Post-treatment Decline Research Articles

Genetic markers of late radiation toxicity in the era of image-guided radiotherapy: lower toxicity rates reduce the predictive value of γ-H2AX foci decay ratio in patients undergoing pelvic radiotherapy

BackgroundA predictive assay for late radiation toxicity would allow more personalized treatment planning, reducing the burden of toxicity for the more sensitive minority, and improving the therapeutic index for the majority. In a previous study in prostate cancer patients, the γ-H2AX foci decay ratio (γ-FDR) was the strongest predictor of late radiation toxicity. The current study aimed to validate this finding in a more varied group of patients with pelvic cancer. Additionally, the potential correlation between the γ-FDR and patient-reported outcomes was investigated.MethodsProstate and gynecological cancer patients with ≥ 24 months of follow-up were included in the current analysis. Toxicity was evaluated by physician (CTCAE version 4) and patient (EORTC questionnaires). γ-FDRs were determined in ex vivo irradiated lymphocytes. Correlation between γ-FDR and toxicity was assessed using both linear and logistic regression analyses. The highest toxicity grade recorded during follow-up was used. The association between global quality of life and γ-FDR was tested by comparing the change in quality of life over time in patients with γ-FDR < or ≥ 3.41, a previously established threshold.ResultsEighty-eight patients were included. Physician-assessed and patient-reported cumulative grade ≥ 2 toxicity was 25% and 29%, respectively; which is much lower than in the previous cohort (i.e., 51% CTCAE grade ≥ 2). Patients with toxicity exhibited less favorable dose-volume parameters. In men, these parameters showed significant improvement compared to the previous cohort. The proportion of patients with a low γ-FDR increased with severity of toxicity, but this trend was not statistically significant. In addition, a γ-FDR < 3.41 was not correlated with the development of moderate to severe toxicity. Post-treatment decline in global quality of life was minimal, and similar for patients with γ-FDR < or ≥ 3.41.ConclusionsIn the present study, the γ-H2AX foci decay ratio could not be validated as a predictor of late radiation toxicity in patients with pelvic cancer. Improved radiotherapy techniques with smaller irradiated bladder and bowel volumes have probably resulted in less toxicities. Future studies on genetic markers of toxicity should be powered on these lower incidences. We further recommend taking persistency, next to severity, into consideration.

Anger treatment via CBAT delivered remotely: Outcomes on psychometric and self-monitored measures of anger.

Studies of anger treatment have often reported on reappraisal and relaxation techniques delivered in person to forensic and psychiatric samples. The present study evaluated an integrative programme of cognitive-behavioural affective therapy (CBAT) delivered remotely to chronic pain sufferers with comorbid anger. Volunteers (N = 54) were randomly assigned to either CBAT or an Emotional Education (EE) group, both receiving hour-long videorecorded sessions twice a week for 4weeks plus weekly calls by telephone. At 1-month post-treatment, follow-up was conducted. Outcomes were measured using the Anger Parameters Scale (APS) and its five subscales (frequency, duration, intensity, latency and threshold) as well as daily self-monitored anger logs. As hypothesized, pre- to post-treatment decline in APS total scores was significant for CBAT, Hedges' g = 0.65, 95% CI [0.14, 1.16] but nonsignificant and small for EE, g = 0.17, CI [-0.41, 0.75]. At the primary endpoint (post-treatment), APS total scores were significantly lower for CBAT than for EE. Treatment gains were maintained till follow-up. On all five APS subscales, pre-post effect sizes were medium-sized for CBAT and generally small for EE. This picture was mirrored in the self-monitored frequency, duration and intensity of anger. Findings support the efficacy of CBAT over time, its comparative efficacy over EE and its ecological generalizability. Future research could expand sample size, reduce sample imbalance, extend follow-up and strengthen treatment potency with more sessions. The present study renews enthusiasm for teletherapy and is the first to demonstrate CBAT efficacy in treating maladaptive anger in the chronic pain population.

Neurodegenerative disease after hematopoietic stem cell transplantation in metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology. Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients. The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients. Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation.

