The Endocrine Treatment Landscape for Patients with HR+ HER2- Early-stage Breast Cancer in Germany Before the Introduction of CDK4/6 Inhibitor Therapy - A Real-World Analysis.

Introduction: While premenopausal patients with HR+ HER2- early breast cancer are treated with tamoxifen +/- ovarian suppression with a GnRH analog or an aromatase inhibitor (AI) + GnRH, the majority of postmenopausal women receive an AI due to its higher efficacy compared to tamoxifen. As the introduction of CDK4/6 inhibitors into the treatment of early-stage breast cancer with a higher risk of recurrence will probably result in a shift in the endocrine treatment landscape, the question is what treatment did potential candidates for CDK4/6 inhibitors in Germany receive before CDK4/6 inhibitors were available. Patients and Methods: As part of a retrospective multicenter analysis, anonymized data were collected of patients with HR+ HER2- early-stage breast cancer who received endocrine therapy in the period between 10/2021 and 03/2022. Potential candidates for CDK4/6 inhibitor treatment were classified into different risk cohorts using the inclusion criteria of the NATALEE and monarchE trials. Results: The data of 238 patients from 29 different centers were analyzed. While 20.6% of patients met the monarchE criteria, the subgroup which met the NATALEE inclusion criteria consisted of 46.2% of patients. 53.8% of patients did not meet the inclusion criteria for either the NATALEE or the monarchE trial. More than half of the patients did not receive chemotherapy. 28.6% of patients in the whole cohort were premenopausal. 67.6% of premenopausal women received neo-/adjuvant chemotherapy. 61.8% of premenopausal patients received tamoxifen as adjuvant endocrine therapy, 19.1% received an AI + GnRH and 10.3% were treated with tamoxifen + GnRH. Conclusion: Despite the high percentage of premenopausal patients who received aggressive treatment in the form of chemotherapy, only one third of premenopausal patients received GnRH in addition to their standard endocrine therapy. Studies carried out at a later point in time and registry studies will be necessary to see how the endocrine therapy landscape in Germany has changed following the introduction of CDK4/6 inhibitors.

Does the Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer Patients Predict the Site of First Metastasis-Results from the Adjuvant SUCCESS A Trial.

The prognostic relevance of circulating tumor cells (CTCs) in breast cancer is well established. However, little is known about the association of CTCs and site of first metastasis. In the SUCCESS A trial, 373 out of 3754 randomized high-risk breast cancer patients developed metastatic disease. CTC status was assessed by the FDA-approved CellSearch®-System (Menarini Silicon Biosystems, Bologna, Italy) in 206 of these patients before chemotherapy and additionally in 159 patients after chemotherapy. CTCs were detected in 70 (34.0%) of 206 patients before (median 2 CTCs, 1-827) and in 44 (27.7%) of 159 patients after chemotherapy (median 1 CTC, 1-124); 16 (10.1%) of 159 patients were CTC-positive at both timepoints. The site of first distant disease was bone-only, visceral-only, and other-site-only in 44 (21.4%), 60 (29.1%), and 74 (35.9%) patients, respectively, while 28 (13.6%) patients had multiple sites of first metastatic disease. Patients with CTCs at both timepoints more often showed bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs before and/or after chemotherapy (p = 0.027). In conclusion, the presence of CTCs before and after chemotherapy is associated with multiple-site or bone-only first-distant disease and may trigger intensified follow-up and perhaps further treatment.

Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer.

PURPOSE: To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS). EXPERIMENTAL DESIGN: A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes. RESULTS: One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE. CONCLUSIONS: Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

MUC1 (CA27.29) before and after Chemotherapy and Prognosis in High-Risk Early Breast Cancer Patients.

