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Andrew D Seidman

Publications and source records attributed to Andrew D Seidman.

At least 19 recordsLinked to original sources
PubMed2007

Increased dose density is feasible: a pilot study of adjuvant epirubicin and cyclophosphamide followed by paclitaxel, at 10- or 11-day intervals with filgrastim support in women with breast cancer.

PURPOSE: Because Cancer and Leukemia Group B 9741 trial showed a benefit for every 14-day administration of chemotherapy compared with every 21-day treatment, we hypothesized that even greater dose density would be more effective. We conducted a pilot trial to assess the feasibility of dose-dense chemotherapy consisting of a standard regime at 10- to 11-day intervals in the adjuvant/neoadjuvant setting. A 2-day window was allowed for scheduling logistics. EXPERIMENTAL DESIGN: Thirty-nine women with early-stage breast carcinoma were accrued from April 2004 to October 2004. Median age was 47 years (range, 26-67 years). Patients received therapy with 100 mg/m(2) epirubicin and 600 mg/m(2) cyclophosphamide (EC) q 10 to 11 days for four cycles followed by 175 mg/m(2) paclitaxel q 10 to 11 days for four cycles, all with filgrastim support (300 microg s.c. daily) from day 2 to 24 h before the next treatment. RESULTS: Thirty-five (90%) patients completed all planned therapy. The median intertreatment interval was 10 days (range, 8-28 days). Cycles (80.7%) were delivered at no more than 10- to 11-day intervals. There were five dose reductions of 25% for grade 3 nonhematologic toxicity in five patients. Six (16%) patients developed febrile neutropenia defined as temperature >38 degrees C with absolute neutrophil count <1,000/microL. All febrile neutropenia was during therapy with EC. Other grade 3 toxicities included bone pain, hand and foot syndrome, neuropathy, mucositis, nausea, and vomiting. CONCLUSIONS: Therapy with EC for four cycles followed by paclitaxel for four cycles at 10- to 11-day intervals is feasible. The approximately 30% reduction in intertreatment interval compared with every 14-day treatment could increase the efficacy of adjuvant chemotherapy.

Adult↗
PubMed2007

Taxanes in breast cancer: an update.

Over the past decade the taxanes have proved to be fundamental in the treatment of breast cancer. Initially found to have efficacy in metastatic breast cancer, the taxanes are now vital components in the treatment of early-stage disease, in which their addition to adjuvant treatment of early breast cancer has been shown to improve overall survival. In addition, the taxanes have demonstrated a role in first-line therapy for metastatic disease, with some of the highest efficacy of any class of chemotherapy. Targeted therapies in combination with the taxanes have further improved survival for both early and metastatic disease. New formulations of taxanes may both improve antitumor activity and reduce toxicity.

Antineoplastic Agents↗
PubMed2006

Cardiac dysfunction associated with trastuzumab.

The HER2/neu gene is amplified in approximately 25% of breast cancers, leading to HER2 protein overexpression and shortened overall survival and time to relapse. Trastuzumab is a humanised, monoclonal antibody against HER2, which improves survival for women with metastatic HER2-overexpressing breast cancer and reduces the risk of recurrence in women with early stage HER2-overexpressing breast cancer. Cardiac toxicity was an unexpected finding in the pivotal Phase III trial leading to the approval of trastuzumab, and prospective cardiac monitoring has, therefore, been incorporated into more recent clinical trials of trastuzumab. This article reviews the cardiac toxicity findings in key trastuzumab clinical trials and clinical characteristics of trastuzumab-associated cardiac toxicity.

Antibodies, Monoclonal↗
PubMed2006

A phase I study of cetuximab/paclitaxel in patients with advanced-stage breast cancer.

