Anthracycline-taxane Regimens Research Articles

The Evolving Role of Adjuvant Chemotherapy.

Abstract Decision-making for the medical oncologist was once far simpler than it is today. Following the 2000 NIH Consensus Conference on the treatment of early stage breast, almost all women with tumors > 1cm or positive lymph nodes were offered a course of adjuvant chemotherapy. There were some choices to be made in terms of the specific adjuvant regimen, but the oncologist could rely upon the results of large, randomized trials and choose a regimen that had been shown to be beneficial. Indeed, some might argue that a medical oncologist in 2009 could take the same approach. But the breast cancer world has evolved substantially over the past 5-7 years, and such an approach would not take full advantage of our understanding of breast cancer in 2009. We now understand that there is a great degree of intrinsic heterogeneity across breast tumors, and that the benefits associated with adjuvant chemotherapy vary substantially by subtype of disease. At minimum, we should consider three groups of patients separately: 1) individuals with HER2 positive disease; 2) individuals with triple negative disease; and 3) individuals with ER+ and HER2 non-amplified, non-overexpressed disease, who represent the vast majority of the patients with breast cancer in the United States. For patients with HER2+ disease, trastuzumab-based therapy has become the standard of care for all but women who have very small (T1a) tumors in the setting of negative lymph. Even in those women, there are physicians who would recommend a course of adjuvant trastuzumab-based chemotherapy. The major question is what chemotherapy to use in combination with trastuzumab, and this is a matter of considerable debate. In addition, uncertainty exists surrounding the optimal treatment for individuals who have indeterminate HER2 test results. For women with triple negative breast cancer, chemotherapy is also given to almost all patients apart from those with the very smallest tumors in the context of negative lymph nodes. For most patients, one of the standard anthracycline-taxane regimens remains the usual course of therapy. For patients with a low disease burden, first or second generation regimens such as AC, TC, or CMF are reasonable considerations. The most difficult questions arise concerning the use of chemotherapy in women with ER+ and HER2 normal disease. In this setting, the average benefit associated with chemotherapy is far less than in women with HER2+ or triple negative disease. Recent retrospective studies suggest that there are large groups of women who likely derive almost no or almost no benefit from chemotherapy. Increasingly, assays such as the Oncotype Dx Recurrence Score are used to aid clinical decisions, but even these complex genetic assays do not always provide a clear roadmap. Controversies and practical considerations surrounding the use of chemotherapy in women with ER+ and HER2 normal disease will be discussed in detail. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr CS1-2.

The ADEBAR trial: Final toxicity analysis of a phase III study evaluating the role of docetaxel in the adjuvant therapy of breast cancer patients with extensive lymph node involvement

585 Background: Taxane based adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. However, toxicity concerns of combined anthracycline-taxane regimens have compromised its acceptance. We analyzed the toxicity of a sequential anthracycline-taxane chemotherapy compared to a conventional anthracycline regimen. Patients and Methods: ADEBAR was a multicenter phase III trial (n=1,502) to evaluate whether breast cancer (BC) pts with > 3 axillary lymph metastases benefit from a sequential anthracycline-docetaxel regimen (E90C-D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21 days followed by 4 cycles docetaxel [D] 100mg/m2 q21 days) compared to dose-intensive anthracycline-containing polychemotherapy (FE120C: 6 cycles E 60 mg/m2 d 1+8, 5-FU 500mg/m2 d 1+8 and C 75 mg/m2 d 1–14, q4 weeks). We present the final toxicity analysis. Results: Complete toxicity data were available from 1,338 pts. Treatment was stopped prematurely in 3.7% of the pts in the E90C-D arm and in 8.0% in the FE120C arm due to toxicity (p=0.0009). Antibiotic treatment was given in 10.4% (E90C-D) vs. 19.7% (FE120C), G-CSF support in 39.2% vs 61.4 % and erythropoietin stimulation in 8.7% vs. 20.0%, respectively (p<0.0001). Hematologic and non-hematological grade 3–4 toxicities are summarized in the table . In summary, haematological toxicity (leucopenia, infection thrombocytopenia, anemia) was significantly greater in the FE120C-arm. Skin toxicity, edema and vomiting occurred significantly more often in pts treated with E90C-D. Conclusion: Different toxicity profiles given, overall toxicity of a sequential anthracycline-taxane regimen is not necessarily greater than that of an adequately dosed anthracycline chemotherapy, which needed to be interrupted more frequently due to toxicity. [Table: see text] No significant financial relationships to disclose.

Evidence-based use of neoadjuvant taxane in operable and inoperable breast cancer.

