levoleucovorin and Nervous-System-Diseases

Over the last 2 decades, the standard fluoropyrimidine-based chemotherapy backbone for metastatic colorectal cancer has been complemented by the addition of novel biological agents, achieving impressive increases in 5-year survival rates. Nonetheless, these new combinations have also entailed increases in toxicity, leading to evaluation of de-escalated chemotherapy regimens and "drug holiday" periods in attempts to reduce side effects and optimise quality of life without impairing efficacy. Here, we review the current and emerging evidence for maintenance schedules with chemotherapy and targeted agents, versus continuous treatment after induction treatment, in metastatic colorectal cancer patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; Disease Progression; Erlotinib Hydrochloride; Fluorouracil; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Maintenance Chemotherapy; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Panitumumab; Withholding Treatment

Over the past decade, a syndrome consisting of low folate values in the cerebrospinal fluid (CSF) has been described. The syndrome has been associated with both genetic and acquired conditions that affect folate transport and metabolism and can result in severe neurological disorders. There is a wide range of underlying pathophysiological mechanisms, but a common feature in most patients is a good clinical response to folate therapy, especially when the syndrome is diagnosed early. In this review, we focus our attention on the genetic diseases leading to profound cerebral folate deficiency (CFD) and review current clinical, metabolic and therapeutic approaches.

Topics: Betaine; Cerebral Cortex; Folic Acid; Folic Acid Deficiency; Genetic Predisposition to Disease; Humans; Intestinal Absorption; Leucovorin; Nervous System Diseases; Tetrahydrofolates

Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures.. We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12.. After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority).. Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Intention to Treat Analysis; Leucovorin; Male; Medication Adherence; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Young Adult

In mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer.. Patients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion.. The maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination.. This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Diarrhea; Dose-Response Relationship, Drug; Feasibility Studies; Female; Fluorouracil; Hedgehog Proteins; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Nausea; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Signal Transduction; Treatment Outcome; Veratrum Alkaloids; Vomiting

The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer. We present safety information in advance of the planned analysis of efficacy.. Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks x 26, experimental group).. Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms (15.2% and 15.0%, respectively). Six-month mortality rates were 0.96% and 0.90% for the control and experimental groups, respectively. Grade 3+ toxicities that occurred more often in the experimental arm versus control arm included hypertension (12% v 1.8%, respectively), wound complications (abdominal incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, respectively). Grade 2+ neuropathy was increased in the experimental arm versus the control arm (grade 2, 33% v 29%, respectively; grade 3, 16% v 14%, respectively; and grade 4, < 1% each). In the experimental arm versus control arm, significantly less thrombocytopenia (1.4% v 3.4%, respectively) and fewer allergic reactions (3.1% v 4.7%, respectively) were observed. Advanced age was associated with a significantly greater rate of grade 4 and 5 toxicities regardless of treatment.. Bevacizumab with modified FOLFOX6 is well tolerated in the surgical adjuvant setting in these patients. No significant increase in GI perforation, hemorrhage, arterial or venous thrombotic events, or death with the addition of bevacizumab to modified FOLFOX6 has been observed. Follow-up for potential delayed adverse effects and efficacy is ongoing.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colonic Neoplasms; Diarrhea; Disease-Free Survival; Fatigue; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Nervous System Diseases; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pain; Treatment Outcome

