Dose-dense treatment prolongs disease-free survival of women with node positive breast cancer.
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Adult↗
Biomedical subjects
Andrew D Seidman
Publications and source records attributed to Andrew D Seidman.
Cardiac effects of adjuvant therapy for early breast cancer.
Adjuvant chemotherapy is an established standard of care for most patients diagnosed with early breast cancer, and its popularity is gaining worldwide. The systemic armamentarium presently includes anthracyclines and taxanes, alkylating agents, fluoropyrimidines, and antimetabolites; in the future, it may include platinum compounds and the recombinant humanized anti-HER2 monoclonal antibody, trastuzumab, as well. Anti-estrogens continue to play an important role in the adjuvant setting for hormone-sensitive primary breast cancer. Adjuvant radiotherapy is common in the setting of early-stage disease as breast conservation gains popularity, and radiation is often employed in the postmastectomy setting as well. As treatment guidelines continue to evolve with newer data, the relative benefits of treatment in many situations continues to grow. Refinement of the optimal identification of patients at risk for local and distant relapse is a continued challenge facing the treating clinician. Parallel to this effort, and of equal importance, is the ability to shield patients that will gain little, if any, benefit from treatment and to identify those who may be at greater risk to suffer from potential toxicities. Until these factors are better defined, the recognition by clinicians of long-term side effects associated with adjuvant therapy is obligatory. Acute toxicities from treatment are often reversible, but late onset adverse effects of therapy can increase morbidity and mortality in long-term survivors, and continue to be of concern. One of the most serious side effects of adjuvant therapy of early breast cancer is cardiac toxicity. This article will provide an overview of the cardiac effects of adjuvant therapy in the treatment of early breast cancer.
Anthracyclines↗
Monotherapy options in the management of metastatic breast cancer.
Anthracyclines and taxanes are the most active agents in the first-line treatment of metastatic breast cancer. Among the options following clinical resistance to anthracycline and/or taxane treatment, the most widely used cytotoxic agents are the vinca alkaloid vinorelbine, the fluoropyrimidine capecitabine, and the nucleoside analogue gemcitabine. No direct comparisons of these agents have been reported in single-agent treatment or in single-agent versus combination treatment. Review of data from phase II trials in metastatic breast cancer indicates that the agents produce comparable response rates and are well tolerated. Review of the relatively smaller amount of data on effects in exclusively anthracycline- or anthracycline-taxane-refractory patient groups yields a similar conclusion. Given the absence of definitive comparisons of these agents, and any marked survival difference on informal comparison, treatment decisions should be aimed at maximizing patient benefit by considering the overall benefit of treatment in relation to the potential harm. A similar approach should be applied when considering use of combinations of these agents versus single-agent treatment.
Antineoplastic Agents↗
Assessment of molecular markers of clinical sensitivity to single-agent taxane therapy for metastatic breast cancer.
PURPOSE: The taxanes affect tubulin polymerization and interfere with mitotic transition. A checkpoint blockade at the G(1)-S boundary would be expected to promote taxane-induced apoptotic cell death through a mechanism that may involve p27. Other proposed determinants of clinical taxane sensitivity/resistance include p53, members of the epidermal growth factor receptor (EGFR) superfamily (e.g., HER2, EGFR), and estrogen receptors and progesterone receptors. These molecular markers and their correlation with clinical taxane sensitivity are investigated in this retrospective clinicopathologic study. PATIENTS AND METHODS: We performed immunohistochemistry (IHC) for estrogen receptors, progesterone receptors, HER2, EGFR, p53, and p27 on 144 breast tumor specimens from patients treated for metastatic breast cancer on a series of clinical trials of single-agent taxane chemotherapy for correlation with clinical response (complete or partial response). Patient characteristics that could influence response (i.e., performance status, extent of disease, and prior therapy) were also examined. RESULTS: In univariate analysis, Karnofsky performance status > or = 90% and no prior history of anthracycline therapy correlated with a good clinical response to single-agent taxane (P =.003 and P =.041, respectively). None of the IHC variables tested were predictive of clinical response to taxane therapy, although p27 negativity showed a trend toward significance (P =.075). Concordance between the polyclonal antibody with HercepTest (DAKO, Carpinteria, CA) and the monoclonal antibody CB-11 (BioGenex, San Ramon, CA) was noted (kappa = 0.943); however, neither univariate nor multivariate analysis demonstrated an association between HER2 status and response to taxane chemotherapy. CONCLUSION: The IHC biomarkers studied were not predictive of response to single-agent taxane chemotherapy in patients with metastatic breast cancer. Identification of molecular correlates of taxane response remains an important goal.
Antineoplastic Agents, Phytogenic↗
An update on epidermal growth factor receptor inhibitors.
The epidermal growth factor receptor (EGFR) is part of a family of plasma membrane receptor tyrosine kinases that control many important cellular functions, from cell growth and proliferation to cell death. Dysregulation of the EGFR signal transduction pathway has been implicated in tumorigenesis and cancer progression, making it a clinically relevant target for novel anticancer treatments. This paper reviews recent progress in the development of cancer therapies that are directed toward particular aspects of the extracellular and intracellular domains of EGFR. Promising new compounds in the advanced stages of clinical testing are emphasized.
Animals↗
Critical review of current treatment strategies for advanced hormone insensitive breast cancer.
