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Biomedical subjects

A D Seidman

Publications and source records attributed to A D Seidman.

At least 19 recordsLinked to original sources
PubMed2005

Serum HER2 extracellular domain in metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel: association with HER2 status by immunohistochemistry and fluorescence in situ hybridization and with response rate.

PURPOSE: We explored the relationship between circulating HER2 extracellular domain (ECD) and tissue HER2 status as determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). We also examined its predictive value in a cohort of metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel. METHODS: Eligible patients had pre- and post-treatment stored serum specimens and were treated on a previously reported phase II trial. Retrospective analysis evaluated: the association between pretreatment serum HER2 ECD and tissue HER2 status by IHC and FISH; and the association between change in serum HER2 ECD after 12 weeks of therapy and response proportion. RESULTS: Stored serum samples were available for 55/95 (58%) patients. Statistically significant associations were found between HER2 status as assessed by IHC and FISH, and baseline serum HER2 ECD level. Patients whose ECD normalized after 12 weeks of therapy had a higher response proportion compared with patients with persistently high ECD levels (68% versus 15%, P=0.005). A relative decline of over 55% from baseline HER2 ECD predicted response to therapy. CONCLUSION: A statistically significant association was observed between pretreatment serum HER2 ECD and tissue HER2 status as assessed by IHC and FISH. A decrease in serum HER2 ECD level was a significant predictor of response to trastuzumab-based therapy.

Adult↗
PubMed2001

Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification.

PURPOSE: This phase II study evaluated weekly trastuzumab and paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic breast cancer. Efficacy was correlated with immunohistochemical and fluorescent in situ hybridization (FISH) assay results. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable metastatic breast cancer. Up to three prior chemotherapy regimens, including prior anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel 90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel 90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four different immunohistochemical assays and FISH. RESULTS: Patients received a median of 25 weekly infusions (range, one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk (range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4% (4.5% complete response, 56.8% partial response) was observed in 88 fully assessable patients. In patients with HER2-overexpressing tumors, overall response rates ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression (ranges reflect the different assay methods used to assess HER2 status). Differences in response rates between patients with HER2-overexpressing tumors and those with normal HER2 expression were statistically significant for all assay methods, with CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy was generally well tolerated, although three patients had serious cardiac complications. CONCLUSION: Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.

Adult↗
PubMed2001

Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial.

Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50 mg per day. Gossypol plasma levels were measured (n = 8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n = 4). Grade I-II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50 mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with > 50% decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.

Administration, Oral↗
PubMed2001

The evolving role of gemcitabine in the management of breast cancer.

Despite the common clinical use of numerous active cytotoxic agents for breast cancer therapy, and the combinations that are derived from them, the median survival for patients with metastatic breast cancer has not been dramatically improved over the past two decades. Furthermore, when the expected outcome of treatment is not cure, optimizing the dynamic equilibrium between chemotherapy-induced side effects and the benefits attributable to chemotherapy-mediated relief of cancer-related symptomatology becomes paramount. The search for active agents to this end has recently included the clinical evaluation of the novel nucleoside analogue gemcitabine (2',2'-difluorodeoxycytidine). This review summarizes the recent and current development of this agent.

Antimetabolites, Antineoplastic↗
PubMed2001

Gemcitabine as single-agent therapy in the management of advanced breast cancer.

Many active cytotoxic agents exist for breast cancer therapy, and numerous combination chemotherapy regimens are derived from them. Creating these combinations is sometimes empirically motivated by non-overlapping toxicities or the expectation of non-cross resistance. Yet, there is usually no absolute division of these aspects among cytotoxic agents, and the median survival for patients with metastatic breast cancer has not been dramatically prolonged by this approach. When the outcome of treatment is palliation rather than cure, it becomes paramount to optimize the dynamic equilibrium between chemotherapy-induced side effects and the benefits attributable to relief of cancer-related symptoms. To this end, several recent clinical trials have evaluated the novel nucleoside analog gemcitabine (Gemzar) as single-agent therapy for advanced breast cancer. This article reviews these trials.

Antimetabolites, Antineoplastic↗
PubMed2001

Doxorubicin followed by sequential paclitaxel and cyclophosphamide versus concurrent paclitaxel and cyclophosphamide: 5-year results of a phase II randomized trial of adjuvant dose-dense chemotherapy for women with node-positive breast carcinoma.