Oxaliplatin is effective in the treatment of metastatic colorectal cancer (MCRC) patients; however, severe neurotoxicity develops frequently. To assess the efficacy of oral glutamine for preventing neuropathy induced by oxaliplatin, a pilot study was performed. A total of 86 patients with MCRC treated at Taipei Veterans General Hospital were enrolled. Oxaliplatin (85 mg/m(2), days 1 and 15) plus weekly bolus 5-fluorouracil (5-FU; 500 mg/m(2)) and folinic acid (FA; 20 mg/m(2)) on days 1, 8, and 15 were given every 28 days as first-line treatment. Patients were randomized to receive (glutamine group; n = 42) or not receive (control group; n = 44) glutamine (15 g twice a day for seven consecutive days every 2 weeks starting on the day of oxaliplatin infusion). Efficacy of chemotherapy, neurological toxicity, and electrophysiological alterations were assessed. A lower percentage of grade 1-2 peripheral neuropathy was observed in the glutamine group (16.7% versus 38.6%) after two cycles of treatment, and a significantly lower incidence of grade 3-4 neuropathy was noted in the glutamine group after four cycles (4.8% versus 18.2%) and six cycles (11.9% versus 31.8%). By adding glutamine, interference with activities of daily living was lower (16.7% versus 40.9%), and need for oxaliplatin dose reduction was lower (7.1% versus 27.3%). There were no significant between-group differences in response to chemotherapy (52.4% versus 47.8%), electrophysiological abnormalities, grade 3-4 non-neurological toxicities (26.2% versus 22.8%), or survival. These data indi-cate that oral glutamine significantly reduces the incidence and severity of peripheral neuropathy of MCRC patients receiving oxaliplatin without affecting response to chemotherapy and survival.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Chi-Square Distribution; Colorectal Neoplasms; Female; Fluorouracil; Glutamine; Humans; Leucovorin; Male; Middle Aged; Nervous System Diseases; Neuroprotective Agents; Organoplatinum Compounds; Oxaliplatin; Pilot Projects; Treatment Outcome

Patients with metastatic colorectal cancer (MCC) usually receive FOLFOX-4, or other oxaliplatin (L-HOP)-based regimens, until the occurrence of progressive disease, with an increase in the incidence of neurotoxicity which is correlated to the cumulative dose of L-HOP. The aim of this study was to evaluate if FOLFOX-4 stop and go and capecitabine maintenance chemotherapy is associated with a low incidence of severe neurotoxicity in the treatment of MCC patients.. Thirty-three patients were treated with FOLFOX-4 (L-HOP 85 mg/m(2) day 1, leucovorin 200 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) and 22 h 600 mg/m(2) days 1 and 2, every 2 weeks). Patients who achieved objective response (OR) or stable disease (SD) then received oral capecitabine 2,500 mg/m(2) days 1-14 every 3 weeks; L-HOP was reintroduced as soon as progression occurred.. Twenty-eight of the 29 patients who achieved OR or SD then received capecitabine. FOLFOX-4 was reintroduced in 18 patients (56.2%). The median response duration (RD) was 9.2 months and median progression-free survival (PFS) was 8.6 months. Twenty-eight patients (87.5%) had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 1 patient (3.1%).. FOLFOX-4 stop and go and capecitabine maintenance chemotherapy was associated with a very low incidence of grade 3 neurotoxicity. Although the number of patients enrolled was far too low for a definite conclusion, RD and PFS were comparable to those usually reported in the treatment of MCC patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Humans; Incidence; Leucovorin; Male; Middle Aged; Neoplasm Staging; Nervous System; Nervous System Diseases; Organoplatinum Compounds; Severity of Illness Index; Treatment Outcome

Studies of bimonthly 48-hour regimens of high-dose leucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusion combined with OXaliplatin (FOLFOX) in pretreated patients with metastatic colorectal cancer suggest that oxaliplatin dose intensity is an important prognostic factor for response rate and progression-free survival (PFS). To help define the optimal dose schedule for oxaliplatin in pretreated metastatic colorectal cancer, we retrospectively analyzed data from three phase II studies using different FOLFOX regimens (FOLFOX2, 3 and 6).. Data on 126/161 patients were analyzed. FOLFOX2 included oxaliplatin 100 mg/m2; FOLFOX3, 85 mg/m2; and FOLFOX6, 100 mg/m2 (added to a simplified LV-5-FU regimen), all as two-hour infusions. A total of 47 patients received low dose intensity oxaliplatin (LDI: < or = 85 mg/m2/2 weeks) and 79 patients high dose intensity oxaliplatin (HDI: > 85 mg/m2/2 weeks).. Objective responses occurred in 31 (39%) HDI patients and 9 (19%) LDI patients (P = 0.03). Median PFS was 28 weeks, with 52% of HDI patients progression free at 6 months, and 26 weeks with 36% of LDI patients progression free at six months (P = 0.02). Increased oxaliplatin dose intensity was not associated with increased neurotoxicity or other toxicities. FOLFOX are among the most effective regimens for treating LV-5-FU-resistant metastatic colorectal cancer.. This study shows that oxaliplatin dose intensification significantly improves response rate and PFS in pretreated metastatic disease without increasing severe toxicity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Leucovorin; Life Tables; Male; Middle Aged; Neoplasm Metastasis; Nervous System Diseases; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Prognosis; Remission Induction; Retrospective Studies; Salvage Therapy; Treatment Outcome

