H.-J. Lück

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer—results at the time of surgery

BACKGROUND Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. PATIENTS AND METHODS Patients received neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) followed by paclitaxel 175 mg/m(2) (EC→T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m(2) followed by paclitaxel 225 mg/m(2) with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), fluorouracil 600 mg/m(2)) on days 1 and 8 (E(dd)→T(dd)→CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377). RESULTS Pathological complete response (pCR) rate (breast) was higher with E(dd)→T(dd)→CMF, 18.7% versus 13.2% with EC→T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). E(dd)→T(dd)→CMF regimen showed more grade 3-4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055). CONCLUSION Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)→T(dd)→CMF was potentially superior to EC→T in terms of pCR. Primary use of DA did not affect pCR.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis.

BACKGROUND The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. PATIENTS AND METHODS A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2) every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m(2) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E(dd)→T(dd)→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E(dd)→T(dd)→CMF compared with EC→T. RESULTS Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with E(dd)→T(dd)→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). CONCLUSION Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

The Patient's Anastrozole Compliance to Therapy (PACT) Program: a randomized, in-practice study on the impact of a standardized information program on persistence and compliance to adjuvant endocrine therapy in postmenopausal women with early breast cancer

BACKGROUND Compliance and persistence are often overlooked in adjuvant breast cancer treatment. PATIENTS AND METHODS PACT was a prospective, multicenter, randomized, open, parallel-group study assessing whether educational materials (EMs) enhanced compliance with aromatase inhibitor (AI) therapy in postmenopausal women with early, hormone-receptor-positive (HR+) breast cancer. The primary end points were compliance (proportion taking ≥ 80% anastrozole) at 12 months and persistence (proportion reporting anastrozole intake during the study period). RESULTS Four thousand eight hundred and forty-four patients were randomly assigned 1:1 to receive standard therapy or standard therapy with EMs. There was no difference between arms in compliance (N = 2740; 88.5%/88.8%, respectively, P = 0.81) or persistence rates (N = 2740; 40.5%/43.0%, respectively, P = 0.18). Modified end point analyses found no differences in compliance between arms based on the classification of: (i) patients with missing documentation or follow-up visit <9 months as non-compliant (N = 4397, P = 0.15); (ii) patients with early (≤ 292 days) 12-month follow-up documentation excluded (N = 4091, P = 0.19); (iii) patients reaching ≥ 80% compliance during individual follow-up as compliant (N = 4397, P = 0.26). Modified persistence analyses found no difference between arms (N = 4397, P = 0.37). CONCLUSIONS Addition of EMs to standard therapy did not significantly affect compliance and persistence with adjuvant anastrozole. CLINICALTRIALS ID: NCT00555867.

S2-4: GAIN Study: A Phase III Trial To Compare ETC vs. EC-TX and Ibandronate vs. Observation in Patients with Node-Positive Primary Breast Cancer – 1st Interim Efficacy Analysis.

