Julia Lawrence

Low to Moderate Dose Anthracycline-Based Chemotherapy Is Associated With Early Noninvasive Imaging Evidence of Subclinical Cardiovascular Disease

OBJECTIVES The goal of this study was to determine if low to moderate doses of anthracycline-based chemotherapy (Anth-bC) are associated with subclinical cardiovascular (CV) injury. BACKGROUND Cancer survivors who receive Anth-bC experience premature CV events. It is unknown whether low to moderate doses of anthracyclines promote early subclinical CV disease manifested by deteriorations in left ventricular ejection fraction (LVEF) or increases in aortic stiffness, or if these doses are associated with changes in quality of life (QOL). METHODS In 53 men and women with breast cancer, leukemia, or lymphoma, we assessed left ventricular volumes, LVEF, circumferential strain, aortic pulse wave velocity, late gadolinium enhancement, serum B-type natriuretic peptide, troponin I, and the impact of treatment on QOL before and 1, 3, and 6 months after receipt of Anth-bC. RESULTS Participants averaged 50 ± 2 (range 19 to 80) years in age, 58% were women, 17% were black, and they each received a range of 50 to 375 mg/m(2) of doxorubicin-equivalent chemotherapy. Left ventricular end-systolic volume (48 ± 3 ml to 54 ± 3 ml; p = 0.02), left ventricular strain (-17.7 ± 0.4 to -15.1 ± 0.4; p = 0.0003), pulse wave velocity (6.7 ± 0.5 m/s to 10.1 ± 1 m/s; p = 0.0006), and QOL deterioration (15.4 ± 3.3 to 28.5 ± 3.9; p = 0.008) increased, whereas LVEF (58 ± 1% to 53 ± 1%; p = 0.0002) decreased within 6 months after low to moderate doses of Anth-bC. All findings persisted after accounting for age, gender, race (white/black), doxorubicin-equivalent dose, doxorubicin administration technique, comorbidities associated with CV events, and cancer diagnosis (p = 0.02 to 0.0001 for all). There were no new late gadolinium enhancement findings after 6 months. CONCLUSIONS In these study patients, low to moderate doses of Anth-bC were associated with the early development of subclinical abnormalities of cardiac and vascular function that in other populations are associated with the future occurrence of CV events.

Aortic Stiffness Increases Upon Receipt of Anthracycline Chemotherapy

PURPOSE Cancer survivors exposed to anthracyclines experience an increased risk of cardiovascular (CV) events. We hypothesized that anthracycline use may increase aortic stiffness, a known predictor of CV events. PATIENTS AND METHODS We performed a prospective, case-control study involving 53 patients: 40 individuals who received an anthracycline for the treatment of breast cancer, lymphoma, or leukemia (cases), and 13 age- and sex-matched controls. Each participant underwent phase-contrast cardiovascular magnetic resonance measures of pulse wave velocity (PWV) and aortic distensibility (AoD) in the thoracic aorta at baseline, and 4 months after initiation of chemotherapy. Four one-way analyses of covariance models were fit in which factors known to influence thoracic aortic stiffness were included as covariates in the models. Results At the 4-month follow-up visit, aortic stiffness remained similar to baseline in the control participants. However, in the participants receiving anthracyclines, aortic stiffness increased markedly (relative to baseline), as evidenced by a decrease in AoD (P < .0001) and an increase in PWV (P < .0001). These changes in aortic stiffness persisted after accounting for age, sex, cardiac output, administered cardioactive medications, and underlying clinical conditions known to influence aortic stiffness, such as hypertension or diabetes (P < .0001). CONCLUSION A significant increase in aortic stiffness occurs within 4 months of exposure to an anthracycline which was not seen in an untreated control group. These results indicate that previously regarded cardiotoxic cancer therapy adversely increases thoracic aortic stiffness, a known independent predictor of adverse cardiovascular events.

Longitudinal Assessment of Concurrent Changes in Left Ventricular Ejection Fraction and Left Ventricular Myocardial Tissue Characteristics After Administration of Cardiotoxic Chemotherapies Using T1-Weighted and T2-Weighted Cardiovascular Magnetic Resonance

Background—In a murine anthracycline-related cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially cardiotoxic chemotherapy. Methods and Results—In 65 individuals with breast cancer (n=51) or a hematologic malignancy (n=14), we measured left ventricular volumes, ejection fraction, and contrast-enhanced T1-weighted and T2-weighted signal intensity before and 3 months after initiating potentially cardiotoxic chemotherapy using blinded, unpaired analysis of cardiovascular magnetic resonance images. Participants were aged 51±12 years, of whom 55% received an anthracycline, 38% received a monoclonal antibody, and 6% received an antimicrotubule agent. Overall, left ventricular ejection fraction decreased from 57±6% to 54±7% (P<0.001) because of an increase in end-systolic volume (P<0.05). T1-weighted signal intensities also increased from 14.1±5.1 to 15.9±6.8 (P<0.05), with baseline values trending higher among individuals who received chemotherapy before study enrollment (P=0.06). Changes in T1-weighted signal intensity did not differ within the 17 LV myocardial segments (P=0.97). Myocardial edema quantified from T2-weighted images did not change significantly after 3 months (P=0.70). Conclusions—Concordant with previous animal studies, cardiovascular magnetic resonance measures of contrast-enhanced T1-weighted signal intensity occur commensurate with small but significant left ventricular ejection fraction declines 3 months after the receipt of potentially cardiotoxic chemotherapy. These data indicate that changes in T1-weighted signal intensity may serve as an early marker of subclinical injury related to the administration of potentially cardiotoxic chemotherapy in human subjects.

