And Paclitaxel Research Articles

Neoadjuvant Doxorubicin-Paclitaxel Combined Chemotherapy in Patients with Inoperable Stage III Breast Cancer: A Retrospective Cohort Study with 10 Years of Follow-Up in Vietnam.

The combination of doxorubicin and paclitaxel (AP) is widely used in our country for the neoadjuvant treatment of breast cancer as well as metastatic breast cancer. The AP regimen has shown promise as a neoadjuvant therapy for breast cancer that improves pathological complete response (pCR), increases the rate of conservative surgery, and improves the survival of patients. However, up to now, no research has evaluated the response of this regimen for the neoadjuvant treatment of advanced breast cancer, especially with a 10-year period of follow-up. This retrospective analysis reviewed 126 patients with inoperable stage III breast cancer who received neoadjuvant chemotherapy with doxorubicin 50mg/m2 plus paclitaxel 175mg/m2 every 3weeks for a maximum of six courses followed by surgery. pCR was evaluated. Survival was analyzed for all breast cancer patients using Kaplan-Meier and log-rank models. Of 126 women treated with neoadjuvant chemotherapy (NAC), the overall pCR rate was 25.4% and was significantly higher in patients with tumor stage cT1-T2, hormone receptor-negative (HR-negative), and human epidermal growth factor receptor 2 (HER2)-positive disease. Patients achieving pCR had significantly longer disease-free survival (DFS) and overall survival (OS). Ten-year DFS rates were 43.8% vs. 25.0% (p = 0.030) and 10-year OS rates were 59.4% vs. 28.9% (p = 0.003) for patients with pCR and non-pCR, respectively. The cumulative 10-year DFS was 19.6% for patients with HR-negative disease and 37.3% for those with HR-positive disease. Achieving pCR was associated with improved 10-year OS and DFS. Several clinicopathological features were closely associated with pCR in the inoperable stage III breast cancer patients who were treated by neoadjuvant chemotherapy. Achieving pCR was associated with improved 10-year OS and DFS. Patients with advanced breast cancer with HR-negative and HER2-positive status who benefited from the AP neoadjuvant therapy regimen were significantly more likely to achieve pCR.

Oxidative stress in breast cancer after chemotherapy.

It is of interest to evaluate the influence of breast cancer on oxidative stress, liver function tests, renal biomarkers, action of doxorubicin, cyclophosphamide and paclitaxel (AC-T) in the treatment and mechanism over altering the measured markers in breast cancer. Sixty histopathological confirmed cases of female patients suffering with breast carcinoma from the Department of Oncology at Omega Cancer Hospital, Visakhapatnam were included in the study. The investigation was performed in 3 groups: a control group containing 30 healthy females of similar age, 30 breast cancer patients without treatment and 30 patients receiving treatment with anticancer combination drugs AC-T. The venous blood samples from both controls and patients were measured for total antioxidant status (TAS), nitric oxide (NO), malondialdehyde, alanine aminotransferase, aspartate aminotransferase, and blood urea, serum creatinine. One-way ANOVA and Tukey-Kramer multiple comparisons post-test were applied as statistical analysis tools through SPPS software version 20.0. P<0.05 was regarded as significant. According to the findings, higher stages of breast cancer were linked to considerable increase in oxidative stress markers during AC-T treatment. The findings of the study revealed that oxidative stress is linked to breast cancer, and that chemotherapy exacerbates this oxidative stress, causing damage to a variety of cellular targets. Monitoring serum oxidative stress markers may aid in the evaluation of chemotherapy effects in breast cancer patients. According to our findings, AC-T chemotherapy will elevate malondialdehyde, a lipid peroxidation marker, and lowers the total antioxidant status.

Identifying Circulating Tumor DNA Mutations Associated with Neoadjuvant Chemotherapy Efficacy in Local Advanced Breast Cancer.

Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer. Neoadjuvant chemotherapy (NACT) has become standard therapy for local advanced breast cancer (LABC). The aim of our study was to investigate plasma ctDNA as a prognostic marker for outcome in patients with LABC treated with NACT. A total of 56 patients with LABC were involved in this study. ctDNA mutations were investigated by using a 100 gene panel-target capture next-generation sequencing. The patients then received standard NACT therapy: adriamycin and cyclophosphamide and paclitaxel (AC-T) or AC-TH (AC-T+ Trastuzumab) regimen. The efficacy of NACT was evaluated by Miller-Payne grading system. A predictive and weight model was used to screen ctDNA point mutation biomarkers for NACT. The ctDNA mutational profile of LABC patients was identified. For nonsynonymous mutations, the top 5 mutated genes were MTHFR (51/56, 91.1%), XPC (50/56, 89.3%), ABCB1 (48/51, 94.1%), BRCA2 (38/56, 67.9%), and XRCC1 (38/56, 67.9%). In addition, the mutation frequencies of PIK3CA and TP53 were 32.1% (18/56) and 26.8% (15/56), respectively. The predictive model indicated that XRCC1 44055726 (TG>-) mutation (25/56, 44.6%) was significantly associated with Miller-Payne 4-5 and Miller-Payne 3-5 responses. While mTOR 11249132(G>C) mutation (23/56, 41.1%) was associated with Miller-Payne 1-4 or Miller-Payne 1-3 responses. Furthermore, XRCC1 44055726 (TG>-) accompanied by mTOR wild type predicted a good NACT efficacy in all response classification systems. The ROC curves to discriminate good neoadjuvant chemotherapy efficiency (Miller-Payne 4-5) and poor efficiency (Miller-Payne 1-3) were created, and AUC value was 0.77. Our results suggested that ctDNA mutation of XRCC1 44055726 (TG>-) might be a positive biomarker for NACT therapy in LABC, while mTOR 11249132(G>C) mutation was potentially associated with NACT resistance.

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment.

Background: Chemotherapy treatment for breast cancer can induce cognitive impairments often involving oxidative stress. The brain, as a whole, is susceptible to oxidative stress due to its high-energy requirements, limited anaerobic respiration capacities, and limited antioxidant defenses. The goal of the current study was to determine if the manganese porphyrin superoxide dismutase mimetic MnTnBuOE-2-PyP (MnBuOE) could ameliorate the effects of doxorubicin, cyclophosphamide, and paclitaxel (AC-T) on mature dendrite morphology and cognitive function. Methods: Four-month-old female C57BL/6 mice received intraperitoneal injections of chemotherapy followed by subcutaneous injections of MnBuOE. Four weeks following chemotherapy treatment, mice were tested for hippocampus-dependent cognitive performance in the Morris water maze. After testing, brains were collected for Golgi staining and molecular analyses. Results: MnBuOE treatment preserved spatial memory during the Morris water-maze. MnBuOE/AC-T showed spatial memory retention during all probe trials. AC-T treatment significantly impaired spatial memory retention in the first and third probe trial (no platform). AC-T treatment decreased dendritic length in the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) areas of the hippocampus while AC-T/MnBuOE maintained dendritic length. Comparative proteomic analysis revealed affected protein networks associated with cell morphology and behavior functions in both the AC-T and AC-T/MnBuOE treatment groups.

Abstract P2-18-07: Weight and body composition’s analysis in chemotherapy-treated women with breast cancer under nutritional follow up in a private oncology service in Brazil

