Volker Moebus

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials.

BACKGROUND Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

Intense Dose-Dense Sequential Chemotherapy With Epirubicin, Paclitaxel, and Cyclophosphamide Compared With Conventionally Scheduled Chemotherapy in High-Risk Primary Breast Cancer: Mature Results of an AGO Phase III Study

PURPOSE Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional adjuvant therapy. We compared intense dose-dense (IDD) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer. PATIENTS AND METHODS In this randomized, phase III trial, a total of 1,284 eligible patients with four or more involved axillary lymph nodes were randomly assigned to receive IDD sequential epirubicin, paclitaxel, and cyclophosphamide (IDD-ETC) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks. The primary end point was event-free survival (EFS). RESULTS At a median follow-up of 62 months, 5-year event-free survival rates were 62% in the conventional arm and 70% in the IDD-ETC arm, representing a 28% reduction of the relative risk of relapse (P < .001). This benefit was independent of menopausal, hormone receptor, or human epidermal growth factor receptor 2 status. The 5-year overall survival rates were 77% versus 82%, representing a 24% reduction of the relative risk of death (P = .0285). IDD therapy was associated with significantly more nonhematologic and hematologic toxicities, but no treatment-related death occurred. Four occurrences of acute myeloid leukemia or myelodysplastic syndrome (MDS) were observed in the IDD-ETC arm. No severe congestive heart failure was reported. CONCLUSION IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes.

Second-line carboplatin and gemcitabine in platinum sensitive ovarian cancer—a dose-finding study by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Ovarian Cancer Study Group

BACKGROUND Despite the progress that has been achieved in the last years, recurrence rates in ovarian cancer patients are still considerably high and the majority of patients ultimately become candidates for second-line treatment. Carboplatin reinduction is a broadly adopted regimen in patients with recurrences occurring six months or later after first-line treatment. Gemcitabine is among the candidates as combination partner in second-line regimens. PATIENTS AND METHODS We performed a study with escalating doses of gemcitabine combined with carboplatin in 26 platinum-pretreated patients with recurrent ovarian cancer and a treatment-free interval of 6+ months. Dose-limiting toxicity (DLT) and a maximum tolerable dose (MTD) recommendable for further trials was evaluated. RESULTS The DLT was myelosuppression, mainly thrombocytopenia. No dose limiting non-hematological toxicities were observed. The MTD of gemcitabine was 1,000 mg/m2 given on days 1 + 8 of a three-week schedule combined with carboplatin AUC 4 given on day 1. The majority of evaluable patients showed an objective response (62.5%), and median progression-free and overall survival were 10 and 18+ months, respectively. CONCLUSION Gemcitabine-carboplatin given according to the MTD is well tolerated and active against recurrent platinum-sensitive disease. A randomized trial comparing carboplatin with or without gemcitabine in platinum-sensitive ovarian cancer has already been initiated.

Adenoviral Transduction Efficiency of Ovarian Cancer Cells Can Be Limited by Loss of Integrin β3 Subunit Expression and Increased by Reconstitution of Integrin αvβ3

Recombinant adenoviruses expressing a therapeutic gene are currently used in clinical studies for treatment of advanced ovarian cancer. We therefore tested whether the expression level of primary (CAR) and secondary adenovirus receptors (integrins) was predictive of the efficacy of adenoviral gene transfer in ovarian cancer cells. Adenoviral transduction efficiency (ATE) was determined with an E1-deleted adenovirus type 5 expressing β-galactosidase under a CMV promoter (AdGal). ATE was studied in relationship to the expression level of both CAR (coxsackie and adenovirus receptor) and integrins. A representative sample of 25 permanent human cell lines established from advanced ovarian cancer in our laboratory and the OV-2774 cell line were tested. Overall, ATE increased with increasing titers of AdGal. At a given titer of 50 infectious units per cell, transduction efficiency varied from 6 to 94% among the individual cell lines. All cell lines expressed CAR and integrin αvβ5, but no relation between ATE and...

