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Sandra M Swain

Publications and source records attributed to Sandra M Swain.

At least 37 records · Page 2Linked to original sources
PubMed2005

Concepts and clinical trials of dose-dense chemotherapy for breast cancer .

This article will review the strategy of dose-dense administration of chemotherapy for breast cancer. Increased dose density is achieved by reducing the interval between each dose of chemotherapy. The cumulative drug dose remains constant, but the same amount of drug is administered over a shorter period. Mathematical models of tumor growth have provided the basis for the clinical application of dose-dense chemotherapy. The Norton-Simon model suggests that increasing the dose density of chemotherapy will increase efficacy by minimizing the opportunity for regrowth of tumor cells between cycles of chemotherapy. Intergroup trial 9741, coordinated by the Cancer and Leukemia Group B (CALGB), tested the 2 hypotheses that dose-dense and sequential administration of chemotherapy regimens incorporating doxorubicin, cyclophosphamide, and paclitaxel would improve disease-free survival and overall survival. A statistically significant 4-year disease-free survival advantage was detected for the 2 dose-dense regimens compared with the regimens administered every 3 weeks. The mathematical concepts and previous clinical trials of dose density that contributed to the design of CALGB 9741 will be reviewed. The strengths and limitations of CALGB 9741 will then be discussed before the presentation of future directions of research and recommendations for clinical practice today.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

A phase II trial of neoadjuvant docetaxel and capecitabine for locally advanced breast cancer.

PURPOSE: This study evaluated the toxicity and efficacy of docetaxel/capecitabine as neoadjuvant treatment for stage 2/3 breast cancer. EXPERIMENTAL DESIGN: Subjects with newly diagnosed invasive stage 2 and 3 breast cancer were eligible. The first cohort of patients was treated at dose A with neoadjuvant docetaxel (75 mg/m(2) i.v. day 1) and capecitabine (1000 mg/m(2) orally twice daily days 2-15) for four cycles. A second cohort of subjects was treated with a reduced dose, dose B, of docetaxel (60 mg/m(2) i.v. day 1) and capecitabine (937.5 mg/m(2) orally twice daily days 2-15). RESULTS: Thirty patients were enrolled. Eight of 10 patients treated at dose A required dose reductions of either docetaxel or capecitabine secondary to grade 3 or 4 toxicities: mucositis (1), hand-foot syndrome (3), diarrhea (2), perirectal abscess (1), and neutropenia (2). Because of a high rate of dose reductions, the next 20 patients were treated at dose B. The mean cumulative administered dose of docetaxel was 285 and 231 mg/m(2) at dose A and dose B, respectively. For capecitabine, the mean cumulative dose at dose A and B were similar at 1585 and 1627 mg/m(2)/day, respectively. The overall clinical response rate was 90% with 31% of patients having a complete response and 59% having a partial response. A pathological complete response in the breast was achieved in 10% of patients after four cycles of docetaxel/capecitabine. CONCLUSIONS: Docetaxel/capecitabine is a highly active regimen in the neoadjuvant setting. Neoadjuvant therapy with 75 mg/m(2) docetaxel and 1600 mg/m(2)/day days 2-15 is recommended.

Administration, Oral↗
PubMed2004

Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy.

PURPOSE: To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. PATIENTS AND METHODS: Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. RESULTS: OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. CONCLUSION: Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook.

Adult↗
PubMed2004

Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer.

PURPOSE: The purpose of this study was to determine the toxicities and characterize the pharmacokinetics of docetaxel and flavopiridol in patients with metastatic breast cancer. EXPERIMENTAL DESIGN: Docetaxel was administered at an initial dose of 60 mg/m(2) followed in 24 hours by a 72-hour infusion of flavopiridol at 50 mg/m(2)/d every 3 weeks. Because dose-limiting myelosuppression occurred, the schedule was amended to docetaxel, 50 mg/m(2), followed by escalating doses of flavopiridol (starting dose, 26 mg/m(2)/d) as a 1-hour infusion daily for 3 days. Pharmacokinetic studies were performed. Ki67, p53, and phosphorylated retinoblastoma protein (phospho-Rb) in paired tumor and buccal mucosa biopsies (obtained pre- and posttreatment) were examined by immunohistochemistry. RESULTS: Eleven patients were enrolled. Five patients received docetaxel and 72-hour flavopiridol. Dose-limiting toxicity was grade 4 neutropenia. Six patients received docetaxel and 1-hour flavopiridol, and the dose-limiting toxicity was grade 3 hypotension. Pharmacokinetics of flavopiridol and docetaxel were consistent with historical data. Nuclear staining with p53 increased and phospho-Rb decreased in 10 pairs of buccal mucosa biopsies posttreatment (P = 0.002 and P = 0.04, respectively). No significant changes in Ki67, p53, or phospho-Rb were detected in six paired tumors. Two patients sustained stable disease for >3 months (72-hour flavopiridol), and one partial response was observed (1-hour flavopiridol). CONCLUSIONS: Docetaxel combined with 72-hour flavopiridol was not feasible because of dose-limiting neutropenia. Dose escalation of a 1-hour infusion of flavopiridol with docetaxel was also not possible. The changes in p53 and phospho-Rb in buccal mucosa suggest that a biological effect with flavopiridol was achieved.