5-Fluorouracil plus folinic acid and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic breast cancer patients. Paclitaxel and 5-fluorouracil have additive cytotoxicity in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic breast cancer. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 neutropenia requiring hospitalization; seven (4%) cycles in two patients required granulocyte colony-stimulating factor due to neutropenia; no patient required platelet transfusions. Grade 3/4 nonhematologic toxicities were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior doxorubicin exposure, 11 (58%) responded compared with nine of 15 (60%) without prior doxorubicin. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Fatigue; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mucous Membrane; Neoplasm Metastasis; Nervous System Diseases; Paclitaxel

Advanced transitional cell carcinoma (TCC) of the urothelial tract is usually fatal despite high response rates to platinum-based chemotherapy regimens. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated marked single-agent activity in TCC, and combinations of carboplatin and paclitaxel have been well tolerated in other solid tumors. Methotrexate is also active in TCC. Due to unexpectedly severe myelosuppression and mucositis when methotrexate and paclitaxel were combined, we undertook a phase I trial of paclitaxel, carboplatin, and escalating doses of methotrexate with granulocyte colony-stimulating factor and leucovorin support in advanced TCC to determine the feasibility of this combination. Nineteen previously untreated patients with locally advanced or metastatic TCC were eligible. Median age was 62 years. In sequence, paclitaxel 200 mg/m2 (3-hour infusion), carboplatin dosed to an area under the concentration-time curve of 6 mg/mL x min, and methotrexate 10 mg/m2, increasing in 10-mg/m2 increments, were administered on day 1 every 21 days. Granulocyte colony-stimulating factor 300 microg/d or 480 microg/d (in patients <60 kg or >60 kg, respectively) was administered on days 2 through 11 and leucovorin 15 mg orally every 6 hours for 3 days. At this time, the methotrexate dose has been escalated to 50 mg/m2. There were no dose-limiting toxicities in cycle 1. Sixty-eight cycles have been administered (range, one to eight cycles; median, three cycles). Significant hematologic toxicity including neutropenic sepsis (two episodes) occurred in subsequent cycles, but was infrequent. The major nonhematologic toxicity was neuropathy. Sixteen patients are evaluable for response. One patient has achieved a complete response, seven are partial responders, seven have stable disease, and one progressed on therapy. The overall response rate is 50% (95% confidence interval, 25% to 75%). The combination of paclitaxel, carboplatin, and methotrexate holds promise to be well tolerated and active in advanced TCC.

Topics: Administration, Oral; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Carcinoma, Transitional Cell; Confidence Intervals; Disease Progression; Drug Administration Schedule; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Nervous System Diseases; Neutropenia; Paclitaxel; Remission Induction; Salvage Therapy; Sepsis; Urinary Bladder Neoplasms

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: Adolescent; Adult; Aged; Agranulocytosis; Alopecia; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Drug Combinations; Female; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Nervous System Diseases; Radiography, Thoracic; Remission, Spontaneous; Vincristine

Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing.. The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin).. Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk.. Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Databases, Factual; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Logistic Models; Male; Middle Aged; Nausea; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Sex Factors; Stomatitis; Thrombocytopenia; Vomiting

