Low-dose Trial Research Articles

Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial

Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.

Abstract PS7-30: Differential efficacy, safety and tolerability of low-dose versus standard dose tamoxifen as breast cancer prophylaxis: A network meta-analysis

Abstract BACKGROUND: Despite reduction in the risk of breast cancer occurrence, the use of prophylactic tamoxifen does not improve longer term outcomes such as survival and comes at the cost of toxicity. As such, chemoprophylaxis is utilized poorly in routine practice. Lower dose tamoxifen has been proposed as a more acceptable alternative for breast cancer prevention. Here, we explore efficacy and treatment-related adverse events (TRAEs) comparing the two tamoxifen dosing regimens in a network meta-analysis. METHOD: We searched PubMed to identify randomized trials (RCTs) of tamoxifen for breast cancer prophylaxis in high-risk patients (as defined in individual trials). Low-dose tamoxifen was defined as less than 20mg per day. We extracted the hazard ratio (HR) for breast cancer events relative to placebo. We also collected data on common and serious TRAE, and calculated odd ratios (OR) for each TRAE relative to placebo. Data were then included in a network meta-analysis comparing low-dose (experimental group) to standard dose tamoxifen (control group). Associations between TRAEs and patient charactericstics were explored using meta-regression which comprised a weighted linear regression using mixed effects modelling. RESULTS: Ten RCTs comprising 35,505 patients were included in the analysis (4 low-dose trials (n=3712 patients) and 6 standard dose trials (n=31,793 patients). There were no significant differences between low-dose and standard dose trials in age (53.3 vs 50.8, p=0.25), post-menopausal status (77.5% vs 49%, p=0.63) or BMI (24.1kg/m2 vs 26.95 kg/m2, p=0.40). Efficacy was similar between the two dosage regimens (HR for breast cancer recurrences: 1.04, 95% CI 0.77-1.41, p=0.78 and for invasive breast cancer: 1.04, 95% CI 0.69-1.56, p=0.85). Differences in TRAEs are shown in the Table. There was a statistically significant reduction in headache with low-dose tamoxifen, and a non-significant reduction in endometrial cancers, other cancers, cardiovascular diseases and all-cause deaths. Hot flashes, vaginal bleeding and endometrial polyps were non-significantly higher with low-dose tamoxifen. In meta-regression analysis, age was associated with lower risk of endometrial carcinoma (p=0.049) and hot flashes (p=0.03). CONCLUSION: The use of prophylactic low-dose tamoxifen provides similar efficacy to standard dosing, but may reduce the risk of certain common and serious TRAEs. TRAEOR95% CIp-valueDeaths0.630.14-2.860.55Endometrial cancer0.320.08-1.240.10Endometrial polyps1.660.84-3.280.15Other cancer0.710.40-1.260.24DVT or PE0.900.12-7.580.93 Coronary heart disease0.720.24-2.150.56Cerebrovascular disease1.600.29-8.970.59Hot flashes1.340.63-2.860.45Vaginal dryness0.840.34-2.030.69Vaginal bleeding1.260.52-3.060.61Vaginal discharge1.080.58-1.990.81Headache0.110.05-0.860.04 Citation Format: Alexandra Desnoyers, Michelle B Nadler, Brooke E Wilson, Eitan Amir. Differential efficacy, safety and tolerability of low-dose versus standard dose tamoxifen as breast cancer prophylaxis: A network meta-analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-30.

Phytotherapeutic interventions in the management of biochemically recurrent prostate cancer: a systematic review of randomised trials.

