Regimen For Breast Cancer Patients Research Articles

Biomarker alterations with metronomic use of low-dose zoledronic acid for breast cancer patients with bone metastases and potential clinical significance

Zoledronic acid has direct and indirect antitumor effects. However, the optimal regimen for breast cancer patients remains to be determined. This study aimed to compare biomarker changes between a weekly low dose (metronomic arm) and a conventional dosage of zoledronic acid (conventional arm), and to explore correlations between biomarkers and progression-free survival (PFS). Sixty breast cancer patients with bone metastases were randomized to receive either zoledronic acid 1 mg IV weekly for 4 doses or a single dose of zoledronic acid 4 mg IV. Administration of other treatments was delayed for 1 month. Serial blood samples were collected on days 1, 15, 29, and at 3 months. Serum VEGF alteration was the primary endpoint. Compared to the conventional arm, the metronomic arm resulted in a significantly greater reduction in serum levels of VEGF and N-telopeptide of type I collagen (NTx) over time during the first month of treatment. Serum CA 15-3 level stabilized over time in the metronomic arm, but increased in the conventional arm. Independent prognostic factors for PFS included chemotherapy received (HR, 8.042; P = 0.000), estrogen receptor status (HR, 2.837; P = 0.020), VEGF levels at 3 months after intervention (HR, 2.026; P = 0.045), and baseline NTx (HR, 1.051; P = 0.001). Metronomic low-dose zoledronic acid is more effective than the conventional regimen and generates sustained reductions in circulating VEGF and NTx levels, as well as stabilization of serum CA 15-3 levels (ClinicalTrials.gov number, NCT00524849).

Abstract 1767: Gene expression signatures as predictors of chemotherapeutic response in breast cancer

Abstract The purpose of this study is to evaluate a novel 22-gene signature as a predictor of response to chemotherapy in breast cancer. The extent of residual viable tumor following chemotherapy is the most important predictor of long-term outcome in breast cancer. It is essential to identify patients who will not respond to chemotherapy to avoid ineffective therapies as well as unnecessary side effects. The rate of complete pathologic response to chemotherapy is relatively low, ranging from 3% to 27% of patients. Much work has been performed to predict chemotherapy responsiveness, but, as of yet, no test is effective and widely used in the clinic. Gene expression signatures are a multifaceted approach to characterizing disease states. They offer the potential to tailor a chemotherapy regimen to an individual patient. Here we compare the ability of multiple gene signatures, including the 70-gene prognostic signature (MammaPrint) and the 22-gene signature among others, to accurately predict response to multiple different regimens of primary chemotherapy in breast cancer. Predictive ability is compared in independent microarray datasets totaling approximately 157 breast cancer patients treated with primary chemotherapy. Sensitivity, specificity, and overall accuracy were evaluated by receiver operating characteristics (ROC) graphs, a technique for visualizing, organizing, and selecting classifiers based on their performance. Results show that the 22-gene signature accurately predicts response to multiple primary chemotherapies (p<0.05). Importantly, the 22-gene signature outperformed other signatures with highly significant p-values in all datasets tested. This signature potentially represents a clinically useful method to select a personalized chemotherapy regimen for breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1767.

Mitochondrial DNA Content as a Potential Marker to Predict Response to Anthracycline in Breast Cancer Patients

Mutations and reduced mitochondrial DNA (mtDNA) content are commonly observed in breast cancer, yet their functional significance is not clear. This study aimed to determine whether the mtDNA content in breast cancer plays an important role in modulating the response to anthracycline treatment in vivo and in vitro. The mtDNA content in tumor cells was analyzed using quantitative polymerase chain reaction in 60 Taiwanese breast cancer patients to correlate with their survival. In addition, human breast cancer MDA-MB-231 cells were treated with ethidium bromide to decrease mtDNA copy number. Cell survival was determined by trypan blue exclusion assay and intracellular reactive oxygen species (ROS) were determined by flow cytometry. After an anthracycline-based regimen, the disease-free survival of patients with higher mtDNA content breast cancer was significantly lower than that of patients with lower mtDNA content breast cancer (p = 0.03). Moreover, the MDA-MB-231 cells with low copies of mtDNA had higher sensitivity to doxorubicin treatment and increased ROS production when compared with higher mtDNA parental cells. Our results suggest that the level of mtDNA copy number in breast cancer may be a potential biomarker for prediction of the response to anthracycline-containing regimens in breast cancer patients.

