Christoph Wiltschke’s research while affiliated with Medical University of Vienna and other places

Introduction Prediction of venous thromboembolism (VTE) occurrence in cancer patients using individual risk factors may contribute to preventing the burden of disease associated with VTE. Congestive heart failure in patients with cancer may increase the risk of VTE and worsen the prognosis. Aim We sought to investigate the association of congestive heart failure and occurrence of VTE in cancer patients, specifically with consideration for the poor prognosis in patients with heart failure and cancer. Materials and Methods Hospitalized and ambulatory cancer patients were included in the prospective Vienna Cancer and Thrombosis Study (CATS) in search of risk factors for occurrence of VTE. Cancer entities and comorbidities were recorded at baseline and verified using medical documentation including a diagnosis of congestive heart failure. The occurrence of VTE events was compiled via mail and telephone follow-ups for two years. Risk of VTE occurrence was calculated in the competing risk regression model, considering death as a competing event during follow-up.Fig. 1 Results In the current analysis 1,433 patients (632 women, 44.1%) with a median age of 61 years (25th-75th percentile: 52-75) were included. During the observation period, 108 (7.5%) VTE events and 522 (36.4%) deaths occurred. The median observation time was 729 days (233–731), and 34 patients (2.3%) had diagnosed congestive heart failure at the time of study inclusion, 12 of which had NYHA II-IV and 22 unspecified congestive heart failure. In the group of heart failure patients, 6 had VTE events and 23 died. In univariate competing risk analysis, the risk of VTE occurrence was increased 2.6-fold in patients with heart failure compared to those without a diagnosis of heart failure (SHR 2.58, 95% CI 1.13-5.92, p=0.025). After multivariable adjustment for age, BMI, gender, diabetes, history of myocardial infarction or stroke, use of antiplatelet drugs, cancer site, hypertension, D-Dimer level and peripheral arterial disease, the risk of VTE in heart failure patients was 3-times the risk of patients without heart failure (HR 3.07, 95% CI 1.15-8.19, p=0.025). Further, congestive heart failure was a strong predictor of mortality (HR 1.70, 95% CI 1.10-2.65, p=0.018). Conclusions Congestive heart failure is not only a risk factor for mortality in cancer patients, but also an independent predictor of VTE occurrence. In order to prevent VTE and the associated burden, patients with cancer and congestive heart failure may benefit from thromboprophylaxis.

Upon disease progression on trastuzumab-based therapy, patients with HER-2 positive metastatic breast cancer (MBC) may switch to lapatinib or continue on trastuzumab. We aimed to assess the impact of both strategies on overall survival (OS) in all patients treated for HER-2 positive MBC at the Medical University Vienna from 1999 until 2009. A total of 201 patients were identified from a breast cancer data base. Of these 115 (57.2%) received multiple lines of trastuzumab-based therapy, whereas 58 (28.9%) were treated with a single line. A control group of 28 patients (13.9%) had never received trastuzumab as they were treated before 1999, when trastuzumab was registered. OS from diagnosis of metastatic disease was defined as primary study endpoint. Trastuzumab significantly prolonged OS in HER-2 positive MBC (41 versus 13 months; p < 0.001). Administration of multiple lines further improved OS; this, however, did not reach statistical significance (47 versus 28 months; p = 0.069). Positive estrogen receptor (ER) status (HR 1.6; 95% CI 1.13-2.27) was associated with better outcome compared to negative estrogen receptor status (p = 0.02). Addition of lapatinib did not improve OS significantly in patients with prior trastuzumab-based therapy (62 versus 47 months; p = n.s.). Patients receiving lapatinib after diagnosis of BM, however, experienced an improvement of OS (22 versus 5 months; p = 0.022). Trastuzumab improves OS in patients with HER-2 positive MBC with further nonsignificant improvement when administered in multiple lines. Lapatinib did not further improve OS in the entire population; however, lapatinib might improve OS in patients with BM.

572 Background: Trastuzumab (T) prolongs OS over chemotherapy alone in pts with HER2+ MBC. Upon disease progression, pts may switch to lapatinib (L) or continue on T. We aimed at assessing the impact of both strategies on OS in all pts treated for HER2+ MBC at the Department of Medicine 1, Medical University of Vienna, from 1999-2009. Methods: 201 pts were identified from a BC databank. 115 pts (572%) received multiple lines of T, whereas 58 (28.9%) were treated with a single line of T-based palliative therapy. A control group of 28 pts (13.9%) had never received T as they were treated before 1999, when T was introduced. HER2 was determined by immunohistochemistry and reanalyzed by FISH if a score of 2+ was gained. OS from diagnosis of metastatic disease was defined as primary study endpoint and estimated using the Kaplan-Meier method. A Cox proportional hazards model was applied to correct for other factors associated with OS. Results: T significantly prolonged OS in HER2+ MBC (41 vs. 13 months; p<0.001)...

