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Biomedical subjects

Joyce A O'Shaughnessy

Publications and source records attributed to Joyce A O'Shaughnessy.

At least 19 recordsLinked to original sources
PubMed2006

Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer.

PURPOSE: The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant chemotherapy regimen. Studies of docetaxel and cyclophosphamide (TC) in metastatic breast cancer (MBC) showed promise in MBC. In 1997, we initiated a randomized adjuvant trial of TC compared with standard-dose AC with a primary end point of disease-free survival (DFS). PATIENTS AND METHODS: Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1997 and December 1999, 1,016 patients were randomly assigned to four cycles of either standard-dose AC (60 and 600 mg/m2, respectively; n = 510) or TC (75 and 600 mg/m2, respectively; n = 506), administered intravenously every 3 weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor-positive disease, were administered after completion of chemotherapy. RESULTS: Both treatment groups (TC and AC) were well balanced with respect to major prognostic factors. Patients were observed through 2005 for a median of 5.5 years. At 5 years, DFS rate was significantly superior for TC compared with AC (86% v 80%, respectively; hazard ratio [HR] = 0.67; 95% CI, 0.50 to 0.94; P = .015). Overall survival rates for TC and AC were 90% and 87%, respectively (HR = 0.76; 95% CI, 0.52 to 1.1; P = .13). More myalgia, arthralgia, edema, and febrile neutropenia occurred on the TC arm; more nausea and vomiting occurred on the AC arm as well as one incident of congestive heart failure. CONCLUSION: At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.

Adult↗
PubMed2006

Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer.

PURPOSE: The taxanes and capecitabine have synergistic antitumor activity in preclinical models. This trial was designed to determine the efficacy and tolerability of weekly paclitaxel plus capecitabine as first-line treatment for metastatic breast cancer (MBC). PATIENTS AND METHODS: Participants had histologically proven breast cancer, with measurable metastatic disease by Response Evaluation Criteria in Solid Tumors Group. Exclusion criteria included prior taxane therapy or any prior capecitabine or infusional fluorouracil. Participants received capecitabine 825 mg/m2/dose orally bid (1,650 mg/m2/d) for days 1 to 14. Paclitaxel 80 mg/m2 was administered intravenously weekly on days 1 and 8. Cycles were repeated every 3 weeks. Responders (complete or partial) or those with stable disease were treated until progression of disease or intolerable toxicity. RESULTS: Fifty-five women were enrolled; 94% received study therapy as first-line treatment for MBC. In the intent-to-treat population, objective responses (partial) were achieved in 30 patients (55%; 95% CI, 40% to 69%), and six additional patients had stable disease for 6 months or longer (clinical benefit rate of 65%). The median duration of response was 10 months (range, 2.5 to 18.7 months). Dose modifications and reductions were common, particularly for capecitabine, leading to a delivered dose-intensity of 75% for capecitabine and 91% for paclitaxel. The most frequent grade 3 to 4 treatment-related adverse events were hand-foot skin reaction (n = 10); neutropenia (n = 7); fatigue (n = 4); and leukopenia, diarrhea, and pain (n = 3 each). CONCLUSION: Capecitabine in combination with weekly paclitaxel is an active and tolerable regimen as first-line therapy for women with MBC.

Administration, Oral↗
PubMed2006

Phase II trial of weekly docetaxel/ gemcitabine as first-line chemotherapy in patients with locally recurrent or metastatic breast cancer.

PURPOSE: A phase II study evaluated weekly docetaxel/gemcitabine as first-line chemotherapy for locally recurrent or metastatic breast cancer in a multicenter community oncology practice setting. PATIENTS AND METHODS: Eligible patients who had not received chemotherapy for metastatic disease received docetaxel 30 mg/m2 followed by gemcitabine 800 mg/m2, each administered weekly for 3 weeks (days 1, 8, and 15), followed by a 1-week rest period (28-day cycle). Patients also received oral dexamethasone to reduce the incidence/severity of fluid retention and hypersensitivity reactions. Of the 46 enrolled patients, 45 were treated as part of the intent-to-treat (ITT) population and were evaluable for safety. RESULTS: There were 3 complete responses and 12 partial responses among the 39 evaluable patients, for an objective response rate (ORR) of 39% (95% confidence interval [CI], 24%-54%). The ORR in the ITT population was 33% (95% CI, 18%-48%). Median time to response was 3.4 months, with a median response duration of 6.7 months. Median survival was 15.8 months, and median time to progression was 5.8 months. The most common grade 3/4 hematologic toxicity was neutropenia (13.3%); there was a low incidence of other grade 3/4 hematologic toxicities. Grade 3 fatigue (15.6%) was the most common grade 3/4 nonhematologic toxicity, and grade 2 alopecia occurred in 47% of patients. One patient who had been receiving chronic corticosteroid therapy died from treatment-related neutropenia and acute respiratory distress syndrome. CONCLUSION: These phase II results suggest that weekly docetaxel/gemcitabine is moderately active and well tolerated as first-line therapy for locally recurrent or metastatic breast cancer. No clear advantage for combined weekly docetaxel/gemcitabine was observed compared with published results on the efficacy of docetaxel and gemcitabine given as single agents.