BACKGROUND: The epidermal growth factor receptor (EGFR) is part of the ErbB family of receptor tyrosine kinases and is known to be variably expressed in breast cancers. Cetuximab is a humanized monoclonal antibody directed against the EGFR that works by blocking the downstream signaling function of this protein and thereby interfering with cancer cell proliferation. Preclinical studies have indicated a synergistic effect for the combination of anti-EGFR therapy plus paclitaxel in breast cancer models. PATIENTS AND METHODS: Hence, we conducted a dose-escalation phase I trial using cetuximab/paclitaxel in patients with metastatic breast cancer to evaluate the feasibility of this combination. Patients with EGFR-positive metastatic breast cancer treated with <or= 1 previous therapy, excluding taxanes, were eligible. Treatment consisted of weekly cetuximab therapy and every-3-week paclitaxel, with dose escalation of cetuximab until the maximum tolerated dose was reached. RESULTS: Twelve patients were enrolled to 3 treatment cohorts. Two of 6 patients on the second cohort (cetuximab 100 mg/m2) developed dose-limiting toxicities, presenting as grade 3 rash. The third cohort was amended to allow the same cetuximab dose but to modify the paclitaxel to a weekly schedule. Despite this, 1 of 3 patients in this group also developed grade 3 skin toxicity as a dose-limiting toxicity; thus, the trial was stopped. Ten of the 12 patients were evaluable for response, and of these, 2 patients experienced stable disease, and 8 patients experienced disease progression. CONCLUSION: Because of prohibitive dermatologic toxicity and disappointing preliminary efficacy, the combination of paclitaxel/cetuximab was not considered promising in this population, although further study of this regimen might be warranted.

Adult↗
PubMed2006

Systemic treatment of breast cancer. Two decades of progress.

Over the past 20 years we have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. In addition, the list of cytotoxic chemotherapeutic agents useful in the control of breast cancer has grown considerably. The emergence ofanthracyclines was a major chemotherapeutic step forward in the 1980s, and the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that disrupt specific cellular targets and pathways. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select patients who could forgo adjuvant chemotherapy. Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. This review will highlight some of the landmark accomplishments during this time, and offer a glimpse at where we might be 20 years from now.

Antineoplastic Agents↗
PubMed2005

Current status of dose-dense chemotherapy for breast cancer.

In an effort to improve the effectiveness of chemotherapy for breast cancer, examination of the impact of dose intensity, dose density, and treatment duration may have as much relevance as the specific antineoplastic agents utilized. After several years of pilot feasibility studies of dose-dense chemotherapy regimens, whose delivery has been made safe and feasible by the use of hematopoietic growth factor support (in particular, filgrastim), we now have phase III data demonstrating the advantages of this approach in the adjuvant treatment of breast cancer.

Antineoplastic Agents↗
PubMed2005

A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer.

BACKGROUND: Imatinib mesylate is a potent inhibitor of Abl, KIT, and PDGFR tyrosine kinases. Breast cancer has variable expression of KIT and PDGFR therefore we conducted a phase II trial to evaluate the safety and efficacy of imatinib in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients had measurable and progressive MBC, with no limits on prior chemo- or hormonal therapy. Imatinib was initially administered at a dose of 400 mg orally twice a day with provisions for dose reductions based on toxicities. The primary endpoint was clinical benefit based on RECIST criteria. Tumor specimens were tested for expression of KIT and PDGFR tyrosine kinases. RESULTS: Sixteen patients were enrolled and treated. Median age was 55 years (range: 35-73); median number of prior chemotherapy regimens for MBC was 4 (range 1-8). The main non-hematologic toxicities were (Grades 1/2; Grade 3): fatigue (56%; 6%), edema (38%; 19%), nausea (31%; 19%), vomiting (38%; 0%), anorexia (38%; 0%), diarrhea (19%; 6%), and rash (25%; 6%). Grade 3/4 hematologic and biochemical abnormalities were minimal. There was no evidence of clinical benefit. The median duration of therapy on trial was 28 days (range 2-71). Of the 13 testable cases: 1 was KIT positive and 4 were PDGFR positive. CONCLUSION: Imatinib therapy at doses of 800 mg/day was associated with significant toxicity in patients with heavily pre-treated MBC. Our results do not indicate activity for imatinib monotherapy in these unselected patients.

Adult↗
PubMed2005

Phosphorylated/activated HER2 as a marker of clinical resistance to single agent taxane chemotherapy for metastatic breast cancer.

