Folinic Acid Regimen Research Articles

Two nanoformulations induce reactive oxygen species and immunogenetic cell death for synergistic chemo-immunotherapy eradicating colorectal cancer and hepatocellular carcinoma

BackgroundFOLFOX is a combinational regimen of folinic acid (FnA, FOL), fluorouracil (5-Fu, F) and oxaliplatin (OxP, OX), and has been long considered as the standard treatment of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Recent developments of nano delivery systems have provided profound promise for improving anticancer efficacy and alleviating side effects of FOLFOX. Previously, a nanoformulation (termed Nano-Folox) containing OxP derivative and FnA was developed in our laboratory using nanoprecipitation technique. Nano-Folox induced OxP-mediated immunogenic cell death (ICD)-associated antitumor immunity, which significantly suppressed tumor growth in the orthotopic CRC mouse model when administrated in combination with free 5-Fu.MethodsA nanoformulation (termed Nano-FdUMP) containing FdUMP (5-Fu active metabolite) was newly developed using nanoprecipitation technique and used in combination with Nano-Folox for CRC and HCC therapies.ResultsSynergistic efficacy was achieved in orthotopic CRC and HCC mouse models. It resulted mainly from the fact that Nano-FdUMP mediated the formation of reactive oxygen species (ROS), which promoted the efficacy of ICD elicited by Nano-Folox. In addition, combination of Nano-Folox/Nano-FdUMP and anti-PD-L1 antibody significantly inhibited CRC liver metastasis, leading to long-term survival in mice.ConclusionThis study provides proof of concept that combination of two nano delivery systems can result in successful FOLFOX-associated CRC and HCC therapies. Further optimization in terms of dosing and timing will enhance clinical potential of this combination strategy for patients.Graphical abstract

Sulfadiazine plasma concentrations in women with pregnancy-acquired compared to ocular toxoplasmosis under pyrimethamine and sulfadiazine therapy: a case\u2013control study

BackgroundDosing recommendations for the treatment of pregnancy-acquired toxoplasmosis are empirical and widely based on experimental data. There are no pharmacological data on pregnant women with acute Toxoplasma gondii infection under treatment with pyrimethamine (PY) and sulfadiazine (SA) and our study intends to tighten this gap.MethodsIn this retrospective case–control study, we included 89 pregnant women with primary Toxoplasma infection (PT) treated with PY (50 mg first dose, then 25 mg/day), SA (50 mg/kg of body weight/day), and folinic acid (10–15 mg per week). These were compared to a group of 17 women with acute ocular toxoplasmosis (OT) treated with an initial PY dose of 75 mg, thereafter 25 mg twice a day but on the same SA and folinic acid regimen. The exact interval between drug intake and blood sampling and co-medication had not been recorded. Plasma levels of PY and SA were determined 14 ± 4 days after treatment initiation using liquid chromatography–mass spectrometry and compared using the Mann–Whitney U test at a p < 0.05 level.ResultsIn 23 PT patients (26%), SA levels were below 20 mg/l. Fifteen of these 23 patients (17% of all patients) in parallel presented with PY levels below 700 µg/l. Both drug concentrations differed remarkably between individuals and groups (PY: PT median 810 µg/l, 95% CI for the median [745; 917] vs. OT 1230 µg/l [780; 1890], p = 0.006; SA: PT 46.2 mg/l [39.9; 54.4] vs. OT 70.4 mg/l [52.4; 89], p = 0.015) despite an identical SA dosing scheme.ConclusionsSA plasma concentrations were found in the median 34% lower in pregnant women with PT compared to OT patients and fell below a lower reference value of 50 mg/l in a substantial portion of PT patients. The interindividual variability of plasma concentrations in combination with systematically lower drug levels and possibly a lower compliance in pregnant women may thus account for a still not yet supportable transmission risk. Systematic drug-level testing in PT under PY/SA treatment deserves to be considered.

