measurements. The toxicity of this regimen was tolerable. The most common toxicities were diarrhea, fatigue, flu-like symptoms, nausea/vomiting, and mucositis. However, no fatal or life-threatening toxicities were observed. We conclude that the combination of 5-FU, LCV, and rIFN-alpha-2b can be safely administered and recommend further evaluation of this regimen in patients with tumors of gastrointestinal origin using doses of 5-FU 600 mg/m2, LCV 500 mg/m2, and rIFN-alpha-2b 10 x 10(6) U.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Kidney Neoplasms; Leucovorin; Male; Middle Aged; Neoplasms; Pancreatic Neoplasms; Recombinant Proteins

Twenty-seven patients with advanced cancer were entered in a phase I study of bolus i.v. 5-fluorouracil at a dose of 370 mg/m2/day for 5 days combined with a continuous i.v. infusion of (6S)-folinic acid for 5.5 days, starting 24 h in advance of the first 5-fluorouracil dose. The dose of (6S)-folinic acid was escalated in cohorts of patients from 250 mg/m2/day to a maximum of 1000 mg/m2/day. The pharmacokinetics of (6S)-folinic acid were studied in the 3 patients given 250 mg/m2/day and in 6 patients given 1000 mg/m2/day. The mean steady-state plasma concentrations of (6S)-folinic acid and its principal metabolite (6S)-5-methyltetrahydrofolate at the 250 mg/m2/day dose were 2.7 and 5.1 microM, respectively. Both concentrations were comparable to the concentrations produced when (6S)-folinic acid was administered as half of a (6R,S)-folinic acid mixture (E. M. Newman et al., Cancer Res., 49:5755-5760, 1989). At the 1000 mg/m2/day dose of (6S)-folinic acid, the concentration of (6S)-folinic acid was 15.3 microM, more than the 4-fold increase predicted by linear pharmacokinetics, while the concentration of (6S)-5-methyltetrahydrofolate was only 16.5 microM. The change in the ratio of the parent compound to its metabolite was accounted for by a decrease in the nonrenal clearance of (6S)-folinic acid, probably indicating saturation of its metabolism. The toxicities observed in this phase I trial, including stomatitis, diarrhea, neutropenia, and anemia, did not differ in nature or severity from those produced by 5-fluorouracil and (6R,S)-folinic acid when administered on the same schedule. Finally, the degree of toxicity did not appear to depend on the dose of (6S)-folinic acid over the range of doses tested.

Topics: Adult; Aged; Drug Administration Schedule; Drug Evaluation; Drug Synergism; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms

A phase I trial of 5-fluorouracil (FUra) and leucovorin (LV) given with and without dipyridamole (DP) by concurrent 120-h continuous infusion was performed in 27 patients with advanced solid malignancies, 8 of whom had previously received FUra. The LV and DP doses were fixed at 500 mg/m2 daily and 7.7 mg/kg daily, respectively, whereas the FUra dose was escalated. Level 3 (450 mg/m2 FUra daily) represented the maximum tolerated dose for both FUra/LV+DP and FUra/LV. Dose-limiting stomatitis (greater than or equal to grade 3 or grade 2 occurring during the infusion) was encountered in 75% of the first courses given at level 4 (600 mg/m2 daily). Stomatitis was observed in 44/78 (56%) courses. Diarrhea was infrequent and mild. DP infusions were complicated by mild to moderate headache, which was controlled with narcotic analgesics, and mild to moderate nausea/vomiting. FUra-related toxicity was not enhanced by DP administration. Limited pharmacokinetic sampling at levels 3 and 4 revealed mean steady-state FUra concentrations of around 1.0 microM with infusions of FUra/LV+DP. Among three paired courses given with and without DP, no statistically significant difference was found in the total body clearance of FUra (P = 0.44). One partial response was seen in a patient with metastatic gastric carcinoma. For phase II trials, we recommend that concurrent 120-h continuous infusions of FUra (450 mg/m2 daily) and LV (500 mg/m2 daily) be given with and without DP (7.7 mg/kg daily) every 21 days.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dipyridamole; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Drug Synergism; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Stomach Neoplasms; Stomatitis

Sixty-two patients with metastatic disease were treated with continuous infusion folinic acid (leucovorin calcium; Lv) and 2-deoxy-5-fluorouridine (floxuridine; FUDR). Lv was given by constant intravenous (IV) infusion at 500 mg/m2/d, days 1 to 6, while FUDR was given by IV push, days 2 to 6, at 3:00 PM daily with doses ranging from 294 to 1,214 mg/m2/d. This program was well tolerated with dose-limiting toxicities of diarrhea and stomatitis, while hematologic toxicity was minimal. Eighty-two percent of the assessable patients (46 of 56) had failed at least one chemotherapy regimen. One complete remission lasting 9 months and 10 partial remissions ranging from 5 to 10 months were observed in this heavily pretreated patient population for an overall response rate of 20%. These data suggest that the combination therapy with Lv and FUDR may have clinical use. Because of differing patient sensitivity to this drug combination, the recommended dose of FUDR for the initial therapy cycle is 500 mg/m2/d, days 2 to 6, with subsequent escalation to 900 mg/m2/d in those patients without extreme sensitivity. Phase II studies are now in progress with these doses.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Female; Floxuridine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Remission Induction

Fluorodeoxyuridine (FUdR) interferes with cellular metabolism by inhibiting thymidylate synthase. Therefore, we sought to modulate its activity with leucovorin (LV) and to identify the maximally tolerated dose given as a 5-day continuous intravenous infusion in combination with oral administration of LV at a dose of 100 mg every hour for four doses immediately preceding the start of the FUdR infusion and then every 4 h for the entire duration of FUdR treatment. Patients were evaluated at six FUdR dose levels ranging from 0.1 to 0.375 mg/kg per day. Severe or life-threatening mucositis was first observed in two of six patients treated at 0.25 mg/kg daily. Further escalation of the dose to 0.3 mg/kg per day resulted in grade 2 mucositis in four of six patients and in grade 3 mucositis in two cases. A dose of 0.375 mg/kg daily resulted in grade 3 toxicity in all three patients treated. Other types of toxicities included skin rash and hand-foot syndrome, but no hematologic toxicities were observed. Stable disease was observed in 11 of 24 evaluable patients, including 3 subjects with renal cell carcinoma. Our recommended dose for phase II trials is 0.3 mg/kg FUdR per day.

Topics: Aged; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy, Combination; Female; Floxuridine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Remission Induction; Time Factors

Oral hydroxyurea (HU) was added to a regimen of 5-fluorouracil (5-FU) plus leucovorin (LCV) administered as a continuous 24-hour infusion for 14 days. A previous report of the 5-FU plus LCV infusion established optimal dosages of 200 mg/m2/d and 5 mg/m2/d, respectively, for each agent. Oral HU was added to the regimen in total dosages of 0.5 g/d, 1.0 g/d, 1.5 g/d, or 2.0 g/d. Twenty-two patients received a total of 45 courses of treatment. Stomatitis was the dose-limiting side effect; it occurred in 3 of 14 courses with HU at 0.5 g/d (21%) and 9 of 17 courses with HU at 1.0 g/d (53%). Dosage escalation to 1.5 g/d or 2.0 g/d was possible in only 3 of 22 patients (17%). The median time to stomatitis was 10 days (range, 7 to 12 days). One response was observed in this heavily pretreated population. Phase II trials of HU plus LCV dual modulation of infusional 5-FU should use initial HU dosages of 0.5 g/d for the 14-day regimen described, with dose escalation as tolerated. Variable oral absorption presumably accounts for the small group of patients who can tolerate the higher doses of HU.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Evaluation; Female; Fluorouracil; Humans; Hydroxyurea; Infusion Pumps; Leucovorin; Male; Middle Aged; Neoplasms; Stomatitis

Twenty-eight patients with refractory advanced malignancies were treated with a 24-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable to assess toxicity and antitumor activity. The PALA was administered as an intravenous bolus over 15 minutes at a fixed dose (250 mg/m2) 24 hours before the start of the 5-FU and leucovorin infusions. Initially the dose of 5-FU was 750 mg/m2; this was increased incrementally to 2600 mg/m2. The LV was administered in a fixed dose of 500 mg/m2 concurrently with the 5-FU over a 24-hour period. This regimen was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among the dose-limiting toxicities. Others were hand-foot syndrome, hair loss of the scalp and eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. The maximum tolerated dose of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated with 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose reductions, but most received 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients were treated previously. Eight patients had a partial response; five of these were treated previously. A complete response was observed in one patient with pancreatic carcinoma, previously untreated. The overall response rate for patients treated with 2100 or 2600 mg/m2 of 5-FU was nine of 18 patients (50%). Three of four previously untreated patients with pancreatic cancer responded to this treatment (two responded partially, and one had a complete response). One of three heavily pretreated patients with non-small cell lung cancer had a partial response as did a patient with breast cancer. Four of ten patients with colorectal cancer responded to the treatment (four partial responses), of whom three had been treated previously.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Breast Neoplasms; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasms; Phosphonoacetic Acid; Prognosis

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.

Topics: Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Drug Administration Schedule; Drug Evaluation; Drug Synergism; Drug Therapy, Combination; Female; Fluorouracil; Humans; Infant; Leucovorin; Male; Neoplasms; Stereoisomerism; Tetrahydrofolates

A phase I clinical, pharmacologic, and biochemical evaluation of escalating oral zidovudine (AZT) given over 2 days with a fixed dose of continuous-infusion fluorouracil (800 mg/m2 per day X 3 days) and oral leucovorin calcium was performed. Eighteen patients were treated with doses of AZT ranging from 1.0 to 9.0 g/m2 per day. Nausea and vomiting were dose limiting, with a maximally tolerated dose of 7.5 g/m2 per day. Rash and mucositis occurred but were not dose limiting. A dose-related increase in peak plasma levels of AZT was observed, and the alpha half-life of AZT in plasma (75 min) was unaffected by these high doses. At doses above 4.0 g/m2 per day, trough levels significantly increased, perhaps reflecting prolonged absorption from the gut. No responses were observed; however, a significant increase in DNA single-strand breaks was observed in peripheral blood cells after a threshold dose of 4.0 g/m2 per day, confirming a biological effect of AZT in this regimen. Further trials with an intravenous formulation capable of maintaining plasma levels and circumventing dose-limiting toxicity are warranted.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; DNA; DNA Damage; Dose-Response Relationship, Drug; Drug Evaluation; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Zidovudine

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Neoplasms; Prostatic Neoplasms

Three cooperative groups are currently accruing patients to randomized Phase III studies of 5-FU plus leucovorin. These studies should provide data allowing more definitive conclusions regarding the therapeutic utility of this combination. Until results of these studies are available, 5-FU plus leucovorin (CF) remains an investigational treatment, not suitable for routine use.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoplasms; Randomized Controlled Trials as Topic

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bleomycin; Bone Marrow Transplantation; Carcinoma; Cells, Cultured; Child; Cisplatin; Clinical Trials as Topic; Colonic Neoplasms; Combined Modality Therapy; Cytarabine; Doxorubicin; Drug Therapy, Combination; Fluorouracil; Hepatic Artery; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Mechlorethamine; Melanoma; Meningeal Neoplasms; Methotrexate; Neoplasms; Osteosarcoma; Peritoneal Cavity; Pleura

We have conducted a Phase 1 study of aminopterin (AMT) with leucovorin (LV) in 17 patients. AMT was administered by bolus injection every 7 to 14 days in dosages from 25 to 425 mg/sq m. LV rescue was instituted at 24 hr and continued for 48 to 72 hr. At dosages above 50 mg/sq m, we observed nephrotoxicity defined as greater than or equal to a 25% increase in serum creatinine 24 hr after AMT administration, but its incidence was not strictly dose related. Urinary alkalinization and volume expansion appeared to reduce the incidence of nephrotoxicity. Nephrotoxic drug courses were associated with 24-hr plasma AMT levels [3.6 +/- 2.0 (S.D.) X 10(-6) M] which were significantly higher than nonnephrotoxic courses (1.6 +/- 1.0 x 10(-6) M) (p less than 0.05). In nonnephrotoxic courses, serum elimination pharmacokinetics appeared to be biphasic with a t1/2 alpha of 1.08 +/- 0.01 hr and t1/2 beta of 12.31 +/- 0.06 hr. Systemic toxicity (myelosuppression and mucositis) could be prevented in patients with impaired AMT clearance by the administration of LV at an increased dose rate. In several courses, systemic toxicity occurred in spite of apparently normal plasma clearance, suggesting that 24-hr plasma levels may not accurately reflect intracellular drug effects. Cytokinetic studies on bone marrow aspirates allowed determination of the rescue effect of LV and may prove useful in predicting marrow protection.

Topics: Aminopterin; Bone Marrow; Clinical Trials as Topic; Drug Administration Schedule; Humans; Kidney; Leucovorin; Leukopenia; Methotrexate; Neoplasm Metastasis; Neoplasms; Solubility

Topics: Adult; Aged; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasms; Time Factors

One hundred and thirty-four patients with advanced malignant disease were treated with 496 infusions of high-dose methotrexate (HD-MTX) followed by citrovorum factor rescue. Most patients had failed to respond to previous combination chemotherapy. The overall response rate was 29% with 33 partial responses and six complete responses observed in patients with a variety of tumors. Plasma MTX levels were monitored in all patients during each course of therapy in order to identify those patients with delayed plasma MTX clearance. Patients with abnormally slow rates of plasma MTX decay received escalated doses of citrovorum factor rescue in order to prevent drug-induced toxicity. In general, during this study HD-MTX was well-tolerated. Because serious toxicity was neither frequent, severe, nor unpredictable, its use was not limited. HD-MTX should now be evaluated in well-designed controlled clinical trials to compare its antitumor activity to that of conventional- or standard-dose MTX regimens in diseases where HD therapy appears to have efficacy.