A new cognitive safety monitoring plan for interventional studies involving patients with advanced dementia: Insights from the ECT-AD Study

<h3>Introduction</h3> Many pharmacological and some non-pharmacological treatments (e.g., electroconvulsive therapy, ECT) are associated with adverse cognitive effects in older adults, and this is particularly true for those with advanced dementia. Thus, it is imperative that studies investigating new treatments with potential cognitive side effects include a robust cognitive safety monitoring plan when the target population includes older adults with advanced dementia. However, detecting adverse cognitive events (ACEs) in this population poses unique challenges for two reasons: (1) the extant literature offers no recommendations or guidelines for defining what level of decline constitutes an ACE in this population, and (2) these patients are more likely to show floor effects on baseline cognitive testing, making it difficult to measure treatment-related adverse cognitive effects. To address these challenges, we created a new, empirically derived, and individually tailored cognitive safety monitoring plan that accounts for potential floor effects on pre-treatment cognitive testing. This plan was developed in the context of an ongoing, randomized controlled trial (the NIA supported "ECT-AD" study) to investigate the safety and efficacy of ECT for refractory agitation and aggression in patients with severe Alzheimer's disease (AD) <h3>Methods</h3> An extensive literature review was conducted to identify cognitive measures that have been found to be psychometrically sound for use in patients with advanced dementia, as well as psychometric data from those scales that could be used to define floor effects. Additionally, we inquired informant-rated scales of daily functioning that could serve as a proxy measure of cognitive status when patients exhibit baseline floor effects on cognitive testing. The team specifically focused on daily functioning scales for this purpose, given the robust association between cognition and activities of daily living in AD – an association that becomes stronger with disease progression (Liu-Seifert et al., 2016). Lastly, we reviewed the literature on statistical approaches to measuring reliable change on these kinds of cognitive/functional scales to define what constitutes statistically meaningful decline. <h3>Results</h3> The Severe Impairment Battery-8 (SIB-8) was chosen as the primary cognitive measure. The SIB-8 is a brief, clinician-administered test that has strong psychometric properties in patients with advanced dementia (Schmitt et al., 2009; Schmitt et al., 2013). Baseline floor effects on the SIB-8 were defined as a total score of ≤ 5/16. This value was chosen because it is approximately two standard deviations below the modal SIB-8 score in a large sample (N > 1300) of patients with moderate-to-severe dementia (Schmitt et al., 2013). For patients who <i>do not</i> exhibit baseline floor effects on the SIB-8, a post-treatment decline of ≥ 6 points would be considered an ACE. This threshold was empirically derived from the review of evidence-based approaches to measuring reliable change. Specifically, we used the Standard Deviation Index (SDI) method that uses the normative psychometric properties of a given test, along with an individual's test scores at two time points to derive a reliable change score. Using normative SIB-8 data from a large sample of comparable patients with AD (Schmitt et al., 2013), the SDI indicates that a decline of ≥ 5.6 points from baseline represents a statistically meaningful change. For patients who <i>do</i> exhibit baseline floor effects on the SIB-8, we will use the Barthel Index (BI) as a proxy measure of cognitive function (Mahoney & Barthel, 1965). The BI is an informant-rated scale (score range: 0-100) that assesses performance in basic activities of daily living (e.g., feeding, bathing). An ACE will be defined as a decline of ≥ 30 points on the BI from baseline, which was derived from the SDI method using normative BI data from a large sample (N=341) of comparable patients with AD (Kamiya et al., 2014). If an ACE is detected (using either the SIB-8 or BI) on the morning of, but prior to, a patient's next scheduled ECT treatment, then treatment will be held until the next treatment day. If a patient exhibits persistent decline prior to treatment on three consecutive days, then ECT will be discontinued. <h3>Conclusions</h3> By accounting for practical and statistical challenges in assessing cognitive function in patients with advanced dementia, we have designed a new, empirically derived, and conditional approach to monitoring for ACEs in real-time in clinical trials targeting this patient population. While the proposed cognitive safety monitoring plan was developed in the context of an inpatient ECT study, the procedures are agnostic to the specific type of treatment and can be readily adapted to a variety of interventional research contexts involving patients with severe dementia. <h3>This research was funded by</h3> National Institute of Health/National Institute on Aging (R01AG061100-01, NCT03926520)