Soluble MUC1 has been discussed as a biomarker for predicting prognosis, treatment efficacy, and monitoring disease activity in breast cancer (BC) patients. Most studies in adjuvant settings have used preoperative assessment. This study, part of the SUCCESS-A trial (NCT02181101), assessed the prognostic value of soluble MUC1 before and after standard adjuvant chemotherapy. Patients with high-risk BC were treated within the SUCCESS-A trial with either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide followed by three cycles of docetaxel or three cycles of FEC followed by three cycles of docetaxel and gemcitabine. Cox regression analyses were performed to investigate the prognostic value of CA27.29 before and after chemotherapy relative to disease-free survival (DFS), along with established BC prognostic factors such as age, body mass index, tumor size, nodal status, estrogen receptor, progesterone receptor, HER2 status, and grading. Pre-chemotherapy and post-chemotherapy CA27.29 assessments were available for 2687 patients of 3754 randomized patients. Pre-chemotherapy CA27.29 assessment was associated with DFS in addition to established prognostic factors. It had no prognostic value in node-negative patients, but there was a clear association in node-positive patients. Post-chemotherapy CA27.29 assessment did not add any prognostic value, either on its own or in addition to pre-chemotherapy CA27.29 assessment.

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: Bisphosphonate treatment in patients with early breast cancer has become part of care, but the optimal treatment duration is still unclear. OBJECTIVE: To compare 2 vs 5 years of zoledronate treatment following adjuvant chemotherapy in patients with early breast cancer. DESIGN, SETTING, AND PARTICIPANTS: The SUCCESS A phase 3 multicenter randomized open-label clinical trial with a 2 × 2 factorial design enrolled 3754 patients from September 21, 2005, to March 12, 2007 (last patient out, May 7, 2014). Final data analysis was conducted from September 2019 to October 2020. In 250 German study centers, patients were eligible for participation in the SUCCESS A trial if they had either node-positive or high-risk node-negative (defined as at least 1 of the following: tumor size ≥ pT2, histologic grade 3, negative hormone receptor status, or age ≤35 years) primary invasive breast cancer. INTERVENTIONS: Patients were first randomized to adjuvant chemotherapy with 3 cycles of fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine (not presented in this report). After chemotherapy, patients underwent a second randomization of 5 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years, followed by 4 mg intravenously every 6 months for 3 years) vs 2 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years). MAIN OUTCOMES AND MEASURES: The primary end point of the study was disease-free survival; secondary end points were overall survival, distant disease-free survival, and the incidence of skeletal-related adverse events. Survival times were measured from 2 years after the start of zoledronate treatment (landmark analysis). RESULTS: Overall, data on 2987 patients were available for analysis; median age was 53 (range, 21-86) years. Disease-free survival, overall survival, and distant disease-free survival did not differ significantly between the 2 treatment arms (5 vs 2 years) as shown by adjusted multivariable Cox proportional hazards regression models (disease-free survival: hazard ratio [HR], 0.97; 95% CI, 0.75-1.25; P = .81; overall survival: HR, 0.98; 95% CI, 0.67-1.42; P = .90; distant disease-free survival: HR, 0.87; 95% CI, 0.65-1.18; P = .38). Adverse events were observed more often in the 5-year (46.2%) vs 2-year (27.2%) zoledronate treatment arm, which was particularly true for the skeletal-related events bone pain (5 years, 8.3% vs 2 years, 3.7%) and arthralgia (5 years, 5.1% vs 2 years, 3.1%). CONCLUSIONS AND RELEVANCE: The results of this phase 3 randomized clinical trial indicate that extending the zoledronate treatment beyond 2 years does not improve the prognosis of high-risk patients with early breast cancer receiving chemotherapy, suggesting that the currently recommended bisphosphonate treatment duration of 3 to 5 years could be reduced. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02181101.

The effect of surgical gastric plication on obesity and diabetes mellitus type 2: a systematic review and meta-analysis.