Topics: Adolescent; Adult; Aged; Child; Clinical Trials as Topic; Drug Evaluation; Humans; Infusions, Parenteral; Leucovorin; Methotrexate; Middle Aged; Neoplasms

DDMP, a diaminopyrimidine folate antagonist, was given to 26 tumor patients in a dosage of 50 mg/m2 per week orally, simultaneously with 3 mg CF i.m. or i.v. The CF dose was increased to 30 mg in patients showing evidence of toxicity, and withdrawn in the absence of toxicity. The dose-limiting toxicity was seen in myelosuppression, particularly thrombopenia and skin rashes. At the 3 mg CF level, 18 out of 26 patients developed toxicity. No toxicity was seen at the 30 mg CF level in 11 patients. After cessation of CF, toxicity occurred in five out of seven patients. After the onset of toxicity, CF was added as a delayed rescue, in a dosage of 15 mg every 8 h or 30-60 mg daily. One patient died of sepsis with agranulocytosis. All other patients recovered from myelosuppression within 1 or 2 weeks. Objective responses were observed in seven patients, four of the ten with epidermoid cancer of the head and neck, two out of eight with epidermoid cancer of the lung, and one out of three with melanoma.

Topics: Adult; Aged; Antineoplastic Agents; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Pyrimethamine

Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Dehydration; Drug Therapy, Combination; Female; Hematologic Diseases; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Infant; Kidney Diseases; Kidney Function Tests; Leucovorin; Liver Diseases; Liver Function Tests; Male; Methotrexate; Neoplasms; Pleural Effusion; Prognosis; Time Factors; Vomiting

Topics: Bicarbonates; Drug Interactions; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms; Time Factors

Dihydropyrimidine dehydrogenase (DPD) status is an indicator of a marked risk for toxicity following fluoropyrimidine (FP)-based chemotherapy. This notion is well-established for low DPD status but little is known about the clinical impact of high DPD activity. This study examined the possible link between high intrinsic lymphocytic DPD activity and overall survival, progression free survival and response to FP-based treatment in patients treated in our institution.. Lymphocytic DPD activity was assessed in a group of 136 patients receiving FP-based chemotherapy from 2004 to 2016. There were 105 digestive (77.2%), 24 breast (17.6%) and 7 head and neck cancers (5.2%). Cox or logistic regression models were applied with adjustment on all confounding factors that could modify OS, PFS or response. All models were stratified on the three cancer locations. A cut-off for DPD activity was assessed graphically and analytically.. An optimal cut-off for DPD activity at 0.30 nmol/min/mg protein was identified as the best value for discriminating survivals and response. In multivariate analysis, individual lymphocytic DPD activity was significantly related to overall survival (p = 0.013; HR: 3.35 CI95%[1.27-8.86]), progression-free survival (p < 0.001; HR: 3.15 CI95%[1.75-5.66]) and response rate (p = 0.033; HR: 0.33 CI95%[0.12-0.92]) with a marked detrimental effect associated with high DPD activity.. DPD status screening should result in a two-pronged approach with FP dose reduction in case of low intrinsic DPD and, inversely, an increased FP dose for high intrinsic DPD. In a context of personalized FP-based treatment, this innovative strategy needs to be prospectively validated.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Capecitabine; Dihydrouracil Dehydrogenase (NADP); Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Prognosis; Retrospective Studies; Survival Rate

Methotrexate has a wide dosing range. High-dose methotrexate is a dose of 1000 mg/m. In this retrospective chart review, 37 patients received 119 cycles of high-dose methotrexate before the protocol implementation (1 January 2009 through 31 December 2010) and 45 patients received 106 cycles of high-dose methotrexate after protocol implementation (1 January 2013 through 31 December 2014). Patient characteristics, protocol data, and complications were analyzed.. Protocol implementation significantly reduced the deviation of methotrexate level timing at 24, 48, and 72 h: median 7.47 vs. 1.46 h, 7.23 vs. 1.35 h, and 7.00 vs. 1.52 h before and after implementation, respectively (p < 0.0001 for each). The protocol significantly reduced deviation of the first dose of leucovorin administration: median 5.2 vs. 0.675 h before and after implementation, respectively (p<0.0001). After protocol implementation, there was an increase in the use of leucovorin prescriptions written appropriately for patients discharged before methotrexate levels reached a value of ≤0.05 µmol/L.. Implementation of a protocol for the administration of high-dose methotrexate improved the adherence to consensus recommendations. Further analysis is needed to assess clinical pharmacist involvement and the cost savings implications within this protocol.

Topics: Adult; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Folic Acid Antagonists; Guideline Adherence; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms; Outcome Assessment, Health Care; Retrospective Studies; United States

Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer-induced and chemotherapy-induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments.. The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer-induced cachexia. In vivo administration of Folfiri (5-fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy-induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance-based and mass spectrometry-based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling.. The study involved four groups of CD2F1 male mice (n = 4-5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (-3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (-38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (-47% in CC vs. V; P < 0.001) and depletion of liver glucose (-51% in CC vs. V; P < 0.001) and glycogen (-74% in CC vs. V; P < 0.001). The cancer-induced and chemotherapy-induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and β-oxidation pathways. Cancer-induced cachexia was uniquely characterized by a dramatic elevation in low-density lipoprotein particles (+6.9-fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001).. The results of this study demonstrated for the first time that cancer-induced and chemotherapy-induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer-induced and chemotherapy-induced cachexia must take into account the specific metabolic defects imposed by the pathological or pharmacological drivers of cachexia.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cachexia; Camptothecin; Cell Line, Tumor; Energy Metabolism; Fluorouracil; Glucose; Leucovorin; Liver; Male; Metabolomics; Mice; Muscle Strength; Muscle, Skeletal; Neoplasms; Reactive Oxygen Species; Receptors, LDL

Cholinergic syndrome is an acute adverse reaction associated with irinotecan. Development of cholinergic syndrome can be ameliorated or prevented by administering various anticholinergics, including atropine sulfate or scopolamine butylbromide. Although many of the side effects are transient and non-life-threatening, their onset is painful and can lower a patient's quality of life (QoL). This retrospective study was performed to identify predictive factors of the development of irinotecan-related cholinergic syndrome in order to develop future strategies for improving the QoL of patients undergoing chemotherapy. We enrolled 150 cancer patients who underwent chemotherapy, which included irinotecan, in our outpatient chemotherapy center between October 2014 and January 2017. For regression analysis, variables related to the development of irinotecan-related cholinergic syndrome were extracted from the patient's clinical records. The degree of cholinergic syndrome was classified as follows: grade 0 = not developed; grade 1 = developed but did not require anticholinergic drugs; and grade 2 = developed and required anticholinergic drugs or stopping the chemotherapy due to cholinergic syndrome. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of irinotecan-related cholinergic syndrome. Threshold measurements were determined using a receiver operating characteristic analysis (ROC) curve. Significant factors identified for the development of cholinergic syndrome included female sex [odds ratio (OR) 2.183, 95% confidence interval (CI) 1.010-4.717; P = 0.0471] and irinotecan dose (OR 1.014, 95% Cl 1.007-1.021; P = 0.0001). ROC curve analysis of the group likely to develop cholinergic syndrome indicated that the threshold for the irinotecan dose was 175 mg or above (area under the curve = 0.69). In conclusion, female sex and irinotecan dose were identified as significant predictors of the development of cholinergic syndrome.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blood Pressure; Camptothecin; Diarrhea; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Logistic Models; Male; Middle Aged; Neoplasms; Predictive Value of Tests; Quality of Life; Retrospective Studies; Salivation; Syndrome; Young Adult

To determine the extent of damage to oral epithelium caused by high dose methotrexate (HDMTX) and the ameliorating role of folinic acid (FA) on damaging effect of methotrexate.. Experimental study.. Anatomy Department of Post Graduate Medical Institute (PGMI), Lahore, from March to September 2013.. Forty-two albino rats were randomly allocated to 3 groups: Exp group-I was given HDMTX intramuscularly (I/M) on alternate days, Exp group-II was given both MTX and FA(I/M) on alternate days, and the control group received no intervention. After 16 days, buccal mucosa was excised for histological analysis under light microscope using H & E stains to see the effect of intervention.. Exp group-I showed marked reduction in epithelial thickness compared to Exp group-II, and the control (F = 46.44, p < 0.001) had significantly depleted basal layer (F = 6.32, p < 0.004), as well as inflammatory infiltrate with evidence of erosion and ulceration. Exp group-II showed less atrophic changes, a few inflammatory cells, no erosion and ulceration compared to the Exp group-I. Assuming epithelial thickness of control group 100% intact, the Exp group-II was found to have 78% intact and Exp group-I had only 38% thickness intact. Thus FArescued epithelial thickness by 40%.. Folinic acid considerably saved oral mucosa from the damaging effect of HDMTX, improving quality of life of patients.

Topics: Animals; Antidotes; Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Epithelium; Leucovorin; Methotrexate; Mouth Mucosa; Neoplasms; Random Allocation; Rats; Stomatitis

The objective of this phase II study was to evaluate the potential of pharmacokinetic (PK) drug-drug interactions between ramucirumab and irinotecan or its metabolite, SN-38, when administered with folinic acid and 5-fluorouracil (FOLFIRI).. Patients received intravenous infusions of FOLFIRI and ramucirumab 8 mg/kg on Day 1 of a 2-week cycle. FOLFIRI was administered alone in Cycle 1; ramucirumab followed by FOLFIRI was administered in all subsequent cycles. Blood was collected at regular intervals after infusions in Cycles 1 and 2 to determine irinotecan, SN-38, and ramucirumab concentrations. PK parameters were derived by noncompartmental analysis.. Twenty-nine patients received treatment. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0-∞)] and the maximum observed concentration (C max) of irinotecan and SN-38 were comparable between Cycle 1 (FOLFIRI alone) and Cycle 2 (ramucirumab + FOLFIRI). The ratios of geometric least squares (LS) means for irinotecan were 0.93 (90 % CI 0.83-1.05) for AUC(0-∞) and 1.04 (90 % CI 0.97-1.12) for C max. The ratios of geometric LS means for SN-38 were 0.95 (90 % CI 0.88-1.04) for AUC(0-∞) and 0.97 (90 % CI 0.85-1.12) for C max. The most common treatment-emergent adverse events, regardless of grade, were fatigue (19 patients, 65.5 %), diarrhea, (16 patients, 55.2 %), and neutropenia (15 patients, 51.7 %). Grade ≥3 neutropenia was reported in 7 (24.1 %) patients.. There was no PK drug-drug interaction between ramucirumab and irinotecan or its metabolite, SN-38. Ramucirumab with FOLFIRI was well tolerated in this study, with no new safety concerns.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Area Under Curve; Asian People; Camptothecin; Drug Interactions; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms; Ramucirumab

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Neoplasms; Organoplatinum Compounds

Topics: Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Neoplasms; Organoplatinum Compounds

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Hypersensitivity; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasms; Organoplatinum Compounds

The robustness of the circadian timing system (CTS) was correlated to quality of life and predicted for improved survival in cancer patients. However, chemotherapy disrupted the CTS according to dose and circadian timing in mice. A continuous and repeated measures longitudinal design was implemented here to characterize CTS dynamics in patients receiving a fixed circadian-based chemotherapy protocol. The rest-activity rhythm of 49 patients with advanced cancer was monitored using a wrist actigraph for 13 days split into four consecutive spans of 3-4 days each, i.e., before, during, right after and late after a fixed chronotherapy course. The relative amount of activity in bed vs. out of bed (I

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Circadian Rhythm; Fatigue; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Monitoring, Physiologic; Motor Activity; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Rest; Weight Loss

Patients with cancer often receive chemotherapeutic agents concurrently with other medications to treat comorbidity. The practical effects of concomitant medications, especially polypharmacy, on adverse drug reactions related to irinotecan-based chemotherapy are not well documented.. Associations of adverse drug reactions related to irinotecan monotherapy or a combination of irinotecan, 5-fluorouracil, and L-leucovorin (FOLFIRI) with concomitant medicines used to treat comorbidity were retrospectively investigated in Japanese patients with cancer.. Of the 172 patients, 118 received concomitant medications. Twenty-one patients had grade 4 neutropenia and/or grade 3 or 4 diarrhea. Univariate and multivariate analyses revealed that concomitant medications were significantly associated with irinotecan-related severe neutropenia and/or diarrhea (P = 0.023 and 0.044). Multiple concomitant medications were significantly related to severe irinotecan-related toxicity in patients given monotherapy or FOLFIRI (P = 0.01). The incidence of severe irinotecan-related toxicities increased in parallel with the number of concomitant medications.. We found that multiple concomitant medicines were significantly associated with severe irinotecan-related toxicity, indicating that polypharmacy must be effectively managed to decrease the risk of adverse drug reactions in patients with cancer who received irinotecan-based chemotherapy.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Diarrhea; Female; Fluorouracil; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Logistic Models; Male; Middle Aged; Neoplasms; Neutropenia; Polypharmacy; Retrospective Studies

Oxaliplatin hypersensitivity is a well-known adverse reaction but the prevalence varies and data for frequency and clinical features have not been reported for Korea. Here we evaluates the prevalence and risk factors for hypersensitivity reactions to oxaliplatin after chemotherapy.. Clinical information on all patients treated with oxaliplatin was retrospectively reviewed in electronic medical records between August 2009 and July 2010 in Seoul National University Bundang Hospital. Patients who experienced hypersensitivity reactions to oxaliplatin were compared with those who did not.. A total of 393 patients received oxaliplatin, with 42 (10.7%) experiencing hypersensitivity reactions including three cases of anaphylaxis. Median cycle of the first hypersensitivity reaction was 8. Reactions correlated with lower dexamethasone doses. Other variables were not significant.. The prevalence of hypersensitivity reactions was 10.7%, symptoms being mostly mild and cutaneous. Lower dexamethasone doses could be a predictor for hypersensitivity reactions to oxaliplatin.

