Cost-effectiveness analysis of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-positive breast cancer: modeling the downstream effects

Purpose BCIRG 001 demonstrated prolonged disease-free (DFS) and overall survival (OS) but increased toxicity for adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) versus 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) in women with node positive breast cancer (BC). This study evaluates quality-adjusted survival and cost-effectiveness of adjuvant TAC versus FAC, taking downstream decisions and events into account, including palliative chemotherapy with taxanes. Methods We developed a Markov model for a cohort of women with node positive BC eligible for adjuvant anthracyclines. Data input included clinical and resource utilization data collected prospectively from BCIRG 001. Treatment decisions and outcomes with disease recurrence were based on a systematic literature review with validity reviewed by a national panel of Canadian BC oncologists. Direct costs for resource utilization following Canadian practice patterns were included. Unit costs were obtained from provincial cost list and published drug list prices. Utility scores were derived from the literature. An incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-years (QALY) gained for TAC versus FAC was calculated. Results For 1,000 women with node positive BC, the model showed that TAC would lead to a gain of 313 QALY (370 life years) at an additional cost of $5.8 Million Canadian dollars (Cdn) compared to FAC, over a 10-year time horizon. The ICER of TAC versus FAC was $18,505.54 Cdn per QALY gained. Sensitivity analyses supported the robustness of the model. By one-way sensitivity analyses of over 50 model variables, 95% of the cumulative ICER variation was from $6,000 to $28,000 Cdn/QALY. By multivariate Monte Carlo simulation, there was a 70% probability that the ICER would be under $50,000 CdN/QALY. Conclusion For women with node positive BC, TAC improves DFS and OS compared to FAC and is a cost-effective adjuvant chemotherapy strategy. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. An invited commentary to this article can be found at doi:.     

A multicenter phase II study of cisplatin and docetaxel (Taxotere) in the first-line treatment of advanced ovarian cancer: a GINECO study

Purpose A multicenter phase II study to evaluate the antitumor effect and safety of docetaxel in combination with cisplatin as first-line chemotherapy for advanced ovarian cancer.Methods Enrolled in the study were 45 patients who were to receive six courses of docetaxel 75 mg/m² plus cisplatin 75 mg/m² every 21 days with hydration and steroid prophylaxis after initial debulking surgery. Imaging techniques and radiography were used to assess clinical tumor response, and second-look surgery was required for patients with complete clinical responses and for those without clinically measurable disease.Results The overall clinical response rate in 29 patients with clinically measurable disease was 58% (41% complete response). A complete pathologic response was seen in 9 of 34 patients who underwent second-look laparotomy, while microscopic disease was found in 10 patients. The median time to progression was 14.4 months (95% CI 8.4–20.4 months), with a median overall survival of 43 months (95% CI 21.1–65.0 months). Patients received a median number of six cycles at a dose intensity of 98%. Grade 3–4 neutropenia was seen in 80% of patients, but was manageable. No patients withdrew because of fluid retention.Conclusions The combination of docetaxel with cisplatin confers high clinical and pathologically verified tumor response rates and is well tolerated in the first-line management of advanced ovarian cancer.     

Broad-spectrum modulation of ATP-binding cassette transport proteins by the taxane derivatives ortataxel (IDN-5109, BAY 59-8862) and tRA96023

Purpose The taxanes paclitaxel and docetaxel are substrates for P-glycoprotein (Pgp), an ATP-binding cassette (ABC) transport protein associated with multidrug resistance (MDR). In contrast, the synthetic taxane ortataxel (BAY 59-8862, IDN-5109) is effective against Pgp-expressing cells by virtue of modulation of Pgp-mediated transport. The synthetic taxane tRA96023 also modulates Pgp and is noncytotoxic due to removal of the tubulin-binding side chain at the C-13 position of the taxane backbone. We studied the effects of ortataxel and tRA96023 on the other MDR-associated ABC transport proteins, multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP, MXR, ABCG2).Methods Modulation of mitoxantrone, daunorubicin and doxorubicin retention and cytotoxicity by ortataxel and tRA96023 was studied in established cell lines overexpressing Pgp, MRP-1 and wild type (BCRP^R482) and mutant (BCRP^R482T) BCRP, and was compared with modulation by the established Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C, respectively.Results Ortataxel effectively modulated drug retention and cytotoxicity in cell lines overexpressing MRP-1 and BCRP^R482, in addition to Pgp. tRA96023 modulated drug retention and cytotoxicity in cell lines overexpressing BCRP^R482 and Pgp, but not those overexpressing MRP-1. Neither ortataxel nor tRA96023 modulated BCRP^R482T.Conclusions The synthetic taxane derivatives ortataxel and tRA96023 are broad-spectrum ABC protein modulators. Further studies will seek to identify a noncytotoxic synthetic taxane that modulates Pgp, MRP-1 and BCRP.This work was supported by grants R21 CA098457 and R21 CA89938 (to M.R.B.), R01 CA73872 (to R.J.B.) and T32 CA09072-27 from the National Cancer Institute and R01 GM42798 from the National Institute of General Medical Sciences (to I.O.), by a Leukemia and Lymphoma Society Translational Research Program grant (to M.R.B.), by shared resources of the Roswell Park Cancer Center Support Grant (P30 CA16056) and by the Leonard S. LoVullo Memorial Fund for Leukemia Research and the Dennis J. Szefel, Jr Endowed Fund for Leukemia Research at Roswell Park Cancer Institute.     