INTRODUCTION: All the bariatric procedures have evolved greatly over the past decades and laparoscopic greater curvature plication (LGCP) is one of the quite recently introduced techniques lacking systematic evaluation. AIM: To compare and summarize the current data in the literature in regard to the effect of gastric plication on obesity and diabetes mellitus type 2. MATERIAL AND METHODS: The systematic review and meta-analysis was performed according to the PRISMA guidelines and registered at PROSPERO under the registration number CRD42018114314. The literature in English and German was searched using the MEDLINE (PubMed) and BJS databases for studies published in the last 10 years. A meta-analysis was performed focusing on the effects of this operation on weight loss, glycemia control and improvement of comorbidities. RESULTS: Mean preoperative body mass index (BMI) ranged from 34.42 to 46.3 kg/m2. Most of the patients were female. The operation time was in the range from 50 to 192.23 min. Mean follow-up was from one month to 12 years, with most studies having a follow-up of less than 2 years. The postoperative BMI ranged from 28.59 to 38, with reported excess weight loss (EWL%) in the range 20-70%. Glycated hemoglobin (HbA1c) values decreased by up to 5.1% after surgery, ranging from 5.1% to 7.5%. CONCLUSIONS: Despite the quality of most of the included studies being low, the present meta-analysis revealed that, in the short term, gastric plication is an effective measure for weight loss, while the effect on diabetes mellitus type 2 is not statistically significant.

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial.

BACKGROUND: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. METHODS: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. RESULTS: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. CONCLUSION: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. TRIAL REGISTRATION: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

Treatment patterns, health care resource use and outcomes in metastatic triple-negative breast cancer in Germany: retrospective chart review study (OBTAIN).

Background: There is limited data on the real-life situation and outcomes of patients with metastatic triple-negative breast cancer (mTNBC) in Germany. The aim of this chart review was to describe the current treatment patterns, resource use and outcomes in this patient group. Methods: Retrospective data collection in 30 gyneco-oncological sites (hospitals and office-based) across Germany between January and April 2017. Index date was defined as initiation of treatment with gemcitabine, vinorelbin, capecitabine or eribulin therapy following discontinuation of taxane and/or anthracycline therapy. Results: In the 91 evaluable patients, median time between primary diagnosis and index date was 20.9 months (range 0-187 months). Ten percent of patients had no distant metastases, while 57% had newly diagnosed metastases. Cancer stage at index date was mostly IV (82 patients). A number of 135 different regimens (monotherapy or combination therapy) were used. For first-line chemo treatment, 29 patients received monotherapy and 54 patients combination therapy. Bevacizumab and paclitaxel were also the most frequently used single substances among all therapy lines together and for first-line therapy. While taxanes were at least occasionally administered for second-line therapy, no patient received taxanes for third-line therapy. Chemotherapy modifications in terms of dose reduction or treatment interruption were rare. However, the therapy was terminated in more than two thirds of all cases. Fifty-nine patients were hospitalized at least once. For first-, second- and third-line therapy, median overall survival was 19.1/10.8/14.6 months, and median progression-free survival was 7.7/2.5/5.6 months. Conclusion: In clinical routine, a wide variety of treatment approaches is applied, while outcomes in terms of survival are poor. New treatment options are needed for this challenging tumor type.

Clinical validation of genetic variants associated with in vitro chemotherapy-related lymphoblastoid cell toxicity.

Hematotoxicity is one of the major side effects of chemotherapy. The aim of this study was to examine the association between single nucleotide polymorphisms (SNPs) and hematotoxicity in breast cancer patients in a subset of patients of the SUCCESS prospective phase III chemotherapy study. All patients (n = 1678) received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel or docetaxel/gemcitabine, depending on randomization. Germline DNA was genotyped for 246 SNPs selected from a previous genome-wide association study (GWAS) in a panel of lymphoblastoid cell lines, with gemcitabine toxicity as the phenotype. All SNPs were tested for their value in predicting grade 3 or 4 neutropenic or leukopenic events (NLEs). Their prognostic value in relation to overall survival and disease-free survival was also tested. None of the SNPs was found to be predictive for NLEs during treatment with docetaxel/gemcitabine. Two SNPs in and close to the PIGB gene significantly improved the prediction of NLEs after FEC, in addition to the factors of age and body surface area. The top SNP (rs12050587) had an odds ratio of 1.38 per minor allele (95% confidence interval, 1.17 to 1.62). No associations were identified for predicting disease-free or overall survival. Genetic variance in the PIGB gene may play a role in determining interindividual differences in relation to hematotoxicity after FEC chemotherapy.