Purpose. To determine the association of phosphorylated/activated HER2 (P-HER2) and response to taxane chemotherapy in patients with metastatic breast cancer (MBC). Materials and Methods. Archived tumor specimens of patients with MBC treated on clinical trials with taxane monotherapy were analyzed by immunohistochemistry (IHC) for the presence of phosphorylated HER2 using the PN2A monoclonal antibody. Chi-squared analysis was performed to evaluate the association of P-HER2 status and efficacy of single agent taxane therapy. Results. One hundred twenty-six cases were identified as evaluable for both IHC and clinical outcome. Twelve cases (10 percent) were positive for P-HER2, of which 5 had evidence of clinical progression and 7 had evidence of clinical benefit with taxane therapy. Of the 114 cases that were negative for P-HER2, 20 demonstrated progression and 94 had clinical benefit. Chi-squared analysis revealed a significant correlation between the presence of P-HER2 and resistance to taxane therapy, chi2 = 3.9724 and p = 0.046. Conclusions. Phosphorylated/activated HER2 is associated with clinical resistance to single agent taxane therapy for MBC. The likelihood of direct progression of disease on taxane was greater in cases of PN2A-positive tumors (42 percent) as opposed to PN2A-negative ones (18 percent, p = 0.046). Functional assessment of HER2 status may provide unique predictive information not seen with conventional assessments.

Antibodies, Monoclonal↗
PubMed2005

A phase II trial of gemcitabine in patients with metastatic breast cancer previously treated with an anthracycline and taxane.

PURPOSE: This study was designed to evaluate the efficacy and safety of single-agent gemcitabine for the treatment of patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Eligible patients were required to have bidimensionally measurable MBC that had been treated with 2-4 prior chemotherapy regimens that included an anthracycline and a taxane. Gemcitabine was delivered at a dose of 800 mg/m2 on days 1, 8, and 15 of a 28-day cycle until evidence of disease progression. PATIENTS AND METHODS: Twenty-two patients were enrolled and included in the safety analysis; 18 patients were evaluable for response. The median age of patients was 54 years (range, 36-70 years). The mean number of prior chemotherapy regimens for metastatic disease was 2.3, and the mean dose of gemcitabine delivered was 911 mg/m2 (range, 600-1600 mg/m2). RESULTS: Overall, gemcitabine was well tolerated with minimal grade 3 toxicities; the only grade 4 toxicity was 1 case of pulmonary embolus. Three patients had evidence of partial tumor regression (17%; 95% CI, 4%-41%), and 1 patient had a 41% decrease in tumor volume, including liver metastasis. CONCLUSIONS: Gemcitabine is active and well tolerated as monotherapy given in heavily pretreated patients with MBC after anthracyclines and taxanes. The activity and safety reported in this trial are consistent with previous reports in similar patients.

Adult↗
PubMed2005

Emerging targeted therapies for breast cancer.

Targeted therapies offer a new approach to breast cancer treatment. Rather than eliminating both malignant and normal cells nonspecifically, these so-called "rational" therapies exploit second messenger proteins, ligands, and receptors that are known to be upregulated in neoplastic cells, or are implicated in cancer metastasis. This review will highlight a number of these targets and the mechanisms that have been targeted in drug design. We will also describe recently completed and currently ongoing clinical trials investigating targeted therapies and their potential to augment standard breast cancer therapy.

Antibodies, Monoclonal↗
PubMed2004

Phase II study of feasibility of dose-dense FEC followed by alternating weekly taxanes in high-risk, four or more node-positive breast cancer.

PURPOSE: To develop a potentially superior adjuvant chemotherapy regimen, we conducted a pilot study of dose-dense 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly alternating taxanes. The primary objective was to determine the feasibility of the regimen; the secondary objective was to estimate the disease-free and overall survival. EXPERIMENTAL DESIGN: Patients with >/=4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m(2), respectively, x6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m(2)) alternating with docetaxel (35 mg/m(2)) x18. RESULTS: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26-63 years), median number of positive nodes was 9 (range, 4-32), and median tumor size was 2.5 cm (range, 0.6-11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study. CONCLUSION: FEC x6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.

Adult↗
PubMed2004

Phase II study of celecoxib and trastuzumab in metastatic breast cancer patients who have progressed after prior trastuzumab-based treatments.

