taxane and Neoplasm-Metastasis

Cases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent approximately 15% to 20% of all breast cancers. Historically, this subtype of breast cancer was associated with an increased risk for the development of systemic and brain metastases and poor overall survival. The introduction of trastuzumab dramatically changed the outcomes of patients with HER2-positive disease, with many demonstrating outcomes similar to those of patients with luminal tumors. Currently, the first-line standard of care for patients with HER2-positive metastatic breast cancer is dual HER2 antibody therapy with pertuzumab/trastuzumab plus a taxane. After progression, the standard of care is trastuzumab emtansine (T-DM1). Although the treatment choices for patients whose disease has progressed on these agents are more limited, promising new drugs have emerged as effective options, including tucatinib and trastuzumab deruxtecan, which were recently approved by the US Food and Drug Administration. Finding the best treatment sequencing for each patient, developing reliable predictive biomarkers, and understanding the mechanisms of resistance to these drugs are necessary to maximize patient outcomes and quality of life. In this review, we analyze the management strategies for metastatic HER2-positive breast cancer, address specific situations, such as the treatment of patients with brain metastases, and discuss future directions in the treatment of this subtype.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Camptothecin; Female; Humans; Immunoconjugates; Neoplasm Metastasis; Oxazoles; Pyridines; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab

The aim of this review was to systematically evaluate the safety and efficacy of the addition of pertuzumab to trastuzumab emtansine (T-DM1) ± taxane in patients with human epidermal growth factor receptor 2 (HER2)-positive, locally advanced breast cancer (LABC) or metastatic breast cancer (MBC).. Several databases were searched for relevant clinical trials. The study characteristics, details of adverse events (AEs) and details of treatment efficacy were extracted for analysis.. Six studies with 996 patients were included. Common AEs of T-DM1 + pertuzumab ± taxane included fatigue, diarrhea, nausea, epistaxis, peripheral neuropathy, increased aspartate transaminase (AST), increased alanine transaminase (ALT) and thrombocytopenia. Major grade ≥3 AEs of T-DM1 + pertuzumab ± taxane included thrombocytopenia, neutropenia, fatigue, increased ALT, anemia and peripheral neuropathy. The addition of pertuzumab to T-DM1 ± taxane led to higher risks of diarrhea (especially grade ≥3 diarrhea), rash and vomiting, and decreased risks of thrombocytopenia and grade ≥3 increased AST. The relative risks of the addition of pertuzumab to T-DM1 ± taxane for objective response (1.068, 95% CI 0.945-1.207) and clinical benefit (1.038, 95% CI 0.974-1.106) were not statistically significant.. Common AEs should be carefully monitored in HER2-positive LABC or MBC patients treated with T-DM1 + pertuzumab ± taxane. The addition of pertuzumab to T-DM1 ± taxane showed noninferior, but not superior, objective response rate and clinical benefit rate. However, more studies are needed to further verify these findings.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids; Trastuzumab

Despite the significant survival benefit of taxane therapy in metastatic castration-resistant prostate cancer (mCRPC), all patients inevitably develop treatment resistance. An understanding of resistance mechanisms has led to new therapies for prostate cancer (cabazitaxel, abiraterone and enzalutamide), all of which have improved survival following first-line docetaxel. Another treatment, currently in development, targets the prosurvival molecule clusterin. Custirsen, an antisense molecule that inhibits clusterin production, has shown promise in combination with docetaxel in mCRPC patients at risk for poor outcomes. Although optimal sequence and combination of available therapies is unclear, the heterogeneity of mCRPC suggests a continuing need for personalized treatment regimens and improved abilities to predict which patients will respond to the available treatment options.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Humans; Inflammation; Male; Microtubules; Molecular Chaperones; Neoplasm Metastasis; Patient Selection; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Taxoids; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Combined Modality Therapy; Head and Neck Neoplasms; Humans; Induction Chemotherapy; Neoplasm Metastasis; Organ Sparing Treatments; Radiotherapy, Intensity-Modulated; Taxoids; Treatment Outcome

The first-generation taxanes, conventional paclitaxel and docetaxel, are established treatment options for adjuvant and metastatic breast cancer (MBC). However, these agents have limitations, including primary/secondary resistance and harsh toxicities. The introduction of paclitaxel albumin represents a significant advance in taxane therapy as the first of a new generation of taxanes. This agent utilizes albumin pathways to achieve enhanced and targeted drug delivery to the tumour. The lack of solvent also means that it is well tolerated, despite the lack of premedications. Paclitaxel albumin is licensed in the United States and Europe as ≥2nd-line therapy in MBC (260mg/m(2) once every three weeks), but emerging evidence suggests it has activity in various settings as weekly therapy and in combination with other agents. Additional strategies to optimize taxane-based therapy are also being evaluated, including the possibility of tailoring treatment according to patient/disease characteristics, identifying predictive biomarkers and evaluating other novel taxanes.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials as Topic; Female; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Taxoids; Treatment Outcome

This paper presents a summary of the evidence review group (ERG) report into the use of bevacizumab (Avastin®, Roche) in combination with a taxane for the treatment of untreated metastatic breast cancer (mBC). The main clinical effectiveness data were derived from a single, open-label randomised controlled trial (RCT) (E2100) that evaluated the addition of bevacizumab to weekly (q.w.) paclitaxel in patients with human epidermal growth factor receptor 2-negative mBC who had not previously received chemotherapy for advanced disease. This trial reported statistically significant increases in median progression-free survival (PFS) for the addition of bevacizumab (5.8-11.3 months). Median overall survival was not significantly different between the two groups; whether this is a true null finding or due to crossover between treatment arms cannot be established, as relevant data were not collected. The manufacturer reported that the addition of bevacizumab to paclitaxel q.w. therapy was associated with a significant improvement in quality of life, as measured by FACT-B (functional assessment of cancer therapy for breast cancer) scores. However, the ERG noted that these results were based on extreme imputed values, the removal of which led to non-significant differences in quality of life. The manufacturer conducted an indirect comparison. However, owing to methodological limitations and concerns about the validity and exchangeability of the included trials, the ERG did not consider the findings to be reliable. One additional relevant RCT [AVADO (Avastin and Docetaxel); BO17708] evaluating the addition of bevacizumab to docetaxel was excluded from the manufacturer's submission. This was summarised by the ERG. In terms of response rate and PFS, AVADO reported a markedly smaller benefit of adding bevacizumab to docetaxel than that reported for adding bevacizumab to q.w. paclitaxel in E2100. AVADO also reported no statistically significant effect of combination therapy versus docetaxel in terms of overall survival. The manufacturer developed a de novo economic model that considered patients with the same baseline characteristics as women in the E2100 trial. The model assessed BEV + PAC - bevacizumab 10 mg/kg every 2 weeks in combination with paclitaxel 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; PAC q.w. - paclitaxel (monotherapy) 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; DOC - docetaxel (monotherapy) 75 mg/m2 on day 1 every 21 days (consid

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Disease-Free Survival; Docetaxel; Drug Therapy, Combination; Female; Gemcitabine; Humans; Neoplasm Metastasis; Paclitaxel; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Taxoids

One of the major recent clinical advances in cancer treatment is the use of antiangiogenic drugs such as bevacizumab, sorafenib, and sunitinib. Bevacizumab, the monoclonal anti-VEGF antibody, has been approved for the first line treatment of metastatic breast cancer (MBC) when combined with taxane. However, the clinical benefits are modest; despite a doubling of response rates and significant prolongation of progression free survival times, no increase in overall survival is attained. This review summarizes some of the possibilities to account for this discrepant result. These include rapid development of acquired drug resistance due to the redundancy of proangiogenic growth factors, acceleration of tumor growth after antiangiogenic drug treatments are stopped, and increases in tumor cell malignant aggressiveness driven by mechanisms such as increased tumor hypoxia. Some possible strategies to improve the benefits of antiangiogenic drug therapy are discussed such as prolonging the treatment beyond tumor progression, combination with other therapeutic modalities, e.g. long term ('maintenance') low-dose metronomic chemotherapy or additional targeted/biologic drugs, e.g. trastuzumab.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Drug Delivery Systems; Drug Resistance, Neoplasm; Female; Humans; Neoplasm Metastasis; Taxoids; Vascular Endothelial Growth Factor A

Proof of principle that molecularly targeted therapy is a valid therapeutic approach for squamous cell carcinoma of the head and neck (SCCHN) has emerged with epidermal growth factor receptor targeting agents. Other interesting targets, such as Src, insulin-like growth factor 1 receptor, and the proteasome, have been shown in vitro to play key roles in SCCHN, and their inhibition is currently being studied in phase II trials. Identification of predictive biomarkers of resistance or sensitivity to these therapies remains one of the main challenges in the optimal selection of patients most likely to benefit from them. However, clinical trials with these novel agents need to be designed rationally to improve the overall outcome of patients. Given the emerging evidence that human papilloma virus-related SCCHN is a distinct disease, it should be studied in specific trials.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Squamous Cell; Cetuximab; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Drug Delivery Systems; Fluorouracil; Head and Neck Neoplasms; Humans; Multicenter Studies as Topic; Neoplasm Metastasis; Neoplasm Recurrence, Local; Survival Rate; Taxoids; Time Factors

The management of early breast cancer has evolved rapidly in recent years. Consequently, the range of first-line treatment options for metastatic breast cancer (MBC) is becoming increasingly complicated and therapy depends on a complex interaction of tumor, patient, and physician variables. Arguably one of the most important factors determining choice of first-line chemotherapy is prior adjuvant therapy. We have reviewed data from large, randomized clinical trials to identify the most effective regimens and help clinicians to select first-line treatment based on previous adjuvant therapy. In this review we provide recommendations on the most appropriate first-line therapy according to the type of previous adjuvant therapy. With such a wide array of treatment options available, none is likely to become the gold-standard first-line treatment for MBC. Furthermore, as increasing emphasis is placed on the quality as well as the duration of survival after development of MBC, treatment decisions should take into account tumor characteristics, toxicity, convenience, potential impact on quality of life, and patient preference, in addition to robust efficacy data.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Genes, erbB-2; Humans; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

Management of metastatic breast cancer (MBC) is difficult and overall response rates (ORR) resulting from anthracycline and taxane-based regimens remain modest. The antimetabolite drug gemcitabine has been shown to have high activity when used as first-line treatment of MBC, particularly when incorporated into combined therapy regimens. Gemcitabine-containing regimens have also been used successfully as salvage therapy in women with anthracycline or taxane-pretreated MBC. Phase II clinical studies have demonstrated high ORR with gemcitabine-docetaxel (ORR: 36-65.5%) and gemcitabine-paclitaxel (ORR: 40-68%) combination regimens. A highly favourable risk-benefit ratio has also been reported for gemcitabine-containing triplets such as gemcitabine-paclitaxel-epirubicin (ORR: 92%) and gemcitabine-paclitaxel-doxorubicin (ORR: 80.4%). Gemcitabine-containing regimens have a favourable toxicity profile with few serious toxic events reported. An important step forward in the evaluation of novel chemotherapeutic regimes for MBC is establishing a correlation between disease markers and response to therapy. Preliminary data suggest that there is a close relationship between HER2 extracellular domain levels (>30 ng/ml) and treatment outcome. HER2-positive patients had a lower ORR to gemcitabine-paclitaxel chemotherapy than women who were HER2-negative. Further studies to establish a link between other breast cancer markers and predicted response to treatment are warranted.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Female; Gemcitabine; Humans; Neoplasm Metastasis; Remission Induction; Taxoids; Treatment Outcome

Until recently, standard adjuvant chemotherapy for metastatic breast cancer (MBC) consisted of anthracycline-based regimens, followed by a taxane. However, data suggest that taxane-based combinations can be more effective than taxanes alone for the second part of treatment. Synergy between paclitaxel and gemcitabine was demonstrated in vitro when paclitaxel was followed by gemcitabine. Dose-dense regimens administered every 2 weeks are more effective than standard 3 weekly regimens. In a phase II study, gemcitabine plus paclitaxel every 2 weeks as first-line chemotherapy of MBC was associated with an overall response rate (ORR) of 71%. Women with HER2 ECD-positive tumours have a poor ORR (40%) to first-line chemotherapy. The addition of trastuzumab to dose-dense paclitaxel-gemcitabine as first-line chemotherapy in women with HER2-positive MBC was associated with a dramatic increase in ORR to 78%, with no serious toxicity observed. Two phase III clinical trials of gemcitabine-paclitaxel as adjuvant chemotherapy in women with histologically-confirmed MBC are currently underway. Preliminary data show that this drug combination is well-tolerated, and the efficacy results are eagerly awaited.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Drug Administration Schedule; Drug Synergism; Female; Gemcitabine; Humans; Neoplasm Metastasis; Paclitaxel; Receptor, ErbB-2; Remission Induction; Taxoids; Trastuzumab

As anthracycline-based regimens have become a standard treatment and are frequently used in the adjuvant therapy of breast cancer, the number of anthracycline-resistant cancers has begun to increase. Taxanes have also become more commonly used in the first-line metastatic and adjuvant setting, producing a need for new treatment options that are not cross-resistant with anthracyclines or taxanes and that have a relative non-overlapping toxicity profile with these agents. The combination of gemcitabine/cisplatin has been shown to have synergistic cytotoxic activity in vitro in breast cancer cell lines. In addition, several phase II trials have suggested that this combination is feasible and active in patients who have received prior anthracycline and/or taxane therapy.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Cisplatin; Clinical Trials as Topic; Deoxycytidine; Female; Gemcitabine; Humans; Neoplasm Metastasis; Taxoids

In patients with advanced breast cancer, treatment with paclitaxel and doxorubicin has been shown to produce impressive overall response rates (up to 94%) and to prolong overall survival significantly over a combination of fluorouracil (5-FU), doxorubicin, and cyclophosphamide (Cytoxan, Neosar) in one prospective phase III clinical study. These results have been challenged, however, by other data demonstrating no survival advantage for taxane-based therapies. In addition, the combination of paclitaxel and doxorubicin has repeatedly been shown to be complicated by the development of treatment-related congestive heart failure, when cumulative doxorubicin doses exceed 300-360 mg/m2. Consequently, attempts have been made to increase the complete remission rate and overall survival resulting from first-line treatment of metastatic breast cancer without compromising patient safety. Gemcitabine (Gemzar)--a relatively effective, well-tolerated and partially non-cross-resistant antitumor compound with limited toxicity--represents an attractive alternative to paclitaxel/anthracycline combinations. Initial studies of combination therapy with gemcitabine and paclitaxel have produced an average response rate of 52%, with time to progression ranging between 7.0 and 14.5 months. Three-drug regimens containing gemcitabine, an anthracycline, and paclitaxel have been tested in phase II studies and have produced impressive response rates of 82.9% with gemcitabine, doxorubicin, and paclitaxel and 92% with gemcitabine, epirubicin (Ellence), and paclitaxel (GET). The Central European Cooperative Oncology Group has evaluated the GET regimen vs a regimen containing 5-FU, epirubicin, and cyclophosphamide (FEC) in a randomized, prospective phase III study. Interim toxicity analysis showed that the GET regimen was well tolerated but produced more grade 4 neutropenia (64% vs 42%, P = .084) and significantly more grade 4 thrombocytopenia (12% vs 0%; P < .001) than FEC. Anaphylactic/allergic reactions, peripheral polyneuropathy, nausea, and cardiotoxicity constituted rare events and did not exceed grade 1 or 2 in severity. Although final data from this phase III trial are not yet available, preliminary analysis suggests the GET regimen represents an attractive option for patients with advanced breast cancer.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Disease-Free Survival; Female; Follow-Up Studies; Gemcitabine; Humans; Middle Aged; Neoplasm Metastasis; Severity of Illness Index; Taxoids

