A systematic review of taxane-containing regimens for metastatic breast cancer

We compared the results of randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing a taxane in women with metastatic breast cancer. The specialised register of the Cochrane Breast Cancer Group was searched in March 2004. Eligibility was assessed and data extracted from eligible studies by two reviewers. Hazard ratios (HR) were derived for time-to-event outcomes, and a fixed-effect model was used for meta-analysis. Tumour response rates were analysed as dichotomous variables. Of 21 eligible trials, 16 had published some results and 12 data on overall survival. An estimated 2621 deaths among 3643 women suggest a significant difference in overall survival in favour of taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.86-1.00, P=0.05). The treatment effect on survival was similar if only trials of first-line chemotherapy were included, although not statistically significant. There appeared to be an advantage for taxanes in time to progression (HR 0.92, 95% CI 0.85-0.99, P=0.02) and overall response (odds ratio (OR) 1.34, 95% CI 1.18-1.52, P<0.001). There was significant heterogeneity across the trials (P<0.001), partly because of the varying efficacy of the comparator regimens. Taxane-containing regimens improved overall survival in women with metastatic breast cancer. Taxane-containing regimens are more effective than some, but not all, nontaxane-containing regimens.     

早期乳腺癌术后辅助治疗现状

辅助性化疗、内分泌治疗、放射治疗已成为乳腺癌综合治疗的重要组成部分,但如何合理使用仍有争论.本文系统综述当前研究结果,为临床规范化治疗提供帮助.     

Emergence of nonanthracycline regimens in the adjuvant treatment of breast cancer

Long-term toxicity of adjuvant regimens is a critical consideration given improvements in survival and consequential management of treatment-related side effects. Despite their well-documented long-term side effects, including a cumulative dose-dependent cardiotoxicity and an increase in the incidence of secondary leukemia, anthracyclines remain an integral component of many adjuvant regimens for breast cancer. The utility of HER-2/TOP2A coamplification in predicting sensitivity to anthracycline chemotherapy has been widely suggested but requires substantiation. The recent maturation of two large phase III trials that directly examined the substitution of a taxane for an anthracycline in the adjuvant setting provides further data to critically evaluate the standard use of anthracyclines in the treatment of early-stage breast cancer. Results from both US Oncology 9735 and BCIRG 006 demonstrated equivalent efficacies in taxane- and anthracycline comparator arms. However, in both trials, the taxane-based regimen(s) resulted in less relative toxicity than the anthracycline-based regimen(s). These trial results pose legitimate questions regarding the future application of anthracyclines in the adjuvant breast cancer setting.     

Chemotherapy for invasive bladder cancer: neoadjuvant versus adjuvant

The treatment of a patient with an invasive bladder tumor is based on the original urologic assessment. The global recommendation of a single treatment plan such as radical surgery, chemotherapy, radiation, or variations thereof, for all patients is clearly an antiquated approach. Case selection criteria for each single or multimodality approach need to be defined. Neoadjuvant therapy has the advantage of an in vivo response evaluation and the potential for bladder preservation. However, before treatment, the therapeutic goal--bladder preservation, treatment of micrometastases, or both--should be outlined. Patients with T2 or T3a tumors can be considered for bladder salvage by chemotherapy alone, chemotherapy plus radiation therapy or, chemotherapy followed by partial cystectomy. For those with higher stage tumors, therapy is directed more to the treatment of micrometastases, with bladder preservation as a secondary goal. In most cases additional therapy directed at the primary is required and clinical understaging remains significant. For some patients, initial surgery with the definition of the prognosis on firm pathologic grounds, may represent a better strategy. Those with positive nodes should be offered chemotherapy in the postoperative setting. Refinements in the techniques of ileo neo-bladders are of importance in improving quality of life, but when used alone will not alter the natural history of the disease. Drug resistance remains a major therapeutic obstacle. More effective agents, and the prospective identification of intrinsic or acquired resistance, invasion, and metastatic potential are required to optimize therapy for an individual patient. Ultimately, large scale randomized trials will be required to negate the heterogeneity of this patient population. Only then will individualization of treatment be possible.     