PURPOSE: Preclinical studies demonstrate a link between overexpression of HER-2/neu and cyclooxygenase-2 (COX-2) activity. To explore the possibility that COX-2 is a therapeutic target, we conducted a phase II study of celecoxib, a selective COX-2 inhibitor, and trastuzumab in patients with HER-2/neu-overexpressing metastatic breast cancer that had progressed while receiving trastuzumab. EXPERIMENTAL DESIGN: Eligible patients had bi-dimensionally measurable or evaluable HER-2/neu-overexpressing metastatic breast cancer. HER-2/neu overexpression, defined as 2+ or 3+ by the HercepTest, was required. Patients had to have progressed despite prior trastuzumab-based therapy. Treatment consisted of celecoxib (400 mg twice daily) and trastuzumab. RESULTS: Twelve patients were enrolled (42% status post 1 regimen for metastatic disease 58% status post > 2 prior regimens (range of 2-6). Eleven patients were evaluable. There were no responses. Median duration of treatment was 9 weeks. One patient had stable disease at 3 months but progressed at 6 months. A second patient stopped treatment at 3 months because of unresolved grade 2 rash, felt to be related to celecoxib. Toxicities were generally grade 1 or 2. One patient (8%) experienced grade 3 toxicity (abdominal pain). CONCLUSIONS: Celecoxib combined with trastuzumab is well tolerated. However, this combination in patients with HER2/neu-overexpressing, trastuzumab-refractory disease, was not active.

Adult↗
PubMed2004

Single-agent gemcitabine in the treatment of advanced breast cancer.

Despite the availability of a number of active cytotoxic agents and combination regimens derived from them, the median survival of patients with metastatic breast cancer (MBC) has not been dramatically prolonged and it remains largely an incurable disease. As such, common goals of treatment in this setting are to ameliorate cancer-related symptoms and maintain or improve patient quality of life for as long as possible. Achieving optimal palliation, however, requires balancing the toxicities of therapy with the cancer-controlling benefits, and, to this end, the development of effective and well-tolerated regimens is a priority. Gemcitabine, a novel nucleoside analogue with demonstrated antitumor activity and a favorable safety profile, has been evaluated in a number of recent clinical trials as single-agent therapy for MBC, including studies of first- and second-line therapy, as well as the salvage setting for patients with taxane- and anthracycline-refractory advanced disease.

Antimetabolites, Antineoplastic↗
PubMed2004

Gemcitabine and docetaxel in metastatic breast cancer.

Use of the gemcitabine (Gemzar) plus docetaxel (Taxotere) combination in metastatic breast cancer is motivated by the different mechanisms of action of the drugs, partially nonoverlapping toxicity profiles, and good single-agent activities of both drugs in treatment-naive and anthracycline-pretreated patients. In phase II trials, combinations of gemcitabine at 900 or 1,000 mg/m2 on days 1 and 8 and docetaxel at 75 to 100 mg/m2 on either day 1 or day 8 every 3 weeks, or gemcitabine at 800 mg/m2 on days 1, 8, and 15 and docetaxel at 35 mg/m2 on days 1, 8, and 15 or 100 mg/m2 on day 1 every 4 weeks, have produced response rates of 36% to 79% in patients receiving primarily second-line treatment; response rates were greater than 50% in five of six studies. In phase II trials using every-2-week regimens of gemcitabine at 1,500 or 2,000 mg/m2 on day 1 and docetaxel at 50 or 65 mg/m2 on day 1 or 55 mg/m2 on day 8, response rates were 50% in pretreated patients and 66% in treatment-naive patients. Neutropenia is the primary toxicity of the combination; in phase II studies performed with or without growth factor support, rates of grade 3/4 neutropenia ranged from 29% to 79% and rates of febrile neutropenia ranged from 0% to 18%. An ongoing phase III trial is comparing gemcitabine at 1,000 mg/m2 on days 1 and 8 plus docetaxel at 75 mg/m2 on day 1 every 21 days, vs capecitabine at 1,000 mg/m2 twice daily for 14 days plus docetaxel at 75 mg/m2 on day 1 every 21 days in patients with metastatic breast cancer. Results of this trial will help to determine optimal use of taxane-based combinations in patients with advanced disease.

Antimetabolites, Antineoplastic↗