Androgen deprivation therapy remains the mainstay of therapy for patients with advanced prostate cancer and for selected patients with localized prostate cancer. Androgen deprivation therapy is the model of target-based therapies in this disease. Although it is clear that other target-based therapies need to be developed, cytotoxic chemotherapy is emerging as an effective form of treatment for men with prostate cancer. The early studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic hormone-refractory prostate cancer with minimal toxicity, and significant palliation could be provided. Since then, it has been recognized that estramustine, when combined with a variety of microtubular inhibitors, is very active in hormone-refractory prostate cancer. Doublets combining estramustine plus a taxane seem to be the most active. Although it appears that estramustine may add some activity to taxanes, the mechanism of its activity is uncertain, and its overall value is similarly questioned, particularly in light of its significant toxicity. Regimens that omit estramustine are being explored (ie, either taxane alone or taxane plus biologic agents). In addition, triplet therapy (combining estramustine plus a taxane plus a third drug, such as carboplatin or etoposide) is being explored. Finally, the utility of chemotherapy is beginning to be explored in the context of earlier disease in the neoadjuvant, adjuvant, or serologically relapsing group of patients. Data from these studies are just beginning to be gathered.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Hormones; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

The anthracyclines doxorubicin and epirubicin, and the taxanes paclitaxel and docetaxel, are effective chemotherapeutic agents for the first-line and second-line treatment of metastatic breast cancer, and their clinical use is widespread. However, for women whose disease has progressed despite receiving these drugs, treatment options are limited. These women often have a good performance status, and may survive for many months or even years, so they should be given the opportunity to benefit from further chemotherapy. The goals of chemotherapy in these patients are to obtain maximum control of symptoms, prevent serious complications, and increase survival without diminishing quality of life. Several agents are used for this purpose, including fluorouracil, docetaxel (in patients who have already received paclitaxel), vinorelbine, and mitomycin c, but because data from controlled trials are limited, a standard regimen has not yet been established. Moreover, these agents may be inconvenient to administer and can be associated with adverse events requiring hospitalisation. Therefore, there is a clear need for additional therapeutic options for patients with metastatic breast cancer. Ideally, agents should have a convenient method of administration, eg, oral, and should be suitable for home-based rather than hospital-based therapy. Treatment should control disease in at least 20-30% of patients with an acceptable side-effect profile. Novel oral therapies have now been developed and are being used increasingly in patients whose disease has progressed following taxane therapy.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Drug Resistance, Neoplasm; Europe; Female; Humans; Neoplasm Metastasis; Patient Care Planning; Salvage Therapy; Taxoids

The combination of gemcitabine and cisplatin has proven effective as first-line chemotherapy for patients with breast cancer, inducing a response rate of 80% in one phase II study. Five additional studies in intensively pretreated breast cancer patients demonstrated a median response rate of 43% (range, 26%-50%). The toxicity profile was moderate, with thrombocytopenia and neutropenia as the main side effects. The gemcitabine/ cisplatin combination, therefore, offers a tolerable and effective treatment option, particularly for patients whose disease progressed after treatment with anthracyclines and/or taxanes.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Clinical Trials, Phase II as Topic; Deoxycytidine; Female; Gemcitabine; Humans; Neoplasm Metastasis; Taxoids; Trastuzumab; Treatment Failure; Treatment Outcome

More than 40,000 women in the United States die each year from metastatic breast cancer. Elucidation of HER2 and its role in malignant transformation has helped define a subset of aggressive breast cancer that may be relatively resistant to non-anthracycline-based therapies and hormonal agents, but responds to targeted molecular therapy. Trastuzumab, an antibody against HER2, has proven effective as single agent therapy in women with HER2 overexpressed metastatic breast cancer. Moreover, in combination with chemotherapy, trastuzumab has been shown to delay disease progression and improve overall survival for women with HER2-positive advanced breast cancer. The combination of chemotherapy and trastuzumab is emerging as a standard of care in women with HER2 overexpressed metastatic breast cancer. Several combination regimens using trastuzumab with taxanes, vinca alkaloids, or platinum compounds have demonstrated efficacy in first- and second-line treatment settings. However, the development of anthracycline-based combinations has been limited by concerns of related cardiotoxicity. Newer multi-agent regimens are in development. The optimal combination, duration, and sequence of trastuzumab therapy remain unknown in patients with HER2-positive metastatic disease. The role of continuing treatment after disease progression is also unclear. Evidence from some retrospective analyses suggest HER2-positive tumors are relatively resistant to tamoxifen and perhaps more responsive to aromatase inhibitors, although such data are inconclusive. HER2 status should not be used routinely for clinical decision making regarding hormonal therapy options. Several ongoing trials are attempting to address these and other issues related to HER2 testing to select the most appropriate candidates for these emerging therapies. While many questions remain, the treatment of HER2 overexpressing metastatic breast cancer is rapidly evolving, and represents a new approach to treatment in oncology.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Neoplasm Metastasis; Platinum Compounds; Practice Guidelines as Topic; Taxoids; Trastuzumab; Vinca Alkaloids

Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical activity as a single agent, but preclinical studies suggest that it is an effective modulator of antitubulins. This paper reviews the rationale for the combination of estramustine with antitubulins and the clinical toxicity profile of estramustine. Also discussed are data from phase II studies in hormone-resistant prostate cancer and in taxane-resistant breast cancer that suggest that the modulation of antitubulins by estramustine that has been demonstrated in vitro is indeed clinically relevant. Finally, current approaches to improving the tolerability of estramustine are described.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy, Combination; Estramustine; Female; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

Cisplatin-based combination chemotherapy such as methotrexate, vinblastine, adriamycin and cisplatin produces durable improvements in survival in only a minority of patients. Therefore, other therapeutic options and strategies are clearly needed. Strategies include increasing the dose of chemotherapy, modifying the sequencing of chemotherapy, and new therapeutic agents. This paper reviews recent work on high-dose chemotherapy, currently available chemotherapeutic agents and combinations, with an emphasis on gemcitabine and the taxanes. New strategies such as monoclonal antibody therapy and molecular targeted small molecule therapy are becoming a reality in the treatment of many diseases. The rationale for using epidermal growth factor receptor targeted therapies is also reviewed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Doxorubicin; Female; Gemcitabine; Humans; Male; Methotrexate; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Randomized Controlled Trials as Topic; Severity of Illness Index; Survival Analysis; Taxoids; Treatment Outcome; Urinary Bladder Neoplasms; Urologic Neoplasms; Urothelium; Vinblastine

Transitional cell carcinoma of the urothelium is considered a chemosensitive malignancy. Until recently, the methotrexate, vinblastine, doxorubicin and cisplatin combination has been considered the standard for treating this disease. The development of new chemotherapeutic agents such as gemcitabine and the taxanes has opened up promising new perspectives in the treatment of this disease. However, the preliminary phase II data must be confirmed in adequately conducted phase III trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Transitional Cell; Cisplatin; Clinical Trials as Topic; Deoxycytidine; Dose-Response Relationship, Drug; Doxorubicin; Drug Combinations; Female; Gemcitabine; Humans; Male; Methotrexate; Neoplasm Metastasis; Platinum; Prognosis; Severity of Illness Index; Survival Analysis; Taxoids; Urinary Bladder Neoplasms; Vinblastine

The 1990s have seen the emergence of several classes of new efficacious drugs which have become established as treatment for breast cancer. Thus, aromatase inhibitors, taxanes and herceptin have all emerged as potentially valuable therapeutic agents for treatment of advanced breast cancer. Bisphosphonates have found a place in preventing skeletal complications in breast cancer patients with bone metastasis. Tamoxifen has a new role in chemoprevention in patients at high risk of breast cancer. This paper summarises these results.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cholesterol; Clinical Trials as Topic; Diphosphonates; Estrogens; Female; Guidelines as Topic; Humans; Neoplasm Metastasis; Postmenopause; Receptors, Estrogen; Tamoxifen; Taxoids; Trastuzumab

Breast cancer is relatively sensitive to chemotherapy. However, although response rate to chemotherapy is reported to be from 50 to 70% in metastatic breast cancer, it is incurable. Current standard chemotherapeutic regimens do not provide a large survival benefit according to the evidence obtained from clinical studies. Before developing a treatment program, we should therefore realize that the aims of chemotherapy for metastatic breast cancer are improvement of quality of life through relief of symptoms, and prolonging survival.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Evidence-Based Medicine; Female; Humans; Meta-Analysis as Topic; Neoplasm Metastasis; Quality of Life; Taxoids

The combination of methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) has been the standard therapy for transitional cell carcinoma for over a decade. Despite evidence that MVAC can improve outcome in comparison with single drugs or other combinations in this disease, only a small fraction of patients (less than 4%) become long-term survivors, and the regimen is quite toxic. Attempts to improve upon the MVAC regimen have partially ameliorated its toxicity, but they have not clearly improved outcome. Recently, a number of new chemotherapeutic agents have become available. This report summarizes the current experience with these agents and combinations.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Doxorubicin; Gallium; Gemcitabine; Humans; Ifosfamide; Methotrexate; Neoplasm Metastasis; Taxoids; Urinary Bladder Neoplasms; Vinblastine

The taxanes paclitaxel and docetaxel are the prototype drugs of a new class of anticancer drugs that exploits a completely new mechanism of action. Their testing in metastatic breast cancer has been extensive. The results indicating very high response rate with either taxane have given rise to an unprecedented effort in the scientific community to define their optimal application in all stages of the disease. In metastatic breast cancer, initial data suggest that paclitaxel may increase the survival obtained with standard combinations such as CMFP, and similarly promising studies of docetaxel are almost complete. Significant therapeutic benefit has also been observed by the addition of sequential paclitaxel after adjuvant doxorubicin plus cyclophosphamide in operable breast cancer. Overall, more than 20 randomized studies with paclitaxel or docetaxel, either as single agents or in combination, are ongoing or planned in women with high-risk operable breast cancer. This massive effort is mainly based on empirical study designs. However, some preclinical characteristics of the taxanes, such as their increased antitumor effect in tumors overexpressing HER2/neu, the preclinical and clinical evidence of potential synergism with monoclonal antibodies directed against the HER2 receptor, and preclinical evidence of antiangiogenic properties should be pursued to test whether the use of taxanes in breast cancer could be tailored to individual tumor characteristics rather than following the usual pattern of indiscriminate application.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Female; Genes, erbB-2; Humans; Neoadjuvant Therapy; Neoplasm Metastasis; Neovascularization, Pathologic; Patient Selection; Taxoids

The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.. MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing.. Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]).. With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy.. European Commission Sixth Framework Programme.

Topics: Adolescent; Adult; Age Factors; Aged; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Metastasis; Taxoids; Transcriptome; Treatment Outcome; Young Adult

We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.. In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in. The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.. Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Bridged-Ring Compounds; Cyclin-Dependent Kinases; Genes, BRCA1; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Taxoids

Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC.. Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1-positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival.. All enrolled patients (N = 170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. Disease control rate (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3-21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs.. Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.. ClinicalTrials.gov, NCT02447003.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Bridged-Ring Compounds; Cohort Studies; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoplasm Metastasis; Progression-Free Survival; Taxoids; Triple Negative Breast Neoplasms

Eribulin has efficacy in patients with progression after ≥ 1 chemotherapeutic regimen for metastatic breast cancer (MBC). A short disease-free interval (DFI) and previous use of taxanes in the neoadjuvant or adjuvant setting have been associated with worse outcomes for patients receiving first-line chemotherapy for HER2-negative MBC. The aim of the present trial was to evaluate the efficacy and safety of eribulin as first-line therapy for patients with HER2-negative MBC with these poor prognostic factors.. Eribulin monotherapy was administered until disease progression or unacceptable toxicity. The principal selection criteria were HER2 negativity without previous chemotherapy for MBC, the previous use of taxanes for early-stage breast cancer, and a DFI of < 36 months (subsequently amended to 48 months). The primary endpoint was the investigator-assessed time to progression. The secondary endpoints included overall survival, progression-free survival, objective response rate, clinical benefit rate, duration of response, and toxicity profile. A total of 53 patients were enrolled and received ≥ 1 dose of eribulin.. The median patient age was 47 years (range, 23-82.8 years). The median DFI was 15.7 months (range, 0.1-46.4 months). The median investigator-assessed time to progression was 4.1 months (range, 0.2-27.8 months; 95% confidence interval, 3.2-6.2 months). The objective response and clinical benefit rate was 20.8% and 26.4%, respectively. All-grade and grade 3/4 adverse events developed in 96.2% and 69.8% of patients, respectively. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and anemia.. Eribulin is effective and safe as first-line therapy for aggressive taxane-pretreated HER2-negative MBC.

Topics: Adult; Aged; Aged, 80 and over; Antimitotic Agents; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids; Treatment Outcome; Young Adult

Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting.. In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS).. Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%).. Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.. NCT01572038.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Receptor, ErbB-2; Survival Rate; Taxoids; Trastuzumab; Young Adult

In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial.. Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to trastuzumab emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197.. Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to trastuzumab emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to trastuzumab emtansine. Overall survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice (median 22·7 months [95% CI 19·4-27·5] vs 15·8 months [13·5-18·7]; hazard ratio 0·68 [95% CI 0·54-0·85]; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the trastuzumab emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (three [1%] of 403 patients in the trastuzumab emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [<1%] vs seven [4%]); whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [<1%] of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related).. In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy.. F Hoffman-La Roche/Genentech.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Chemotherapy-Induced Febrile Neutropenia; Diarrhea; Early Termination of Clinical Trials; Female; Hemorrhage; Humans; Lapatinib; Male; Maytansine; Middle Aged; Neoplasm Metastasis; Neutropenia; Practice Patterns, Physicians'; Quinazolines; Receptor, ErbB-2; Retreatment; Survival Rate; Taxoids; Thrombocytopenia; Trastuzumab

Metastatic breast cancer (MBC) remains an incurable disease despite major therapeutic advances. Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) has been established to have anti-proliferative effects against breast cancer cells in preclinical experiments, and is indicated for treatment of cancer in China. We performed a phase II trial combining PA-MSHA with capecitabine in patients with heavily pretreated MBC.. Eligibility criteria included human epidermal growth factor receptor 2-negative MBC, prior therapy with anthracyclines and taxanes, at least one prior chemotherapy regimen for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. PA-MSHA 1 mg was administered subcutaneously every other day and capecitabine 1000 mg/m2 orally twice a day for 2 weeks on, 1 week off. The primary end point was progression-free survival.. A total of 97 patients were enrolled. Median progression-free survival (PFS) was 4.0 months [95 % confidence interval (CI) 3.0-4.9], which was not significantly different from that in historical controls. However, median PFS was significantly longer (8.2 months; 95 % CI 6.7-9.7) in 24 patients with moderate immune-related adverse events (irAEs) such as fever or skin induration at the injection site than in those with no or mild irAEs (3.1 months, 95 % CI 2.5-3.6; p = 0.003). Overall survival was also improved in these patients (25.4 vs. 16.4 months; p = 0.044). PA-MSHA has a good safety profile, with only 6 patients (6.2 %) discontinuing treatment. PA-MSHA did not increase capecitabine-related toxicities such as hand-foot syndrome, nausea, and vomiting.. Adding PA-MSHA to capecitabine has a good safety profile in patients with heavily pre-treated MBC, although benefit from this regimen might occur only in patients with moderate PA-MSHA-related adverse events.. ClinicalTrials.gov NCT01380808.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Female; Hemagglutinins; Humans; Mannose; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Pseudomonas aeruginosa; Receptor, ErbB-2; Safety; Salvage Therapy; Taxoids; Young Adult