Positron Emission Tomography–Derived Metrics Predict the Probability of Local Relapse After Oligometastasis-Directed Ablative Radiation Therapy

PurposeEarly positron emission tomography–derived metrics post–oligometastasis radioablation may predict impending local relapses (LRs), providing a basis for a timely ablation. Methods and MaterialsPositron emission tomography data of 623 lesions treated with either 24 Gy single-dose radiation therapy (SDRT) (n = 475) or 3 × 9 Gy stereotactic body radiation therapy (SBRT) (n = 148) were analyzed in a training data set (n = 246) to obtain optimal cutoffs for pretreatment maximum standardized uptake value (SUVmax) and its 3-month posttreatment decline (ΔSUVmax) in predicting LR risk, validated in a data set unseen to testing (n = 377). ResultsAt a median of 21.7 months, 91 lesions developed LRs: 39 of 475 (8.2%) after SDRT and 52 of 148 (35.1%) after SBRT. The optimal cutoff values were 12 for SUVmax and –75% for ΔSUVmax. Bivariate SUVmax/ΔSUVmax permutations rendered a 3-tiered LR risk stratification of dual-favorable (low risk), 1 adverse (intermediate risk) and dual-adverse (high risk). Actuarial 5-year local relapse-free survival rates were 93.9% versus 89.6% versus 57.1% (P < .0001) and 76.1% versus 48.3% versus 8.2% (P < .0001) for SDRT and SBRT, respectively. The SBRT area under the ROC curve was 0.71 (95% CI, 0.61-0.79) and the high-risk subgroup yielded a 76.5% true positive LR prediction rate. ConclusionsThe SBRT dual-adverse SUVmax/ΔSUVmax category LR prediction power provides a basis for prospective studies testing whether a timely ablation of impending LRs affects oligometastasis outcomes.

Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma.

Post-treatment decline in serum alpha-foetoprotein (AFP) levels has been shown to predict the treatment efficacy of antiangiogenic therapy for advanced hepatocellular carcinoma (HCC). We explored whether a decline in AFP levels was also associated with treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with advanced HCC. We reviewed all patients who received ICI therapy for advanced HCC. AFP response was evaluated in patients with the pretreatment AFP level of >20ng/mL. We defined early AFP response as a >20% decline in serum AFP levels within the first 4weeks of treatment initiation relative to pretreatment levels. We then studied whether early AFP response was associated with treatment outcomes. Sixty patients were enrolled in this study; 43 of them were evaluable for early AFP response. The objective response rate of early AFP responders was significantly higher than that of early AFP nonresponders (73% vs. 14%, P<.001). Early AFP responders, compared with early AFP nonresponders, exhibited significantly longer overall survival (OS) (median, 28.0 vs 11.2months, P=.048) and progression-free survival (PFS) (median, 15.2 vs 2.7months, P=.002). After adjusting for other clinicopathological variables and treatments, early AFP response remained an independent predictor for longer OS (hazard ratio [HR]=0.089, 95% confidence interval [CI]=0.018-0.441; P=.003) and PFS (HR=0.128, 95% CI=0.041-0.399; P<.001). Early AFP response was associated with higher treatment efficacy of ICIs for advanced HCC. Additional validation studies are nonetheless warranted.

Forms of attunement during the initial stages of music therapy for patients with acute psychosis - A multicentre clinical study

ABSTRACTThe aim of this non-experimental follow-up study was to specify and quantify rhythmic attunement processes within free improvisations in the early phase of psychodynamic music therapy in order to investigate its predictive value for therapeutic change. Twenty-one in-patients diagnosed with psychosis (ICD-10F20, 23, 25) were included in the study. Participants received five sessions of individual music therapy as per usual. Improvisations were audio recorded. The initial and final improvisations were analysed with the Rhythmic Attunement Scale for Psychosis (RAS-P), which was specifically developed for the project. Clinical measures included external and self-report assessments (BPRS, Dührsen and Happach, TAS 20). Analysis of the audio recordings revealed early occurrence of rhythmic attunement on a stable and qualitatively high level. BPRS scores showed a post-treatment decline of 20%. There was no significant difference for the Dührsen and Happach and TAS 20 scores. Statistical analysis revealed that when initial rhythmic attunement occurred further into the first session, it was a predictor for the decline of psychotic symptoms. Evidence of carefully organised rhythmic attunement suggests beneficial effects on patients with psychosis through improvisational music therapy. Results are limited due to a small sample size and lack of a control comparison.