Abstract INTRODUCTION: The obesity/overweight is closely related to poorer breast cancer prognosis, as well as higher mortality rates. In postmenopausal women, the main source of estrogen is in the adipose tissue. Due to that, overweight/obesity leads to an increase in breast cancer development and disease progression. This is a consequence of not only to high estrogen levels, but also to an increase in circulating factors that influence in inflammatory pathway activations and insulin resistance increase. OBJECTIVES: This study aims at analyzing weight and body composition variation in breast cancer women under nutritional monitoring during adjuvant chemotherapy (CT). METHOD/DESIGN: This is an observational, prospective study with estrogen receptor (ER) and/or progesterone receptor (PR) positives, HER2 negative breast cancer women, who underwent adjuvant CT, from 07/17/2018 to 06/19/2019. Nutritionists followed up these patients during all of CT cycles, and data on body composition were collected through bioelectric impedance in the first and last days of chemotherapy. In between cycles, body weight assessments, nutritional guidelines orientations adherence were checked against the information, which had been offered. RESULTS: 51 women were selected and 4 excluded according to study criteria (3 patients turned HER2 positive by FISH and 1 patient had metastatic cancer confirmation). By the data analysis, 36 patients completed chemotherapy. The CT regimens used were doxorrubicin, cyclophosphamide and paclitaxel (ACT) (59%), AC plus docetaxel (4%), cyclophosphamide, methotrexate and Fluorouracil (CMF) (10%), AC (6%) and docetaxel and cyclophosphamide (TC) (21%). The mean age was 51 years, with 12 women aged ≥ 60 years. At the beginning the mean Body Mass Index (BMI) was 27.94 kg / m2. 37% of them were classified as eutrophic, 33% were overweight and 30% obese, according to the World Health Organization (WHO) criteria. Weight gain was observed in 64% of patients, with a significant increase in lean mass (kg) as well as body water (in 75% of patients). There was a reduction in fat percentage due to the reduction of fat mass in kilos (52.8% of patients) and the increase of lean mass (kg). The mean BMI at the end of treatment was 27.08 kg / m2, with a decrease in obesity and eutrophic index (reduction of 5.8% and 32.9%, respectively) and an increase in overweight by 41.7%. If considered the weight variation per CT protocol, the women submitted to the ACT scheme had a higher prevalence of weight gain, distributed in lean mass (80%), body water (75%) and fat mass reduction in 55% of these patients. On the other hand, there was a reduction in the mean of BMI value between the first evaluation (26.7 kg / m2) and the last one (22.4 kg / m2), as well as a lower fat mass in 62.5% of women who were submitted to TC protocol. In addition, in CMF and AC protocol, only one patient in each regimen finished the treatment until the deadline. In this case, the results were immature and not been reported in this abstract. CONCLUSIONS: There was an improvement in body composition, considering lean and fat mass in the study population, probably due to the nutritional monitoring during all cycles of chemotherapy. Nutritional therapy certainly influenced adherence to better eating habits. Full data of the 51 patients will be presented during the meeting. It should reinforce the need of developing prospective controlled studies, targeting nutritional intervention in breast cancer treatment. Citation Format: Flavia Rocha Paes, Anna Nogueira Verano, Julia SM de Sá, Rafaela M Peixoto, Juliana CO Pena, Maria Clara A Zocrato, Patricia C Christo, Fernanda CMJ Oliveira, Bruno L Ferrari. Weight and body composition’s analysis in chemotherapy-treated women with breast cancer under nutritional follow up in a private oncology service in Brazil [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-07.

Abstract P3-12-13: First analysis of ASTER study AT for 3 cycles followed by CMF for 3 cycles as neo or adjuvant chemotherapy in early stage breast cancer. A single institution experience

Abstract Background: The ECTO study demonstrated the efficacy of concurrent doxorubicin and paclitaxel (AT) for 4 cycles followed by cyclophosphamyde/ methotrexate/fluorouracil (CMF) for 4 cycles in the neoadjuvant and adjuvant treatment of operable breast cancer (Gianni L. et al. JCO 2009). With the purpose of ameliorating the tolerability of the regimen, we designed the ASTER study to reduce both the duration and the total dose of treatment with AT followed by CMF. Herein we report on the first data of efficacy of the study and the toxicity. Methods: A total of 345 patients with operable breast cancer were enrolled between September 2008 and November 2011. Median age was 50 years (range 23-74); 74.5% of patients presented with hormonal receptor positive (HR +) and 23,5% of patients with both hormonal receptor negative (HR-PgR-); 19% of patients presented HER2 over expression/amplification; half patients had Ki67 &amp;gt;14%, almost of patients had pT1 (66%) or pT2 (30%) with 27,5% of pN0. Patients were treated with Adriamycin (60 mg/mq) + Paclitaxel (200 mg/mq) q21 for 3 cycles followed by CMF i.v. 1, 8q28 for 3 cycles (73 as neo-adjuvant and 272 as adjuvant regimen). After chemotherapy in patients with HER2+ trastuzumab was delivered for 1 yr and in patients with HR+ tumors hormonal treatment was recommended for 5 yr. Breast irradiation was mandatory after conserving surgery (64% of cases). Results: At a median follow-up of 36 months, the relapse free survival (RFS) and overall survival (OS) were 92% and 96% respectively. As expected in patients HR+/HER2- RFS were 95% and OS 99%, in patients HER2+ RFS were 90% and OS 97% and in those HR-/HER2- 83% and 79% respectively. In the neoadjuvant subset tnpCR, defined as the absence of invasive cells in the primary tumor and in nodes, was obtained in 10% of cases. A tnpCR was achieved in 27% of patients with triple negative cancer and only in 5% of HR positive cancer. Peripheral neuropathy toxicity was reported in 37% of cases and was essentially mild to moderate. Only 8,7% of patients experienced neutropenia G 3, 4,3% GI toxicity G3 and 2,3% mucositis G3. No cardiotoxicity was documented even in the 65 patients who received postoperative trastuzumab to date. Conclusions: This results of Aster study AT for 3 cycles followed by CMF for 3 cycles showed similar efficacy and very favorable toxicity compared whit our previous experience of eighth cycle of sequential and non cross resistant chemotherapy in early stage breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-12-13.