Anthracycline and taxane are classes of drugs that are frequently used in the adjuvant and palliative settings of metastatic breast cancer (MBC); however, treatment failure occurs in most cases. Limited data demonstrated favorable response in MBC after previous taxane-based treatment. The aim of this study was to evaluate the efficacy and safety of pegylated liposomal doxorubicin (Lipo-Dox®) used as part of a combination salvage therapy for patients with MBC whose tumors progressed during or after taxane-based treatment.. Patients with MBC who failed to respond to previous taxane-based treatments were recruited. Treatment with pegylated liposomal doxorubicin (40 mg/m(2)), cyclophosphamide (500 mg/m(2)), and 5-fluorouracil (500 mg/m(2)) was administered every 3 weeks. Tumor response to treatment was determined by using the Response Evaluation Criteria in Solid Tumor criteria version 1.0, and left ventricular ejection fraction was measured before and after treatment using echocardiography. Each patient was followed for 30 days after the last dose of study medication or until resolution/stabilization of any drug-related adverse event.. Forty-five patients were recruited. As of December 2012, the median follow-up duration was 29.8 months, the overall response rate was 41.9 %, the median progression-free survival was 8.2 months, and the median overall survival was 36.6 months for all treated patients. Grade 3/4 neutropenia, leucopenia, and neutropenic fever were observed in 14 %, 9 %, and 1 % of the cycles, respectively. Other non-hematologic adverse effects were mild to moderate and were manageable. No decrease in left ventricular ejection function was noted.. This regimen of combined of pegylated liposomal doxorubicin, cyclophosphamide, and 5-fluorouracil exhibited a promising overall response rate, progression-free survival rate, and overall survival rate, with a safe cardiac toxicity profile and manageable adverse effects. This regimen could be considered as a treatment option for patients with MBC whose tumors progressed during or after taxane-based treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Polyethylene Glycols; Retreatment; Salvage Therapy; Survival Analysis; Taxoids; Treatment Outcome

DISRUPT evaluated whether adding the vascular-disrupting agent ombrabulin to a taxane-platinum doublet in the first-line setting improved progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC).. Patients were randomised to ombrabulin 35 mg/m(2) or placebo followed by a taxane-platinum regimen every 3 weeks.. Overall, 176 patients were randomised. After 124 events, median PFS was not significantly improved with ombrabulin vs placebo (5.65 vs 5.45 months; HR 0.948; 60% CI 0.813-1.106; one-sided P=0.39). The two groups showed similar overall survival (median 11.0 months in both groups), objective response rate (32% ombrabulin; 31% placebo) and safety profiles.. This study did not meet its primary endpoint of improving PFS by adding ombrabulin to a taxane-platinum regimen for first-line treatment of metastatic NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Platinum; Serine; Taxoids; Treatment Outcome

Data from two phase 3 studies of eribulin were pooled in analyses initially requested by the European Medicines Agency to assess whether specific patient subgroups, previously treated with an anthracycline and a taxane, benefited from eribulin. Study 305/EMBRACE included women after two-to-five lines of chemotherapy for advanced breast cancer who were randomized to eribulin mesylate (1.4 mg/m(2) on days 1 and 8 every 21 days) or treatment of physician's choice. In Study 301, patients who had received up to two prior chemotherapy regimens for advanced disease were randomized to eribulin (as above) or capecitabine (1.25 g/m(2) b.i.d. on days 1-14 every 21 days). In the pooled population, overall survival (OS), progression-free survival and response rates were analysed in the intent-to-treat population and selected subgroups. Overall, 1,062 patients were randomized to eribulin and 802 patients to control. Median OS was 15.2 months with eribulin versus 12.8 months with control (hazard ratio [HR] 0.85; 95% CI 0.77, 0.95; P = 0.003). In all subgroups assessed, OS data favoured eribulin; significant improvements occurred in some subgroups, notably in women with human epidermal growth factor receptor 2 (HER2)-negative disease (HR 0.82; P = 0.002), although the effect in those with HER2-negative but hormone-receptor-positive disease did not reach statistical significance; benefits were also seen, among others, in those with estrogen-receptor-negative and triple-negative disease. Eribulin improves OS in various patient subgroups with advanced/metastatic breast cancer who had previously received an anthracycline and a taxane. Women with HER2-negative disease are among those who may obtain benefit from eribulin.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids

Oral administration of cyclophosphamide (CTX) and capecitabine may have a greater potential for treatment of metastatic breast cancer (MBC) due to anti-angiogenesis resulting from the metronomic dosage and upregulation of thymidine phosphorylase by CTX. The purpose of this phase II study was to evaluate the efficacy and safety profile of an all-oral combination of metronomic CTX plus capecitabine for women with anthracycline- and taxane-pretreated MBC.. In this prospective single-center, open-label, phase II trial, patients with measurable disease received oral metronomic CTX 65 mg/m(2) daily on days 1-14 plus capecitabine 1,000 mg/m(2) twice daily on days 1-14. The treatment was repeated every 3 weeks, and continued until disease progression, unacceptable toxicity or withdrawal of informed consent. The primary endpoint of the study was time to progression (TTP).. A total of 68 patients were enrolled and received 537 cycles of chemotherapy with a median of 8 cycles (range: 1-30 cycles) per patient. Sixty-six patients were evaluated for efficacy with all patients for toxicity. With a median follow-up time of 26 months, the median time to progression was 5.2 months (95% CI, 4.2-6.2 months), and the median overall survival was 16.9 months. The overall response rate was 30.3% (95% CI, 20-43%). Clinical benefit rate was 53.0% (95% CI, 38-62%). The doublet was well tolerable, with anorexia (7.5%), the only grade 3/4 adverse events occurring in more than 5% of patients. Grade 3 hand-foot syndrome was 4.4%.. The all-oral combination of metronomic CTX plus capecitabine is an effective and convenient and well-tolerated regimen for MBC. (ClinicalTrials.gov number, NCT00589901).

Topics: Administration, Oral; Adult; Aged; Anorexia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Hand-Foot Syndrome; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Prospective Studies; Taxoids; Treatment Outcome

To determine whether the antibody-drug conjugate trastuzumab emtansine (T-DM1), which combines human epidermal growth factor receptor 2 (HER2) -targeted delivery of the potent antimicrotubule agent DM1 with the antitumor activity of trastuzumab, is effective in patients with HER2-positive metastatic breast cancer (MBC) who have previously received all standard HER2-directed therapies.. In this single-arm phase II study, T-DM1 3.6 mg/kg was administered intravenously every 3 weeks to patients with HER2-positive MBC who had prior treatment with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. The primary objectives were overall response rate (ORR) by independent review and safety.. Among 110 pretreated patients (median, seven prior agents for MBC; median follow-up, 17.4 months), the ORR was 34.5% (95% CI, 26.1% to 43.9%), clinical benefit rate was 48.2% (95% CI, 38.8% to 57.9%), median progression-free survival (PFS) was 6.9 months (95% CI, 4.2 to 8.4 months), and median duration of response was 7.2 months (95% CI, 4.6 months to not estimable). In patients with confirmed HER2-positive tumors (n = 80 by retrospective central testing), the response rate was 41.3% (95% CI, 30.4% to 52.8%), and median PFS was 7.3 months (95% CI, 4.6 to 12.3 months). Most adverse events were grades 1 to 2; the most frequent grade ≥ 3 events were thrombocytopenia (9.1%), fatigue (4.5%), and cellulitis (3.6%).. T-DM1 is well tolerated and has single-agent activity in patients with HER2-positive MBC who have previously received both approved HER2-directed therapies and multiple chemotherapy agents. T-DM1 may be an effective new treatment for this patient population.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Immunotoxins; Lapatinib; Male; Maytansine; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab

To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).. Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n = 29; 100 %) and taxanes (n = 11; 37.9 %) were treated with oral capecitabine 950 mg/m(2) twice daily on days 1-14 and docetaxel 75 mg/m(2) on day 1 every 3 weeks. Nineteen (65.5 %) patients received this regimen as second line and 10 (34.5 %) as ≥3rd line of therapy. All patients were evaluable for response and toxicity.. Complete response occurred in two (6.9 %) patients and partial response in eleven (37.9 %) for an overall response rate of 44.8 % (95 % CI 26.7-62.9 %). Eleven women (37.9 %) had stable disease and five (17.2 %) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5 %) responded to DC combination. The median duration of response was 5.7 months (range 3.4-64.2), the median time to disease progression 9.3 months (range 1.2-58), and the median overall survival 25.5 months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6 % of patients and three of them (10.3 %) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9 % of the patients, fatigue in 3.4 %, and neurotoxicity in 3.4 %.. The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease Progression; Docetaxel; Drug Administration Schedule; Fatigue; Female; Fever; Fluorouracil; Hand-Foot Syndrome; Humans; Middle Aged; Neoplasm Metastasis; Nervous System Diseases; Neutropenia; Remission Induction; Salvage Therapy; Taxoids; Treatment Outcome

In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine.. Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval.. This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS).. Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%).. Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Female; Gemcitabine; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Survival Rate; Taxoids

Angiogenesis is an established target for the treatment of MBC. Aflibercept (VEGF-Trap) is a humanized fusion protein, which binds VEGF-A, VEGF-B, and PIGF-1 and -2.. A 2-stage phase II study with primary end points of confirmed tumor response and 6-month progression-free survival (PFS). If either end point was promising after the initial 21 patients, an additional 20 patients would be enrolled. Measurable disease, <2 previous chemotherapy treatments, previous anthracycline or taxane therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1 were required. Aflibercept was given at a dose of 4 mg/kg intravenous every 14 days.. Twenty-one patients were enrolled; 71% had visceral disease, 57% were estrogen receptor negative, 19% had HER2(+) disease with previous trastuzumab treatment, and 33% had 2 previous chemotherapy regimens. Partial response rate was 4.8% (95% confidence interval [CI], 0.1%-23.8%) and 6-month PFS was 9.5% (95% CI, 1.2%-30.4%). Neither primary end point met efficacy goals and the study was terminated. A median of 3 cycles was given. Median PFS was 2.4 months. Common grade 3 or 4 adverse events were hypertension (33%), fatigue (19%), dyspnea (14%), and headache (14%). Two cases of severe left ventricular dysfunction were noted.. Aflibercept did not meet efficacy goals in patients previously treated with MBC. Toxicity was as expected for anti-VEGF therapy.

Topics: Adenocarcinoma; Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Drug Resistance, Neoplasm; Female; Humans; Medical Oncology; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Societies, Medical; Survival Analysis; Taxoids; United States

We performed a single-institution phase II study to evaluate the efficacy and toxicities of vinorelbine monotherapy in patients previously treated with anthracyclines and taxanes. Vinorelbine was administered at a dose level of 25 mg/m² intravenously on days 1, 8, 15 and 22, every four weeks, and responses were assessed after every two cycles of treatment. All of the patients had previously been treated with anthracyclines and taxanes. A total of 26 patients were enrolled in this study between April 2004 and August 2009. The median age of the patients was 47 years (range, 37 to 71 years), and 80.8% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Out of 24 evaluable patients, five partial responses were observed, giving an overall response rate of 20.8%, with a median response duration of 2.8 months. The median time to progression was 3.7 months (range, 0.5 to 22.6 months), and median overall survival duration was 10.4 months (range, 1.3 to 57.6 months). The major toxicities observed were neutropenia, anemia and peripheral neuropathy. Grade 3 or 4 hematologic toxicities included neutropenia in 18 patients (69.2%) and anemia in four patients (15.3%). Grade 1 or 2 peripheral neuropathy was observed in 11 patients (42.3%), however there were no cases of grade 3 or 4 peripheral neuropathy. The results of this study indicate that vinorelbine monotherapy was feasible regimen with manageable toxicities in patients with metastatic breast cancer who were previously exposed to anthracyclines and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

Effective treatment options for patients with metastatic breast cancer pretreated with or resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed as a prospective clinical trial to evaluate the efficacy and safety of ixabepilone plus capecitabine in both anthracycline-pretreated and resistant and taxane-resistant metastatic breast cancer of Chinese women.. Patients with measurable disease who had anthracycline and taxanes as prior neoadjuvant, adjuvant or metastatic therapy were treated with ixabepilone at 40 mg/m(2) intravenously on day 1 of 21-day cycle plus capecitabine 2,000 mg/m(2) orally on day 1 through 14 of a 21-day cycle. The primary end point was the objective response rate. The secondary end points were time to progression, overall survival, and toxicity profiles.. Twenty-one patients received 146 cycles with a median of 5 cycles (range 1-13 cycles) per patients. Fourteen patients (66.7%) had partial response, 5 patients (23.8%) had stable disease, and 2 patients (9.5%) had progressive disease. Median time to progression and duration of response were 6.2 and 6.0 months, respectively. The median overall survival was 16.7 months. Eight (38.1%) patients required dose reduction and 14 (66.7%) patients discontinued treatment for adverse effect. Grade 3/4 treatment-related events included fatigue (28.6%), peripheral sensory neuropathy (33.3%), neutropenia (61.9%), anemia (4.7%), hypokalemia (4.7%), hand and foot syndrome (19.0%) and infection (9.5%). Resolution of grade 3/4 peripheral neuropathy was reversible after a median period of 6 weeks.. Ixabepilone plus capecitabine demonstrated a clear activity and an acceptable safety profile in Chinese patients with anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer, and the majority of patients completed 6 cycles of the therapy with manageable neuropathy toxicities.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Asian People; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; China; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Prospective Studies; Survival Rate; Taxoids; Treatment Outcome

Enzastaurin is a potent, serine-threonine kinase inhibitor which selectively targets PKCβ and PI3K/AKT signaling pathways to reduce cell proliferation, induce apoptosis, and inhibit angiogenesis. As PKCbeta and PI3K/AKT signaling are both involved in breast cancer pathogenesis, this phase II study evaluated the efficacy and toxicity of enzastaurin in previously treated patients with metastatic breast cancer (MBC).. Eligible patients had histologically confirmed MBC with measurable disease, and must have received prior anthracycline and taxane chemotherapy, but not more than two prior regimens for MBC. Human epidermal growth factor 2 (HER2)-positive patients must have progressed on prior trastuzumab therapy. Enzastaurin, 1,125-mg loading dose on day 1 followed by 500 mg daily, was administered orally in 28-day cycles. Response was assessed every 2 cycles according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.. Twenty-one patients enrolled between November 2006 and September 2007. Fourteen (66.7%) patients completed at least two cycles of therapy. No patients developed Grade 3/4 hematologic toxicity. Grade 3 nonhematologic toxicity was rare (<5%) and most commonly attributed to MBC progression. There were no objective responses and no patients with stable disease for >/=6 months. Median progression-free survival was 1.68 months (95%CI: 1.02, 1.74).. Enzastaurin monotherapy was well tolerated, but demonstrated no activity in patients with heavily pretreated MBC.