新辅助化疗TE与CEF方案治疗乳腺癌的临床效果比较

目的比较新辅助化疗TE（紫杉类联合蒽环类）及CEF（环磷酰胺、表阿霉素、氟尿嘧啶）方案治疗乳腺癌的疗效，不良反应及其与组织病理学的关系；探讨新辅助化疗对ER、PR、HER-2、P53表达状况的影响。方法收集天津肿瘤医院2001年1月至2006年12月临床分期Ⅱ～Ⅲ期的行TE新辅助化疗患者167例，行CEF新辅助化疗患者256例。化疗皆以21d为1个周期。所有患者均完成3个周期以上的化疗后对两组患者临床效果的差异进行评价。结果乳腺癌原发肿瘤的总缓解率（RR），TE组为86％（144／167），CEF组为67％（172／256），两组间比较差异无统计学意义（P〈0．01）。临床完全缓解率（cCR），TE组为32％（54／167），CEF组为23％（59／256），两组间比较差异有统计学意义（P〈0．05）。病理完全缓解率（pCR），TE组为19％（32／167），CEF组为14％（36／256），两组间比较差异无统计学意义（P〉0．05）。两组各有2例患者出现疾病进展（PD）。主要不良反应为白细胞下降、胃肠道反应，TE组脱发较严重。两组化疗方案对ER、PR、HER-2、P53表达的差异均无统计学意义。结论新辅助化疗TE与CEF方案对乳腺癌均有较高的缓解率，且TE方案优于CEF方案。化疗的不良反应均在可耐受范围之内，而TE组患者的脱发等副反应要高于CEF组。两组新辅助化疗对ER、PR、HER-2、P53表达的影响无统计学意义。     

Liposomal anthracyclines: adjuvant and neoadjuvant therapy for breast cancer

Conventional anthracyclines, particularly doxorubicin, have played an important role in the treatment of patients with breast cancer for many decades. Conventional doxorubicin has shown excellent antitumor activity in the metastatic, neoadjuvant, and adjuvant settings. However, its clinical utility is limited due to acute and chronic toxicities, particularly cardiotoxicity, myelosuppression, nausea and vomiting, and alopecia. Liposomal doxorubicin formulations (liposomal doxorubicin [D-99] and pegylated liposomal doxorubicin) currently under investigation for the treatment of breast cancer have demonstrated similar efficacies and favorable toxicity profiles compared with conventional doxorubicin in patients with metastatic breast cancer. These agents have also shown efficacy and tolerability in several small studies as neoadjuvant therapy in patients with locally advanced breast cancer. While there are currently no studies with liposomal doxorubicin or pegylated liposomal doxorubicin as adjuvant therapy, their demonstrated activities and tolerabilities in the metastatic and neoadjuvant settings provide the rationale for the future study of these agents in adjuvant therapy for patients with early-stage breast cancer.     

Addition of bevacizumab to three docetaxel regimens as adjuvant therapy for early stage breast cancer

Docetaxel-containing chemotherapy improves disease-free survival (DFS) and overall survival in patients with early stage breast cancer. Bevacizumab improves response rate and DFS in metastatic breast cancer. However, adding antivascular endothelial growth factor therapy to anthracycline-containing chemotherapy may increase cardiotoxicity. This trial evaluates the feasibility of adding bevacizumab to three standard adjuvant docetaxel regimens with a primary endpoint of grade ≥3 congestive heart failure (CHF). Phase IIb, randomized, non-comparative study of women with previously untreated node-positive or high-risk node-negative breast cancer. Human epidermal growth factor receptor 2 (HER2)-negative patients were randomized to: (arm A) doxorubicin + cyclophosphamide followed by docetaxel or (arm B) docetaxel + doxorubicin + cyclophosphamide. HER2-positive patients (arm C) received docetaxel + carboplatin + trastuzumab for 52 weeks. All patients received bevacizumab beginning on day 1 for 52 weeks. Safety data in 212 women (mean age = 53.1 years) show that 1 patient each in arm A (1.3 %) and arm C (1.7 %), and 3 patients in arm B (4.0 %) experienced clinical CHF grade ≥3. A decreased ejection fraction was observed in 1 patient each in arms A and C, and cardiac disorder was observed in 12.8, 22.7, and 8.5 % in arms A, B, and C, respectively. A grade 3/4 treatment-emergent adverse event was reported in 82.1, 84.0, and 52.5 % of participants in arms A, B, and C, respectively. Kaplan–Meier estimates of DFS show rates at 24 months of 85.5, 90.4, and 90.4 % in arms A, B, and C, respectively. Adding bevacizumab to three standard docetaxel-based chemotherapy regimens as adjuvant treatment in patients with node-positive and high-risk node-negative breast cancer resulted in a low rate of clinical CHF grade ≥3. Maintenance bevacizumab monotherapy did not identify any new safety signals. Breast cancer recurrence/relapse, secondary malignancies, and death were uncommon, although the follow-up time in this study was relatively short.     