To evaluate the evidence from randomised trials for the efficacy and safety of phytotherapeutic interventions in the management of biochemically recurrent (BCR) prostate cancer, indicated by prostate-specific antigen (PSA) progression, numbers progressing to/time to initiation of androgen-deprivation therapy or salvage therapy. MEDLINE (Ovid), EMBASE (Ovid), AMED (Ovid), CINAHL (EBSCO) and the Cochrane Library databases were searched. Clinical trials investigating phytotherapeutic interventions as dietary supplements or dietary components, including multi-component herbal formulations, in men with BCR prostate cancer were located. Eight of nine authors contacted for further information responded. Methodological quality was assessed using the Cochrane Collaboration's risk of bias assessment tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews was followed. Of 23 full-text articles assessed for eligibility, five met the criteria for inclusion. Two studies were placebo controlled; two were active control trials; and one a high-/low-dose trial. The interventions were administered as isolated phytochemicals (sulphoraphane), phytotherapeutic extracts [Pomi-T (pomegranate, turmeric, green tea and broccoli sprout extract), soy, lycopene, and POMx (pomegranate extract)], or plant-derived dietary items (soy and lycopene). All studies found serum PSA levels to stabilise, decrease or rise more slowly in a significant number of men, and three studies reported stabilising or lengthening of PSA-doubling time. Studies were generally of good quality, but sample sizes were predominantly small, and durations short. High-quality studies in this area are lacking. Sulphoraphane, lycopene, soy isoflavones, POMx, and Pomi-T are safe and well tolerated. There is limited evidence that they can affect PSA dynamics. No recommendation can be made for the use of these agents in managing prostate cancer morbidity and mortality until high-quality, fully powered studies are available. Recommendations are made for improving reproducibility and translation of findings with regard to study population, study endpoints, design, and the reporting of phytotherapeutic interventions.

Statin Use and Incident Diabetes Explained by Bias Rather Than Biology

The evidence supporting a link between statin use and incident diabetes is seemingly robust; it has been observed in multiple prospective randomized trials and confirmed by meta-analyses. However, differences in survival among statin vs placebo-treated patients in randomized trials might have caused bias with respect to diabetes surveillance. Bias might have been further exaggerated from the strong association between diabetes and cardiovascular events, which were the primary end points in major statin trials. Meta-analyses of randomized trials have demonstrated a 9% increase in the odds of incident diabetes among patients who receive statins compared with placebo (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.17) and a 12% increase of high-dose statin therapy vs low doses (OR, 1.12; 95% CI, 1.04-1.22). To simulate the possible effect of bias in these meta-analyses, each pooled trial was modified by assuming that 10% of the patients who experienced primary end points subsequently developed diabetes undetected. Meta-analyses of these simulated trials attenuated the association to a nonsignificant level among placebo-controlled trials (simulated OR, 1.04; 95% CI, 0.98-1.10), and high- vs low-dose trials (simulated OR, 1.07; 95% CI, 1.00-1.15). Our results demonstrate how a small influence of bias in each randomized trial could have contributed substantially to the observed association between statin use and diabetes.

Treatment of Essential Tremor with Long-Chain Alcohols: Still Experimental or Ready for Prime Time?

<strong>Aim:</strong> To review current literature on long-chain alcohols and their derivatives as novel pharmacotherapy for the treatment of essential tremor (ET). <strong>Background:</strong> Currently available and recommended pharmacotherapies for ET are often limited by suboptimal treatment effects, frequent adverse effects, and drug interactions. While ethanol is reported to profoundly decrease tremor severity in the majority of patients with ET, preclinical experience suggests that longchain alcohols such as 1-octanol might lead to a comparable tremor reduction without ethanol’s typical side effects of sedation and intoxication. Here, we review the literature on the first clinical trials on 1-octanol and its metabolite octanoic acid (OA) for the treatment of ET. <strong>Methods:</strong> The literature on preclinical and clinical trials on long-chain alcohols as well as OA was reviewed and summarized, and an outlook given on next phases of development. <strong>Discussion:</strong> 1-octanol was demonstrated to be safe and effective in a double-blind, placebo-controlled low-dose trial, and open-label data showed excellent tolerability and dose-dependent efficacy up to 128 mg/kg. Despite 1-octanol’s efficacy, its future viability as an effective therapy is limited by its pharmacological properties that require large volumes to be orally administered. Pharmacokinetic data indicate that OA is the active metabolite of 1-octanol. Preclinical efficacy data for OA are positive, and human pilot data demonstrated excellent safety as well as efficacy in secondary outcome measures of tremor amplitudes. OA also has more favorable pharmacological properties for drug delivery; hence, OA may be worth developing as a pharmaceutical.

Treatment of essential tremor with long-chain alcohols: still experimental or ready for prime time?