Progress in systemic adjuvant therapy of early-stage breast cancer

Despite major improvements in the treatment of early-stage breast cancer over the past 15 years, many controversies exist surrounding the optimal adjuvant therapies for these patients. Adjuvant chemotherapy has been demonstrated to reduce recurrence and improve mortality, but questions persist as to what is the optimal regimen and how much adjuvant therapy should be administered. Among the adjuvant chemotherapy issues that remain controversial are the role of the taxanes and the optimal number of adjuvant chemotherapy treatment cycles. In the realm of adjuvant endocrine therapy, the early results of the Anastrozole, Tamoxifen and Combination (ATAC) trial have led to confusion as to how best to treat postmenopausal patients with estrogen receptor-positive, early-stage breast cancer. Clinicians are faced with the decision of choosing between tamoxifen and anastrozole. The enthusiasm for so-called targeted therapies, such as trastuzumab, in patients with metastatic disease, is now being carried over into the adjuvant setting. Multiple clinical trials around the world are evaluating the potential benefit of adding trastuzumab to chemotherapy in patients with HER2-positive, early-stage breast cancer. In the United States, clinicians are faced with many decisions on how to optimally treat patients with early-stage breast cancer. Evidence-based treatment guidelines such as those developed by the National Comprehensive Cancer Network (NCCN) provide a useful algorithm for assisting in making treatment decisions. It is hoped that, in the next few years, the results of ongoing clinical trials now underway will lead to further improvements in the outcome of patients with early-stage breast cancer.Presentation made at the ASCO-JSCO Joint Symposium held at Tokyo, Japan, on October 18, 2002.     

紫杉烷类药物相关心脏器官不良事件信号挖掘研究

目的 对美国食品和药品管理局不良反应报告系统（FAERS）中紫杉烷类药物相关心脏不良事件（ADE）数据进行挖掘,为临床合理用药提供参考。方法 自FAERS数据库提取2017年第一季度至2021年第四季度紫杉烷类药物ADE报告,从中筛选出累及心脏器官疾病报告,采用报告比值比法（ROR）和英国药品和保健品管理局综合标准法（MHRA）检测信号。结果 高位组语（HLGT）层面,紫杉醇的信号有报告744份,分布于心律失常类疾病,心肌类疾病,各类心脏衰竭、心脏相关疾病,症状和体征,冠状动脉类疾病和心包类疾病;多西他赛的信号有报告74份,分布于心肌类疾病和各类心脏衰竭、心脏相关疾病;紫杉醇（白蛋白结合型）的信号有报告85份,分布于心律失常类疾病,心肌类疾病,各类心脏衰竭和心包类疾病。结论 心脏器官相关ADE中,紫杉醇和紫杉醇（白蛋白结合型）多见心律失常、心脏传导阻滞和心肌缺血,多西他赛多见左心室功能障碍和心肌缺血,可供临床参考。     

Thalidomide/estramustine/paclitaxel in metastatic androgen-independent prostate cancer

Background

This is a phase I/II trial of thalidomide with estramustine and paclitaxel in men with androgen-independent prostate cancer (AIPC) who underwent previous chemotherapy.

Patients and Methods

Men with progressive AIPC were treated with oral thalidomide (200 mg, 400 mg, or 600 mg daily), intravenous paclitaxel (100 mg/m² over 3 hours on days 3 and 10), and oral estramustine (140 mg 3 times daily on days 1-5 and days 8-12) every 21 days.

Results

Phase I: first cycle dose-limiting toxicity occurred in 0 of 3 patients at 200 mg thalidomide daily, 0 of 3 at 400 mg daily, and 1 of 3 at 600 mg daily (the designated maximum tolerated dose). Phase II: twenty-nine of 38 evaluable patients (76%; 95% confidence interval, 67%-87%) experienced a 50% decrease in prostate-specific antigen level. Five of 18 patients (28%) with measurable disease exhibited an objective response. Nine of 14 patients (64%) with disease refractory to previous taxane therapy had 50% decreases in prostate-specific antigen level. Grade 3/4 adverse events included neutropenia (9 of 39 [23%]), fatigue (9 of 39 [23%]), dyspnea (8 of 39 [21%]), and thromboembolic events (7 of 39 [18%]). Cumulative dose-limiting toxicity rates were minimal (13%) with thalidomide at 200 mg daily.