We have previously shown in mice that vaccination with three Her-2-peptides representing B-cell epitopes of the extracellular domain of Her-2/neu induces Her-2/neu-specific IgG antibodies with strong anti-tumor activity in vitro and in vivo. We have now finalized a phase I clinical trial with an anti-Her-2/neu vaccine-construct of immunopotentiating reconstituted influenza virosomes with the three peptides in patients with metastatic breast cancer (MBC). Ten MBC patients with low protein overexpression of Her-2/neu of MBC (+ or ++ upon immunohistochemistry, FISH negative) and positive hormone receptor status were enrolled in a single center phase I study. The virosomal formulated vaccine, consisting of 10 microg/peptide, was intramuscularly applied three times on days 1, 28, and 56. The primary endpoint of the study, which lasted 12 weeks, was safety, the secondary endpoint immunogenicity. Local erythema at the injection site was the only vaccine-related side effect occurring in four patients. In 8 of 10 patients an increase in peptide-specific antibody titer measured by ELISA was found. Importantly, the induced antibodies were also directed against the native Her-2/neu protein. Cellular immune responses, as measured by in vitro production of IL-2, IFN-c, and TNF-a of PBMCs showed a marked increase after vaccination in the majority of vaccinees. Notably, the number of CD4+CD25+Foxp3+T regulatory cells, which were significantly increased compared to healthy controls prior to vaccination, was markedly reduced following vaccination. In all, the immunological responses after vaccination indicated that the patients in stage IV of disease were immunocompetent and susceptible to vaccination. The Her-2/neu multipeptide vaccine was safe, well tolerated and effective in overcoming immunological tolerance to Her-2/neu. The induction of anti-Her-2-specific antibodies could result in clinical benefit comparable to passive anti-Her-2 antibody therapy.

In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression). Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy. Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP) on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS) were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression) were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. p values < 0.05 were considered to indicate statistical significance. Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26), and 8 months (95% CI 6.25-9.74) on first-line, respectively (n.s.). In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter. Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.

Docetaxel (D) plus gemcitabine (G) is an active combination in anthracycline pre-treated breast cancer. Impact of sequential administration of these drugs is unclear. This trial aimed to compare concomitant DG with sequential D --> G. Patients were randomised to eight cycles of gemcitabine 1,000 mg/m2 on days 1 + 8 plus docetaxel 75 mg/m2 on day 8, or 4 cycles of docetaxel 100 mg/m2 on day 1, followed by four cycles of gemcitabine 1,250 mg/m2 on days 1 + 8, in a 21-day schedule. Time to progression (TTP) was defined as primary endpoint; secondary endpoints were overall response rate (ORR), response duration (RD), overall survival (OS) and toxicity. Due to poor recruitment, the trial was terminated after 100 of a pre-planned 430 patients. Patient characteristics were well balanced. No significant difference was observed in terms of TTP, ORR, RD and OS. Grade 3/4 adverse events encompassed leucopoenia (29 vs.68%, P < 0.001), neutropoenia (49 vs. 83%, P < 0.001) and febrile neutropoenia (4 vs. 9%, n.s.), all favouring D --> G. No difference in efficacy was observed between concomitant and sequential treatment. D --> G produced significantly more episodes of haematological toxicity due to the administration of docetaxel at 100 mg/m2 without GCSF support.

Treatment options for patients with metastatic breast cancer (MBC) include a rapidly expanding repertoire of medical, surgical and supportive care measures. To provide timely and evidence-based recommendations for the diagnostic workup and treatment of patients with MBC, an international expert panel reviewed and discussed the evidence available from clinical trials regarding diagnostic, therapeutic and supportive measures with emphasis on their impact on the quality of life and overall survival of patients with MBC. Evidence-based recommendations for the diagnostic workup, endocrine therapy, chemotherapy, use of targeted therapies and bisphosphonates, surgical treatment and supportive care measures in the management of patients with MBC were formulated. The present consensus manuscript updates evidence-based recommendations for state-of-the-art treatment of MBC depending on disease-associated and biological variables.

The present consensus manuscript defines evidence-based recommendations for state-of-the-art treatment of metastatic breast cancer depending on disease-associated and biologic variables.