Publications by authors named "Volker Kunzmann"

58 Publications

Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.

Leukemia 2021 Feb 18. Epub 2021 Feb 18.

Medizinische Klinik und Poliklinik I, Universitätsklinikum der Technischen Universität Dresden, Dresden, Germany.

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01148-xDOI Listing
February 2021

Decitabine treatment in 311 patients with acute myeloid leukemia: outcome and impact of mutations - a registry based analysis.

Leuk Lymphoma 2021 Jan 5:1-15. Epub 2021 Jan 5.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany.

We performed a registry-based analysis of 311 AML patients treated with decitabine in a standard of care setting to assess response and survival data with a distinct focus on the impact of the mutation status. Median age was 73 years. 172 patients received decitabine first-line and 139 in r/r disease. The ORR (whole cohort) was 30% with a median overall survival of 4.7 months. First-line patients achieved better responses than r/r-patients (ORR: 38% vs. 21%) resulting in a median OS of 5.8 months vs. 3.9 months. NGS based mutation analysis was performed in 180 patients. 20 patients (11%) harbored a mutation. Response rates and survival did not differ significantly between mutated patients and wild-type patients. This analysis of a large cohort of AML patients provides response rates and OS data after decitabine treatment. Interestingly, outcome was not negatively influenced by a mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1864354DOI Listing
January 2021

Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial.

Lancet Gastroenterol Hepatol 2021 02 16;6(2):128-138. Epub 2020 Dec 16.

Department of Medical Oncology and Comprehensive Cancer Center, Ludwig Maximilians University - Grosshadern, Munich, Germany.

Background: The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer.

Methods: In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m plus gemcitabine 1000 mg/m (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m, leucovorin 400 mg/m, irinotecan 180 mg/m, fluorouracil 400 mg/m by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136.

Findings: Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3-48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7-56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35-1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8-27·6), median overall survival was 18·5 months (95% CI 14·4-21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9-28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55-1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase.

Interpretation: Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival.

Funding: Celgene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2468-1253(20)30330-7DOI Listing
February 2021

Interferon-Induced Protein With Multiple Tetratricopeptide Repeats 3 Is Associated With Response to Chemotherapy and Recurrence but Not With Survival.

Pancreas 2020 Nov/Dec;49(10):1307-1314

From the Department of General, Visceral, Cancer and Transplantation Surgery.

Objectives: The interferon-induced protein with multiple tetratricopeptide repeats 3 (IFIT3) seems to be associated with the prognosis in pancreatic cancer. Here we clarify whether the heterogeneity of IFIT3 expression affects previous IFIT3 analysis.

Methods: This retrospective study analyzes pancreatic cancer tissue samples retrieved by surgery from 2 independent patient cohorts. Patients underwent either primary surgery (n = 72) or received neoadjuvant chemotherapy (n = 12). Immunohistochemistry assessed IFIT3 expression and its heterogeneity. Complementarily, we analyzed publicly available transcriptomic data (n = 903).

Results: Of the primarily resected tumors, 16.4% were heterogeneous. Patients with IFIT3-negative tumors did not survive longer compared with patients with IFIT3-positive tumors. An analysis of publicly available data confirmed this result. Patients developing lung metastases had the best prognosis (4.8 years) with significantly lower IFIT3 expression compared with liver metastasis (P = 0.0117). Patients receiving neoadjuvant therapy who are IFIT3 negative had a longer disease-free survival (1.2 vs 0.3 years, P = 0.0081).

Conclusions: Low IFIT3 expression is not associated with longer survival. Divergent results from tissue microarray analyses could be explained with tumor heterogeneity. As a single biomarker, IFIT3 is not suitable for predicting disease prognosis. Recurrence of lung metastases and response to neoadjuvant chemotherapy are associated with low IFIT3 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPA.0000000000001691DOI Listing
October 2020

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper.

Oncol Res Treat 2020 23;43(11):628-636. Epub 2020 Oct 23.

Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim, Mannheim, Germany.

Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1.0%.

Summary: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000510258DOI Listing
March 2021

Quality of life and outcome of patients with metastatic pancreatic cancer receiving first-line chemotherapy with nab-paclitaxel and gemcitabine: Real-life results from the prospective QOLIXANE trial of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer registry.

Int J Cancer 2021 Mar 23;148(6):1478-1488. Epub 2020 Oct 23.

Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany.

Few data exist on health-related quality of life (QoL) in patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy (Awad L ZE, Mesbah M Boston, MA. Applying survival data methodology to analyze quality of life data, in Mesbah M, Cole BF, Ting Lee M-L (eds): Statistical Methods for Quality of Life Studies: Design, Measurements and Analysis. Kluwer Academic Publishers 2002). The QOLIXANE study is a prospective, noninterventional, multicenter substudy of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer (PARAGON) registry, which evaluated QoL in patients with mPC receiving first-line gemcitabine and nab-paclitaxel chemotherapy in real-life setting. QoL was prospectively measured via EORTC QLQ-C30 questionnaires at baseline and every month thereafter. Therapy and efficacy parameters were prospectively collected. Main objectives were the rate of patients without deterioration of Global Health Status/QoL (GHS/QoL) at 3 and 6 months. Six hundred patients were enrolled in 95 German study sites. Median progression-free survival was 5.9 months (95% confidence interval [CI], 5.2-6.3). Median overall survival (OS) was 8.9 months (95% CI, 7.9-10.2), while median time to deterioration of GHS/QoL was 4.7 months (95% CI, 4.0-5.6). With a baseline GHS/QoL score of 46 (SD, 22.8), baseline QoL of the patients was severely impaired, in most cases due to loss in role functioning and fatigue. In the Kaplan-Meier analysis, 61% and 41% of patients had maintained GHS/QoL after 3 and 6 months, respectively. However, in the QoL response analysis, 35% and 19% of patients had maintained (improved or stable) GHS/QoL after 3 and 6 months, respectively, while 14% and 9% had deteriorated GHS/QoL with the remaining patients being nonevaluable. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a hazard ratio of 0.86 (P < .0001). Patients with mPC have poor QoL at baseline that deteriorates within a median of 4.7 months. Treatment with gemcitabine and nab-paclitaxel is associated with maintained QoL in relevant proportions of patients. However, overall, results remain poor, reflecting the aggressive nature of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33336DOI Listing
March 2021

Impact of Borderline Resectability in Pancreatic Head Cancer on Patient Survival: Biology Matters According to the New International Consensus Criteria.

Ann Surg Oncol 2020 Sep 12. Epub 2020 Sep 12.

Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Würzburg, Germany.

Background: International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important.

Methods: Patients' tumours were retrospectively defined borderline resectable according to ICC. The study cohort was grouped into either BR-A or BR-B and compared with patients considered primarily resectable (R). Differences in postoperative complications, pathological reports, overall (OS), and disease-free survival were assessed.

Results: A total of 345 patients underwent resection for PDAC. By applying ICC in routine preoperative assessment, 30 patients were classified as stage BR-A and 62 patients as stage BR-B. In total, 253 patients were considered R. The cohort did not contain BR-C patients. No differences in postoperative complications were detected. Median OS was significantly shorter in BR-A (15 months) and BR-B (12 months) compared with R (20 months) patients (BR-A vs. R: p = 0.09 and BR-B vs. R: p < 0.001). CA19-9, as the determining factor of BR-B patients, turned out to be an independent prognostic risk factor for OS.

Conclusions: Preoperative staging defining surgical resectability in PDAC according to ICC is crucial for patient survival. Patients with PDAC BR-B should be considered for multimodal neoadjuvant therapy even if considered anatomically resectable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09100-6DOI Listing
September 2020

Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia?

Blood 2020 Aug;136(7):823-830

Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany.

In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. All registered non-acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019004583DOI Listing
August 2020

Butyrophilin-2A1 Directly Binds Germline-Encoded Regions of the Vγ9Vδ2 TCR and Is Essential for Phosphoantigen Sensing.

Immunity 2020 03 9;52(3):487-498.e6. Epub 2020 Mar 9.

Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany. Electronic address:

Vγ9Vδ2 T cells respond in a TCR-dependent fashion to both microbial and host-derived pyrophosphate compounds (phosphoantigens, or P-Ag). Butyrophilin-3A1 (BTN3A1), a protein structurally related to the B7 family of costimulatory molecules, is necessary but insufficient for this process. We performed radiation hybrid screens to uncover direct TCR ligands and cofactors that potentiate BTN3A1's P-Ag sensing function. These experiments identified butyrophilin-2A1 (BTN2A1) as essential to Vγ9Vδ2 T cell recognition. BTN2A1 synergised with BTN3A1 in sensitizing P-Ag-exposed cells for Vγ9Vδ2 TCR-mediated responses. Surface plasmon resonance experiments established Vγ9Vδ2 TCRs used germline-encoded Vγ9 regions to directly bind the BTN2A1 CFG-IgV domain surface. Notably, somatically recombined CDR3 loops implicated in P-Ag recognition were uninvolved. Immunoprecipitations demonstrated close cell-surface BTN2A1-BTN3A1 association independent of P-Ag stimulation. Thus, BTN2A1 is a BTN3A1-linked co-factor critical to Vγ9Vδ2 TCR recognition. Furthermore, these results suggest a composite-ligand model of P-Ag sensing wherein the Vγ9Vδ2 TCR directly interacts with both BTN2A1 and an additional ligand recognized in a CDR3-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2020.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083227PMC
March 2020

Plasma Next Generation Sequencing and Droplet Digital-qPCR-Based Quantification of Circulating Cell-Free RNA for Noninvasive Early Detection of Cancer.

Cancers (Basel) 2020 Feb 4;12(2). Epub 2020 Feb 4.

German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.

Early detection of cancer holds high promise for reducing cancer-related mortality. Detection of circulating tumor-specific nucleic acids holds promise, but sensitivity and specificity issues remain with current technology. We studied cell-free RNA (cfRNA) in patients with non-small cell lung cancer (NSCLC; n = 56 stage IV, n = 39 stages I-III), pancreatic cancer (PDAC, n = 20 stage III), malignant melanoma (MM, n = 12 stage III-IV), urothelial bladder cancer (UBC, n = 22 stage II and IV), and 65 healthy controls by means of next generation sequencing (NGS) and real-time droplet digital PCR (RT-ddPCR). We identified 192 overlapping upregulated transcripts in NSCLC and PDAC by NGS, more than 90% of which were noncoding. Previously reported transcripts (e.g., HOTAIRM1) were identified. Plasma cfRNA transcript levels of POU6F2-AS2 discriminated NSCLC from healthy donors (AUC = 0.82 and 0.76 for stages IV and I-III, respectively) and significantly associated ( = 0.017) with the established tumor marker Cyfra 21-1. cfRNA yield and POU6F2-AS transcript abundance discriminated PDAC patients from healthy donors (AUC = 1.0). POU6F2-AS2 transcript was significantly higher in MM ( = 0.044). In summary, our findings support further validation of cfRNA detection by RT-ddPCR as a biomarker for early detection of solid cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12020353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073169PMC
February 2020

Prognostic impact of simultaneous venous resections during surgery for resectable pancreatic cancer.

HPB (Oxford) 2020 Oct 21;22(10):1384-1393. Epub 2020 Jan 21.

Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Centre Mainfranken, Julius Maximilians University Wuerzburg, Wuerzburg, Germany.

Background: The aim of this study was to evaluate the prognostic impact of simultaneous venous resection during pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) that was preoperatively staged resectable according to NCCN guidelines.

Methods: A retrospective analysis of 153 patients who underwent PD for PDAC was performed. Patients were divided into standard PD and PD with simultaneous vein resection (PDVR). Groups were compared to each other in terms of postoperative morbidity and mortality, disease free (DFS) and overall survival (OS).

Results: 114 patients received PD while 39 patients received PDVR. No differences in terms of postoperative morbidity and mortality between both groups were detected. Patients in the VR group presented with a significantly shorter OS in the median (13 vs. 21 months, P = 0.011). In subgroup analysis, resection status did not influence OS in the PDVR group (R0 13 vs. R1 12 months, P = 0.471) but in the PD group (R0 23 vs. R1 14 months, P = 0.043). PDVR was a risk factor of OS in univariate but not multivariable analysis.

Conclusion: PDVR for PDAC preoperatively staged resectable resulted in significantly shorter OS regardless of resection status. Patients who require PDVR should be considered for adjuvant chemotherapy in addition to other oncological indications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hpb.2019.12.017DOI Listing
October 2020

Patient-doctor relationship and adherence to capecitabine in outpatients of a German comprehensive cancer center.

Patient Prefer Adherence 2018 21;12:1875-1887. Epub 2018 Sep 21.

