Heather Shaw

Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil–Based Paclitaxel in Women With Breast Cancer

PURPOSE ABI-007, the first biologically interactive albumin-bound paclitaxel in a nanameter particle, free of solvents, was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with standard paclitaxel. PATIENTS AND METHODS Patients were randomly assigned to 3-week cycles of either ABI-007 260 mg/m(2) intravenously without premedication (n = 229) or standard paclitaxel 175 mg/m(2) intravenously with premedication (n = 225). RESULTS ABI-007 demonstrated significantly higher response rates compared with standard paclitaxel (33% v 19%, respectively; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 weeks, respectively; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% v 22%, respectively; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% v 2%, respectively; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time. CONCLUSION ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.

Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors

PURPOSE Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy. PATIENTS AND METHODS Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state. RESULTS Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting > or = 6 months. CONCLUSION Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.

Milk Thistle Nomenclature: Why It Matters in Cancer Research and Pharmacokinetic Studies

Extracts of milk thistle have been recognized for centuries as “liver tonics” and are well-known to prevent or reverse hepatotoxicity of reactive drug metabolites or naturally occurring toxins. Milk thistle extracts are now under intense study in the experimental therapeutics of cancer for chemoprevention, treatment, and amelioration of chemotherapy side effects. Precision in nomenclature, however, has lagged behind this progress. The crude commercial product of milk thistle is termed silymarin, a complex of at least 7 flavonolignans and 1 flavonoid that comprises 65% to 80% of milk thistle extract. From silymarin is derived silibinin, a semipurified fraction once thought to be a single compound but now recognized as a 1:1 mixture of 2 diastereoisomers, silybin A and silybin B. The distinction between silymarin and silibinin is not only important to understanding the historical literature, but thorough characterization and use of chemically defined mixtures in preclinical and clinical studies are essential to the progress of these botanical compounds as human therapeutics. As a result, we urge clinicians and preclinical investigators alike to exercise rigor in nomenclature and use pure compounds or precisely defined chemical mixtures in subsequent studies. Herein, we provide a guide to the proper nomenclature and composition of milk thistle extracts and discuss the known pharmacokinetic studies of these botanical medicines. The drug-interaction potential of these extracts appears to be quite low, and in fact, silibinin appears to synergize with the antitumor effects of some commonly used chemotherapeutics. However, some precautions are advised as high-dose, phase II studies are conducted.

Effect of Exercise on Biomarkers, Fatigue, Sleep Disturbances, and Depressive Symptoms in Older Women With Breast Cancer Receiving Hormonal Therapy

PURPOSE/OBJECTIVES To compare the effectiveness of a prescribed home-based walking exercise intervention with usual care in older women receiving hormonal treatment for breast cancer, and to examine relationships among levels of the cortisol, serotonin, interleukin-6, and bilirubin biomarkers and fatigue, sleep disturbances, and depressive symptoms. DESIGN Longitudinal randomized clinical trial. SETTING A National Cancer Institute-designated cancer center in the southeastern United States. SAMPLE 20 women (aged 55 years or older) with breast cancer receiving hormonal treatment. METHODS Participants were randomized to a walking exercise intervention or usual care. Laboratory samples and the Pittsburgh Sleep Quality Index (PSQI), the Piper Revised Fatigue Scale, and the Center for Epidemiological Studies-Depression Scale were collected at the initial clinic visit and at 12 weeks from the groups. Questionnaires also were collected at weeks 2 and 14. MAIN RESEARCH VARIABLES Fatigue, sleep disturbances, depressive symptoms, biomarkers, and exercise. FINDINGS Effect of the exercise intervention on sleep scores was highly significant between groups. Exercise group scores on the PSQI decreased significantly over time (indicating improved sleep quality), although scores did not change significantly within the control group. Sleep actigraphy also showed significantly shorter actual wake time and less movement in the exercise group. Serotonin levels also were significantly affected by the intervention. CONCLUSIONS Data suggest that a walking exercise intervention improves sleep in older women receiving hormonal treatment for their breast cancer. Serotonin levels may be a useful biomarker when assessing sleep disturbances in this group. IMPLICATIONS FOR NURSING Clinicians need to be aware that older women receiving hormonal treatment for their breast cancer may experience fatigue, sleep disturbances, and depressive symptoms. Homebased walking activity may reduce symptom severity in this group.

Improving Health Care Efficiency and Quality Using Tablet Personal Computers to Collect Research-Quality, Patient-Reported Data

OBJECTIVE To determine whether e/Tablets (wireless tablet computers used in community oncology clinics to collect review of systems information at point of care) are feasible, acceptable, and valid for collecting research-quality data in academic oncology. DATA/SETTING: Primary/Duke Breast Cancer Clinic. DESIGN Pilot study enrolling sample of 66 breast cancer patients. METHODS Data were collected using paper- and e/Tablet-based surveys: Functional Assessment of Cancer Therapy General, Functional Assessment of Cancer Therapy-Breast, MD Anderson Symptom Inventory, Functional Assessment of Chronic Illness Therapy (FACIT), Self-Efficacy; and two questionnaires: feasibility, satisfaction. PRINCIPAL FINDINGS Patients supported e/Tablets as: easy to read (94 percent), easy to respond to (98 percent), comfortable weight (87 percent). Generally, electronic responses validly reflected responses provided by standard paper data collection on nearly all subscales tested. CONCLUSIONS e/Tablets offer a valid, feasible, acceptable method for collecting research-quality, patient-reported outcomes data in outpatient academic oncology.