AimTo review current literature on long-chain alcohols and their derivatives as novel pharmacotherapy for the treatment of essential tremor (ET).BackgroundCurrently available and recommended pharmacotherapies for ET are often limited by suboptimal treatment effects, frequent adverse effects, and drug interactions. While ethanol is reported to profoundly decrease tremor severity in the majority of patients with ET, preclinical experience suggests that long-chain alcohols such as 1-octanol might lead to a comparable tremor reduction without ethanol’s typical side effects of sedation and intoxication. Here, we review the literature on the first clinical trials on 1-octanol and its metabolite octanoic acid (OA) for the treatment of ET.MethodsThe literature on preclinical and clinical trials on long-chain alcohols as well as OA was reviewed and summarized, and an outlook given on next phases of development.Discussion1-octanol was demonstrated to be safe and effective in a double-blind, placebo-controlled low-dose trial, and open-label data showed excellent tolerability and dose-dependent efficacy up to 128 mg/kg. Despite 1-octanol’s efficacy, its future viability as an effective therapy is limited by its pharmacological properties that require large volumes to be orally administered. Pharmacokinetic data indicate that OA is the active metabolite of 1-octanol. Preclinical efficacy data for OA are positive, and human pilot data demonstrated excellent safety as well as efficacy in secondary outcome measures of tremor amplitudes. OA also has more favorable pharmacological properties for drug delivery; hence, OA may be worth developing as a pharmaceutical.

Rapid response to antipsychotic treatment on psychotic prodrome: Implications from a case series

The feasible intervention strategy at the prodromal state of psychosis is under debate. We report nine subjects clinically in a putative prodromal state of psychosis who responded to low-dose aripiprazole within the first week of medication. We conjecture that the pathophysiological processes might be easier to modify by antipsychotics in the prodromal state and we believe a short-term low-dose trial of antipsychotic agents is a convenient option for subjects at ultra high risk of psychosis. We urge specific attention to monitor the dissolution of psychotic-like symptoms carefully in order to have a better understanding of the pathogenesis and pharmacotherapy in the inception of psychosis.

Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective

IntroductionCurrent low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.MethodsRCTs were identified (1950-September 2008) by multiple data-base electronic search (MEDLINE via OVID, OVID PreMedline, OVID Embase, Cochrane Central Register of Controlled trials, Cochrane database of systematic reviews, Health Technology Assessment Database and Database of s of Reviews of Effects) and hand search of references, reviews and scientific society proceedings. Three investigators independently assessed trial inclusion and data extraction into standardised forms; differences resolved by consensus.ResultsCorticosteroid efficacy, compared with control, for hospital-mortality, proportion of patients experiencing shock-resolution, and infective and non-infective complications was assessed using Bayesian random-effects models; expressed as odds ratio (OR, (95% credible-interval)). Bayesian outcome probabilities were calculated as the probability (P) that OR ≥1. Fourteen RCTs were identified. High-dose (>1000 mg hydrocortisone (equivalent) per day) corticosteroid trials were associated with a null (n = 5; OR 0.91(0.31-1.25)) or higher (n = 4, OR 1.46(0.73-2.16), outlier excluded) mortality probability (P = 42.0% and 89.3%, respectively). Low-dose trials (<1000 mg hydrocortisone per day) were associated with a lower (n = 9, OR 0.80(0.40-1.39); n = 8 OR 0.71(0.37-1.10), outlier excluded) mortality probability (20.4% and 5.8%, respectively). OR for shock-resolution was increased in the low dose trials (n = 7; OR 1.20(1.07-4.55); P = 98.2%). Patient responsiveness to corticotrophin stimulation was non-determinant. A high probability of risk-related treatment efficacy (decrease in log-odds mortality with increased control arm risk) was identified by metaregression in the low dose trials (n = 9, slope coefficient -0.49(-1.14, 0.27); P = 92.2%). Odds of complications were not increased with corticosteroids.ConclusionsAlthough a null effect for mortality treatment efficacy of low dose corticosteroid therapy in severe sepsis and septic shock was not excluded, there remained a high probability of treatment efficacy, more so with outlier exclusion. Similarly, although a null effect was not excluded, advantageous effects of low dose steroids had a high probability of dependence upon patient underlying risk. Low dose steroid efficacy was not demonstrated in corticotrophin non-responders. Further large-scale trials appear mandated.

