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Biomedical subjects

A D Seidman

Publications and source records attributed to A D Seidman.

At least 37 records · Page 2Linked to original sources
PubMed1997

HER2 overexpression and paclitaxel sensitivity in breast cancer: therapeutic implications.

Overexpression by the HER2 gene plays a significant role in breast cancer pathogenesis, and the phenomenon is commonly regarded as a predictor of a poor prognosis. HER2 overexpression has been linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoruracil) and anthracyclines. Studies of patients with advanced disease demonstrate that, despite the association of HER2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to taxanes were greater than three times those of HER2-negative patients. Further studies in preclinical models used combination therapy for breast cancer cells that overexpress HER2, and the use of agents that interfere with HER2 function plus paclitaxel (Taxol) resulted in significant antitumor effects.

Antibodies, Monoclonal↗
PubMed1997

Docetaxel and paclitaxel in breast cancer therapy: present status and future prospects.

The taxoids are important novel drugs in the treatment of patients with metastatic breast cancer, including those patients with extensive prior therapy and even patients with anthracycline-refractory disease. The emerging role of taxoid therapy and its optimal integration into new treatment strategies for patients with breast cancer is a major focus of active clinical and laboratory research. The incomplete clinical cross-resistance with anthracyclines observed thus far with both paclitaxel and docetaxel is particularly encouraging, as therapeutic options for patients after anthracycline failure are few and often of limited clinical value. Results of ongoing randomized multicenter trials addressing important clinical questions of optimal dose level, infusion duration, definition of worthwhile combinations, and comparative efficacy and tolerability of taxoid monotherapy or combination therapy with other standard regimens will, in the near future, provide guidelines for the best use of these drugs. Beyond the demonstrated single-agent activity of the taxoids in metastatic breast cancer, trials evaluating the taxoids in combination with various chemotherapeutic agents and monoclonal antibodies are in progress. Pharmacokinetic evaluation of the taxoids as monotherapy and in combination should help to define optimal and safe drug delivery. Clinical and laboratory studies will ultimately define clinically relevant mechanisms of resistance to this class of drugs, and may thus direct the development of rational strategies to overcome resistance and/or to guide analogue development. Finally, follow-up of women participating in present randomized adjuvant trials evaluating the taxoids will determine the potential impact of these important agents on the curability of early stage breast cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Dose-dense therapy with paclitaxel via weekly 1-hour infusion: preliminary experience in the treatment of metastatic breast cancer.

In an ongoing effort to establish the most appropriate dose and administration schedule for paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the feasibility and safety of weekly 1-hour infusions were evaluated in 16 women with metastatic breast cancer previously treated with at least one chemotherapy regimen. Paclitaxel was administered on an outpatient basis at a starting dose of 100 mg/m2/wk for 4 consecutive weeks, with 4-week cycles continued until disease progression or the onset of intolerable toxicity. With 215 weekly infusions administered so far (median, 13 per patient), no episodes of febrile neutropenia have occurred, and no hematopoietic growth factors have been used. Plans for dose escalation were abandoned after grade 3 sensorimotor neuropathy developed in five of nine patients treated at paclitaxel 110 to 120 mg/m2. With dose escalation eliminated, further severe neurotoxicities were rare, but some degree of cumulative peripheral neuropathy was noted in all but three patients. No acute hypersensitivity reactions were noted. To date, six of 15 evaluable patients have achieved a major response to therapy, with one complete response and five partial responses. Four other patients had a minor response to therapy, one patient had an early death due to autopsy-proven extensive pulmonary microvascular carcinomatosis, and five patients have stable disease. Although the potential neurotoxicity of this regimen merits attention, the overall profile of a high therapeutic index, manageable toxicity, and convenient administration schedule makes this an attractive treatment alternative for patients with metastatic breast cancer.

Adult↗
PubMed1996

Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer.

PURPOSE: Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study. PATIENTS AND METHODS: Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed > or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity. RESULTS: Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+). CONCLUSION: Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.

Adult↗
PubMed1996

Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.