Preference of elderly patients' to oral or intravenous chemotherapy in heavily pre-treated recurrent ovarian cancer: final results of a prospective multicenter trial.

BACKGROUND: Palliative systemic treatment in elderly gynaecological cancer patients remains a major challenge. In recurrent ovarian cancer (ROC), treosulfan an active alkylating drug showed similar cytotoxicity whether as oral (p.o.) or intravenous (i.v.) application. The aim of this innovative trial was to evaluate the preference of elderly patients (≥65 years) for p.o. or i.v. chemotherapy focusing compliance, outcome, toxicities, and geriatric aspects as secondary endpoints. METHODS: Patients with ROC had the free choice between treosulfan i.v. (7000 mg/m2 d1, q29d) or p.o. (600 mg/m2 daily d1-28, q57d). Only indecisive participants were randomized. RESULTS: Overall 123 patients with 2nd to 5th recurrence were registered and 119 received at least one cycle of chemotherapy. 85.7% preferred treosulfan i.v. and 14.3% oral, where only three patients were randomized. Main reasons for i.v. preference associated with individual expectations of lower rate of gastrointestinal disorders, higher activity and tolerability of treatment. Median of applied chemotherapies was three (range 1-12 cycles), with most common grade 3/4 toxicities thrombopenia (18.7%), leukopenia (15.7%), ascites (7.6%), bowel obstruction (6.7%), and abdominal pain (4.2%). Median time until progression/overall survival was 5.2/7.8 months (i.v.), and 5.6/10.4 months (p.o.), respectively, without significant differences in efficacy. CONCLUSIONS: Elderly patients with recurrent ovarian cancer asked and demonstrated active participation in the decision-making process of their oncological treatment and favoured predominantly the i.v. application. Treosulfan was generally well-tolerated despite comorbidities and heavy pre-treatment. Our study demonstrates that patients' preference did not influence prognosis negatively and remains important in gynaecologic oncology decision practice. EUDRACT NR: 2004-000719-25; NCT 00170690.

Prevalence of Circulating Tumor Cells After Adjuvant Chemotherapy With or Without Anthracyclines in Patients With HER2-negative, Hormone Receptor-positive Early Breast Cancer.

BACKGROUND: Use of anthracycline-based chemotherapy in patients with early breast cancer (EBC) has been well-established but is often associated with cardiotoxicity. Based on data suggesting a limited benefit of anthracyclines in human epidermal growth factor receptor 2 (HER2)-negative patients, the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C study randomized patients to either anthracycline-containing or anthracycline-free chemotherapy. Given the proven prognostic value of circulating tumor cells (CTCs) in EBC, we compared the prevalence of CTCs after chemotherapy between both treatment arms for a preliminary efficacy assessment. METHODS: The SUCCESS C trial (NCT00847444) is an open-label, phase III study randomizing 3547 patients with HER2-negative EBC to either 3 cycles of epirubicin, 5-fluorouracil, and cyclophosphamide followed by 3 cycles of docetaxel (FEC-DOC) or 6 cycles of docetaxel and cyclophosphamide (DOC-C). CTC status was prospectively evaluated in hormone receptor-positive patients at the time of last chemotherapy cycle using the US Food and Drug Administration-approved CellSearch System (Janssen Diagnostics). RESULTS: Data on CTC status were available for 1766 patients. Overall, CTCs were found in 221 (12.5%) patients. Univariate analyses revealed that presence of CTCs at time of last chemotherapy cycle was not significantly associated with tumor or patient characteristics (all P > .1). There was no significant difference with respect to presence of CTCs between patients randomized to FEC-DOC or DOC-C (11.5% vs. 13.6%; P = .18). CONCLUSIONS: The comparable prevalence of CTCs at the time of last chemotherapy cycle may indicate that anthracycline-free chemotherapy is equally effective to anthracycline-containing chemotherapy in HER2-negative, hormone receptor-positive EBC. However, efficacy data from the final survival analysis of SUCCESS C have to be awaited to confirm these preliminary findings.

