Publications by authors named "Thorsten Fuereder"

35 Publications

Pembrolizumab plus docetaxel for the treatment of recurrent/metastatic head and neck cancer: A prospective phase I/II study.

Oral Oncol 2022 Jan 26;124:105634. Epub 2021 Nov 26.

Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1090, Austria.

Background: Taxane-based checkpoint inhibitor combination therapy might improve the outcome in recurrent/metastatic (R/M) head and neck cancer (HNSCC) patients. Thus, we investigated the efficacy and safety of docetaxel (DTX) plus pembrolizumab (P) in a prospective phase I/II trial.

Methods: Platinum-resistant R/M HNSCC patients received DTX 75 mg/m^ plus P 200 mg for up to six cycles followed by P maintenance therapy. The primary endpoint was overall response rate (ORR) and safety. Secondary endpoints comprised disease control rate (DCR), overall survival (OS) and progression free survival (PFS).

Results: Twenty-two patients were enrolled. Nine patients (40.9%) had a primary tumor in the oropharynx, 8 (36.4%) in the oral cavity, 3 (13.6%) in the hypopharynx and 2 (9.1%) in the larynx. The ORR was 22.7% (95% CI 10.1%-43.4%) and one (4.5%) complete response was achieved. The DCR was 54.6% (95% 34.7%-73.1%). The median PFS was 5.8 months (95% CI 2.7-11.6) and the median OS 21.3 months (95% CI 6.3-31.1). The 1-year PFS and OS rates were 27.3% and 68.2%, respectively. While the most frequent adverse event (AE) was myelosuppression, which was reported in all 22 patients, 3 (13.6%) patients experienced grade 3 febrile neutropenia. The most common immune-related AEs were grade skin rash (40.9%) and hypothyroidism (40.9%). One patient (4.5%) experienced grade 5 immune thrombocytopenia.

Conclusion: DXT in combination with P shows promising activity accompanied with a manageable side effect profile in pre-treated R/M HNSCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2021.105634DOI Listing
January 2022

Overweight as a Favorable Clinical Biomarker for Checkpoint Inhibitor Therapy Response in Recurrent Gynecologic Cancer Patients.

Biomolecules 2021 11 16;11(11). Epub 2021 Nov 16.

Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Despite increasing clinical interest in adapting checkpoint inhibitor (CPI) therapies for patients with gynecologic malignancies, no accurate clinical biomarkers to predict therapy response and prognosis are currently available. Therefore, we aimed to assess the predictive and prognostic value of pretherapeutic body mass index (BMI) for recurrent gynecologic cancer patients as previously validated for other solid tumors. We evaluated patients with programmed cell death ligand 1 (PD-L1) positive and, in endometrial cancer, also mismatch repair deficient (MMR) gynecologic malignancies, who received the PD-1 inhibitor pembrolizumab as monotherapy (200 mg fixed-dose q3 w) from 2017 to 2020 (n = 48). Thirty-six patients receiving at least four courses were included in the final analysis. Associations between a BMI increase per 5 kg/m and overall response rate (ORR; complete + partial response), disease control rate (DCR; ORR + stable disease), progression-free (PFS), and overall survival (OS) were assessed. An elevated BMI was univariately associated with ORR (OR 10.93 [CI 2.39-49.82], = 0.002), DCR (OR 2.19 [CI 0.99-4.83], = 0.048), prolonged PFS (HR 1.54 [CI 1.03-2.34], = 0.038), and OS (HR 1.87 [CI 1.07-3.29], = 0.028). All results could be confirmed in the multivariate analyses. Pretherapeutic BMI therefore appears to be a promising readily available biomarker to identify patients with PD-L1-positive and/or MMR-deficient gynecologic malignancies who could particularly benefit from CPI treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom11111700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615494PMC
November 2021

Humoral Immune Response in Hematooncological Patients and Health Care Workers Who Received SARS-CoV-2 Vaccinations.

JAMA Oncol 2022 Jan;8(1):106-113

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Importance: To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer.

Objective: To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination.

Design, Setting, And Participants: This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination.

Main Outcomes And Measures: Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively.

Results: In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001).

Conclusions And Relevance: In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2021.5437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485209PMC
January 2022

Impact of COVID-19 lockdown on routine oncology versus emergency care at a high volume cancer centre.

Eur J Clin Invest 2021 Aug 4;51(8):e13623. Epub 2021 Jun 4.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: We investigated the influence of population-wide COVID-19 lockdown measures implemented on 16, March 2020 on routine and emergency care of cancer outpatients at a tertiary care cancer centre in Vienna, Austria.

Methods: We compared the number/visits of cancer outpatients receiving oncological therapies at the oncologic day clinic (DC) and admissions at the emergency department (ED) of our institution in time periods before (pre-lockdown period: 1 January - 15 March 2020) and after (post-lockdown period: 16 March- 31 May 2020) lockdown implementation with the respective reference periods of 2018 and 2019. Additionally, we analysed Emergency Severity Index (ESI) score of unplanned cancer patient presentations to the ED in the same post-lockdown time periods. Patient outcome was described as 3-month mortality rate (3-MM).

Results: In total, 16 703 visits at the DC and 2664 patient visits for the respective time periods were recorded at the ED. No decrease in patient visits was observed at the DC after lockdown implementation (P = .351), whereas a substantial decrease in patient visits at the ED was seen (P < .001). This translates into a 26%-31% reduction of cancer-related patient visits per half month after the lockdown at the ED (P < .001 vs. 2018 + 2019). There was no difference in the distribution of ESI scores at ED presentation (P = .805), admission rates or 3-MM in association with lockdown implementation (P = .086).

