Troponins for predicting cardiotoxicity from cancer therapy.
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Antibiotics, Antineoplastic↗
Biomedical subjects
A C Wolff
Publications and source records attributed to A C Wolff.
Systemic therapy.
Our knowledge base on systemic therapy for breast cancer continues to expand, including further information regarding hormonal prevention in high-risk women, beneficial effects of tamoxifen in noninvasive disease, an update on primary systemic therapy, and optimization of adjuvant strategies, including data on adjuvant chemoendocrine regimens. The proper evaluation of high-dose strategies has been jeopardized by a serious episode of scientific misconduct. New data are also available on palliative options, bisphosphonates, antibody therapies, and novel targets. Data continue to evolve on the role and optimal schedules of taxanes in early-stage and advanced breast cancer. These and other important recent findings are discussed in this review article.
Antibodies, Monoclonal↗
Primary systemic therapy in operable breast cancer.
PURPOSE: Laboratory studies suggest that primary systemic therapy (PST) could improve control of micrometastatic disease and impact on overall survival (OS). This article examines the rationale for and preclinical and clinical data of PST in operable breast cancer and the potential role of intermediate biomarkers as predictive and/or prognostic factors for response and survival. DESIGN AND METHOD: We conducted an extensive literative review (including MEDLINE) on preclinical studies, single-arm feasibility studies, large randomized single- and multi-institutional trials, and laboratory correlate studies of PST in breast cancer. RESULTS: Small trials in locally advanced disease showed high initial rates of response and local control. Six randomized clinical trials (RCTs) of PST for palpable, operable breast cancer have been reported since 1991 (from 204 to 1,523 patients each). These data clearly show a small but significant (less than 10%) absolute increase in the use of breast-conservation treatment (BCT) with similar rates of local control. Although one study showed better disease-free survival (DFS) and another showed better OS, most studies did not show any survival advantage of primary versus adjuvant systemic therapy. Thus far, pathologic complete response seems to be the best predictor of survival, but clinical response assessment correlates poorly with pathologic response. Pilot studies demonstrated feasibility of procuring tissue at diagnosis and after treatment for assays of potential intermediate biomarkers. Initial data suggest a potential correlation between markers of proliferation and apoptosis and in vivo chemotherapy sensitivity. CONCLUSION: Thus far, RCTs of PST versus standard adjuvant therapy have not shown any clear benefit for DFS or OS in early breast cancer. Ongoing trials should determine if specific subsets of patients at risk would benefit from additional systemic therapy and the potential role of intermediate biomarkers in identifying such women. Although PST results in a small increase in the rate of BCT with similar rates of local control, current PST strategies should not replace standard adjuvant approaches. Rather, they represent an acceptable alternative to women with palpable, operable tumors and an excellent arena for clinical trials.
Antineoplastic Combined Chemotherapy Protocols↗
New data on adjuvant therapy for breast cancer.
In the past year, the results of the third Oxford Overview and recommendations from the St. Gallen International Consensus Panel on adjuvant treatment for breast cancer were published. Reports of trials addressing the role of anthracyclines and taxanes, as well as the optimal dosing schedule for cyclophosphamide, methotrexate, and 5-fluorouracil, also appeared. Data show that primary therapy increases the rate of breast conservation but not survival rates. The initial results of trials of high-dose chemotherapy with autologous hematopoietic support have been mixed. The usefulness of sentinel node biopsy in minimizing surgical morbidity and of biologic markers in predicting response to adjuvant therapy are areas of active research.
Antineoplastic Combined Chemotherapy Protocols↗
Adjuvant systemic management of early stage carcinoma of the breast.
In the last three decades, there has been a gradual, though significant change in the treatment of early stage breast cancer. For almost a century, physicians advocated an "anatomical view" of the dissemination of this disease, which justified a more radical and mutilating treatment strategy. Finally in the mid-1970s, results from large randomized trials began to show that either mastectomy or lumpectomy with radiation therapy were appropriate treatment for women with early stage disease. These results suggested that breast cancer can actually be a systemic disease ("biological view") even in early stages. This hypothesis was confirmed when large randomized clinical trials demonstrated the effectiveness of adjuvant systemic therapy in controlling micrometastatic disease in women with node-positive and node negative disease. As we approach the end of this century, most patients with early stage disease will be offered some form of adjuvant systemic therapy, before or after local treatment with surgery, with or without local radiation therapy. There has been a lot of interest on the proper sequence of the therapeutic modalities, in particular with the recent publication of larger randomized trials of primary systemic therapy. This specific topic is discussed elsewhere in this issue by Singletary.
Breast Neoplasms↗
Systemic therapy.