Is a Dexamethasone-Sparing Strategy Capable of Preventing Acute and Delayed Emesis Caused by Combined Doxorubicin and Paclitaxel for Breast Cancer? Analysis of a Phase II Trial

Objective: The effectiveness of palonosetron without delayed dexamethasone dosing against emesis was investigated in patients scheduled to receive the corticosteroid-containing combination of doxorubicin and paclitaxel (AT) for 3 cycles. Methods: Chemo-naïve women with breast cancer receiving doxorubicin (60 mg/m²) and paclitaxel (200 mg/m²) were eligible. Patients received palonosetron 0.25 mg intravenously before chemotherapy, however, all patients also received a premedication consisting of prednisone (25 mg orally the evening before therapy) and hydrocortisone (250 mg intravenously just before paclitaxel). The primary end point was complete control (CC; no vomiting, no rescue anti-emetics, and no more than mild nausea) during the overall phase (days 1-5) following cycle 1. Results: Seventy-six patients were enrolled and evaluable (median age 50 years). Fifty-six patients (74%; 95% CI 62-83%) achieved overall CC. Acute (day 1) and delayed (days 2-5) CC rates were 78 and 74%, respectively. No vomiting rates for the acute, delayed and overall phases were 85, 85 and 83%, respectively. An exploratory analysis showed only a small decrease in the probability of achieving CC between cycle 1 (74%) and cycle 3 (66%). Conclusion: The dexamethasone-sparing strategy prevented emesis in more than 70% of breast cancer patients receiving their initial cycle of AT chemotherapy.

269P - Neoadjuvant Chemotherapy in Operable Breast Cancer: Data From the Aster Study (At for 3 Cycles Followed by CMF for 3 Cycles)

ABSTRACT Background The ECTO-1 study demonstrated the efficacy of concurrent doxorubicin and paclitaxel (AT) for 4 cycles followed by cyclophosphamyde/methotrexate/fluorouracil (CMF) for 4 cycles in the neoadjuvant treatment of operable breast cancer (Gianni L. et al. Clin Cancer Res 2005). With the purpose of ameliorating the tolerability of the regimen, we designed the ASTER study to reduce both the duration and the total dose of neo-/adjuvant treatment with AT followed by CMF. Herein we report on the efficacy of the neoadjuvant portion of the trial. Methods A total of 70 patients with operable breast cancer were enrolled between September 2008 and November 2011. Median age was 51 years (range 32-73); 74% of patients presented with hormone receptor positive (HR +) and 26% of patients with hormone receptor negative (HR -); 8% of patients presented HER2 overexpression/amplification; most of the patients had cT2 (96%); half presented with node involvement cN1 (54%). Patients were treated with neoadjuvant Adriamycin (60 mg/mq) + Paclitaxel (200 mg/mq) q21 for 3 cycles followed by CMF i.v. 1, 8q28 for 3 cycles. Results The pathological complete response (pCR), defined as the absence of neoplastic cells in the primary tumor was obtained in 11.5% of cases; tnpCR, defined as the absence of neoplastic cells in the primary tumor and in nodes, was obtained in 10% of cases. Overall, 29% of patients with triple negative breast cancer achieved a pCR, while only 6% of HR positive breast cancer achieved a pCR. Conclusions Neoadjuvant treatment with three cycles of AT followed by three cycles of CMF is effective in patients with operable breast cancer. The rate of pCR matched perfectly with the data obtained with the original schema AT x 4 followed by CMF x 4 in 69 patients treated with primary chemotherapy at our institute, within the ECTO-1 study. The ASTER study sets the base for developing a less toxic chemotherapy regimen sequential and non-cross resistant containing anthracycline and taxane for the treatment of operable breast cancer. Disclosure All authors have declared no conflicts of interest.