Predicting pathological response to neoadjuvant chemotherapy in breast cancer with quantitative 1H MR spectroscopy using the external standard method

To assess the efficacy of quantitative (1)H MR spectroscopy (MRS) using the external standard method to predict the pathological response to neoadjuvant chemotherapy with an anthracycline-based regimen in breast cancer patients. Sixteen patients with breast cancer were included. Tumor response to chemotherapy was evaluated after the second cycle using MRI and MRS. Final histopathology following surgery after four cycles of chemotherapy served as reference. The average normalized choline (Cho) signal was 1.2 (range, 0.40 to 2.8). There were no significant differences in the baseline tumor size and normalized Cho signals between the pathological responders (n = 8) and nonresponders (n = 8). The reduction rates of the normalized Cho signal were statistically significantly different between the pathological responders and nonresponders (P = 0.004), whereas the reduction rates of the lesion size were not significantly different between the two groups. When 40-50% of the reduction rates of the normalized Cho was chosen as the cutoff value, the positive and negative predictive values of MRS were 89% (8/9) and 100% (7/7), respectively. The changes in Cho after the second cycle of chemotherapy as determined by quantitative MRS may be more sensitive than changes in the tumor size to predict the pathological response.

Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial

Background:Breast cancer becomes lethal when visceral metastases develop. At this stage, anti-cancer treatments aim at relieving symptoms and delaying death without resulting in additional toxicity. On the basis of their differential anti-oxidant defence level, tumour cells can be made more sensitive to chemotherapy than non-tumour cells when membrane lipids are enriched with docosahexaenoic acid (DHA), a peroxidisable and oxidative-stress-inducing lipid of marine origin.Methods:This open-label single-arm phase II study evaluated the safety and efficacy (response rate), as primary end points, of the addition of 1.8 g DHA daily to an anthracycline-based chemotherapy (FEC) regimen in breast cancer patients (n=25) with rapidly progressing visceral metastases. The secondary end points were time to progression (TTP) and overall survival (OS).Results:The objective response rate was 44%. With a mean follow-up time of 31 months (range 2–96 months), the median TTP was 6 months. Median OS was 22 months and reached 34 months in the sub-population of patients (n=12) with the highest plasma DHA incorporation. The most common grade 3 or 4 toxicity was neutropaenia (80%).Conclusion:DHA during chemotherapy was devoid of adverse side effects and can improve the outcome of chemotherapy when highly incorporated. DHA has a potential to specifically chemosensitise tumours.

Clinical Studies on Hormonal Status in Breast Cancer and its Impact on Quality of Life(QOL)

Breast cancer is a steroid hormone–dependent tumor. Stratification of patients according to hormone (ER/ PR) receptor status and nodal metastasis is of great therapeutic importance. In this investigation, we could enroll 79 pre and post-menopausal breast cancer patients voluntarily. We classified these cases into four categories of the combinations of ER/PR positive, negative and mixed statuses. Their hormone receptor status as determined by immunohistochemistry correlated with therapy regimens like chemotherapy, hormone therapy and QOL responses. We found that in ER+/PR- and ER-/PR- tumors were more frequent in postmenopausal women than ER+/PR+ tumors. The ER+/PR- tumors were larger than ER+/PR+ tumors. In addition, 21.51% of ER+/PR- and 17.72% of ER-/PR- patients had four or more axillary nodes involved with tumors compared to patients with ER+/PR+ tumors (7.59%). Postmenopausal women with ER+/PR- and ER-/PR- who received adjuvant hormonal therapy or combination of chemo drugs like Cyclophosphamide, Adriamycin, 5-FU (FAC) and Cyclophosphamide, Alurubicin, 5-FU (CAF) showed good response than premenopausal women. Forty patients receiving tamoxifen (hormone therapy) along with other chemo- drugs also showed good response. Tamoxifen induced substantial tumor regression and increased disease free survival. It is concluded that hormone receptor status is important in deciding the choice of treatment for all subgroups and influenced the QOL. Another significant observation was that the frequency of ER+/PR- and ER-/PR- tumors was higher in this study group compared to ER+/PR+ tumors. This is the first report from south Indian population indicating the importance of hormonal status in deciding therapeutic regimens in breast cancer patients affecting their QOL.