21st century climate change in the European Alps--a review.

Reliable estimates of future climate change in the Alps are relevant for large parts of the European society. At the same time, the complex Alpine region poses considerable challenges to climate models, which translate to uncertainties in the climate projections. Against this background, the present study reviews the state-of-knowledge about 21st century climate change in the Alps based on existing literature and additional analyses. In particular, it explicitly considers the reliability and uncertainty of climate projections. Results show that besides Alpine temperatures, also precipitation, global radiation, relative humidity, and closely related impacts like floods, droughts, snow cover, and natural hazards will be affected by global warming. Under the A1B emission scenario, about 0.25 °C warming per decade until the mid of the 21st century and accelerated 0.36 °C warming per decade in the second half of the century is expected. Warming will probably be associated with changes in the seasonality of precipitation, global radiation, and relative humidity, and more intense precipitation extremes and flooding potential in the colder part of the year. The conditions of currently record breaking warm or hot winter or summer seasons, respectively, may become normal at the end of the 21st century, and there is indication for droughts to become more severe in the future. Snow cover is expected to drastically decrease below 1500-2000 m and natural hazards related to glacier and permafrost retreat are expected to become more frequent. Such changes in climatic parameters and related quantities will have considerable impact on ecosystems and society and will challenge their adaptive capabilities.

Relevance of Health Economics in the Medical Treatment of Breast Cancer: The View of the Professional Association of Practicing Gynecologic Oncologists e.V. (BNGO).

In this article, the position of the Professional Association of Practicing Gynecologic Oncologists e.V. (BNGO) on the health economics of medical breast cancer therapy is presented. The BNGO unites professionals and employees whose principal activity lies in highly specialized gynecologic oncology. In Germany, 139 specialists are united in 128 professional practices. According to § 12 of the Social Code, the oncological services provided by members must be 'sufficient, effective and economical; they must not exceed what is necessary'. People who are covered by statutory health insurance in Germany are entitled to sufficient benefits. Sufficient measures are measures that benefit the patient with breast cancer and have a positive effect on the course of the disease. In § 35b of the Social Code, the benefit of the patient is defined as 'improvement in health, shortening of the duration of illness, lengthening of lifespan, reduction of side effects and an improvement in the quality of life'. In the adjuvant situation, the ideal goal is healing; in the palliative situation, the most basic marker is overall survival, while surrogate markers are the progression-free interval, improved quality of life, or diminished symptoms. At the same time, the law on economic assessment stipulates 'appropriateness and reasonableness of reimbursement by the insured community'.

HER2 Dimerization Inhibitor Pertuzumab - Mode of Action and Clinical Data in Breast Cancer.

The humanized monoclonal antibody pertuzumab prevents the dimerization of HER2 with other HER receptors, in particular the pairing of the most potent signaling heterodimer HER2/HER3, thus providing a potent strategy for dual HER2 inhibition. It binds to the extracellular domain of HER2 at a different epitope than trastuzumab. Pertuzumab and trastuzumab act in a complementary fashion and provide a more complete blockade of HER2-mediated signal transduction than either agent alone. Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and/or cytotoxic agents, and implied an improved clinical efficacy of the combination of pertuzumab and trastuzumab in early and advanced HER2-positive breast cancer. Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastuzumab significantly prolonged progression-free and overall survival without increasing cardiac toxicity. Currently, the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early HER2-positive breast cancer. Dual HER2 inhibition with the HER2 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in HER2-positive first-line metastatic breast cancer treatment.