Which is your choice? Neoadjuvant doxorubicin hydrochloride and doxetaxel (AD) versus doxorubicin hydrochloride, cyclophosphamide, and paclitaxel (AC-T) in locally advanced breast cancer.

e11559 Background: It is well known that neoadjuvnat chemotherapy is acceptable for women with locally advanced breast cancer. However, it is not achieving consensus that what kind of regimen is most effective and tolerable, although lots of regimens and dosages were clinically used. Methods: We compared the patients who were received adriamycine and doxetaxel (AD) and adriamycin, cyclophosphamide followed by paclitaxel (AC-T) as neoadjuvant chemotherapy and then received operation from 1 January 2006 to 30 September 2011. The group of AD regimen was scheduled for 3 cycles of AD (50mg/m2 and 75mg/m2, respectively) with 3 weeks interval and then completes resection. The group of AC-T was scheduled for 4 cycles of AC regimen (50mg/m2 and 500mg/m2, respectively) and then 4 cycles of paclitaxel(175mg/m2) with 3 weeks interval and then completes resection. Results: The patients who were enrolled in this study were totally 78(AD and AC-T were equally 38.) The significant differences of patients’ characteristics between two groups were not observed. However, the significant differences were identified in hematologic toxicity including neutropenia more than grade 3 p&lt;0.001), neutropenic fever p&lt;0.001), dose reduction rate due to hematologic toxicity (p=0.012) and chemotherapy induced anemia (p=0.012)), although chemotherapy induced thrombocytopenia (p=1.0) was not different between two groups. No differences were identified in non-hematologic toxicity including hepatic toxicity, gastrointestinal toxicity and peripheral neuropathy. The response of chemotherapy was no difference between two groups, which was estimated by conversion rate of breast conserving surgery, clinical response of chemotherapy (p=0.148), clinically downstaging rate (p=0.464) and pathologic complete response rate (p=1.0). There is no factor to predicting pathologic complete response or conversion to breast conservation in this study. Conclusions: The neoadjuvant AC-T regimen is more tolerable with similar clinical outcome compared to AD regimen.

3P Which is Your Choice? Neoadjuvant Doxorubicin and Doxetaxel (Ad) Versus Doxorubicin, Cyclophosphamide and Paclitaxel (Act) in Locally Advanced Breast Cancer

ABSTRACT Background It is well known that neoadjuvnat chemotherapy is acceptable for women with locally advanced breast cancer. However, it is not achieving consensus that what kind of regimen is most effective and least adverse effect, although lots of regimens and dosages were clinically used. Materials and methods We compared the patients who were received adriamycine and doxetaxel (AD) and adriamycin, cyclophosphamide and paclitaxel (ACT) as neoadjuvant chemotherapy and then received operation from 1 January 2008 to 30 September 2011. The group of AD regimen was scheduled for 6 cycles of AD (50mg/m2 and 75mg/m2, respectively) with 3 weeks interval and then completes resection. The group of ACT was scheduled for 4 cycles of AC regimen (50mg/m2 and 500mg/m2, respectively) and then 4 cycles of paclitaxel (175mg/) with 3 weeks interval and then completes resection. Results The patients who were enrolled in this study were totally 78 (AD and ACT were equally 38.) The significant differences of patients' characteristics between two groups were not observed. However, the significant differences were identified in hematologic toxicity including neutropenia more than grade 3 (p Conclusions The neoadjuvant ACT regimen is more tolerable with similar clinical outcome compared to AD regimen. Disclosure All authors have declared no conflicts of interest.

Increased efficacy of a dose-dense regimen of neoadjuvant chemotherapy in breast carcinoma: a retrospective analysis