Conclusion: We demonstrate the feasibility of maintaining antineoplastic therapy administration during the COVID-19 pandemic. However, our data underline the need for adapted management strategies for emergency presentations of cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/eci.13623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209914PMC
August 2021

Outcome of Targeted Therapy Recommendations for Metastatic and Recurrent Head and Neck Cancers.

Cancers (Basel) 2020 Nov 15;12(11). Epub 2020 Nov 15.

Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients' molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with R/M head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, microsatellite instability (MSI) testing, and immunohistochemistry (IHC). In 31 cases (62.0% of all patients), a molecular-driven targeted therapy approach was recommended. Eventually, 14 patients (28%) received the suggested targeted therapy. Six of fourteen patients (43%) achieved stable disease conditions and four patients (29%) experienced a progressive disease. The median time to treatment failure was 2.8 months. Therapy recommendations were significantly more often issued for men ( = 0.037) than for women. This analysis demonstrated that precision medicine provided the basis for molecular-driven therapy recommendations in over half of the patients with advanced therapy refractory head and neck cancers, with significantly more therapy recommendations for men. Our analysis showed that although precision medicine approaches are implementable and feasible for the management of recurrent/metastatic head and neck cancers in daily clinical routine, there are major limitations and challenges that have to be overcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12113381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696688PMC
November 2020

Targeted Therapy Recommendations for Therapy Refractory Solid Tumors-Data from the Real-World Precision Medicine Platform MONDTI.

J Pers Med 2020 Oct 23;10(4). Epub 2020 Oct 23.

Department of Medicine I, Division of Clinical Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men ( = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm10040188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712019PMC
October 2020

Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy.

Blood 2021 03;137(12):1669-1678

Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, and.

The risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with immune checkpoint inhibitors is currently unclear. Our aim was to quantify the risk of VTE/ATE in patients with cancer treated with immune checkpoint inhibitors, explore clinical impact, and investigate potential clinical risk factors. Patients treated with immune checkpoint inhibitors at the Medical University of Vienna from 2015 to 2018 were identified using in-house pharmacy records (n = 672; most frequent entities: 30.4% melanoma, 24.1% non-small cell lung cancer; 86% stage IV disease). A retrospective chart review was performed to screen for VTE and/or ATE. Cumulative incidences and between-group differences were estimated in competing-risk analysis. The impact of VTE/ATE on mortality was studied by multistate modelling. Over a median follow-up of 8.5 months, 47 VTEs and 9 ATEs were observed. Cumulative incidences of VTE and ATE were 12.9% (95% confidence interval [CI], 8.2-18.5) and 1.8% (95% CI, 0.7-3.6). Occurrence of VTE was associated with increased mortality (transition hazard ratio, 3.09; 95% CI, 2.07-4.60). History of VTE predicted VTE occurrence (subdistribution hazard ratio [SHR], 3.69; 95% CI, 2.00-6.81), and distant metastasis was nonsignificantly associated with VTE risk (SHR, 1.71; 95% CI, 0.62-4.73). No association of VTE with Eastern Cooperative Oncology Group performance status, Charlson comorbidity index, or Khorana score was observed, and rates of VTE were comparable between tumor types and checkpoint-inhibitory agents. In conclusion, patients with cancer under immune checkpoint inhibitor therapy are at high risk of thromboembolism, especially VTE. Furthermore, VTE occurrence was associated with increased mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020007878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016631PMC
March 2021

Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field.

ESMO Open 2020 10;5(5):e000880

Division of Oncology, Department for Medicine I, Medical University of Vienna, Wien, Austria.

Background: Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology.

Methods: Numbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system.

Results: A patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported.

Conclusions: We present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2020-000880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555099PMC
October 2020

Gemcitabine and Platinum-Based Agents for the Prediction of Cancer-Associated Venous Thromboembolism: Results from the Vienna Cancer and Thrombosis Study.

Cancers (Basel) 2020 Sep 3;12(9). Epub 2020 Sep 3.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria.

Gemcitabine and platinum-based agents could increase the risk of venous thromboembolism (VTE) in patients with cancer. We evaluated the additive predictive utility of these agents towards cancer-associated VTE beyond a recently developed and externally validated clinical prediction model, which was based on tumor entity and continuous D-dimer levels. Analysis was performed in the derivation cohort of this model, obtained from the Vienna Cancer and Thrombosis Study (CATS), a prospective observational cohort study ( = 1409). Patients were followed for the occurrence of VTE for a maximum of two years. Competing-risk analysis was performed to obtain cumulative incidences and to conduct between-group comparisons of VTE risk. Cumulative two-year incidences of VTE were not elevated with gemcitabine treatment (10.2% vs. 7.5%, = 0.148), whereas they were higher for platinum-based therapy (11.6% vs. 5.9%, < 0.001). In a multivariable analysis, adjusting for tumor site category and D-dimer, gemcitabine was not associated with increased risk of VTE (subdistribution hazard ratio (SHR) 0.82, 95% confidence interval (CI) 0.53-1.28, = 0.390), whereas platinum-based therapy predicted for a numerically increased VTE risk (SHR 1.44, 95% CI 0.96-2.17, = 0.080). Similar results were obtained in a sensitivity analysis (updated cohort, = 1870). Our findings suggest limited additional value of chemotherapy for the prediction of cancer-associated VTE, beyond a validated clinical prediction model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12092493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564761PMC
September 2020

SARS-CoV-2 seroprevalence in oncology healthcare professionals and patients with cancer at a tertiary care centre during the COVID-19 pandemic.