A Pilot Study of Predictive Markers of Chemotherapy-Related Amenorrhea Among Premenopausal Women with Early Stage Breast Cancer

Background: Premenopausal women treated for early stage breast cancer (ESBC) are at risk for chemotherapy-related amenorrhea (CRA). Prospectively-validated, predictive markers of CRA are needed. Patients and Methods: Premenopausal women with ESBC and planned chemotherapy (≥ 25% risk of amenorrhea) were evaluated. Follicle stimulating hormone (FSH), estradiol, Inhibin A and B, anti-Müllerian hormone (AMH), and quality of life (QOL) were prospectively evaluated pre-, post-, 6 months and 1 year post-chemotherapy and correlated with age and menstrual status. CRA was defined as absence of menses 1 year post-chemotherapy. Results: Forty-four women were evaluated at the time of analysis. Median age at diagnosis and FSH 1 year post-chemotherapy were higher among women with CRA (44 yrs [33–51] vs. 40 yrs [31–43]; p = 0.03; 39.8 vs. 5.0 mLU/mL, p = 0.0058, respectively). Median estradiol 1 year post-chemotherapy was higher among women who resumed menses (108.3 vs. 41.3 pg/mL, p = 0.01). Pre-chemotherapy median Inhibin B and AMH were lower among women with CRA (33.2 vs. 108.8 pg/mL; p = 0.03; 0.16 vs. 1.09 ng/mL, p = 0.02, respectively). The risk of CRA was increased among women with lower pre-chemotherapy Inhibin B (RR = 1.67, p = 0.15) and AMH (RR = 1.83, p = 0.05). Amongst women whose pre-chemotherapy Inhibin B and AMH values were below the median, the incidence of CRA was 87.5%. Conclusions: Results indicate that pre-chemotherapy Inhibin B and AMH are lower among women experiencing CRA and may be predictive of CRA among premenopausal women facing chemotherapy for ESBC.

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0–1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours

Background:PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly.Methods:Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data.Results:A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23–3.6 mg m−2) and 20 patients on the 3-h schedule (1.8–3.5 mg m−2). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m−2. With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m−2. Common PM00104-related adverse events at the RP2D comprised grade 1–2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ⩾6 months.Conclusion:PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.British Journal of Cancer (2012) 106, 1379–1385. doi:10.1038/bjc.2012.99 www.bjcancer.com

Letrozole in the treatment of breast cancer

Over the last 30 years the role of tamoxifen in breast cancer treatment has been progressively expanded by clinical investigation to encompass the entire spectrum of disease from cancer chemoprevention to palliation of advanced disease. The primacy of tamoxifen for these indications in postmenopausal women is now under challenge by the selective aromatase inhibitors, a class of endocrine agent that induces oestrogen deprivation rather than oestrogen receptor blockade. This review considers the biochemical, pharmacological and clinical properties of the nonsteroidal aromatase inhibitor letrozole. This agent is superior to tamoxifen for the treatment of metastatic breast cancer, a finding that suggests that letrozole may ultimately eclipse tamoxifen for other indications, including chemoprevention. Further clinical investigation will be necessary to establish the risks and benefits of letrozole versus tamoxifen for each new indication, with adjuvant therapy being the next in line. The object of this review is to provide a reference source on the biochemical, pharmacological and clinical properties of letrozole for clinicians to consider both established and future indications.

Effects of chemotherapy and tamoxifen on cervical and vaginal smears in bone marrow transplant recipients

OBJECTIVE To clarify the importance of squamous and glandular atypia in the genital tracts of women undergoing high-dose chemotherapy and receiving tamoxifen. STUDY DESIGN The pathology records of 769 female bone marrow transplant recipients from a five-year period at Duke University Medical Center were reviewed. One hundred fifteen cervicovaginal smears from 78 patients were available for evaluation; of these, 85 smears from 61 patients were selected. Only cases from patients with a complete medical history, including menopausal status and therapeutic regimen, were included in this study. Forty-five cases were from patients treated with chemotherapy alone, and 40 were from patients treated with a combination of chemotherapy and tamoxifen. RESULTS A normal cellular pattern was the most common finding. Reactive cellular changes associated with therapy effect were identified in 21% of cases. In patients treated with chemotherapy alone, an atrophic smear pattern in a premenopausal woman was identified in 27% of cases. Squamous epithelial cell abnormalities were identified in approximately the same proportion of patients whether they received chemotherapy alone or with tamoxifen. Glandular changes were uncommon. CONCLUSION The most common finding was a normal smear pattern. An atrophic smear was more commonly found in patients treated with chemotherapy alone than in those treated with both chemotherapy and tamoxifen. Squamous epithelial cell abnormalities are most probably independent of treatment effect. Glandular changes were rare in patients treated with chemotherapy, alone or in combination with tamoxifen.