Background: We previously showed that intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) results in a superior DFS and OS compared to conventionally dosed EC-T in pts with primary breast cancer (PBC) and ≥4 involved lymph nodes (LN) (Mobus et al JCO 2010). In the GAIN study, the intense dose-dense strategy has been further investigated as well as the adjuvant application of ibandronate (I). We here report on the planned interim efficacy analysis after 50% (N>401) of the required events have occurred. Methods: A prospective, multi-center, controlled, non-blinded, randomized phase III trial investigating ETC (E: 150 mg/m 2 , T:225 mg/m 2 , C:2500–2000 mg/m 2 , i.v. day 1, q15 for 3 cycles each: A1); or EC→TX (E: 112.5 mg/m 2 + C: 600 mg/m 2 , i.v. day 1, q 15 for 4 cycles→T: 67.5 mg/m 2 i.v. day 1, q 8 for 10 weeks + X: 2000 mg/m 2 p. o. day 1–14, q 22 for 4 cycles: A2). Pts were further randomized in a 2:1 ratio to receive ibandronate: 50 mg/day p.o. for 2 years (B1) or observation (B2). Pts received a primary prophylaxis with either epoetin β or darbepoetin α and pegfilgrastim during ETC or EC. After recruitment of 1500 pts prophylactic ciprofloxacin was implemented and the dose of C was reduced to 2000 mg/m 2 . Eligibility : Females ≥18 and Primary objective:compare DFS A1 vs. A2 and B1 vs.B2. Secondary objectives: OS, safety, incidence of secondary primaries, and EFS in subgroups of hormone sensitivity and number of pos. LN between arms; assessment of compliance; determine prognostic factors. 3000 pts with 801 events were needed to show an increase of 5-year DFS from 75% to 79% for pts receiving EC→TX and 728 events to show an increase of 5-year DFS from 75% to 79.5% for pts receiving I, assuming a drop-out rate of 5%, α=0.05 (two-sided)and 1-β =80%. An interim analysis for both primary objectives was planned after 50% of the expected events occurred. Safety results have been reported previously (Mobus et al. SABCS 2009). Results: 3023 patients were randomized between 06/2004 and 08/2008.1512 received ETC and 1511 EC→TX. 29pts never started therapy, 14 in ETC, 15 in EC→TX. Median follow-up is 38.7 months. Median age was 50 years; pN1 (37.7%), pN2 (35.4%); pN3 (26.9%); 77.4% had ductal invasive carcinoma, 46.6% were grade 3; 76.7% had hormone receptor-positive tumors, 22% were HER2−positive. 405 events have occurred by 12.05.2011.380pts relapsed and 25pts. died w/o relapse. The interim futility boundary for chemotherapy was not crossed. For the ibandronate question the futility boundary was reached. There was no difference in DFS and OS between the patients with and without ibandronate (DFS log-rank p=0.593; HR 1.059; 95%CI 0.861−1.301; OS log-rank p=0.801 HR 0.961; 95% CI 0.705−1.31). Conclusion: The GAIN study demonstrated that adjuvant ibandronate does neither improve DFS nor OS in primary node positive breast cancer after treatment with dose-intensified chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-4.

German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients

Background Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine. Patients and methods Women (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4. Results From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10). Conclusion Adding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.

Abstract P1-13-05: GAIN-2: Adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: Results of the second safety interim analyses

Background: GAIN-2 compares the effectiveness and safety of a predefined intense dose-dense regimen (EnPC) vs. a dose-dense regimen with modification of single doses depending on individual hematological and non-hematological toxicities (dtEC-dtD) (NCT01690702). Moreover, the Trastuzumab substudy compares the subcutaneous administration of the drug to the abdominal wall vs. thigh. Methods: The primary objective of the GAIN-2 trial is to compare the invasive disease-free survival (iDFS) in patients with high-risk primary breast cancer (luminal A ≥4 N+; luminal B N+; HER2+ and TNBC N0/N+). Patients are randomized between EnPC (epirubicin 150 mg/m 2 q2w x 3, nab-Paclitaxel 330 mg/m 2 q2w x 3, cyclophosphamide 2000 mg/m 2 q2w x 3) or dtEC-dtD (dd/tailored epirubicin/cyclophosphamide q2w x 4 followed by dd/tailored docetaxel q2w x 4) Two safety interim analyses after 200 (Noeding et al. Ann Oncol 2014) and 900 patients who have completed chemotherapy were planned. We present the results of the second safety analysis. In addition to the standard analyses for hematological and non-hematological toxicities, any affections of the cranial nerves as well as the rate of macula degenerations and anaphylactic reactions are of special interest. Results: Between 09/2012 and 05/2015 a total of 1473 patients have been randomized (EnPC n=734; dtEC-dtD n=739). Among those, 84 patients have been included in the trastuzumab substudy. No safety data are currently available for the substudy. Median age was 52 years and median body-mass-index 26. In terms of hematological adverse events, the rate of febrile neutropenia grade 3-4 (12% vs. 8%) and thrombopenia grade 3-4 (12% vs. 5%) was significantly increased in the EnPC arm. As for non-hematological side effects, there were significantly more patients developing an increase in alkaline phosphatase (59% vs. 40%), ALAT (69% vs. 59%), peripheral sensory neuropathy (83% vs. 68%), arthralgia (63% vs. 49%), myalgia (48% vs. 41%) and bone pain (25% vs. 17%) in the EnPC arm, whereas nosebleed (10% vs. 25%), edema (13% vs. 26%) and hand-foot syndrome (12% vs. 28%) were more common in the dtEC-dtD arm. We observed two treatment related deaths, both in the dtEC-dtD arm (cause of death: acute respiratory distress syndrome and pneumonia). There were no differences between the treatment arms for the toxicities of special interest. In the EnPC arm, overall 30% of the patients required dose-reductions due to hematological toxicities compared with only 10% in the dtEC-dtD arm (p 2 followed by docetaxel 100 mg/m 2 ) in more than one third of the patients receiving dtEC-dtD. In 9% of women a reduction was required in the 4th cycle of docetaxel. Conclusion: This interim safety analysis from a prospectively randomized trial investigating iddEnPC with predefined doses and a toxicity adapted idd/tailored strategy (dtEC-dtD) showed no additional or unexpected safety signals in the iddEnPC or dtEC-dtD arm. Therefore, no modifications in the conduction of the study are necessary and the study continues as expected. Citation Format: Mobus V, Luck H-J, Forstbauer H, Wachsmann G, Ober A, Schneeweiss A, Christensen B, von Abel E, Grischke E-M, Hoffkes H-G, Klare P, Yon-Dschun K, Schmatloch S, Furlanetto J, Burchardi N, von Minckwitz G, Loibl S. GAIN-2: Adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: Results of the second safety interim analyses. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-05.

