Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients.

Letrozole (trademark Femara) is a new orally active, potent and selective aromatase inhibitor for the hormonal treatment of advanced breast cancer in postmenopausal women. The pharmacokinetics of letrozole and the suppression of peripheral estrogens were studied in 28 breast cancer patients after a single dose and at steady state. The pharmacokinetics of two distinct age groups (> or =50, < or =65, N=15 and > or =70 years old, N=9) were compared. There were no significant differences in area under the curve (AUC) or terminal half-life between the two age groups neither after a single dose nor at steady state. However, when comparing steady state to single dose kinetics, half-life and AUC increased significantly by 42% (90% CI: 1.13, 1.78) and 28% (90% CI: 1.12, 1.47), respectively. This deviation from linearity was probably due to a partial saturation or auto-inhibition of the dominant metabolic clearance mechanism of letrozole. At steady state, approximately 70% of the administered dose was excreted in urine as unchanged letrozole (6.0+/-3.8%) or as the glucuronide of the major, pharmacologically inactive metabolite CGP44645 (64.2+/-22.7%). A single dose of letrozole caused suppression of serum estrogen levels close to the quantification limit of the assay. No difference between single dose suppression and suppression at steady state could be detected.     

他莫昔芬片、莱曲唑片治疗乳腺癌引起骨质疏松的临床观察

目的观察他莫昔芬片、莱曲唑内分泌治疗乳腺癌过程中,不良反应引起骨质疏松的差异。方法对绝经后60例乳腺癌患者,随机抽取30例口服他莫昔芬片,30例口服莱曲唑片,分别测口服药0、1、2年时每例患者的骨密度,进行统计学分析。结果口服他莫昔芬片、莱曲唑片1、2年测得骨密度值分别为（0．965±0．021）、（0．923±0．017）、（0．915±0．019）、（0．896±0．013）g／cm^2。结论口服他莫昔芬片、莱曲唑片都可使骨密度减低,用药时间越长,骨密度减低越明显;口服莱曲唑片骨密度减低比口服他莫昔芬片使骨密度减低更明显。     

The role of bisphosphonates in breast cancer management: review article

Bone metastases are a common problem in the management of breast cancer and are associated with considerable morbidity. Bone pain, hypercalcaemia, fractures and cord compression all occur requiring interventions such as analgesia, radiotherapy and surgery. Bisphosphonates are drugs that are active in the bone microenvironment. Their effects on osteoclasts are well described: they potently inhibit osteoclast mediated bone resorption by delaying the maturation of immature osteoclasts and by directly inducing osteoclast apoptosis. It has been known for some time that bisphosphonates, in combination with intravenous rehydration, effectively treat hypercalcaemia associated with solid malignancies. It has now been demonstrated In clinical trials in breast cancer patients that regular bisphosphonate administration reduces the morbidity associated with osteolytic skeletal metastases. There is an emerging suggestion from clinical trial work that bisphosphonates may be able to reduce or delay the development of skeletal metastases although this remains controversial as the three published trials present conflicting results. The more potent third-generation bisphosphonates, such as zoledronate, are now being tested for each of these indications with promising results and may replace other bisphosphonates in the future. Laboratory studies have recently demonstrated that bisphosphonates have direct cytotoxic effects against breast cancer cells in vitro, inducing apoptosis and preventing adhesion to bone. This adds support to the hypothesis that bisphosphonates may have a genuine beneficial effect in the adjuvant setting.     

Comparative review of anastrozole,letrozole and exemestane in the management of early breast cancer

The hormonal therapy of patients with endocrine-sensitive early breast cancer has mainly consisted, for several decades, of the gold standard tamoxifen. The efficacy and favorable toxicity profiles of third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, in advanced disease led to their development in early breast cancer. Recent results consistently show the superiority of these agents over tamoxifen. Adjuvant trials evaluated AIs using four different therapeutic approaches: (1) Upfront strategy: randomization of newly diagnosed patients: tamoxifen for 5 years versus AI for 5 years. (2) Sequencial strategy: randomization of newly diagnosed patients: tamoxifen (2 – 3 years) followed by AI or the inverse for a total of 5 years versus upfront AI for 5 years. (3) Switch strategy: delayed randomization (or analysis) after 2 – 3 years of tamoxifen (patients free of disease): 2 – 3 years of tamoxifen versus 2 – 3 years of AI (total treatment 5 years). (4) Extended strategy: delayed randomization after 5 years of tamoxifen (patients free of disease): 2 – 5 years of AI versus placebo. Overall, AIs show evidence of superiority over tamoxifen in the adjuvant setting with proven improved efficacy and better toxicity profile. Despite some common characteristics, a body of evidence on AIs indicates some specific differences between the three agents in mechanism of action, pharmacokinetics, efficacy as well as toxicity profiles. Consequently, these hormonal agents may not be considered interchangeable in clinical practice. This review explores available results from AI trials and tries to define their present role in the adjuvant management of postmenopausal patients with breast cancer.     