Multiplex PCR screening detects small p53 deletions and insertions in human ovarian cancer cell lines

Mutations at the p53 tumor suppressor gene locus are a frequent genetic alteration associated with human ovarian carcinoma. Little information exists regarding whether mutational events occur other than point mutations and large deletions, causing loss of heterozygosity. Small intragenic deletions and insertions in the p53 gene have been observed in various human neoplasias. We developed a multiplex polymerase chain reaction (MPCR) screening assay to amplify the complete p53 coding region from genomic DNA in a single step. Deletions and/or insertions were found in six out of 11 newly established ovarian carcinoma cell lines. MPCR detected deletions as small as 2bp, as confirmed by nucleotide sequence analysis. Most of the observed alterations (6/7) were homozygous or hemizygous. Structural aberrations of the p53 gene possibly leading to loss of p53 cell cycle control may be a consequence of a slipped-mispairing mechanism in rapid DNA replication during repetitious ovulation and wound repair of ovarian epithelial cells. MPCR may be a valuable tool for screening for possible p53 deletion and insertion mutations not only in ovarian cancer but also in other malignancies.

Abstract S3-04: The phase III ICE study: Adjuvant Ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer

Background: Although approximately 50% of newly diagnosed breast cancers arise in women above 65 years old they are underrepresented in clinical trials. The ICE study was designed to investigate if a mono-chemotherapy with capecitabine in addition to the third generation bisphosphonate ibandronate will improve the outcome compared to ibandronate alone in elderly breast cancer patients with medium and high risk primary breast cancer not suitable for standard chemotherapy. Methods : This is a prospective, multi-center, controlled, open-label, randomized phase III trial. Female patients ≥ 65 years with unilateral or bilateral breast cancer who are either node-positive or high-risk node-negative (tumor size ≥2 cm, grade >I, and/or ER-and PR-negative); and a Charlson Comorbidity Index (CMI) ≤2 received either ibandronate alone for 2 years, 50 mg p.o. daily alternatively 6 mg i.v. every 4 weeks or the same ibandronate regimen together with capecitabine 2000 mg/m 2 on day 1 – 14 q day 22 for 6 cycles to be started within 6 months after axillary dissection. Patients with hormone-sensitive disease received an endocrine therapy according to guidelines. The primary objective is disease-free survival. A total of 1,394 patients were needed (5-year DFS improvement from 65% with ibandronate to 71.5% with ibandronate/capecitabine; α=0.05, s=80%) and we expected 497 events during a median 5 year follow up. Results: Between 06/2004 and 08/2008, 1409 patients were randomized to ibandronate (N=702) or ibandronate/capecitabine (N=668) in 172 German centers, of whom 1380 patients started treatment (689 and 691 respectively). Median age was 71 (range 74-80) years; 58.6% of patients had a CMI≥1, 48.2% had N+, 35.2% grade 3, and 19.2% had ER/PgR negative disease. 83.8% of patients received all 6 capecitabine cycles. Capecitabine grade 3/4 toxicities were Conclusion: CALGB 49907 showed that AC or CMF was superior to capecitabine in patients aged ≥65 years but was associated with twice as many moderate to severe toxic effects (64% vs 33%) (Muss H et al, NEJM 2012). The ICE study will provide evidence if capecitabine monotherapy is as active as adjuvant treatment and if it might be an option for frail and/or elderly patients where standard chemotherapy is considered to be too toxic. Citation Format: Gunter von Minckwitz, Toralf Reimer, Jochen Potenberg, Bettina Conrad, Ulrike Schurer, Holger Eidtmann, Marianne Just, Stefan Paepke, Elmar Stickeler, Georg Heinrich, Michael Untch, Volker Moebus, Christoph Thomssen, Christian Jackisch, Jens Huober, Sibylle Loibl, Valentina Nekljudova, Ulrike Nitz. The phase III ICE study: Adjuvant Ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-04.

Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis

BACKGROUND New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin α, epoetin β, darbepoetin α, biosimilars). PATIENTS AND METHODS A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control. RESULTS Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups [OR, 1.20; 95% confidence interval (CI) 1.03-1.40]. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94-1.34). In seven studies reporting progression-related end points (N = 4197; ESA n = 2088; control n = 2109), the OR was 1.01 (95% CI 0.87-1.16) for ESA compared with control. CONCLUSIONS After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.

Superiority of sequential docetaxel over standard FE100C in patients with intermediate risk breast cancer: survival results of the randomized intergroup phase III trial EC-Doc.