Topics: Administration, Oral; Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Indoles; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

Using data from a recent randomized trial, we evaluated the cost effectiveness of ixabepilone plus capecitabine versus capecitabine alone in patients with predominantly metastatic breast cancer considered to be taxane-resistant and previously treated with or resistant to an anthracycline.. We developed a stochastic decision-analytic model to represent data collected in the trial on medical resource use, health-related quality of life, and clinical outcomes. Estimates of overall survival were conditional on level of tumor response. We assigned monthly costs and utility weights according to periods defined by the duration of study treatment, time from discontinuation of the study drug until disease progression, and from progression until death and were specific to the level of response and receipt of subsequent therapy. Medical resources were valued in 2008 US dollars. We performed Monte Carlo simulations and sensitivity analyses to evaluate model uncertainty.. Overall survival was significantly associated with level of tumor response (P < .001). Total costs were estimated at $60,900 for patients receiving ixabepilone plus capecitabine and $30,000 for patients receiving capecitabine alone. The estimated gain in life expectancy with ixabepilone was 1.96 months (95% CI, 1.36 to 2.64 months); the estimated gain in quality-adjusted survival was 1.06 months (95% CI, 0.09 to 2.03 months). The resulting incremental cost-effectiveness ratio was $359,000 per quality-adjusted life-year (95% CI, $183,000 to $4,030,000). In sensitivity analyses, the results were robust to changes in numerous inputs and assumptions.. Addition of ixabepilone to capecitabine adds approximately $31,000 to overall medical costs and affords approximately 1 additional month of quality-adjusted survival.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cost-Benefit Analysis; Deoxycytidine; Disease Progression; Drug Costs; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Quality-Adjusted Life Years; Taxoids

Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC).. MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate.. Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%.. Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Microtubules; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline-pretreated/ resistant and taxane-resistant metastatic breast cancer (MBC).. A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21- day cycle).. No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption.. Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline-pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

Our aim was to evaluate the activity and toxicity of capecitabine and cisplatin (CapCisp) combination in anthracycline- and taxane-pretreated metastatic breast cancer patients. Thirty-three patients, 20-61 years of age (median 41), were included. They received Cap 2,000 mg/m(2) on days 1-14 and Cisp 60 mg/m(2) on day 1, repeated every 3 weeks. Twelve nonprogressive patients continued single-agent Cap therapy until progression or until intolerable toxicity after Cisp cessation. The disease control rate in 154 cycles was 81.8%: complete response 3.0% (n = 1), partial response 48.5% (n = 16) and stable disease 30.3% (n = 10). The median time to disease progression was 6.3 months (95% CI 3.8-8.8). The median overall survival was 11.5 months (95% CI 6.9-16.1). The only grade 3 toxicity was neutropenia, observed in 4 patients (12.1%). CapCisp has an encouraging anti-tumor activity with a low toxicity rate in anthracycline- and taxane-pretreated metastatic breast cancer patients.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cisplatin; Deoxycytidine; Disease Progression; Drug Tolerance; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Survival Rate; Taxoids

To evaluate the efficacy and toxicity of a combination of intravenous vinorelbine and 5-fluorouracil (5-FU) given by continuous infusion in the treatment of metastatic breast cancer previously treated with anthracyclines and taxanes.. Sixty-one patients with metastatic breast cancer were treated with intravenous vinorelbine 30 mg/m2 on days 1 and 8 of each 21-day cycle together with 5-FU 200 mg/m2/day by continuous infusion. All had previously been treated with an anthracycline and 41% had also been previously treated with a taxane. All had normal haematological, renal and hepatic function and all but three had an Eastern Cooperative Oncology Group performance score of 2 or better.. The overall response rate by World Health Organization criteria was 46% (28 patients); excluding nine non-evaluable patients gave a response rate of 54%. In patients who had previously been treated with both an anthracycline and a taxane, a response rate of 50% was observed (12 of 24 patients). Severe toxicity was uncommon, as was toxicity attributable to infusional 5-FU. Myelosuppression was rarely severe, but was common and led to delay or dose reduction in 38% of treatments. Eleven patients (18%) were admitted with fever and/or neutropenia and one patient died. The median received dose intensity was vinorelbine 16 mg/m2/week and 5-FU 143 mg/m2/day.. The combination of vinorelbine and infusional 5-FU is active in metastatic breast cancer, including in patients previously treated with an anthracycline and a taxane. Toxicity is generally manageable, but myelosuppression is significant at this dose regimen. Recommended doses for routine clinical use are 5-FU 200 mg/m2/day and intravenous vinorelbine 30 mg/m2 days 1 and 15 on a 28-day cycle.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Survival Analysis; Taxoids; Vinblastine; Vinorelbine

Gemcitabine and cisplatin are the active agents in metastatic breast cancer pretreated with anthracycline and/or taxane as a second line treatment. The present study was designed to assess the efficacy and safety of this regimen given biweekly schedule in these patients. Twenty-seven women, median age 57, with metastatic breast cancer previously treated with anthracycline and taxane were eligible for enrollment. Gemcitabine was administered intravenously on days 1 and 15 at a dose of 2,000 mg/m(2) and Cisplatin was given intravenously on day 1 and 15 at a dose of 50 mg/m(2). Treatment cycles were repeated on an outpatient basis every 28 days. Of all 27 evaluable patients, the overall response rate was 26% (7 of 27; 95% CI: 11-46%) with seven all partial responses. The stable diseases were found in 9 (33%) patients. At the time of last follow-up, 11 (41%) of the patients died of their disease progression. The median overall survival duration was 7.4 +/- 2.8 months. The 1-year overall survival rate was 46.9% +/- 12.3. Hematological toxicity was not found as the principal dose-limiting toxicity. Severe (grade III/IV) neutropenia was observed only one (4%) patients. No patient was complicated by febrile neutropenia and G-CSF usage was not performed. Grade III and IV anemia were seen in only 4 (15%) and thrombocytopenia was noted only one (4%) patients. Severe hepatic (n = 2) and renal toxicity (n = 1) were observed and these all recovered completely without complication. Several other severe non-hematological side effects were managed easily. Permanent dose reductions were necessary in 9 (33%) patients and chemotherapy administration was also delayed in 7 (26%) patients because of delayed both hematological and non-hematological toxicity recovery. Treatment was discontinued in one (4%) patient due to severe fatigue and deteriorating performance status. In conclusion, gemcitabine and cisplatin combination therapy with this biweekly schedule and dosage is moderately active and extremely safe in patients with metastatic breast cancer previously treated with anthracycline and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Survival Rate; Taxoids; Treatment Outcome

Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC.. Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m(2) was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated.. One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%).. Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Diarrhea; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Fatigue; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Neutropenia; Prospective Studies; Taxoids; Time Factors; Treatment Outcome

To determine the safety and efficacy of gemcitabine and cisplatin in patients with taxane resistant metastatic breast cancer.. Thirty-three taxane resistant metastatic breast cancer patients were treated with gemcitabine 1,250 mg/m2 IV infusion over 30 min on days 1 and 8, and with cisplatin 75 mg/m2 by IV infusion over 1 h on day 1 in 21 day cycles.. Of the 30 evaluable patients, there were 9 (30%) partial responses and no complete response, an overall objective response rate of 30%. Median time to progression and median survival duration for all study subjects were 7 (95% CI 5.1-8.9 months) and 15 months (95% CI 10.5-19.5 months), respectively. Toxicities included grade 3 and 4 leucopenia in 10 (30%), thrombocytopenia in 6 (18%), anemia in 2 (6%) and oral mucositis in 2 (6%). No grade 3 or 4 peripheral neuropathy, renal dysfunction, hepatic dysfunction, or nausea/vomiting was observed, and no treatment-related deaths occurred.. The described gemcitabine plus cisplatin combination was found to be an active and tolerable salvage regimen in patients with taxane resistant metastatic breast cancer.

Topics: Adult; Aged; Alopecia; Anemia; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Gemcitabine; Humans; Infusions, Intravenous; Leukopenia; Middle Aged; Neoplasm Metastasis; Recurrence; Severity of Illness Index; Stomatitis; Survival Rate; Taxoids; Thrombocytopenia; Treatment Outcome

Pre-RT ND in patients with HNSCC undergoing organ preservation treatment is safe, advantageous, poses no additional morbidity owing to the elective neck dissection, and may possibly improve survival outcomes.. Establish the role of pre-radiation neck dissection (pre-RT ND) in patients with head & neck squamous cell carcinoma (HNSCC) undergoing organ preservation treatment.. Fourteen patients with histologically confirmed HNSCC in stages III approximately IV with proven regional metastasis were enrolled in the organ preservation approach incorporating pre-RT ND at a tertiary referral center between May 1998 and August 2004. Site matched patients treated with organ preservation intent in the conventional fashion were used as controls. Data were collected for their diagnosis, management, treatment outcome, and follow up.. Disease free survival was significantly better for the pre-RT ND group. There was no significant difference in overall survival, pattern of recurrence, and primary organ preservation rate between the two groups. No significant morbidity owing to neck dissection was noted in patients who underwent neck dissection. Although the delivery of radiation to the primary site was delayed for patients in the pre-RT ND group, it did not influence the major outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neck Dissection; Neoplasm Metastasis; Neoplasm Recurrence, Local; Radiotherapy Dosage; Radiotherapy, Adjuvant; Taxoids

Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer.. Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m(2) intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m(2) on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review.. Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [>/= grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.. Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease Progression; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

We compared trastuzumab alone therapy (A-group) (n=6) to trastuzumab plus taxane therapy (B-group) (n=12) in patients of advanced and metastatic breast cancers. The response rate of A-group was 33.3%. Six months after, A-group was switched to trastuzumab plus taxane therapy. The response rate of A-group after addition of taxane was improved to 83.3%. The mean duration of response was 6.8 months in A-group after addition of taxane. The response rate of B-group was 83.3%. The mean duration of response was 7.5 months in B-group. The combination therapy of trastuzumab and taxane therapy showed a high response rate. We think that it is possible to start trastuzumab alone therapy because A-group after addition of taxane showed a high response rate. There were no significant differences of immunosuppressive acidic protein (IAP) from the course of chemotherapy in all cases.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Follow-Up Studies; Humans; Immunotherapy; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Taxoids; Trastuzumab

Currently, there is no standard treatment for patients with anthracycline and taxane-refractory metastatic breast cancer (MBC). Capecitabine or vinorelbine plus cisplatin is an effective palliative regimen for taxane-refractory MBC. In this study, we analyzed the efficacy and toxicity of sequential therapy with capecitabine followed by biweekly vinorelbine plus cisplatin in 37 patients with anthracycline and taxane-refractory MBC in Taipei Veterans General Hospital.. Capecitabine (2,500 mg/m2 twice daily for 2 weeks, followed by 1 week of rest) was repeated every 3 weeks until the disease progressed. Patients then received biweekly vinorelbine (25 mg/m2) plus cisplatin (40 mg/m2) (arm A, n = 17) or best supportive care (BSC) (arm B, n = 20) in accordance with patient preference and clinical judgment. The clinical variables and response to capecitabine were well balanced in both arms.. The overall response rate to capecitabine was 32%, with a complete response rate of 5% and a partial response rate of 27%. Stable disease was achieved in an additional 46%. The disease control rate with capecitabine was 78%. Median progression-free survival and overall survival with capecitabine were 5.9 and 9.5 months, respectively. There was a trend toward better overall survival in arm A patients compared with arm B (BSC) patients, though statistical significance was not reached (10.4 vs. 7.4 months; p = 0.08); however, a significantly better overall survival rate was observed in the subgroup with capecitabine-controlled disease (10.8 vs. 6.9 months; p = 0.015). The safety profile of vinorelbine/cisplatin was acceptable: only 6% developed grade 4 neutropenia.. We suggest that sequential therapy is not necessarily effective compared with capecitabine alone, but is probably effective in patients initially controllable with capecitabine.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cisplatin; Deoxycytidine; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Prospective Studies; Taxoids; Vinblastine; Vinorelbine

The objective of this study was to assess the efficacy and safety of pemetrexed in pretreated patients with advanced-stage breast cancer.. Patients with advanced-stage or metastatic breast cancer, Eastern Cooperative Oncology Group performance status 0-2, and progressive or relapsed disease after treatment with regimens containing anthracyclines and taxanes were eligible. Pemetrexed 500 mg/m2 was administered as a 10-minute intravenous infusion on day 1 every 21 days.. Seventy-nine women were enrolled. After protocol amendment, 43 patients received folic acid and vitamin B12 supplementation to control pemetrexed-related toxicity. A median of 4 cycles (range, 1-23 cycles) was administered. Overall response rate was 9% (95% confidence interval, 3.7%-17.6%), median duration of response was 5.5 months, median progression-free survival was 3.1 months, and median survival was 10.5 months. Major grade 3/4 toxicities were lymphopenia (53.3%), neutropenia (36.4%), leukopenia (26.9%), and anemia (7.7%). In general, the toxicities were less frequent in patients who received vitamin supplementation than in those who did not receive vitamin supplementation.. The response to pemetrexed salvage treatment was low in this study of heavily pretreated patients with breast cancer. Pemetrexed was generally well tolerated in patients with previously treated breast cancer. Vitamin supplementation appeared to ameliorate toxicity.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Folic Acid; Glutamates; Guanine; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pemetrexed; Premedication; Salvage Therapy; Taxoids; Vitamin B 12; Vitamin B Complex

To determine the efficacy and safety of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase with additional activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously treated metastatic breast cancer.. Eligible patients had histologically confirmed metastatic breast cancer and had received prior treatment with an anthracycline and taxane; measurable disease was required. Patients were enrolled sequentially into one of two dose cohorts, 100 or 300 mg orally once daily; 28 days defined one cycle. The primary end point was objective response rate; pharmacokinetics and serial pharmacodynamic studies were obtained.. Forty-six patients were enrolled between May 2002 and April 2003, and 44 were evaluable for response. Diarrhea was the most commonly reported toxicity and seemed dose related (grade >/=2: 4.5% and 37.5% in the 100 and 300 mg cohorts, respectively). Rash was reported by 26% of patients but was never worse than grade 2. Seven patients in the 300 mg cohort had asymptomatic grade 1 prolongation of the QTc interval. Hypertension requiring treatment was not reported. There were no objective responses; one patient in the 300 mg cohort had stable disease >/=24 weeks. All patients in the 300 mg cohort and 90% of patients in the 100 mg cohort achieved steady-state concentrations exceeding the IC(50) for VEGF inhibition in preclinical models.. ZD6474 monotherapy was generally well tolerated but had limited monotherapy activity in patients with refractory metastatic breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Bridged-Ring Compounds; Diarrhea; Dose-Response Relationship, Drug; ErbB Receptors; Female; Humans; Middle Aged; Nausea; Neoplasm Metastasis; Piperidines; Quinazolines; Taxoids; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC) represents a significant challenge to oncologists. The tumour-activated oral fluoropyrimidine, capecitabine, is the only treatment approved for these patients. Our study evaluated the efficacy, safety and impact on quality of life (QOL) of capecitabine in this setting. Patients (n=126) with anthracycline- and taxane-pretreated metastatic breast cancer received capecitabine 1250 mg/m(2) twice daily, days 1-14, followed by a 7-day rest period. Median time to progression was 4.9 months (95% Confidence Interval (CI): 4.0-6.4). Thirty-five patients (28%) achieved an objective response (95% CI: 20-36%), including five (4%) complete responses. Median overall survival was 15.2 months (95% CI: 13.5-19.6 months). Capecitabine demonstrated a favourable safety profile, with a low incidence of treatment-related grade 3/4 adverse events. The most common adverse events were hand-foot syndrome and gastrointestinal effects. QOL assessment showed that capecitabine treatment was associated with an increase in mean Global Health Score. Capecitabine is active, well tolerated and improves the QOL of patients with anthracycline- and taxane-pretreated metastatic breast cancer. Based on the consistently high activity demonstrated in clinical trials, capecitabine has become the reference treatment in this setting.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Humans; Middle Aged; Neoplasm Metastasis; Quality of Life; Taxoids; Treatment Outcome

An open-label, non-randomized, compassionate-use study was carried out to investigate the effects of oral capecitabine at a dose of 1 250 mg/m2 twice daily on days 1 to 14 every 21 days in anthracycline- and taxane-pretreated advanced/metastatic breast cancer patients. Forty-eight patients were enrolled from April 2000 to December 2001. Twenty-four patients (50%) had metastases to the liver, 18 to bone, 13 to lung, 10 to regional lymph nodes, 8 to pleura, 7 to the thoracic wall, 5 to skin, 3 to the mediastinum, 1 to breast and 1 had metastasis to the abdomen. Thirty-three patients (69%) had metastases to more than one site. Median age of the patients was 55 years (range 35-74). Three patients had an ECOG performance status (PS) of 0, 32 PS 1 and 13 PS 2, respectively. Fourteen patients (29%; 95% CI 16 to 42%) obtained a partial response (PR) while 16 (33%) had stable disease (SD) as the best response, of whom 6 had stabilization for more than 24 weeks. This gives a clinical benefit (PR + SD > 24 weeks) of 42% (95% CI 28 to 56). Dose reduction was necessary in 29% of the patients. Median dose reduction was 25%. Grades 2 and 3 hand-foot syndrome (PPE) was observed in 17 patients (36%). Eleven patients experienced grades 2 and 3 gastrointestinal toxicity, and haematological toxicity grade 3 was observed in 3 patients (6%). Median time to progression was 107 days (CI 95% 85 to 129), and median overall survival was 281 days (CI 95% 164 to 398). Third-line, oral capecitabine in anthracycline- and taxane-pretreated metastatic breast cancer appears to be effective and has an acceptable toxicity profile.