Chronic Statin Administration May Attenuate Early Anthracycline-Associated Declines in Left Ventricular Ejection Function

Background Recent studies show an association between statin therapy and a reduced risk of heart failure among breast cancer survivors. Our goal was to evaluate whether statin therapy for prevention of cardiovascular disease (CVD) would ameliorate declines in left ventricular ejection fraction (LVEF) often observed during anthracycline-based chemotherapy (Anth-bC). Methods In 51 participants (33 women and 18 men; aged 48±2 years), we performed CV magnetic resonance (CMR) measurements of LVEF before and 6 months after initiation of Anth-bC for patients with breast cancer, leukemia, or lymphoma. Fourteen individuals received statin therapy, and 37 received no statin. MR image analysts were blinded to participant identifiers. Results Those receiving statins were older and often had diabetes (DM), hypertension (HTN), and hyperlipidemia (HLD). For those receiving statins, LVEF was 56.6±1.4% at baseline and 54.1±1.3% 6 months after initiating anthracycline (p=0.15). For those not receiving a statin, LVEF was 57.5±1.4% at baseline and decreased to 52.4±1.2% over a similar 6 month interval (p=0.0003). In a multivariable model accounting for age, sex, DM, HTN, HLD, and cumulative amount of anthracycline received, LVEF remained unchanged in participants receiving a statin (+ 1.1±2.6%) versus a −6.5±1.5% decline among those not receiving a statin (p=0.03). Conclusion In conclusion, these data highlight that individuals receiving statin therapy for prevention of CVD may experience less deterioration in LVEF upon early receipt of Anth-bC than individuals not receiving a statin. Further studies with large numbers of participants are warranted to determine if statins protect against LVEF decline in patients receiving Anth-bC.

Cognitive Factors Associated with Adherence to Oral Antiestrogen Therapy: Results from the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) Study

Little is known about the cognitive factors associated with adherence to antiestrogen therapy. Our objective was to investigate the association between domain-specific cognitive function and adherence among women in a clinical prevention trial of oral antiestrogen therapies. We performed a secondary analysis of Co-STAR, an ancillary study of the STAR breast cancer prevention trial in which postmenopausal women at increased breast cancer risk were randomized to tamoxifen or raloxifene. Co-STAR enrolled nondemented participants ≥65 years old to compare treatment effects on cognition. The cognitive battery assessed global cognitive function (Modified Mini-Mental State Exam), and specific cognitive domains of verbal knowledge, verbal fluency, figural memory, verbal memory, attention and working memory, spatial ability, and fine motor speed. Adherence was defined by a ratio of actual time taking therapy per protocol ≥80% of expected time. Logistic regression was used to evaluate the association between cognitive test scores and adherence to therapy. The mean age of the 1,331 Co-STAR participants was 67.2 ± 4.3 years. Mean 3MS score was 95.1 (4.7) and 14% were nonadherent. In adjusted analyses, the odds of nonadherence were lower for those with better scores on verbal memory [OR (95% confidence interval): 0.75 (0.62–0.92)]. Larger relative deficits in verbal memory compared with verbal fluency were also associated with nonadherence [1.28 (1.08–1.51)]. Among nondemented older women, subtle differences in memory performance were associated with medication adherence. Differential performance across cognitive domains may help identify persons at greater risk for poor adherence. Cancer Prev Res; 7(1); 161–8. ©2013 AACR.

Comorbidity, age, and mortality among adults treated intensively for acute myeloid leukemia (AML)

INTRODUCTION Our goal was to characterize comorbidities among adults receiving intensive therapy for AML, and investigate their association with outcomes. METHODS We retrospectively analyzed 277 consecutive patients with newly diagnosed AML treated intensively at the Comprehensive Cancer Center of Wake Forest University from 2002 to 2009. Pretreatment comorbidities were identified by ICD-9 codes and chart review. Comorbidity burden (modified Charlson Comorbidity Index [CCI]) and specific conditions were analyzed individually. Outcomes were overall survival (OS), remission, and 30-day mortality. Covariates included age, gender, cytogenetic characteristics, hemoglobin, white cell count, lactate dehydrogenase, body mass index, and insurance type. Cox proportional hazards models were used to evaluate OS; logistic regression was used for remission and 30-day mortality. RESULTS In this series, 144 patients were ≥ 60 years old (median age 70 years, median survival 8.7 months) and 133 were <60 years (median age 47 years, median survival 23.1 months). Older patients had a higher comorbidity burden (CCI≥1 58% versus 26%, P<0.001). Prevalent comorbid conditions differed by age (diabetes 19.2% versus 7.5%; cardiovascular disease 12.5% versus 4.5%, for older versus younger patients, respectively). The CCI was not independently associated with OS or 30-day mortality in either age group. Among older patients, diabetes was associated with higher 30-day mortality (33.3% vs. 12.0% in diabetic vs. non-diabetic patients, p=0.006). Controlling for age, cytogenetic characteristics and other comorbidities, the presence of diabetes increased the odds of 30-day mortality by 4.9 (CI 1.6-15.2) times. DISCUSSION Diabetes is adversely associated with 30-day survival in older AML patients receiving intensive therapy.