Antidepressant use and cognitive decline in community-dwelling elderly people \u2013 The Three-City Cohort

BackgroundCognitive impairment is very common in late-life depression, principally affecting executive skills and information processing speed. The aim of the study was to examine the effect of antidepressant treatment on cognitive performances over a 10-year period.MethodsThe community-based cohort included 7381 participants aged 65 years and above. Five cognitive domains (verbal fluency, psychomotor speed, executive function, visuospatial skills and global cognition) were assessed up to five times over 10 years of follow-up. Treatment groups included participants under a specific antidepressant class at both baseline and the first follow-up and their follow-up cognitive data were considered until the last consecutive follow-up with a report of antidepressant use of the same class. Linear mixed models were used to compare baseline cognitive performance and cognitive decline over time according to antidepressant treatment. The models were adjusted for multiple confounders including residual depressive symptoms assessed by the Center for Epidemiologic Studies-Depression scale.ResultsAt baseline, 4.0% of participants were taking antidepressants. Compared to non-users, tricyclic antidepressant users had lower baseline performances in verbal fluency, visual memory and psychomotor speed, and selective serotonin reuptake inhibitor users in verbal fluency and psychomotor speed. For the two other cognitive abilities, executive function and global cognition, no significant differences were found at baseline irrespective of the antidepressant class. Regarding changes over time, no significant differences were observed in comparison with non-users whatever the cognitive domain, except for a slight additional improvement over the follow-up in verbal fluency skills for tricyclic antidepressant users.ConclusionsIn this large elderly general population cohort, we found no evidence for an association between antidepressant use and post-treatment cognitive decline over 10 years of follow-up in various cognitive domains.

Urodynamic assessment of short-term effects of pelvic radiotherapy on bladder function in patients with gynecologic cancers.

To determine the short-term effects of adjuvant or primary curative radiotherapy (RT) on the urinary system in women with gynecologic cancer. This is a prospective, concurrent cohort study including 55 patients with gynecologic cancer who were divided into three groups. Group 1 included 10 patients who were administered adjuvant RT following a radical hysterectomy (RH); Group 2 included 36 patients who were administered adjuvant RT following a type 1 hysterectomy and Group 3 included 9 patients who were administered primary curative RT. Urogynecologic assessments were carried out on patients before and six months after the treatment. Compared to pretreatment, no significant differences were observed in any of the three groups after treatment in terms of incontinence, first urge to urinate, normal urge to urinate, severe urge to urinate and changes in residual urine volumes. There was a significant decrease in maximal vesical pressure after treatment in Group 1 and Group 3. The maxi-mum detrusor pressure decreased significantly in Group 1. The post-treatment decline in bladder capacity in Group 1 and Group 2 was also significant. RH and pelvic RT cause lower urinary system dysfunction. Especially patients who receive primary curative RT and patients who are administered RT after RH, where more pelvic denervation occurs, are at higher risk due to high doses of RT.

Hypofractionated SBRT Versus Conventionally Fractionated EBRT for Prostate Cancer: Comparison of PSA Slope and Nadir