Topics: Administration, Oral; Adult; Aged; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Prodrugs; Taxoids; Treatment Outcome

To compare the efficacy of pegylated liposomal doxorubicin (PLD) with that of a common salvage regimen (comparator) in patients with taxane-refractory advanced breast cancer.. Following failure of a first- or second-line taxane-containing regimen for metastatic disease, 301 women were randomly assigned to receive PLD (50 mg/m(2) every 28 days); or comparator-vinorelbine (30 mg/m(2) weekly) or mitomycin C (10 mg/m(2) day 1 and every 28 days) plus vinblastine (5 mg/m(2) day 1, day 14, day 28, and day 42) every 6 to 8 weeks. Patients were stratified before random assignment based on number of previous chemotherapy regimens for metastatic disease and presence of bone metastases only.. Progression-free survival (PFS) and overall survival (OS) were similar for PLD and comparator (PFS: hazard ratio [HR], 1.26; 95% CI, 0.98 to 1.62; P =.11; median, 2.9 months [PLD] and 2.5 months [comparator]; OS: HR, 1.05; 95% CI, 0.82 to 1.33; P =.71; median, 11.0 months [PLD] and 9.0 months [comparator]). In anthracycline-naïve patients, PFS was somewhat longer with PLD, relative to the comparator (n = 44; median PFS, 5.8 v 2.1 months; HR, 2.40; 95% CI, 1.16 to 4.95; P =.01). Most frequently reported adverse events were nausea (23% to 31%), vomiting (17% to 20%), and fatigue (9% to 20%) and were similar among treatment groups. PLD-treated patients experienced more palmar-plantar erythrodysesthesia (37%; 18% grade 3, 1 patient grade 4) and stomatitis (22%; 5% grades 3/4). Neuropathy (11%), constipation (16%), and neutropenia (14%) were more common with vinorelbine. Alopecia was low in both the PLD and vinorelbine groups (3% and 5%).. PLD has efficacy comparable to that of common salvage regimens in patients with taxane-refractory metastatic breast cancer, thereby representing a useful therapeutic option.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Liposomes; Middle Aged; Mitomycin; Neoplasm Metastasis; Salvage Therapy; Taxoids; Vinblastine; Vinorelbine

To evaluate the activity and toxicity of gemcitabine and vinorelbine (GemVin), in patients with advanced breast cancer, previously treated with anthracyclines alone or with taxanes. Patients and methods. Nine patients were entered into the phase I and 50 patients were entered into the phase II study. Gemcitabine was administered beginning with the dose of 800 mg/m2 and vinorelbine was given at the fixed dose of 25 mg/m2, both on days 1 and 8, every 21 days. Escalated dose levels of gemcitabine were planned by increments of 200 mg/m2 per level. The median age of the 50 assessable patients for the phase II study was 56.5 years (range 30-70) and median performance status (PS, ECOG score), 1 (range 0-2). The dominant sites of metastases were viscera in 40, bone in five and soft tissue in five patients. First-line chemotherapy for metastatic disease with taxanes and anthracyclines or with anthracyclines alone was administered in 36 and 14 patients, respectively.. The optimal schedule for the combination was gemcitabine 800 mg/m2 and vinorelbine 25 mg/m2. The maximum tolerated dose of gemcitabine was 1000 mg/m2, with grade 4 neutropenia occurring in two cases at this dose level. Overall, 267 cycles were given to the 50 patients enrolled into the phase II (mean 5.3; range 3-9). The schedule was well tolerated: three patients experienced grade 4 neutropenia and another four patients experienced grade 3 anemia. Non-hematological toxicities were moderate. A major objective response was observed in 42% of patients (95% confidence interval (CI), 28-57%), with complete remission in four (8%) and partial response in 17 (34%) patients. The median time to progression was 6 months. Activity as well as toxicity were similar in the subgroups of the patients pretreated either with combinations of taxanes and anthracyclines or anthracyclines alone.. The optimal GemVin schedule is an effective and well tolerated second-line therapy in patients with metastatic breast cancer pre-treated with anthracycline-based schedules or with combinations of anthracyclines and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Drug Combinations; Female; Gemcitabine; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Taxoids; Vinblastine; Vinorelbine

To model the cost-effectiveness of adopting capecitabine/docetaxel combination therapy in place of single-agent taxane therapy for women in the province of Ontario, Canada, receiving treatment for anthracycline-pretreated metastatic breast cancer.. Clinical effectiveness and economic data were combined in a population model, from the perspective of a universal health care system. Estimates of clinical effectiveness and medical resource utilization were derived prospectively during a phase III randomized controlled trial comparing single-agent docetaxel with capecitabine/docetaxel combination therapy. Population data were obtained from the Cancer Care Ontario Registry and provincial prescription claims data.. During 1999-2000, 542 patients were eligible for taxane monotherapy. As capecitabine/docetaxel treatment confers a median 3-month survival benefit compared with docetaxel monotherapy, the projected survival gain in these patients was 136 life-years. The results of the cost-effectiveness analysis demonstrate that the survival benefit provided by the addition of capecitabine to single-agent docetaxel is afforded at a small incremental cost of Canadian $3,691 per life-year gained. Hospitalization costs for treatment of adverse events were less for patients receiving capecitabine/docetaxel combination therapy than for those receiving docetaxel monotherapy. The results were robust for adjustments in treatment costs and adverse effects costs.. Due to its 3-month survival gain and small incremental treatment cost, capecitabine/docetaxel is judged to be a highly cost-effective treatment in anthracycline-pretreated advanced breast cancer. From the perspective of the Ontario health care system, the addition of capecitabine to docetaxel in this patient population is a clinically appropriate and economically acceptable treatment strategy.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Budgets; Capecitabine; Cost-Benefit Analysis; Deoxycytidine; Docetaxel; Dose-Response Relationship, Drug; Female; Fluorouracil; Follow-Up Studies; Humans; Neoplasm Metastasis; Ontario; Paclitaxel; Population Surveillance; Survival Analysis; Taxoids; Trastuzumab; Treatment Outcome; Vinblastine; Vinorelbine; Women's Health

Capecitabine is a rationally designed oral, tumor-activated fluoropyrimidine carbamate with high activity in metastatic breast cancer. This multicenter phase II study was designed to evaluate further the efficacy and safety of capecitabine in patients with metastatic breast cancer previously treated with a taxane-containing regimen.. All patients had to have documented progression after paclitaxel- or docetaxel-containing chemotherapy. Treatment comprised 3-week cycles of oral capecitabine 1250 mg/m(2) twice-daily for 14 days followed by a 7-day rest period.. One hundred and thirty-six patients were enrolled. Disease stabilization occurred in 63 patients (46%) and the overall response rate was 15% (95% confidence interval 10% to 23%), providing an overall tumor control rate of 62%. Median time to progression was 3.5 months, median duration of response was 7.5 months and median overall survival was 10.1 months. Capecitabine was generally well-tolerated: most treatment-related adverse events were grade 1/2 in intensity; grade 3/4 treatment-related adverse events were hand-foot syndrome (13%), diarrhea (8%), vomiting (4%) and nausea (3%). There were no treatment-related deaths.. This study confirms that capecitabine achieves a high tumor control rate in heavily pretreated patients with metastatic breast cancer. Due to its favorable safety profile and convenient oral administration, capecitabine can be given as an outpatient therapy. Capecitabine should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Confidence Intervals; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Probability; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes.. Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned.. Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61).. The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Survival Rate; Taxoids

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Taxoids

A phase II study was performed to investigate the efficacy and tolerability of gemcitabine as third-line chemotherapy for patients with metastatic breast cancer, previously treated with both an anthracycline- and taxane-containing regimen. Twenty-three patients were treated with gemcitabine 1200 mg/m2 in a 30-min infusion on day 1, 8 and 15 of a 28 day cycle. Seventy-four percent of the patients had visceral metastases. No complete or partial responses were observed. Six patients (26%) had stable disease with a median duration of 4.0 months. The median time to progression was 1.9 months and the median survival time was 7.8 months. Neutropenia grade 3 and 4 was observed in four patients (18%). Non-hematological toxicity grade 3 included nausea and vomiting in 14%, skin toxicity in 9% and elevation of transaminases in 23% of the patients. Gemcitabine is ineffective as third-line single agent therapy in patients failing anthracycline and taxane treatment for metastatic breast cancer.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Gemcitabine; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Palliative Care; Taxoids; Treatment Failure

The purpose of this study was to evaluate the activity and tolerance of high-dose leucovorin (LV) and infusional 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) as salvage chemotherapy in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. 41 patients (median age 59 years) with MBC refractory or resistant to anthracyclines and taxanes were enrolled. The patients' performance status (WHO) was 0 in 10 patients (24%), 1 in 22 (54%), and 2 in 9 (22%). 30 (73%) patients had received 2 or more prior chemotherapy regimens. Cyclophosphamide (600 mg m(-2)) was given i.v. bolus on day 1 and LV (500 mg m(-2) d(-1)) as a 2-h infusion followed by 5-FU (1.5 g m(-2) d(-1)) over a 22 h c.i. for 2 consecutive days. Cyclophosphamide was administered every 28 days while 5-FU/LV every 14 days. In an intention-to-treat analysis, complete response (CR) was achieved in 2 (4.9%) patients and partial response (PR) in 9 (22%) (overall response rate 26.9%; 95% CI: 13.27-40.39%). Stable disease (SD) and progressive disease (PD) were observed in 9 (22%) and 21 (51%) patients, respectively. The overall response rate was 6% and 40% in patients with primary and secondary resistance to anthracyclines/taxanes, respectively (P = 0.047). The median duration of response and the median time to disease progression was 8 and 9.5 months, respectively. The median overall survival was 13 months and the probability for 1-year survival 51%. Grade 3/4 neutropenia occurred in 9 (22%) patients and 4 (9%) patients developed grade 3/4 thrombocytopenia. Non-haematological toxicity was mild. There were no cases of febrile neutropenia, toxic deaths or treatment-related hospital admissions due to toxicity. The combination of high-dose 5-FU/LV with conventional doses of cyclophosphamide is a well tolerated and effective salvage regimen in patients with MBC heavily pretreated with both anthracyclines and taxanes.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

Currently, there is no gold standard for the treatment of patients with metastatic breast carcinoma who have experienced failure with anthracyclines and taxanes. A biologic rationale suggests that the mechanism of taxane resistance could be because of an excess of depolymerized tubulin that could enhance sensitivity to vinorelbine. The objective of the study was to assess the tolerance and efficiency of weekly vinorelbine in metastatic breast carcinoma after failure with taxanes.. Patients with measurable disease, a World Health Organization performance status of less than 3 and a life expectancy longer than 3 months were eligible. Persistent taxane-induced neuropathy higher than Grade 1 was an exclusion criterion. The initial planned dose was 30 mg/m(2)/week on an outpatient basis without granulocyte colony-stimulating factor (G-CSF). Neutrophil and platelet counts of 1.0 and 80 g/L, respectively, were required before each new injection; otherwise vinorelbine was delayed for 7 days with a dose reduction of 5 mg/m(2) at the second episode. The dose also was reduced if Grade 3 or 4 toxicity occurred. If the adverse event persisted or if the delay exceeded 14 days between 2 injections given at a dose of 20 mg/m(2), vinorelbine was definitively discontinued.. Between November 1997 and March 1999, 40 patients with a median age of 49 (range, 39-69) were enrolled. All of them had previously received anthracyclines and taxanes. Because of the delays in neutrophil recovery, the median dose intensity did not exceed 22.5 mg/m(2)/week (range, 11.25-30), and the initial planned dose of 30 mg/m(2)/week appeared unfeasible without G-CSF. The starting dose therefore was 25 mg/m(2)/week after the first 6 patients. Neutropenia led to fever in only three patients. Other severe toxicities were Grade 2-3 neuropathy (n = 5), Grade 2-3 ileus (n = 7), Grade 3 anemia (n = 4), and Grade 3 sepsis (n = 1). Objective responses were observed in 10 of 40 patients (25%), 7 of whom had visceral metastases and 4 who were refractory to taxanes (including 2 patients with liver involvement > 50%). The median time to failure was 6 months (range, 4-12) for responding patients. Disease stabilization was achieved in 9 patients (23%) for a median duration of 5 months (range, 4-6). The median survival duration for the whole population was 6 months (range, 2-18+).. Weekly vinorelbine is an active salvage therapy for metastatic breast carcinoma after failure with anthracyclines and taxanes, even in patients with taxane-refractory metastatic breast carcinoma. This confirms that vinorelbine and taxanes are not cross-resistant.