Does chemotherapy-induced neutropaenia result in a postponement of adjuvant or neoadjuvant regimens in breast cancer patients? Results of a retrospective analysis

In 2005, 224 patients received adjuvant/neoadjuvant chemotherapy for breast cancer in a single institution according to daily practices. Regimens consisted of epirubicin-based chemotherapy (FEC100, four or six cycles), or three cycles of FEC100 followed by three cycles of docetaxel. An absolute blood count was carried out every 3 weeks, 1–3 days before planned chemotherapy cycle. Overall, 1238 cycles were delivered. An absolute neutrophil count (ANC) <1.5 × 109 l−1 before planned chemotherapy was found in 171 cycles. Of these, 130 cycles (76%) were delivered as planned regardless of whether ANC levels recovered, and 41 (24%) were delayed. None of these patients developed a febrile neutropaenia. Haematopoietic support (granulocyte colony-stimulating factor (G-CSF)) was required in 12 cycles. We found that the majority of patients with an ANC <1.5 × 109 l−1 before planned chemotherapy received planned doses, without complications and need for G-CSF.

Selection of a phase 3 dose regimen for denosumab based on pharmacokinetic (PK), pharmacodynamic (PD), and safety data from multiple subcutaneous (SC) dosing regimens in breast cancer patients (pts) with bone metastases (BM)

3086 Background: Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation, function, and survival. PK and PD of denosumab (AMG 162), a fully human monoclonal IgG2 antibody to RANKL, from a randomized, double-blind, active-controlled, multidose study in breast cancer pts with BM were evaluated and modeled to assist in dose selection for the pivotal phase 3 study. Methods: Five dosing cohorts (∼40/cohort) received 30-, 120-, or 180-mg denosumab SC Q4W; 60- or 180-mg denosumab SC Q12W. Data through 12 weeks were used for PK/PD modeling and dose decisions. Validated methods were used to quantify all serum and urine analytes. The bone resorption marker uNTx (reported as uNTx/Cr ratio) was used as the PD endpoint, and population PK/PD model parameters were estimated using nonlinear mixed effects modeling methods (NONMEM). A combination of PK/PD trial simulation (TS), clinical chemistries, and safety profiles was utilized for phase 3 dose selection. Results: Exposure to denosumab increased approximately dose-proportionally for both the Q4W and Q12W schedules, and accumulation (3rd vs 1st Q4W dose) ranged from 2.37- to 2.56-fold. The population typical half-maximal inhibitory concentration (IC50) for denosumab to affect uNTx and the typical maximum suppression were estimated to be 12.2 ng/mL and 77.8%, respectively. While denosumab in all cohorts caused rapid and sustained suppression of uNTx from baseline (&gt;60%), TS showed that for a dose of 120 mg Q4W, 97% of subjects would be expected to attain denosumab serum concentrations above their individual IC90 at steady state. TS did not suggest that higher doses (180 mg Q4W) would result in further uNTx suppression, and more asymptomatic decreases in calcium were noted in pts dosed above 120 mg Q4W. Conclusions: The PK and PD of denosumab in pts with BM are consistent with those in other pt populations and demonstrate rapid and substantial suppression of uNTx. Population PK/PD analysis and TS suggests a dose of 120mg Q4W is appropriate for use in a phase 3 program in this study population. [Table: see text]

Therapy prediction in a breast cancer primary systemic chemotherapy (PST) study applying docetaxel/epirubicin/cyclophosphamide (TEC) by gene expression profiling