ESMO Open 2020 09;5(5):e000889

Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: During the COVID-19 outbreak, healthcare professionals (HCP) are at the frontline of clinical management and at increased risk for infection. The SARS-CoV-2 seroprevalence of oncological HCP and their patients has significant implications for oncological care.

Methods: HCP and patients with cancer at the Division of Oncology, Medical University of Vienna were included between 21 March and 4 June and tested for total antibodies against SARS-CoV-2 employing the Roche Elecsys Anti-SARS-CoV-2 immunoassay. Reactive samples were confirmed or disproved by the Abbott SARS-CoV-2 IgG test. Additionally, a structured questionnaire regarding basic demographic parameters, travel history and COVID-19-associated symptoms had to be completed by HCP.

Results: 146 subjects (62 HCP and 84 patients with cancer) were enrolled. In the oncological HCP cohort, 20 (32.3%) subjects were medical oncologists, 28 (45.2%) nurses at our ward and 14 (22.6%) fulfil other functions such as study coordinators. In the patient cohort, most individuals are on active anticancer treatment (96.4%). 26% of the HCP and 6% of the patients had symptoms potentially associated with COVID-19 since the end of February 2020. However, only in 2 (3.2%) HCP and in 3 (3.6%) patients, anti-SARS-Cov-2 total antibodies were detected. The second assay for anti-SARS-Cov-2 IgG antibodies confirmed the positive result in all HCP and in 2 (2.4%) patients, suggesting an initial assay's unspecific reaction in one case. In individuals with a confirmed test result, an active COVID-19 infection was documented by a positive SARS-CoV-2 RNA PCR test.

Conclusion: Specific anti-SARS-CoV-2 antibodies were found solely in persons after a documented SARS-CoV-2 viral infection, thus supporting the test methods' high sensitivity and specificity. The low prevalence of anti-SARS-CoV-2 antibodies in our cohorts indicates a lack of immunity against SARS-CoV-2. It highlights the need for continued strict safety measures to prevent uncontrolled viral spread among oncological HCPs and patients with cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2020-000889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470513PMC
September 2020

Circumnavigating the challenges of COVID-19 in oncology.

Memo 2020 May 7:1-4. Epub 2020 May 7.

3Department of Oncology, Hematology and Palliative Care, Wilhelminen Hospital, Montleartstraße 37, 1160 Vienna, Austria.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12254-020-00611-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203542PMC
May 2020

PD-L1 Expression on Tumor Cells Is Associated With a Poor Outcome in a Cohort of Caucasian Nasopharyngeal Carcinoma Patients.

Front Oncol 2019 29;9:1334. Epub 2019 Nov 29.

Department of Internal Medicine I & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Nasopharyngeal carcinoma (NPC) is endemic in East Asia but rare in the western world. Programmed death ligand 1 (PD-L1) expression on NPC correlates with clinical outcomes. However, data for Caucasian NPC patients are missing. Thus, we performed this retrospective analysis for investigating the potential association of immune checkpoint protein expression with outcome parameters in Caucasian NPC patients. Fifty-five patients with NPC treated between 1993 and 2018 at the Medical University of Vienna were identified. After the exclusion of Asian patients, data on baseline demographic, tumor stage, overall survival (OS), and disease-free survival (DFS) of 30 patients were analyzed. Their tumor samples were stained and scored (low vs. high) for PD-L1, programmed death receptor 1 (PD-1), lymphocyte activating gene 3 (LAG3), and cluster of differentiation 8 (CD8) antibodies. Statistical analysis was performed with Kaplan-Meier plots and log-rank test. Estimated hazard ratios of dichotomized analysis were calculated, together with 95% confidence intervals and -values of Wald tests. PD-L1 expression was ≥50% in 6 (20%) patients, whereas 19 (63%) had ≥1% expression and 5 (17%) tumor samples were PD-L1-negative. While sex and age had no impact on DFS or OS, <50% PD-L1 expression on tumor cells (TC) was associated with a significantly longer OS (log rank test = 0.037; HR 0.275; 95% CI 0.073-1.03). There was no influence on DFS (log rank test = 0.34; HR 0.599; 95% CI 0.208-1.728). However, <10% PD-L1 expression on tumor infiltrating lymphocytes (TILs) was correlated with a worse DFS (log rank test = 0.0057; HR 4.06; 95% CI 1.389-11.868). LAG3 expression or the number of TILs did not play any prognostic role in our population. The PD-L1 expression rate on Caucasians was comparable to that in Asian patients. Although these results have to be interpreted with caution due to the limited number of Caucasian patients available, our data suggest that ≥50% PD-L1 expression on TC is associated with a poor outcome, while ≥10% PD-L1 expression on TILs is correlated with improved DFS. A prospective biomarker analysis of a predefined Caucasian NPC subpopulation would be desirable in future trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895019PMC
November 2019

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.

Lancet 2019 11 1;394(10212):1915-1928. Epub 2019 Nov 1.

Peter MacCallum Cancer Centre, Melbourne, VIC, Austrialia; University of Melbourne, Melbourne, VIC, Australia.