Neoadjuvant chemotherapy (NC) is standard therapy for patients with locally advanced breast cancer and is increasingly used for early-stage operable disease. The aim of NC is a pathological complete response (pCR) in the breast and axillary lymph nodes, which is the best predictor of improved outcome and prolonged survival. The taxanes docetaxel and paclitaxel are potent agents in breast cancer management, with promising single-agent activity and acceptable tolerability in the neoadjuvant setting. In this review of the taxanes as NC for operable and inoperable breast cancer, we include all fully published Phase II-III studies enrolling > or =30 patients. Current evidence suggests that the sequential administration of taxane- and anthracycline-based therapy may be superior to concomitant administration. Indeed, until the recent Phase III Aberdeen study (n = 162), it was uncertain whether NC could prolong survival. In this study, sequential docetaxel after anthracycline-based NC significantly enhanced the clinical response rate and pathological complete response, and yielded a significant 3-year survival advantage, versus anthracycline-based NC alone. Recently, the Phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B27 trial (n = 2411) showed that sequential docetaxel after doxorubicin-cyclophosphamide significantly increased both clinical and pathological response rates for operable breast cancer, with the benefit evident in both estrogen receptor-positive and estrogen receptor-negative patients. This apparent superiority of a sequential anthracycline-taxane regimen is limited to docetaxel, with no similar Phase III trials of paclitaxel versus a non-taxane-based comparator having been conducted to date. In conclusion, current evidence supports the inclusion of a taxane in NC schedules for patients with large and locally advanced breast cancer.

Combined anthracycline-taxane regimens in the adjuvant setting

Combined anthracycline-taxane regimens in the adjuvant setting

Combined anthracycline-taxane regimens in the adjuvant setting

Within the past decade there has been enormous interest in integrating the taxanes into the adjuvant breast cancer setting. Adjuvant trial designs in the early 1990s were absent of taxanes. By the mid 1990s, the taxanes were included in adjuvant trials, but were mainly limited to trials conducted in node-positive patients. Currently, taxanes are a chemotherapeutic modality in the majority of ongoing adjuvant trials in both node-negative and node-positive patients. These trials are being conducted in thousands of patients world-wide by several of the cooperative research organizations. Most of the adjuvant trials have focused on defining the clinical efficacy and toxicity of the concurrent or sequential use of taxanes with anthracyclines. The collective experience with taxanes over the next 3 to 5 years will make them one of the most intensely studied treatments in the history of patients with breast cancer. The outcome of these trials is greatly anticipated because they have the potential of changing the current standards of care in the adjuvant treatment of patients with breast cancer.

NEOADJUVANT WEEKLY NAB-PACLITAXEL PLUS CARBOPLATIN FOLLOWED BY DOXORUBICIN PLUS CYCLOPHOSPHAMIDE WITH BEVACIZUMAB ADDED CONCURRENTLY TO CHEMOTHERAPY FOR OPERABLE TRIPLE-NEGATIVE INVASIVE BREAST CANCER

Purpose: This phase II neoadjuvant study investigated whether nab paclitaxel, carboplatin and bevacizumab given before neoadjuvant doxorubicin/cyclophosphamide (AC) produced higher pathologic complete response (pCR) rates in triple- negative breast cancer (TNBC) compared with historical results achieved with standard anthracycline/taxane regimens. Patients and Methods: Eligible patients with operable TNBC ≥2 cm received four cycles of carboplatin (area under the curve 6, day 1) plus nab-paclitaxel (100 mg/m2, days 1, 8 and 15) every 28 days, followed by four 14-day cycles of AC neoadjuvantly, with bevacizumab 10 mg/kg every 14 days for the rst 6 cycles of neoadjuvant chemotherapy, resuming postoperatively to complete 1 year of antibody treatment. In breast pCR and pCR (breast + nodes) were primary and secondary endpoints, respectively. Results: Due to slow accrual, the study was closed after enrollment of 42 of 60 planned patients. Of the 38 patients who underwent surgery (ef cacy population), 22 (58%) achieved an in-breast pCR and 19 (50%) achieved a pCR (breast + nodes). Neutropenia was the most common Grade 3/4 adverse event (57% Grade 3 and 31% Grade 4), but only 1 patient required hospitalisation and IV antibiotics for neutropenic fever. Other Grade 3/4 events included anaemia (24%), thrombocytopenia (29%) and peripheral neuropathy (Grade 3, 5%). Conclusion: Our results demonstrate a substantially higher pCR rate, both in-breast and breast + nodes, with the combination of nab paclitaxel plus carboplatin followed by AC, with concurrent bevacizumab, versus historic pCR rates with anthracycline-taxane regimens alone, supporting further investigation of this regimen, preferably in molecularly driven subsets, for the neoadjuvant treatment of patients with TNBC. Key words: Bevacizumab, breast cancer, carboplatin, nab-paclitaxel, neoadjuvant, triple-negative