Topics: Aged; Anaphylaxis; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dexamethasone; Drug Eruptions; Drug Hypersensitivity; Female; Fluorouracil; Gemcitabine; Glucocorticoids; Histamine H1 Antagonists; Humans; Hydrocortisone; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Prevalence; Republic of Korea; Retrospective Studies; Risk Factors

The management of high-dose methotrexate (MTX) therapy in patients with cancer depends on the routine monitoring of drug exposures in conjunction with leucovorin (LV), urine pH, patient hydration, and other clinical indices of patient well-being. A key factor in patient oversight is the facilitation of MTX clearance to minimize drug-related toxicity. The aim of this investigation was to evaluate the performance of a clinical decision support system and Bayesian forecasting algorithm in the prediction of MTX concentrations and assessment of LV dosing requirements in pediatric and young adult patients with cancer based on the current practice at the Children's Hospital of Philadelphia. Fifty patients ranging in age from 8 months to 21 years (weight range, 7.6-163.3 kg) contributing 80 total dosing events (183 MTX serum concentrations) were studied. The forecasting model was able to consistently predict future MTX concentrations with the knowledge of one prior concentration and continued to improve with additional concentration data made available through daily therapeutic drug monitoring. Precision was good at 12.9% with low bias at 2.2%. Comparison between the decision support system recommendations for LV rescue relative to the actual LV administration was also made. Sixteen patients would have initiated rescue therapy earlier, seven patients would have received a larger dose (42 smaller), and LV would have been given less often for 37 patients. The forecasting algorithm in the MTX dashboard was reasonably accurate in predicting MTX concentrations and should improve further as the underlying model and prediction algorithm evolves. This decision support system can be useful in helping physicians decide if a patient is clearing MTX as expected or if more aggressive rescue therapy is warranted.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Bayes Theorem; Child; Child, Preschool; Decision Support Systems, Clinical; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Infant; Leucovorin; Male; Methotrexate; Neoplasms; Software; Standard of Care; Young Adult

Antiangiogenic therapies are frequently used with concomitantly administered cancer chemotherapy to improve outcomes, but the mechanism for the benefit of the combination is uncertain. We describe a mechanism by which a specific, cytotoxic antivascular agent causes vascular remodeling and improved chemotherapy results. By selectively killing tumor neovasculature using short-ranged α-particles targeted to vascular endothelial (VE)-cadherin on vascular endothelial cells (by use of 225Ac-labeled E4G10 antibody) we were able both to reduce tumor growth and to increase the efficacy of chemotherapy, an effect seen only when the chemotherapy was administered several days after the vascular targeting agent, but not if the order of administration was reversed. Immunohistochemical and immunofluorescence studies showed that the vasculature of 225Ac-E4G10-treated tumors was substantially depleted; the remaining vessels appeared more mature morphologically and displayed increased pericyte density and coverage. Tumor uptake and microdistribution studies with radioactive and fluorescent small molecule drugs showed better accumulation and more homogenous distribution of the drugs within 225Ac-E4G10-treated tumors. These results show that 225Ac-E4G10 treatment leads to ablation and improvement of the tumor vascular architecture, and also show that the resulting vascular remodeling can increase tumor delivery of small molecules, thus providing a process for the improved outcomes observed after combining antivascular therapy and chemotherapy. This study directly shows evidence for what has long been a speculated mechanism for antiangiogenic therapies. Moreover, targeting the vessel for killing provides an alternative mode of improving chemotherapy delivery and efficacy, potentially avoiding some of the drawbacks of targeting a highly redundant angiogenic pathway.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dideoxynucleosides; Drug Synergism; Female; Fluorine Radioisotopes; Fluorouracil; Humans; Indium Radioisotopes; Leucovorin; Mice; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Positron-Emission Tomography; Tumor Burden; Xenograft Model Antitumor Assays

Allergic reactions to oxaliplatin can be severe and are an important cause of discontinuation of treatment. A retrospective review was performed for 105 patients who received FOLFOX regimens between May 2005 and June 2007. Twenty-five cases (23.8%) of allergic reactions were identified, including 9 late onset reactions (8.6%) and 16 immediate reactions (15.2%). Severe allergy (Grades 3 and 4) occurred in seven patients (6.7%). Re-introduction of FOLFOX was attempted for seven immediate onset patients with a severity grade of 1 or 2, and three of these patients (42.9%) showed relapse of allergy. In approximately 10% of the patients, FOLFOX had to be discontinued due to allergy before the disease became refractory to the regimen. Our experience indicates that allergy to oxaliplatin may be a significant concern and that methods are required for suppression of this allergy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Hypersensitivity; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Medical Records; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Risk Factors; Survival Rate

alpha-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Membrane; Fatty Acids; Folic Acid Antagonists; Humans; Jurkat Cells; Leucovorin; Lipids; Methotrexate; Neoplasms; Oleic Acids; Substrate Specificity; Tetrahydrofolate Dehydrogenase

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; DNA-Binding Proteins; Drug Delivery Systems; Drug Resistance, Neoplasm; Endonucleases; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins

FOLFOX/FOLFIRI chemotherapy is usually applied through central venous catheters because of possible occurrence of phlebitis during application of these regimen via peripheral vein. However, the exact frequency and degree of the problems at peripheral venous access site during FOLFOX/FOLFIRI chemotherapy via peripheral vein in the clinical setting has not been reported previously. We investigated the frequency of infusion failure and phlebitis in 43 patients with advanced or recurrent colorectal cancer who received FOLFOX4, mFOLFOX6 or FOLFIRI chemotherapy in our institution. After informed consent, FOLFOX/FOLFIRI chemotherapy was applied via peripheral vein in 29 cases; all courses (13.1+/-8.1 (Mean+/-SD)courses, 5-FU: 3,510+/-743 mg/body/course) were completed via peripheral vein in the 20 cases (70%). In the other 9 cases, the access site was converted to the central vein because of the problems of access site following completion of 5.9+/-2.0 courses via peripheral vein. Fifty eight times of phlebitis were recognized during total of 301 courses; severe phlebitis requiring medical treatment was not recognized in any case. Seventy seven times of the change of venous access site were required during total of 301 courses. These data would be essential for the exact informed consent for choosing the access site for FOLFOX/FOLFIRI chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Feasibility Studies; Female; Fluorouracil; Humans; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Organoplatinum Compounds; Phlebitis; Time Factors; Venules

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Breast Neoplasms; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Mass Screening; Medical Oncology; Neoplasms; Organoplatinum Compounds; Societies, Medical

Folate is a B vitamin, deficiency of which appears to increase the risk of developing several malignancies including colorectal cancer. In contrast to the cancer-promoting effect of folate deficiency in normal tissues, several lines of evidence indicate that folate depletion suppresses the progression of existing neoplasms and enhance the sensitivity of cancer cells to chemotherapy. Folate mediates the transfer of one-carbon necessary for the de novo biosynthesis of purines and thymidylate, and hence is an essential factor for DNA synthesis and repair, and the maintenance of DNA integrity and stability. Folate deficiency induces DNA strand breaks, increases uracil misincorporation into DNA, impairs DNA repair and appears to induce apoptosis. Although the effects of folate depletion on DNA integrity and apoptosis and on subsequent cancer development, progression and treatment in colonic epithelial cells have been well characterized, it is largely unknown at present how folate depletion modulates specific upstream genes in apoptosis and cancer pathways that regulate these processes. We therefore investigated the effects of folate depletion on expression of genes involved in apoptosis and cancer pathways in four human colon adenocarcinoma cell lines in an in vitro model of folate deficiency. Apoptosis and cancer pathway-specific mini-microarray were used to screen for differentially expressed genes in response to folate deficiency, and the expression of seven most notably and consistently affected genes was confirmed by real time RT-PCR. Our data suggest that folate deficiency affects the expression of key genes that are related to cell cycle control, DNA repair, apoptosis and angiogenesis in a cell-specific manner. Cell-specificity in gene expression changes in response to folate deficiency is likely due to significant differences in molecular and phenotypic characteristics, growth rates and intracellular folate concentrations among the four cell lines.

Topics: Adenocarcinoma; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Deoxyuridine; DNA; Folic Acid Deficiency; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Models, Biological; Neoplasms; Reverse Transcriptase Polymerase Chain Reaction

In metastatic colorectal cancer, a combination of Leucovorin (LV) and fluorouraci (l FU) with oxaliplatin (FOLFOX) is a standard first-line regimen. The two limiting toxicities of FOLFOX are neutropenia and the specific reversible sensory neuropathy of oxaliplatin. The cumulative neurotoxicity often requires therapy to be stopped. Immediate hypersensitive reactions (anaphylaxis) have been noted as often as to 0.6 percent. We should pay sufficient attention to side effects of FOLFOX.

Topics: Anaphylaxis; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Fluorouracil; Guideline Adherence; Humans; Leucovorin; Neoplasms; Neutropenia; Organoplatinum Compounds; Practice Guidelines as Topic

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoplasms; Organoplatinum Compounds; Quality of Life; Time

CPT-11 (irinotecan hydrochloride, trade name: Campto or Topotecin) was launched in 1994. L-OHP (oxaliplatin, trade name: Elplat) was approved based on the fast track evaluation system and launched in 2005. Originally, both of these drugs were synthesized in Japan. Just after the launch of CPT-11, the severity of its toxicity was reported more frequently than its efficacy, therefore it spent much time to spread the use of this drug. As for L-OHP, the approved regimen is FOLFOX in spite the regimen was not actually studied in its registration studies in Japan. However, L-OHP is widely used after its launch. Thus, we find a progress in terms of regulatory system to introduce the widely accepted standard chemotherapy to the Japanese practice sites rapidly. We also find a further understanding for cancer chemotherapy in Japanese society. Recently, mass media reported cancer patients who were eager to receive the standard chemotherapy and requesting the regulatory authorities its quick approval. We have never seen such a scene 10 years ago. These patients' activities could be a key factor to change the infrastructure of cancer therapy.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Clinical Trials Data Monitoring Committees; Drug Approval; Fluorouracil; Humans; Irinotecan; Japan; Leucovorin; Neoplasms; Organoplatinum Compounds; Oxaliplatin

We report our outpatient cases for home anti-cancer chemotherapy using a CV port and a portable pump system. A total of 119 patients with advanced and recurrent cancer were performed at an outpatient clinic or provided home anti-cancer chemotherapy since December 1996 until December 2005. Of these patients, 18 patients were provided home anti-cancer chemotherapy using a CV port and a portable pump system (5 with gastric, 4 colonic, 2 rectal, 1 lung, 1 hepatic, 1 duodenal, 2 breast, and 2 pancreatic). Fifteen patients had died, and 3 patients are alive and undergoing continuous therapy. The response revealed 3 cases with partial response, 13 cases with no change and 2 cases with progressive disease. No severe side effects were seen, and no troubles of catheter and port were experienced as well. Not only the treatment of outpatients for home anti-cancer chemotherapy was effective and maintained the patient's QOL, but also contributed to a marked decrease of medical costs compared to admission therapy.

Topics: Aged; Aged, 80 and over; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Home Care Services, Hospital-Based; Home Infusion Therapy; Humans; Infusion Pumps; Infusion Pumps, Implantable; Leucovorin; Male; Middle Aged; Neoplasms; Organoplatinum Compounds; Outpatients; Quality of Life

The incidence of 5-fluorouracil (5-FU)-related cardiotoxicity seems to be dosage and schedule dependent. It was reported as 1.6-3% with earlier bolus regimens whereas this increased up to 7.6-18% with prolonged (4-5 days) infusion regimens. Knowledge of the cardiotoxicity incidence in patients treated with the widely used de Gramont's regimen (2 days infusional 5-FU) and the long-term follow-up of affected patients is still limited.. We investigated the incidence and clinical characteristics of the cardiotoxicity of de Gramont's regimen and long-term follow-up of the affected patients.. Nine of a total of 231 patients receiving de Gramont's regimen experienced cardiac events, revealing an overall incidence of 3.9%. Four (2.5%) cases were receiving de Gramont's regimen only. Cardiac manifestations were acute coronary syndrome (n = 6), congestive heart failure (n = 2) and atrial fibrillation (n = 1). Cardiotoxicity occurred in the first cycle in eight patients, and in the second cycle in one. The median onset day was day 2. Cardiac symptoms occurred mostly at night time (seven patients) and the onset was a few hours after the bolus part of the regimen in four out of seven patients. After the cardiotoxicity, treatments were continued safely without 5-FU.. de Gramont's regimen has a lower incidence of cardiotoxicity compared with more prolonged 5-FU-based infusion regimens. Nevertheless, patients should still be carefully monitored especially in the first cycles and at night time.

Topics: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Coronary Disease; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Heart; Heart Failure; Humans; Incidence; Leucovorin; Male; Middle Aged; Neoplasms; Survival Rate

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Hemostasis; Humans; Incidence; Leucovorin; Male; Middle Aged; Neoplasms; Organoplatinum Compounds; Platelet Aggregation Inhibitors; Warfarin

Oxaliplatin is a platinum salt that is particularly effective in treating gastrointestinal tumours. Its increased use has resulted in emergence of allergic reactions, including anaphylactic shock. Allergic reactions to oxaliplatin documented over the last 5 years have been analysed using predefined criteria. The 42 analysed patients had cancer and received a FOLFOX regimen in first line or beyond. Two types of allergy were observed: a type I immediate allergic reaction in 39 patients in whom the most frequent signs were respiratory (50%) and cutaneous (40%); anaphylactic shock that occurred in three patients; type II allergy (immunological thrombopenia) was observed in three patients. All the toxicities were reversible on symptomatic treatment. No predictive factor was evidenced. Anaphylactic shock, is rare but serious, and must be considered in the event of any severe blood pressure decrease. For the non-life-threatening reactions, prolonging infusion duration, "Stop and Go" regimen seem to be effective means of preventing recurrence.