Efficacy and cardiac safety of adjuvant trastuzumab-based chemotherapy regimens for HER2-positive early breast cancer

BackgroundTrastuzumab-based adjuvant therapy has become the standard of care for human epidermal growth factor receptor-2 (HER2)-positive early breast cancer (EBC). Both anthracycline- and non-anthracycline-containing trastuzumab regimens are approved in the United States, but cardiotoxicity is increased with anthracycline-containing regimens.DesignThis paper reviews published and reported efficacy and cardiac safety data from the adjuvant trastuzumab trials [National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31/North Central Cancer Treatment Group (NCCTG) N9831, Breast Cancer International Research Group (BCIRG) 006, Herceptin Adjuvant (HERA), FinHer, and Programme Adjuvant Cancer Sein (PACS) 04].ResultsThe addition of trastuzumab to adjuvant chemotherapy significantly improved disease-free survival (from 24% to 58%) in five of the six trials. Overall survival was significantly improved (23%–35%) in the large trials. In NSABP B-31/ NCCTG N9831, 5.0%–6.6% of patients who received doxorubicin and cyclophosphamide (AC) were unable to receive trastuzumab. Cardiac event rate was highest in the anthracycline-containing trastuzumab arms (1.9%–3.8%) and lowest with the regimen of docetaxel, carboplatin, and trastuzumab (TCH) (0.4%).ConclusionsIncorporation of trastuzumab into anthracycline and non-anthracycline adjuvant chemotherapy regimens has substantially improved outcomes in HER2-postive EBC. The TCH regimen has the lowest rates of cardiac dysfunction, but uncertainty exists regarding the relative efficacy of TCH compared with anthracycline-containing trastuzumab regimens. Cardiac risk factor assessment can aid in selection of trastuzumab-based adjuvant therapy regimens.     

两种不同新辅助化疗方案治疗局部晚期乳腺癌的临床疗效比较

背景与目的:新辅助化疗已经成为治疗局部晚期乳腺癌的重要手段,不同化疗方案临床疗效有差异.本研究旨在比较XT方案(卡培他滨联合多西他赛)和传统CEF方案(环磷酰胺、表柔比星、氟尿嘧啶)两种不同的新辅助化疗方案治疗局部晚期乳腺癌的疗效及其不良反应.方法:收集采用xT或CEF方案行新辅助化疗的临床Ⅲ期乳腺癌患者48例,根据化疗方案分组,其中XT组26例,CEF组22例,化疗周期为2～4个,比较两组的近期疗效以及不良反应.结果:XT组的临床有效率(cRR)为88.46%,CEF组的临床有效率为63.64%,两组之间差异有统计学意义(P=0.041).XT组患者获病理完全缓解(pCR)1例(3.85%),CEF组pCR 1例(4.55%),两组差异无统计学意义(P=0.721).主要不良反应为粒细胞减少、恶心呕吐、肝功能损害、脱发、乏力和手足综合征等,但均可耐受.CEF方案的毒性较明显,出现Ⅲ/Ⅳ度的粒细胞减少,恶心呕吐、不同程度的肝功能损害均明显高于XT方案.结论:两种新辅助化疗方案对临床Ⅲ期乳腺癌均有良好的效果,xT组临床有效率优于CEF组,且患者的不良反应较CEF组轻.     

Future scenarios for the treatment of advanced non-small cell lung cancer: focus on taxane-containing regimens

Despite recent progress in the development of new molecularly targeted agents, the chemotherapy regimens considered standard at the end of the last century—that is, two‐drug combinations consisting of either cisplatin or carboplatin plus a third‐generation agent (docetaxel, paclitaxel, gemcitabine, or vinorelbine)—remain the primary treatment option for advanced non‐small cell lung cancer (NSCLC) patients. Most recently, the existing standard of care has been amended to reflect the significant survival advantage of cisplatin–pemetrexed over cisplatin–gemcitabine as first‐line treatment of nonsquamous NSCLC. The addition of a biological drug (bevacizumab, cetuximab) or the use of a single‐agent epidermal growth factor receptor inhibitor may further improve outcomes in selected patients. It has become increasingly clear, primarily through recent meta‐analyses, that although the therapeutic equivalence of any combination of a platinum agent plus either gemcitabine, vinorelbine, docetaxel, or paclitaxel has been long accepted, each regimen has different side effects and therapeutic outcomes that allow clinicians to select the most appropriate treatment for chemotherapy‐naïve patients with stage IIIB/IV NSCLC. In this review, we evaluate the available evidence and explore the role and importance of various modern chemotherapy regimens, with the aim of optimizing treatment selection and combination with biological agents. Emphasis is placed on the role of taxanes (docetaxel versus paclitaxel) in this changing landscape.     