Background: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.

Methods: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.

Findings: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.

Interpretation: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.

Funding: Merck Sharp & Dohme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(19)32591-7DOI Listing
November 2019

Interim analysis of a real-world precision medicine platform for molecular profiling of metastatic or advanced cancers: MONDTI.

ESMO Open 2019 17;4(4):e000538. Epub 2019 Jul 17.

Department of Medicine I, Division of Oncology, Medical University of Vienna, Wien, Austria.

Background: High-throughput genomic profiling of tumour specimens facilitates the identification of individual actionable mutations which could be used for individualised targeted therapy. This approach is becoming increasingly more common in the clinic; however, the interpretation of results from molecular profiling tests and efficient guiding of molecular therapies to patients with advanced cancer offer a significant challenge to the oncology community.

Experimental Design: MONDTI is a precision medicine platform for molecular characterisation of metastatic solid tumours to identify actionable genomic alterations. From 2013 to 2016, comprehensive molecular profiles derived from real-time biopsy specimens and archived tumour tissue samples of 295 patients were performed. Results and treatment suggestions were discussed within multidisciplinary tumour board meetings.

Results: The mutational profile was obtained from 293 (99%) patients and a complete immunohistochemical (IHC) and cytogenetic profile was obtained in 181 (61%) and 188 (64%) patients. The most frequent cancer types were colorectal cancer (12%), non-Hodgkin's lymphomas (9.8%) and head and neck cancers (7.8%). The most commonly detected mutations were (39%), (19%) and (9.5%), whereas ≥1 mutation were identified in 217 (74%) samples. Regarding the results for IHC testing, samples were positive for phospho-mammalian target of rapamycin (phospho-mTOR) (71%), epidermal growth factor receptor (EGFR) (68%), mesenchymal epithelial transition (MET) (56%) and/or platelet-derived growth factor alpha (PDGFRα)-expression (48%). Of the 288 tumour samples with one or more genetic alteration detected, 160 (55.6%) targeted therapy recommendations through 67 multidisciplinary tumour board meetings were made; in 69 (24%) cases, an individual treatment concept was initiated.

Conclusions: The results reveal that the open concept for all solid tumours characterised for molecular profile and immunotherapy could not only match individualised treatment concepts at a high rate but also underscores the challenges encountered when offering molecularly matched therapies to a patient population with an advanced stage cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2019-000538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677998PMC
July 2019

Comparison of RECIST, iRECIST, and PERCIST for the Evaluation of Response to PD-1/PD-L1 Blockade Therapy in Patients With Non-Small Cell Lung Cancer.

Clin Nucl Med 2019 Jul;44(7):535-543

Respiratory Oncology Unit, Otto-Wagner Hospital, Vienna.

Purpose: The aim of this study was to compare the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the immune RECIST (iRECIST) criteria, and the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 in patients with advanced non-small cell lung cancer treated with programmed cell death protein 1 (PD-1)/programmed cell death protein 1 ligand (PD-L1) inhibitors.

Methods: This prospective study of 42 patients treated with a PD-1/PD-L1 inhibitor was approved by our institutional review board, and all patients gave written, informed consent. Tumor burden dynamics were assessed on F-FDG PET/CT before and after treatment initiation. Immunotherapeutic responses were evaluated according to RECIST 1.1, iRECIST, and PERCIST 1.0 for the dichotomous groups, responders versus nonresponders. Cohen κ and Wilcoxon signed rank tests were used to evaluate concordance among these criteria. We assessed progression-free survival and overall survival using the Kaplan-Meier estimator.

Results: The RECIST 1.1 and PERCIST 1.0 response classifications were discordant in 6 patients (14.2%; κ = 0.581). RECIST 1.1 and iRECIST were discordant in 2 patients, who evidenced pseudoprogression after treatment initiation. Median progression-free survival, as well as overall survival, was significantly longer for responders compared with nonresponders for all criteria (P < 0.001), with no significant difference between the 3 criteria (P > 0.05).

Conclusions: RECIST 1.1 and PERCIST 1.0 show only moderate agreement, but both can predict treatment response to PD-1/PD-L1 inhibitor therapy. In case of pseudoprogression, metabolic tumor activity may help to correctly classify treatment response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RLU.0000000000002603DOI Listing
July 2019

Results of the extended analysis for cancer treatment (EXACT) trial: a prospective translational study evaluating individualized treatment regimens in oncology.

Oncotarget 2019 Jan 29;10(9):942-952. Epub 2019 Jan 29.

Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.

Background: The concept of personalized medicine defines a promising approach in cancer care. High-throughput genomic profiling of tumor specimens allows the identification of actionable mutations that potentially lead to tailored treatment for individuals' benefit. The aim of this study was to prove efficacy of a personalized treatment option in solid tumor patients after failure of standard treatment concepts.

Results: Final analysis demonstrates that 34 patients (62%) had a longer PFS upon experimental treatment (PFS1) when compared to previous therapy (PFS0); PFS ratio > 1.0 ( = 0.002). The median PFS under targeted therapy based on molecular profiling (PFS1) was 112 days (quartiles 66/201) and PFS0 = 61 days (quartiles 51/92; = 0.002). Of the 55 patients, 31 (56%) showed disease control (DCR), consisting of 2 (4%) patients which achieved a complete remission, 14 (25%) patients with a partial remission and 15 (27%) patients who had a stabilization of disease. Median OS from start of experimental therapy was 348 days (quartiles 177/664).