Evidence suggests that lean body mass (LBM) may be useful to normalize chemotherapy doses. Data from one prospective and one retrospective study were used to determine if the highest doses of oxaliplatin/kg LBM within FOLFOX regimens would be associated with dose-limiting toxicity (DLT) in colon cancer patients. Toxicity over four cycles was graded according to NCI Common Toxicity Criteria V2 or V3 (Common Terminology Criteria for Adverse Events, National Cancer Institute, Bethesda, MD). Muscle tissue was measured by computerized tomography (CT) and used to evaluate the LBM compartment of the whole body. In prospective randomized clinical trials conducted in France (n = 58), for patients given FOLFOX-based regimens according to body surface area, values of oxaliplatin/kg LBM were highly variable, ranging from 2.55 to 6.6 mg/kg LBM. A cut point of 3.09 mg oxaliplatin/kg LBM for developing toxicity was determined by Receiver Operating Characteristic (ROC) analysis, below this value 0/17 (0.0%) of patients experienced DLT; in contrast above this value 18/41 (44.0%) of patients were dose reduced or had treatment terminated owing to toxicity (≥Grade 3 or neuropathy ≥Grade 2); for 9/41 the DLT was sensory neuropathy. These findings were validated in an independent cohort of colon cancer patients (n = 80) receiving FOLFOX regimens as part of standard care, in Canada. Low LBM is a significant predictor of toxicity and neuropathy in patients administered FOLFOX-based regimens using conventional body surface area (BSA) dosing.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Body Mass Index; Body Surface Area; Canada; Cohort Studies; Colonic Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; France; Humans; Leucovorin; Male; Middle Aged; Nervous System Diseases; Organoplatinum Compounds; Population Surveillance

Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice.. Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan-Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model.. There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68-2.41; p = 0.439).. Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This treatment should be considered regardless of patients' age alone, but consideration should be given to the capacity of patients to tolerate adverse events.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colonic Neoplasms; Digestive System Diseases; Female; Fluorouracil; Follow-Up Studies; France; Hematologic Diseases; Humans; Incidence; Leucovorin; Male; Neoplasm Staging; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate

Folate deficiency has been associated with many adverse clinical manifestations. The blood-brain barrier (BBB), formed by brain capillary endothelial cells, protects the brain from exposure to neurotoxicants. The function of BBB is modulated by multiple ABC transporters, particularly P-glycoprotein. A proton-coupled folate transporter (PCFT)-deficient mouse has been previously described as a model for systemic folate deficiency. Herein, we demonstrate that exposing mouse brain capillaries to the antiepileptic drug, valproic acid (VPA; 5 μM), significantly increased P-glycoprotein transport function in the wild-type animals. A ligand to the aryl hydrocarbon receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produced a similar induction of P-glycoprotein, which tightened the BBB, thereby increasing the neuroprotection. However, VPA- or TCDD-induced P-glycoprotein transport was blocked in the PCFT-nullizygous mice, indicating that multiple neuroprotective mechanisms are compromised under folate-deficient conditions. Brain capillaries from S-folinic acid (SFA; 40 mg/kg)-treated PCFT-nullizygous mice exhibited increased P-glycoprotein transport following VPA exposure. This suggests that SFA supplementation restored the normal BBB function. In addition, we show that tight-junction proteins are disintegrated in the PCFT mutant mice. Taken together, these findings strongly suggest that folate deficiency disrupts the BBB function by targeting the transporter and tight junctions, which may contribute to the development of neurological disorders.

Topics: Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport, Active; Blood-Brain Barrier; Leucovorin; Mice; Mice, Mutant Strains; Nervous System Diseases; Polychlorinated Dibenzodioxins; Proton-Coupled Folate Transporter; Teratogens; Tight Junctions; Valproic Acid; Vitamin B Complex

Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S-transferase pi (GSTP1) Ile(105)Val, and glyoxylate aminotransferase (AGXT) Pro(11)Leu and AGXT Ile(340)Met.. Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment.. Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1(105)Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant (P=0.098). There were similar numbers of patients carrying at least one AGXT(105)Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P=0.725). The AGXT(11)Leu allele was not found in any of our patients or controls.. We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile(105)Val and AGXT Ile(340)Met polymorphisms. Given that no AGXT(11)Leu allele was found among our study population (n=177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Glutathione S-Transferase pi; Humans; Leucovorin; Male; Middle Aged; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Polymorphism, Genetic; Transaminases