PURPOSE: Breast cancer frequently overexpresses the product of the HER2 proto-oncogene, a 185-kd growth factor receptor (p185HER2). The recombinant humanized monoclonal antibody (rhuMAb) HER2 has high affinity for p185HER2 and inhibits the growth of breast cancer cells that overexpress HER2. We evaluated the efficacy and toxicity of weekly intravenous administration of rhuMAb HER2 in patients with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: We treated 46 patients with metastatic breast carcinomas that overexpressed HER2. Patients received a loading dose of 250 mg of intravenous rhuMAb HER2, then 10 weekly doses of 100 mg each. Patients with no disease progression at the completion of this treatment period were offered a maintenance phase of 100 mg/wk. RESULTS: Study patients had extensive metastatic disease, and most had received extensive prior anticancer therapy. Adequate pharmacokinetic levels of rhuMAb HER2 were obtained in 90% of the patients. Toxicity was minimal and no antibodies against rhuMAb HER2 were detected in any patients. Objective responses were seen in five of 43 assessable patients, and included one complete remission and four partial remissions (overall response rate, 11.6%; 95% confidence interval, 4.36 to 25.9). Responses were observed in liver, mediastinum, lymph nodes, and chest wall lesions. Minor responses, seen in two patients, and stable disease, which occurred in 14 patients, lasted for a median of 5.1 months. CONCLUSION: rhuMAb HER2 is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers that had received extensive prior therapy. This is evidence that targeting growth factor receptors can cause regression of human cancer and justifies further evaluation of this agent.

Adult↗
PubMed1996

Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: a phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer.

PURPOSE: A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxane treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated. PATIENTS AND METHODS: Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours. RESULTS: After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predominant toxicities were neutropenia (76% grade > or = 3) and stomatitis (15% grade > or = 3). Despite omission of premedications, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients was 0.047 mumol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01) and increased myelo-suppression and mucosal toxicity. CONCLUSION: Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occurred in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure.

Adult↗
PubMed1996

Motor neuropathy due to docetaxel and paclitaxel.

Paclitaxel and docetaxel are novel chemotherapeutic agents that promote the polymerization and inhibit the depolymerization of microtubules. Sensory neuropathy is common with these agents, particularly paclitaxel. We evaluated 64 patients treated with these drugs; 54 were followed prospectively. Eleven (17%, including six of the 54 prospectively followed patients) developed muscle weakness that was predominantly proximal. The weakness was idiosyncratic, occurring at any stage of treatment, had a variable course, and was reversible upon cessation of drug. All patients developed symptoms or signs of taxane-induced sensory neuropathy. Weakness was likely neuropathic in origin; electrodiagnostic studies suggested a distal axonopathy in some patients and proximal denervation (anterior horn cell or nerve root) in other.

Adult↗
PubMed1996

Chemotherapy for advanced breast cancer: a current perspective.

The systemic management of patients with hormone-refractory breast cancer metastatic to sites beyond regional axillary lymph nodes is classically characterized by the thoughtful, step-wise administration of cytotoxic chemotherapeutic agents. At various junctures in the continuum of care, a patient/physician analysis of the potential risks and benefits of chemotherapy may lead to the decision to proceed with subsequent systemic therapy, to consider an investigational strategy, or to opt for supportive care alone. The emergence of new active agents such as the taxanes has provided a valuable alternative option for such patients. While other cytotoxic agents in development may ultimately prove useful in the management of stage IV breast cancer, including some with novel antineoplastic mechanisms, there is evidence for optimism that the ability to perturb autocrine and paracrine growth factor pathways (eg, with monoclonal antibodies) may afford a viable alternative systemic approach, perhaps with a greater therapeutic index than "conventional" agents. Throughout the process of drug development, an increasing focus on the impact of new systemic regimens on quality of life, and costs associated with the palliative care of metastatic breast cancer should optimize the care of women with this disease.

Antineoplastic Agents↗
PubMed1995

Quality of life in phase II trials: a study of methodology and predictive value in patients with advanced breast cancer treated with paclitaxel plus granulocyte colony-stimulating factor.