Patients with early stage prostate cancer have a variety of curative radiotherapy options, including conventionally-fractionated external beam radiotherapy (CF-EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Although results of CF-EBRT are well known, the use of SBRT for prostate cancer is a more recent development, and long-term follow-up is not yet available. However, rapid post-treatment PSA decline and low PSA nadir have been linked to improved clinical outcomes. The purpose of this study was to compare the PSA kinetics between CF-EBRT and SBRT in newly diagnosed localized prostate cancer. 75 patients with low to low-intermediate risk prostate cancer (T1-T2; GS 3 + 3, PSA 70.2 Gy, <76 Gy) to the prostate only, were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997–2012). Patients were excluded if they failed therapy by the Phoenix definition or had less than 1 year of follow-up or <3 PSAs. 43 patients who were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. PSA nadir and rate of change in PSA over time (slope) were calculated from the completion of RT to 1, 2 and 3 years post-RT. The median PSA nadir and slope for CF-EBRT was 1.00, 0.72 and 0.60 ng/ml and -0.09, -0.04, -0.02 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadirs and slopes were 0.70, 0.40, 0.24 ng and -0.09, -0.06, -0.05 ng/ml/month, respectively. The PSA slope for SBRT was greater than CF-EBRT (p < 0.05) at 2 and 3 years following RT, although similar during the first year. Similarly, PSA nadir was significantly lower for SBRT when compared to EBRT for years 2 and 3 (p < 0.005). Patients treated with SBRT experienced a lower PSA nadir and greater rate of decline in PSA 2 and 3 years following completion of RT than with CF-EBRT, consistent with delivery of a higher bioequivalent dose. Although follow-up for SBRT is limited, the improved PSA kinetics over CF-EBRT are promising for improved biochemical control.

Comparison of PSA slope and nadir between hypofractionated SBRT and conventionally fractionated EBRT.

112 Background: Patients with early stage prostate cancer have a challenge in selecting from a variety of curative radiotherapy options, including external beam radiotherapy (EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Rapid post-treatment PSA decline and low PSA nadir have been associated with improved clinical outcomes. The purpose of this study was to compare the PSA measurements over time between conventionally fractionated EBRT and SBRT in newly diagnosed localized prostate cancer. Methods: 104 patients with low to low-intermediate risk prostate cancer (GS 3+3, PSA &lt; 20 or 3+4, PSA &lt; 15) treated with standard fractionated EBRT (&gt; 70.2 Gy, &lt; 76 Gy) without hormones to the prostate only were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997-2012). Patients were excluded if they failed therapy by the Phoenix definition. All included patients had at least 1 year of follow up and 3 serial PSAs. 35 patients that were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. Of these, 47 and 19 patients treated with EBRT and SBRT, respectively, had a yearly increase in PSA follow-up over 3 years. PSA nadir and rate of change in PSA over time (e.g. slope) were calculated from the completion of RT to 1, 2 and 3 years post RT. Results: The median PSA nadir and slope for patients treated with EBRT was 0.80, 0.50, 0.40 ng and ‑0.07, ‑0.02, ‑0.01 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadir and slope were 0.73, 0.50, 0.24 ng and ‑0.09, ‑0.06, ‑0.05 ng/ml/month. The PSA slope for SBRT was greater than EBRT (p = 0.001) at 2 and 3 years following RT, although similar during the first year. These results were consistent when limited to patients with more complete PSA follow-up each year, with PSA nadir significantly lower 3 years after treatment with SBRT compared with EBRT (p = 0.03). Conclusions: Patients treated with SBRT experienced a more rapid decline in PSA 2 and 3 years following completion of RT than with EBRT, and for those with continuous long term followup, a lower PSA nadir, consistent with delivery of a higher bioequivalent dose.

IS6-4 - Results of Phase 1 Studies of Golvatinib (E7050), A c-Met and EPH Receptor-Targeted Multi-Kinase Inhibitor