Topics: Adult; Aged; Anemia; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Intestinal Obstruction; Middle Aged; Neoplasm Metastasis; Neutropenia; Palliative Care; Salvage Therapy; Sepsis; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

Gemcitabine and vinorelbine have shown activity in breast cancer. A phase II trial was initiated in order to evaluate the response rate (RR) and time to progression (TTP) of the combination of the two drugs in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy.. Thirty-one patients were treated with the combination of gemcitabine 1000 mg/m2 days 1 + 8 and vinorelbine 30 mg/m2 days 1 + 8. The cycles were repeated every three weeks.. Of 27 evaluable patients 1 (4%, 95% confidence interval (95% CI): 0.1%-19%) achieved complete remission (CR), five (18%; 95% CI: 6%-38%) partial remission (PR), eleven (40%; 95% CI: 22%-61%) stable disease and ten patients progressed. The median duration of response was six months (range 4-10+) and the median duration of disease stabilization was five months (range 2-22+). With a median follow-up of 16 months (range 0.4-22+) the median TTP was 3.5 months (range 0.4-22+) and the median survival was 9.5 months (range 0.4-22+). Grade 3-4 toxicities were granulocytopenia 15 patients (48%), rash 3 patients (10%), neuropathy 1 patient (3%) and thrombocytopenia 1 patient (3%). In conclusion the combination of gemcitabine/vinorelbine in the doses administered in this group of patients had a response rate of 22% and needs to be further evaluated in metastatic breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Disease Progression; Drug Resistance, Neoplasm; Female; Gemcitabine; Humans; Middle Aged; Neoplasm Metastasis; Taxoids; Vinblastine; Vinorelbine

HER2-directed therapies enable some patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long-term, durable responses (DR). Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice are lacking in the literature. Patient factors that predict DR continue to be elucidated.. This is a retrospective study of patients with de novo HER2 + MBC. DR is defined as absence of progression/death at any point after diagnosis. Controls are patients with evidence of progression/death. Age, ER/PR status, sites of metastasis, surgical resection of primary tumor, and initial treatment were analyzed.. 96 patients with de novo HER2 + MBC, 28 with DR, and 68 with progression were identified. 75% of patients with DR had a single metastatic site, compared with 47% of patients with progression (OR 3.7, p = 0.01). 64% of patients with DR received a regimen containing trastuzumab, pertuzumab, and a taxane, while 28% of patients who progressed did (OR 4.5, p < 0.001). 57% of patients with DR underwent surgical removal of breast primary, compared with 24% of patients who progressed (OR 4.3, p = 0.002.) Among patients with DR, nine patients have been receiving trastuzumab for over ten years with no evidence of disease and one patient opted to discontinue trastuzumab.. Nearly a third of patients with de novo HER2 + MBC achieved DR. Factors that correlate with DR include single metastatic site, initial trastuzumab, pertuzumab and taxane therapy, and surgical resection of primary tumor. Among patients with DR, indefinite trastuzumab administration is the norm.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Neoplasm Metastasis; Neoplasms, Second Primary; Receptor, ErbB-2; Retrospective Studies; Taxoids; Trastuzumab; Treatment Outcome

Compared to intravenous taxane chemotherapy, newer orally-available and/or less toxic agents for metastatic castration-resistant prostate cancer (MCRPC) may be associated with higher likelihood of starting treatment in patients with adverse prognostic features and limited life expectancy. To test this hypothesis, we analyzed the rates of treatment initiation during the last 30 days of life in a real-world cohort of men with MCRPC.. This was a retrospective analysis of 146 patients.. Seven patients (5%) who started any systemic treatment during the last 30 days of life were identified. The likelihood of treatment initiation in the last 30 days of life correlated significantly with the number of lines of systemic treatment (higher risk for previously treated patients) and non-use of bone-targeted agents.. Initiation of systemic therapy in the last 30 days of life was uncommon. This endpoint might complement other quality-of-care indicators.

Topics: Aged; Bridged-Ring Compounds; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Terminal Care; Treatment Outcome

Topics: Aged; Aged, 80 and over; Bridged-Ring Compounds; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Ligands; Lutetium; Male; Neoplasm Metastasis; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Safety; Taxoids; Time Factors; Treatment Outcome

Median survival of small-cell lung cancer (SCLC) patients is usually around 1 year. The advent of new drugs may have slightly improved their prognosis. We aimed to assess whether SCLC response to chemotherapy and survival had changed over time.. Consecutive SCLC patients were included at Grenoble University Hospital, France. We compared the patients' characteristics, response to chemotherapy and survival between 1997-2009 (period 1) and 2010-2017 (period 2).. A total of 529 patients were identified, of whom 498 received a first line of chemotherapy and 279 a second line. The majority (n = 290, 58%) had extensive disease. The objective response rate (ORR) to first-line chemotherapy in metastatic patients was 63% in period 1 and 62% in period 2; the ORRs to second-line chemotherapy were 39% and 29%, respectively. Median overall survival from first-line chemotherapy was 13.2 months (interquartile range [IQR] 7.4-24.4) in period 1 and 11.2 months (IQR 7.1-21.2) in period 2. Mortality in these two periods did not differ significantly even after adjustment for prognostic factors (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.66-1.00). The factors independently associated with death were cardiovascular comorbidities (HR = 1.28 [95%CI 1.05-1.55]), liver comorbidities (HR = 1.31 [95%CI 1.03-1.65]), poor ECOG performance status (3-4vs. 0-1, HR = 2.45 [95%CI 1.83-3.30]) and extensive disease (HR = 2.69 [95%CI 2.18-3.33]).. Since 1997, there has been no improvement in the survival or response rate to chemotherapy of SCLC patients. There is a desperate need for new approaches in this setting.

Topics: Aged; Bridged-Ring Compounds; Cardiovascular Diseases; Etoposide; Female; France; Humans; Liver Diseases; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Platinum Compounds; Prognosis; Small Cell Lung Carcinoma; Survival Analysis; Taxoids

While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely.. This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival.. The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006).. This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Combined Modality Therapy; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Outcome Assessment, Health Care; Oxonic Acid; Patient Participation; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Tegafur; Treatment Outcome

In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses.. OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted.. The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm.. These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Kaplan-Meier Estimate; Neoplasm Metastasis; Neoplasm Staging; Odds Ratio; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome

Survival of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP-group) compared with trastuzumab-naïve patients (TN-group) in order to investigate the possibility of trastuzumab resistance.. Patients treated with first-line HER2-targeted-containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP-group. OS and TNT were estimated using Kaplan-Meier curves and multivariable Cox proportional hazards models.. Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP-group and 387 were in the TN-group. Median OS and TNT were significantly worse in the TP-group compared with the TN-group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15-2.96],. First-line trastuzumab-containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab-naïve patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2-targeted treatment lines need further investigation.. Evidence on the efficacy of palliative trastuzumab-based therapy after failure of trastuzumab in the adjuvant setting is limited because of a minority of patients treated with adjuvant trastuzumab in clinical trials. In this study, less clinical benefit of palliative trastuzumab-based therapy was observed in patients relapsing after adjuvant trastuzumab compared with no adjuvant trastuzumab treatment. Subgroup analyses and multivariable analyses revealed that this was independent of possible confounding factors, including adjuvant taxane-treatment. This might suggest a clinically meaningful impaired efficacy of trastuzumab after previous, in this case adjuvant, trastuzumab therapy. These results could have implications for treatment decision-making after short progression-free intervals on trastuzumab-containing regimens in the palliative setting.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Palliative Care; Proportional Hazards Models; Receptor, ErbB-2; Taxoids; Trastuzumab

Mutations in BRCA1 or BRCA2 define a subset of prostate cancer patients. Herein, we address the question whether BRCA1/2 mutations have a predictive impact on chemotherapy with docetaxel, a widely used drug in patients with metastatic castration resistant prostate cancer (mCRPC). Fifty-three men treated with docetaxel for mCRPC were tested for somatic BRCA1/2 mutations of the primary tumor. In a subgroup of patients, BRCA1/2 protein expression was tested as a potential surrogate marker for BRCA1/2 inactivation. Eight of 53 patients (15.1%) harbored a deleterious BRCA2 mutation. No BRCA1 mutation was found. Patients with a BRCA2 mutation showed a response rate of 25% to docetaxel in comparison to 71.1% in men with wildtype BRCA2 (p = 0.019). While the time to develop castration resistance was similar in both subgroups, the overall survival was significantly shorter in patients harboring a BRCA2 mutation. No correlation between the BRCA1/2 protein expression and the response to docetaxel was found. While the presence of a BRCA2 mutation does not preclude a response to docetaxel, there is overall a significant correlation between BRCA2 inactivation and a poor response rate. Our results suggest that a close oncological monitoring of patients with BRCA2 mutations for taxane resistance is warranted.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; Cell Line, Tumor; Combined Modality Therapy; Drug Resistance, Neoplasm; Gene Expression; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Male; Mutation; Mutation Rate; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Prostatic Neoplasms; Retrospective Studies; Taxoids; Treatment Outcome

Despite the scientific evidence undoubtedly influencing current guidelines on the management of metastatic Breast cancer (mBC), marketing research data suggests this may not be reflected in EU prescribing behavior. Specifically we would like to understand the use of combination chemotherapy vs monotherapy in mBC patients.. This study is based on IMS Oncology Analyzer™, a web-based physician panel survey set-up by IMS Health, a global company which specializes in health care information including market research data. Analysis was carried out on prescribing behavior reflected in marketing research data from IMS source (from MAT Q42013 till MAT Q32014) and comparing the data with the current guidelines recommendation in mBC (ESO-ESMO 2nd international consensus guidelines).. Despite the recommendation provided by current ESMO guidelines on mBC treatments, indicating the sequential use of single cytotoxic agents is a considerable alternative to standard multidrug chemotherapy regimens, marketing research data suggests this may not be reflected in EU prescribing behavior.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Drug Prescriptions; Europe; Female; Humans; Marketing; Neoplasm Metastasis; Practice Guidelines as Topic; Taxoids

There are few data regarding the role of human papilloma virus (HPV) in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).. A retrospective chart review was carried out using our electronic medical record (EPIC) for all patients diagnosed with HPV-positive R/M HNSCC between 2010 and 2014 with minimum of 6 months of follow-up in order to assess progression-free survival (PFS) and overall survival (OS).. We assessed 11 patients who underwent a variety of treatments. PFS and OS were 7 and 34+ months, respectively. Four patients (36%) were still alive and disease-free (median OS of 39+ months). Three disease-free patients had been treated with taxane, platinum and 5-fluorouracil as aggressive curative systemic therapy. Another patient treated with TPF was disease-free for 25 months and died of disease at 42 months.. Our study demonstrates favorable prognosis for patients with HPV-positive R/M HNSCC and that aggressive systemic treatment can lead to a prolonged disease-free period or possibly cure, even after metastasis.

Topics: Bridged-Ring Compounds; Carcinoma, Squamous Cell; Disease-Free Survival; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Papillomavirus Infections; Prognosis; Retrospective Studies; Squamous Cell Carcinoma of Head and Neck; Taxoids

The purpose of the present study was to prospectively evaluate the efficacy and safety of endostar, a recombinant product of endostatin, combined with taxane-based regimens for HER-2 negative metastatic breast cancer (MBC) patients. Women with ages between 18-70 years with histologically confirmed MBC documented as HER-2-negative were included. Endostar was administered at 7.5 mg/m2, d1-14, q21d and was continued until progressive disease, unacceptable toxicity, consent withdrawal, or completion of 24 months of endostar, whichever came first. Taxane-based chemotherapy was continued until progressive disease, unacceptable toxicity, consent withdrawal, or up to 8 cycles. The primary endpoint was overall response rate (ORR). Fifty-seven patients were recruited. The ORRs for the whole population, first-, second-, and third-line therapy or beyond were 68.4%, 79.3%, 54.5%, and 16.7%, respectively. The median PFS was 10.8 (8.0-12.1) months, yet the median OS was still not attained. For the patients receiving first-, second-, and third-line therapy or beyond, median PFS was 11.9, 7.5, and 7.4 months, respectively (P=0.048). No significant difference in median PFS between hormonal receptor-positive and -negative patients was observed. The most common drug-related grade 3-4 hematologic toxicities were neutropenia (80.7%) and leukopenia (77.2%). Six (10.5%) patients experienced febrile neutropenia. The most frequent drug-related grade 3-4 non-hematologic toxicities were liver dysfunction (10.5%) and peripheral neurotoxicity (8.8%). No treatment-related deaths were reported. We conclude that Endostar combined with taxane-based regimens may be effective and safe for the treatment of HER-2-negative MBC. However, further investigations on its long-term efficacy and toxicity are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Drug Administration Schedule; Endostatins; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Nausea; Neoplasm Metastasis; Neutropenia; Prospective Studies; Receptor, ErbB-2; Recombinant Proteins; Taxoids; Treatment Outcome

Based on data from two multicenter, phase III clinical trials (Studies 301 and 305), eribulin (a microtubule dynamics inhibitor) is indicated in the European Union (EU) for patients with locally advanced or metastatic breast cancer (MBC) after ≥1 prior chemotherapy for advanced disease, including an anthracycline and a taxane in either the adjuvant or metastatic setting. Data from Studies 305 and 301 were pooled to investigate the efficacy of eribulin in various subgroups of patients who matched the EU label, including those with human epidermal growth factor receptor 2 (HER2)-negative and triple-negative disease.. In Study 305 (NCT00388726), patients were randomized 2:1 to eribulin mesylate 1.4 mg/m(2) (equivalent to eribulin 1.23 mg/m(2) [expressed as free base]) intravenously on days 1 and 8 every 21 days] or treatment of physician's choice after 2-5 prior chemotherapies (≥2 for advanced disease), including an anthracycline and a taxane (in early/advanced setting). In Study 301 (NCT00337103), patients were randomized 1:1 to eribulin (as above) or capecitabine (1.25 g/m(2) orally twice daily on days 1-14 every 21 days) following ≤3 prior chemotherapies (≤2 for advanced disease), including an anthracycline and a taxane. Efficacy end points were investigated in the intent-to-treat population and subgroups, pooled as discussed above.. Overall, 1644 patients were included (eribulin: 946; control: 698); baseline characteristics were well matched. Overall survival was significantly longer with eribulin versus control (P < 0.01), as were progression-free survival and clinical benefit rate (both P < 0.05). Significant survival benefits with eribulin versus control were observed in a wide range of patient subgroups, including HER2-negative or triple-negative disease (all P < 0.05).. Our findings underline the survival benefit achieved by eribulin used according to EU label in the overall MBC population and in various subgroups of interest, including patients with HER2-negative and triple-negative disease.

Topics: Adjuvants, Pharmaceutic; Anthracyclines; Antineoplastic Agents; Bridged-Ring Compounds; Clinical Trials, Phase III as Topic; Disease-Free Survival; Female; Furans; Humans; Ketones; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Taxoids; Triple Negative Breast Neoplasms

Metastatic salivary gland carcinoma is a rare malignancy. A subset of these tumors overexpresses the human epidermal growth factor receptor 2 (HER-2), which is considered a poor prognostic marker. Targeted therapy with the monoclonal antibody trastuzumab can be a treatment option in these patients. We describe six cases of metastatic salivary gland carcinoma treated with trastuzumab in combination with a taxane. Three of these patients had salivary duct cancer, two had mucoepidermoid carcinoma and one patient was treated for acinic cell carcinoma. The therapy was well tolerated. We observed five partial responses and a median progression free survival of 10.8 months, which compares favorably with the reported outcome of combination chemotherapy. One patient achieved a complete and durable remission. When HER-2 and androgen receptor were co-expressed, trastuzumab-based treatment appeared to be more active than androgen deprivation in our experience.