PURPOSE: We conducted a randomized Phase II trial to directly compare toxicity, feasibility, and delivered dose intensities of two adjuvant dose-intensive regimens containing doxorubicin, paclitaxel, and cyclophosphamide for patients with node-positive breast carcinoma. EXPERIMENTAL DESIGN: Forty-two patients with resected breast carcinoma involving one or more ipsilateral axillary lymph nodes, were randomized to receive two different schedules of adjuvant chemotherapy using 14-day dosing intervals: either (a) three cycles of doxorubicin 80 mg/m(2) as i.v. bolus followed sequentially by three cycles of paclitaxel 200 mg/m(2) as a 24-h infusion and then by three cycles of cyclophosphamide 3.0 g/m(2) as a 1-h infusion (arm A); or (b) the same schedule of doxorubicin followed by three cycles of concurrent cyclophosphamide and paclitaxel at the same doses (arm B). All cycles were supported by granulocyte colony-stimulating factor administration. RESULTS: Forty-one patients were assessable for toxicity and feasibility; 37 (90%) completed all planned chemotherapy. There was no treatment-related mortality; however, increased toxicity was observed on arm B compared with arm A, manifested by an increase in hospitalization for toxicity, mainly neutropenic fever, and an increased incidence of transfusion of packed RBCs transfusions for anemia. The mean delivered dose intensities for paclitaxel and cyclophosphamide were significantly greater for arm A compared with arm B (P =.01 and P =.05, respectively). There is no long-term, treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSIONS: Dose-dense sequential single-agent chemotherapy is more feasible than doxorubicin with subsequent concurrent paclitaxel and cyclophosphamide.

Adult↗
PubMed2000

Trastuzumab in combination with chemotherapy for the treatment of metastatic breast cancer.

Metastatic breast carcinoma still remains an incurable condition. The relentless search for novel agents that might prove useful for management has evolved toward monoclonal antibodies, in part because of a rapidly expanding understanding of breast cancer biology. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is a recombinant humanized monoclonal antibody against the HER-2 receptor that has shown antitumor activity as a single agent in phase I and II trials of patients with metastatic breast cancer overexpressing HER-2. The observation of increased antitumor activity between trastuzumab and some chemotherapeutic agents in preclinical models has prompted its use in combination with several drugs. Of particular interest is the use of trastuzumab with paclitaxel. Two trials were presented at the 1999 meeting of the American Society of Clinical Oncology that evaluated this combination. One multicenter phase III trial showed clinical benefit and increased survival for patients with HER-2-overexpressing metastatic breast cancer treated with chemotherapy plus trastuzumab. A phase II trial, reviewed in this report, evaluated the efficacy and safety of weekly paclitaxel plus trastuzumab for patients with metastatic breast carcinoma, including those overexpressing and nonoverexpressing HER-2.

Antibodies, Monoclonal↗
PubMed1999

Phase I study of escalating doses of edatrexate in combination with paclitaxel in patients with metastatic breast cancer.