Conclusion: The prospective trial EXACT suggests that treatment based on real-time molecular tumor profiling leads to superior clinical benefit.

Materials And Methods: In this prospective clinical phase II trial, 55 cancer patients, after failure of standard treatment options, aimed to achieve a longer progression-free survival on the experimental treatment based on the individual's molecular profile (PFS1) when compared to the last treatment given before (PFS0). The personalized medicine approach was conceived to be clinical beneficial for patients who show a PFS ratio (PFS 1/PFS0) of > 1.0.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.26604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398177PMC
January 2019

Modified biweekly cisplatin, docetaxel plus cetuximab (TPEx) as first-line treatment for patients with recurrent/metastatic head and neck cancer.

Med Oncol 2018 Feb 7;35(3):32. Epub 2018 Feb 7.

Division of Clinical Oncology, Department of Internal Medicine I & Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Three weekly high-dose chemotherapy regimens in combination with weekly cetuximab are the treatment of choice for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN), although the majority of patients suffer from severe side effects. Thus, we investigated the efficacy and safety of an alternative, more convenient and less toxic biweekly modified cisplatin, docetaxel plus cetuximab (TPEx) regimen in this retrospective analysis. Thirty-eight patients receiving off-protocol cisplatin (50 mg/m) in combination with docetaxel (50 mg/m) plus cetuximab (500 mg/m) every other week were included. Data collection included baseline demographic, response rate (ORR) and toxicity data as well as disease control rate, overall survival (OS) and progression-free survival (PFS). The median age was 60 years, and the majority of patients suffered from oral cavity carcinomas (44.7%) followed by oropharyngeal (28.9%) and laryngeal (17.9%) carcinomas. The ORR was 50%, and four (10.5%) patients achieved a complete response, while 15 (39.5%) patients had a partial response. The OS and PFS were 10.8 months (95% CI 6.7-14.2) and 6.3 months (95% CI 5.7-6.8), respectively. The one-year survival rate was 44.7%. The therapy was well tolerated, and the most common grade 3/4 adverse events were myelosuppression (13.2%), hypomagnesaemia (23.7%) and acne-like rash (13.1%). In conclusion, modified biweekly TPEx is of comparable efficacy with conventional TPEx and represents a well-tolerated regimen in R/M SCCHN patients. Further evaluation of this protocol in prospective clinical trials is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12032-018-1087-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801394PMC
February 2018

Metal drugs become targeted.

ESMO Open 2017 17;2(3):e000239. Epub 2017 Aug 17.

Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2017-000239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604710PMC
August 2017

The European Society for Medical Oncology 'Magnitude of Clinical Benefit Scale' field-tested in infrequent tumour entities: an extended analysis of its feasibility at the Medical University of Vienna.

ESMO Open 2017 16;2(3):e000166. Epub 2017 Jul 16.

Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a new tool to quantify the clinical benefit that may be anticipated from a novel anticancer treatment. We present here an analysis on the feasibility of the ESMO-MCBS in less frequent tumour entities.

Methods: This study evaluates the practicability of the ESMO-MCBS for metastatic neuroendocrine tumours (NETs), soft tissue sarcomas, glioblastoma, thyroid cancer, pancreatic cancer, head/neck cancer, urothelial cancer and ovarian cancer at the Medical University Vienna. A three-step approach including data acquisition, assessment of ESMO-MCBS scores and evaluation of results with a focus on clinical feasibility was applied.

Results: In NET and thyroid cancer, all analysed trials were very comparable in design and efficacy, and the ESMO-MCBS scores appeared to be consistent with the clinical benefit seen in practice. For pancreatic cancer, it was more difficult to compare first-line trials due to diverging populations included in the respective studies. Concerning soft tissue sarcomas, the ESMO-MCBS was applicable for gastrointestinal stromal tumours(GIST) and 'non-GIST' soft tissue sarcoma with respect to data deriving from randomised studies. However, due to the heterogeneity of the disease itself and a limited number of controlled trials, limitations are noted. In ovarian cancer, the ESMO-MCBS supported the use of bevacizumab in high-risk patients. To date, there are only limited data for glioblastoma, head/neck cancer and urothelial cancer but whenever randomised trials were available, the ESMO-MCBS rating supported clinical decisions. Interestingly, nivolumab for salvage treatment of head/neck cancer rated extremely high.

Conclusion: The ESMO-MCBS scores supported our common treatment strategies and highlight the potential of new immunomodulatory drugs. Our results encourage further development of the ESMO-MCBS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2017-000166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519788PMC
July 2017

Docetaxel plus cetuximab biweekly is an active regimen for the first-line treatment of patients with recurrent/metastatic head and neck cancer.

Sci Rep 2016 09 6;6:32946. Epub 2016 Sep 6.

Dept. of Internal Medicine I &CCC, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.

For patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN) limited therapeutic options exist. Only a subset of patients is suitable for combination chemotherapy regimens. Biweekly docetaxel plus cetuximab might be an alternative option. Thus, we performed this retrospective analysis in unselected patients in order to investigate the efficacy and safety of this regimen. Thirty-one patients receiving off protocol docetaxel (50 mg/m(2)) plus cetuximab (500 mg/m(2)) biweekly were included. Data collection included baseline demographic, response rate (ORR), disease control rate (DCR), overall survival (OS), progression free survival (PFS) as well as toxicity. OS and PFS were 8.3 months (95% CI 4.8-11.8) and 4.0 months (95% CI 1.0-7.0), respectively. Three (9.7%) patients achieved a complete response and one patient (3.2%) a partial response. The DCR was 41.9% and we observed an ORR of 12.9%. The one-year survival rate was 25.8%. The therapy was well tolerated and the most common grade 3/4 adverse events were neutropenia (19.4%), hypomagnesaemia (12.9%) and acne-like rash (9.7%). Biweekly cetuximab/docetaxel is an effective regimen and well tolerated in R/M SCCHN patients not suitable for platinum doublet treatment. Further evaluation of this regimen in prospective clinical trials is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep32946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011715PMC
September 2016

The association of medication-related osteonecrosis of the jaw with Actinomyces spp. infection.

Sci Rep 2016 08 17;6:31604. Epub 2016 Aug 17.

Department of Medicine I, Medical University of Vienna, Austria.

Medication-related osteonecrosis of the jaw (MRONJ) represents a complication of bisphosphonate treatment that responds poorly to standard treatment. In a retrospective cohort study we investigated a possible role of Actinomyces spp. in the pathogenesis of MRONJ. Deep biopsies of necrotic bone were collected during surgical treatment of MRONJ and evaluated by histology and microbiology for the presence of Actinomyces spp. Microbiological, demographic and clinicpathological data were analyzed for risk of Actinomyces-associated MRONJ. Between 2005 and 2014, 111 patients suffering from histologically-confirmed MRONJ were identified. Actinomyces spp. were detected in 99 cases (89%) by histology and in six further patients by microbiological culture. A diverse microbial flora was found in all specimens without association with Actinomyces spp. Demographic and clinicopathological characteristics did not separate significantly Actinomyces-positive from Actinomyces-negative cases. Our observations confirm previous reports of a high prevalence of Actinomyces spp. in MRONJ in the single largest cohort available up to now. The high prevalence of Actinomyces spp. and the lack of clinicopathological risk factors underline the prominent role of Actinomyces spp. in MRONJ and may change the current understanding of MRONJ. Established prolonged antimicrobial treatment regimens against Actinomyces spp. infection could therefore be a mainstay of future MRONJ management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep31604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987681PMC
August 2016

Risk factors for Clostridium difficile infection in hemato-oncological patients: A case control study in 144 patients.

Sci Rep 2016 08 11;6:31498. Epub 2016 Aug 11.

Department of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.

Evidence on risk factors for Clostridium difficile infection (CDI) in hemato-oncologic patients is conflicting. We studied risk factors for CDI in a large, well-characterized cohort of hemato-oncological patients. 144 hemato-oncological patients were identified in this retrospective, single center study with a microbiologically confirmed CDI-associated diarrhea. Patients were compared with 144 age and sex matched hemato-oncologic patients with CDI negative diarrhea. Risk factors such as prior antimicrobial therapy, type of disease, chemotherapy and survival were evaluated. CDI-positive patients received more frequently any antimicrobial agent and antimicrobial combination therapy than CDI-negative patients (79% vs. 67%; OR = 2.26, p = 0.038 and OR = 2.62, p = 0.003, respectively). CDI positive patients were treated more frequently with antimicrobial agents active against C. difficile than CDI negative ones (25% vs. 13%; OR = 2.2, p = 0.039). The interval between last chemotherapy and onset of diarrhea was significantly shorter in patients without CDI (median, 17 days vs 36 days; p < 0.001). Our study demonstrates that chemotherapy is not a significant risk factor for CDI but for early onset CDI negative diarrhea. The predominant modifiable risk factor for CDI is in hemato-oncological patients antimicrobial treatment. These findings should be taken into account in the daily clinical practice to avoid CDI associated complications and excess health care costs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep31498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980611PMC
August 2016

Immunotherapy for head and neck squamous cell carcinoma.

Memo 2016;9:66-69. Epub 2016 Jun 20.

Dept. of Internal Medicine I & CCC, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.

Over the past years immuno-oncology has evolved and become a novel promising strategy for cancer therapy. Immune checkpoint inhibitors such as pembrolizumab or nivolumab, which target the interaction between programmed death receptor 1/programmed death ligand 1 (PD-1/PDL-1) and PDL-2, have been recently approved for the treatment of various malignancies and are currently being investigated in clinical phase III trials for head and neck squamous cell carcinoma (HNSCC). Data available from these trials indicate substantial activity accompanied by a favorable safety and toxicity profile in this patient population. This review article focuses on the molecular background, gives an overview of current clinical data of checkpoint inhibitors in HNSCC, and points out future challenges such as the need for appropriate biomarkers for these novel compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12254-016-0270-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923082PMC
June 2016

Response to GEMOX plus erlotinib in pancreatic cancer is associated with ERCC1 overexpression.

Eur J Clin Invest 2014 Oct;44(10):958-64

Department of Internal Medicine I & CCC, Medical University of Vienna, Vienna, Austria.

Introduction: There are no data about the efficacy of gemcitabine in combination with oxaliplatin (GEMOX) and erlotinib for the treatment of metastatic pancreatic cancer (mPC). Thus, we performed this retrospective analysis in mPC patients to investigate the activity and safety of GEMOX plus erlotinib and correlated the benefit with ERCC1 expression, a potential biomarker for treatment response.

Patients And Methods: Patients with untreated mPC receiving off-protocol GEMOX plus erlotinib were included. Data collection included baseline demographic, response and toxicity data as well as PFS and OS. Additionally, immunohistochemistry was performed to stain for ERCC1 expression.