Adult↗
PubMed2004

Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.

PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.

Administration, Oral↗
PubMed2004

Ductal carcinoma in situ, complexities and challenges.

The incidence of ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer, has increased markedly in recent decades, and DCIS now accounts for approximately 20% of breast cancers diagnosed by mammography. Laboratory and patient data suggest that DCIS is a precursor lesion for invasive cancer. The appropriate classification of DCIS has provoked much debate; a number of classification systems have been developed, but there is a lack of uniformity in the diagnosis and prognostication of this disease. Further investigation of molecular markers should improve the classification of DCIS and our understanding of its relationship to invasive disease. Controversy also exists with regard to the optimal management of DCIS patients. In the past, mastectomy was the primary treatment for patients with DCIS, but as with invasive cancer, breast-conserving surgery has become the standard approach. Three randomized trials have reported a statistically significant decrease in the risk of recurrence with radiation therapy in combination with lumpectomy compared with lumpectomy alone, but there was no survival advantage with the addition of radiotherapy. Two randomized trials have suggested an additional benefit, in terms of recurrence, with the addition of adjuvant tamoxifen therapy, although in one trial the benefit was not statistically significant. Current data suggest that tamoxifen use should be restricted to patients with estrogen receptor-positive DCIS. Neither trial demonstrated a survival benefit with adjuvant tamoxifen. Ongoing and recently completed studies should provide information on outcomes in patients treated with lumpectomy alone and on the effectiveness of aromatase inhibitors as an alternative to tamoxifen.

Antineoplastic Agents, Hormonal↗
PubMed2004

Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer.

BACKGROUND: Tamoxifen reduces the risk for contralateral breast cancer by approximately 30%-50%, with benefits probably limited to women with estrogen receptor (ER)-positive primary disease. In a retrospective analysis of data from National Surgical and Adjuvant Breast and Bowel Project trials B-18, B-22, and B-25, we determined whether the ER status of primary breast cancer predicts the ER status of a subsequent contralateral breast cancer and whether tamoxifen treatment affects this relationship. In these trials, tamoxifen at 20 mg/day had been administered only to women aged 50 years or older, rather than to those determined by the ER status of their primary tumor, allowing an assessment of the treatment's effects in ER-negative disease. METHODS: Among the 5513 eligible patients, 176 patients developed a contralateral breast cancer. The ER status of the primary and contralateral tumor was determined and cross-classified for women who did not receive tamoxifen (i.e., those aged 49 years or younger) and for women who did (i.e., those aged 50 years or older). ER data were available for 110 evaluable invasive contralateral breast cancers. RESULTS: Among patients who did not receive tamoxifen (n = 62), 89% with an ER-positive primary cancer had an ER-positive contralateral breast cancer and 70% with an ER-negative primary breast cancer had an ER-negative contralateral breast cancer (odds ratio for the association between primary and contralateral ER status = 14.8, 95% confidence interval = 3.8 to 74.3; P<.001). Among patients who received tamoxifen (n = 48), 56% with an ER-positive primary cancer had an ER-positive contralateral breast cancer and 78% with an ER-negative primary cancer had an ER-negative contralateral breast cancer (odds ratio = 3.4, 95% confidence interval = 0.53 to 39.2; P =.25). CONCLUSION: The ER status of the primary breast cancer was associated with that of the contralateral breast for patients not receiving tamoxifen. Patients with an ER-positive primary cancer who received tamoxifen had a lower concordance rate with fewer ER-positive contralateral breast cancers, which may be a result of tamoxifen treatment.

Age Factors↗
PubMed2004

Rationale and clinical trial design for evaluating gemcitabine as neoadjuvant and adjuvant therapy for breast cancer.

Over the past 30 years, much progress has been made in adjuvant chemotherapy for patients with early-stage breast cancer. The introduction of anthracyclines and, recently, taxanes has significantly improved the efficacy of adjuvant chemotherapy and has provided useful insight regarding future development of even more efficacious regimens. However, despite significant progress, there remains considerable room for improvement. Although the manipulation of chemotherapy doses has not been found to be a successful strategy, manipulation of the interval of chemotherapy administration recently showed promise. It appears, nonetheless, that introducing new chemotherapy agents into the adjuvant setting is a more promising strategy than attempting to optimize the dose and schedule of existing agents. Gemcitabine has demonstrated significant antitumor activity in patients with advanced breast cancer when used either as a single agent or in combination with other active drugs (as a doublet or a triplet). Most of the available information to date has been obtained by combining gemcitabine with anthracyclines and/or taxanes. This approach has shown considerable antitumor activity and a reasonable toxicity profile, making it an important strategy for developing new adjuvant and neoadjuvant chemotherapy regimens. Several currently ongoing and planned adjuvant trials are incorporating gemcitabine (either sequentially or in combination) into anthracycline/taxane regimens. These trials will be important in establishing a role for this agent in the adjuvant setting and will hopefully lead to the development of more effective adjuvant chemotherapy regimens in the future.