Neoadjuvant chemotherapy is being increasingly used in the treatment of breast carcinoma. We performed a single-center retrospective analysis of the results of neoadjuvant therapy in 376 breast carcinoma patients treated with three different regimens combining doxorubicin and paclitaxel (AT), dose-dense doxorubicin and cyclophosphamide with sequential weekly paclitaxel (DD AC-P), or the combination of trastuzumab with chemotherapy (DD AC-PT). The expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor (HER)-2 was determined immunohistochemically. Pathological response was determined in 318 patients. Pathological complete response (pCR) was observed in 18% of patients. The pCR rate was significantly higher in patients treated with DD regimen (22 vs. 13%) and younger than 55 years (23 vs. 13%). The pCR rate was higher in patients with triple negative (TN) tumors (43%) and tumors over-expressing HER-2 (HER-2+; 28%) compared to patients with ER- or PR-positive tumors not expressing HER-2 (ER/PR+HER-2-; 6%). In patients with TN tumors pCR rate was significantly higher after treatment with DD AC-P compared to AT (61 vs. 22%, p=0.005). pCR was associated with significantly improved relapse-free survival (RFS) and overall survival (OS), but when analysis was performed based on tumor phenotype, the difference was significant only in patients with TN tumors. In multivariate analysis, pCR, stage, and ER expression were significant predictors of RFS, while pCR, stage, ER and DD regimen were significant predictors of OS. In conclusion, present data indicate superiority of a DD regimen in obtaining pCR in patients with breast carcinoma treated with neoadjuvant chemotherapy. The difference in efficacy is due mostly to markedly higher pCR rate in patients with TN tumors.

Incidence and time course of bleeding after long‐term amenorrhea after breast cancer treatment

The incidence of chemotherapy-induced amenorrhea (CIA) and the time to subsequent menstrual bleeding in premenopausal breast cancer patients treated with current standard chemotherapy regimens was examined. Four hundred sixty-six women ages 20 to 45 years at the time of diagnosis of a stage I to III breast cancer were recruited between January 1998 and July 2002. Patients completed monthly bleeding calendars from the time of study recruitment. Updated medical history data were obtained at 6-month intervals. Most women received doxorubicin and cyclophosphamide (AC); doxorubicin, cyclophosphamide, and paclitaxel (ACT); or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Approximately 41% of women experienced an initial 6 months of CIA, and an additional 29% had at least 1 year of CIA. Approximately half of the women with 6 months of CIA and 29% of those with 1 year of CIA resumed bleeding within the subsequent 3 years, usually in the year after their amenorrheic episode. Resumption of bleeding differed significantly by treatment regimen after 6 months of CIA (P = .002; 68% with AC, 57% with ACT, and 23% with CMF), but not after 1 year of CIA (P = .5). Of the 23% of women who experienced an initial 2-year period of CIA, 10% resumed bleeding within the ensuing 3 years after their amenorrheic episode, but none had regular menses. A considerable proportion of women treated with chemotherapy will experience periods of CIA, but many will resume bleeding. Newer treatment regimens such as ACT appear to have a higher resumption of bleeding compared with CMF. This finding may have implications for choice of anti-estrogen treatment and for future potential pregnancies/fertility.

Economic evaluation of intensive chemotherapy with prophylactic granulocyte colony-stimulating factor for patients with high-risk early breast cancer in Japan

Objective: This study assessed the cost-effectiveness and budget impact of third-generation chemotherapy regimens with prophylactic granulocyte colony-stimulating factor (G-CSF) relative to second-generation regimens without prophylactic G-CSF for patients with high-risk early breast cancer in Japan. Methods: We conducted a cost-effectiveness analysis with Markov modeling and calculated incremental cost-effectiveness ratios (ICERs) for the comparison between second-generation regimens without prophylactic G-CSF and third-generation regimens with prophylactic G-CSF. The comparisons consisted of fluorouracil, doxorubicin, and cyclophosphamide, a second-generation regimen, versus docetaxel, doxorubicin, and cyclophosphamide (TAC) with G-CSF, a third-generation regimen; and doxorubicin, cyclophosphamide, and paclitaxel (AC-T) q3wk, a second-generation regimen, versus dose-dense (DD) AC-T q2wk with G-CSF, a third-generation regimen. Patients were stratified by the age at which chemotherapy was started into cohorts aged 35, 45, and 55 years. Outcomes were estimated in terms of life-years (LYs) and quality-adjusted LYs (QALYs). ICER calculations were done from a societal perspective. We also estimated the budget impact, which included the additional public medical expenditures that would cover all subsequent changes after the additional cost of choosing third-generation regimens if G-CSF were approved for use in third-generation regimens for breast cancer. Costs were calculated using prescription drug prices as of 2006. Results: Estimated ICER values for TAC with prophylactic G-CSF were ¥956,471/LY and ¥919,443/ QALY for age 35 years, ¥1,125,540/LY and ¥1,078,967/QALY for age 45 years, and ¥1,302,746/LY and ¥1,224,896/QALY for age 55 years. Values for DD AC-T q2wk with prophylactic G-CSF were ¥291,931/LY and ¥311,232/QALY for age 35 years, ¥357,354/LY and ¥380,148/QALY for age 45 years, and ¥377,011/LY and ¥399,761/QALY for age 55 years. TAC or DD AC-T q2wk with prophylactic G-CSF would yield cost savings compared with the respective second-generation regimens if the per-dose cost of G-CSF decreased from ¥31,355 to ¥15,700 (TAC) or to ¥24,300 (DD AC-T). The estimated budget impact is ¥9.5 to ¥11.0 billion per year for the next 5 years. Conclusion: According to a Markov model for patients with high-risk early breast cancer in Japan, third-generation regimens with prophylactic G-CSF will yield improved outcomes at a greater cost, but estimated ICER values are still less than the suggested cost-effectiveness threshold value of ¥6 million (US $60,000, assuming US $1 = ¥100) for a gain of 1 QALY.