Topics: Adult; Aged; Aged, 80 and over; Anaphylaxis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Hypersensitivity; Female; Fluorouracil; Humans; Hypersensitivity, Immediate; Leucovorin; Male; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies

One of the most common and important side effects of 5-fluorouracil (5-FU) is mucositis with ulcerations in the oral cavity. We investigated the effects of local cryotherapy on mucositis incidence administrated durng 5-FU treatment.. In a total of 99 courses, 5-FU and folinic acid combination chemotherapy was given to 40 patients. In our study, we considered every course as a single case, and cryotherapy was given to the same patient in one course but not given in the next.. While mucositis developed in 6.7% of the courses given with cryotherapy, this ratio was 38.9% in courses given without cryotherapy. In the logistic regression analysis, development of mucositis had been found to correlate only with cryotherapy. Odds ratio (OR) = 11.5; in the 95% confidence interval (CI) = 3.2 - 41.9; (p = 0.001).. Results of initial studies evaluating the effects of cryotherapy in preventing mucositis due to 5-FU based chemotherapy regimens were promising. We concluded that oral cooling prevents 5-FU induced mucositis. This effective prophylactic treatment should be used in patients who are at increased risk for developing 5-FU induced mucositis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chi-Square Distribution; Cryotherapy; Female; Fluorouracil; Humans; Leucovorin; Logistic Models; Male; Middle Aged; Mouth Mucosa; Neoplasms; Stomatitis; Treatment Outcome

Whereas the major folate transporter, the reduced folate carrier (RFC), has a physiological pH optimum, transport activities for folates and antifolates have been detected with low pH optima. Because the interstitial pH in solid tumors is generally acidic, the mechanisms by which antifolates are transported at low pH could be an important determinant of drug activity under these conditions. The current study quantitated the low pH methotrexate (MTX) transport activity in human solid tumor cell lines from the National Cancer Institute tumor panel and other sources. MTX influx at pH 5.5 was equal to, or greater than, influx at pH 7.4 in 29 of 32 cell lines. To assess the role of RFC in transport at low pH in one of these cell lines, a HeLa clonal line (R5) was selected for MTX resistance due to a genomic deletion of the carrier gene. MTX influx was depressed by 70% in R5 versus wild-type HeLa cells at pH 7.4. At pH 6.5, influx in these two lines was similar; as the pH was decreased to 5.5 influx increased in both cell lines. Similarly, whereas net MTX uptake over 1 h was markedly decreased in R5 cells at pH 7.4, net uptake in HeLa and R5 cells was comparable at pH 6.5. Also, as compared with MCF7 breast cancer cells, MTX uptake was markedly decreased at pH 7.4, but only minimally at pH 6.5, in the MDA-MB-231 human breast cancer cell line that lacks RFC expression. When grown with folic acid (2 micro M) at pH 7.4, the IC(50) for MTX was 14-fold higher in R5 as compared with wild-type HeLa cells; the difference was only 4-fold when cells when grown at pH 6.9; the IC(50)s were identical at this pH when the medium folate was 25 nM 5-formyltetrahydrofolate. These data demonstrate that transport activity at low pH is prevalent in human solid tumors, is RFC-independent in R5 cells and MDA-MB-231 breast cancer cells, and can preserve MTX activity in the absence of RFC at an acidic pH relevant to solid tumors in vivo.

Topics: Antimetabolites, Antineoplastic; Biological Transport; Blotting, Northern; Blotting, Southern; Cell Division; Cell Line, Tumor; DNA, Complementary; Dose-Response Relationship, Drug; Folic Acid; Gene Deletion; HeLa Cells; Humans; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Leucovorin; Membrane Transport Proteins; Methotrexate; Neoplasms; Reduced Folate Carrier Protein; Time Factors; Transfection

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Drug Delivery Systems; Fluorouracil; Humans; Leucovorin; Medical Oncology; Methotrexate; Neoadjuvant Therapy; Neoplasms; Palliative Care; Quality of Life

Topics: Chromatography, High Pressure Liquid; Drug Monitoring; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Neoplasms; Tetrahydrofolates

Cancer cell lines in standard cell culture medium or in animal models are surrounded by an environment with relatively high folate (HF) levels, compared with folate levels in human plasma. In the present study we adapted 4 colon cancer (C26-A, C26-10, C26-G and WiDr) and 3 squamous cell carcinoma of the head and neck (HNSCC) cell lines (11B, 14C and 22B) to culture medium with low folate (LF) levels (2.5, 1.0 and 0.5 nM, respectively) and investigated whether folate depletion had an effect on sensitivity to antifolates and which mechanisms were involved. All LF cell lines showed a higher sensitivity to 5-fluorouracil (5-FU) alone or in combination with leucovorin (LV) (2-5-fold), to the thymidylate synthase (TS) inhibitors, AG337 (2-7-fold), ZD1694 (3-49-fold), ZD9331 (3-40-fold), LY231514 (2-21-fold) or GW1843U89 (4-29-fold) or to the dihydrofolate reductase (DHFR) inhibitor PT523 (2-50-fold) compared with their HF variants cultured in standard medium containing up to 8 microM folic acid. LV could only increase sensitivity to 5-FU in HNSCC cell lines 14C and 14C/F. The differences in sensitivity could partially be explained by a 2-7-fold increased transport activity of the reduced folate carrier (RFC) in LF cell lines, whereas no significant change in folylpolyglutamate synthetase (FPGS) activity was observed. Furthermore, the protein expression and catalytic activity of the target enzyme TS were up to 7-fold higher in HF colon cancer cells compared with the LF variants (p < 0.05). Although the TS protein expression in LF HNSCC cells was also lower than in HF variants, the TS catalytic activity and FdUMP binding sites were up to 3-fold higher (p < 0.05). Thus, changes in TS levels were associated with differences in sensitivity. These results indicate that folate depletion was associated with changes in TS and RFC levels which resulted in an increase in sensitivity to 5-FU and antifolates. The folate levels in LF medium used in this study are more representative for folate levels in human plasma and therefore these data could be more predictive for the activity of 5-FU and antifolates in a clinical setting than results obtained from cell lines cultured in HF medium or in animal models.

Topics: Animals; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Carrier Proteins; Colonic Neoplasms; Fluorouracil; Folic Acid; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Membrane Proteins; Membrane Transport Proteins; Mice; Multienzyme Complexes; Neoplasms; Peptide Synthases; Reduced Folate Carrier Protein; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase; Tumor Cells, Cultured

Many studies connected with different aspects of the quality of life (QL) have been increasingly reported. In this study we have been used FACT questionnaire to estimate QL in three groups of cancer patients receiving chemotherapy. Questionnaires were completed by 177 patients. Adverse effects of treatment severely influence the cancer patients QL. The most significant worsening of QL was noticed in the group of lung cancer patients receiving the most emetogenic chemotherapy(i.e. cis-platinum, vepesid). In other two groups (gastric and colorectal cancer patients) side effects of chemotherapy caused relatively less QL deterioration. This finding implicates possibility of intensifying the course of treatment (dosage and duration) assuming there is no hematopoetic insufficiency.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Cisplatin; Colorectal Neoplasms; Epirubicin; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasms; Quality of Life; Stomach Neoplasms; Surveys and Questionnaires

To evaluate the effect of N-phosphonacetyl-L-aspartate (PALA), folinic acid (FA), and interferon alfa (IFN-alpha) biomodulation on plasma fluorouracil (5FU) pharmacokinetics and tumor and liver radioactivity uptake and retention after [18F]-fluorouracil (5-[18F]-FU) administration.. Twenty-one paired pharmacokinetic studies were completed on patients with colorectal, gastric, and hepatocellular cancer, utilizing positron emission tomography (PET), which allowed the acquisition of tumor, normal tissue, and plasma pharmacokinetic data and tumor blood flow (TBF) measurements. The first PET study was completed when the patient was biomodulator-naive and was repeated on day 8 after the patient had been treated with either PALA, FA, or IFN-alpha in recognized schedules.. TBF was an important determinant of tumor radioactivity uptake (r = .90; P < .001) and retention (r = .96; P < .001), for which radioactivity represents a composite signal of 5-[18F]-FU and [18F]-labeled metabolites and catabolites. After treatment with PALA, TBF decreased (four of four patients; P = .043), as did tumor radioactivity exposure (five of five patients; P = .0437), with no change in plasma 5FU clearance. With FA treatment, there were no differences observed in whole-body metabolism, plasma 5FU clearance, or tumor and liver pharmacokinetics. IFN-alpha had measurable effects on TBF and 5-[18F]-FU metabolism but had no apparent affect on liver blood flow.. The administration of PALA and IFN-alpha produced measurable changes in plasma, tumor, and liver pharmacokinetics after 5-[18F]-FU administration. No changes were observed after FA administration. In vivo effects may negate the anticipated therapeutic advantage of 5FU biomodulation with some agents.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Area Under Curve; Aspartic Acid; Colorectal Neoplasms; Drug Interactions; Female; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Liver Neoplasms; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neoplasms; Phosphonoacetic Acid; Regional Blood Flow; Stomach Neoplasms; Tomography, Emission-Computed

Knowledge of the exact dose and rate at which an antitumor agent is delivered to its target site is postulated to be crucial to proper patient management. It is now possible to obtain such information using non-invasive 19F-NMRS (nuclear magnetic resonance spectroscopy) following the administration of 5-fluorouracil (5-FU). We have performed such studies in 103 patients with breast, colorectal and other tumors. Measurable 19F signals were detected in 99 of these patients (92.5%). Estimation of the tumoral t1/2 of 5-FU in these patients revealed that 51 of them (51.5%) exhibited a tumoral t1/2 greater than 20 min, a value we had characterized as indicating drug trapping in the tumor. Of these patients, 46 who received regimen bolus 5-FU 600 mg/m2 with leucovorin for their treatment have been evaluated. In these patients, the association between trapping and response remains very high (p<.000001). None of the non-trappers responded to chemotherapy, whereas 70% of the evaluable trappers responded. Details are presented here on the methodology of NMRS data acquisition and on their pharmacokinetic analysis. The potential mechanisms underlying the trapping effect appear to be predicated primarily on transport processes. Suggestions are presented on how such pharmacokinetic imaging studies may extend both our understanding of the mechanism of action of 5-FU, and how they could be used to optimize patient treatment.

Topics: Antimetabolites, Antineoplastic; Breast Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Half-Life; Humans; Leucovorin; Magnetic Resonance Spectroscopy; Neoplasms

The purpose of this study was to investigate folate-related predictors of 5-fluorouracil (5-FU) cytotoxicity in the presence or absence of l-folinic acid (l-FA). Intracellular concentrations of the reduced folates (tetrahydrofolate + 5,10-methylenetetrahydrofolate) and folylpolyglutamate synthetase (FPGS) activity were determined in 14 human cancer cell lines expressing a spontaneous sensitivity to 5-FU. On these 14 cell lines grown without l-FA supplementation, a significant positive correlation was demonstrated between basal intracellular folate concentration and FPGS activity. 5-FU sensitivity (IC50 range 0.6-25.4 microM) was not related to the basal intracellular folate concentration, whereas, significantly, it was linked to FPGS activity (range 2.5-11.1 pmol/min/mg protein): the higher the FPGS activity, the greater the 5-FU sensitivity. Under l-FA supplementation (0.01-300 microM), intracellular reduced folates increased continuously without evidence of saturation in all cell lines; the pattern of accumulation was independent of the FPGS activity. l-FA enhanced 5-FU cytotoxicity by a factor of 1.9-6.4 in 12 of the 14 cell lines. In the 12 FA-sensitive cell lines, the l-FA concentrations allowing 90% of maximum 5-FU potentiation [l-FA]90 ranged between 0.7 and 107.9 micro M (median 1.9); in contrast, the intracellular concentrations of reduced folates allowing 90% of maximum 5-FU potentiation were much less variable (range 7.6-38.3, median 24.8 pmol/mg protein). In the presence of [l-FA]90, 5-FU sensitivity remained significantly correlated to the basal FPGS activity. In addition, reduced folates were measured in 96 tumoral samples (50 head and neck, 16 colon, 30 liver metastases from colorectal cancer) taken before treatment. Almost all investigated tumours had folate concentrations below the median concentration required for optimal 5-FU potentiation in vitro: median levels (range, pmol/mg protein) were 3.8 (0-17.7) for head and neck, 5.8 (2.3-12.0) for colon and 12.1 (1.7-118.5) for liver metastases. Above all, these data establish the relevance of FPGS activity for predicting the efficacy of 5-FU modulated by FA or not and point to the potential clinical interest of FPGS determination in human tumours.

Topics: Antidotes; Antimetabolites, Antineoplastic; Biopsy; Drug Screening Assays, Antitumor; Drug Synergism; Female; Fluorouracil; Folic Acid; Humans; Leucovorin; Neoplasms; Peptide Synthases; Tumor Cells, Cultured

Topics: Administration, Oral; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Drug Therapy, Combination; Humans; Japan; Leucovorin; Neoplasms; Tegafur; United States; Uracil

In the conduct of a clinical trial, unexpectedly high rates of toxicity may cause a researcher to want to terminate the trial early even though no formal stopping rule had been specified. The experience of one such clinical trial is used as an example of the ways in which group sequential methodology can be applied in deciding to stop the study, as well as in reporting the results of the clinical trial. This approach is then compared to a Bayesian analysis.

Topics: Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biometry; Clinical Trials as Topic; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Leucovorin; Leukopenia; Mathematics; Models, Statistical; Mouth Diseases; Mouth Mucosa; Neoplasms; Research Design

There are two distinct levels where dose intensity can be increased by pharmacomodulation. The first level implies the inhibition of clearly identified resistance mechanisms. Among them, MDR type resistance is the most studied currently. MDR resistance is mediated by GP170, a cell membrane protein, which can be inhibited by several pharmacological agents like verapamil, ciclosporine and S 9788 which are currently being clinically investigated. The inhibition of DNA repair mechanisms is another approach and a representative example is the inhibition of O6-alkylguanine DNA alkyltransferase by O6-methylguanine or O6-benzylguanine. Modulation of detoxification pathways has also been considered, with for instance, the use of buthionine sulfoximide (BSO) to deplete intracellular glutathione levels. The second level for pharmacomodulation concerns pharmacological interferences with metabolic pathways controlling the activity of anticancer agents and particularly the antimetabolites like ara-C and 5-FU. The use of hydroxyurea or PALA in the case of 5-FU are good illustrations of pharmacomodulation via specific metabolic routes. Finally, the 5-FU-folinic acid combination could characterise a third level of pharmacomodulation where cytotoxic activity is optimised at the site of interaction between activated drug (5FdUMP) and target (thymidilate synthase).