Results: A total of 51 patients were included. The median age was 62 years and the median ECOG performance score was 1 (range, 0-1). Objective response or disease stabilization was achieved in 54% of the patients. The median PFS was 4·4 months (95% CI 4·4-5·4) and median OS was 8·5 months (95% CI 6·1-10·9). The 27 patients, who benefited from this regimen, had a median PFS of 6·7, a median OS of 11·2 months and an overexpression of ERCC1 (histoscore 10, P ≤ 0·05) compared to nonresponders (histoscore 7·2). Myelosuppression was the most frequent side effect. The most common severe nonhematological toxicities were diarrhoea and skin toxicity in six (12%) patients each.

Conclusions: These data suggest that the combination of GEMOX plus erlotinib is safe and active in about half of the patients. Patients, who had a higher ERCC1 staining pattern, benefited most from this therapy. Prospective biomarker studies are warranted to confirm these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/eci.12329DOI Listing
October 2014

Circulating endothelial progenitor cells in castration resistant prostate cancer: a randomized, controlled, biomarker study.

PLoS One 2014 22;9(4):e95310. Epub 2014 Apr 22.

Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential biomarkers of response to anti-angiogenic treatment regimens. In the current study, we investigated the effect of docetaxel and sunitinib on CEP/CEC kinetics and clinical response in castration resistant prostate cancer (CRPC) patients.

Patients And Methods: Chemonaive patients with CRPC were enrolled in this study to receive either sunitinib (37.5 mg/d), in combination with docetaxel (75 mg/m2) or docetaxel alone. CEP and CEC kinetics were analyzed for every cycle. The primary objective was to compare CEP/CEC pharmacodynamics between both treatment arms. We also investigated if CEC/CEP spikes, induced by MTD docetaxel, are suppressed by sunitinib in patients treated with docetaxel/sunitinib relative to docetaxel monotherapy.

Results: A total of 27 patients were enrolled. We observed a significant increase of CEP/CEC (total/viable) counts over time within each cycle (coefficients 0.29233, 0.22092 and 0.26089, respectively; p<0.001). However, no differences between the treatment groups, in terms of CEP and CEC kinetics, were detected. In the docetaxel monotherapy arm 4 (30%) patients responded to therapy with a 50% PSA decline, while 9 (64%) patients showed a PSA decline in the combination group (n.s.). The median PFS in the docetaxel monotherapy group was 3.1 months (2.6-3.6 months, 95% CI) and 6.2 months (4.9-7.4 months, 95% CI; p = 0.062) in the combination arm. Sunitinib/docetaxel was reasonably well tolerated and toxicity manageable.

Conclusion: In summary, no significant differences in CEC and CEP kinetics between the treatment arms were observed, although a highly significant increase of CEPs/CECs within each cycle over time was detected. These results mirror the challenge we have to face when employing anti-angiogenic strategies in CRPC. Additional preclinical research is needed to elucidate the underlying molecular mechanisms. However, docetaxel/sunitinib therapy resulted in a better response in terms of PSA decline and a trend towards improved PFS.

Trial Registery: clinicaltrialsregister.eu EudraCT 2007-003705-27.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095310PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995874PMC
January 2015

Gastric cancer growth control by BEZ235 in vivo does not correlate with PI3K/mTOR target inhibition but with [18F]FLT uptake.

Clin Cancer Res 2011 Aug 28;17(16):5322-32. Epub 2011 Jun 28.

Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria.

Purpose: In this study, we tested the antitumor activity of the dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo.

Experimental Design: Gastric cancer cell lines (N87, MKN45, and MKN28) were incubated with BEZ235 and assessed for cell viability, cell cycle, and PI3K/mTOR target inhibition. In vivo, athymic nude mice were inoculated with N87, MKN28, or MKN45 cells and treated daily with BEZ235. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake was measured via small animal positron emission tomography (PET).

Results: In vitro, BEZ235 dose dependently decreased the cell viability of gastric cancer cell lines. The antiproliferative activity of BEZ235 was linked to a G(1) cell-cycle arrest. In vivo, BEZ235 treatment resulted in PI3K/mTOR target inhibition as shown by dephosphorylation of AKT and S6 protein in all xenograft models. However, BEZ235 treatment only inhibited tumor growth of N87 xenografts, whereas no antitumor effect was observed in the MKN28 and MKN45 xenograft models. Sensitivity to BEZ235 in vivo correlated with downregulation of the proliferation marker thymidine kinase 1. Accordingly, [(18)F]FLT uptake was only significantly reduced in the BEZ235-sensitive N87 xenograft model as measured by PET.

Conclusion: In conclusion, in vivo sensitivity of gastric cancer xenografts to BEZ235 did not correlate with in vitro antiproliferative activity or in vivo PI3K/mTOR target inhibition by BEZ235. In contrast, [(18)F]FLT uptake was linked to BEZ235 in vivo sensitivity. Noninvasive [(18)F]FLT PET imaging might qualify as a novel marker for optimizing future clinical testing of dual PI3K/mTOR inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-10-1659DOI Listing
August 2011

Sphingosine kinase 1 is a relevant molecular target in gastric cancer.

Anticancer Drugs 2011 Mar;22(3):245-52

Department of Clinical Pharmacology, Medical University, Vienna, Austria.

