Karen E. Wickersham

Characterization of a Novel Prostate-Specific Antigen–Activated Peptide-Doxorubicin Conjugate in Patients With Prostate Cancer

PURPOSE To evaluate safety and pharmacokinetics (PK), and determine the recommended dose for efficacy studies, of L-377202, a novel peptide conjugate of doxorubicin (Dox) that releases the active metabolites leucine-doxorubicin (Leu-Dox) and Dox on cleavage by membrane-bound prostate-specific antigen (PSA). PATIENTS AND METHODS Nineteen patients with advanced hormone-refractory prostate cancer were treated intravenously with 71 cycles of L-377202 at escalating dose levels of 20 (n = 1), 40 (n = 3), 80 (n = 4), 160 (n = 3), 225 (n = 6), and 315 mg/m(2) (n = 2) once every 3 weeks. Toxicity, response, and PK of L-377202 were assessed. RESULTS L-377202 was well tolerated. Dose-limiting grade 4 neutropenia was noted in two of two patients administered 315 mg/m(2) (both patients were able to resume therapy at 225 mg/m(2)). The recommended dose for efficacy studies was 225 mg/m(2), which induced grade 4 neutropenia in one of six patients. PK studies demonstrated that L-377202 was metabolized to Leu-Dox and Dox. PK were linear; after administration of single doses of 225 mg/m(2), the mean area under the concentration-time profiles of L-377202, Leu-Dox, and Dox were 6 micromol x L/h, 4 micromol x L/h, and 1 micromol x L/h, and peak concentrations were 14 micromol/L, 5 micromol/L, and 120 nmol/L, respectively. At 225 and 315 mg/m(2), five patients completed at least three cycles of therapy; two patients had a greater than 75% decrease in PSA, and one patient had a stabilized PSA. No response was noted at dose levels less than 225 mg/m(2). CONCLUSION This is the first study of selective drug delivery in humans using a novel PSA-activated agent. L-377202 was cleaved to produce detectable levels of the active metabolites Leu-Dox and Dox. L-377202 was well tolerated and established a safe dose level for further study.

Assessing Fidelity to an Intervention in a Randomized Controlled Trial to Improve Medication Adherence

Background:Behavioral intervention effectiveness in randomized controlled trials requires fidelity to the protocol. Fidelity assessment tools tailored to the intervention may strengthen intervention research. Objective:The aim of this study was to describe the assessment of fidelity to the structured intervention protocol in an examination of a nurse-delivered telephone intervention designed to improve medication adherence. Methods:Fidelity assessment included random selection and review of approximately 10% of the audiorecorded intervention sessions, stratified by interventionist and intervention session. Audiotapes were reviewed along with field notes for percentage of agreement, addressing whether key components were covered during the sessions. Visual analog scales were used to provide summary scores (0 = low to 5 = high) of interaction characteristics of the interventionists and participants with respect to engagement, demeanor, listening skills, attentiveness, and openness. Results:Four nurse interventionists delivered 871 structured intervention sessions to 113 participants. Three trained graduate student researchers assessed 131 intervention sessions. The mean percentage of agreement was 92.0% (±10.5%), meeting the criteria of 90% congruence with the intervention protocol. The mean interventionist interaction summary score was 4.5 ± 0.4, and the mean participant interaction summary score was 4.5 ± 0.4. Discussion:Overall, the interventionists successfully delivered the structured intervention content, with some variability in both the percentage of agreement and quality of interaction scores. Ongoing assessment aids in ensuring fidelity to study protocol and having reliable study results.

“Keeping the Boogie Man Away”: Medication Self-Management among Women Receiving Anastrozole Therapy

The oral hormonal agent anastrozole improves clinical outcomes for women with breast cancer, but women have difficulty taking it for the five-year course. The unique medication-taking experiences related to self-management of anastrozole therapy for women with early stage breast cancer are not known. Our purpose was to describe the medication-taking experiences for postmenopausal women with early stage breast cancer who were prescribed a course of anastrozole therapy. Twelve women aged 58 to 67 years, midway through therapy, participated in audio-recorded interviews. Womens medication-taking experiences involved a belief in their importance and an imperative to take anastrozole. We found that womens side effect experiences, particularly menopausal symptoms, were significant, but only one woman stopped anastrozole due to side effects. Medication-taking included routinization interconnected with remembering/forgetting and a storage strategy. Some women noted a mutual medication-taking experience with their spouse, but most felt taking anastrozole was something they had to do alone. Our results provide insight into the way some women with early stage breast cancer manage their hormonal therapy at approximately the midpoint of treatment. Next steps should include examinations of patient-provider communication, potential medication-taking differences between pre- and postmenopausal women, and the effects of medication-taking on clinical outcomes.

Pretreatment predictors of short-term nonadherence to oral hormonal therapy for women with breast cancer.

Background:Adjuvant treatment with oral hormonal therapy improves clinical outcomes for breast cancer, but women have difficulty adhering to the 5-year regimen. Objective:The aim of this study was to explore pretreatment predictors of short-term nonadherence to oral hormonal therapy for women with early-stage breast cancer from the pretreatment assessment to 6 months after initiation of hormonal therapy. Methods:A secondary analysis was performed using data collected from 198 women enrolled in one of two longitudinal studies. Nonadherence was defined as the percentage of prescribed doses of hormonal therapy not taken during the first 6 months of therapy measured using electronic medication event monitoring. Information on predictor variables was measured at pretreatment using self-report and medical record review. Linear regression analysis was performed to examine associations between predictor variables and 6-month nonadherence in a bivariate manner to first identify candidate predictors variables at p < .20 and then multivariately considering candidate predictors identified through stepwise and backward elimination regression methods. Results:Participants were White (98.3%), well educated (M = 15.0; SD = 2.9 years of schooling), and on average, 59.1 years old (SD = 7.5 years old). Mean nonadherence was 11.3%. Stepwise and backward elimination modeling algorithms identified a similar set of predictors associated with 6-month nonadherence and explained 13.0% of the variance (adjusted R2 = .11, standard error of the estimate = 0.28). Ductal carcinoma in situ tumor type (p = .004) and higher weight concern scores (p = .003) were associated with nonadherence. Discussion:The findings suggest that additional examinations of associations of tumor type and symptom burden with nonadherence are indicated.

