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Biomedical subjects

H J Burstein

Publications and source records attributed to H J Burstein.

At least 19 recordsLinked to original sources
PubMed2005

Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy.

PURPOSE: The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. METHODS: The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy (doxorubicin/cyclophosphamide or paclitaxel) +/- trastuzumab, and the second was a multicenter phase II trial of vinorelbine + trastuzumab. All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. RESULTS: Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. Trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. CONCLUSIONS: Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.

Antibodies, Monoclonal↗
PubMed2001

Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

Adult↗
PubMed2001

New cytotoxic agents and schedules for advanced breast cancer.

Cytotoxic chemotherapy is important for treatment of women with hormone-insensitive or hormone-refractory advanced breast cancer. A variety of agents are effective, alone or in combination. The clinical activity and side effects of many agents, as well as principles for use of chemotherapy, are reviewed. Recent advances in chemotherapy for breast cancer include important studies on the role of dose-intensity, modifications of available agents to reduce side effects, and the availability of oral chemotherapeutics. Finally, the combination of chemotherapy with novel biological agents may improve outcomes for women with certain types of breast cancer. The growing availability of such biological therapies given in combination with chemotherapy may mean better survival in the future for women with advanced breast cancer.

Antibodies, Monoclonal↗
PubMed2001

Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer.

The decision to receive chemotherapy or chemohormonal therapy involves careful consideration of both the potential benefits and possible risks of therapy. There are substantial short- and long-term side effects from chemotherapy. By convention, short-term side effects include those toxic effects encountered during chemotherapy, while long-term side effects include later complications of treatment arising after the conclusion of adjuvant chemotherapy. These side effects vary, depending on the specific agents used in the adjuvant regimen as well as on the dose used and the duration of treatment. There is also considerable variability in side effect profile across individuals. This review will focus on the short- and long-term toxicity seen with the most commonly used adjuvant chemotherapy and chemohormonal therapy regimens.

Antineoplastic Agents↗
PubMed2001

New combinations with Herceptin in metastatic breast cancer.

Preclinical data indicate that trastuzumab (Herceptin) has the potential for synergistic or additive effects in combination with therapies including chemotherapy and hormonal agents, providing the rationale for a number of clinical trials in women with HER2-positive metastatic breast cancer. A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective (overall response rate 75%) and well tolerated, with the major side effects being typical of single-agent vinorelbine. Other combinations of trastuzumab with a variety of other chemotherapeutic and hormonal agents are also being assessed. In an effort to overcome the cardiotoxicity observed with trastuzumab plus doxorubicin in the pivotal phase III trial, combination regimens involving potentially less toxic anthracyclines such as epirubicin and liposomal formulations of doxorubicin are ongoing. In addition, trials are investigating whether trastuzumab can reverse the resistance to hormonal therapy that develops in most women with metastatic breast cancer. These and other studies will identify the regimens that produce the best outcomes with the fewest possible side effects in women with HER2-positive breast cancer.

Anastrozole↗
PubMed2000

Docetaxel administered on a weekly basis for metastatic breast cancer.

PURPOSE: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.

Adult↗
PubMed1999

Use of alternative medicine by women with early-stage breast cancer.

BACKGROUND: We analyzed the use of alternative medicine by women who had received standard therapy for early-stage breast cancer diagnosed between September 1993 and September 1995. METHODS: A cohort of 480 patients with newly diagnosed early-stage breast cancer was recruited from a Massachusetts statewide cohort of women participating in a study of how women choose treatment for cancer. Alternative medical treatments, conventional therapies, and health-related quality of life were examined. RESULTS: New use of alternative medicine after surgery for breast cancer was common (reported by 28.1 percent of the women); such use was not associated with choices about standard medical therapies after we controlled for clinical and sociodemographic variables. A total of 10.6 percent of the women had used alternative medicine before they were given a diagnosis of breast cancer. Women who initiated the use of alternative medicine after surgery reported a worse quality of life than women who never used alternative medicine. Mental health scores were similar at base line among women who decided to use alternative medicine and those who did not, but three months after surgery the use of alternative medicine was independently associated with depression, fear of recurrence of cancer, lower scores for mental health and sexual satisfaction, and more physical symptoms as well as symptoms of greater intensity. All groups of women reported improving quality of life one year after surgery. CONCLUSIONS: Among women with newly diagnosed early-stage breast cancer who had been treated with standard therapies, new use of alternative medicine was a marker of greater psychosocial distress and worse quality of life.

Adult↗
PubMed1999

Phase I study of Doxil and vinorelbine in metastatic breast cancer.

BACKGROUND: Vinorelbine and Doxil (liposomal doxorubicin) are active chemotherapeutic agents in metastatic breast cancer. A phase I study was designed to evaluate combination therapy. PATIENTS AND METHODS: Thirty women with metastatic breast cancer were enrolled. Dose-limiting toxicity was determined through a dose escalation scheme, and defined for the first treatment cycle, only. Pharmacokinetic studies were performed during the first cycle of treatment. RESULTS: In the first cohort of Doxil 30 mg/m2 day 1 and vinorelbine 25 mg/m2 days 1 and 8, patients experienced severe neutropenia. Vinorelbine administration was changed thereafter to days 1 and 15 of each cycle. Dose limiting toxicity was observed at Doxil 50 mg/m2 and vinorelbine 25 mg/m2. Doxil 40 mg/m2 and vinorelbine 30 mg/m2 was defined as the maximally tolerated dose. Few toxicities (principally neutro penia) were seen at this dose level, with the notable absence of significant nausea, vomiting, or alopecia. Though 63% of patients had received prior anthracycline-based chemotherapy, only one patient developed grade 2 cardiac toxicity. Pharmacokinetic studies revealed prolonged exposure to high doxorubicin concentrations for several days following Doxil administration. CONCLUSIONS: Combination chemotherapy with Doxil and vinorelbine affords treatment with two active drugs in women with metastatic breast cancer, and appears to have a favorable toxicity profile. A schedule of Doxil 40 mg/m2 day 1 and vinorelbine 30 mg/m2 days 1 and 15 given every 28 days is recommended for phase II studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

In vivo role of interleukin 4 in T cell tolerance induced by aqueous protein antigen.