Modified enzyme multiplied immunoassay technique of methotrexate assay to improve sensitivity and reduce cost

BackgroundMethotrexate is an important component in many chemotherapy protocols. The blood concentration of Methotrexate is used to determine the regimen of folinic acid. However, the lower limit of Siemens assay kit is 0.30 μmol/L in China. This study extended the limit from 0.3 to 0.05 μmol/L and reduced the test cost by optimizing the parameters of Enzyme Multiplied Immunoassay Technique assay.MethodsParameters of Enzyme Multiplied Immunoassay Technique assay were modified to decrease the volume of reagents A and B. Then a standard curve with a new custom set of calibrators was prepared to detect low concentration. Intra-day and inter-day imprecision were assessed by control material and samples. The linearity of the modified assay was verified by analyzing a range of quality controls with known concentration from 0.05 to 1.00 μmol/L. At last, the same samples were tested by modified Enzyme Multiplied Immunoassay Technique assay and Liquid Chromatography-tandem Mass Spectrometry assay respectively. A simple linear regression was performed to verify the validity of the modified Enzyme Multiplied Immunoassay Technique assay.ResultsIntra-day and inter-day imprecision show good reproducibility at all levels (0.05, 0.12, 0.43, 0.82 μmol/L). The linearity equation of modified assay was y = 0.9913x + 0.0046, in which y was the mean of measured concentration and x was the target concentration (R2 = 0.9994). In the range of 0.05–10.00 μmol/L, correlation between the Modified assay and Liquid Chromatography-tandem Mass Spectrometry assay was significant (r = 0.9968). In the range of 0.30–10.00 μmol/L, the correlation between modified and commercial assays was significant (r = 0.9987) as well.ConclusionsThe modified assay enhanced the sensitivity of Siemens VIVA-E to 0.05 μmol/L. In addition, the test number of a reagent Kit increased from 140 to 210. This means the cost of detection was reduced about 30%.

Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion.

5-Fluorouracil (5-FU) is a chemotherapy used in colorectal, head and neck (H&N) and other cancers. Dose adjustment is based on body surface area (BSA) but wide variations occur. Pharmacokinetic (PK) dosing is suggested to bring plasma levels into the therapeutic range to promote fewer side effects and better patient outcomes. We investigated the clinical effectiveness and cost-effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy. To systematically review the evidence on the accuracy of the My5-FU assay compared with gold standard methods [high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS)]; the effectiveness of My5-FU PK dosing compared with BSA; the effectiveness of HPLC and/or LC-MS compared with BSA; the generalisability of published My5-FU and PK studies; costs of using My5-FU; to develop a cost-effectiveness model. We searched MEDLINE, EMBASE, Science Citation Index and other databases between January and April 2014. Two reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan-Meier plots for progression-free survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a Markov model to compare My5-FU with BSA dosing which modelled PFS, OS and adverse events, using a 2-week cycle over a 20 year time horizon with a 3.5% discount rate. Health impacts were evaluated from the patient perspective, while costs were evaluated from the NHS and Personal Social Services perspective. A total of 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical effectiveness and cost-effectiveness reviews respectively. There was a high apparent correlation between My5-FU, HPLC and LC-MS/mass spectrometer but upper and lower limits of agreement were -18% to 30%. Median OS were estimated as 19.6 [95% confidence interval (CI) 17.0 to 21.0] months for PK versus 14.6 (95% CI 14.1 to 15.3) months for BSA for 5-FU+folinic acid (FA); and 27.4 (95% CI 23.2 to 38.8) months for PK versus 20.6 (95% CI 18.4 to 22.9) months for BSA for FOLFOX6 in metastatic colorectal cancer (mCRC). PK versus BSA studies were generalisable to the relevant populations. We developed cost-effectiveness models for mCRC and H&N cancer. The base case assumed a cost per My5-FU assay of £ 61.03. For mCRC for 12 cycles of a oxaliplatin in combination with 5-fluorouracil and FA (FOLFOX) regimen, there was a quality-adjusted life-year (QALY) gain of 0.599 with an incremental cost-effectiveness ratio of £ 4148 per QALY. Probabilistic and scenario analyses gave similar results. The cost-effectiveness acceptability curve showed My5-FU to be 100% cost-effective at a threshold of £ 20,000 per QALY. For H&N cancer, again, given caveats about the poor evidence base, we also estimated that My5-FU is likely to be cost-effective at a threshold of £ 20,000 per QALY. Quality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no randomised controlled trials (RCTs) using current regimens. For H&N cancer, two studies of regimens no longer in use were identified. Using a linked evidence approach, My5-FU appears to be cost-effective at a willingness to pay of £ 20,000 per QALY for both mCRC and H&N cancer. Considerable uncertainties remain about evidence quality and practical implementation. RCTs are needed of PK versus BSA dosing in relevant cancers.