Impact of breast cancer chemotherapy on ovarian reserve: a prospective observational analysis by menstrual history and ovarian reserve markers

To determine whether addition of taxanes to anthracycline and cyclophosphamide regimens impact ovarian function as assessed by menstrual history and ovarian reserve markers. Prospective observational analysis. Large university fertility center. Forty-five women with a history of breast cancer of stages I-IIIA who either received anthracycline, cyclophosphamide, and paclitaxel (ACT) or received anthracycline with cyclophosphamide (AC). Menstrual histories were obtained at 6 months and at a mean of 28 months after chemotherapy. Early follicular phase FSH and E(2) samples were obtained at the second follow-up. Incidence of amenorrhea and abnormal laboratory values. There was no statistically significant difference in the rates of amenorrhea at 6 months after chemotherapy (AC group, 41.7%; ACT group, 29%). At the second follow-up, a mean of 28 months after chemotherapy, there was a trend toward higher amenorrhea in the ACT patients (35.7%, vs. 9.1% in the AC group). When the ovarian markers were included, an additional eight menstruating patients were identified with abnormally elevated FSH or E(2) levels. We found no significant long- or short-term impact of taxanes on rates of amenorrhea. Future studies on the reproductive effects of chemotherapeutic agents should incorporate ovarian reserve markers, because menstrual history alone may underestimate the impact of these cytotoxic agents.

Up-Front Tandem High-Dose Chemotherapy Compared With Standard Chemotherapy With Doxorubicin and Paclitaxel in Metastatic Breast Cancer: Results of a Randomized Trial

The role of high-dose chemotherapy (HDCT) in metastatic breast cancer remains controversial. Trials with late intensification HDCT have failed to show an advantage in overall survival. This study was initiated to compare up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer. Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates. A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity. This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects.

Up front tandem high-dose chemotherapy (HD) compared to standard chemotherapy with doxorubicin and paclitaxel (AT) in metastatic breast cancer (MBC): Final results of a randomized trial

641 Background: Trials with late intensification HD have failed to show an advantage in overall survival (OS) for patients with MBC. This trial was initiated to compare up front tandem HD with cyclophosphamide, mitoxantrone and etoposide or standard-dose therapy with AT in patients with MBC. Methods: Between 04/98 and 02/02, 93 pts below 60 ys of age without prior chemotherapy for metastatic disease were randomly assigned to 6–9 courses of AT q3 wks or double HD with PBSCT. G-CSF-mobilized stem cells were collected before and after the 1st course of HD. HD was repeated after 6 weeks. Pts were stratified by menopausal status and hormone receptor (HR) status. HR positive pts received in addition tamoxifen. The primary objective was to compare complete response rates (CR). Results: Due to inadequate accrual the trial was terminated early in 03/02.Treatment groups (HD 48 pts, AT 45 pts) were well balanced for baseline characteristics (median age 49.7 ys, range 27–60; visceral metastases 87.1%; HR+ 71.0%; premenopausal 40.9%). Intent-to-treat (ITT) objective response rate (RR) was 66.7% for HD vs 64.4% for AT (p=0.82). Per protocol (PP) analysis showed 78.0% RR for HD and 64.4% for AT (p=0.26). There was no significant difference in CR (ITT: HD 12.5% vs AT 11.1%; PP: HD 14.6% vs AT 11.1%). After a median follow-up of 22.5 mths, 75 pts have progressed (HD 36, AT 39) and 66 pts have died (HD 34, AT 32). ITT analysis showed no significant difference in median TTP (HD 11.1 mths, AT 10.6 mths; p=0.39), duration of response (DR) (HD 13.9 mths, AT 14.3 mths; p=0.98), treatment-free interval (HD 9.7 mths, AT 6.6 mths; p=0.24) and OS (HD 26.9 mths, AT 23,4 mths; p=0.60). As expected, HD was associated with significantly more grade 3/4 myelosuppression, nausea/vomiting, infection and stomatitis, but less neuropathy than AT. Conclusions: In contrast to our previous analysis (Schmid, ASCO 2002), there are no significant differences in CR, RR, TTP, DR and OS between HD and AT. HD was associated with more acute adverse effects. No significant financial relationships to disclose.