10049 Background: Currently there are no tests to assist in selecting the optimal PST regimen for breast cancer patients. Primary study goals of this prospective, single-armed multicentric investigation are pathologically confirmed tumor response and the rate of breast conserving therapy (BCT). Secondary goals are to find histopathologic and gene profiling patterns best correlating with tumor remission in a taxane- anthracycline based neoadjuvant setting as well as to evaluate cytostatic toxicity and quality of life. Methods: In this phase II study of totally 40 eligible patients with invasive breast cancer Human Genome Survey Microarray (HGSM) expression profiling is performed on jet-biopsy sample basis. The protocol was elaborated for the treatment of patients suffering from a primary tumor with 6 cycles of TEC (3-weekly) prior to the surgical treatment. The selection of predictor genes was done with BRB-ArrayTools Version 3.3 using a model based on the Compound Covariate Predictor, Diagonal Linear Discriminant Analysis, Nearest Neighbor Classification, and Support Vector Machines with linear kernel.We estimated the prediction error of each model using leave-one-out cross-validation (LOOCV) as described by Simon R. 2000 random permutations were used. Clustering was done using Cluster 3.0 and Java TreeView 1.0.12. Results: Tumor response (pCR, pPR) of more than 70% can be achieved using neoadjuvant TEC-regimen. 22% pCR (ypT0; ypN0) and 90% BCT in this study are comparable with data of other published PST trials. Preliminary expression profiling results reveal a subset of 148 genes that classifies all patients with a complete remission (pCR), in one cluster with a very closely related gene expression pattern (n=5; PPV = 100%). Furthermore 10 patients defined as responders due to selected MIB1-expression based criteria (expressing cells in the residual tumor ≤ 5% and a Δ MIB1-expression ≥ 20%) can be correctly classified in 9 of 10 cases. Comparable separation of the groups could not be achieved by established tumor factors. Conclusions: HGSM expression profiling is promising to have the potential to figure out genes that are related to chemotherapy response, especially in PST. No significant financial relationships to disclose.

A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer

BackgroundMany emerging new drugs have recently been trialled for treatment of early and advanced breast cancer. Among these new agents paclitaxel and gemcitabine play a crucial role, mostly in patients with relapsed and metastatic disease after failure of chemotherapy with antracyclines.MethodsA phase II study was started in order to evaluate the activity and toxicity of a combination of paclitaxel and gemcitabine in a biweekly schedule on metastatic breast cancer patients previously treated with antracyclines.ResultsTwenty-five patients received paclitaxel (150 mg/mq) by 3-hours infusion, followed by gemcitabine (2000 mg/mq) given as a 60 min i.v. infusion (day 1–14) for a maximum of eight cycles. In all patients treatment was evaluated for toxicity and efficacy; four patients (16%) achieved a complete response, 12 (48%) a partial response giving an overall objective response rate of 64%. Stable disease was documented in 5 patients (20%) and progressive disease occurred in 4 patients (16%).ConclusionThe schedule of treatment was safe and tolerable from a haematological and non-haematological point of view. These data confirm that the combination of gemcitabine and paclitaxel on a biweekly basis is an effective and well-tolerated regimen in breast cancer patients with prior therapeutic exposure to antracyclines.

Primär systemische Therapie des primären Mammakarzinom mit einer Kombination aus Docetaxel/Epirubicin/Cyclophosphamid (TEC) und begleitender Genexpressionsanalyse mittels cDNA micro array Analysen

Background: Currently there are no tests to assist in selecting the optimal preoperative chemotherapy (Primary Systemic Therapy, PST) regimens for breast cancer patients. Primary study goals of this prospective, single-armed multicentric investigation are pathologically confirmed tumour response and the rate of breast conserving therapy (BCT). Secondary study goals are to find histopathologic and gene profiling patterns best correlating with tumour remission in a taxane- anthracycline based neoadjuvant setting as well as to evaluate cytostatic toxicity and quality of life.

Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients

The aims of the study were (a) to characterise the pharmacokinetics (PK), including inter-individual variability (IIV) and inter-occasion variability (IOV) as well as covariate relationships and (b) to characterise the relationship between the PK and the haematological toxicity of the component drugs of the fluorouracil (5-FU)-epirubicin (EPI)-cyclophosphamide (CP) regimen in breast cancer patients. Data from 140 breast cancer patients, either within one of different studies or in routine clinical management, were included in the analyses. The patients were all treated with the fluorouracil-epirubicin-cyclophosphamide (FEC) regimen every third week for 3-12 courses, either in standard doses, i.e. 600/60/600 mg/m(2) of 5-FU, EPI and CP, respectively, or according to a dose escalation/reduction protocol (tailored dosing). PK data were available from 84 of the patients, whereas time-courses of haematological toxicity were available from 87 patients. The data analysis was carried out using mixed effects models within the NONMEM program. The PK of 5-FU, EPI and 4-hydroxy-cyclophosphamide (4-OHCP), the active metabolite of CP, were described with a one-compartment model with saturable elimination, a three-compartment linear model and a two-compartment linear model, respectively. No clinical significant correlation was found between PK across drugs. The unexplained variability in clearance was found to be less within patients, between courses (inter-occasion variability, IOV) than between patients (inter-individual variability, IIV) for EPI and 5-FU. For 4-OHCP, however, the IIV diminished by approximately 45% when significant covariates were included and the final population model predicts an IIV that is equal to IOV. Significant covariates for elimination capacity parameters were serum albumin (5-FU, EPI and 4-OHCP), creatinine clearance (5-FU), bilirubin (EPI) and body surface area (BSA) (4-OHCP). Elimination capacity of 5-FU and EPI was not related to BSA and for none of the studied drugs did body weight explain the PK variability. The time-course of haematological toxicity after treatment was well described by a semi-physiological model that assumes additive haematological toxicity between CP and EPI with negligible contribution from 5-FU. The influence of G-CSF could be incorporated into the model in a mechanistic manner as shortening the maturation time to 43% of the normal duration and increasing the mitotic activity to 269% of normal activity. The models presented describe the dose-concentration-toxicity relationships for the FEC therapy and may provide a basis for implementation and comparison of different individualisation strategies based on covariates, therapeutic drug monitoring and/or pharmacodynamic (PD) feedback. The PD model extends on previous semi-mechanistic models in that it also takes G-CSF administration into account.

Estrogen receptor as the predictive factor for response to chemotherapy in breast cancer

It has generally been accepted that breast cancer (BC) cells are equally responsive to chemotherapy (CHT) irrespective of ER status. However, subset analyses of disease outcome in recently reported trials on neoadjuvant and adjuvant CHT brought new information about the issue. The subject of this paper is to review these data and to communicate our own results. NSABP B27 was designed to evaluate if adding of docetaxel (D) to conventional neoadjuvant doxorubicin-cyclophosphamide (AC) CHT improves the clinical response rate (cRR) and pathological RR (pRR) in BC patients treated with 4 AC cycles only. Although the adding of D to AC C.T significantly improved RR in both ER-negative and ER-positive BC patients, the pCR was significantly higher in ER-negative than in ER-positive group (16.7% vs. 8.3%) irrespective which regimen was used. ECTO trial and several neoadjuvant studies confirmed the significantly inferior RR to neoadjuvant C.T in ER-positive compared to ER-negative BC patients. Three large randomized Cancer and Leukemia Group B (CALGB) studies (CALGB 8541, CALGB 9344, and CALGB 9741) compared the efficacy of different adjuvant anthracycline-containing or anthracycline/taxane-containing regimens in BC patients. The absolute benefit in 5-year disease-free survival in ER-negative and ER-positive BC patients treated with adjuvant C.T were 22.8% and 7.0%, while corresponding absolute benefits in overall survival were 16.7% and 4.0%. The concept of equal sensitivity of ER-negative and ER-positive BC to CHT has been changing. The future task is to find BC patients with ER-positive BC with no benefit from CHT in whom endocrine therapy is the therapy of first choice. .

Gemcitabine plus cisplatin (GC): A salvage regimen for breast cancer patients who failed anthracycline and/or taxanes