Motivated by the observation of preclinical synergy, a Phase I dose escalation study of edatrexate in combination with a 3-h paclitaxel infusion was performed in patients with advanced breast cancer to determine the maximum tolerated dose (MTD) of edatrexate and the toxicities associated with this combination and to report preliminary observations of efficacy with this novel combination. Thirty-six patients were enrolled in this Phase I trial. Thirty-five eligible patients were treated every 21 days in cohorts of at least three patients and were assessable for toxicity. One patient was ineligible due to hyperbilirubinemia. Stepwise dose escalations of edatrexate were administered until grade >3 nonhematological dose-limiting toxicities were reported. The initial dose level of edatrexate was 180 mg/m2; subsequent cohorts were treated with escalating doses of edatrexate (210, 240, 270, 300, 350, and 400 mg/m2). Edatrexate was administered by i.v. infusion over 1 h. Paclitaxel was administered 24 h later at a fixed dose of 175 mg/m2 as a 3-h infusion with standard dexamethasone, diphenhydramine, and cimetidine premedication. The MTD of edatrexate was reached at the 350 mg/m2 level in this study. Grade 3 diarrhea was seen in one patient at the 300 and 400 mg/m2 dose levels, requiring dose reductions. Two patients experienced grade 4 stomatitis at the 400 mg/m2 dose level and also required dose reduction, establishing the MTD as 350 mg/m2. Grade 3 nausea and vomiting were noted in two of three patients at the highest dose level. Of 35 patients, 4 patients reported grade 3 myalgias and 1 patient reported grade 3 neurosensory complaints, which were seen mostly at the 350 and 400 mg/m2 dose levels; however, 1 patient reported grade 3 myalgias at 180 mg/m2. No cumulative neurotoxicity was observed, and no patient experienced an allergic reaction to paclitaxel. In 23 patients with bidimensionally measurable disease, there were four complete (17%) and seven partial responses, with an overall response rate of 48% (95% confidence interval, 27-69%). All of the responses were seen in patients who had not received prior chemotherapy for stage IV disease. The median duration of response was not assessable because many responding patients went on to receive high-dose chemotherapy treatment with stem cell support. The combination of edatrexate and paclitaxel for treatment of metastatic breast cancer is a feasible and safe regimen. The MTD of edatrexate was 350 mg/m2 when combined with a 3-h infusion of paclitaxel (175 mg/m2) given 24 h later. Activity was noted even among patients who had relapsed shortly after receiving methotrexate- and/or doxorubicin-containing adjuvant regimens. Additional studies evaluating the sequences and dosing schema for this combination are warranted to improve the response proportion and define the duration of the response.

Adult↗
PubMed1999

Update on the management of advanced breast cancer.

Recent trials comparing single-agent vs combination therapy in metastatic breast cancer suggest that it may be time to reconsider the belief that combination chemotherapy is the gold standard of treatment. Based on the limited randomized trial data available to date, high-dose chemotherapy with stem-cell rescue should not be viewed as "state-of-the art" treatment for metastatic disease and should be used only in the context of clinical trials. Recent trials have explored the optimal dosing and scheduling of the taxanes, as well as the possible role of these agents in combination regimens. Capecitabine (Xeloda), a new oral fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and fluorouracil), and preclinical data suggest possible synergy between this agent and the taxanes. Other promising agents under study include liposome-encapsulated doxorubicin (TLCD-99), an immunoconjugate linking a chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important hormonal agent, but new antiestrogens and selective estrogen receptor modulators (SERMs) may provide alternatives. The potential role of new aromatase inhibitors as first-line hormonal agents requires further study. Finally, the possible synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two clinical trials.

Antibodies, Monoclonal↗
PubMed1999

Single-agent paclitaxel in the treatment of breast cancer: phase I and II development.

In oncology, the 1990s has in many respects been the decade of the taxanes, particularly in breast cancer therapy. Preclinical data suggested that scheduling was an important determinant of the antitumor activity of paclitaxel. Initial phase I/II studies established a variety of schedules (based on different doses and infusion durations) for the administration of this drug, with neutropenia or neuropathy being the dose-limiting toxicities. More recently, a regimen in which paclitaxel is infused weekly over 1 hour at doses up to 90 mg/m2 produced little myelosuppression, but substantial antitumor activity. It is hypothesized that this uncoupling of the drug from its expected major toxicity arises due to the shorter period of time in which the plasma paclitaxel concentrations are above a critical level. Along with other approaches, the dose-dense administration of paclitaxel is now subject to randomized, controlled trials.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer.

The HER2/neu proto-oncogene is overexpressed in 25% to 30% of patients with breast cancer. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a recombinant humanized monoclonal antibody with high affinity for the HER2 protein, inhibits the growth of breast cancer cells overexpressing HER2. In this phase II study the efficacy and toxicity of weekly administration of trastuzumab was evaluated in 46 patients with metastatic breast cancer whose tumors overexpressed HER2. A loading dose of 250 mg trastuzumab was administered intravenously, which was followed by 10 weekly doses of 100 mg each. Upon completion of this treatment period, patients with no disease progression could receive a weekly maintenance dose of 100 mg. Patients in this trial had extensive metastatic disease, and most had received prior anticancer therapy. Ninety percent of patients achieved adequate serum levels of trastuzumab. Toxicity was minimal, and no antibodies against trastuzumab could be detected. Objective responses were observed in 5 of the 43 evaluable patients, which included 1 complete remission and 4 partial remissions, for an overall response rate of 11.6%. Responses were seen in mediastinum, lymph nodes, liver, and chest wall lesions. Minor responses (seen in 2 patients) and stable disease (14 patients) lasted for a median of 5.1 months. These results demonstrate that trastuzumab is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers who have received extensive prior therapy. The regression of human cancer through the targeting of putative growth factor receptors such as HER2 warrants further evaluation of trastuzumab in the treatment of breast cancer.