Antimetabolites, Antineoplastic↗
PubMed2003

Liquid-chromatographic determination of erlotinib (OSI-774), an epidermal growth factor receptor tyrosine kinase inhibitor.

A high-performance liquid-chromatographic (HPLC) assay with UV detection has been developed for the quantitative determination of erlotinib (OSI-774) in human plasma. Quantitative extraction was achieved by a single-solvent extraction involving a mixture of acetonitrile and n-butyl chloride (1:4, v/v). Erlotinib and the internal standard hydrochloride salt (OSI-597) were separated on a column packed with Nova-Pak C18 material and a mobile phase composed of acetonitrile and water, pH 2.0 (60:40, v/v). The column effluent was monitored with dual UV detection at wavelengths of 348 nm (erlotinib) and 383 nm (OSI-597). The calibration graph was linear in the range of 100-4500 ng/ml, with values for accuracy and precision ranging from 87.9 to 96.2% and 2.13 to 5.10%, respectively, for three different sets of quality control samples. The developed method was successfully applied to study the pharmacokinetics of erlotinib in a cancer patient at the recommended daily dose of 150 mg.

Breast Neoplasms↗
PubMed2003

Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.

BACKGROUND: Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. A large-scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin-related congestive heart failure (CHF) after a cumulative dose of 550 mg/m(2). To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting, the authors evaluated data from three prospective studies to determine both the incidence of doxorubicin-related CHF and the accumulated dose of doxorubicin at which CHF occurs. METHODS: A group of 630 patients who were randomized to a doxorubicin-plus-placebo arm of three Phase III studies, two studies in patients with breast carcinoma and one study in patients with small cell lung carcinoma, were included in the analysis. RESULTS: Thirty-two of 630 patients had a diagnosis of CHF. Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m(2). Age appeared to be an important risk factor for doxorubicin-related CHF after a cumulative dose of 400 mg/m(2), with older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients (age < or = 65 years). In addition, > 50% of the patients who experienced doxorubicin-related CHF had a reduction < 30% in left ventricular ejection fraction (LVEF) while they were on study. CONCLUSIONS: Doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin.

Adult↗
PubMed2003

Ongoing adjuvant trials with trastuzumab in breast cancer.

Trastuzumab has had a major impact in the treatment of HER2-positive metastatic breast cancer. In combination with chemotherapy, trastuzumab provides significant clinical benefit in terms of increased response rate and extended survival compared with chemotherapy alone in patients with HER2-positive advanced breast cancer. Trastuzumab also has therapeutic activity as monotherapy in the front-line management of HER2-overexpressed or HER2-amplified metastatic breast cancer. Given its proven efficacy in the metastatic setting, the combination and sequential use of trastuzumab with adjuvant and neoadjuvant chemotherapy are the focus of several ongoing clinical studies. In this review, the design of the four major phase III multicenter adjuvant trastuzumab trials will be described and their major differences highlighted. Because therapy with trastuzumab has been associated with cardiac toxicity, especially with prior or concurrent anthracyclines, the evaluation of cardiac dysfunction in the adjuvant trial setting is also a priority. For now, the use of trastuzumab as adjuvant therapy is still investigational, but its integration has tremendous potential to improve treatment outcomes in patients with primary breast cancer.

Antibodies, Monoclonal↗
PubMed2003

Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells.

Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 deaths per year occurring in the US. Genotoxic effects of tobacco components have been described, but effects on signaling pathways in normal cells have not been described. Here, we show activation of the serine/threonine kinase Akt in nonimmortalized human airway epithelial cells in vitro by two components of cigarette smoke, nicotine and the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Activation of Akt by nicotine or NNK occurred within minutes at concentrations achievable by smokers and depended upon alpha(3)-/alpha(4)-containing or alpha(7)-containing nicotinic acetylcholine receptors, respectively. Activated Akt increased phosphorylation of downstream substrates such as GSK-3, p70(S6K), 4EBP-1, and FKHR. Treatment with nicotine or NNK attenuated apoptosis caused by etoposide, ultraviolet irradiation, or hydrogen peroxide and partially induced a transformed phenotype manifest as loss of contact inhibition and loss of dependence on exogenous growth factors or adherence to ECM. In vivo, active Akt was detected in airway epithelial cells and lung tumors from NNK-treated A/J mice, and in human lung cancers derived from smokers. Redundant Akt activation by nicotine and NNK could contribute to tobacco-related carcinogenesis by regulating two processes critical for tumorigenesis, cell growth and apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms.

PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks. PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m(2)/d for 5 days; doses of 50 and 62.5 mg/m(2)/d for 3 days; and doses of 62.5 and 78 mg/m(2)/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules. RESULTS: Dose-limiting neutropenia developed at doses >/= 52.5 mg/m(2)/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 micro mol/L (range, 1.3 to 4.2 micro mol/L), 3.2 micro mol/L (range, 1.7 to 4.8 micro mol/L), and 3.9 micro mol/L (1.8 to 5.1 micro mol/L), respectively. Twelve patients had stable disease for >/= 3 months, with a median duration of 6 months (range, 3 to 11 months). CONCLUSION: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m(2)/d for 5 days, 50 mg/m(2)/d for 3 days, and 62.5 mg/m(2)/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.

Adult↗
PubMed2002

Review of flavopiridol, a cyclin-dependent kinase inhibitor, as breast cancer therapy.

Disrupting the cell cycle through the inhibition of cyclin-dependent kinases (CDKs) is an important therapeutic strategy in the treatment of cancer. Flavopiridol is the first CDK inhibitor to be tested in clinical trials. It has been shown to cause cell cycle arrest, induce apoptosis, inhibit angiogenesis, and potentiate the effects of chemotherapy. In this review, the rationale for using a CDK inhibitor as therapy for breast cancer is described and the preclinical studies performed with flavopiridol in breast cancer cell lines are highlighted. Flavopiridol is currently undergoing phase II testing as monotherapy and phase I and/or II evaluation in combination with traditional chemotherapy agents. The assessment of CDK inhibition as evidence of flavopiridol's targeted effect in serial biopsies of tumor and surrogate tissues is also under investigation in these protocols. The interruption of the cell cycle through modulation of CDKs with an agent such as flavopiridol has potential therapeutic efficacy, especially in combination with chemotherapy.

Animals↗
PubMed2002

Microvessel density, expression of estrogen receptor alpha, MIB-1, p53, and c-erbB-2 in inflammatory breast cancer.

PURPOSE AND EXPERIMENTAL DESIGN: The purpose is to define intratumoral microvessel density (MVD) and potential biological markers that correlate with inflammatory breast cancer (IBC), we examined MVD, estrogen receptor a (ER) status, MIB-1 proliferation index, p53, and c-erbB-2 by immunohistochemistry in archival specimens from 67 women diagnosed with breast cancer with or without the inflammatory phenotype at the Institut Salah Azaiz (Tunis, Tunisia). RESULTS: The moderate (25-50/x400 field) to high microvessel count (>50/x400 field) was observed in 23 (51%) of 45 IBC tumors compared with 3 (14%) of 22 non-IBC tumors (P = 0.0031; chi(2) test). The presence of ER was found in 6 (14%) of 44 cases versus 7 (32%) of 22 cases in IBC and non-IBC, respectively (P = 0.10). In this series of 67 patient tumors, the median MVD count in ER-negative breast tumors was 21, whereas the median count was 4 in ER-positive breast tumors (P = 0.08; Wilcoxon rank-sum test). However, MIB-1, p53, and c-erbB-2 were not significantly different between IBC and non-IBC tumors. The intratumoral MVD between IBC and non-IBC was still statistically significant after adjustment for multiple comparisons (P = 0.02; Bonferroni test). CONCLUSIONS: These data suggest that there is an increased MVD in breast cancer with the inflammatory phenotype as compared with breast cancer without the inflammatory phenotype.

Adenocarcinoma↗
PubMedDate not supplied

CA 125 elevation in breast cancer: a case report and review of the literature.

A 69-year-old postmenopausal woman with newly diagnosed inflammatory breast cancer was evaluated for a pelvic mass found incidentally during staging computed tomography (CT) scans. Her serum cancer antigen (CA) 125 was greater than 900 U/ml, but laparoscopic examination of the ovaries was normal. Her breast cancer was deemed metastatic by virtue of a supraclavicular lymph node, but she had no visceral or bone metastasis. She was begun on primary chemotherapy and her CA 125 normalized. CA 125 is a tumor-associated antigen that is most commonly seen in advanced ovarian cancer. It is predominantly derived from coelomic epithelium, which explains elevations in benign conditions or other malignancies. The significance of CA 125 elevations in breast cancer is uncertain. Although CA 125 production has been demonstrated in the normal breast, it has been reported most often as a marker of pleural involvement with metastatic breast cancer. Further information on CA 125 in breast cancer is required to delineate its role in the management of this disease.

Aged↗