ABSTRACT Background Golvatinib is a highly potent, small-molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. Golvatinib showed preclinical evidence of anti-tumor activity. Two phase 1 studies were conducted: a once daily (QD) dosing study in UK and a twice daily (BID) dosing study in JP to evaluate the MTD, safety, PK, PD and preliminary activity. Methods Golvatinib was administered orally, QD or BID, continuously to patients with advanced solid tumors. Blood samples for PK and PD analysis were collected at multiple time-points. Tumor tissues were collected pre- and post-cycle 1 for PD analysis in an expanded MTD cohort. Results 34 patients were treated at 6 QD doses levels (100, 200, 270, 360, 450 and 400 mg QD) and 16 patients were treated at 4 BID doses levels (50, 100, 200 and 300 mg BID). In the QD dosing, 3 DLTs occurred: Gr3 GGT and alkaline phosphatase (n = 1; 200 mg QD) and repeated Gr2 (n = 1) and Gr3 (n = 1) fatigue, both at 450 mg QD. In the BID dosing, one DLT (Gr3 ALT) and one equivalent DLT (Gr2 vomiting, nausea and anorexia) occurred, both at 300 mg BID. The MTDs were determined to be 400 mg QD and 200 mg BID. Frequently occurring AEs (of which, all ≤G3) across both dosing regimens (n = 50) were fatigue 58% (G3: 10%), nausea 56% (G3: 2%), diarrhea 54%, vomiting 48%, decreased appetite 48% (G3: 8%), ALT increase 44% (G3: 2%) and AST increase 32%. Best response included 6 SDs (>84 days) and 4 SDs (>84 days) in the QD and the BID dosing, respectively. PK showed high variability and plasma concentration increased with dose. The Cmax was reached at a median time of 2–4 h, and declined with a t1/2 of ∼40 h. Plasma PD analysis showed a significant increase in soluble c-Met levels after golvatinib treatment. Tumour tissue PD analysis in five patients at 400 mg QD demonstrated a baseline elevated MET gene copy number, with c-Met over-expression and post-treatment decline phospho (p)-c-Met expression in 1 patient, post-treatment decline in p-c-Met in the second patient, and post-treatment decline in p-ERK in the third patient. Conclusions The MTD of golvatinib was achieved at 400 mg QD and 200 mg BID. Preliminary PD analysis demonstrated evidence of c-Met target modulation. QD dosing was selected for further evaluation of golvatinib in phase 2 studies.

Accumulating Evidence for the Effect of Chemotherapy on Cognition

A strength of meta-analysis is that it provides a technique for examining broad trends in data across studies. However, there is consensus among many investigators associated with the International Cognition and Cancer Task Force that a subgroup of patients may be particularly vulnerable to post-treatment cognitive change. 10 Age and education were not shown to moderate the effects of chemotherapy-induced cognitive change in the present meta-analysis. However, as the authors acknowledge, most studies included relatively young to middle-aged patients who tend to be highly educated. Therefore, there may not have been sufficient numbers of patients who are older or who have lower education levels to yield significant associations. This possibility is illustrated in a recent study that demonstrated that age and cognitive reserve (which is influenced by such factors as education, occupation, and cognitive stimulation) were associated with post-treatment cognitive decline. Those older patients with low levels of pretreatment cognitive reserve who were exposed to chemotherapy were most vulnerable to post-treatment cognitive decline as assessed on measures of processing speed. 4

Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally QD to patients with advanced solid tumors.

3030 Background: Golvatinib is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. Golvatinib showed preclinical evidence of anti-tumor activity. This phase 1 study was performed to determine the MTD, safety, PK, PD and preliminary activity of golvatinib. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, ≥ 18 years (yrs) and adequate organ function were eligible. Golvatinib was administered orally, once daily (QD), continuously. Blood samples for PK and PD analysis were collected at multiple time-points. Mandatory tumor biopsies for PD analysis were taken pre and post Cycle 1 in an expanded MTD cohort. Results: 34 pts (M/F: 21/13; median age 63.5yrs [range 32-78]) were treated at 6 dose levels: 100, 200, 270, 360, 450 and 400 mg. Tumor types were colorectal (n=15), lung (n=4), renal (n=4), esophageal (n=2), melanoma (n=2) and others (n=7). Three DLTs were observed: Gr3 GGT and alkaline phosphatase (n=1; 200mg) and repeated Gr2 (n=1) and Gr3 (n=1) fatigue, both at 450mg. The MTD was determined to be 400 mg QD. Frequently occurring adverse events ([AEs]; all grades) were fatigue: 68% (Gr3: 15%), diarrhea: 65%, nausea: 62%, vomiting: 53%, decreased appetite: 47% (Gr3: 9%), ALT increase: 38% and AST increase: 23%. No Gr4 AEs were observed. Best response was stable disease in 6 pts lasting &gt;84 days. PK showed high variability and plasma concentration increased with dose. The Cmax was reached within a median time of 4 hours. Plasma PD analysis showed an increase in soluble c-Met and Ang 2 levels after golvatinib treatment. Tumor PD analysis in 5 pts at 400 mg demonstrated a baseline elevated MET gene copy number, with c-Met overexpression and post treatment decline in phospho(p)-c-Met expression in 1 pt; post-treatment decline in p-c-Met in a 2nd pt, and post-treatment decline in p-ERK in a 3rd pt. Conclusions: Golvatinib at an MTD of 400 mg QD has manageable toxicity. Preliminary PD analysis demonstrated evidence of c-Met target modulation. Further evaluation will continue in phase 2 combination studies.