Adult↗
PubMed1998

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.

PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.

Adult↗
PubMed1998

Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer.

PURPOSE: To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS: Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS: A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at < or = 100 mg/m2. CONCLUSION: Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.

Adult↗
PubMed1998

One-hour paclitaxel via weekly infusion: dose-density with enhanced therapeutic index.

A preliminary report of phase II trial of paclitaxel (Taxol) administered in a dose-dense manner as first- and second-line therapy for metastatic breast cancer is presented. Patients who had received one or two prior chemotherapy regimens for metastatic disease or in the adjuvant setting were eligible. Prior treatment with an anthracycline was permitted, but patients who had previously received taxanes were excluded. Initial dose was paclitaxel 100 mg/m2 infused over 1 hour weekly until disease progression or intolerable toxicity. To date, significant activity and a highly favorable toxicity profile have been observed with 1-hour paclitaxel < or = 100 mg/m2. Less myelosuppression occurred than would have been expected with a standard regimen (paclitaxel 175 mg/m2 given over 3 hours q3wks). Neurotoxicity became dose limiting at paclitaxel > 100 mg/m2/wk. The apparent safety and high therapeutic index of paclitaxel administered in a dose-dense fashion increases therapeutic options for patients with breast cancer, and further studies are warranted.

Adult↗
PubMed1997

Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing.

BACKGROUND: Paclitaxel-induced peripheral neuropathy (PN) may be severe and dose-limiting at initial doses > or = 275 mg/M2, but its neurotoxicity at doses < or = 250 mg/M2 has been incompletely characterized. The purposes of this study were to characterize and quantify paclitaxel-induced PN and to determine the utility of quantitative sensory testing (QST). METHODS: We prospectively examined clinically and by QST 37 women with metastatic breast cancer, treated with paclitaxel (200-250 mg/m2) (average number of cycles = 7.3 over an average of 20.1 weeks). QST included thermal threshold (TT) and vibration threshold (VT). RESULTS: Paresthesias appeared in 31 (84%) patients after an average of 1.7 cycles and an average cumulative dose of 371.5 mg/M2. Symptoms occurred after the first or second dose in 26 (84%) patients and then stabilized in 10 (32%), improved in 13 (42%) despite continued treatment, resolved completely in 6 (19%), and were progressive in 2 (7%). Paclitaxel was discontinued in only 1 (3%) patient because of neurotoxicity and no patient required dose reduction because of PN. Thirty-six (97%) developed signs of PN. The most sensitive QST was great toe VT but QST did not predict or identify subclinical PN in any patient. Neurologic syndromes other than PN developed in 12 (32%) patients, and 7 were due to metastatic cancer. CONCLUSIONS: 1) Paclitaxel-induced PN is mostly sensory, and begins after the first or second dose. At these doses the neuropathy is mild, and rarely dose-limiting. 2) QST quantified the neuropathy but was less sensitive than the clinical examination. 3) Knowledge of the features of paclitaxel's PN allows it to be differentiated from other neurologic syndromes which may signal tumor progression.

Adult↗
PubMed1997

Docetaxel: a new active agent in the therapy of metastatic breast cancer.

