Standard-dose Therapy Research Articles

Effect of two different doses of oral cholecalciferol supplementation on serum 25-hydroxy-vitamin D levels in healthy Indian postmenopausal women: A randomized controlled trial.

Aim:To compare the effect of two different doses (500 and 1000 IU/day) of oral vitamin D3 (cholecalciferol) on serum 25-hydroxy vitamin D [25(OH)D] levels in apparently healthy postmenopausal Indian women.Materials and Methods:Serum 25(OH)D, calcium with albumin, phosphorus, and alkaline phosphatase were measured in 92 apparently healthy postmenopausal women. The subjects were randomly assigned to one of the three groups and received supplementation for 3 months each. Each group received 1000 mg calcium carbonate daily while groups B and C received 500 and 1000 IU of cholecalciferol in addition, respectively. The tests were repeated after 3 months.Results:At baseline, 83.7% subjects had vitamin D deficiency (≤20 ng/mL). The difference in the percentage change in mean serum 25(OH)D levels from baseline in group A (–30.5 ± 5.3%), group B (+8.9 ± 19.7%), and in group C (+97.8 ± 53.3%) was statistically significant (P < 0.001) between the three groups. Serum 25(OH)D level >20 ng/mL was achieved in 4.7% (1/21), 16% (4/25), and 66.67% (12/18) subjects in groups A, B, and C, respectively. No significant change was found in serum calcium, phosphorus, and alkaline phosphatase levels at 3 months in either of the groups from baseline.Conclusions:Standard dose of cholecalciferol available in “calcium tablets” (250 IU per 500 mg calcium carbonate) is not adequate for achieving optimum serum 25(OH)D levels in Indian postmenopausal women. Higher dose of vitamin D supplementation with 1000 IU/day (500 IU per 500 mg calcium carbonate) daily is superior to the standard dose therapy. For achievement of optimum serum 25(OH)D levels (>30 ng/mL) in Indian postmenopausal women, still higher doses of vitamin D are likely to be required.

PWE-250 Azathioprine and allopurinol co-therapy for IBD patients is a safe and effective treatment option in the district general hospital setting

IntroductionReports from specialist inflammatory bowel disease (IBD) units have demonstrated that allopurinol and low-dose thiopurine co-therapy is an effective treatment option in patients who have failed standard dose therapy. There...

Impact of Platelet Function Test on Platelet Responsiveness and Clinical Outcome After Coronary Stent Implantation: Platelet Responsiveness and Clinical Outcome

Background and ObjectivesThe aim of this study was to confirm the predictive cut-off values for P2Y12 reaction units (PRU) and aspirin reaction units (ARU) and to evaluate the clinical impact of VerifyNow® assays.Subjects and MethodsFrom November 2007 to October 2009, 186 eligible patients were prospectively recruited. Post-treatment platelet reactivity was measured by VerifyNow® assays within 12 to 24 hours after intervention, followed by standard dual maintenance dose therapy for 1 year. All patients had scheduled clinical follow-ups at 1, 3, 6, and 12 months.ResultsThe rate of low responders to clopidogrel, aspirin, and both drugs were 41.4%, 10.2%, and 3.8%, respectively. The predictive factors for low responsiveness to clopidogrel (PRU ≥240) were female sex, age, and non-use of cilostazol medication in our univariate analysis and age ≥65 years and non-use cilostazol in the multivariate analysis. The predictors of low responsiveness to aspirin (ARU ≥550) were male sex and age in both univariate and multivariate analyses. There was no significant difference in the clinical event rate with a cut-off value of PRU ≥240 or ARU ≥550 for 30 days and 1-year (p>0.05).ConclusionHyporesponsiveness to antiplatelet agents (namely aspirin and clopidogrel) was identified in about half of the patients. The cut-off point of PRU ≥240 or ARU ≥550 did not confer predictive value for 30-day or 1-year clinical event rates in patients who had undergone coronary intervention with drug-eluting stents.