Neoadjuvant systemic therapy for breast cancer: an overview and review of recent clinical trials

Neoadjuvant chemotherapy (NAC) is long established as part of the multi-modality management of locally advanced breast cancer or inflammatory breast cancer, leading to significantly improved outcome. Numerous recent studies have compared the use of anthracycline-based NAC with adjuvant chemotherapy in earlier-stage disease, and have shown equivalent disease-free and overall survival rates with increased breast conservation rates. These studies have also shown that a pathological complete response after NAC is associated with improved long-term outcome. More recently, the taxanes have been introduced into clinical trials of NAC with increased overall and pCR rates. However, there is no evidence that the addition of taxanes to neoadjuvant anthracycline-based chemotherapy significantly improves long-term disease free survival or overall survival. This paper reviews these trials, as well as trials of dose-dense and trastuzumab-containing NAC regimens. The review discusses the potential for NAC to replace prolonged adjuvant trials in the assessment of new therapeutic agents (using pathological complete response as a surrogate for long-term outcome), to be used as an in vivo chemosensitivity assay to guide further treatment, and to identify molecular markers that correlate with tumour sensitivity or resistance to chemotherapeutic agents so that the treatment of patients can be individualised.     

Neoadjuvant systemic therapy for breast cancer: an overview and review of recent clinical trials

Neoadjuvant chemotherapy (NAC) is long established as part of the multi-modality management of locally advanced breast cancer or inflammatory breast cancer, leading to significantly improved outcome. Numerous recent studies have compared the use of anthracycline-based NAC with adjuvant chemotherapy in earlier-stage disease, and have shown equivalent disease-free and overall survival rates with increased breast conservation rates. These studies have also shown that a pathological complete response after NAC is associated with improved long-term outcome. More recently, the taxanes have been introduced into clinical trials of NAC with increased overall and pCR rates. However, there is no evidence that the addition of taxanes to neoadjuvant anthracycline-based chemotherapy significantly improves long-term disease free survival or overall survival. This paper reviews these trials, as well as trials of dose-dense and trastuzumab-containing NAC regimens. The review discusses the potential for NAC to replace prolonged adjuvant trials in the assessment of new therapeutic agents (using pathological complete response as a surrogate for long-term outcome), to be used as an in vivo chemosensitivity assay to guide further treatment, and to identify molecular markers that correlate with tumour sensitivity or resistance to chemotherapeutic agents so that the treatment of patients can be individualised.     

Update on the use of letrozole in breast cancer

Endocrine therapy is the mainstay of adjuvant treatment for hormonereceptor-positive early breast cancer. Letrozole is a potent third-generation aromatase inhibitor that suppresses plasma estrogen levels to near-undetectable levels in postmenopausal women. The results of well-controlled clinical trials have demonstrated the efficacy of letrozole over the gold-standard treatment, tamoxifen, in the neoadjuvant and upfront adjuvant settings and over placebo in the extended adjuvant setting (i.e., following 5 years of adjuvant tamoxifen). Important benefits in disease-free survival and especially distant disease-free survival have been demonstrated, in both low- and high-risk subgroups of patients (e.g., node-positive disease, prior chemotherapy). Both the efficacy and safety of letrozole for the adjuvant treatment of breast cancer are reviewed.     

Biological therapy of breast cancer: recent clinical applications

Advances have been made in breast cancer therapy, in both the adjuvant and metastatic settings. For example, in the adjuvant setting, genomic studies of breast cancer tissues have identified women with estrogen receptor-positive tumors who might not require chemotherapy, leading to the development of a diagnostic tool. There have also been significant developments with anticancer agents that target tumor cell surface receptors, such as HER2/neu, and those involved in angiogenesis and kinase-dependent pathways. New areas of research focus on the concept of breast cancer stem cells as well as the prognostic importance of bone marrow micrometastases in early-stage breast cancer. This review summarizes these advances in breast cancer clinical research.     