Abstract OT3-02-09: Seraphina – Safety efficacy and patient reported outcomes of advanced breast cancer patients: Therapy management with NAB-paclitaxel in daily routine

BACKGROUND Treatment of patients with advanced breast cancer (ABC) has evolved significantly. Nevertheless, further improvement in ABC treatment is a high medical need. Besides the prolongation of progression free survival (PFS) and overall survival (OS) the major objective of new therapeutic approaches is the enhancement of quality of life (QoL). A recent advance for the treatment of ABC was the development of the cremophor-free albumin-bound paclitaxel, nab-Paclitaxel. SPECIFIC AIMS/TRIAL DESIGN The aim of this non-interventional study is the analysis of efficacy and safety data of ABC patients within routine treatment with nab-Paclitaxel. A key focus will be the assessment of patient reported outcomes (PRO), health economic aspects and the influence of breast cancer patient characteristics on prognosis, adverse event frequencies, PRO and therapy decision making. Patients with ABC, who experienced failure of first-line treatment for metastatic disease and for whom standard anthracycline-containing therapy is not indicated, will be followed up under real-life conditions. Sixty sites, equally distributed with regard to their organizational structure (hospital and office based) and medical disciplines (gyneco-oncologists and medical oncologists) will document 1,200 patients. The primary objective is the assessment of PFS under real-life conditions. Secondary objectives include the assessment of overall and breast cancer specific survival, the influence of age on prognosis and QoL, as well as the incidence of (serious) adverse events (AE). PRO including FACT-B, FACT-Taxane, and nab-Paclitaxel treatment specific questions will be collected in a web based application and compared to paper based reporting. Furthermore, biomaterials will be collected to allow translational research projects. ELIGIBILITY CRITERIA: Adult women (>18 years) with ABC and treated with nab-Paclitaxel. STATISTICAL METHODS/TARGET ACCRUAL: In Germany nab-Paclitaxel is indicated for patients with metastatic breast cancer after failure of a previous therapy in ABC. In this therapeutic setting several studies have shown high efficacy and acceptable toxicity. However, populations within clinical trials are selected and may be different from the general patient population in clinical practice. Therefore this study aims at the capture of PFS, PRO and AE in the general population for which nab-Paclitaxel is used in clinical practice. Nab-Paclitaxel treatment will be documented over a period of up to 6 months, followed by a 30 months progression/ survival follow-up. Target accrual is 1,200 patients. We assume that at most 10% are lost to follow-up before the median survival time is reached. Kaplan-Meier curves will be calculated, especially the median survival time with 95% confidence interval. Citation Format: Fasching PA, Wallwiener M, Lux MP, Mueller V, Schneeweiss A, Tesch H, Brucker SY, Haeberle L, Spall T, Belleville E, Luck H-J. Seraphina – Safety efficacy and patient reported outcomes of advanced breast cancer patients: Therapy management with NAB-paclitaxel in daily routine. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-09.