Anti-Inflammatory Effects of Statins Beyond Cholesterol Lowering

Anti-Inflammatory Effects of Statins Beyond Cholesterol Lowering

Boceprevir and telaprevir for the treatment of chronic hepatitis C genotype 1 infection: an indirect comparison meta-analysis

BackgroundThe aim of this study was to examine the relative efficacy and safety of boceprevir and telaprevir, when used in combination with pegylated interferon alpha and ribavirin, using an indirect comparison meta-analysis.MethodsPublished phase II and phase III randomized placebo-controlled trials examining the efficacy of boceprevir and telaprevir in chronic hepatitis C virus genotype 1 infected adult populations were included. The primary outcomes were sustained virologic response, relapse, and discontinuation of all study drugs. Secondary outcomes included the adverse events of anemia, neutropenia, rash, and pruritus.ResultsFour boceprevir trials and six telaprevir trials were included. No significant differences were observed for sustained virologic response among either naïve (relative risk [RR] 1.14, 95% confidence interval [CI] 0.93–1.37, P = 0.20) or experienced patients (RR 0.81, 95% CI 0.52–1.23, P = 0.30). Similarly, for relapse among naïve (RR 0.80, 95% CI 0.18–3.45, P = 0.77) and experienced patients (RR 1.71, 95% CI 0.90–3.24, P = 0.10), or discontinuation of therapy for naïve (RR 0.80, 95% CI 0.28–2.29, P = 0.72) and experienced patients (RR 0.88, 95% CI 0.69–1.12, P = 0.30). Telaprevir was more likely to be associated with rash and pruritus, and boceprevir was more likely to be associated with neutropenia in certain patient populations.ConclusionBoceprevir and telaprevir appear comparable in terms of sustained virologic response, relapse, or discontinuation of therapy for patients treated with standard-dose therapy durations and response-guided therapy durations.

Open Label Investigation of Mucosal Healing in Patients with Small Bowel Crohnʼs Disease Treated with Certolizumab Pegol Assessed by Wireless Capsule Endoscopy

Purpose: The efficacy of certolizumab pegol (CZP), a pegylated anti-TNF agent for the induction and maintenance of response and remission in adult patients with active Crohn's disease has been demonstrated in randomized controlled trials. Prior study has shown improvement of mucosal healing associated with improved long term outcomes and lower need for major surgery. The MUSIC trial demonstrated CZP-induced endoscopic response and remission in Crohn's disease at 10 weeks and 54 weeks. Our primary objective is to assess CZP and endoscopic healing using Lewis scoring system (LS) with wireless capsule endoscopy (WCE) in patients with moderate-to-severe Crohn's disease. Methods: We performed a prospective open label trial in 5 patients with documented moderate-to-severe Crohn's disease for a period of six months. All patients were given standard induction dose therapy with CZP at 0, 2, 4 weeks, then every 4 weeks until 6 months. WCE was performed at baseline, 16 weeks and 26 weeks. Blood work including CMP, HEMGPD and CRP were obtained, as well as Crohn's disease activity index (CDAI) and Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Results: Five patients were enrolled in this trial with an average age of 36.2 years; there were 2 males, 3 females, with an average disease duration of 16.6 years. Of the 5 patients, 4 had no prior surgery and one had prior small bowel resection. Four out of five patients were secondary non-responders (SNR) to biologics; 2 having lost response to both infliximab and adalimumab, one each to infliximab and adalimumab alone and one biologically naïve patient. The mean LS at baseline was 1,976 with CDAI of 289 and SIBDQ of 34. At 26 weeks, the LS fell to a mean of 639, with significant mucosal healing in 4 out of 5 patients, with only one patient showing non-healing at the end of the study period. All patients achieved significant reduction in CDAI of greater than 100 points, with a mean CDAI of 133 at 26 weeks and improvement in the SIBDQ to 56.8 at the end of study. Conclusion: This study demonstrates significant mucosal healing in 4 of 5 patients treated with open label CZP as assessed by serial WCE studies in moderate-to-severe CD, despite prior anti-TNF exposure. The study establishes proof of concept that WCE and the use of the LS is a valuable diagnostic test to assess mucosal healing in patients with small bowel Crohn's disease treated with CZP. CZP is well tolerated in this population with no safety issues. Continued study utilizing WCE and treatment with CZP is warranted. Disclosure: Dr. Shafran - Research Support: UCB. This research was supported by an industry grant from UCB.

Optimizing the selection of kinase inhibitors for chronic myeloid leukemia patients

Long-term follow-up of clinical studies has demonstrated the efficacy of imatinib therapy in newly diagnosed chronic phase-chronic myeloid leukemia patients (CML). However, recent updates of two separate randomized Phase III studies demonstrated higher complete cytogenetic and major molecular response rates with dasatinib and nilotinib compared with imatinib 400 mg/day. Hence, for newly diagnosed chronic phase-CML patients there are multiple treatment options, including standard-dose imatinib, high-dose imatinib, and combination therapy of imatinib and interferon, dasatinib and nilotinib. This article critically analyzes the current literature and provides guidelines for the management of newly diagnosed CML. Disease and therapy-related prognostic factors, which may aid in the selection of therapeutic strategies to enable optimal treatment outcomes, are discussed. In addition, we provide commentary on the therapeutic options for patients who fail imatinib therapy.

Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study

AbstractWe conducted a multi-institutional randomized study to determine whether high-dose daunorubicin would be as effective as standard-dose idarubicin in remission-induction therapy for newly diagnosed adult patients younger than 65 years of age with acute myeloid leukemia. Of 1064 patients registered, 1057 were evaluable. They were randomly assigned to receive either daunorubicin (50 mg/m2 daily for 5 days) or idarubicin (12 mg/m2 daily for 3 days) in combination with 100 mg/m2 of cytarabine by continuous infusion daily for 7 days as induction therapy. Complete remission was achieved in 407 (77.5%) of 525 patients in the daunorubicin group and 416 (78.2%) of 532 in the idarubicin group (P = .79). Patients achieving complete remission received intensive postremission therapy that consisted of either 3 courses of high-dose cytarabine or 4 courses of standard-dose therapy. Overall survival rates at 5 years were 48% for the daunorubicin group and 48% for the idarubicin group (P = .54), and relapse-free survival rates at 5 years were 41% and 41% (P = .97), respectively. Thus, high-dose daunorubicin and standard-dose idarubicin were equally effective for the treatment of adult acute myeloid leukemia, achieving a high rate of complete remission and good long-term efficacy. This study is registered at http://www.umin.ac.jp/ctrj/ as C000000157.

High Dose Therapy with Autologous Stem Cell Transplantation Vs Standard Dose Chemotherapy In Multiple Myeloma: A Meta-Analysis

AbstractAbstract 3559 Introduction.Myeloablative high dose chemotherapy (HDT) followed by single autologous stem cell transplantation is currently the standard treatment for patients younger than 65 years in newly diagnosed multiple myeloma (MM). Several randomized controlled trials (RCTs) comparing HDT with standard dose therapy (SDT) have shown some benefit in overall survival (OS) and progression free survival (PFS), whereas other RCTs did not confirm this finding. Koreth et al. (2007) performed a metaanalysis summarizing the existing data of the RCTs including 2,411 patients. These authors found a significant superiority for HDT in PFS but not in OS. Since a number of new studies have been published recently, we attempted to re-analyze the current data in terms of the endpoints OS and PFS. Methods.We searched PubMed, Embase, abstracts of former ASH meetings and ClinicalTrials.gov as well as bibliographies of included trials and recent reviews from september 2009 until may, 20th 2010. Amongst the 3,484 results in this search we identified 10 RCTs comparing HDT with SDT on an intent-to-treat-basis. Treatment characeristics and outcomes of OS and PFS were calculated using R. Furthermore, we tested for statistical heterogenity, publication bias and performed subgroup analyses. Results.9 RCTs including 2,600 patients were fully analyzed. Patients undergoing HDT with stem cell transplantation did have significant PFS benefit (Hazard Ratio 0.73; 95% conficence intervall 0.56–0.95; P=0.02) but not OS benefit (HR 0.90; 95% CI 0.74–1.10; P=0.32) compared to patients undergoing SDT. Additional data from ongoing clinical trials are expected, thus updated results at the meeting including 10 RCTs with about 3,400 patients will be presented. Conclusion.Although there is only a trend to OS benefit with HDT, it is currently still the first line treatment. Additional data from ongoing clinical trials and new studies using novel agents like thalidomide, lenalidomide and bortezomib are egerly warrented to finally evaluate the role of HDT in the treatment management of patients with newly diagnosed MM. Disclosures:No relevant conflicts of interest to declare.