Topics: Base Sequence; Brain; Carrier Proteins; Child, Preschool; Disease Progression; DNA Mutational Analysis; Dose-Response Relationship, Drug; Folate Receptor 1; Folate Receptors, GPI-Anchored; Humans; Leucovorin; Male; Mutation; Nervous System Diseases; Receptors, Cell Surface; RNA; Tetrahydrofolates; Treatment Outcome

This study was performed to determine the prognostic factors of 102 nonresectable locally advanced or metastatic gastric cancer patients prospectively treated with a multimodulation of 5-fluorouracil (5FU), hydroxyurea, leucovorin, and cisplatin. Response rate in 85 patients with measurable disease was 62.4% (95% confidence interval 51.9% to 72.9%). A weight increase (5% or more) was observed in 47% of patients, performance status improved in 70.6%, and symptoms disappeared in 69%. Median times for progression-free survival and overall survival were eight and 11 months, respectively. Liver metastases, more than two involved sites, and increased carcinoembryonic antigen (CEA) were found to be univariate adverse prognostic factors for survival. In a multivariate analysis, only the presence of liver metastasis was found to be an independent prognostic factor. Response rate and survival in patients with gastric linitis or diffuse forms were in the same range as in patients with intestinal forms of gastric adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Cisplatin; Disease-Free Survival; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxyurea; Karnofsky Performance Status; Kidney Diseases; Leucovorin; Life Tables; Liver Neoplasms; Male; Middle Aged; Nervous System Diseases; Prognosis; Proportional Hazards Models; Quality of Life; Risk Factors; Stomach Neoplasms; Survival Analysis; Treatment Outcome; Weight Gain

We describe a 61-year-old man with a multiple neurologic complication of Merkel cell carcinoma, a rare skin cancer. An enhancing brain mass, and cytologically proven leptomeningeal disease produced a succession of symptoms including seizures, bilateral radiculopathies, myoclonus, a cauda equina syndrome and altered mental status. Aggressive treatment prolonged his survival marginally.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Merkel Cell; Cytarabine; Fatal Outcome; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Meningeal Neoplasms; Methotrexate; Middle Aged; Nervous System Diseases; Skin Neoplasms

Temporary neurologic abnormalities were observed in one out of 23 patients undergoing chemotherapy with high-dose methotrexate (HD-MTX) for osteogenic sarcoma. This patient developed sequential symptoms including alternative hemiparesis, dysarthria and altered consciousness 5 days after the second course of HD-MTX (8 gm/m2 by 6 h continuous infusion) with leucovorin rescue. Laboratory evaluations disclosed normal electrolytes, hemograms and non-toxic serum MTX levels at the onset of the symptoms. Computed tomography of the brain was normal but electroencephalography showed focal theta and delta slow waves over the right temporal-parietal-occipital area. The neurological symptoms resolved completely within 72 h.

Topics: Adolescent; Bone Neoplasms; Dose-Response Relationship, Drug; Humans; Leucovorin; Male; Methotrexate; Nervous System Diseases; Osteosarcoma

Thirty-four symptomatic cases of inherited transcobalamin II (TCII) deficiency were analysed in order to determine the frequency and nature of neurologic manifestations. In no instance was there definite evidence of a neurologic disorder at the time of presentation as a young infant. One child of 2 1/2 years transiently lost deep tendon reflexes at a time of suboptimal treatment. A syndrome of mental retardation and other neurologic manifestations was observed in three cases, all with the following in common: (1) an extended duration of illness of 2-17 years; (2) inadequate or not treatment with Cbl; (3) treatment with folic of folinic acid. TCII deficiency rarely if ever presents with neurologic manifestations. However, neurologic disorders can be produced subsequently by improper treatment.