VALIDATION OF THE RUSSIAN-LANGUAGE VERSION OF THE RAPID-3 QUESTIONNAIRE

Система комплексной поддержки и сопровождения научного журнала Elpub позволяет запустить двуязычный сайт журнала со встроенной системой электронной редакции в соответствии с лучшими издательскими практиками, а так же предусматривает техническую и методическую поддержку со стороны специалистов НЭИКОН.

Longitudinal Assessment of Cognitive Changes Associated With Adjuvant Treatment for Breast Cancer: Impact of Age and Cognitive Reserve

To examine the impact of age and cognitive reserve on cognitive functioning in patients with breast cancer who are receiving adjuvant treatments. Patients with breast cancer exposed to chemotherapy (n = 60; mean age, 51.7 years) were evaluated with a battery of neuropsychological and psychological tests before treatment and at 1, 6, and 18 months after treatment. Patients not exposed to chemotherapy (n = 72; mean age, 56.6 years) and healthy controls (n = 45; mean age, 52.9 years) were assessed at matched intervals. Mixed-effects modeling revealed significant effects for the Processing Speed and Verbal Ability domains. For Processing Speed, a three-way interaction among treatment group, age, and baseline cognitive reserve (P < .001) revealed that older patients with lower baseline cognitive reserve who were exposed to chemotherapy had lower performance on Processing Speed compared with patients not exposed to chemotherapy (P = .003) and controls (P < .001). A significant group by time interaction for Verbal Ability (P = .01) suggested that the healthy controls and no chemotherapy groups improved over time. The chemotherapy group failed to improve at 1 month after treatment but improved during the last two follow-up assessments. Exploratory analyses suggested a negative effect of tamoxifen on Processing Speed (P = .036) and Verbal Memory (P = .05) in the no-chemotherapy group. These data demonstrated that age and pretreatment cognitive reserve were related to post-treatment decline in Processing Speed in women exposed to chemotherapy and that chemotherapy had a short-term impact on Verbal Ability. Exploratory analysis of the impact of tamoxifen suggests that this pattern of results may be due to a combination of chemotherapy and tamoxifen.

Interactive effects of O3 exposure on California black oak (Quercus kelloggii Newb.) seedlings with and without N amendment

We examined the short-term separate and combined effects of simulated nitrogen (N) deposition (fertilization) and ozone (O(3)) exposure on California black oak seedlings (Quercus kelloggii Newb.), an ecologically important tree of the San Bernardino Mountains downwind of Los Angeles. Realistic concentrations of O(3) were found to cause statistically and biologically significant negative effects on plant health, including lowered photosynthetic ability, lowered water use efficiency, and increased leaf chlorosis and necrosis. When subjected to abrupt changes in light levels, O(3)-exposed plants showed both a slower and smaller response than O(3)-free plants. Fertilized plants exhibited a significantly greater pre- to post-treatment decline in A at saturated [CO(2)] and a significantly lower level of post-treatment chlorosis than unfertilized plants. Fertilization tended to reduce plant sensitivity to O(3).