Topics: Aged; Antineoplastic Agents; Bridged-Ring Compounds; Drug Therapy, Combination; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Salivary Gland Neoplasms; Salivary Glands; Taxoids; Trastuzumab

Identification of cancer biomarkers that inform clinical decisions and reduce the use of ineffective therapies is a major goal of precision oncology. An abnormal splice variant of the androgen receptor, AR-V7, was recently found to confer resistance to novel hormonal therapies (abiraterone and enzalutamide) in men with metastatic castration-resistant prostate cancer (mCRPC), but did not negatively affect responses to taxane chemotherapies, suggesting that early use of chemotherapy may be a more effective option for AR-V7(+) patients.. We calculated the cost savings of performing AR-V7 testing in mCRPC patients prior to starting abiraterone/enzalutamide (and avoiding these drugs in AR-V7(+) men) versus treating all mCRPC patients empirically with abiraterone/enzalutamide (without use of the biomarker).. We determined that AR-V7 testing would result in substantial cost savings as long as the true prevalence of AR-V7 was >5%. In our prior studies, we estimated that approximately 30% of mCRPC patients may have detectable AR-V7 in circulating tumor cells (CTCs). In this population, upfront testing of AR-V7 status (at a price of $1,000 per test) would result in a net cost savings of $150 Million in the United States per year.. AR-V7 testing in mCRPC patients would be cost-beneficial when considering the current price of treatment, and may reduce the ineffective use of abiraterone/enzalutamide, leading to a significant net cost savings to the healthcare system. Clinical-grade AR-V7 testing is currently available at our institution. Prostate 76:1484-1490, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Androstenes; Benzamides; Biomarkers; Bridged-Ring Compounds; Cost Savings; Costs and Cost Analysis; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Taxoids

Tau is a member of microtubule-associated proteins (MAPs) and expressed in normal breast epithelium and breast cancer cells. Tau expression levels in early breast cancer were correlated with the responsiveness of taxane-containing chemotherapy. However, it is unknown whether Tau contributes to breast cancer progression. Herein, Tau expression in recurrent and metastatic breast cancer (RMBC) and its predictive significance in taxane-containing palliative chemotherapy were investigated. Immunohistochemical (IHC) staining was conducted to detect Tau protein expression levels in biopsies from 285 patients with RMBC, and the correlation between Tau expression and sensitivity to taxane was evaluated. One hundred twenty-one (42.46 %, 121/285) patients were Tau positive in their tumor. One hundred ninety-four (68.07 %, 194/285) patients were effective clinical remission, which evaluated with response evaluation criteria in solid tumors (RECIST) criteria. In this group, 141 (85.98 %, 141/194) patients were Tau negative. We further analyzed the correlation between Tau expression and clinicopathological characteristics. Tau expression was positively correlated to estrogen receptor (ER) status. Multivariate logistic regression analysis showed that Tau expression significantly differentiated patients with effective response to treatment (95 % confidence interval (CI): 4.230-13.88, P < 0.01). Tau expression was identified as an independent factor to predict the sensitivity of tumors to taxane-containing palliative chemotherapy in RMBC, suggesting that Tau expression in RMBC may serve as a clinical predictor for taxane-containing palliative chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Palliative Care; Prognosis; tau Proteins; Taxoids

The purpose of this study was to evaluate predictive factors and the clinical characteristics of durable responders to capecitabine monotherapy in heavily-treated patients with metastatic breast cancer (MBC).. Between December 2000 and May 2012, a total of 236 evaluable patients with MBC who had been treated with second- or greater-line palliative capecitabine monotherapy after a previous treatment regimen with anthracycline and taxane were included. Capecitabine (1250 mg/m(2) twice daily) was administered for 2 weeks followed by a 1-week rest period.. The response rate was 23.3% and median progression-free survival (PFS) was 4.7 months (95% confidence interval, 4.0-5.5). Among 236 patients, 33 patients (14.0%) showed durable response (>12 months) to capecitabine monotherapy. Patients with durable response showed significantly greater incidence of estrogen receptor (ER) positivity (81.8% vs. 59.1%; P = .012), single-organ metastasis (51.5% vs. 32.0%; P = .047), and absence of lymph node metastasis (75.8% vs. 54.2%; P = .023), compared with patients without durable response. In multivariate analysis, ER positivity and single-organ metastasis retained a significant association with better PFS to capecitabine monotherapy (hazard ratio [HR], 0.51; P < .001 and HR, 0.62; P = .004).. Our data suggest that ER positivity and single-organ metastasis can be useful predictive markers for better PFS to second- or greater-line palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients.

Topics: Administration, Oral; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Disease-Free Survival; Female; Follow-Up Studies; Humans; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids; Treatment Outcome

Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Moreover, many chemotherapeutic agents need to be interrupted due to toxicity. Here we report an extremely long duration of chemotherapy with eribulin (11 courses) in a taxane-pretreated metastatic breast cancer patient. Therapy was well tolerated with no worsening of pre-existing neuropathy, achieving excellent outcomes and a good quality of life. This report adds to the pool of knowledge regarding the use of this important new metastatic breast cancer chemotherapeutic agent.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Female; Furans; Humans; Ketones; Neoplasm Metastasis; Retreatment; Taxoids; Treatment Outcome

Currently, there is no preferred standard chemotherapy regimen available for patients with metastatic triple negative breast cancer (mTNBC) and no cohort studies on the efficacy of vinorelbine plus platinum (NP) regimen in patients with mTNBC who failed to anthracyclines and/or taxanes have been reported. We present the single-center, retrospective experience of NP regimen in a total of 41 patients with mTNBC.All patients were treated with NP regimen, main combination used was vinorelbine-cisplatin in 34 patients (82.9%).The median follow-up was 36.8 months. Objective response rate was 34.1% (n = 14) in the whole study group. Three patients experienced complete response (7.3%), 11 patients acquired partial response (26.8%), stable disease was observed in 14 patients (34.1%), and 10 patients (24.4%) had progressive disease. Response evaluation was not applicable in 3 patients who received the treatment of NP regimen after surgical removal of the metastatic lesions. The median overall survival and progression-free survival were 18.9 months (95% confidence interval, 15.6-22.1 months) and 6.7 months (95% confidence interval, 2.9-10.5 months), respectively. The main adverse events were grade 3/4 neutropenia (n = 20, 48.8%) and grade 1/2 gastrointestinal toxicity (n = 20, 48.8%).NP regimen is active and tolerable in patients with mTNBC pretreated with anthracyclines and/or taxanes. Therefore, among other chemotherapy regimens, NP combination may provide a rational treatment option for this patient subset.

Topics: Anthracyclines; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Cisplatin; Female; Humans; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Taxoids; Treatment Outcome; Triple Negative Breast Neoplasms; Vinblastine; Vinorelbine

Phase III trials have shown that the addition of a taxane to cisplatin/5FU-based induction chemotherapy (TPF) improves response rates and overall survival in unresectable stage III/IV head and neck cancer. We sought to assess the tolerability, compliance and clinical outcomes of this treatment regime.. A retrospective study of patients treated within a single centre between September 2007 and November 2010. Toxicities were graded according to CTCAE version 3.0. Survival, distant metastasis and local control rates are expressed as percentages at two years using the Kaplan-Meier method.. A total of 100 patients were identified (11% stage III, 86% stage IV) and 32% of patients were admitted as an emergency after TPF. The rate of neutropenic fever was 31%, this number fell to 9% when prophylactic G-CSF was used. In addition, 89% of patients underwent radical chemoradiation. Of these, 96% completed the full radiotherapy course. However, only 64% of patients received a minimum of two cycles of concurrent platinum chemotherapy. The two-year overall survival, metastasis free survival and local control rates were 62.6%, 88.5% and 73.3%, respectively.. TPF chemotherapy can be delivered safely in a non-trial cohort of patients. There is, however, a significant reduction in concurrent chemotherapy dose intensity. The long-term impact of this remains unclear.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Chemoradiotherapy; Cisplatin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Kaplan-Meier Estimate; Male; Neoplasm Metastasis; Retrospective Studies; Taxoids

Stathmin is a prognostic marker in many cancers, including endometrial cancer. Preclinical studies, predominantly in breast cancer, have suggested that stathmin may additionally be a predictive marker for response to paclitaxel. We first evaluated the response to paclitaxel in endometrial cancer cell lines before and after stathmin knock-down. Subsequently we investigated the clinical response to paclitaxel containing chemotherapy in metastatic endometrial cancer in relation to stathmin protein level in tumors. Stathmin level was also determined in metastatic lesions, analyzing changes in biomarker status on disease progression. Knock-down of stathmin improved sensitivity to paclitaxel in endometrial carcinoma cell lines with both naturally higher and lower sensitivity to paclitaxel. In clinical samples, high stathmin level was demonstrated to be associated with poor response to paclitaxel containing chemotherapy and to reduced disease specific survival only in patients treated with such combination. Stathmin level increased significantly from primary to metastatic lesions. This study suggests, supported by both preclinical and clinical data, that stathmin could be a predictive biomarker for response to paclitaxel treatment in endometrial cancer. Re-assessment of stathmin level in metastatic lesions prior to treatment start may be relevant. Also, validation in a randomized clinical trial will be important.

Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; Cell Line, Tumor; Endometrial Neoplasms; Female; Gene Knockdown Techniques; Humans; Neoplasm Metastasis; Paclitaxel; Stathmin; Taxoids; Treatment Outcome

Existing treatments for metastatic breast cancer (mBC) are often effective but can cause adverse events (AEs). This study aimed to identify AEs associated with chemotherapies commonly used in mBC treatment (phase 1) and to quantify the economic impact of these AEs (phase 2).. Patients in phase 1 had at least one claim for therapy for mBC, with at least one episode with single or multiple agents. The most common chemotherapy-related complications were identified using medical and pharmacy claims data. In phase 2, patients meeting study criteria were divided into four treatment cohorts by the line of treatment and chemotherapy received: first-line taxane-treated patients, second-line taxane-treated patients, first-line capecitabine-treated patients, and second-line capecitabine-treated patients. Average monthly AE-related health care costs per cohort were stratified by cost component. Total monthly costs per number of AEs were also calculated.. On average, patients in phase 1 (n = 1,551) had 2 episodes of treatment, with a mean duration of 131 days. The most frequently noted complications were anemia (50.7% of mBC treatment episodes), bilirubin elevation (26.4%), and leukopenia (24.8%). In phase 2, costs related to AEs were primarily driven by incremental inpatient, outpatient, and pharmacy costs. Increases in average monthly costs ranged from $854 (9.0%) to $5,320 (69.5%), according to cohort. Overall costs increased with increasing numbers of AEs.. Chemotherapy-related AEs in patients with mBC are associated with a substantial economic burden that increases with the number of AEs reported.

Topics: Aged; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Costs and Cost Analysis; Deoxycytidine; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Health Care Costs; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

Clinical outcomes, including adverse events, in 52 advanced breast cancer patients treated with eribulin chemotherapy after taxane treatment (TX) were analyzed to confirm the effectiveness and safety of this treatment.The objective response rate (ORR) in patients was 34.6% (TX group 31.6%, non-TX group 36.4%). There were no significant differences in overall survival, time to treatment failure, or progression-free between three TX and non-TX groups. Further, adverse events did not differ between groups expression of neutropenia of Grade 3 or more. On the other hand, the number of patients with sensory peripheral neuropathy of Grade 1 or more was significantly more in the TX group than in the non-TX group. Eribulin chemotherapy was effective for the treatment of advanced breast cancer regardless of a history of taxane treatment.In addition, sensory peripheral neuropathy is a possible complication that can occur in advanced breast cancer patients treated with eribulin chemotherapy with taxane treatment history.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Taxoids

Castration-refractory prostate cancer (CRPC) is treated with taxane-based chemotherapy, but eventually becomes drug resistant. It is thus essential to identify novel therapeutic targets for taxane resistance in CRPC patients. We investigated the role of the chemokine (C-C motif) receptor 1 (CCR1) and its ligand, chemokine (C-C motif) ligand 5 (CCL5), in taxane-resistant CRPC using paclitaxel-resistant prostate cancer cells (PC3PR) established from PC3 cells. We found that the expression levels of CCR1 mRNA and protein were up-regulated in PC3PR cells compared to PC3 cells. In order to investigate the role of increased CCR1 in PC3PR cells, we stimulated cells with CCL5, one of the chemokine ligands of CCR1. In CCL5-stimulated PC3PR cells, siRNA-mediated knockdown of CCR1 expression reduced phosphorylation of ERK1/2 and Rac1/cdc42. Furthermore, CCR1 knockdown and MEK1/2 inhibition decreased CCL5-stimulated secretion of MMPs 2 and 9, which play important roles in cancer cell invasion and metastasis. In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells. Finally, the serum CCL5 protein level as measured by ELISA was not different among the three groups of patients: those with negative prostate biopsy, those at initial diagnosis of prostate cancer, and those with taxane-resistant prostate cancer. These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling. Our findings suggest that CCR1 could be a novel therapeutic target for taxane-resistant CRPC.

Topics: Aged; Bridged-Ring Compounds; cdc42 GTP-Binding Protein; Cell Line, Tumor; Cell Movement; Chemokine CCL5; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; rac1 GTP-Binding Protein; Receptors, CCR1; RNA Interference; RNA, Messenger; RNA, Small Interfering; Taxoids

Class III β-tubulin (TUBB3) is a prognostic marker in various tumors, but the role of TUBB3 in advanced gastric cancer is not clearly defined. We analyzed the significance of TUBB3 expression, along with that of excision repair cross-complementation group 1 (ERCC1) in recurrent and metastatic gastric cancer patients receiving taxane-based first-line palliative chemotherapy.. We reviewed the cases of 146 patients with advanced gastric adenocarcinoma who received taxane-based first-line palliative chemotherapy between 2004 and 2010 at Chonnam National University Hwasun Hospital (Gwangju, Korea). Immunohistochemical staining for TUBB3 and ERCC1 was performed using paraffin wax-embedded tumor tissues. We evaluated the patients' response to chemotherapy, progression-free survival (PFS), and overall survival (OS).. In total, 146 patients with advanced gastric cancer received docetaxel and cisplatin (n = 15) or paclitaxel and cisplatin (n = 131). The median PFS was significantly shorter for patients with high-level TUBB3 expression than for patients with low-level TUBB3 expression (3.63 vs. 6.67 months, P = 0.001). OS was not associated with TUBB3 expression (13.1 vs. 13.1 months, P = 0.769). By multivariate analysis, only TUBB3 was related to a shorter PFS (HR 2.74, 95% CI 1.91-3.91, P = 0.001). Patients with high-level ERCC1 expression showed a lower response rate than patients with low-level ERCC1 expression (24 vs. 63.2%, P = 0.001); however, ERCC1 had no clinical effect on PFS or OS.. TUBB3 was a strong predictive marker in recurrent and metastatic gastric cancer patients receiving taxane-based first-line palliative chemotherapy. No clinical impact of ERCC1 was evident in this setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged-Ring Compounds; DNA-Binding Proteins; Endonucleases; Female; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Prognosis; Recurrence; Stomach Neoplasms; Taxoids; Treatment Outcome; Tubulin

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival.. Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (200 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 600 mg/m(2) in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (400 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 2400 mg/m(2) in a 46-h continuous infusion) on day 1.. A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS.. The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Signet Ring Cell; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Platinum; Retrospective Studies; Salvage Therapy; Stomach Neoplasms; Survival Rate; Taxoids; Treatment Outcome

Currently, there is no clinically validated test for the prediction of response to tubulin-targeting agents in non-small cell lung cancer (NSCLC). Here, we investigated the significance of nuclear expression of the mitotic checkpoint gene checkpoint with forkhead and ringfinger domains (CHFR) as predictor of response and overall survival with taxane-based first-line chemotherapy in advanced stage NSCLC.. We studied a cohort of 41 patients (median age 63 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. CHFR expression by immunohistochemistry (score 0-4) was correlated with clinical outcome using chi-square test and Cox proportional models. A cutoff score of "3" was determined by receiver operator characteristics analysis for "low" CHFR expression. Results were validated in an additional 20 patients who received taxane-based chemotherapy at Emory University Hospital and the Atlanta VAMC.. High expression (score = 4) of CHFR is strongly associated with adverse outcomes: the risk for progressive disease after first-line chemotherapy with carboplatin-paclitaxel was 52% in patients with CHFR-high versus only 19% in those with CHFR-low tumors (P = 0.033). Median overall survival was strongly correlated with CHFR expression status (CHFR low: 9.9 months; CHFR high: 6.2 months; P = 0.002). After multivariate adjustment, reduced CHFR expression remained a powerful predictor of improved overall survival (HR = 0.24; 95% CI, 0.1-0.58%; P = 0.002). In the validation set, low CHFR expression was associated with higher likelihood of clinical benefit (P = 0.03) and improved overall survival (P = 0.038).. CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy.