Weekly methotrexate (50 mg/m 2) without dose escalation as a primary regimen for low-risk gestational trophoblastic neoplasia

Objectives The aim of this study was to compare the efficacy and toxicity of an 8-day methotrexate–folinic acid regimen and a weekly methotrexate regimen (50 mg/m 2 without dose escalation) for low-risk gestational trophoblastic neoplasia (GTN) according to the revised FIGO 2000 scoring system in a single institution. Methods Between January 1997 and June 2007, 107 patients with low-risk GTN were treated with an 8-day methotrexate–folinic acid regimen (MTX–FA group; n = 59) or a weekly methotrexate regimen (50 mg/m 2 without dose escalation) (MTX group; n = 48). The primary remission rate, change of chemotherapy because of drug resistance or toxicity, and relapse rate were compared. Results All 107 patients with low-risk GTN were cured. The primary remission rates were 69.5% and 70.8% for the MTX–FA and MTX groups, respectively ( P > 0.99). The commonly reported toxic effects in the MTX–FA and MTX groups, respectively, were as follows: hepatotoxicity (31/59 and 9/48), neutropenia (7/59 and 4/48), stomatitis (3/59 and 2/48), alopecia (2/59 and 2/48), and thrombocytopenia (2/59 and 0/48). Drug toxicity necessitating changes in chemotherapy were reported to be 13.6% (8/59) in the MTX–FA group and 2.1% (1/48) in the MTX group ( P < 0.05). The overall duration of treatment was 8.6 weeks in the MTX–FA group and 6.4 weeks in the MTX group ( P < 0.001). Conclusions The weekly methotrexate regimen was as effective as the 8-day methotrexate–folinic acid regimen for low-risk GTN. The weekly methotrexate regimen was less toxic, better tolerated, and more convenient for patients compared to the 8-day methotrexate–folinic acid regimen.

The impact of new treatment options for advanced colorectal cancer on routine care: results of a retrospective analysis of 206 consecutive patients treated in a community-based oncology group practice in Germany

Due to necessary selection criteria, the results obtained in clinical trials may not reflect the actual impact of current treatment options for unselected general populations. We analysed the treatment modalities and the outcome in 206 consecutive patients with advanced colorectal cancer who started treatment between 1/1999 and 11/2004. The median age of this cohort was 66 years (range 30-87) and 39 patients (19%) were ≥ 75 years old. First-line treatment consisted of low-dose bolus 5-fluorouracil and folinic acid regimens in 68 patients (33%), weekly 24-h 5-fluorouracil infusion and folinic acid in 36 patients (17%), weekly 24-h 5-fluorouracil infusion plus oxaliplatin or irinotecan in 60 patients (29%), capecitabine regimens in 22 patients (11%), monotherapy with oxaliplatin or irinotecan in six patients (3%) and other regimens in 14 patients (7%). A total of 166 patients (81%) received a second-line treatment and third-line chemotherapy was given to 122/206 patients (59%). With a minimum follow-up of 18 months, the median survival of the cohort is 21 months (range 1-85) and 17 months (range 3-57) for patients ≥ 75 years. We conclude that the increased survival seen in prospective studies can be transferred to routine care for unselected patients with advanced colorectal cancer.

Capecitabine, Alone and in Combination, in the Management of Patients with Colorectal Cancer

Capecitabine, an oral prodrug of fluorouracil (5FU), has shown efficacy in terms of progression-free and overall survival at least equivalent to standard folinic acid (leucovorin)-modulated intravenous 5FU bolus regimens in patients with metastatic colorectal cancer. Moreover, capecitabine has demonstrated a better tolerability profile, producing a significantly lower occurrence of severe stomatitis than 5FU plus folinic acid regimens, making this drug particularly attractive for treating elderly patients. In addition, capecitabine can be combined with other active drugs such as irinotecan or oxaliplatin. Indeed, the combination of capecitabine plus oxaliplatin (XELOX regimen) now represents a new standard of care for the metastatic disease and is also under evaluation in the adjuvant setting. The combination of new biological drugs, such as bevacizumab, with the XELOX regimen was shown to further prolong the time to progression of metastatic disease, and might reduce the risk of recurrence for those with resected colon cancer with poor risk factors. Cost-effectiveness analyses have demonstrated that, despite higher acquisition costs, capecitabine appears to be more cost effective than standard treatments for the management of colorectal cancer patients.