Topics: Antineoplastic Agents; Arabinofuranosylcytosine Triphosphate; ATP Binding Cassette Transporter, Subfamily B, Member 1; DNA Repair; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple; Fluorouracil; Leucovorin; Neoplasms

Topics: Adult; Aged; Humans; Leucovorin; Middle Aged; Neoplasms; Seizures

Topics: Antimetabolites, Antineoplastic; Fluorouracil; Folic Acid; Humans; Leucovorin; Levamisole; Neoplasms

Topics: Drug Resistance; Drug Therapy, Combination; Humans; Interferons; Leucovorin; Neoplasms; Pyrimidine Nucleotides; Thymidylate Synthase

We have measured the levels of interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta, and IL-2 in the whole blood cell culture supernatants of 43 tumor patients undergoing a treatment with biological response modifiers or a conventional therapy with 5-fluorouracil and leucovorin. In the blood cell cultures of the 16 patients who received 5-fluorouracil and leucovorin IFN gamma levels decreased (P < or = 0.01) and TNF alpha levels rose (P < or = 0.05) during each therapy cycle. However, in the blood samples a declining number of total leukocytes and lymphocytes was measured (P < or = 0.05). Progressive disease could be correlated to a tendency towards lower IFN gamma levels in the pretherapeutic cultures of these patients. The second group analyzed consisted of 8 patients receiving a low-dose IL-1 beta therapy. In this group we found either an unchanged or an augmented IFN gamma production of the blood cells during treatment. In the group of 13 patients receiving low-dose recombinant IL-2 (< or = 4.5 x 10(6) IU m-2 day-1) significantly increasing IFN gamma levels were seen in the blood cell cultures during the therapy (P < or = 0.05), although total leukocyte counts decreased. In this group, 4 had stable disease for at least 2 months and 9 patients had tumor progression under therapy. In the cultures of the latter a tendency towards lower IFN gamma values was found. Finally, the cytokine production in the blood cell cultures of 6 patients receiving a combination therapy of IFN alpha and high-dose IL-2 was studied. During this therapy a dramatically reduced production not only of IFN gamma but also of all other measured cytokines was found. In this group all patients had tumor progression under therapy. It is concluded that the measurements of cytokine production in a reproducible whole blood culture system may be useful for monitoring immunological therapies and may help us to find out which doses of biological response modifiers have enhancing or suppressive effects on the functions of the immune cells.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cells, Cultured; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Fluorouracil; Humans; Immunity, Cellular; Immunologic Factors; Interferon-alpha; Interferon-gamma; Interleukin-1; Interleukin-2; Leucovorin; Leukocytes; Male; Middle Aged; Neoplasms; Recombinant Proteins; Tumor Necrosis Factor-alpha

In a previous trial in which methotrexate and N-phosphonacetyl-L-aspartate (PALA) were used to modulate 5-fluorouracil (5-FU), four of six patients could not tolerate treatment at the 600 mg/m2 5-FU dose level because of mucositis, diarrhea, and a decrease in performance status. The current study examines the ability of uridine rescue to prevent such toxic effects in the same regimen and, thereby, allow additional dose escalation of 5-FU.. Twenty-nine patients with advanced malignant neoplasms received PALA and MTX, each at 250 mg/m2, followed 24 hours later by increasing bolus doses of 5-FU (600-750 mg/m2) with a leucovorin rescue (10 mg orally every 6 hours for eight doses) and uridine rescue (3 g/m2/hour, for a 72-hour infusion, 3 hours on, 3 hours off). Treatment was repeated weekly with either 2 weeks on, 2 weeks off, or 3 weeks on, 1 week off.. Mucositis, which occurred in 4 of 12 patients treated at the 750 mg/m2 5-FU dose level, was the only significant chemotherapy-induced toxic effect. However, uridine-related central venous catheter complications (cellulitis in six patients and superior vena cava syndrome in one patient) precluded additional treatment on this protocol.. In the current regimen, uridine allowed dose escalation of 5-FU to 750 mg/m2, which some patients tolerated on a 3-week on, 1-week off schedule. Because of the vascular toxic effects associated with intravenous uridine, the authors recommend additional studies with oral uridine to determine whether the increase in 5-FU dose that uridine allows is associated with improved response rates.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Diarrhea; Drug Synergism; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Mouth Mucosa; Neoplasms; Phosphonoacetic Acid; Stomatitis; Uridine

At this time, folinic acid (FA) is commercially available as the racemic mixture d,l-FA, whose biological activity is supported by natural l-FA. The administration of d,l-FA results in the accumulation of d-FA in plasma relative to the active l-FA form; in vitro studies have shown that d-FA can compete with the polyglutamation of methotrexate (MTX).. Our purpose was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture d,l-FA with the pure l-FA in rescue of high-dose MTX therapy (5 g/m2) in children with acute lymphocytic leukemia (ALL).. Eighteen children with ALL were entered in this trial, which was planned with a crossover design. Four cycles of MTX were administered to each patient, and rescue was achieved orally every 6 hours at a dose of 12 mg/m2 for d,l-FA and 6 mg/m2 for pure l-FA. The d,l-FA and l-FA rescues were alternated from one cycle to the next. d-FA, l-FA, and the active metabolite 5-methyltetrahydrofolate (5-MTHF) were measured in plasma using a stereospecific high-performance liquid chromatography assay.. Considering total active folate levels (l-FA + 5-MTHF), mean residual concentrations were similar for rescue by d,l-FA and l-FA, after two and six intakes, respectively: 92 and 186 nM for d,l-FA rescue versus 100 and 184 nM for l-FA rescue. Intra-individual comparison of total active folates (l-FA + 5-MTHF) did not show any significant difference between d,l-FA rescue and l-FA rescue. After administration of d,l-FA, the accumulation of d-FA in plasma was confirmed. For both types of FA rescue, MTX terminal half-lives were identical (average value, 13.9 hours). Considering each type of toxic effect (hematologic, hepatic, renal, and digestive), there was no significant difference in the proportion of toxic cycles following l-FA rescue or d,l-FA rescue.. The administration of the pure l-FA, compared with the administration of the racemic mixture, results in comparable blood profiles of active folates and MTX, leads to equivalent treatment tolerance, and avoids the plasma accumulation of d-FA.

Topics: Adolescent; Child; Child, Preschool; Drug Therapy, Combination; Female; Folic Acid; Humans; Infant; Leucovorin; Male; Methotrexate; Neoplasms; Stereoisomerism

A polymerase chain reaction (PCR)-based method was used to quantitate the expression levels of low abundance genes relevant to cancer drug activity. RNA from tumor samples as small as 20 mg was isolated and converted to cDNA using random hexamers. The 5' primers for the PCR contained a T7 polymerase promoter sequence, allowing the PCR-amplified DNA to be transcribed to RNA fragments. In each sample, the linear ranges of amplification of each cDNA of interest were established. Relative gene expressions were calculated by extrapolating the amounts of PCR products generated within the linear amplification regions of each gene to equal volumes of the cDNA solution. The method was accurate to less than a 2-fold difference in expression levels. Using beta 2-microglobulin and beta-actin gene expressions as internal reference standards and cDNA from HT-29 cells as an external linearity standard, we measured the relative expressions of thymidylate synthase, dihydrofolate reductase, and DT-diaphorase in a number of clinical tumor samples. The expressions of these genes varied from 50- to 100-fold among different tumors, although most of the values were grouped within about a 10-fold range. The amount of thymidylate synthase gene expression in tumor tissues was directly proportional to the content of thymidylate synthase protein. Those tumors with the lowest thymidylate synthase expression had the best response to both the 5-fluorouracil-leucovorin and 5-fluorouracil-cisplatin combinations.

Topics: Actins; Base Sequence; DNA, Neoplasm; Fluorouracil; Gene Amplification; Humans; Leucovorin; Molecular Sequence Data; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Polymerase Chain Reaction; Reproducibility of Results; RNA, Messenger; RNA, Neoplasm; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase; Transcription, Genetic

Twenty-eight patients with refractory advanced malignancies were treated with a 24 hr infusion of 5-fluorouracil (5-FU), Leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable for the assessment of toxicity and anti-tumor activity. PALA was administered as intravenous bolus over 15 min at a fixed dose, 250 mg/m2 24 hr before the start of 5-FU and LV infusions. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 2600 mg/m2. LV was administered in a fixed dose of 500 mg/m2 concurrently with 5-FU over a 24-hr period. The course was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among dose-limiting toxic effects. Other toxicities observed were hand-foot syndrome, hair loss of scalp/eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. Maximum tolerated dose (MTD) of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated at 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose de-escalation, a majority of whom contained 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients had been previously treated. Eight patients achieved a partial response, all of whom were previously treated, except three patients. A complete response was observed in a patient with pancreatic carcinoma, previously untreated. Overall response rate for the patients who were treated at the 5-FU dose of 2100 mg/m2 or 2600 mg/m2 is 9 of 18 patients (50%).

Topics: Adult; Aged; Antineoplastic Agents; Aspartic Acid; Drug Evaluation; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Phosphonoacetic Acid

Topics: Anti-Inflammatory Agents, Non-Steroidal; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms; Poisoning; Renal Dialysis

Both arterial infusion chemotherapy and biochemical modulation are effective for unresectable and recurrent cancer patients. Thus, we tried to combine these methods and studied their combined efficacy in 30 cancer patients. Overall effectiveness was 40% with this method. The efficacy of each regimen, such as beta-MF and CF, was approximately 36.4% and 66.7%, respectively. The effectiveness of cannulation into the proper hepatic artery and aorta was 48.6% and 16.7%, respectively. In this study, there were no serial or severe side effects. These findings suggested that arterial infusion chemotherapy in combination with biochemical modulation was a safe and effective method for treating cancer patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Fluorouracil; Humans; Immunologic Factors; Infusions, Intra-Arterial; Interferon Type I; Leucovorin; Methotrexate; Mitomycin; Mitomycins; Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoplasms; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Floxuridine; Fluorouracil; Humans; Leucovorin; Methotrexate; Neoplasms

Optically pure l-leucovorin was synthesized on a large scale by the combination of chemical and enzymatic processes. After reduction of folate with zinc, dihydrofolate was reduced asymmetrically to (6)-tetra-hydrofolate by use of dihydrofolate reductase from E. coli C600/pTP600, with simultaneous NADPH cofactor recycling using glucose dehydrogenase from Gluconobacter scleroideus KY3613. Calcium l-leucovorin.4H2O (113 g) was obtained from (6S)-tetrahydrofolate via 5,10-methyenyltetrahydrofolate by formylation, reflux, addition of calcium ions and floricil column chromatography, with an overall yield of 50% based on folate. The l-leucovorin showed optical purity of 99.9% de as (6S)-form.

Topics: Escherichia coli; Fluorouracil; Isomerism; Leucovorin; NAD; Neoplasms; Oxidation-Reduction; Plasmids; Promoter Regions, Genetic; Tetrahydrofolate Dehydrogenase

We previously reported that fluorouracil (5FU) accumulation and metabolism in human livers and tumors can be studied by in vivo nuclear magnetic resonance spectroscopy (NMRS). We have extended these observations by evaluating the pharmacokinetics of 5FU in the tumors of 11 patients with carcinoma of the breast, colon, endometrium, cervix, and kidney, using 19F-NMRS in a 1.5 Magnetom (Siemens Medical Systems, Cerrito, CA) magnetic resonance imaging unit (MRI). These NMRS measurements detected a long-lived tumor pool of 5FU in six of 11 tumors in our patients including carcinomas in the pelvis, breast, lung, and liver. The half-life (T1/2) of this tumor pool of "trapped" 5FU was 0.33 to 1.3 hours (20 to 78 minutes), much longer than the T1/2 of 5FU in blood (5 to 15 minutes). Neither the anabolites of 5FU (fluorinated nucleosides, nucleotides, 5FU-RNA, or 5FU-thymidylate synthase) nor the catabolites (eg, fluorobetaalanine [FBAL]) were detectable by 19F NMRS. Patient response to chemotherapy appeared to correlate with the extent of trapping of free 5FU in the human tumors: in the seven patients receiving 5FU, or 5FU or FUdR plus leucovorin, four of four patients whose tumors trapped 5FU responded to fluorinated pyrimidine chemotherapy, whereas three patients in whom there was a failure to detect tumor trapping were resistant to 5FU. We conclude that NMRS is clinically feasible, and enables investigators to study 5FU pharmacokinetics and metabolism in tumors in vivo. 19F-NMRS of 5FU allows for in vivo evaluation of 5FU metabolic modulation and might be able to guide therapeutic decisions.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorine; Fluorouracil; Half-Life; Humans; Leucovorin; Magnetic Resonance Spectroscopy; Neoplasms

We report the results of a phase I study of intravenously administered cisplatin, 5-fluorouracil and high-dose folinic acid. This trial was designed to exploit potential biochemical interactions between these three agents. The maximum tolerated doses were cisplatin, 75 mg/m2, day 1; 5-fluorouracil, 375 mg/m2, days 1-5 and leucovorin 500 mg/m2, days 1-5. The dose-limiting toxic effect of this regimen was myelosuppression. Mild non-hematologic toxic effects were also observed and included nausea, vomiting, stomatitis, and diarrhea. Phase II trial of this regimen are underway, however randomized studies will eventually be necessary to establish whether cisplatin contributes clinically significant activity to this regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cisplatin; Dose-Response Relationship, Drug; Drug Evaluation; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Research Design

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms; Phosphonoacetic Acid; Uridine

Two consecutive Phase I trials of continuous infusion 5-fluorouracil (5-FU) or floxuridine (5-FUdR) admixed with leucovorin (LCV) were performed and involved 19 and 24 patients, respectively. The studies were carried out to identify the optimal dose rate of delivery for the two admixtures (5-FU + LCV and 5-FUdR + LCV) administered for 14 days, and to determine if biochemical modulation could be identified. The optimal dose rates for 5-FU plus LCV were 200 mg/m2/d and 5 mg/m2/d, respectively. The optimal dose rates for 5-FUdR plus LCV were 0.075 mg/kg/d and 5 mg/m2/d, respectively. The dose rate limiting toxicity for 5-FU plus LCV was stomatitis and for 5-FUdR plus LCV it was diarrhea. LCV administered as an admixture with either 5-FU or 5-FUdR on an infusion schedule decreases the optimally tolerated dose rates for these two agents to 83% and 60%, respectively. This is achieved with low-dose LCV infusions.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Drug Administration Schedule; Drug Evaluation; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Remission Induction; Stomatitis