Sphingosine kinase 1 (Sphk1), a lipid kinase implicated in cell transformation and tumor growth, is overexpressed in gastric cancer and is linked with a poor prognosis. The biological relevance of Sphk1 expression in gastric cancer is unclear. Here, we studied the functional significance of Sphk1 as a novel molecular target for gastric cancer by using an antisense oligonucleotide approach in vitro and in vivo. Gastric cancer cell lines (MKN28 and N87) were treated with Sphk1 with locked nucleic acid-antisense oligonucleotides (LNA-ASO). Sphk1 target regulation, cell growth, and apoptosis were assessed for single-agent Sphk1 LNA-ASO and for combinations with doxorubicin. Athymic nude mice xenografted with gastric cancer cells were treated with Sphk1 LNA and assessed for tumor growth and Sphk1 target regulation, in vivo. In vitro, nanomolar concentrations of Sphk1 LNA-ASO induced an approximately two-fold reduction in Sphk1 mRNA in both the cell lines. This resulted in a 1.6-fold increase in apoptosis and inhibited the growth of gastric cancer cells by more than 50% (P < 0.05). The combination of Sphk1 LNA-ASO with doxorubicin resulted in significant chemosensitization. In vivo, Sphk1 LNA-ASO displayed neither mRNA target regulation in xenografts nor antitumor activity in two independent nude mouse xenograft models. In conclusion, the potent single-agent activity and the synergistic effect of Sphk1 LNA-ASO in combination with chemotherapy in vitro highlight Sphk1 as a biologically relevant molecular target for gastric cancer. Further studies are warranted to overcome the challenge of delivering Sphk1-targeting RNA-therapeutics to solid tumors in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/cad.0b013e328340bd95DOI Listing
March 2011

Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo.

J Invest Dermatol 2011 Feb 4;131(2):495-503. Epub 2010 Nov 4.

Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, Medical University of Vienna, Vienna, Austria.

The phosphatidyl inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway has been shown to be involved in the development of melanoma. PI-103 is a kinase inhibitor blocking PI3K class IA and mTOR complex 1 and 2. Here, we studied the effect of targeting the PI3K/mTORC1/mTORC2 pathway by PI-103 and rapamycin in melanoma cells and in a melanoma mouse model. Dual targeting of PI3K and mTOR by PI-103 induced apoptosis and cell-cycle arrest, and inhibited viability of melanoma cells in vitro. Combined treatment with PI-103 and the prototypic mTORC1 inhibitor rapamycin led to the synergistic suppression of AKT and ribosomal S6 protein phosphorylation and to the induction of apoptosis. In vivo, PI-103 and rapamycin displayed only modest single-agent activity, but the combination significantly reduced the tumor growth compared with both single agents. These data show that blocking the PI3K/mTORC1/mTORC2 pathway using the combination of two distinct small-molecule inhibitors ("vertical inhibition") leads to superior efficacy against malignant melanoma in vitro and in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jid.2010.327DOI Listing
February 2011

Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis.

Arthritis Rheum 2010 Aug;62(8):2294-302

Medical University of Vienna, Vienna, Austria.

Objective: Activation of the mammalian target of rapamycin (mTOR) pathway is important for immune cell activation and bone metabolism. To date, the contribution of mTOR signaling to joint inflammation and structural bone and cartilage damage is unknown. The aim of this study was to investigate the potential of inhibiting mTOR as a treatment of inflammatory arthritis.

Methods: Human tumor necrosis factor-transgenic mice in which inflammatory arthritis was developing were treated with 2 different mTOR inhibitors, sirolimus or everolimus. The effects of treatment on clinical disease activity, inflammation, and localized joint and cartilage destruction were studied. In addition, the effects of mTOR inhibition on osteoclast survival and expression of key molecules of osteoclast function were analyzed in vitro. Moreover, synovial tissue from patients with rheumatoid arthritis (RA) was assessed for activation of the mTOR pathway.

Results: Inhibition of mTOR by sirolimus or everolimus reduced synovial osteoclast formation and protected against local bone erosions and cartilage loss. Clinical signs of arthritis improved after mTOR inhibition, and histologic evaluation showed a decrease in synovitis. In vitro, mTOR inhibition down-regulated the expression of digestive enzymes and led to osteoclast apoptosis. Moreover, mTOR signaling was shown to be active in the synovial membrane of patients with RA, particularly in synovial osteoclasts.

Conclusion: Signaling through mTOR is an important link between synovitis and structural damage in inflammatory arthritis. Current pharmacologic inhibitors of mTOR could be effective in protecting joints against structural damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.27504DOI Listing
August 2010

mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves anti-tumor activity against gastric cancer in vivo.

Cancer Lett 2010 Oct 14;296(2):249-56. Epub 2010 May 14.

Department of Clinical Pharmacology, Medical University Vienna, Austria.

VEGF receptor blockage has been reported to increase serum VEGF. We hypothesized that mTOR inhibition by everolimus counteracts VEGF induction by sunitinib resulting in an improved anti-tumor activity of sunitinib. In vitro, sunitinib in combination with everolimus did not outperform the respective monotherapies. In vivo, monotherapies reduced tumor growth by 60%, whereas the combination of sunitinib and everolimus led to an almost complete tumor growth inhibition. This superior anti-tumor activity coincided with attenuation of VEGF peaks. In conclusion mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and results in significant reduction of tumor burden and long-lasting tumor growth control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2010.04.015DOI Listing
October 2010
-->