Abstract P6-14-05: Final Overall Survival Analysis of the TBP Phase III Study (GBG 26/BIG 3-05): Capecitabine vs. Capecitabine + Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing during Trastuzumab Treatment

Background: In women with HER2-positive breast cancer progressing during trastuzumab treatment, continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone (von Minckwitz et al, J Clin Oncol 27:1999-2006, 2009). Here we report the final analysis of overall survival (OS). Methods: Patients (pts) with HER2-positive, locally advanced or metastatic breast cancer who progressed during treatment with trastuzumab with or without adjuvant and/or 1 st -line metastatic chemotherapy were prospectively randomized to X (2500 mg/m2 on days 1-14, q3w) or XH (6 mg/kg, q3w). OS was a pre-specified secondary endpoint of the study. Results: Median follow up at June 2010 was 20.7 months. 59 of 74 and 60 of 77 pts died in the X alone and XH arm, respectively. Median OS was 20.6 and 24.9 months with X alone and XH, respectively. This difference was not statistically significant (HR=0.94 [0.65-1.35]; p=0.73). Cox proportional hazard model showed performance status, hormone receptor status and metastatic site as independent prognosticators for survival. No difference between treatment arms was observed for pts with a clinical response or clinical benefit, respectively. Pts who continued/restarted anti-HER2 treatment (trastuzumab or lapatinib) after 2 nd progression (N=88) had an OS of 18.8 compared with 13.3 months for those who did not receive 3 rd line treatment with anti-HER2 agents (N=52) (HR 0.63; p=0.02). Pts who continued treatment after progression as initially randomized (anti-HER2 treatment after XH (N=31) or no anti-HER2 treatment after X alone (N=53)) had an OS of 26.7 months and 20.4 months (HR 0.71; p=0.2). Conclusions: Final OS analysis of the GBG-26 study could not demonstrate a survival benefit for treatment beyond progression with trastuzumab. However in a post-hoc analysis, pts receiving anti-HER2 treatment as 3 rd line therapy showed a better OS than those not receiving this targeted treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-05.

Entwicklung der Therapie des Ovarialkarzinoms

Die Kombination von Cisplatin und Paclitaxel erwies sich in zwei randomisierten Pha- se-III-Studien gegenuber dem alteren Standard (Platin plus einem Alkylans) uberlegen [1,2] und wurde deshalb als neuer Standard in der Primartherapie des fortgeschrittenen Ovarialkarzinoms akzeptiert. Die besseren Resultate wurden mit mehr Toxizitat, speziell Neurotoxizitat, erkauft. Die Substitution von Cisplatin durch Carboplatin sollte den Effektivitatsvorteil dieser neuen Kombination mit einem gunstigeren Toxizitatsprofil verbinden. 7 Phase-I/II-Studien entwickelten eine Kombination von Carboplatin-Paclitaxel [3,4, 5,6,7,8,9]; die Erfahrungen dieser Studien fuhrten zur Initiierung von 3 Pha- se-III-Studien zum Vergleich der Cisplatin-Paclitaxel-Standardtherapie mit einer Carbo- platin-Paclitaxel-Kombination. Die Interimsanalyse der AGO-Studie OVAR-3 [10] wird hier vorgestellt. Zwischen 10/95 und 11/97 wurden 798 Patientinnen in diese prospektiv randomisierte Studie eingeschlossen. Die Therapiearme bestanden aus Carboplatin dosiert nach AUC 6 [11] plus Paclitaxel 185 mg/m2 (Arm A) und Cisplatin 75 mg/m2 plus Paclitaxel 185 mg/m2 (Arm B). Paclitaxel wurde als 3-Stunden-Infusion verabreicht, die Pramedikation bestand aus einer Einmaldosis von Dexamethason, einem 5-HT3-, einem H1 und einem H2-Antagonisten. In beiden Armen wurden 6 Zyklen alle 3 Wochen verabreicht. 790 der 798 rekrutierten Patientinnen erfullten die Einschluskriterien mit einem Ovarialkarzinom FIGO IIB-IV und einem Intervall ≤ 6 Wochen zur Primaroperation.