757 Background: GC has demonstrated safety and efficacy in both heavily and minimally pretreated advanced breast cancer (BC) with response rate from 29%–63% (median 46%). All of studies had different schedule and dose of GC. We evaluated the activity and toxicity of another GC regimen in BC patients who failed chemotherapy with anthracycline and/or Taxanes as adjuvant or neoadjuvant or primary therapy. Methods: 30 BC patients who failed Anthracycline and/or Taxanes-based therapy, had measurable disease and a performance status 0–2 were recruited, of whom 29 were evaluable for response. Patients received Gemcitabine 1000 mg/m2 over 1-hour infusion on day 1 and 8 and Cisplatin 75 mg/m2 over 2-hour infusion on day 1 every 3 weeks up to 6 cycles or until disease progression or unacceptable toxicity. Results: After a median follow up of 6 month (range: 2–16). Of 30 patients, there were 29 female and 1 male, median age 45 years (24–65). 22 of patients (73%) were metastatic breast cancer, 6 (20%) were locally advanced breast cancer, 2 (7%) were locoregional recurrent. Prior treatment included up to 3 prior regimens: anthracyclines (27 patients), taxane (11 patients). A total of 106 cycles were administered (median 4 cycles per patients). Overall response rate was 51%, 1 achieved complete response (3%), 14 (48%) had partial response. There were 10 (35%) stable disease and 4 (14%) progression disease. The median time to disease progression was 8.1 months (2–10.8). The median time to response was 4 weeks (3–15). The median survival time was 11.8 months. Myelosuppresion was the most frequent side effect; grade 3/4 thrombocytopenia occurred in 17%, grade 3/4 neutropenia in 37%. Grade 3 Nausea-vomiting was found in 12% of cycles. There were no treatment related death. Treatment delays or omission due to hematotoxicity and renal toxicity in 7% and 6% of cycles. Conclusions: This schedule of GC proved clinical efficacy in salvage treatment in anthracycline and/or taxane pretreated breast cancer with manageable toxicity. No significant financial relationships to disclose.

Model Describing the Relationship Between Pharmacokinetics and Hematologic Toxicity of the Epirubicin-Docetaxel Regimen in Breast Cancer Patients

The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients. Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m(2). Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m(2)) or reduced (minimum, 40/50 mg/m(2)). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment. In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data. The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.

Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1.

Intrinsic or acquired resistance to chemotherapy is responsible for failure of current treatment regimens in breast cancer patients. The Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug-resistant tumor phenotype. In human breast cancer, overexpression and nuclear localization of YB-1 is associated with upregulation of P-glycoprotein. In our pilot study, we analyzed the clinical relevance of YB-1 expression in breast cancer (n = 83) after a median follow-up of 61 months and compared it with tumor-biologic factors already used for clinical risk-group discrimination, i.e., HER2, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1). High YB-1 expression in tumor tissue and surrounding benign breast epithelial cells was significantly associated with poor patient outcome. In patients who received postoperative chemotherapy, the 5-year relapse rate was 66% in patients with high YB-1 expression. In contrast, in patients with low YB-1 expressions, no relapse has been observed so far. YB-1 expression thus indicates clinical drug resistance in breast cancer. Moreover, YB-1 correlates with breast cancer aggressiveness: in patients not treated with postoperative chemotherapy, those with low YB-1 expression are still free of disease, whereas the 5-year relapse rate in those with high YB-1 was 30%. There was no significant correlation between YB-1 expression and either HER2 expression or uPA and PAI-1 levels. Risk-group assessment achieved by YB-1 differed significantly from that by HER2 or uPA/PAI-1. In conclusion, YB-1 demonstrated prognostic and predictive significance in breast cancer by identifying high-risk patients in both the presence and absence of postoperative chemotherapy, independent of tumor-biologic factors currently available for clinical decision making.

Frequent Dose Delays and Growth Factor Requirements with the Sequential Doxorubicin-CMF Schedule

Doxorubicin for four cycles plus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) for eight cycles is an effective adjuvant regimen for breast cancer patients with more than three involved axillary lymph nodes. We reviewed the incidence of dose delays and growth factor requirements when this regimen is administered to patients receiving concurrent irradiation. Thirty-six patients with more than three involved axillary lymph nodes were treated with the sequential regimen doxorubicin-CMF and irradiation. Patients with two or more dose delays G-CSF treatment. Seventy-five percent of the patients required dose delays for day-22 neutropenia, and growth factors were needed for half of the patients in order to maintain a dose intensity of 0.940. The first delayed cycle occurred in 74% of the patients while receiving concomitant chemoradiotherapy. Frequent dose dealys were required when the sequential regimen doxorubicin-CMF was administered along with radiotherapy. Growth factors are needed to maintain dose intensity similar to that achieved in the original trial.

Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients.