Up front tandem high-dose chemotherapy (HD) compared to standard chemotherapy with doxorubicin and paclitaxel (AT) in metastatic breast cancer (MBC): Final results of a randomized trial

641 Background: Trials with late intensification HD have failed to show an advantage in overall survival (OS) for patients with MBC. This trial was initiated to compare up front tandem HD with cyclophosphamide, mitoxantrone and etoposide or standard-dose therapy with AT in patients with MBC. Methods: Between 04/98 and 02/02, 93 pts below 60 ys of age without prior chemotherapy for metastatic disease were randomly assigned to 6–9 courses of AT q3 wks or double HD with PBSCT. G-CSF-mobilized stem cells were collected before and after the 1st course of HD. HD was repeated after 6 weeks. Pts were stratified by menopausal status and hormone receptor (HR) status. HR positive pts received in addition tamoxifen. The primary objective was to compare complete response rates (CR). Results: Due to inadequate accrual the trial was terminated early in 03/02.Treatment groups (HD 48 pts, AT 45 pts) were well balanced for baseline characteristics (median age 49.7 ys, range 27–60; visceral metastases 87.1%; HR+ 71.0%; premenopausal 40.9%). Intent-to-treat (ITT) objective response rate (RR) was 66.7% for HD vs 64.4% for AT (p=0.82). Per protocol (PP) analysis showed 78.0% RR for HD and 64.4% for AT (p=0.26). There was no significant difference in CR (ITT: HD 12.5% vs AT 11.1%; PP: HD 14.6% vs AT 11.1%). After a median follow-up of 22.5 mths, 75 pts have progressed (HD 36, AT 39) and 66 pts have died (HD 34, AT 32). ITT analysis showed no significant difference in median TTP (HD 11.1 mths, AT 10.6 mths; p=0.39), duration of response (DR) (HD 13.9 mths, AT 14.3 mths; p=0.98), treatment-free interval (HD 9.7 mths, AT 6.6 mths; p=0.24) and OS (HD 26.9 mths, AT 23,4 mths; p=0.60). As expected, HD was associated with significantly more grade 3/4 myelosuppression, nausea/vomiting, infection and stomatitis, but less neuropathy than AT. Conclusions: In contrast to our previous analysis (Schmid, ASCO 2002), there are no significant differences in CR, RR, TTP, DR and OS between HD and AT. HD was associated with more acute adverse effects. No significant financial relationships to disclose.

THE PERIPHERAL BLOOD LEUKOCYTE PHENOTYPE IN PATIENTS WITH BREAST CANCER: EFFECT OF DOXORUBICIN/PACLITAXEL COMBINATION CHEMOTHERAPY

Presence of functional immune system is critical for any attempt aimed at improving survival of breast cancer patients by strategies based on immune system manipulation. We evaluated by flow cytometry the phenotype of peripheral blood leukocyte of 43 breast cancer patients. In 11 patients, the phenotype was evaluated before and during the chemotherapy by combination of doxorubicin and paclitaxel (AT). Compared with controls breast cancer patients had significantly higher relative and absolute numbers of CD3−HLADR+, CD3−CD69+ and CD14+CD16−, and significantly lower percentages of CD3− and CD8−CD28+ cells. After one cycle of AT, the absolute numbers of CD3+, CD3−CD4−, CD3+CD8+ and CD8−CD28+ cells increased significantly. Present data show a presence of T-cell activation in breast cancer patients. Administration of AT may lead to an increase in functional T-cells in peripheral blood, indicating a potential for combining chemotherapy with immunotherapy in the treatment of breast cancer patients.