Breast cancer is the most common malignancy in women, accounting for about 18% of female cancers, and over half a million new cases are diagnosed worldwide each year. Its incidence increases with age and is currently rising. Although the increased availability of screening programs has allowed earlier detection and treatment of primary breast cancers, many patients relapse with metastases after apparently successful treatment of their primary tumor and over 15,000 women in the UK and about 50,000 in the USA die from advanced disease each year. The natural course of breast cancer is very variable even after the development of metastases, and depends on a variety of tumor characteristics and prognostic factors. This is reflected in the large number of treatments currently employed. However, despite this wide choice and considerable research over the years, treatment of metastatic breast cancer (MBC) prolongs average survival times only slightly. Current therapy is aimed at achieving a balance between producing maximal tumor shrinkage to produce the most effective possible palliation of symptoms, and minimizing adverse effects. Anticancer chemotherapy is the preferred option in patients who do not respond to hormones, those with hormone-independent tumors, those with aggressive breast cancer subtypes. A variety of anticancer chemotherapy regimens, using both single and combined agents, have been shown to be effective in achieving tumor regression in MBC. Anthracyclines (doxorubicin, epirubicin) are the most active of the established monotherapies, typically producing response rates of 50-60% during initial (first-line) treatment for metastatic disease, but being effective in fewer than 25% of patients requiring second-line therapy. The drawbacks of anthracyclines include dose-limiting cumulative cardiotoxicity and the development of resistant tumor clones after the use of anthracyclines for adjuvant or first-line therapy, especially if subsequent courses are required within a year. The success of these established chemotherapeutic agents depends greatly on the number and location of metastatic sites. Lymph node and soft tissue secondaries tend to respond well, while visceral metastases (especially in the liver) carry a particularly poor prognosis despite treatment. The outlook for patients with metastases involving more than two organ systems is also bleak. Although some patients can live for years with metastatic disease, the average survival time in patients with MBC is 18-24 months, while in those with liver metastases, life expectancy averages only 6 months. High-dose anticancer chemotherapy with granulocyte-colony stimulating factor (G-CSF) or autologous bone marrow transplantation has allowed the dose intensity of anthracyclines to be increased, and has improved the response rate to about 70% in selected patients with MBC. However, this approach has not been proven to improve survival, involves the risk of greater toxicity and drug-related mortality, and patients with reduced clearance of anthracyclines due to hepatic dysfunction from liver metastases may not be suitable candidates. A number of new anticancer agents have also recently been introduced in an attempt to improve on the performance and avoid the tolerability problems associated with anthracyclines. Among these, antitubulin agents (taxoids and vinorelbine) have shown highly promising activity in MBC. This paper reviews the preclinical, phase I and phase II data for one taxoid, docetaxel. Docetaxel (Taxotere) belongs to the taxoid class of cytotoxic agents, the development of which began more than 20 years ago. In 1971, paclitaxel (Taxol) was identified as the active compound of the crude extract of the bark of the Pacific Yew tree Taxus brevifolia. However, at that time the development of paclitaxel was hampered because of the limited source of the drug and difficulties with isolation, extraction and formulation. The second active taxoid, docetaxel, was isolated by Potier et al. in 1986. Docetaxel is prepared from a non-cytotoxic precursor, extracted from the needles of the European Yew tree Taxus baccata, that is condensed with a chemically-synthesized side-chain. As the docetaxel precursor is freely available because of the regenerating capacity of the needles the development of docetaxel has thus been rapid.

Journal Article↗
PubMed1997

Paclitaxel for breast cancer: the Memorial Sloan-Kettering Cancer Center experience.

The proven safety profile and antitumor activity of paclitaxel (Taxol) in the treatment of metastatic breast cancer led investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) to further examine the agent's potential in the treatment of advanced breast cancer. Efficacy and tolerability studies of paclitaxel as single-agent therapy were undertaken, along with parallel investigations of quality-of-life parameters. The studies examined the effects of 96-hour infusion schedules of paclitaxel and are currently assessing the feasibility of a weekly 1-hour infusion schedule. Researchers at MSKCC also compared the results of a variety of two- and three-drug paclitaxel-containing regimens to determine possible synergism and better define safety profiles. They examined the combination of paclitaxel and edatrexate, as well as a promising combination of paclitaxel and a monoclonal antibody directed at growth factor receptors. The latter ongoing trial will include both laboratory studies that examine possible cellular mechanisms for the combination's observed synergy and a clinical trial that combines paclitaxel with a monoclonal antibody directed against the epidermal growth factor. In conclusion, the investigators discuss the optimal integration of paclitaxel into doxorubicin/cyclophosphamide (Cytoxan, Neosar)-based adjuvant therapy for node-positive stage II-III resectable breast cancer.

Antineoplastic Agents, Phytogenic↗