Abstract #78 Background: Taxane based adjuvant chemotherapy (CHT) is standard of care in node-positive breast cancer. Several pre-planned subgroup analyses detected the maximum benefit from taxanes in patients with 1-3 positive lymph nodes (LN).
 According to the St. Gallen consensus CHT in endocrine responsive tumors is optional in these patients. Recently the ABCSG reported excellent survival data after endocrine therapy +/- bisphosphonates without CHT in low to intermediate risk breast cancer (Gnant et al., ASCO 2008). The EC-Doc trial compares a modern sequential taxane-based regimen with standard FE100C in patients with 1-3 positive LN.
 Methods: Patients from 18 to 65 years with primary breast cancer and 1 to 3 positive LN were eligible if they had operable breast cancer with histologically confirmed free margins. M0 status was assessed by conventional staging. 2011 patients were randomized to a phase III trial comparing 4 cycles E90C600 q3w followed by 4 cycles of Docetaxel100 q3w (n=1008) (Arm A) versus 6 cycles of F500E100C500 q3w (n=828) or C600M40F600 d1, 8 q4w (n=175) (Arm B). The primary endpoint is EFS. Secondary endpoints are OS, toxicity and quality of life.
 Results: Baseline characteristics were well balanced between both study arms. Arm A/B: mean age 51.5/51.5 years, median tumor size 2.0/2.0, HR positive 77.7% / 78.3%, G3 34.1% / 34.4%. Toxicity data from the EC-Doc trial were recently presented (Nitz et al. , ASCO 2008). After a median follow up of 41 months both estimated 5-year EFS (91% vs. 86%, p=0.005) and OS (95% vs. 90%, p=0.004) were significantly better in the EC-Doc arm.
 For the comparison of EC-Doc vs. FE100C the respective values were: HR 0.58, p=0.004, estimated 5 year EFS 91% / 85% and 5 year estimated OS 95% / 91% (p =0.03). For the hormone receptor positive subpopulation the HR was 0.51 in favour of EC-Doc (p= 0.007).
 Conclusions: Our study indicates a superiority of sequential taxane-based EC-Doc CHT in terms of EFS and OS over standard FE100C in an intermediate risk group. The addition of modern third generation taxane based CHT to conventional endocrine treatment is associated with excellent EFS and OS in patients with 1-3 positive LN.
 As shown even for the subgroup of patients with HR positive disease the benefit from third generation taxane based CHT is substantial so that an endocrine only adjuvant strategy may result in undertreatment. With respect to the excellent survival rates prospective randomized trials testing the existing genetic tests are mandatory.
 Updated survival and efficacy analysis in distinct molecular subtypes (Her-2/neu, triple-negative) will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 78.

Zurich Consensus: German Expert Opinion on the St. Gallen Votes on 15 March 2009 (11th International Conference at St. Gallen: Primary Therapy of Early Breast Cancer)

A German working group of 23 breast cancer experts discussed the results from the vote at this year’s St. Gallen Consensus Conference on Primary Therapy for Early Breast Cancer (March 11–14, 2009) and came up with some concrete recommendations for day-to-day therapeutic decisions in Germany. Due the fact that the concept of the St. Gallen Consensus Conference merely allows for a minimal consensus, the objective of the working group was to provide practice-related recommendations for day-to-day clinical decisions in Germany. One area of emphasis at St. Gallen was tumor biology as a starting point for reaching individual therapeutic decisions. Intensive discussion was necessary with respect to the clinical relevance of predictive and prognostic factors. A new addition to the area of systemic therapy was a first-ever discussion of the adjuvant administration of bisphosponates and the fact that therapy with trastuzumab in HER2 overexpressing breast cancer has been defined as the standard for neoadjuvant therapy. The value of taxanes as a component of (neo)adjuvant chemotherapy as well as the value of aromatase inhibitors for the endocrine adjuvant treatment of postmenopausal patients were affirmed.

Survival effects of erythropoiesis-stimulating agents (ESAs) in patients with breast cancer: A meta-analysis.

120 Background: New data are available from two trials of ESA use in patients with breast cancer receiving chemotherapy. We conducted a meta-analysis of trials of ESA use in this population. METHODS A literature search identified reports from 1997-2012 that included mortality data from controlled ESA trials (epoetin alfa, epoetin beta, darbepoetin alfa, biosimilars) in patients with breast cancer receiving chemotherapy. We used data from company databases for Amgen Inc. or Janssen Products LP studies and published data for other studies. Random-effects odds ratios (OR) were calculated to compare results for patients randomized to ESA to patients randomized to control. Analyses were stratified by metastatic stage; mixed stage or treatment; and adjuvant/neoadjuvant treatment. RESULTS We analyzed 9 studies (N = 4,713; ESA n = 2,346, control n = 2367) (Table).The overall stratified random-effects OR for death was 1.17 (95% confidence interval, 0.99-1.39). Details are presented in the Table. CONCLUSIONS Overall survival OR remains consistent with prior data after including recent results. [Table: see text].