Breast cancer is the most common cancer diagnosis in American women. Over the past several decades, there has been a steady increase in the incidence of this disease. Fortunately, the death rates in the last decade has showed a decrease. Patients with breast cancer now have more treatment options and a better chance of long term survival than ever before. Patients with metastatic disease are considered candidates for chemotherapy if they are symptomatic, have rapidly progressing or bulky disease, or if they are inappropriate candidates for hormonal therapy either because of negative hormonal receptor status or progression of disease on hormonal therapies. Patients are often treated with a chemotherapy regimen until progression of disease, or prohibitive toxicity, at which time the therapy is changed to a second or a third line therapy. This manuscript will provide a review of the current treatment strategies for advanced hormone insensitive breast cancer.
Antibodies, Monoclonal↗
Incorporating oral capecitabine into the treatment of breast cancer. Introduction.
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Administration, Oral↗
Single-agent capecitabine: a reference treatment for taxane-pretreated metastatic breast cancer?
The treatment of patients with metastatic breast cancer that has progressed despite previous anthracycline- and taxane-based therapy is a challenge for oncologists. Several agents, including vinorelbine, gemcitabine, pemetrexed, and particularly capecitabine, have been evaluated in this setting, either alone or in combination with other cytotoxic agents. The efficacy of many of these agents has not yet been clearly established in this setting, as the majority have been evaluated in a limited number of patients and predominantly in single-center trials. Furthermore, some agents with clinically meaningful activity are often associated with significant toxicity, particularly myelosuppression and neuropathy, while less toxic agents/regimens often exchange improved tolerability for reduced activity. Capecitabine, an oral chemotherapeutic, is the agent that has been evaluated most extensively in this setting. A large, phase II trial (n = 163) conducted in North America demonstrated a disease control rate of 63%, including an objective response rate of 20%, median time to disease progression of 3.0 months, and median survival of approximately 1 year. Adverse events were typically mild to moderate in intensity and could be controlled with treatment interruption or, if necessary, dose adjustment to each individual's tolerable dose. Data recently reported from three other large trials in taxane-pretreated patients have revealed similar efficacy and tolerability. Together, these four trials show that single-agent capecitabine, in a population of 500 patients, consistently produced clinically meaningful efficacy, including median survival of approximately 1 year, with a favorable safety profile. Myelosuppression and alopecia were particularly rare. In addition, the oral administration of capecitabine, which enables convenient, patient-oriented therapy, makes it an attractive treatment for patients. Based primarily on the results of the pivotal trial, capecitabine received regulatory approval as treatment for anthracycline- and taxane-pretreated (paclitaxel-pretreated in the U.S.) metastatic breast cancer. In light of the confirmatory results of subsequent large trials, capecitabine is now considered a reference treatment in this setting, as no other agent has consistently demonstrated such high efficacy in as large a patient population.
Administration, Oral↗
Safety and efficacy of the multidrug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel.
PURPOSE: VX-710 (biricodar, Incel) restores drug sensitivity to P-glycoprotein (MDR1) and multidrug resistance-associated protein (MRP1)-expressing cells. This Phase II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with locally advanced or metastatic breast cancer who were refractory to prior paclitaxel therapy. EXPERIMENTAL DESIGN: Eligible patients had paclitaxel-refractory disease defined as progressive disease after a minimum of two cycles of paclitaxel (weekly or 3-week schedule) or relapsed/progressive disease within 6 months of prior paclitaxel therapy. Patients received 80 mg/m(2) paclitaxel over 3 h starting 4 h after initiation of a 24-h continuous i.v. infusion of 120 mg/m(2)/h VX-710. Cycles were repeated every 3 weeks. RESULTS: Thirty-seven patients received study treatment and 35 were evaluable for response. VX-710 + paclitaxel therapy was generally well tolerated. Myelosuppression was the principal toxicity, with a median nadir ANC cycle 1 of 0.76 x 10(9) cells/liter and a 40% overall incidence of Grade 4 neutropenia. Nonhematological side effects (asthenia, paresthesia, headache, myalgia, nausea, and diarrhea) were generally mild to moderate and reversible. Paclitaxel AUC (16.8 +/- 5.0 microg x h/ml) and clearance (5.1 +/- 1.3 liters/h/m(2)) during the first treatment cycle were comparable with standard 175 mg/m(2) paclitaxel administered in a 3-h schedule. Four patients achieved partial responses (three of the four had progressive disease on prior paclitaxel) with a mean response duration of 5.5 months. CONCLUSIONS: The 11.4% (4 of 35) objective response rate observed in this study suggests that VX-710 can resensitize a subgroup of paclitaxel-refractory patients to paclitaxel. The safety and pharmacokinetics of the VX-710/pacitaxel regimen support further evaluation in breast cancer patients with initial paclitaxel therapy to prevent emergence of the MDR phenotype in recurrent disease.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Combination versus sequential single-agent therapy in metastatic breast cancer.
The optimal treatment approach in metastatic breast cancer is controversial. Until recently, the arguments for administering antitumor agents sequentially in the metastatic setting have traditionally outweighed those for administering agents in combination. Older, often empirically designed drug combinations were no more effective and often more toxic than monotherapy, compromising quality of life for little or no clinical benefit. However, more recent studies show that combination and sequential therapy both have their place in the treatment of metastatic breast cancer, with the heterogeneity of breast cancer demanding flexibility in approach. Newer drug combinations, such as paclitaxel/trastuzumab or capecitabine/docetaxel, show survival advantages over single-agent therapy and have manageable safety profiles. Such combination treatments may be preferable to sequential therapy for patients requiring urgent reduction in their tumor burden. Sequential therapy allows the optimal delivery of single-drug therapy and potentially reduces the risk of toxicity, which may improve quality of life. Sequential therapy may be especially appropriate in frail or elderly patients, who may be unable to tolerate the toxicity of combination therapy, or in patients with slowly growing tumors. This article expands on these issues by reviewing trials comparing combination regimens with sequential approaches.
Antibiotics, Antineoplastic↗