Adult↗
PubMed2006

Capecitabine/Taxane combination therapy: evolving clinical utility in breast cancer.

Capecitabine is approved as a single agent and in combination with docetaxel for the treatment of metastatic breast cancer. Preclinical and clinical research suggests that the activity of capecitabine is enhanced in combination with taxanes and several biochemical mechanisms of synergy have been described. Recent data suggest that novel doses and schedules os capecitabine can improve safety without compromising efficacy. More than 50 publications and abstracts describing capecitabine/taxane combination therapy studies were reviewed to evaluate the available data on efficacy, safety, and quality of life for patients with breast cancer. Several ongoing randomized adjuvant and neoadjuvant clinical trials are assessing the clinical utility of capecitabine/taxane combinations in early-stage and locally advanced breast cancer.

Adult↗
PubMed2005

Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.

Impaired cognition, fatigue, and diminished quality of life (QOL) are commonly associated with breast cancer chemotherapy. This randomized, double-blind, placebo-controlled pilot trial assessed the feasibility of quantifying the effects of epoetin alfa on cognitive function and mood, and evaluated its effects on fatigue and QOL in patients with breast cancer treated with anthracycline-based adjuvant or neoadjuvant chemotherapy. Patients were randomized to receive epoetin alfa 40,000 U subcutaneously once weekly or placebo at the beginning of 4 cycles of chemotherapy administered over 12 weeks. Cognitive function was assessed by Executive Interview (EXIT25) and Clock Drawing Tasks; mood by Profile of Mood States; anemia-related symptoms, including fatigue, by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale; and QOL by Linear Analog Scale Assessment. Ninety-four patients were evaluable for efficacy and safety. Mean change in EXIT25 scores from baseline to cycle 4 in the epoetin alfa group was 1.3 +/- 3.3; the mean change was 0.3 +/- 2.4 in the placebo group (a negative change indicates improved executive function). There was no difference between groups in mean change in EXIT25 score from baseline to 6-month follow-up assessment. Mean hemoglobin levels were higher in the epoetin alfa group compared with the placebo group after 4 cycles of chemotherapy. Epoetin alfa recipients had less of a decrease in FACT-An subscale scores from baseline to cycle 4 and improvement in FACT-An subscale scores at 6-month follow-up assessment compared with placebo. Epoetin alfa therapy was well tolerated. These data suggest that epoetin alfa may have attenuated the cognitive impairment and fatigue that occurred during adjuvant breast cancer chemotherapy.

Adult↗
PubMed2005

Phase II study of pemetrexed in patients pretreated with an anthracycline, a taxane, and capecitabine for advanced breast cancer.

BACKGROUND: This phase II study evaluated the efficacy, safety, and health outcomes of pemetrexed treatment in heavily pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Women with metastatic breast cancer, Karnofsky performance status > or = 70, and previous treatment with > or = 3 regimens containing anthracyclines, taxanes, and capecitabine were eligible. Pemetrexed 500 mg/m2 intravenous infusion was administered on day 1 of a 21-day treatment cycle. RESULTS: Eighty patients were enrolled, and 60 received concurrent folic acid and vitamin B12 supplements per protocol amendment to minimize possible pemetrexed-related toxicity. The median numbers of cycles delivered were 3 for vitamin-supplemented patients and 2 for non-vitamin-supplemented patients. Regardless of vitamin supplementation, the overall response rate was 8% (95% CI, 3%-16.6%), stable disease was exhibited in 36% of patients, median time to disease progression was 2.9 months, and median survival was 8.2 months. Improvements in patient-reported symptoms ranged from 16.2% for pain intensity to 32.1% for nausea. Major grade 3/4 toxicities were hematologic, with grade 4 neutropenia in 10% of patients and grade 3 toxicities consisting primarily of neutropenia (29%) and leukopenia (21%). There were no clear trends of the effect of supplementation on toxicity. CONCLUSION: Pemetrexed has modest antitumor activity and is well tolerated in heavily pretreated patients with breast cancer. Further evaluation of this multitargeted antifolate in advanced breast cancer is warranted.

Adult↗
PubMed2005

The global breast cancer burden: variations in epidemiology and survival.

Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. However, the burden is not evenly distributed, and, according to the best available data, there are large variations in the incidence, mortality, and survival between different countries and regions and within specific regions. Many complex factors underlie these variations, including population structure (eg, age, race, and ethnicity), lifestyle, environment, socioeconomic status, risk factor prevalence, mammography use, disease stage at diagnosis, and access to high-quality care. We review recent breast cancer incidence and mortality statistics and explore why these vary so greatly across the world. Further research is needed to fully understand the reasons for variations in breast cancer outcomes. This will aid the development of tailored strategies to improve outcomes in general as well as the standard of care for underserved populations and reduce the burden of breast cancer worldwide.

Africa↗
PubMed2004

Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.

PURPOSE: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. EXPERIMENTAL DESIGN: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. RESULTS: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. CONCLUSION: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.

Anticarcinogenic Agents↗
PubMed2004

Current comprehensive assessment and management of women at increased risk for breast cancer.

The potential for reducing the risk of breast cancer through selective estrogen receptor modulators, aromatase inhibitors, and surgery has generated interest in the use of quantitative models of risk assessment. With the addition of ductal lavage cytology to traditional epidemiologic risk factors, a discovery of cellular atypia can result in refinement of assigned risk values, while simultaneously optimizing patient selection for selective estrogen receptor modulators utilization. In view of increasing complexity in this arena, a Risk Assessment Working Group was formed to outline management strategies for the patient at an elevated risk for the development of breast cancer. No longer a statistical exercise, quantitative risk assessment is part of basic breast care and comprehensive management includes a discussion of the following: ductal lavage for improved risk stratification, multiple options for risk reduction, and high risk surveillance strategies that might incorporate investigational imaging protocols.

Adult↗
PubMed2004

Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer.

We evaluated the efficacy and toxicity of trastuzumab plus gemcitabine in patients with HER2-positive metastatic breast cancer (MBC). Sixty-four patients were enrolled, the majority of whom (95%) had been treated with an anthracycline and a taxane before study enrollment. Eligible women were treated with gemcitabine (1200 mg/m(2) weekly for 2 weeks with the third week off on a 21-day cycle) plus weekly doses of trastuzumab (4-mg/kg loading dose; 2 mg/kg thereafter) until disease progression. The median patient age was 55 years, and the median number of previously administered (including adjuvant) chemotherapy regimens was 3. Twenty-two patients were scored as 2+ for HER2 expression by immunohistochemistry; 39 patients scored 3+. Three patients were assessed as HER2-negative on central pathology review and were ineligible for evaluation. Fifty-nine of the 61 patients remained evaluable for response. The objective response rates were 38% in the intent-to-treat population (23 of 61) and 44% among the 39 patients with HER2 3+ expression. The median response duration was 5.8 months, median overall survival was 14.7 months, and median time to disease progression was 5.8 months. Trastuzumab plus gemcitabine was well tolerated. No cases of clinical congestive heart failure occurred. Grade 3/4 toxicities included asthenia in 4 patients, fever in 4, neutropenia in 18, dyspnea in 6, abdominal or back pain in 3, and edema and nausea in 1 patient each. The combination of trastuzumab plus gemcitabine appears to be well tolerated and effective for patients with HER2-positive MBC previously treated with chemotherapy.

Adult↗
PubMed2004

Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial.

In a large phase III trial of 511 patients with anthracycline-pretreated advanced/metastatic breast cancer, capecitabine/docetaxel combination therapy was shown to have significantly superior efficacy compared with single-agent docetaxel, including superior progression-free and overall survival and objective response rate. An updated survival analysis with >/= 27 months follow-up shows that patients receiving combination therapy maintained significantly superior survival (hazard ratio [HR], 0.777 [95% CI, 0.645-0.942]; P < 0.01; median survival, 14.5 months vs. 11.5 months) compared with those receiving single-agent docetaxel. Following the failure of docetaxel monotherapy, 35% of patients did not receive additional cytotoxic chemotherapy. Among patients randomized to single-agent docetaxel, only those given poststudy single-agent capecitabine had significantly prolonged survival compared with those given any other poststudy chemotherapy (HR, 0.500; P = 0.0046; median survival, 21.0 months vs. 12.3 months, respectively). By contrast, poststudy vinorelbine-containing chemotherapy did not affect survival following progression on single-agent docetaxel compared with other poststudy chemotherapy regimens (HR, 1.014; P = 0.94; median survival, 13.5 months vs. 12.6 months, respectively). Among patients randomized to combination therapy, discontinuing docetaxel of capecitabine has a similar effect on survival (HR, 0.720; P = 0.20; median survival, 15.8 months vs. 18.3 months, respectively). Median survival was 18.3 months in patients who discontinued docetaxel and continued to receive capecitabine versus 15.8 months in patients who discontinued capecitabine and continued to receive docetaxel, with a trend toward improved survival in patients continuing to receive capecitabine. Although this is a retrospective analysis, these data suggest that the sequential administration of docetaxel followed by capecitabine is associated with prolonged survival in patients who are candidates for sequential single-agent therapy.