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoplasms

From 1977 to 1982, 62 patients with various advanced malignant solid tumors were treated by HD-MTX-CFR therapy and totally 129 courses were given. Majority of the patients suffered from malignant lymphoma (10), osteogenic sarcoma (11), lung cancer (16), esophageal cancer (3), breast cancer (3) and malignant melanoma (4). All were confirmed by cytology or pathology except one primary liver cancer. There were clinically measurable lesions in 59 patients for evaluation of the treatment, and 3 osteogenic sarcoma patients without metastasis were given a postoperative adjuvant chemotherapy. 33 out of 62 had received chemotherapy and/or radiotherapy before. Dose of MTX ranged from 2 to 3 gm per course in most patients and dose of CF, from 9 to 12 mg every 6 hours for 3 days. 2 (3.4%) patients achieved complete remission (1 osteogenic sarcoma and 1 malignant lymphoma) and 8 (13.6%), partial remission (1 osteogenic sarcoma, 5 malignant lymphoma, 1 esophageal cancer and 1 breast cancer) with a total response rate of 15.9%. No response was observed in all 16 lung cancers. The main side effects of HD-MTX-CFR therapy were leukopenia, thrombocytopenia, elevation of SGPT, nausea, vomiting, mucositis, skin rash, fever and fatigue. All patients were followed more than 3 years. 4 patients are still alive (9, 9, 4 and 7 years, respectively), including 3 osteogenic sarcoma patients who received postoperative adjuvant chemotherapy and 1 mycosis fungoides.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Leucovorin; Lung Neoplasms; Lymphoma; Male; Methotrexate; Middle Aged; Neoplasms; Osteosarcoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Evaluation; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Neoplasms; Stereoisomerism; Tetrahydrofolates

High-dose methotrexate (HDMTX) regimens were initially designed to overcome methotrexate (MTX) resistance due to defective transport of the drug. At high concentrations, enough MTX diffuses into resistant cells to saturate and inhibit the target enzyme, dihydrofolate reductase (DHFR). The high doses of MTX needed to achieve these high drug concentrations must be administered with the reduced folate antidote, leucovorin (LV; 5-formyltetrahydrofolate), to prevent increased toxicity. To increase MTX therapeutic index, LV rescue must be selective, i.e., more effective in normal than in tumor cells. In experimental models, selective rescue can be achieved if strict LV administration guidelines are respected. Since both MTX and LV use the membrane transport system, it was hypothesized that selective rescue occurred because transport-deficient, MTX-resistant tumor cells also transported LV poorly. The unsatisfactory clinical results frequently obtained with HDMTX regimens suggest a need to re-evaluate this underlying rationale, especially in view of recent findings concerning the mechanisms of MTX resistance and LV rescue. Experimentally, cells resistant to MTX because of an increased or altered DHFR, decreased metabolism to polyglutamates, or decreased thymidylate synthase activity are not always significantly more sensitive to higher concentrations of MTX. Furthermore, recent studies on human small cell lung cancer cell lines suggest that decreased MTX polyglutamate metabolism and thymidylate synthase activity might be prevalent MTX-resistant mechanisms in human tumors. Selective LV rescue could also occur through mechanisms other than selective uptake by normal tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biological Transport; Biotransformation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Folic Acid; Humans; Leucovorin; Methotrexate; Neoplasms; Polyglutamic Acid; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase

Thirty-six children and adolescents received 42-h methotrexate (MTX) infusions in doses of 5.5-22 g/m2 as a single drug or as part of a combination chemotherapy for relapsed childhood leukemias or solid tumors. In a total of 109 courses serum MTX concentrations were maintained at 2 x 10(-5) -2 x 10(-4) M for 42 h before leukovorin rescue was started. There were responses in one of two hemangiopericytomas, two of five Ewing's sarcomas, and six of eight rhabdomyosarcomas. In ALL, NHL, and neuroblastomas, responses were seen with 42-h MTX infusions as part of a combination chemotherapy. The major toxicities were mucositis in 45%, nausea and vomiting in 35%, and hepatic toxicity in 25% of the courses. Bone marrow depression as well as neuro- and nephrotoxicity were rare. Long-term MTX infusions in high doses are strongly recommended for the treatment of relapsed childhood malignancies because of their efficacy and mild toxicity.

Topics: Adolescent; Adult; Child; Child, Preschool; Combined Modality Therapy; Drug Evaluation; Humans; Infusions, Intravenous; Leucovorin; Methotrexate; Neoplasm Recurrence, Local; Neoplasms

A reversed-phase HPLC method is described for the simultaneous determination of folinic acid, MTX, and their plasma metabolites 5-CH3-FH4 and 7-OH-MTX respectively. In addition, this technique allows the separation of FA another naturally occurring folate, and of AMT, used as internal standard. Separation of these compounds was achieved on a Waters Spherical C18 column at a flow rate of 0.8 ml.min-1. Elution was carried out with 0.1 M sodium acetate buffer (pH 5.5) as solvent A and 7.5% acetonitrile 92.5% bidistilled water as solvent B. UV detection was performed at 280 nm. This method was applied in a pharmacokinetic study of folinic acid and its plasma metabolite 5-CH3-FH4 following two different protocols: (1) i.v. bolus injection of 50 mg calcium folinate in six healthy volunteers and (2) simultaneous i.v. bolus injections of 50 mg/m2 MTX and 50 mg/m2 folinic acid in four cancer patients. Mean apparent half-life values for folinic acid and its metabolite were 7.02 +/- 1.81 h and 3.90 +/- 0.86 respectively in the first protocol, 4.80 +/- 1.48 h and 4.74 +/- 1.47 h in the second protocol. MTX and 7-OH-MTX were also quantified in the second protocol and were found not to affect the pharmacokinetics of folinic acid and 5-CH3-FH4. Since in vitro studies on metabolism of folinic acid might be of great interest in trying to assess the mechanism of action of the folates and the potential interaction of MTX and 7-OH-MTX in this mechanism via the metabolism, the chromatographic method we describe here has been adapted for the separation of all the potential intracellular monoglutamyl metabolites of folinic acid.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Female; Half-Life; Humans; Kinetics; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms; Tetrahydrofolates

This paper reports experience with high-dose folinic acid (HDFA) and 5-fluorouracil (5-FU) in the treatment of 130 patients with various types of tumor. While the objective results obtained from gastrointestinal malignancies (response rate = 15%) are no better than those usually gained by 5-FU alone, impressive results were achieved in patients with advanced and mainly pretreated breast cancer (response rate = 44%). Haematological toxicity was generally mild, while oral mucositis, diarrhoea and conjunctivitis were major side effects. Our data suggest that HDFA and 5-FU seem a very promising combination and warrant further investigation.

Topics: Adult; Aged; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasms

We have treated eight patients with various tumours producing hCG or AFP with the high risk gestational choriocarcinoma regimen EMA/CO. Marker response was seen in two of three tumours producing AFP and in all of five tumours producing hCG. Three further patients were treated with EpPt/OMB, a regimen used in relapsed germ cell tumors. All responded biochemically. All complete biochemical responses were accompanied by anatomical response. These responses may reflect particular sensitivity in the marker producing tumours and marker measurements would identify this subgroup. These findings do not preclude the possibility that these cytotoxic regimens may have activity against a wide range of solid tumours.

Topics: alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Chorionic Gonadotropin; Cisplatin; Dactinomycin; Doxorubicin; Etoposide; Hormones, Ectopic; Humans; Leucovorin; Methotrexate; Neoplasms; Vincristine

Topics: Anesthesia, General; Child; Child, Preschool; Drug Interactions; Humans; Leucovorin; Methotrexate; Neoplasms; Nitrous Oxide

A Phase I trial of intraperitoneally administered 5-FU and citrovorum factor was performed in eight patients with a variety of malignancies. Both drugs were given according to a single weekly dose schedule in a volume estimated to be 2000 cc, including residual ascites. Citrovorum factor 50 mg was given first, immediately followed by 5-FU 1000-3400 mg, according to a dose-escalating schedule. Myelosuppression proved to be the dose-limiting toxicity, though mucositis, diarrhea, nausea, and abdominal pain were also produced. Six patients failed to respond to therapy. One patient with malignant mesothelioma showed a significant decrease in the production of malignant ascites and a transient conversion of peritoneal fluid cytologies from positive to negative, while a second patient with pancreatic cancer showed conversion of peritoneal fluid cytologies from positive to negative and demonstrated an objective partial response of an hepatic metastasis. Dosage adjustment according to body surface area would seem indicated by the toxicity data, with a 5-FU dose of 1200 mg/m2 body surface area and citrovorum factor 50 mg/m2 being recommended for Phase II trials of this combination of drugs given according to this weekly schedule.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Evaluation; Fluorouracil; Humans; Injections, Intraperitoneal; Leucovorin; Neoplasms

Topics: Biotransformation; Chromatography, High Pressure Liquid; Humans; Infusions, Intravenous; Leucovorin; Liver; Methotrexate; Microbial Sensitivity Tests; Neoplasms; Oxidation-Reduction

High dose administration of anticancer drugs was discussed putting an emphasis on methotrexate and cytosine arabinoside. High dose methotrexate in combination with leucovorin rescue was effective on various kinds of cancer which had become resistant to conventional doses of anti-cancer drugs. The administration of high-dose methotrexate, however, should be performed with meticulous precautions to prevent serious side effects. Side effects included gastrointestinal mucositis, hepatic dysfunction, nausea and vomiting. Central nervous system manifestations were sometimes observed. High-dose cytosine arabinoside of 3 g/m2 per 12 hours X 12 was given by 2-hours infusion to patients with acute leukemia who had become resistant to conventional combination chemotherapy, or to relapsed patients. This regimen in combination with L-asparaginase or anthracyclines resulted in a fairly high remission rate among those intractable cases. High-dose cytosine arabinoside in combination with anthracyclines has recently been tried on patients with acute leukemia as an initial treatment for remission induction and consolidation. In this case, no intensification treatment was performed to maintain remission. Patients treated with this regimen as an initial medication showed a high remission induction rate and long remission duration. Forty percent of the patients were still alive after 3 years.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Humans; Infusions, Parenteral; Leucovorin; Leukemia; Methotrexate; Neoplasms

Clinical toxicities and pharmacokinetics of methotrexate (MTX), associated with reduced citrovorum factor (CF) neutralization, were studied on 279 infusions in 25 children with various malignancies. MTX, at 1000-8400 mg/m2, was infused during six to 24 hours with multiple schedules of reduced CF rescue. Plasma MTX levels ranged from 7.0 X 10(-5) to 7.0 X 10(-4) M during MTX infusion. The levels declined rapidly with a two-phase elimination pattern (t1/2 = 1.2-2.5 hours, t1/2 = 18-32 hours). The folate level in the plasma ranged from 5 X 10(-7) M to 1.4 X 10(-6) M when CF was administered every six hours or every three hours, respectively. Limited bone marrow suppression was seen in only seven percent of infusions, with moderate elevation of GOT and GPT in 20% of infusions, and stomatitis in only 2.6% of infusions, despite reduction in the total dose of CF from 225 mg to 105 mg and despite delaying CF initiation from nine hours to thirty-six hours after the start of MTX infusion.

Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Bone Marrow; Child; Child, Preschool; Drug Therapy, Combination; Female; Folic Acid; Humans; Infusions, Parenteral; Leucovorin; Leukocyte Count; Male; Methotrexate; Neoplasms; Time Factors

Bleeding symptoms complicating HDMTX and CFR therapy have been reported, Thrombocytopenia and disturbed plasmatic coagulation could not explain all bleeding episodes. Platelet function had not been investigated in HDMTX and CFR treatment so far. In vitro tests showed a dose-dependent inhibition of platelet aggregation post incubation with MTX. Platelet factor 3 availability was decreased as well. Ex vivo investigations in 10 children undergoing HDMTX and CFR treatment (6 or 12 g/m2) showed impaired platelet factor 3 release whereas aggregation tests were normal. No severe platelet function disturbances could be seen under HDMTX with CFR treatment. However, platelet function should be tested in cases of unexplained bleeding tendency under HDMTX/CFR treatment, since the impairment of platelet function observed in vitro might become relevant in the individual condition.

Topics: Adult; Blood Coagulation; Blood Platelets; Depression, Chemical; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms; Platelet Aggregation; Platelet Factor 3

Biochemical investigations show a decreased bioavailability of 5-methyl-tetrahydrofolic acid in vitamin B12 deficient human cell cultures and bone marrow cells. Tetrahydrofolic acid cannot be liberated from its storage form. This so-called methyl-folate-trap results in a functional folic acid deficiency which is the pathogenetic principle of the defect in the cell proliferation in patients with vitamin B12 deficiency. This knowledge of biochemical mechanisms leads to the identification of rare disorders in the metabolism of vitamin B12 and folic acid. After methotrexate treatment a rescue effect with its antidote Leucovorin can only be achieved, if the ratio antidote: methotrexate is at least 10:1. This ratio is important in cell cultures as well as in bone marrow cells in vivo. The results lead to a formula for the calculation of the optimal dosis to reach a secure rescue for individual patients after high-dose methotrexate treatment. This makes the high-dose methotrexate regimen a treatment modality for malignant tumors without any side effects.

Topics: DNA; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Methotrexate; Neoplasms; Vitamin B 12; Vitamin B 12 Deficiency

Although clinical trials of high-dose methotrexate (MTX) sequenced before 5-fluorouracil (FUra) with leucovorin (LV) rescue apparently have resulted in increased numbers of tumor responses, this increased antitumor activity often has been accompanied with toxicity. The present report describes an attempt to improve therapeutic results with this drug combination by appropriate metabolic modulation in the preclinical BALB/c X DBA/8 F1 murine breast tumor model. A LV rescue schedule consisting of 300 mg/kg administered at 4.5 and 19.5 hr after high-dose MTX (300 mg/kg/week for 3 weeks) prevented MTX toxicity. When FUra was administered 2.5 hr after MTX (with LV rescue), the dose of FUra had to be decreased, and we could not obtain convincing evidence for a differential cytotoxic effect on tumor versus normal host tissue. However, when a delayed uridine rescue schedule was added to protect the host from the toxic activity of FUra, the FUra dose could be increased even in the presence of high-dose MTX, and the therapeutic result was enhanced significantly without an increase in host toxicity. Finally, it was possible to add N-phosphonacetyl-L-aspartate to this drug combination (in the appropriate sequence: N-phosphonacetyl-L-aspartate before high-dose MTX-before high-dose FUra, followed by double rescue with LV and uridine) without producing increased toxicity to yield a significant increase in partial tumor regression rate. The biochemical rationale for the selection and sequence of administration of these agents is discussed.