Analysis of prostate-specific antigen decline as a surrogate for overall survival in metastatic hormone-refractory prostate cancer (HRPC)

5009 Background: A 30% PSA decline following initiation of cytotoxic chemotherapy has been identified as a potential surrogate for overall survival in metastatic HRPC. We sought to examine whether various levels of PSA decline were surrogates for overall survival in TAX327, a randomized trial of q3w docetaxel and prednisone (DP), q1w DP, and q3w mitoxantrone and prednisone (MP). Methods: In this trial of 1006 men with HRPC, 943 men had sufficient data on 3-month post-treatment PSA decline for analysis, and 646 had sufficient data for analysis for a change in PSA kinetics with therapy. Surrogacy was examined for a range of PSA decline from 0% to 90% and PSA normalization, and for post-treatment changes in PSA kinetics. We investigated the Prentice Criteria for surrogacy using Cox proportional hazards models and calculated the proportion of treatment effect explained (PTE) by each surrogate marker. Results: In this analysis, a 30% or greater PSA decline with therapy was identified as the optimal cutoff that correlated with overall survival, based on the highest PTE point estimate (0.66, 95% CI 0.23–1.0), with 1.0 being a perfect surrogate. A 30% decline in PSA in the first 3 months after treatment occurred in 65% of subjects receiving q3w DP, 67% q1w DP, and 44% q3w MP, despite the significant survival benefits seen only with q3w DP. A 30% PSA decline was associated with a hazard ratio (HR) of 0.43 (95% CI 0.36–0.51) for overall survival after adjusting for treatment effect, while treatment effect itself lost significance, indicating surrogacy. Additionally, PSA normalization, changes in PSA kinetics, and pain response were significant prognostic variables, yet were only modest surrogates for the survival benefit seen with q3w DP therapy. Conclusions: In this trial of two schedules of DP as compared to MP for HRPC, a PSA decline of 30% in the first three months following initiation of cytotoxic chemotherapy was found to have the highest degree of surrogacy for overall survival, thus confirming data from the SWOG 9916 trial. However, given that the confidence interval for the estimate of this surrogate effect is wide, overall survival should remain the preferred endpoint for phase III trials of cytotoxic agents in HRPC. No significant financial relationships to disclose.

Development of a New Psychosocial Treatment for Adult ADHD

Objective: The purpose of this study was to assess the effectiveness of a new manualized group Meta-Cognitive Therapy (MCT) for adults with ADHD that extends the principles and practices of cognitive-behavioral therapy to the development of executive self-management skills. Method: Thirty adults diagnosed with ADHD completed an 8- or 12-week program designed to target impairments in time management, organization, and planning skills. Treatment efficacy was measured using pre- and posttreatment self-report standardized measures (CAARS-S:L & Brown ADD Scales). Results: General linear modeling revealed a robust significant posttreatment decline on the CAARS DSM-IV Inattentive symptom scale (p < .001) as well as improvement on the Brown ADD Scales (p < .001). Conclusion: The findings indicate that participants in the MCT program showed marked improvement with respect to core ADHD symptoms of inattention, as well as executive functioning skills, suggesting that this program has promise as a treatment for meta-cognitive deficits in adults with ADHD. (J. of Att. Dis. 2008; 11(6) 728-736)

Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials

To the investigator and clinician, prostate-specific antigen (PSA) level is a seemingly perfect outcome measure because it is easily assessable, quantitative, reproducible, and inexpensive. Whether post-therapy decline in PSA reflects true clinical benefit, and whether post-therapy declines can be used as an intermediate endpoint for accelerated drug approval is still open to question. At present, no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Post-therapy PSA changes have been associated with improved survival in patients with castrate metastatic disease. The role of PSA changes as potential surrogates of clinical benefit have only been explored to a limited degree because to date, only two prospective randomized trials showing a survival benefit have been reported. Such trials are necessary, but not a sufficient pre-requisite to explore the potential role of any outcome measure as an intermediate endpoint. The clear demonstration that a post-therapy PSA change can account for all of the treatment effects seen is not yet available. A cytotoxic drug that does not produce any PSA decline is unlikely to be effective, but the converse is not always true because not all PSA rises represent a treatment failure. It is important to recognize that there are a range of clinical benefits to patients that can improve the quality and possibly the duration of survival, independent of PSA.