不同新辅助化疗方案治疗乳腺癌的临床观察

目的 比较两组不同新辅助化疗方案治疗乳腺癌的疗效及毒性反应。方法 用FEC、ET化疗方案治疗Ⅱ、Ⅲ期乳腺癌48例,3－4周为1个周期。所有患者完成2个周期新辅助化疗后评价疗效。FEC方案：氟尿嘧啶（5－Fu）500mg/m^2,d1,8,静脉注射。ET方案：EPI60mg/m^2,d1,静脉注射;紫杉醇（TAX）150mg/m^2,d2,持续3h静脉滴注。结果 FEC组的总有效率为50.0%（12／24）,其中临床完全缓解（cCR）1例,部分缓解（PR）11例,无变化（NC）12例;ET组的总有效率为79.2%（19／24）,其中cCR1例,PR18例,NC5例。两组均无病理完全缓解及进展者,Ⅱ期疗效高于Ⅲ期。48例患者新辅助化疗前患侧腋窝均可触及肿大淋巴结,化疗2个周期后,FEC组有12例（50.0%）未触及肿大淋巴结,ET组有16例（66.7%）未触及肿大淋巴结。两组白细胞下降、胃肠道反应相似;ET组脱发程度较重,并伴有关节肌肉疼痛、神经毒性以及面色潮红等毒性反应。结论 两组新辅助化疗方案对乳腺癌治疗均有效,毒性反应均可耐受。ET组疗效及毒性反应均高于FEC组。     

Patients’ preferences for surgical and adjuvant systemic treatment in early breast cancer: A systematic review

Purpose

Treatment decisions in early breast cancer can revolve around type of surgery and whether or not to have adjuvant systemic therapy. This systematic review aims to give an overview of patient self-reported factors affecting preferences for breast conserving surgery (BCS) versus mastectomy (MAST), the minimal benefit patients require from adjuvant chemotherapy (aCT) and/or adjuvant hormonal therapy (aHT) to consider it worthwhile, and factors influencing this minimally-required benefit.

Methods

PubMed and EMBASE were searched for relevant articles. Two reviewers independently selected articles and extracted data.

Results

We identified 15 studies on surgical and six on adjuvant systemic treatment decision-making. Factors affecting patient preference for BCS most frequently related to body image (44%), while factors influencing preference for MAST most often related to survival/recurrence (46%). To make adjuvant systemic therapy worthwhile, the median required absolute increase in survival rate was 0.1–10% and the median required additional life expectancy was 1 day to 5 years. The range of individual preferences was wide within studies. Participants in the aHT studies required larger median benefits than those in the aCT studies. Factors associated with judging smaller benefits sufficient most often (44%) related to quality of life (e.g., less treatment toxicity).

Conclusion

Decisive factors in patients’ preferences for surgery type commonly relate to body image and survival/recurrence. Most participants judged small to moderate benefits sufficient to consider adjuvant systemic therapy worthwhile, but individual preferences varied widely. Clinicians should therefore consider the patient’s preferences to tailor their treatment recommendations accordingly.     

Emerging modalities for adjuvant therapy of breast cancer: neoadjuvant chemotherapy

There is evidence from theoretical models and experimental studies that indicates that preoperative timing of chemotherapy (neoadjuvant treatment) may be a superior treatment strategy than its use postoperatively. We have shown in our pilot study of 43 premenopausal patients with newly diagnosed cancer of the breast that administration of one cycle of CMF chemotherapy preoperatively was safe. Subsequently, a randomized study of preoperative against postoperative adjuvant chemotherapy has been started and to the present time, 98 patients have been randomized. Preliminary assessment of the randomized study confirmed the safety of the adjuvant chemotherapy with one course of cyclophosphamide, methotrexate, and 5-fluorouracil given preoperatively and also showed that the interval between diagnosis and the first course of chemotherapy can be substantially reduced. In addition to the preoperative timing, other aspects of the neoadjuvant approach are discussed. They include a more frequent utilization of fine needle aspiration so that the tissue diagnosis of breast cancer can be obtained and also refinement of diagnostic techniques, used before the preoperative treatment for the selection of high-risk patients (the neoadjuvant staging). The purpose of our presentation is not to recommend presently preoperative chemotherapy routinely but rather to indicate a need for well-controlled studies testing its appealing theoretical rationale. Its use in adjuvant therapy of breast cancer represents a major departure from the conventional management and, therefore, if the cooperation of practitioners and cooperative groups is to be secured, its rationale and safety must be well-defined.