Targeted therapy use in adults with cancer ≥85 years of age

Purpose: Assess patient‐ and clinical‐related variables associated with targeted cancer treatments (TTs) for adults ≥85 years of age. Rationale: TTs have pathway‐specific side effects that negatively affect QoL and medication adherence, which may reduce TT efficacy. Research has not focused on patients aged ≥85 years; therefore, the scope of TT use in this age group is not understood. Methods: We conducted an electronic medical record review to identify individuals ≥85 years treated with TT. Results: The sample (N = 295) was 53.5% male, 41% married/partnered, and 73.7% Caucasian. Common cancer types included breast (26.3%), prostate (31.3%), and leukemia (14.1%). Only one‐third (n = 98) of the sample had TT side effects noted in their patient chart. Conclusions: Patients aged ≥85 years took similar TTs and experienced similar side effects as reported by research of younger patients; however, symptom experience was not well‐reported.

Conducting Biobehavioral Research in Patients With Advanced Cancer: Recruitment Challenges and Solutions:

Despite significant advances in cancer treatment and symptom management interventions over the last decade, patients continue to struggle with cancer-related symptoms. Adequate baseline and longitudinal data are crucial for designing interventions to improve patient quality of life and reduce symptom burden; however, recruitment of patients with advanced cancer in longitudinal research is difficult. Our purpose is to describe challenges and solutions to recruitment of patients with advanced cancer in two biobehavioral research studies examining cancer-related symptoms. Study 1: Symptom data and peripheral blood for markers of inflammation were collected from newly diagnosed patients receiving chemotherapy on the first day of therapy and every 3–4 weeks for up to 6 months. Study 2: Symptom data, blood, and skin biopsies were collected from cancer patients taking epidermal growth factor receptor inhibitors at specific time points over 4 months. Screening and recruitment results for both studies are summarized. Timing informed consent with baseline data collection prior to treatment initiation was a significant recruitment challenge for both the studies. Possible solutions include tailoring recruitment to fit clinic needs, increasing research staff availability during clinic hours, and adding recruitment sites. Identifying solutions to these challenges will permit the conduct of studies that may lead to identification of factors contributing to variability in symptoms and development of tailored patient interventions for patients with advanced cancer.

P4-12-12: Patient-, Illness-, and/or Treatment-Related Baseline Predictors of Nonadherence to Oral Hormonal Therapy.

Background: Nonadherence to oral hormonal therapy is problematic for women with breast cancer. Patient-, illness-, and treatment-related factors have been associated with nonadherence, but with inconsistent findings. Therefore, our aim was to explore predictors of nonadherence to hormonal therapy for women with early stage breast cancer from the baseline assessment (pre-hormonal therapy) to 6 months post-treatment. Methods: A secondary analysis was performed to explore potential patient-, illness-, and treatment-related predictors of nonadherence for 198 women enrolled in either: 1) The Anastrozole Use in Menopausal Women Study (AIM Study, n=162), or, 2) Predictors of Adherence to Hormonal Therapy in Breast Cancer (ONS Study, n=36). Nonadherence was defined as the percentage of prescribed administrations of hormonal therapy that were not taken during the first 6 months of therapy as measured using an electronic Drug Exposure Monitor (eDEM) (AARDEX, Ltd.). Chi-square tests of independence and Mann-Whitney U tests were performed to determine whether data from the two studies could be pooled. Descriptive statistics were performed to characterize the sample. Multiple linear regression analyses were performed to identify the best model in two stages: 1) univariate relationships between each candidate predictor variable and the outcome variable (6-month nonadherence) were assessed using a cut-off of p=.20; and, 2) candidate predictors meeting the criteria were retained for further exploration in model-building multiple linear regression analyses (stepwise and backward) to determine the predictors of 6-month nonadherence summary scores. Candidate predictors were retained in the model if they remained associated at p Results: Women were 98.3% Caucasian with a mean age 59.1 years (SD 7.5) and mean number of years of education of 15.0 (SD 2.9). Overall mean nonadherence was 11.6% (13.2% AIM Study, 4.6% ONS Study). Chi-square and Mann-Whitney U tests demonstrated that the two samples could be pooled, given the data were similar on key variables (number of years of education, depression, anxiety, fatigue, symptoms, and nonadherence). Both stepwise and backward elimination modeling algorithms demonstrated evidence of 3 significantly significant variables associated with nonadherence; however, the backward elimination model best represented the sample (R 2 =.106, adjusted R 2 =.086, s=0.28490). Women who worked (p=.082), whose primary occupation was clerical or administrative (p=.029), had DCIS tumor type (p=.017), or who had higher gastrointestinal (GI) symptoms scores (p=.013) were associated with nonadherence. The potential for interactions between primary occupation, DCIS tumor type, and higher GI symptoms was explored and was not significant. In addition, while all tumor types were examined as candidate predictors, participants with DCIS also had another tumor to be eligible for the parent studies. Conclusions: Our study offers insight into potential predictors of nonadherence for women participating in one of two cohort studies. The findings suggest additional examinations of nonadherence concerning work and symptom burden and their relationship to nonadherence are indicated. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-12.