Topics: Central Nervous System Diseases; Folic Acid; Humans; Infant; Infant, Newborn; Intellectual Disability; Leucovorin; Nervous System Diseases; Time Factors; Transcobalamins; Vitamin B 12

Our current protocol for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to assess the efficacy of methotrexate (MTX) plus L-asparaginase and of etopisode (VP-16) plus cytarabine (ARA-C) during intensive consolidation and continuation therapies and to determine the feasibility of intensifying MTX therapy by the use of divided oral doses of MTX. The protocol was associated with unexpected acute neurotoxicity. There are few reports of such toxic effects during therapy for ALL.. This report describes these toxic effects and outlines our successful approach to the problem.. The standard four-drug induction regimen consisted of vincristine, L-asparaginase, daunorubicin, and prednisone. In consolidation therapy, oral MTX was given in divided doses (dMTX) of 25 mg/m2 every 6 hours four times daily in four weekly courses concomitant with weekly triple intrathecal therapy--MTX, ARA-C, and hydrocortisone--plus one dose of leucovorin 24 hours after triple intrathecal therapy. Consolidation treatment ended with three daily doses of intravenous VP-16 and ARA-C. The first 16 months of continuation therapy included 6-week cycles of dMTX and L-asparaginase, both given every other week for 5 weeks, with 6-mercaptopurine nightly, and then two doses of VP-16 plus ARA-C and one dose of triple intrathecal therapy.. Twenty-five of the 138 patients evaluated had acute neurotoxicity. Ten of the first 72 experienced a seizure or episode of transient neurological deficit 9-11 days following the administration of intravenous ARA-C, VP-16, and triple intrathecal therapy. Despite discontinuation of intrathecal ARA-C, which eliminated simultaneous intravenous and intrathecal treatment with ARA-C, acute neurotoxicity was observed in six previously unaffected patients and six of 42 patients treated after the elimination of intrathecal ARA-C. Therefore, as a second amendment, oral leucovorin was given 24 and 36 hours after dMTX and intrathecal MTX in continuation therapy. No acute neurotoxicity has been seen in 24 patients subsequently entered in the study.. These findings suggest that folate replacement due to administration of leucovorin modulated MTX toxicity and/or modified an interaction among VP-16, ARA-C, intrathecal therapy, and the central nervous system.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cytarabine; Etoposide; Female; Humans; Infant; Leucovorin; Male; Methotrexate; Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma

In a murine model system, folinic acid demonstrated host-protective properties during administration of repetitive and lethal doses of vincristine (VCR). Subsequently, folinic acid was evaluated in patients receiving VCR during an adjuvant chemotherapy program for stage II carcinoma of the breast. The toxicities, cumulative VCR dosage, and percentage of ideal dosage observed in 18 patients receiving folinic acid have been compared with those observed in 70 patients who previously received VCR without folinic acid in the same chemotherapy program. All patients ideally were intended to receive VCR 1.0 mg/m2 weekly for 6 weeks, with dose modification for neurotoxicity. Treatment patients received folinic acid 800 mg PO daily in three divided doses during the 6-week course. The degree of neurotoxic manifestations of VCR was similar in the treatment and comparison patients. Absent to mild neurotoxicity was observed in approximately 70% of patients in both groups; moderate or greater neurotoxicity occurred in about 30% of patients in both groups. Full dosage (6.0 mg/m2) was attained in 7 (39%) treatment patients and 17 (24%) comparison patients (P = 0.21). The mean percentage of the ideal dosage of VCR was 73.7 +/- 28.7 in patients receiving folinic acid and 76.1 +/- 20.5 in those given only VCR (P = 0.69). Hematologic toxicities were similar in both groups, but nausea occurred more frequently in the folinic acid group. Folinic acid in this dose and schedule afforded no protection from the neurotoxic side effects of VCR.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Evaluation; Female; Humans; Leucovorin; Middle Aged; Nervous System Diseases; Vincristine

Temporary neurologic abnormalities were detected in 9 of 60 patients undergoing treatment with high-dose methotrexate and citrovorum factor rescue (MTX-CF) for osteosarcoma. The incidence of abnormalities and abnormalities themselves were more severe than previously reported. This was attributed to an increased dose and more frequent administration of MTX-CF. In view of the transient nature of the abnormalities, a biochemical cause is implicated, and the mechanisms by which it may occur are discussed.

Topics: Bone Neoplasms; Child; Female; Humans; Leucovorin; Male; Methotrexate; Nervous System Diseases; Osteosarcoma

Topics: Anemia; Anemia, Pernicious; Antimetabolites; Folic Acid; Leucovorin; Nervous System Diseases