BACKGROUND: Despite the clinical benefit that may be associated with reduction of tumor volume, chemotherapy may produce physical or psychological distress that could compromise a patient's quality of life. Although palliation may be as relevant as tumor response in patients with metastatic breast cancer, quality of life is not commonly evaluated in phase II clinical trials of new therapeutic agents. PURPOSE: We evaluated the utility of quality-of-life assessment in two phase II clinical trials of patients receiving paclitaxel (Taxol) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) as salvage therapy for metastatic breast cancer. METHODS: A battery of instruments (i.e., Memorial Symptom Assessment Scale [MSAS], Functional Living Index-Cancer [FLIC], Rand Mental Health Inventory [MHI], Brief Pain Inventory [BPI], and Memorial Pain Assessment Card [MPAC]) designed to capture information about social, psychological, and functional aspects of quality of life, as well as symptom prevalence and distress, was completed prior to treatment; serial assessments were obtained at regular intervals during the treatment period. Univariate and multivariate analyses were performed evaluating base-line quality-of-life parameters and standard prognostic factors in relation to outcome measures of survival, tumor response, and toxicity. For 30 consecutive patients with extensive prior chemotherapy for metastatic disease, longitudinal data were analyzed associating tumor response to changes in quality-of-life scores throughout the course of treatment with paclitaxel. RESULTS: Base-line scores of two validated quality-of-life instruments, the MSAS and the FLIC, independently predicted the overall survival (P < .01 for each). In this model, however, neither standard prognostic factors nor quality of life instruments predicted the likelihood of tumor response or the probability of encountering grade 3 or grade 4 nonhematologic toxicity. With serial assessments of quality of life, the majority of patients who achieved partial tumor response or stable disease reported improved or unchanged quality-of-life scores, while those patients with progressive disease experienced rapid deterioration in quality of life. CONCLUSIONS: Base-line quality-of-life assessment may provide prognostic information distinct from that obtained through standard prognostic indicators alone. The combination of two factors--extent of disease and a base-line quality-of-life assessment--predicted survival more accurately than either used separately. Evaluation of quality-of-life outcomes in relation to tumor response may illuminate previously unmeasured palliative effects of chemotherapy, such as pain relief, as well as the burdens it imposes. IMPLICATIONS: Information obtained from quality-of-life assessment in conjunction with phase II testing of new chemotherapeutic agents for metastatic breast cancer can guide quality-of-life evaluation planned in large, randomized future studies.

Adult↗
PubMed1995

Central nervous system progression of metastatic breast cancer in patients treated with paclitaxel.

BACKGROUND: The possibility of tumor sanctuary sites in the central nervous system (CNS) of patients receiving paclitaxel has been suggested by laboratory data identifying low concentrations of drug in the brain and cerebrospinal fluid (CSF) of rats. METHODS: The pattern of disease progression in patients with metastatic breast cancer who had an initial response to paclitaxel treatment in five Phase II trials at the Memorial Sloan-Kettering Cancer Center was reviewed. RESULTS: Of 152 patients, 53 had a partial or complete response, and 25 had a minor response. Of the 78 patients who responded to paclitaxel, 52 had subsequent disease progression, 22 changed treatments before progression occurred (as specified by the protocol and/or to receive high dose consolidation chemotherapy), 2 stopped receiving treatment because of toxicity, 1 continued receiving treatment, and 1 died with no evidence of disease progression. Six of the 52 patients who progressed after initially responding to paclitaxel had isolated CNS progression while maintaining their systemic response (leptomeningeal metastasis in three, brain metastases in two, brain and leptomeningeal metastases in one). One patient had CNS progression (brain metastases) associated with other systemic sites of progression. All patients with CNS disease developed neurologic symptoms, prompting neurologic evaluation; one had only a mild headache, which was not recognized until evaluation for paclitaxel-related peripheral neuropathy. CONCLUSIONS: These data suggest that the CNS, and particularly the CSF, is an important sanctuary site for patients with metastatic breast cancer receiving paclitaxel.