A stochastic economic evaluation of letrozole versus tamoxifen as a first-line hormonal therapy: for advanced breast cancer in postmenopausal patients

BACKGROUND: Letrozole is a third-generation aromatase inhibitor that is a feasible alternative to tamoxifen as a first-line hormonal therapy for patients with advanced breast cancer. OBJECTIVE: This paper presents the results of an economic evaluation comparing letrozole and tamoxifen as first-line hormonal therapies in postmenopausal women diagnosed with advanced breast cancer. PERSPECTIVE: UK National Health Service. DESIGN: A decision model (Markov process) was built describing possible patient pathways from the point of diagnosis to death. The model was populated using patient-specific clinical trial data, data from the existing literature, and expert opinion. Stochastic analyses of the model were undertaken, whereby the majority of the input parameters were described as probability distributions to represent the uncertainty about their true value. Costs were presented in year 2000 values. RESULTS: The baseline results showed that letrozole is a cost-effective alternative to tamoxifen with a mean incremental cost per life-year gained of pound 2342, whilst the incremental cost increases to just over pound 10,000 at the 95th percentile of the cost-effectiveness range (2000 values). CONCLUSIONS: The results of the economic analysis indicate that letrozole is a cost-effective alternative first-line therapy compared with tamoxifen for postmenopausal women with advanced breast cancer, achieving additional life-years with a modest increase in costs.     

来曲唑一线治疗绝经后妇女晚期乳腺癌

目的：研究来曲唑一线治疗绝经后妇女晚期乳腺癌的临床疗效和不良反应。方法：采用多中心协作开放临床试验，入组患者共32例，口服来曲唑2.5mg,qd，共服4－6周，疗前2周内及治疗6周后的3d内检测血中雌二醇（E2）水平，同时评价疗效和不良反应。结果：入组32例均可评价疗效，CR1例，PR14例，有效率为46.9%。其中，绝经时间＜5年与≥5年者的有效率分别33.3%及55.0%；ER与PR均阳性、ER或PR阳性、受体未测者的有效率分别为75.0%(3/4),66.7%(4/6)与36.4%(8/22)；表明绝经时间长的患者疗效优于绝经时间短者；ER与PR均阳性的疗效好，而受体未测者疗效较差的原因可能是这部分患者中有一部分为受体阴性；另外，皮肤、淋巴结与软组织转移的疗效亦优于实质器官转移的疗效。疗后对E2的平均有效抑制率为66.7%。主要不良反应为乏力、头晕。结论：来曲唑作为一线药物对绝经后晚期乳腺癌疗效肯定，不良反应轻微，值得临床推广应用。     

重新审视蒽环类药物在乳腺癌辅助化疗中的地位

蒽环类药物以其卓越的疗效成为乳腺癌术后辅助化疗的里程碑。多项随机临床试验结果表明:含蒽环类药物方案的辅助化疗可提高生存率,降低复发率和死亡率。近年研究还显示,蒽环类药物尤其使HER-2和Top-Ⅱ共同扩增的患者获益更大。蒽环类药物疗效确切,相关毒性可预测和预防,性价比更佳。蒽环类药物仍然是乳腺癌术后辅助化疗的基石,在辅助治疗中仍占有重要的地位。     

The role of the Chinese police in methadone maintenance therapy: A literature review

BackgroundThe behavior of police is an important factor in drug users’ access to preventive and therapeutic health services. In China, opiate users must be registered and approved by police before accessing methadone maintenance treatment (MMT).MethodsWe conducted a literature review to identify studies reporting original data about the influence of Chinese drug policing activities on MMT access and outcomes. Searches were conducted in PubMed, the Law Journal Library of HeinOnline, the Social Science Citation Index and China Academic Journals of CNKI for empirical studies conducted in China and published in academic journals between 2005 and April 2012.ResultsThe initial literature search retrieved 276 records, of which 85 were included in the review and 191 were excluded. The majority of the included papers were single-clinic observational studies. These studies reported that: (1) fear of incarceration deterred users from initiating and continuing MMT; (2) the rates of MMT referral by police were considerably lower than those by drug user peers and by community and the media; (3) police sending users to compulsory detoxification (DETOX) and reeducation through labor (RTL) centers contributed to higher rates of MMT patient dropout; (4) arrests in and around MMT clinics were not uncommon; (5) cooperation between local police and public health agencies was difficult to achieve; and (6) a limited number of trial programs were conducted to refer detainees in DETOX to MMT clinics after release, but the outcomes were not promising.ConclusionReviewed studies report drug policing practices that appear to be impeding MMT access and reducing successful treatment outcomes. Research focusing on the nature, prevalence and severity of these effects is urgently needed. Health and public security officials in China should review and reform policies and practices of registering, monitoring, and incarcerating drug users.     

Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer

Lapatinib is a dual (ErbB-1 and ErB-2) receptor tyrosine kinase inhibitor (TKI) that was recently approved by the FDA for the treatment of advanced breast cancer. It shows synergy with trastuzumab, and has demonstrated clinical activity in trastuzumab-resistant tumour. This paper reviews the drug development of lapatinib from preclinical studies to the pivotal Phase III trial and ongoing clinical studies. Areas of interest include the advantages of small molecule TKIs versus antibodies in targeting HER receptors and the efficacy of lapatinib in the treatment of cerebral metastases. The surprisingly high response rate in inflammatory breast cancer raises the possibility of other novel predictive biomarkers. The potential for combination and sequencing with other biological and cytotoxic agents is both exciting and challenging.     

Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer

Lapatinib is a dual (ErbB-1 and ErB-2) receptor tyrosine kinase inhibitor (TKI) that was recently approved by the FDA for the treatment of advanced breast cancer. It shows synergy with trastuzumab, and has demonstrated clinical activity in trastuzumab-resistant tumour. This paper reviews the drug development of lapatinib from preclinical studies to the pivotal Phase III trial and ongoing clinical studies. Areas of interest include the advantages of small molecule TKIs versus antibodies in targeting HER receptors and the efficacy of lapatinib in the treatment of cerebral metastases. The surprisingly high response rate in inflammatory breast cancer raises the possibility of other novel predictive biomarkers. The potential for combination and sequencing with other biological and cytotoxic agents is both exciting and challenging.     

The role of the clinical pharmacist in mental health hospital-in-the-home: A scoping review

BackgroundThe concept of integrating a clinical pharmacist (CP) within a Hospital-in-the-Home (HiTH) program is relatively new. Little is known about the role of a pharmacist in HiTH programs focused on mental health (MH).ObjectivesTo describe the role of a CP within an MH-HiTH program, focusing on the specific tasks performed by a pharmacist in this position, their benefits and limitations.MethodsMEDLINE, CINAHL, EMBASE, Cochrane Database of Systematic Reviews, PsycINFO, Web of Science and the grey literature were searched without any date limits for references in English that included 2 or more of the following key terms (or their synonyms): “HiTH”, “clinical pharmacist” and “mental health”. Two reviewers independently screened and analysed the data.ResultsOf 60,482 screened references, 6 included all 3 key terms: 2 were HiTH guideline documents, 2 were conference abstracts and 2 were journal articles. These papers discussed MH-HiTH programs or similar home-care services where a CP was incorporated in the treating team to address medication management and adherence during a home visit. There is evidence that MH-HiTH CPs identify and resolve medication-related problems (MRPs), as well as improve medication adherence, patient care, hospital admission rates and emergency department presentations. An additional 54 references including 2 key terms provided corroborating evidence of an MH-HiTH CP role focused on improving patient care via 4 key groups of tasks: clinical pharmacy, mental healthcare, home medicines review and facilitation of care transition through medication reconciliation and follow-up.ConclusionsAlthough there is currently a paucity of literature describing the incorporation of a CP in an MH-HiTH program, preliminary evidence shows it can improve medication management. This has potential to improve patient outcomes as has been seen in similar home-based settings, but limitations such as time constraints are notable barriers. More robust studies are needed to evaluate these outcomes.     

The role of taxanes in breast cancer treatment

Cancer of the breast is a serious public health problem throughout the world. Chemotherapy remains the mainstay of treatment of both early stage and metastatic breast cancer. New advances in chemotherapy include paclitaxel and docetaxel. This article reviews the historical background to the introduction of these highly active agents, their biochemistry, mechanism of action and pharmacology, dose and schedule in the treatment of breast cancer, first- and second-line use as well as anthracycline/taxane combinations. Adjuvant, neoadjuvant use and the emergence of weekly taxanes is discussed. (c) 2001 Prous Science. All rights reserved.     

来曲唑治疗绝经后妇女晚期乳腺癌临床研究

目的：研究来曲唑治疗绝经后妇女晚期乳腺癌的临床疗效和不良反应。方法：采用多中心随机对照方法。101例和31例分别口服来曲唑2.5mg,qd与氨鲁米特（AG）250mg,tid-qid及泼尼松10mg,qd。连服4－6周,疗前2周内及治疗4周后的3d内检测血中雌二醇（E2）水平,同时评价疗效和不良反应。结果：来曲唑组和AG组分别有98例和29例可评价疗效和不良反应。有效率分别为27．6％和20．7％,绝经时间长者疗效明显优于绝经时间短者,雌激素受体（ER）阳性疗效较阴性好,软组织和骨转移的疗效亦明显优于肝转移的疗效。疗后对E2的平均有效抑制率分别为57％和54％。来曲唑组乏力、头晕等不良反应显著低于AG组。结论：来曲唑对E2的抑制作用和对绝经后晚期乳腺癌疗效肯定,不良反应轻微,值得临床推广应用。