Prolonged Regression of Metastatic Leptomeningeal Breast Cancer That Has Failed Conventional Therapy: A Case Report and Review of the Literature

Approximately 5% of breast cancer patients develop leptomeningeal metastases over the course of their disease. Though several treatments options are available for these patients, their prognosis is typically considered to be poor. We report a case of leptomeningeal failure after a patient underwent prior radiotherapy, radiosurgery, surgery, chemotherapy, and biologic therapy. This patient experienced a prolonged response after receiving bevacizumab and capecitabine. The literature currently contains several reports regarding the use of systemic therapy to manage leptomeningeal metastases from breast cancer, which we summarize. Finally, we review the relevant effects of the patients treatment modalities and provide a rationale for the mechanism that led to her prolonged response.

Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D2) in women receiving chemotherapy for metastatic breast cancer: A feasibility trial

The vitamin D hormone, [1,25(OH)2D, calcitriol], inhibits proliferation and angiogenesis in breast cancer but its therapeutic use is limited by hypercalcemia. Synthetic analogs of 1,25(OH)2D that are less calcemic, such as paricalcitol (19-nor-1,25-Dihydroxyvitamin D2), are used to treat hyperparathyroidism associated with chronic kidney disease. We sought to determine the safety and feasibility of taking oral paricalcitol with taxane-based chemotherapy in women with metastatic breast cancer (MBC). Oral paricalcitol was considered safe if it did not result in excessive toxicity, defined as grade 3 or higher serum calcium levels. It was considered feasible if the majority of women could take eight weeks of continuous therapy in the first three months. Serum calcium was monitored weekly and the paricalcitol dose was adjusted based on its calcemic effect. Intact parathyroid hormone (iPTH) was monitored as a marker of paricalcitol activity. Twenty-four women with MBC were enrolled. Twenty women (83%) received eight weeks of continuous therapy. Paricalcitol was well-tolerated with no instances of hypercalcemia grade 2 or greater. Fourteen women (54%) were able to escalate the dose. The dose range of paricalcitol in the first 3 mo was 2–7 ug/day. Serum iPTH levels at baseline were significantly higher in women with serum 25-Hydroxyvitamin D (25-OHD) levels less than 30 ng/ml (96.4 ± 40.9 pg/ml) vs. 46.2 ± 20.3 pg/ml (p = 0 0.001) (iPTH reference 12–72 pg/ml). We conclude that paricalcitol is safe and feasible in women with MBC who are receiving chemotherapy.

Phase I Study and Biomarker Analysis of Lapatinib and Concurrent Radiation for Locally Advanced Breast Cancer

PURPOSE This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways. METHODS Eligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry. RESULTS Doses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per response evaluation criteria in solid tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation. CONCLUSIONS The combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen.

Weight Loss Intervention in Survivors of ER/PR-negative Breast Cancer

Numerous studies have found that increased body size (weight or body mass index) is a risk factor for breast cancer development, recurrence, and death. The detrimental relationship between body size and breast cancer recurrence may be more pronounced among women with estrogen receptor (ER)/progesterone receptor (PR)-negative breast cancer. Considering the limited availability of treatments, and the association between body size and recurrence, alternative treatments are needed for ER/PR-negative breast cancer survivors, particularly overweight survivors. The objective of this pilot study was to examine the feasibility of a 12-week, multi-component meal-replacement weight loss intervention among overweight or obese ER/PR-negative breast cancer survivors; and to obtain preliminary data on changes in anthropometrics, biomarkers, and health-related quality of life (QOL). The 12-week intervention included a portion-controlled diet (including meal replacements) and a multi-component intervention (including behavioral techniques, diet modification, physical activity, and social support). The goal of the intervention was to help participants lose 5% or more of their initial weight by reducing their caloric intake and increasing their physical activity (to at least 15 minutes each day). Paired t-tests assessed changes in continuous measures. Body weight was measured weekly and mixed-model regression analysis assessed change in weight over time. Nineteen ER/PR-negative breast cancer survivors with a mean age of 59 years participated in the study. All but two of the participants completed the 12-week intervention. Women lost an average of 6.3 ± 4.9 kg (P < 0.001), equivalent to 7.5% of their baseline weight. There were significant reductions in waist circumference (P = 0.001), percent fat mass (P < 0.001), total cholesterol (P = 0.026), and triglycerides (P = 0.002); and improvements in health-related QOL (P = 0.017). Findings suggested that a meal-replacement weight loss approach among ER/PR-negative breast cancer survivors was feasible and was well received.