High-dose chemotherapy with hematopoietic stem cell transplantation for the treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare B-cell lymphoid neoplasm for which current regimens utilizing standard-dose chemotherapy and/or radiation therapy lead to high relapse rates and/or unacceptable neurologic sequelae. High-dose chemotherapy followed by hematopoietic stem cell transplantation may overcome limitations of current treatment schemas. A search was performed of all English-language literature (1968 to June 2009) within the MEDLINE, EMBASE and Cochrane Library databases to identify relevant clinical trials using the terms stem cell transplantation, bone marrow transplantation, primary central nervous system lymphoma, and PCNSL. Bibliographies were reviewed to extract other relevant articles. Use of high-dose chemotherapy followed by hematopoietic stem cell transplantation for the treatment of PCNSL in a predominantly elderly population is feasible. Use of this treatment modality for newly diagnosed and recurrent or relapsed disease is burdened by a paucity of data guiding patient selection, optimal induction regimen, stem cell mobilization and conditioning chemotherapy. Data are also sparse and confounding regarding timing of initiation of this procedure relative to the natural history of the disease and timing of each chemotherapy regimen relative to each other. High-dose chemotherapy followed by hematopoietic stem cell transplantation remains an experimental procedure with insufficient data to guide clinicians. However, the data are encouraging and merit continued research to guide patient selection and treatment regimens which may produce optimal outcomes.

A randomized trial of preemptive therapy for prevention of cytomegalovirus disease after allogeneic hematopoietic stem cell transplantation

We studied the efficacy of two different doses of ganciclovir to prevent cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. We randomly assigned allogeneic HSCT recipients who had CMV infection to receive preemptive ganciclovir therapy with or without induction phase (5 mg/kg twice daily for 1 week). Thirty-two and thirty-six patients were randomized to the standard and the low-dose therapy group, respectively. The median time to CMV antigenemia or viremia clearance was 7 days (3-25 days) in the standard therapy group versus 11 days (3-69 days) in the low-dose therapy group (P = 0.540). The incidence of CMV disease was similar between the two groups (P = 0.366). The Kaplan-Meier estimate of event-free survival by day 180 after HSCT was 76.2% in the standard therapy group versus 66.7% in the low-dose therapy group (P = 0.590). Severe neutropenia (<0.5 x 10(9)/L) was observed in four (12.5%) patients in the standard therapy group versus two (5.6%) patients in the low-dose therapy group (P = 0.314). This study suggests that a low-dose ganciclovir preemptive therapy can be as effective as the standard-dose ganciclovir preemptive therapy for the prevention of CMV disease in allogeneic HSCT recipients.

Imatinib dose escalation in 74 failure or suboptimal response chronic myeloid leukaemia patients at 3‐year follow‐up

We report here on the long-term efficacy of imatinib dose escalation in 74 patients after failure to imatinib conventional dose (13 with hematologic failure and 57 patients with cytogenetic resistance) or suboptimal response (four patients for cytogenetic or molecular). Fifty-four patients received imatinib dose escalation from 400 to 600 mg and 20 patients to 800 mg. A major cytogenetic response was achieved in 41 patients (72%) who escalated imatinib dose for cytogenetic failure and in six patients (46%) with hematologic failure (P = 0.002). Complete cytogenetic response (CCyR) was achieved in 27 (37%) patients: 38% of the hematological failure patients and 42% of the cytogenetic resistant patients (P = 0.345). Cytogenetic suboptimal response patients obtained complete molecular response, whereas the patient, who escalated the dose for molecular suboptimal response at 18 months, did not obtain improvement. After 3 years of follow-up all responding patients are in sustained CCyR. The estimated 2-year PFS and OS is 87% and 85%, respectively. In conclusion, imatinib dose escalation appears to induce sustained responses in CML patients with cytogenetic resistance, in particular in those with acquired resistance. In hematological failure patients, a rapid switch to second generation TKI is instead recommended.

Low Dose vs Standard Dose of Antipsychotics for Relapse Prevention in Schizophrenia: Meta-analysis

It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention. To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia. Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009). Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis. Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P = .05) superiority in risk of relapse. The very low-dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose. Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia.

High-dose versus Standard-dose Radiation Therapy in Combined-modality Therapy for Esophageal Cancer

High-dose versus Standard-dose Radiation Therapy in Combined-modality Therapy for Esophageal Cancer

Advances in hormone replacement therapy: making the menopause manageable

The importance of the results of some large, randomized controlled trials (RCTs) on Hormone Replacement Therapy (HRT) has modified the risk/benefit perception of HRT. Recent literature review supports a different management.The differences in age at initiation and the duration of HRT are key points. HRT appears to decrease coronary disease in younger women, near menopause; yet, in older women, HRT increases risk of a coronary event. Although HRT is a recognized method in the prevention and treatment of osteoporosis, it is not licensed for the prevention of osteoporosis as a first-line treatment. The effectiveness of low and ultra-low estrogen doses has been demonstrated for the treatment of vasomotor symptoms, genital atrophy and the prevention of bone loss, with fewer side-effects than the standard dose therapy. Further research, however, is needed to determine the effect both on fractures, as well as on cardiovascular and breast diseases. Newer progestins show effects that are remarkably different from those of other assays. The effectiveness of testosterone at improving both sexual desire and response in surgically and naturally postmenopausal women is shown by the testosterone patch.The intention, dose and regimen of HRT need to be individualized, based on the principle of choosing the lowest appropriate dose in relation to the severity of symptoms and the time and menopause age.