Blood-Brain Barrier↗
PubMed1995

Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer.

PURPOSE: To evaluate the efficacy and safety of paclitaxel administered by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Forty-nine patients with metastatic breast cancer received paclitaxel via 3-hour intravenous infusion after standard premedication. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used, and chemotherapy was cycled every 3 weeks. For 25 patients who received paclitaxel as initial therapy (group I), the starting dose was 250 mg/m2. Twenty-four patients who had received two or more prior regimens, including an anthracycline (group II), started at 175 mg/m2. Paclitaxel pharmacokinetics were evaluated in 23 patients in group I. RESULTS: Grade 3 and 4 toxicities included (groups I/II) neutropenia (36%/33%), thrombocytopenia (0%/8%), anemia (0%/13%), neuropathy (8%/0%), arthralgia/myalgia (16%/4%), and mucositis (4%/4%). No significant hypersensitivity-type reactions or cardiac arrhythmias were seen. Six patients who received paclitaxel at > or = 250 mg/m2 experienced transient photopsia, without apparent chronic neuro-ophthalmologic sequelae. The mean peak plasma paclitaxel concentration was 5.87 mumol/L (range, 1.99 to 7.89) for these patients, and 6.08 mumol/L (range, 0.81 to 13.81) for 17 of 19 patients who did not experience visual symptoms. In 25 assessable patients in group I at a median follow-up time of 12 months, one complete response (CR) and seven partial responses (PRs) have been observed, for a total response rate of 32% (95% confidence interval [CI], 15% to 53%). In group II, five PRs were noted in 24 assessable patients (20.8%; 95% CI, 7% to 42%). Median response durations were 7 months for group I and 4 months for group II. CONCLUSION: Paclitaxel via 3-hour infusion, without prophylactic G-CSF, is active and safe as initial and subsequent therapy for metastatic breast cancer. The transient visual symptoms noted at higher doses seem unrelated to peak plasma paclitaxel concentration. Further studies that compare 3- and 24 hour (or other) infusion schedules are necessary to determine the optimal administration of paclitaxel in metastatic breast cancer.

Adult↗
PubMed1995

Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response.

PURPOSE: Two phase II clinical trials were performed to determine efficacy and tolerability of paclitaxel (Taxol; Bristol-Myers Squibb Co, Wallingford, CT) and granulocyte colony-stimulating factor ([G-CSF] Neupogen; Amgen, Inc, Thousand Oaks, CA) as second or subsequent therapy for metastatic breast cancer. PATIENTS AND METHODS: Paclitaxel plus G-CSF was administered as a second stage IV regimen to 25 patients with metastatic breast cancer at a dose of 250 mg/m2 intravenously over 24 hours. Fifty-two patients received paclitoxel plus G-CSF at 200 mg/m2 as a third or subsequent regimen (no restriction on number of prior regimens or on prior high-dose chemotherapy). All patients had received prior anthracycline treatment, and ultimately had progressive bidimensionally measurable disease. RESULTS: Twenty-five of 76 patients (32.8%) had a major objective response (95% confidence interval [CI], 14% to 37%). The median duration of response was 7 months (range, 1 to 20+). Responses were as likely in patients with disease demonstrated to be unresponsive to anthracycline, ie, de novo resistance (11 of 37, or 30%) as in those with disease that once exhibited anthracycline sensitivity, ie, acquired resistance, (10 of 31, or 32%). G-CSF administration was associated with febrile neutropenic episodes in 36 of 402 cycles (9%) in 16 of 76 patients (21%). CONCLUSION: Paclitaxel's clinically significant activity against metastatic breast cancer extends to patients with many prior chemotherapy regimens. The lack of impact of prior doxorubicin therapy on the likelihood of subsequent response to paclitaxel suggests an important role for this agent in the treatment of refractory metastatic breast cancer.

Adult↗
PubMed1995

Memorial Sloan-Kettering Cancer Center experience with paclitaxel in the treatment of breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is the most important new cytotoxic agent to be introduced for the management of breast cancer in many years. During this decade, investigators at Memorial Sloan-Kettering Cancer Center have conducted multiple clinical and laboratory investigations aimed at optimally integrating this agent into therapeutic strategies for breast cancer. These studies address both single-agent and combination regimens in the metastatic and adjuvant settings. This report will review previous results, but focus on active studies and future avenues of research.