Topics: Adult; Aged; Biomarkers, Tumor; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Poly-ADP-Ribose Binding Proteins; Prognosis; Taxoids; Ubiquitin-Protein Ligases

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Neoplasm Metastasis; Research; Taxoids

To carry out a cost minimisation analysis including a comparison of the costs arising from first-line treatment by bevacizumab plus docetaxel (BD) versus bevacizumab plus paclitaxel (BP) of patients with metastatic breast cancer (mBC).. All consecutive patients with human epidermal growth receptor 2-negative mBC and treated at Besançon University hospital between 2006 and 2010 by a first-line therapy containing bevacizumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization and healthcare travel.. Progression-free survival difference between the two treatments was insignificant (p-value=0.31). BP treatment was associated with a higher mean total cost than that of BD treatment, €53,093 ± 34,395 versus €60,196 ± 48,766, respectively.. Whereas bevacizumab is recommended for first-line treatment of mBC with paclitaxel-based chemotherapy, our study has shown that BD treatment is the most cost-efficient regimen. It could be an attractive option in France, with a potential cost saving of €24,000,000 per year.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Docetaxel; Female; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

Capecitabine is a widely accepted option in pre-treated metastatic breast cancer (MBC) patients. However, little is known about specific activity in molecularly defined subgroups of patients. Here, response, survival and prognostic factors were examined in a prospectively characterized cohort of human epidermal growth factor receptor 2 (HER2) negative MBC patients receiving capecitabine following anthracycline and taxane failure.. Medical records from 75 HER2-negative MBC pre-treated with anthracycline and/or taxane and receiving capecitabine monotherapy at the Institut Paoli-Calmettes between 2002 and 2009 were reviewed. Univariate and multivariate analysis according the Cox regression model were employed to identify factors predictive for response, progression-free survival (PFS) and overall survival (OS).. Overall, the objective response rate (ORR) was 29.3% (95% CI: 20-40). The ORR in HER2-negative/hormonal receptor (HRe) positive and HER2-negative/HRe-negative patients were 37% (95% CI: 26-50) and 0% (95% CI: 0-19), respectively, (p=0.003, Fisher's test). With a median follow-up of 35.2 months after capecitabine initiation, median PFS was 6.6 months (95% CI: 4.7-10.4) and median OS was 18.4 months (95% CI:14.1-24.9). In univariate analysis, HRe-negative status was the strongest prognostic factor for PFS (hazard ratio (HR)=2.09; p-value=0.015, log-rank test). In multivariate analysis, only three variables (HRe-negative status, initial disease-free interval <24 months and extra-regional lymph node involvement) were considered independently associated with poor PFS, while five variables (grade 2/3, initial disease-free interval <24 months, central nervous system metastases, interval between diagnosis of metastases and capecitabine initiation <24 months, and number of metastatic sites on capecitabine initiation) were associated with poor OS.. The median OS of pretreated patients with HER2-negative MBC receiving capecitabine is approximately 18 months, but HER2-negative/HRe-negative patients have a low probablility of response/disease control to capecitabine and require innovative therapies.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Prognosis; Receptor, ErbB-2; Taxoids; Treatment Outcome

Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that taxanes can also affect AR signaling. Here, we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired β-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy.

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Bridged-Ring Compounds; Cell Line, Tumor; Cell Nucleus; Cytoplasm; Drug Resistance, Neoplasm; Dyneins; Female; Humans; Male; Microtubules; Neoplasm Metastasis; Neoplastic Cells, Circulating; Ovarian Neoplasms; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Taxoids

Trastuzumab is an established treatment for HER2-positive breast cancer (BC). We analyzed Swiss patterns of care in patients with HER2-positive BC after disease progression on trastuzumab-containing therapy for metastatic BC (MBC).. A retrospective analysis was performed in six Swiss BC centers. Patients with HER2-positive MBC treated with at least one infusion of trastuzumab for advanced disease between January 2006 and December 2007 were identified. Treatment patterns in first and further lines were analyzed.. All of the 72 identified patients received trastuzumab as their first palliative anti-HER2 therapy, either as monotherapy (n = 23) or in combination with chemotherapy (typically taxane or vinorelbine; n = 49). Median time to progression was 8.1, 8.0 and 7.9 months in the monotherapy, trastuzumab-taxane and trastuzumab-vinorelbine cohorts, respectively. After progression on first-line anti-HER2 therapy, trastuzumab was continued in 67 of 68 patients who received further therapy. One patient received second-line lapatinib plus capecitabine. The median duration of anti-HER2 therapy was 20 months. Patients received a median of 4 lines of anti-HER2 therapy.. Durable responses were achieved with repeated exposure to anti-HER2 therapy. In a selected patient population, trastuzumab monotherapy appears to be a reasonable first-line treatment option.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Disease Progression; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Retrospective Studies; Switzerland; Taxoids; Trastuzumab; Vinblastine; Vinorelbine

Treatments for inflammatory breast cancer (IBC) have changed over the last 15 to 20 years. The authors of this report undertook a retrospective review of patients who were treated at the Royal Marsden Hospital (RMH) to determine whether recurrence-free survival (RFS) and overall survival (OS) have improved as treatment regimens have altered.. Detailed clinical-pathologic data were collected on patients who were treated for primary IBC at RMH between 1990 and 2007. A Cox regression model was used to investigate the factors that influenced OS.. The median OS was 3 years and 4 months, and the median RFS was 1 year and 10 months. RFS was better in patients who had received taxane-containing regimens; however, there was no OS benefit. A pathologic complete response (pCR) was observed in 13 of 89 patients (15%), and those who achieved a pCR had significantly better RFS but no improvement in OS. The type of chemotherapy did not affect the pCR rate. One hundred thirty of 155 patients received radiotherapy, and those who did not receive radiotherapy had significantly worse outcomes. A multivariate Cox regression analysis indicated that the date of diagnosis, estrogen receptor (ER) status, and the presence of metastatic disease at diagnosis were significant prognostic factors. Patients who were diagnosed during or after 2000 had a relative risk of mortality of 0.5 compared with patients who were diagnosed before 2000. ER-positive patients had a median OS of 4.5 years and a median of RFS of 2.6 years versus 2.9 years and 1.4 years, respectively, for ER-negative patients. Patients who had metastatic disease at presentation had an OS of 1.7 years versus 3.9 years for those without metastatic disease at presentation.. Achieving a pCR improved RFS but had no impact on OS. Patients who had metastatic disease at the outset fared much worse, and positive ER status conferred a better outlook.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Inflammation; Neoplasm Metastasis; Prognosis; Retrospective Studies; Taxoids; Time Factors

To summarize the clinical experience of trastuzumab treatment in neoadjuvant, adjuvant, metastatic setting of Chinese patients with Her-2 positive breast cancer and evaluate the efficacy of trastuzumab in combination with chemotherapy.. From January 2004 to December 2008, 141 outpatients with breast cancer treated with trastuzumab were investigated retrospectively. The follow-up time ranged from 3 to 319 months. The disease free survival time (DFS) of metastatic setting was calculated. The overall survival time (OS), time to treatment failure (TTF) and clinical response rate (CRR, including complete response, partial response and stable disease) of adjuvant, first-line, second-line therapy were analyzed statistically.. In the neoadjuvant regimen, paclitaxel plus carboplatin in combination with trastuzumab accounted for 66.7%, which achieved pathological complete response in 10 of 16 patients. In the adjuvant regimen, anthracycline or anthracycline followed by taxane accounted for 53.9%. The median DFS of 57 cases with metastatic diseases was 17 months. The CRR of first-line trastuzumab use in metastatic setting was 84.5%, compared with 44.4% of second-line use. The median TTF of first-line treatment was 24 months compared with 5 months of second-line treatment. Statistically significant differences were observed.. The regimen of paclitaxel plus carboplatin in combination with trastuzumab deserves wide clinical use. In metastatic setting, first-line treatment of trastuzumab plus chemotherapy can achieve a higher response rate than second-line treatment. Continued trastuzumab therapy combined with different chemotherapy treatment after disease progression may obtain additive clinical advantage.

Topics: Adult; Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Follow-Up Studies; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Receptor, ErbB-2; Retrospective Studies; Survival Rate; Taxoids; Trastuzumab; Treatment Failure

The aim of this study was to evaluate the role of platinum-containing chemotherapy for metastatic triple-negative breast cancer (TNBC) patients in terms of the response rate (RR) and progression-free survival. A second aim was to characterize the clinical behavior at the time of relapse of TNBC. We retrospectively analyzed the clinical outcomes of patients with metastatic breast cancer who received taxane-platinum chemotherapy as the first- or second-line treatment, focusing on the TN phenotype. In total, 257 patients with metastatic breast cancer received platinum-containing chemotherapy at Samsung Medical Center from 1999 to 2006. Of these patients, 106 patients with available data on estrogen (ER), progesterone (PgR) and human epidermal growth factor receptor-2 (HER2) receptor status received taxane-platinum regimen as the first- or second-line treatment. The overall RR of patients with TNBC was 39%. This rate did not differ significantly from those of patients with other phenotypes. The time to death after chemotherapy (19 vs. 50 months, p = 0.037) and overall survival (OS) (21 vs. 56 months, p = 0.030) differed significantly between patients with TNBC and non-TNBC. TNBC showed a unique locoregional infiltration pattern at relapse, which might reflect its aggressive clinical behavior. Despite the similar response to platinum-containing chemotherapy, patients with TNBC had a shorter OS than patients with non-TNBC. The implication of TN phenotype as poor prognostic factor is uncertain, because it needs to be defined whether poor outcome is related to the rapid growing characteristics of tumor itself or the resistance to drug therapy. Further prospective studies are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Phenotype; Platinum Compounds; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Recurrence; Retrospective Studies; Taxoids; Treatment Outcome; Young Adult

The most commonly used chemotherapeutic regimens in the treatment of metastatic breast cancer (MBC) include anthracyclines and taxanes. In our study, we investigated the efficacy and tolerability of cisplatin plus gemcitabine combination chemotherapy regimen in patients with MBC, who exhibited disease progression after anthracycline- and taxane-based chemotherapy.. Thirty-three patients with taxane/anthracycline-resistant MBC have been treated with gemcitabine 1,000 mg/m(2) intravenously and cisplatin 30 mg/m(2) intravenously on days 1 and 8 of a 3-week treatment cycle.. Thirty-one patients were assessable for response. One of the 31 patients (3.2%) showed complete response, while 7 patients (22.6%) showed partial response; the objective response rate was 25.8%. Stable and progressive disease was observed in 6 (19.4%) and 17 patients (54.8%), respectively. The median time to progression was 4 months (95% CI 2.15-5.85). The median survival time of all patients was 9.5 months (95% CI 7.86-11.14).. Gemcitabine and cisplatin combination therapy is moderately active and safe in patients with MBC previously treated with anthracycline and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Gemcitabine; Humans; Middle Aged; Neoplasm Metastasis; Survival Rate; Taxoids

Taxanes (TX) were administered to 246 of 292 patients with recurrent/metastatic breast cancer (MBC) who were treated in Hiei Hospital between January 2001 and May 2006. Recently, TX has been increasingly prescribed for preoperative treatment and postoperative adjuvant therapy. To improve the prognosis of MBC, regimens effective for TX-resistant cancer patients should be developed. In this study, with respect to hormone receptor (HR) and Her 2/neu (HER 2), we retrospectively investigated whether our series responded to the regimens used after TX resistance was acquired. As post TX-resistance therapy (trastuzumab was combined in HER2-positive patients), 387 treatment regimens were administered to 166 patients. The following regimens achieved a response rate (patients achieving PR or CR/patients who could be evaluated) of 10% or more: combination therapy with TX and capecitabine (11/61, 18%), CPT-11 (10/57, 17.5%), vinorelbine (5/46, 10.9%), MFL-P (continuous treatment with MTX, 5-FU, LV, and CDDP) (12/47, 25.5%), and DMpC (5'-DFUR, MPA, CPA p.o.) (5/16, 31.2%). The latter 2 regimens achieved a high response rate,and some HR (-) and HER 2 (-) patients also responded to these regimens. In HR (+) or HER 2 (+) patients who responded to TX, survival was longer than that of non-responders. However, there was no difference in the treatment responsiveness of post-TX regimens between TX-responders and non-responders, suggesting the survival-prolonging effect of TX.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Receptor, ErbB-2; Retrospective Studies; Survival Rate; Taxoids; Trastuzumab

Purpose. To determine the association of phosphorylated/activated HER2 (P-HER2) and response to taxane chemotherapy in patients with metastatic breast cancer (MBC). Materials and Methods. Archived tumor specimens of patients with MBC treated on clinical trials with taxane monotherapy were analyzed by immunohistochemistry (IHC) for the presence of phosphorylated HER2 using the PN2A monoclonal antibody. Chi-squared analysis was performed to evaluate the association of P-HER2 status and efficacy of single agent taxane therapy. Results. One hundred twenty-six cases were identified as evaluable for both IHC and clinical outcome. Twelve cases (10 percent) were positive for P-HER2, of which 5 had evidence of clinical progression and 7 had evidence of clinical benefit with taxane therapy. Of the 114 cases that were negative for P-HER2, 20 demonstrated progression and 94 had clinical benefit. Chi-squared analysis revealed a significant correlation between the presence of P-HER2 and resistance to taxane therapy, chi2 = 3.9724 and p = 0.046. Conclusions. Phosphorylated/activated HER2 is associated with clinical resistance to single agent taxane therapy for MBC. The likelihood of direct progression of disease on taxane was greater in cases of PN2A-positive tumors (42 percent) as opposed to PN2A-negative ones (18 percent, p = 0.046). Functional assessment of HER2 status may provide unique predictive information not seen with conventional assessments.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; Neoplasm Metastasis; Phosphorylation; Receptor, ErbB-2; Retrospective Studies; Taxoids; Treatment Outcome

As many breast cancer patients receive adjuvant chemotherapy using anthracyclines or anthracenediones and taxanes, more therapeutic options are needed for subsequent lines of therapy. Pemetrexed (ALIMTA, multitargeted antifolate, LY231514) is a novel antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis. This paper reports on a subset analysis of a phase II clinical trial of pemetrexed in heavily pretreated metastatic breast cancer (MBC) patients. Patients were required to have received prior first-line anthracycline therapy for metastatic disease. Prior adjuvant chemotherapy and prior taxanes were allowed. A substantial subset of the study population (31 of 72 patients, 43%) had also received a taxane in the metastatic setting. All patients were treated with pemetrexed, 600 mg/m2 by intravenous infusion, once every 21 days. In the study subset, 23 of 31 (74%) patients were anthracyclines failures (progression > 30 days following treatment), and eight (26%) patients were anthracyclines refractory (progression during or < or = 30 days of treatment). The median age was 55 years (range, 30-75 years) and the median World Health Organization performance status was 0. Metastases were present in the liver (61%), lung (29%), bone (6%), and soft tissue (19%). The overall response rate for this subset was 26%, with one complete response, seven partial responses, and 13 (42%) patients with stable disease. The median duration of response was 5.4 months and median survival was 12.8 months. Pemetrexed was well tolerated by patients in the study. This post hoc analysis suggests promising activity in MBC patients previously treated with both anthracyclines and taxanes. An ongoing trial is prospectively evaluating activity in this same population.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Folic Acid Antagonists; Glutamates; Guanine; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Pemetrexed; Survival Rate; Taxoids; Thymidylate Synthase; Treatment Outcome