Topics: Animals; Antineoplastic Agents; Aspartic Acid; Drug Therapy, Combination; Female; Fluorouracil; Leucovorin; Male; Methotrexate; Mice; Neoplasms; Organophosphorus Compounds; Phosphonoacetic Acid; Uridine

Four separate groups of patients have been studied: (1) The effect of high-dose methotrexate (MTX) administration on glomerular filtration rate was determined by pre- and posttreatment inulin and creatinine clearances in nine patients. Measurements were made prior to and 24-40 hr after drug administration. Inulin and creatinine clearances both decreased a mean of 43%. No signs of systemic toxicity occurred. (2) Three other patients given high-dose courses of MTX developed MTX toxicity. Their creatinine clearance decreased an average of 61%. (3) In a separate group of five patients undergoing weekly MTX treatment, comparison of serum MTX pharmacokinetics with and without alkalinization of the urine demonstrated no significant difference in peak serum MTX levels or serum MTX decay. (4) Eight additional patients with severe renal dysfunction secondary to MTX were treated with increased doses of leucovorin and a continuous infusion of thymidine (8 g/m2/day) once renal failure was recognized. When high-dose leucovorin and thymidine were begun 48-72 hr after the MTX infusion, severe toxicity in the form of leukopenia, thrombocytopenia, diffuse mucositis, stomatitis, or skin rash was averted. We concluded the following: (1) high-dose MTX causes a subclinical decrease in glomerular filtration rate with each administration, even in nontoxic courses; (2) alkalinization of the urine with sodium bicarbonate does not alter plasma MTX decay, while volume expansion (hydration) is maintained constant; and (3) rigorous monitoring of serum creatinine and serum MTX levels 24-48 hr after MTX administration allows for the institution of rescue measures, including leucovorin and thymidine, which will abort the systemic toxicity that accompanies MTX-induced renal failure.

Topics: Adolescent; Adult; Child; Creatinine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Inulin; Kidney Diseases; Kinetics; Leucovorin; Methotrexate; Neoplasms; Thymidine

Topics: Animals; Chemical Phenomena; Chemistry; Goats; Haptens; Humans; Leucovorin; Methotrexate; Neoplasms; Rabbits; Radioimmunoassay; Sheep; Tetrahydrofolates

Topics: Adult; Aged; Bone Marrow; Drug Therapy, Combination; Female; Fluorouracil; Half-Life; Humans; Kinetics; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms

A total of 15 patients with advanced neoplastic disease, 13 with different solid tumors, one with lymphoma, and one with acute lymphocytic leukemia, underwent treatment consisting of continuous infusion of methotrexate (2 g/sq m/day) with concomitant thymidine (8 g/sq m/day) and leucovorin (1 mg/sq m/day). The dose of methotrexate was increased progressively by lengthening the methotrexate infusion from 2 to 7 days. After cessation of methotrexate infusion, thymidine and leucovorin were continued until the plasma level of methotrexate decreased to 2 X 10(-8) M. Toxicity was mucositis (23 of 27 evaluable courses), leukopenia (15 of 26 evaluable courses), thrombocytopenia (10 of 26 evaluable courses), renal and hepatic toxicity and diarrhea. Plateau levels of plasma methotrexate or methotrexate plasma half-life did not correlate with toxicity.

Topics: Adult; Aged; Drug Evaluation; Female; Humans; Kinetics; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms; Thymidine

Topics: Adult; Aged; Altretamine; Antineoplastic Agents; Cell Adhesion; Drug Therapy, Combination; Fluorouracil; Humans; Immunity, Cellular; Indomethacin; Leucovorin; Lymphocyte Activation; Methotrexate; Middle Aged; Mitomycins; Monocytes; Neoplasms; Phytohemagglutinins; T-Lymphocytes, Regulatory; Time Factors

18 patients with malignant effusions were treated with continuous intraperitoneal, intrapleural, or intrapericardial infusion of methotrexate (MTX) 30 mg/m2 per d combined with simultaneous intravenous administration of leucovorin at a dose rate calculated to yield an equimolar concentration in the serum. In the serum the geometric mean steady-state MTX concentration was 0.95 microM, whereas it was 24 microM in the peritoneal, 213 microM in the pleural, and 434 microM in the pericardial cavities. Mean clearance was 6.6 ml/min from the peritoneal cavity, 2.6 ml/min from the pleural cavity, and 0.14 ml/min from the pericardial cavity. Leucovorin provided sufficient protection to allow the duration of infusion to be escalated from 24 to 120 h before myelosuppression was encountered. Marrow thymidylate synthetase activity was inhibited by an average of 46% compared to 86% inhibition in malignant cells in the effusions. Flow cytometric analysis showed no perturbation of the cell cycle phase distribution of marrow cells. All eight of the evaluable patients have responded: three received no other form of therapy, five also received systemic hormonal or chemotherapy. This study demonstrated that tumors confined to third space body fluids can be given very high concentration x time exposures to MTX with minimal systemic toxicity.

Topics: Drug Therapy, Combination; Exudates and Transudates; Female; Humans; Infusions, Parenteral; Kinetics; Leucovorin; Methotrexate; Neoplasms

Escalating doses of DDMP (metoprine) (15-280 mg/m2) were administered as single oral doses 24 h before a fixed leucovorin (CF) rescue (15 mg IM every 6 h for 72 h). CNS toxicity was dose-limiting and cumulative when the drug was given more frequently than at 3-week intervals. DDMP has a very long half-life (150 h) and is extensively bound to serum proteins (88%). It diffuses into the CSF and concentrates in brain tumours and normal brain tissue (brainserum ratio 3.8-5.3). DDMP is a potentially useful drug against brain tumors. Tumor regressions were seen in two patients with epidermoid carcinomas.

Topics: Antineoplastic Agents; Drug Evaluation; Humans; Kinetics; Leucovorin; Neoplasms; Protein Binding; Pyrimethamine

DDMP, a 2-4 diaminopyrimidine folate antagonist was administered PO once every 3 weeks at a fixed dose level (90 mg/m2), 24 h before a single IM injection of folinic acid (CF), to 77 patients with advanced solid tumors. CF doses were escalated in sequential sets of patients from 9-108 mg/m2. Therapeutic activity was documented against epidermoid tumors of head and neck and lung only at the lower CF doses (9 and 15 mg/m2). Increasing CF resulted in the absence of hematologic toxicity and therapeutic activity. There was no evidence of selective bone marrow protection in this clinical study.

Topics: Antineoplastic Agents; Bone Marrow Diseases; Drug Evaluation; Humans; Leucovorin; Neoplasms; Pyrimethamine

Topics: Adolescent; Adult; Aged; Child; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms

Topics: Antineoplastic Agents; Bone Marrow Diseases; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leucovorin; Neoplasms; Pyrimethamine

Topics: Cisplatin; Humans; Leucovorin; Methotrexate; Neoplasms

Topics: Adolescent; Adult; Animals; Child; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasms; Rabbits

Methotrexate (MTX) in high doses (3 to 7.5 g/m2) with leucovorin rescue (HDMTX-LCV) can be delivered on a weekly basis in a setting of proper pharmacologic monitoring. Myelosuppression occurs in 28 per cent of the patients and in 8 per cent of the courses and usually results from delayed MTX excretion secondary to mild reversible nephrotoxicity. The incidence of tumor regression was 50 per cent in head and neck cancer; 59 per cent in non-Hodgkin's lymphoma; 40 per cent in small cell lung cancer; 24 to 50 per cent in breast cancer and 50 per cent in osteogenic carcinoma, for an over-all response rate of 39 per cent (70 of 178) in patients with disseminated cancer. HDMTX-LCV is not recommended for the conventional treatment of metastatic cancer because of the potential for toxicity and the fact that the response rates cited are probably not superior to those which can be achieved by conventional doses of MTX. However, the relative lack of myelosuppression and mucositis, when compared to conventional unrescued MTS, and the achievement of therapeutic concentrations of MTX in the central nervous system with the HDMTX-LCV program have led to its incorporation into clinical trials of combination chemotherapy.

Topics: Adult; Bone Marrow; Bone Neoplasms; Breast Neoplasms; Drug Administration Schedule; Female; Gastrointestinal Neoplasms; Head and Neck Neoplasms; Humans; Kidney; Leucovorin; Lung Neoplasms; Lymphoma; Methotrexate; Neoplasms; Urogenital Neoplasms

Topics: Humans; Leucovorin; Methods; Methotrexate; Neoplasms

High-dose methotrexate/Leucovorin rescue therapy is based on the assumption of differences in the transport system for folate compounds between normal and malignant proliferating cells. Thus, under normal conditions, methotrexate (MTX) and Leucovorin (citrovorum factor, CF) in low doses can enter the cells by an active transport system, whereas in some malignancies - such as osteosarcoma - these substances only penetrate through the cell membrane by passive diffusion if they are given in very high doses. Therefore, after high-dose MTX treatment, the cytotoxic effect of the folate antagonist is compensated for by rescue with Leucovorin in low doses only in the normal cell system. The consequence of this kind of treatment is a selective antitumor effect. To avoid cytotoxic side effects, this therapeutic regimen must be monitored carefully. The decrease of the ratio of 3H-deoxyuridine (dUR) beta H-thymidine (dTR) incorporation into the DNA of the cells is a good biochemical parameter for estimating the MTX effect on rapidly proliferating cell systems. Using this indicator, it was shown that the usually administered dose of Leucovorin is not sufficient for an effective rescue of the bone marrow cells as long as the MTX serum concentration is equal or higher than 10(-6) M. If in critical cases the MTX elimination is retarded, a rescue can only be achieved by Leucovorin at doses tenfold higher than the actual amount of MTX in the whole body system. The Leucovorin rescue does under such circumstances can be calculated according to the formula Leucovorin (mg) = 10 x MTX (mg/l) x 0.76 x body weight (kg).

Topics: Bone Marrow; Bone Marrow Cells; Deoxyuridine; DNA; Humans; Leucovorin; Methotrexate; Neoplasms; Thymidine; Thymidine Kinase

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Child; Drug Evaluation; Drug Therapy, Combination; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Leucovorin; Leukocyte Count; Melanoma; Neoplasms; Platelet Count; Pyrimethamine; Sarcoma

Topics: Animals; Antineoplastic Agents; Carboxypeptidases; Drug Resistance; Drug Therapy, Combination; Fluorouracil; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Neoplasms; Uracil Nucleotides

Topics: Adolescent; Ambulatory Care; Day Care, Medical; Hospitals, Special; Humans; Leucovorin; Methotrexate; Neoplasms; New York City; Professional-Patient Relations

The cytokinetics of marrow recovery were compared in patients receiving a standard exposure to high-dose methotrexate followed by either thymidine rescue, leucovorin rescue at the doses used in most clinical protocols (10 mg/sq m every 6 hr), or leucovorin rescue at a 5-fold higher dose rate (50 mg/sq m every 6 hr). Thymidine rescue initiated a prompt recovery of DNA synthesis, as detected by [3H]deoxycytidine incorporation, and progression of cells through the cell cycle monitored by flow cytometry, even in the presence of methotrexate levels that prevented initiation of rescue by the lower doses of leucovorin. Dose dependency for leucovorin in vivo in humans was suggested by the observation that the higher leucovorin dose rate was successful in initiating recue within the first 24 hr, whereas the lower dose was not. Recovery of DNA synthesis is more rapid and/or complete with thymidine rescue than with either dose of leucovorin. Thymidine rescue was accomplished without requirement for purines over and above those present in plasma. These results suggest that the kinetics of marrow recovery is quite different for thymidine and leucovorin rescue.

Topics: Bone Marrow; Cell Cycle; DNA, Neoplasm; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms; Thymidine

Topics: Adult; Aged; Bone Marrow; Drug Evaluation; Drug Therapy, Combination; Female; Half-Life; Humans; Infusions, Parenteral; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms; Stomatitis

High dose methotrexate followed by citrovorum factor reversal has been utilized in twenty-six patients with advanced cancer. Four of 10 patients with head and neck cancer had an objective response. One of 7 patients with metastatic osteosarcoma to the lungs had stabilization with twenty treatments over 23 months. One patient with acute lymphocytic leukemia developed marrow aplasia but did not attain remission. The regimen was well tolerated when meticulous attention was paid to hydration, urine alkalinization, renal function and third space fluid accumulation. Life-threatening or lethal toxicity was encountered when these phenomena were not scrupulously observed.

Topics: Adolescent; Adult; Aged; Female; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Middle Aged; Neoplasms; Osteosarcoma

High-dose methotrexate was administered by constant infusion over 24 h to children with various malignancies. Citrovorum factor was given at the completion of methotrexate infusion and continued for 72 h. Serum concentration of 10(-4) M could be sustained for 24 h with doses of methotrexate over 100 mg/kg. This infusion regimen was well tolerated and only mild neutropenia and mouth sores were seen in most patients. Severe toxicity was seen in one patient and was related to prolonged retention of methotrexate in the circulation. Careful monitoring of serum drug level is mandatory in the use of any high-dose methotrexate regimen.

Topics: Adolescent; Adult; Child; Child, Preschool; Creatinine; Humans; Infant; Infusions, Parenteral; Kinetics; Leucovorin; Liver; Methotrexate; Neoplasms; Time Factors

Topics: Body Fluids; Folic Acid; Humans; Leucovorin; Methods; Methotrexate; Neoplasms; Tetrahydrofolate Dehydrogenase

Topics: Adolescent; Adult; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasms

We used MTX as single drug treatment on the basis of an incremental dosage schedule, with doses increased from 250 mg/m2 to 750 mg/m2 or from 5 to 10 g, at intervals of 10 days. Moderately high MTX doses (750 mg/m2 at most) plus citrovorum factor rescue, failed to result in objective tumor regression in all of the 18 patients thus treated. High-dose MTX with CF rescue, by contrast, was found to produce partial remissions in 3 of the 19 cases treated thus far. Meticulous clinical monitoring and MTX serum level determinations are imperative for minimizing complications, if this drastic treatment regimen is employed.