Antineoplastic Agents, Phytogenic↗
PubMed1995

Memorial Sloan-Kettering Cancer Center experience with paclitaxel in the treatment of breast cancer: from advanced disease to adjuvant therapy.

The novel chemotherapeutic agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has received more attention than perhaps any other drug in the past two decades in its development for the treatment of breast cancer. Its unique mechanism of action, demonstrated safety profile, and significant antitumor activity in thousands of patients treated in clinical trials thus far have led to recent US Food and Drug Administration approval of its use against chemotherapy-refractory metastatic breast cancer. This report will summarize the series of clinical investigations with paclitaxel in patients with metastatic breast cancer that have been completed over the past 3 years at Memorial Sloan-Kettering Cancer Center and address present and future avenues of research.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Sequential adjuvant therapy with doxorubicin/paclitaxel/cyclophosphamide for resectable breast cancer involving four or more axillary nodes.

The results of both retrospective and prospective studies suggest that the effectiveness of systemic adjuvant chemotherapy with doxorubicin and cyclophosphamide for breast cancer may be related to the dose intensity of these agents. Recent trials also have demonstrated the high activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) against metastatic breast cancer. Clinically, paclitaxel appears to be noncross-resistant with doxorubicin, but the unique and overlapping toxicities of these three agents might preclude concurrent adjuvant administration. A possible solution is sequential rather than concurrent administration, an approach that kinetic modelling predicts to be superior. A pilot study testing dose-intensive sequential administration of doxorubicin/paclitaxel/cyclophosphamide enrolled 42 patients with a median age of 42 years who had resected breast cancer metastatic to four or more ipsilateral axillary lymph nodes. Intravenous treatment, given at 14-day intervals, began with three cycles of doxorubicin 90 mg/m2, followed by three cycles of paclitaxel 250 mg/m2, given as a 24-hour infusion, and, finally, three cycles of cyclophosphamide 3 g/m2. Selected patients received radiotherapy. The median number of positive lymph nodes was eight (range, four to 25), and the median tumor size was 3.0 cm (range, 0 to 11.0 cm). Granulocyte colony-stimulating factor support was given. Both hematologic and non-hematologic toxicity were substantial but manageable. Hospital admission was necessary in 62 (17%) of 369 chemotherapy cycles in 29 patients (69%). As planned, the median intertreatment interval was 14 days through all nine cycles of therapy, and the median delivered dose intensity exceeded 98% for all three agents. The median follow-up from local control surgery in December 1994 was 448 days (range, 82 to 632 days). Three patients (7.2%) had disease relapses, one during the doxorubicin portion of treatment and two (4.9%) who had completed treatment with all three agents. Sequential dose-intensive therapy with doxorubicin/paclitaxel/cyclophosphamide has manageable toxicity and, with short follow-up, is a promising new regimen suitable for randomized testing.

Adult↗
PubMed1994

Taxol (paclitaxel): a novel anti-microtubule agent with remarkable anti-neoplastic activity.

Taxol (paclitaxel), an anti-microtubule agent extracted from the needles and bark of the Pacific yew tree Taxus brevifolia, has shown a remarkable anti-neoplastic effect in human cancer in phase I studies and early phase II and III trials thus far conducted. This has been reported primarily in advanced ovarian and breast cancer, although significant activity has also been documented in small-cell and non-small-cell lung cancer, head and neck cancers, and with lower activity in metastatic melanoma. The clinical utilization of Taxol had been previously somewhat restricted by its limited availability, a limitation that has recently been overcome by combined efforts of pharmaceutical, agricultural, and governmental agencies. In this review we shall address the pre-clinical data which have led to the use of Taxol in man, the main clinical results thus far obtained, the toxicities associated with its use, current ongoing trials and future clinical directions of this promising agent.

Animals↗