IFLUX for advanced bowel cancer

IFLUX, a chemotherapy regimen that combines irinotecan, 5-fl uorodeoxyuridine (FUdR), and folinic acid, might increase the median survival of patients with advanced colorectal cancer (Anticancer Drugs, 2007; 18: 955–61). In a phase II study of IFLUX, Bach Ardalan (University of Miami, FL, USA) and colleagues report that median patient survival was 31·3 months (95% CI 20·9– 38·0); in comparison, median survival with the widely used regimen of folinic acid, fl uorouracil, oxaliplatin (FOLFOX) is 19·5 months. Fluorouracil kills tumours partly through its activation, via FUdR, to fl uorodeoxyuridine monophosphate. This inhibits thymidylate synthase, which causes DNA damage and cell death. “Fluorouracil’s conversion to FUdR requires the addition of a deoxyribose sugar, which is often rate-limiting in cancer cells”, explains Ardalan, “so giving FUdR should bypass the ratelimiting step in fl uorouracil activation”. 38 patients with untreated, advan ced colorectal cancer received fi ve 6-week cycles (on average) of IFLUX. Each cycle comprised four weekly intravenous infusions of 110 mg/m irinotecan followed by a 24 h continuous intravenous infusion of 120 mg/kg FUdR and 500 mg/m folinic acid, and 2 weeks’ rest. Median time to tumour progression was 11·5 months (6·8–12·9). IFLUX was well-tolerated; toxic eff ects included vomiting (24%) and diarrhoea (16%). “Although this is a small study, it’s exciting to see the survival fi gures reported here”, comments Anne Thomas (University of Leicester, Leicester, UK). “However, I think it’s unlikely that the average patient with colorectal cancer could tolerate the toxicity associated with this regimen, which might also make it diffi cult to combine IFLUX with targeted agents. We await with interest the outcome of a phase II study combining IFLUX with bevacizumab that Ardalan is currently recruiting to.” Initial toxicity studies, notes Ardalan, indicate that this combination is acceptable to patients.

Splenic infarction and bevacizumab

A 49-year-old man with metastatic sigmoid adenocarcinoma who had received six cycles of chemotherapy with fl uorouracil, folinic acid, irinotecan, and bevacizumab was seen in the emergency department with a 36 h history of abdominal pain in the left-upper quadrant. The patient was afebrile and had no recent history of trauma. Physical examination showed tenderness in the left-upper quadrant. Blood pressure and pulse were normal. Laboratory studies, including complete blood-cell count, were unrevealing. CT scan (fi gure A) showed liver metastases (green arrows) and several wedge-shaped defects in the spleen with the apex directed toward the hilum, consistent with splenic infarcts (blue arrow). Physical examination, electrocardiogram, laboratory tests, and blood cultures ruled out common causes of splenic infarction (eg, thromboembolic disease stemming from atrial fi brillation or myocardial infarction, haematological malignant disease, or sepsis). No underlying thrombophilia or coagulation disorder was seen. PET ruled out splenic metastases from colon carcinoma. Bevacizumab was immediately withdrawn. The patient was treated conservatively, and abdominal pain resolved spontaneously within 72 h. 2 months later, after four further chemotherapy cycles (without bevacizumab), a follow-up CT scan showed partial regression of the splenic infarcts (fi gure B, white arrow). Liver metastases were still present (red arrow). The patient died 6 weeks later from metastatic progression. No post mortem was done. Decreased concentrations of protein C, protein S, and antithrombin; activation of factor X; heightened fi brinogen and platelet catabolism; and direct generation of thrombin have been implicated in the hypercoagulability in patients with cancer. Whether, and to what extent, chemotherapy drugs, and even the drug administration method (eg, bolus vs infusional fl uorouracil) contribute to this complex remains unknown. In contrast to fl uorouracil and folinic acid regimens a retrospective analysis of two early randomised trials has shown that combinations of irinotecan, fl uorouracil, and folinic acid cause a signifi cantly higher incidence of acute myocardial infarction, pulmonary embolism, and cerebral events immediately after the start of treatment (the so-called vascular syndrome). However, this association was not confi rmed in subsequent randomised trials. Moreover, to our knowledge, none of these drugs, whether given alone or in combination, have been reported to cause splenic infarcts. Bevacizumab, however, a recombinant, humanised, monoclonal antibody that binds and inhibits vascular endothelial growth factor, has been clearly associated with arterial thrombotic events. This case draws attention to the importance of considering new angiogenesis inhibitors as a potential cause of splenic infarction in patients with cancer.