Collective dynamics in optomechanical arrays.

Optomechanical systems couple light stored inside an optical cavity to the motion of a mechanical mode. Recent experiments have demonstrated setups, such as photonic crystal structures, that in principle allow one to confine several optical and vibrational modes on a single chip. Here we start to investigate the collective nonlinear dynamics in arrays of coupled optomechanical cells. We show that such "optomechanical arrays" can display synchronization, and that they can be described by an effective Kuramoto-type model.

Clinical management of borderline tumours of the ovary - experience from the "Berlin online tumour conference for gynaecological malignancies".

Borderline ovarian tumour (BOT) represents a rare and special tumour entity. Despite a generally favourable prognosis for patients with BOT, the presence of invasive peritoneal implants decreases the survival rate to 30-50%. In contrast to ovarian cancer, only few data exist concerning the current clinical management of patients with BOT. For this reason, the present analyses were performed for patients with BOT who were admitted into our online tumor conference for patients with gynaecological malignancies. Based on the results discussed in this article, the current aspects and problems regarding the diagnostic, surgical and conservative treatment and aftercare management of patients with BOT are considered.

Phase I dose finding study evaluating the combination of bendamustine with weekly paclitaxel in patients with pre-treated metastatic breast cancer: RiTa trial.

PURPOSE: The aim of the RiTa trial is to establish a feasible combination of bendamustine and paclitaxel in a weekly schedule in anthracycline pre-treated metastatic breast cancer patients. METHODS: Starting dose of bendamustine was 50 mg/m(2) and was stepwise increased by 10 mg/m(2) up to 70 mg/m(2). The starting dose of paclitaxel was 60 mg/m(2) and was increased up to 90 mg/m(2). There are five pre-defined dose levels with three patients per dose level (maximum six patients) and six patients in the last dose level according to the Goodman design. Dose-limiting toxicities were defined as severe neutropenia and thrombocytopenia as well as non-haematological toxicities >/=NCI-CTC grade 3 in the first cycle. RESULTS: No dose-limiting toxicity up to 70 mg/m(2) bendamustine and 90 mg/m(2) paclitaxel occurred during the first cycle. Over all cycles, the following severe haematological toxicities (grade 3 and 4) were documented: neutropenia five patients and anaemia one patient. Relevant grade 3 and 4 non-haematological toxicities over all cycles were fatigue two patients, dyspnoea one patient, infection four patients and bone pain in one patient. Five serious adverse events, but no therapy related death occurred. Five patients showed a complete or partial remission, six patients stable disease and six progressed during treatment. The median progression-free survival was 8 months. CONCLUSION: Treatment with weekly bendamustine and paclitaxel is a feasible and effective regimen in patients with metastatic breast cancer. The recommended dose for forthcoming phase II study is 70 mg/m(2) bendamustine and 90 mg/m(2) paclitaxel.

Primary systemic chemotherapy with sequential, dose-dense epirubicin and docetaxel for inoperable, locally advanced inflammatory breast cancer: a phase II study.

Sequential, dose-dense epirubicin plus docetaxel was evaluated as primary systemic therapy for women with inoperable, locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients (LABC n=27; IBC n=7) received 3 cycles of epirubicin 120 mg/m2 every 2 weeks followed by 3 cycles of docetaxel 100 mg/m2 every 2 weeks, with granulocyte colony-stimulating factor. Grade 3-4 toxicities were observed in 21 of 195 cycles (10.8%). Grade 3 anemia and leukopenia each occurred in 1% of cycles. Following chemotherapy, all patients underwent surgery. Eight patients (23.5%) had a clinical complete response and 15 (44.1%) had a partial response. In patients with IBC, median skin thickness decreased from 5.85 mm (range: 3.1-6.2 mm) to 4 mm (range: 2.7-5.1 mm) (p<0.005). Sequential, dose-dense epirubicin plus docetaxel achieved a high response rate among patients with LABC or IBC with only moderate toxicity.