High doses of aqueous protein antigens induce a form of immunological tolerance in which interleukin 2 (IL-2)- and interferon gamma (IFN-gamma)-secreting T helper type 1 (Th1) cells are inhibited, but IL-4-secreting (Th2) cells are not. This is manifested by reduced proliferation of antigen-specific T cells upon in vitro restimulation, and marked suppression of specific antibody responses of the immunoglobulin (Ig)G2a, IgG2b, and IgG3 isotypes, but not of IgG1 and IgE. The role of the immunomodulatory cytokine IL-4 in this model of unresponsiveness to protein antigens has been examined. Administration of tolerizing antigen itself primes splenic CD4+ T cells for secretion of lymphokines, both IL-2 and IL-4. Neutralization of IL-4 in vivo with the anti-IL-4 antibody 11B11 during tolerance induction augments IFN-gamma production by T cells of tolerant mice, and reverses the suppression of IgG2a, IgG2b, and IgG3. This blockade of IL-4 function does not, however, restore the proliferative responses of T cells, suggesting that reduced T cell proliferation is due to direct T cell inactivation or anergy. Inhibiting the activity of IL-4 in vivo also inhibits the expansion of antigen-specific Th2-like cells, which are resistant to the induction of unresponsiveness. Thus, the immunologic consequences of high-dose tolerance are due to a combination of clonal T cell anergy and IL-4-mediated immune regulation.

Animals↗
PubMed1993

Determinants of helper T cell-dependent antibody production.

Multiple factors regulate the development and maintenance of humoral immune responses. The cytokines produced by helper T cells are major determinants of the magnitude and phenotype of antibody responses to protein antigens. Th2-derived cytokines are most effective at initiating primary B cell responses, whereas Th1 cells are effective helpers for B cells exposed to multivalent antigens and for previously activated B cells. In addition, different cytokines stimulate B cell switching to particular antibody isotypes. Cytokine production can be regulated in vivo by the conditions of antigen exposure, and by the nature of antigens. Tolerogenic antigens alter the phenotypes of antibody responses by preferentially inactivating selected subsets of helper T cells. Morphologic techniques provide potentially valuable approaches for studying T/B cell interactions and the nature and consequences of local cytokine production in situ, in lymphoid tissues.

Animals↗
PubMed1992

Aqueous antigens induce in vivo tolerance selectively in IL-2- and IFN-gamma-producing (Th1) cells.

As a model for understanding in vivo immune responses, we have exposed mice to aqueous haptenated-protein Ag, and examined immune responses to subsequent immunization with Ag in adjuvant. Pretreating mice with soluble, TNP-conjugated Ag induces selective nonresponsiveness to Ag for both humoral and cell-mediated immune functions. Specific T cell proliferation in response to Ag is inhibited, and Ag-induced secretion of the lymphokines IL-2 and IFN-gamma, but not IL-4, is reduced. B cell responses after pretreatment are also affected. Although levels of TNP-specific IgG1 and IgE are similar in treated and untreated mice, soluble Ag pretreatment diminishes production of TNP-specific IgG2a and IgG2b. This is due to lack of T cell help and is not caused by tolerance in the B cell compartment. These results indicate that pretreatment of mice with aqueous Ag induces selective unresponsiveness in Th1-like Th cells, which secrete IL-2 and IFN-gamma, but not in Th2-like Th cells, which secrete IL-4.

Animals↗
PubMed1991

Humoral immune functions in IL-4 transgenic mice.

We have analyzed mice expressing IL-4 as a transgene, and found that expression of this lymphokine has profound effects on B cell function. B cells from transgenic mice exhibit phenotypic changes, including an increase in size and elevated expression of class II MHC. IL-4 increases the quantity of IgE produced by transgenic-derived B cells in response to LPS stimulation. In vivo, IL-4 markedly affects the serum Ig isotype repertoire. Serum levels of IgG1 and IgE are elevated, and levels of IgG2a, IgG2b, and IgG3 are depressed in IL-4 transgenic mice. Ag-specific antibody responses to immunization with hapten-carrier conjugates are also affected by IL-4. Transgenic mice show increased anti-hapten IgE and IgG1 and reduced anti-hapten IgG2a, IgG2b, and IgG3, compared with wild-type mice. Ag-specific IgE is substantially induced by T cell-dependent Ag, but not T cell-independent Ag, suggesting that cognate T-B interactions in addition to IL-4 are required for generating IgE responses in vivo. In vivo treatment with the anti-IL-4 mAb 11B11 reverses many of the isotype alterations in the transgenic mice, indicating that these changes arise as a direct consequence of IL-4 secretion.

Animals↗
PubMed1991

T-cell-mediated activation of B cells.

Antibody responses to protein antigens are dependent on helper T lymphocytes, which provide necessary growth and differentiation, inducing stimuli to antigen-specific B cells. Recent investigations have focused on the mechanisms of T-B interactions, and the nature of the T-cell-derived signals that are needed for activation and expansion of B cells.

Animals↗