Topics: Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms

During 1972-1976, when the incidence of cancer rose only slightly in the United Kingdom and the number of cancer patients seen at a large metropolitan teaching hospital and oncological centre remained largely unchanged, the use of cytotoxic drugs rose from 5.1% to 14% of the hospital's total drug budget. Most of the rise in cost can be ascribed to the increased use and increased unit cost of four effective but expensive drugs. Although the cost of drugs is but a small proportion of the cost of care of the cancer patient, it is argued that cytotoxic chemotherapy cannot offer a "cheap alternative" to surgery and radiotherapy. In a health service with cash spending limits the use of the more expensive cytotoxic drugs should be limited to the treatment of patients in whom "cure" or long-term ablation of disease is being attempted or to protocol studies in which their effectiveness is compared with that of other, possibly less expensive, drugs. Further studies are required of the use of the less expensive cytotoxic drugs in order to maximise their usefulness in the palliative treatment of advanced disease.

Topics: Antineoplastic Agents; Bleomycin; Cancer Care Facilities; Costs and Cost Analysis; Cyclophosphamide; Doxorubicin; Hospital Bed Capacity, 500 and over; Hospitals, Special; Hospitals, Teaching; Humans; Leucovorin; London; Medication Systems, Hospital; Methotrexate; Neoplasms; Pharmacy Service, Hospital; Vincristine

Topics: Humans; Leucovorin; Methotrexate; Neoplasms

Topics: Bone Neoplasms; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms; Osteosarcoma; Vincristine

Topics: Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms

Topics: Animals; Antineoplastic Agents; Azacitidine; Bleomycin; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin; Doxorubicin; Female; Fluorouracil; Heart; Humans; Leucovorin; Lung; Male; Methotrexate; Neoplasms; Nitrosourea Compounds; Procarbazine; Triazenes; Vinblastine; Vincristine

Eighty-six adults with malignant disease were given high doses of methotrexate with folinic acid rescue, with acceptable toxicity. Protocal violations in two cases led to death. The results of therapy in some diagnostic groups are encouraging.

Topics: Adult; Carcinoma, Squamous Cell; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Lymphoma; Methotrexate; Neoplasms

Methotrexat (250-1100 mg/m2) was administered to 38 patients with malignant tumors by infusion of either 6 hours or of 75 minutes duration. MTX-infusion and continued at 3-6 hours interval for Citrovorum factor rescue was started 2 hours after 24 to 72 hours. 7 different MTX doses and rescue schedules were tested. It could be shown that MTX in the dose range used is effective in various tumors when CF-rescue is not higher than 7% of the administered MTX-dose, only occasionally therapeutic success was observed with higher doses. In the group of patients where CF-rescue was lower than 7% of the MTX dose on 9/14 patients objective tumor-regressions could be achieved. Conclusions drawn are discussed and the necessity of further investigations is emphasized.

Topics: Administration, Oral; Adult; Aged; Female; Humans; Injections, Intramuscular; Injections, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasms

Topics: Animals; Asparaginase; Breast Neoplasms; Carboxypeptidases; Child; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia; Lung Neoplasms; Lymphoma; Melanoma; Methotrexate; Neoplasms; Osteosarcoma; Tetrahydrofolates; Thymidine

A review of 498 patients treated with high-dose methotrexate (MTX) with citrovorum factor rescue revealed 29 drug-related deaths. Until the important factors in those deaths are identified, the use of high-dose MTX should be limited to institutions that possess the necessary supportive facilities and the ability to measure serum levels of the drug.

Topics: Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms; United States

To correlate the pharmacokinetics and toxicity of methotrexate, we measured the drug's clearance from plasma after 395 high-dose, six-hour infusions given to 78 patients. After 375 infusions, 48 hour methotrexate levels fell within 2 standard deviations of the mean for nontoxic infusions, and myelosuppression did not occur. Methotrexate concentrations exceeded the range for nontoxic patients (mean +/- 2 standard deviations) after 20 infusions. Serious myelosuppression occurred after six of these 20 infusions, including five of 12 infusions associated with 48-hour drug concentrations above 9 X 10(-7) M. In seven patients with 48-hour concentrations above 9 X 10(-7) M, the absence of toxicity could be attributed to subsequent rapid clearance of the drug; four of these patients also received large doses of supplemental leucovorin (50 to 100 mg per square meter every six hours). Determination of methotrexate concentration in plasma thus identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue.

Topics: Blood Cell Count; Blood Platelets; Bone Marrow; Creatinine; Humans; Infusions, Parenteral; Kidney; Leucovorin; Leukocyte Count; Methotrexate; Neoplasms; Time Factors

Topics: Bone Marrow; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Neoplasms; Pyrimethamine; Remission, Spontaneous

Topics: Adult; Glomerular Filtration Rate; Humans; Infusions, Parenteral; Kidney Glomerulus; Leucovorin; Methotrexate; Neoplasms; Time Factors

A rapid propidium iodide staining method was used for analysis of single-cell suspensions of bone marrow and tumor biopsies by flow microfluorometry. With this technique, information on the proliferative status of target tissues can be obtained within 10 min of sample removal. DNA histograms and labeling index of sequential bone marrow biopsies from a patient with Stage IV diffuse lymphocytic leukemia and treated with 1-beta-D-arabinofuranosylcytosine infusion showed pronounced reduction in the percentage of cycling cells. In contrast, sequential tumor biopsies from a melanoma patient on methotrexate-citrovorum factor rescue therapy showed no changes. In sequential bone marrow biopsies of 3 patients on high-dose methotrexate-citrovorum factor rescue, initial accumulation of cells in G1-S (Day 1) was followed by a significant proliferative response (Days 4 to 7) and return to pretherapy values. In contrast, no recovery similar to that of the bone marrow was seen in tumor cells.

Topics: Antineoplastic Agents; Bone Marrow Cells; Cell Division; Cytarabine; Ethidium; Fluorometry; Humans; Leucovorin; Leukemia, Lymphoid; Melanoma; Methotrexate; Neoplasms; Staining and Labeling

Topics: Female; Humans; Leucovorin; Methotrexate; Neoplasms; Skin Diseases; Sunburn

In clinical studies performed during 111 infusions of high dose methotrexate (MTX) we have evolved a clinical and laboratory protocol which permits such therapy without prohibitive risk to the patient. The plasma MTX data obtained indicate that pharmacokinetic disposition is dose related during these infusions and that such data are useful in identifying patients at risk from serious toxicity.

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Drug Therapy, Combination; Humans; Leucovorin; Melanoma; Methotrexate; Middle Aged; Neoplasms; Sarcoma; Soft Tissue Neoplasms

Most chemotherapeutic agents utilized in the treatment of cancer have toxic effects, not only on tumor cells but also on the normal replicating cells of the body. Some of these toxic effects on the normal tissues by the drug may be diminished, or more promising is the utilization of more selective drugs based on differences between the normal and the neoplastic cell.

Topics: Drug Evaluation; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Neoplasms

Methodichlorophen was given to 26 patients with terminal malignant disease. Eight patients received adequate doses, and five of them showed objective evidence of tumour regression while three failed to respond. Those who responded included four out of five patients with lung cancer (three with squamous-cell carcinoma and one with oat-cell carcinoma) and a patient with hypernephroma. Two patients with testicular teratomas and one with acute myeloid leukemia failed to respond. The drug may be given safely by mouth to outpatients if certain precautions are taken.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Bone Marrow Diseases; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chlorobenzenes; Drug Therapy, Combination; Erythema; Headache; Humans; Kidney Neoplasms; Leucovorin; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pyrimethamine; Pyrimidines; Teratoma; Testicular Neoplasms

Topics: Adult; Animals; Biological Transport; Bone Marrow; Creatinine; DNA, Neoplasm; Doxorubicin; Drug Therapy, Combination; Humans; Kidney; Leucovorin; Leukemia L1210; Lung Neoplasms; Methotrexate; Mice; Neoplasm Metastasis; Neoplasms; Osteosarcoma; Purines; Thymidine; Thymine Nucleotides

Topics: Adult; Aged; Blood Cells; Cobalt Radioisotopes; Humans; Leucovorin; Methotrexate; Middle Aged; Mouth; Neoplasms; Radioisotope Teletherapy

Topics: Adolescent; Age Factors; Aspartate Aminotransferases; Child; Child, Preschool; Female; Half-Life; Hematopoiesis; Humans; Kidney; Leucovorin; Liposarcoma; Methotrexate; Neoplasm Metastasis; Neoplasms; Osteosarcoma; Ovarian Neoplasms; Rhabdomyosarcoma; Sarcoma, Ewing; Teratoma

Topics: Animals; Antibody Specificity; Antigen-Antibody Complex; Dialysis; Goats; Hemocyanins; Humans; Leucovorin; Methotrexate; Neoplasms; Rabbits; Radioimmunoassay; Time Factors; Tritium

Topics: Alkaloids; Alkylating Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Binding Sites; Cytarabine; Drug Synergism; Enzyme Therapy; Folic Acid Antagonists; Humans; Hydroxyurea; Leucovorin; Mechlorethamine; Mercaptopurine; Methotrexate; Mitomycins; Neoplasms; Nucleic Acids; Purines; Pyrimidines; Steroids; Thioguanine; Vinblastine; Vincristine

Topics: Anti-Bacterial Agents; Cerebrospinal Fluid; Drug Combinations; Fluorescent Antibody Technique; Hemagglutination Tests; Humans; Immunosuppressive Agents; Leucovorin; Neoplasms; Pneumonia, Pneumocystis; Pyrimethamine; Sulfadiazine; Toxoplasma; Toxoplasmosis

Topics: Administration, Oral; Adult; Aged; Carbon Isotopes; Chromatography, Ion Exchange; Female; Folic Acid Antagonists; Humans; Injections, Intramuscular; Injections, Intravenous; Intestinal Absorption; Leucovorin; Male; Middle Aged; Neoplasms; Tritium

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Division; Choriocarcinoma; Chorionic Gonadotropin; Dactinomycin; Drug Resistance; Drug Therapy, Combination; Female; Folic Acid Antagonists; Humans; Kinetics; Leucovorin; Methotrexate; Mice; Mitosis; Neoplasm Metastasis; Neoplasms; Pregnancy; Trophoblastic Neoplasms; Vinblastine

Topics: Antidotes; Female; Hodgkin Disease; Humans; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Neoplasms

Topics: Breast Neoplasms; Choriocarcinoma; Female; Head; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Pregnancy; Remission, Spontaneous; Uterine Cervical Neoplasms

Topics: Acute Disease; Drug Synergism; Humans; Injections, Intravenous; Leucovorin; Leukemia; Methotrexate; Neoplasms

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Catheterization; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Fluorouracil; Follow-Up Studies; Head; Head and Neck Neoplasms; Humans; Injections, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Mechlorethamine; Methotrexate; Neoplasms; Pelvic Neoplasms; Thoracic Neoplasms

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Jaw Neoplasms; Laryngeal Neoplasms; Leucovorin; Leukopenia; Male; Methotrexate; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Neoplasms; Paranasal Sinus Neoplasms; Pharyngeal Neoplasms; Salivary Glands; Thrombocytopenia; Tongue Neoplasms; Tonsillar Neoplasms

Topics: Antineoplastic Agents; Blood Cell Count; Chemotherapy, Cancer, Regional Perfusion; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Neoplasms

Topics: Animals; Antineoplastic Agents; Brain; Brain Neoplasms; Carotid Arteries; Catheterization; Cattle; Cerebral Angiography; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy; Leucovorin; Methotrexate; Neoplasms

Topics: Animals; Cyclophosphamide; Fluorouracil; Leucovorin; Methotrexate; Neoplasms; Rats; Wound Healing

Topics: Antimetabolites; Antineoplastic Agents; Bone Marrow; Carcinoma, Bronchogenic; Humans; Infusions, Intra-Arterial; Injections, Intra-Arterial; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Mouth Neoplasms; Neoplasms; Pelvic Neoplasms; Radiography; Tongue Neoplasms; Tonsillar Neoplasms

Topics: Blood Platelet Disorders; FIGLU Test; Histidine; Humans; Infusions, Intra-Arterial; Injections; Injections, Intra-Arterial; Leucovorin; Methotrexate; Neoplasms; Pathology; Perfusion; Thrombocytosis; Toxicology

Topics: Administration, Topical; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Humans; Injections, Intra-Arterial; Leucovorin; Mitomycin; Mitomycins; Neoplasms; Thymidine; Tritium

Topics: Carcinoma; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Geriatrics; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Laryngeal Neoplasms; Leucovorin; Maxillary Neoplasms; Methotrexate; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasms; Orbital Neoplasms; Palatal Neoplasms; Temporal Arteries; Tongue Neoplasms; Toxicology

Topics: Floxuridine; Geriatrics; Hemiplegia; Hemorrhage; Infusions, Intra-Arterial; Infusions, Parenteral; Leucovorin; Mechlorethamine; Methotrexate; Mortality; Neoplasms; Thiotepa; Toxicology; United States; United States Department of Veterans Affairs

Topics: Catheterization; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Drug Therapy; Fluorouracil; Humans; Leucovorin; Methotrexate; Neoplasms; Pelvic Neoplasms; Pelvis; Perfusion; Tourniquets

Topics: Antineoplastic Agents; Fluorouracil; Humans; Injections; Injections, Intramuscular; Leucovorin; Methotrexate; Neoplasms

Topics: Brain Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Melanoma; Methotrexate; Neoplasms; Palliative Care; Pelvic Neoplasms

Topics: Catheters; Fluorouracil; Infusions, Parenteral; Leucovorin; Methotrexate; Neoplasms; Pelvic Neoplasms; Pelvis

Topics: Folic Acid; Folic Acid Antagonists; Hyaluronoglucosaminidase; Infusions, Intra-Arterial; Leucovorin; Methotrexate; Mouth; Mucous Membrane; Neoplasms; Pharynx

Topics: Head; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Mouth Neoplasms; Neoplasms

Topics: Folic Acid; Leucovorin; Leukemia; Neoplasms; Recurrence

Topics: Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Leukemia; Neoplasms

Topics: Antimetabolites; Biochemical Phenomena; Folic Acid; Leucovorin; Leukemia; Neoplasms

Topics: Aminopterin; Animals; Antineoplastic Agents; Cobalt; Folic Acid; Folic Acid Antagonists; Leadership; Leucovorin; Mice; Neoplasms