Adult↗
PubMed2003

Phase II, randomized, double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer.

PURPOSE: To select a daily dose of arzoxifene (LY353381), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR). PATIENTS AND METHODS: This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity. RESULTS: Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P >.05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P >.05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study. CONCLUSION: Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.

Adult↗
PubMed2003

Ductal lavage: clinical utility and future promise.

This article discusses the use of ductal lavage to enhance the tolerability, efficiency, and reproducibility of collecting breast duct epithelial cells for analysis for breast cancer risk assessment. Aspects discussed include the rationale for use of ductal lavage, identification of appropriate candidates for the procedure, clinical implications, ongoing evaluation of the procedure, and its future utility.

Breast↗
PubMed2003

Pegylated liposomal doxorubicin in the treatment of breast cancer.

Anthracyclines, particularly conventional doxorubicin, play an important role in the treatment of breast cancer, both in the adjuvant and metastatic settings. However, the benefits of conventional doxorubicin in terms of antitumor activity are limited by its therapeutic index. Liposomal formulations were developed to increase the therapeutic index of conventional doxorubicin. Pegylated liposomal doxorubicin, the most widely studied liposomal doxorubicin formulation in breast cancer, has been evaluated in > 20 clinical trials. Pegylated liposomal doxorubicin provides tumor-targeted efficacy without many of the toxicities associated with conventional doxorubicin, including myelosuppression, alopecia, nausea and vomiting, and most importantly, cardiac toxicity. As a single agent, pegylated liposomal doxorubicin has demonstrated similar efficacy to that of conventional doxorubicin in patients with metastatic breast cancer. It has also demonstrated efficacy in combination with other agents or modalities, including cyclophosphamide, paclitaxel, docetaxel, gemcitabine, vinorelbine, and hyperthermia. Response rates in patients with metastatic breast cancer receiving pegylated liposomal doxorubicin either alone or in combination regimens range from 27% to 83%, with median survival estimated at 7-20 months. Small studies also suggest a role for pegylated liposomal doxorubicin in the treatment of locally advanced breast cancer. Preliminary results suggest that pegylated liposomal doxorubicin may be safely administered in combination with docetaxel and trastuzumab in patients with HER2-positive disease. Owing to its comparable efficacy and favorable safety profile, pegylated liposomal doxorubicin may be a useful alternative to conventional doxorubicin, as well as other agents commonly used in the treatment of breast cancer.

Breast Neoplasms↗
PubMed2003

The evolving role of capecitabine in breast cancer.

Breast cancer is the most common cancer and the second greatest cause of cancer-related death among women in the United States. Capecitabine is a selectively tumor-activated fluoropyrimidine carbamate that is converted to 5-fluorouracil by the sequential activity of these enzymes, the final of which is thymidine phosphorylase, which is overexpressed in many human cancers. Capecitabine as a single agent and in combination with other drugs is efficacious in previously treated and untreated metastatic breast cancer (MBC). The integration of capecitabine, either as a single agent or in combination with docetaxel, into adjuvant breast cancer therapy is justified due to its high antitumor activity in previously treated and untreated MBC, its tolerability, lack of cross-resistance with the anthracyclines and taxanes, and because combined docetaxel/capecitabine improves the overall survival of patients with MBC. Capecitabine is being evaluated as preoperative therapy in patients with operable breast cancer, as adjuvant therapy in patients with high-risk node-negative or node-positive disease, and as oral single-agent therapy in women > or = 65 years of age. This article is an overview of published studies of capecitabine in MBC and the studies that are planned or have been proposed to evaluate capecitabine as adjuvant therapy for breast cancer.

Age Factors↗
PubMed2003

Chemotherapy-induced cognitive dysfunction: a clearer picture.

Chemotherapy-associated cognitive dysfunction occurs in a subset of patients treated with adjuvant chemotherapy. Recent data suggest that development of chemotherapy-related anemia predisposes patients to cognitive dysfunction. Endogenous erythropoietin (EPO) is well recognized for its central role in erythropoiesis, and recombinant human EPO (epoetin alfa) is established as a safe and effective treatment for chemotherapy-related anemia. Treatment with epoetin alfa also improved health-related quality of life in anemic cancer patients undergoing chemotherapy, and several controlled studies have documented increases in quality-of-life scores correlated with increases in hemoglobin. Erythropoietin also plays a role in neuroprotection, presumably by activation of antiapoptotic genes. Erythropoietin and its receptor are expressed in neural cells of the human brain, and their expression is upregulated after hypoxic or ischemic injury. In animal models, systemic administration of epoetin alfa protects against such neural injury. Ongoing and future studies will determine whether epoetin alfa can provide neuroprotection with respect to the development of cognitive dysfunction in patients undergoing adjuvant chemotherapy treatment for breast cancer.

Anemia↗