New data continue to refine our knowledge of systemic therapy for breast cancer. These include the third Oxford Overview on adjuvant systemic therapy, a small advantage of anthracycline regimens over CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), and renewed interest in the "classic CMF" regimen. Primary chemotherapy offers a greater chance of breast conservation (although no survival advantage), and tamoxifen also benefits women with noninvasive disease. New data are available on biphosphonates, ovarian ablation, anti-estrogens, anti-HER-2 (human epidermal growth factor receptor-2) antibody, and HER-2 expression as a predictive or prognostic factor. Early results of high-dose chemotherapy have been released, and the role of taxanes in early and advanced disease continues to expand. This article reviews these and other recent advances.
Breast Neoplasms↗
Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: an Eastern Cooperative Oncology Group Study.
PURPOSE: Several groups have reported that the combination of doxorubicin plus paclitaxel given as a 3-hour intravenous (IV) infusion for up to eight cycles produces a high response rate (> 80%) and complete response rate (> 20%) in metastatic breast cancer, but is also complicated by a 20% incidence of congestive heart failure (CHF). The purpose of this phase II trial was to evaluate the antineoplastic activity of the regimen in a multi-institutional setting and to reduce the incidence of cardiotoxicity by limiting treatment to a maximum of six cycles. PATIENTS AND METHODS: Fifty-two patients with advanced breast cancer received doxorubicin (60 mg/m(2) by IV injection) followed 15 minutes later by paclitaxel (200 mg/m(2) by IV infusion over 3 hours) every 3 weeks for four to six cycles. RESULTS: Objective responses occurred in 25 of 48 assessable patients (52%; 95% confidence interval [CI], 38% to 66%), including four complete responses (8%; 95% CI, 0% to 16%). The median cumulative doxorubicin dose given was 240 mg/m(2) (range, 132 to 360 mg/m(2)). Eleven patients (21%) were documented as having a decrease in the LVEF below normal, including three patients (6%; 95% CI, 0% to 12%) who developed CHF. CONCLUSION: The doxorubicin/paclitaxel regimen that we used is unlikely to produce an objective response rate of more than 70% and a complete response rate of more than 20% in patients with metastatic breast cancer, and proved to be excessively cardiotoxic for use in the adjuvant setting.
Adenocarcinoma↗
Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group pilot study.
PURPOSE: A phase II study of ifosfamide, carboplatin, and prolonged oral administration of etoposide (ICE) in patients with untreated extensive-disease (ED) small-cell lung cancer (SCLC) was conducted to assess toxicities, response, and median survival. PATIENTS AND METHODS: Between July 1990 and August 1992, 35 patients were treated. ICE doses were ifosfamide 5 g/m2 by 24-hour continuous intravenous (CIV) infusion with mesna on day 1, carboplatin 300 mg/m2 intravenously (IV) on day 1, and etoposide 50 mg/m2 orally on days 1 to 21 every 4 weeks for up to six to eight cycles (schedule I). Because of severe hematologic toxicity in the first 18 patients, the last 17 patients received ifosfamide 3.75 mg/m2 IV on day 1, carboplatin 300 mg/m2 IV on day 1, and etoposide 50 mg orally on days 1 to 14 (schedule II). RESULTS: Nine of 18 patients (50%) on schedule I had 13 episodes of severe hematologic toxicity (one death), and only two (11%) received full doses on cycle 2. However, with schedule II, only four of 17 patients (24%) developed severe hematologic toxicity, and eight (47%) received full doses on cycle 2. Objective responses were observed in 29 of 35 patients (83%) (schedule 1, 16 of 18 patients [89%]; schedule II, 13 of 17 patients [76%]). There were eight (23%) complete responses (CRs) and 21 (60%) partial responses (PRs). The median survival duration was 8.3 months, and 1- and 2-year survival rates were 37% and 14%, respectively. CONCLUSION: ICE with oral etoposide has comparable activity with other regimens in ED SCLC. However, the 2-year survival rate may be higher and ICE with the lower doses of schedule II could be given safely with acceptable toxicity. Further studies of ICE compared with standard two-drug regimens are warranted.
Administration, Oral↗
The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia.
The p53 protein is a critical participant in a signal transduction pathway which mediates a G1 cell cycle arrest and apoptotic cell death in mammalian cells after ionizing irradiation. Cells from patients with the cancer-prone, radiation-sensitive disorder, ataxia-telangiectasia (AT), exhibit suboptimal (delayed and/or defective) induction of p53 protein after ionizing radiation with some dependence on dose. Other protein products which participate in this signal transduction pathway, including p21WAF1/CIP1, Gadd45, and Mdm2, are also suboptimally induced in AT cells after ionizing radiation. Induction of p53 is also abnormal in AT cells following treatment with methylmethanesulfonate and bleomycin but appears relatively normal following treatment with UV-C irradiation or the topoisomerase inhibitors, etoposide and camptothecin. These results demonstrate a specific defect in this p53-dependent signal transduction pathway in AT cells. Potential models for this observed specificity of the AT defect as measured by p53 induction include problems with responses to: (a) single-strand, but not double-strand, DNA breaks; or (b) chemically, but not enzymatically, generated DNA ends.
Ataxia Telangiectasia↗
Planning and conducting a work study.
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Efficiency↗