Glyceryl triacetate for Canavan disease: A low‐dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model

Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. Wild-type and tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 through 14, and at 5.8 g/kg from day 15 through 23, and thereafter in food (7.5%) and water (5%). At the end of the trial (approximately 90 to 120 days) sera and tissues from rats were analysed for changes in blood chemistry and histopathology. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. In the high-dose animal studies, no significant differences in the mean blood chemistry values occurred between treated and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues examined. Lack of GTA toxicity in two CD patients in low-dose trials, as well as in high-dose animal studies, suggests that higher, effective dose studies in human CD patients are warranted.

Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure

In the Swiss heroin substitution trials, patients are treated with self-administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high-dose oral diacetylmorphine is considerably higher than would be predicted from low-dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose. Opioid-naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium-labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose. The maximum plasma concentration (C(max)) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 micromol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 micromol). Oral absorption of opioids is substance-, dose- and patient collective-dependent, suggesting that there may be a saturation of first-pass processes, the exact mechanism of which is not yet understood.

Detection of recombinant human erythropoietin in urine for doping analysis: Interpretation of isoelectric profiles by discriminant analysis

The detection in urine of recombinant human erythropoietin (rHuEPO), a hormone misused by endurance athletes as a doping agent, is based on the differentiation of its isoelectric pattern from that of the corresponding natural hormone. Different empirical criteria have been proposed for discriminating the images of the patterns but none of them have been elaborated from a rational statistical approach. Discriminant analysis was applied to a dataset of profiles defined as positive (116 profiles from 26 subjects) (presence of rHuEPO and possibly residual natural endogenous hormone) and negative (131 profiles from 131 subjects) (presence of natural endogenous hormone only). The different bands were numbered according to a template of 16 possible positions and their relative intensities constituted the 16 variables of the statistical analysis. This method was then tested with data from an administration trial of low doses (6.7-10 IU/kg) following high-dose (265 IU/kg) injections (71 profiles from one subject). The analysis of the dataset clearly separated the negative and positive profiles. A cross-validation procedure confirmed that the analysis was extremely stable: with ten-fold cross-validation, no false positives were observed even with 100,000 simulations. Furthermore, the detection of rHuEPO in the profiles from the low-dose trial was greatly improved in comparison with a previously validated empirical criterion.

Adjuvant Therapy of Melanoma

The purpose of this article was to review the current state of knowledge regarding the efficacy of adjuvant therapy for melanoma. We reviewed the published literature, focusing on randomized clinical trials. There have been no meaningful trials addressing adjuvant chemotherapy in melanoma because all trials have been underpowered. Adjuvant interferon-alpha has been tested both at high dose and at lower doses. None of the trials have shown a reproducible benefit in survival, although the high-dose trials and some of the low-dose trials have shown improvement in time to relapse. These experiences raise the question of whether chronic administration is more important than dose. An adjuvant pegylated interferon-alpha trial using a 5-year treatment period is currently under investigation. At least 7 randomized adjuvant vaccine trials have been published, but none have shown a beneficial effect on relapse-free or overall survival except in subset analyses. To date, no adjuvant therapy has resulted in improved overall survival. To be attractive as an adjuvant therapy, experience from other tumor types indicates that a chemotherapy regimen should have a response rate of at least 20% in metastatic melanoma. Currently, biochemotherapy is being tested as an adjuvant treatment but other, less toxic, regimens should be sought. Once such a regimen with acceptable toxicity is identified, it would be reasonable to test it as an adjuvant therapy in a properly powered randomized trial. High-dose interferon-alpha for 1 year remains the only U.S. Food and Drug Administration-approved adjuvant therapy for melanoma, but long-term chronic dosing of interferon-alpha may prove more effective than short-term dose schedules. Development of melanoma vaccines remains an appealing and important goal. New technologies and understanding of the immune response against melanoma are leading to novel vaccine strategies designed to break immunologic tolerance against melanoma.

Swedish aspirin low-dose trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebral ischaemic events: The Salt Collaborative Group. Lancet 1991;338:1345-9

Swedish aspirin low-dose trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebral ischaemic events: The Salt Collaborative Group. Lancet 1991;338:1345-9