A randomized phase II trial of irinotecan in combination with infusional or two different bolus 5-fluorouracil and folinic acid regimens as first-line therapy for advanced colorectal cancer

Three different therapeutic regimens of irinotecan (CPT-11) in combination with 5-fluorouracil (5-FU) and folinic acid (FA) were evaluated for efficacy and safety in the first-line therapy of advanced colorectal cancer. Patients were randomly assigned to receive intravenously either: CPT-11 125 mg/m(2), FA 20 mg/m(2) followed by 5-FU 500 mg/m(2) bolus, weekly for 4 weeks (arm A, Saltz regimen); or CPT-11 180 mg/m(2) day 1 then FA 200 mg/m(2) over 2 h and 5-FU 400 mg/m(2) bolus and 5-FU 600 mg/m(2) 22-h infusion on days 1 and 2, every 2 weeks (arm B, Douillard regimen); or CPT-11 350 mg/m(2) (days 1 and 43) alternating with FA 20 mg/m(2)/day followed by 5-FU bolus 425 mg/m(2)/day during 5 days (days 22-26) (arm C, Mayo Clinic regimen). A total of 154 patients were included in the study (arm A, 51 patients; arm B, 53; arm C, 50). Overall response rates for the intention-to-treat populations were 33% [95% confidence interval (CI) 21% to 48%], 42% (95% CI 28% to 56%) and 30% (95% CI 18% to 45%) for arms A, B and C, respectively. Median times to progression were 6, 8 and 7 months for arms A, B and C, respectively. Median survival times were 15, 12 and 17 months for arms A, B and C, respectively. Overall response rates for the evaluable patient populations were 40% (95% CI 24% to 58%) in arm A, 44% (95% CI 29% to 60%) in arm B and 31% (95% CI 17% to 47%) in arm C. Neutropenia was the main serious adverse event in arms A (30% of patients) and C (22% of patients) but occurred in only 8% of patients in arm B. Delayed diarrhea was the main severe adverse event for the three regimens, from 15% to 22%. All three regimens were highly active. The biweekly combination of CPT-11 and 5-FU/FA (arm B) was notable for its low incidence of grade 3/4 neutropenia. The incidence of grade 3/4 delayed diarrhea was equivalent for the three treatment arms.

Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial

The liver is the most frequent site for metastases of colorectal cancer, which is the second largest contributor to cancer deaths in Europe. We did a randomised trial to compare an intrahepatic arterial (IHA) fluorouracil and folinic acid regimen with the standard intravenous de Gramont fluorouracil and folinic acid regimen for patients with adenocarcinoma of the colon or rectum, with metastases confined to the liver. We randomly allocated 290 patients from 16 centres to receive either intravenous chemotherapy (folinic acid 200 mg/m2, fluorouracil bolus 400 mg2 and 22-h infusion 600 mg/m2, day 1 and 2, repeated every 14 days), or IHA chemotherapy designed to be equitoxic (folinic acid 200 mg/m2, fluorouracil 400 mg/m2 over 15 mins and 22-h infusion 1600 mg/m2, day 1 and 2, repeated every 14 days). The primary endpoint was overall survival, and analysis was by intention to treat. 50 (37%) patients allocated to IHA did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. The IHA group received a median of two cycles (0-6), compared with 8.5 (6-12) for the intravenous group. 45 (51%) IHA patients who did not start or did not receive six cycles switched to intravenous treatment. In both groups, grade 3 or 4 toxicity was uncommon. Median overall survival was 14.7 months for the IHA group and 14.8 months for the intravenous group (hazard ratio 1.04 [95% CI 0.80-1.33], log-rank test p=0.79). Similarly, there was no significant difference in progression-free survival. Our results showed no evidence of an advantage in progression-free survival or overall survival for the IHA group; thus continued use of this regimen cannot be recommended outside of a clinical trial.

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

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

Serum human chorionic gonadotropin clearance curves in patients with interstitial pregnancy treated with systemic methotrexate

To evaluate short-term effectiveness of systemic methotrexate (MTX) in interstitial pregnancy. Case series. Two Dutch teaching hospitals. Eight consecutive patients with an unruptured interstitial pregnancy. Four doses of 1.0 mg/kg IM MTX alternated with 0.1 mg/kg oral folinic acid. Serum hCG concentrations were determined before the first MTX injection and followed until levels were undetectable. A second MTX course was started on day 14, if by then serum hCG concentrations were > 40% of the initial value. Serum hCG clearance curves of all patients in the present study were compared with those from our earlier studies, in which a different folinic acid regimen (15 mg orally) was used. Serum hCG clearance curves. All patients were treated successfully: five with one course and three with two courses. Serum hCG clearance curves of these patients tended to decline more rapidly than those successfully treated with the 15 mg folinic acid regimen. Systemic MTX is an attractive therapeutic option in the conservative treatment of unruptured interstitial pregnancy. The regimen of four doses of 1.0 mg/kg IM MTX alternated with 0.1 mg/kg folinic acid is effective. Serum hCG clearance curves may serve as a guideline for monitoring MTX treatment, thus enabling a timely detection of impending treatment failure.