Dose Escalation of Imatinib After Failure of Standard Dose in Korean Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumor

We evaluated the results of imatinib dose escalation in patients with advanced gastrointestinal stromal tumors (GISTs) after disease progression on standard-dose imatinib. Clinical data from patients with metastatic or unresectable GISTs whose dose of imatinib was increased after disease progression on imatinib 400 mg/day were retrospectively reviewed. The 24 patients studied had a median age of 52 years. Imatinib dosing was escalated to 600 mg/day in 12 patients, then to 800 mg/day in four patients. The other 12 patients had dose escalation directly to 800 mg/day. Two patients (8.3%) achieved a partial response, and seven (29.2%) had stable disease. Six-month progression-free and overall survival rates were 33.3 and 70.7%, respectively. Dose escalation to 600 or 800 mg/day was generally well tolerated. Imatinib dose escalation is feasible and well tolerated in patients with advanced GIST who progress on standard-dose therapy, producing clinical benefit in approximately 37% of patients.

High-Dose Etoposide: From Phase I to a Component of Curative Therapy

High-Dose Etoposide: From Phase I to a Component of Curative Therapy

Imatinib in advanced gastrointestinal stromal tumour: when is 800 mg the correct dose?

Gastrointestinal stromal tumour patients with exon 9 KIT mutations have a worse outcome, but progression-free survival is improved by treatment with imatinib 800 mg daily. This review looks at the evidence and asks whether this should be standard treatment from diagnosis. The phase III trial in advanced gastrointestinal stromal tumour, EORTC 62005, demonstrated increased progression-free survival for imatinib 800 mg daily versus 400 mg. Mutational analysis showed the benefit was primarily due to patients with exon 9 mutations. A meta-analysis has confirmed this finding. Patients who progress on standard dose imatinib may also experience disease stabilization. The significance of this in relation to data on pharmacokinetics and secondary mutations will be discussed. Mutational analysis of KIT and PDGFRA should ideally be performed in all patients with advanced gastrointestinal stromal tumour. Patients with mutations in exon 9 of KIT should be considered for treatment with imatinib 800 mg daily, but current data do not indicate whether there is a survival advantage for immediate treatment at 800 mg. There still appears to be a role for the higher dose in patients progressing after an initial response to the standard dose therapy.

Optimizing the dose of imatinib for treatment of gastrointestinal stromal tumours: Lessons from the phase 3 trials

Imatinib therapy for unresectable or metastatic gastrointestinal stromal tumour (GIST) is typically initiated at a dosage of 400 mg/d. Two phase 3 studies investigated whether the higher dose of 800 mg/d – administered initially or upon progression on the 400-mg dose – would improve outcomes. Both the studies confirmed the 400 mg/d starting dose for most patients. However, two groups benefited from the treatment with 800 mg/d of imatinib: patients with disease progression on standard-dose therapy, and patients whose tumour harbours an exon 9 mutation in KIT. Initial treatment with 800 mg/d of imatinib (400 mg BID) should be considered for patients with KIT exon 9–mutant GIST. In unselected patients, dose optimisation to 800 mg/d may be warranted as a first step in managing progressive disease; such patients should be closely monitored.

182: Conventional Chemotherapy with Interferon Versus Conventional Chemotherapy followed by High Dose Chemotherapy and Autologous Stem Cell Transplantation in Untreated Patients with Advanced Follicular Lymphoma. A Meta-Analysis of Randomized Clinical Trials

Purpose: High dose chemotherapy (HDT) followed by autologous stem cell transplantation has been used as part of the initial therapy of patients with untreated advanced follicular lymphoma and has been compared with standard dose therapy (SDT) with variable benefit in randomized clinical trials (RCT). Therefore, to address the variability in results, we undertook a systematic review of all RCT that evaluated the outcome of upfront use of HDT versus SDT. Patients and Methods: We performed a wide search in the main computerized databases of interest (MEDLINE, EMBASE, LILACS, CANCERLIT, and Cochrane Library).