Conclusion

The profile of activity of thalidomide/paclitaxel/estramustine in taxane-refractory AIPC warrants further investigation.     

Adjuvant chemotherapy for early-stage non-small-cell lung cancer. Single-centre experience and literature review

Background In recent years platinum-based chemotherapy has become the standard of care for patients with good performance status after complete resection in stages IB-IIIA non-small-cell lung cancer (NSCLC), although the benefit is mainly in stages II and IIIA. Patients and methods In a retrospective trial we evaluate the clinical efficacy and toxicity profile of a platinum- and taxanes-based adjuvant chemotherapy in completely resected IB-IIIA NSCLC. The primary end point was relapse- free survival (RFS); principal secondary end points were overall survival (OS) and safety of the regimen. Potential predictive factors of efficacy and clinical patterns of relapse were also analysed. Results From January 2003 to December 2006, 41 patients met the inclusion criteria and were evaluable. Median age at diagnosis was 68.1 years (CI 95% 54-72; range 45-78). Most patients were males (87.7%) and had an Eastern Cooperative Oncology Group performance status score (PS) of 0-1 (87.8%), and 53.6% had adenocarcinomas. Pathological stages were as follow: 48.7% stage IB, 24.3% stage II and 26.8% stage IIIA. 75.6% of patients underwent a lobectomy and mediastinal lymphadenectomy and were treated with a combination of carboplatin AUC6 and paclitaxel 200 mg/m(2) (85.36%) for 3 or 4 cycles. With a median follow-up of 18.2 months (range 5.1-46.5), 26 patients (63%) were free of disease and 32 of them were alive (78%). Median RFS was 12.1 months (CI 95% 9.8-14.9) and median OS had not been reached at the time of analysis. Patients with PS相似文献   

Phase II study of dose-dense doxorubicin and docetaxel as neoadjuvant chemotherapy with G-CSF support in patients with large or locally advanced breast cancer

Introduction  To evaluate the efficacy and safety profile of the concomitant dose-dense administration of doxorubicin and docetaxel as primary chemotherapy for patients with large or locally advanced breast cancer. Materials and methods  Forty-seven patients were included and received 50 mg/m² of doxorubicin and 75 mg/m² of docetaxel every two weeks for four cycles. Primary prophylaxis with granulocyte colony stimulating factor was administered. Results  Patients included had mainly stage III disease (66%). Efficacy and toxicity analyses were carried out on an intention-to-treat basis. After study treatment, the rate of clinical responses was 85% (95% CI: 75–95) with 6% judged as clinical complete responses. Surgery was performed on 94% patients for whom the breast was conserved in 27%. Only one patient obtained a pathological complete response (with no evidence of invasive or non-invasive tumour in the breast and the lymph nodes). In three additional patients, malignant cells were detected only in one lymph node. The single severe haematological toxicity was neutropenia, occurring in one patient (2%) and two cycles (1%), being grade 3 in one and grade 4 in the other. Severe non-haematological toxicities were grade 3, and the most common was asthenia (8% of patients), followed by cutaneous toxicity, arthromyalgia and stomatitis, which occurred in fewer than 4% of patients in each case. Conclusions  The concomitant dose-dense administration of doxorubicin and docetaxel as neoadjuvant chemotherapy with granulocyte colony stimulating factor support is a feasible and effective schedule with a safe toxicity profile for women with large or locally advanced breast cancer.     

A phase 1/2 of a combination of Cetuximab and Taxane for “triple negative” breast cancer patients

50–70% of tumors of the so called “triple negative” subtype of breast cancer express EGFR. We hypothesized that addition of anti EGFR to Taxanes will result in increased effectiveness in EGFR expressing tumors. Here we set out to obtain data regarding the safety, tolerability and also the effectivity of the combination of weekly Taxane treatments with Cetuximab -an anti EGFR antibody in this subgroup of breast cancer. 18 triple negative breast cancer patients were treated with weekly Cetuximab and Taxane therapy. Addition of Cetuximab resulted in controllable Dermatologic toxicity in most patients –with grade 3 in two patients. Some impressive results were noted including one CR, one near CR and regression of chemotherapy and radiation resistance skin metastasis. Median TTF -and overall survival −6 and 12 months. Administration of Taxane Cetuximab weekly therapy for triple negative breast cancer patients is feasible. Use of anti EGFR-Taxane combinations should be assessed in larger clinical trials in this patient population perhaps in a similar manner to the lung cancer patients only in those with strong EGFR expression.