The aim of this study was to investigate the covariance between the pharmacokinetics of the three components of the FEC regimen, epirubicin (EPI), fluorouracil (5-FU), and the cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP), in breast cancer patients. Data from 21 women were collected over a total of 35 cycles. 5-FU (300 to 600 mg/m2) and CP (300 to 600 mg/m2) were administered as bolus injections, whereas EPI (15 to 60 mg/m2) was administered either as a bolus injection or as an infusion. The pharmacokinetics of the component drugs were monitored using a limited sampling scheme. Population pharmacokinetic models for each of the three drugs were developed using the program NONMEM. The data for 5-FU were best described by a one-compartment model with nonlinear elimination, where the maximal rate of elimination (Vmax) and the concentration at which the elimination was half-maximal (Km) were 105 mg/L.h and 27 mg/L, respectively. EPI concentration-time profiles showed a triexponential decline, with a mean terminal half-life of 24 hours and a clearance (CL) of 59 L/h. The elimination of 4-OHCP was monoexponential, with a mean half-life of 7 hours. The interindividual coefficients of variation (CVs) in CL were 30%, 22%, and 41% for 5-FU, EPI, and 4-OHCP, respectively. The corresponding values for intrapatient course-to-course variability in CL were 11%, 8%, and 27%. No significant correlation in any of the pharmacokinetic parameters between the drugs was found. Individualization of dosing of the FEC regimen using therapeutic drug monitoring and attempts to find concentration-response relationships may be successful, but requires that the exposure of all three drugs is considered simultaneously.

16 P Chemotherapy induced emesis. management of early and delayed emesis in milder emetogenic regimens

The objective of the study was to examine the problem of control of nausea and vomiting induced by non-cisplatin cyclophosphamide-based chemotherapic regimens in breast cancer patients. This was a randomized double-blind, parallel-group and placebo controlled study comparing the efficacy of four antiemetic therapeutic regimens (A:Ondansetron for 3 days; B:Ondasetron plus Metoclopramide; C:Granisetron given a single dosis and D:Ondansetron given in a single dosis) in breast cancer patients receiving Cyclophosphamide, Methotrexate and 5-Fluoracil (CMF) regimen (174 cycles) and Cyclophosphamide, 4-Epiadryamicin and 5-Fluoracil (FEC) regimen (132 cycles). Both, number of emetic episodies (early and delayed emesis) and quality of life were evaluated. In patients receiving CMF there were no differences between regimens A, B and C in controlling early emesis. The single dose Ondansetron regimen (D) showed the worst resuts (p=0.003). Delayed emesis was best controlled by the “3 days-regimens” (A and B). In patients administered a FEC treatment, the antiemetic efficacy was superior for the single Granisetron regimen (C) if early emesis was considered. Moreover, efficacy of single Granisetron dosis (C) was similar to the 3-days Ondansetron regimen (A) in controlling delayed emesis after FEC treatment. The single Ondansetron regimen showed again the worst results (p=0.007). Despite different antiemetic schedules, nausea and emesis are significant problems in patients receiving cyclophosphamide-based chemotherapy.

Oral ondansetron in the prophylaxis of nausea and vomiting induced by cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in women with breast cancer. Results of a prospective, randomized, double-blind, placebo-controlled study

The combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) is a widely used chemotherapy regimen in breast cancer patients. However, the control of nausea and vomiting induced by oral CMF is a rarely examined problem. Therefore we felt a randomized, placebo controlled study justified in order to improve currently available antiemetic therapy. In a randomised double-blind trial ondansetron given orally, 8 mg three times a day for 15 days, was compared with placebo in 82 breast cancer patients receiving chemotherapy with CMF (cyclophosphamide 100 mg/m2 orally days 1-14, methotrexate 40 mg/m2 i.v. days 1 and 8 and 5-fluorouracil 600 mg/m2 i.v. days 1 and 8). The patients recorded nausea and the number of vomits and retches daily on diary cards. Forty-two patients received ondansetron and 40 received placebo. Significantly more patients who received ondansetron experienced neither vomiting nor retching (emesis) compared to those receiving placebo over a 15 day treatment period (60% vs. 35%, p = 0.027). The difference, with 95% confidence limits, was estimated at 25 (4.45%). Furthermore, there was a trend in favour of ondansetron in the control of nausea. Ondansetron was well tolerated, with 25 patients (59%) reporting at least 1 adverse event compared to 18 patients (45%) receiving placebo (p = 0.191). The results indicate that ondansetron given orally for 15 days is safe and effective in the control of emesis induced by CMF. It is however too early to recommend ondansetron as standard antiemetic therapy for oral CMF, as the treatment of nausea and vomiting in this setting has not been studied thoroughly enough.