Section of Clinical Oncology, Department of Internal Medicine II, University of Wuerzburg, Bavaria, Germany.

Purpose: The prescribing of oral chemotherapy agents has introduced the new challenge of ensuring patients' adherence to therapy. Aspects of a close patient-doctor relationship are reported to be correlated with adherence to oral anticancer drugs, but data on capecitabine are scarce.

Patients And Methods: Sixty-four outpatients with a diagnosis of cancer and prescribed capecitabine were recruited from a German Comprehensive Cancer Center. We used the Patient-Doctor Relationship Questionnaire (PDRQ-9), the Medical Adherence Rating Scale (MARS), the Beliefs about Medicines Questionnaire (BMQ), and the Satisfaction with Information about Medicines Scale (SIMS) to assess patients' perceptions and behavior. Medical data were extracted from the charts.

Results: Non-adherence was reported by 20% of the 64 participants. The perceived quality of the patient-doctor relationship was high in general, but it did not emerge as a predictor of adherence in our survey (odds ratio [OR]=0.915, =0.162, 95% CI=0.808-1.036). However, beliefs about medicine (OR=1.268, <0.002; 95% CI=1.090-1.475) as well as satisfaction with information about medicine (OR=1.252, <0.040, 95% CI=1.010-1.551) were predictors of adherence and the quality of the patient-doctor relationship was correlated with both variables (=0.373, =0.002 for SIMS sum score; =0.263, =0.036 for BMQ necessity/concern difference). Overall, adherence to capecitabine was high with a conviction that the therapy is necessary. However, concerns were expressed regarding the long-term effect of capecitabine use. Patients have unmet information needs regarding interactions of capecitabine with other medicines and the impairment of their intimate life.

Conclusions: In order to ensure adherence to capecitabine, our results seem to encourage the default use of modern and perhaps more impersonal means of information brokerage (eg, email, internet). However, the contents of some of patients' informational needs as well as the associations of patients' beliefs and satisfaction about the information received suggest a benefit from a trustful patient-doctor relationship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/PPA.S169354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159803PMC
September 2018

Randomised phase II trial to investigate catumaxomab (anti-EpCAM × anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer.

Br J Cancer 2018 08 10;119(3):296-302. Epub 2018 Jul 10.

University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany.

Background: Peritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC.

Methods: This prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery.

Results: Median follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms.

Conclusions: Addition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-018-0150-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070920PMC
August 2018

Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia.

Blood Adv 2018 07;2(13):1572-1579

Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Telomere length (TL) in peripheral blood (PB) cells of patients with chronic myeloid leukemia (CML) has been shown to correlate with disease stage, prognostic scores, response to therapy, and disease progression. However, due to considerable genetic interindividual variability, TL varies substantially between individuals, limiting its use as a robust prognostic marker in individual patients. Here, we compared TL of BCR-ABL, nonleukemic CD34CD38 hematopoietic stem cells (HSC) in the bone marrow of CML patients at diagnosis to their individual BCR-ABL leukemic stem cell (LSC) counterparts. We observed significantly accelerated telomere shortening in LSC compared with nonleukemic HSC. Interestingly, the degree of LSC telomere shortening was found to correlate significantly with the leukemic clone size. To validate the diagnostic value of nonleukemic cells as internal controls and to rule out effects of tyrosine kinase inhibitor (TKI) treatment on these nontarget cells, we prospectively assessed TL in 134 PB samples collected in deep molecular remission after TKI treatment within the EURO-SKI study (NCT01596114). Here, no significant telomere shortening was observed in granulocytes compared with an age-adjusted control cohort. In conclusion, this study provides proof of principle for accelerated telomere shortening in LSC as opposed to HSC in CML patients at diagnosis. The fact that the degree of telomere shortening correlates with leukemic clone's size supports the use of TL in leukemic cells as a prognostic parameter pending prospective validation. TL in nonleukemic myeloid cells seems unaffected even by long-term TKI treatment arguing against a reduction of telomere-mediated replicative reserve in normal hematopoiesis under TKI treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018017772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039661PMC
July 2018

Perioperative chemotherapy with or without epidermal growth factor receptor blockade in unselected patients with locally advanced oesophagogastric adenocarcinoma: Randomized phase II study with advanced biomarker program of the German Cancer Society (AIO/CAO STO-0801).

Eur J Cancer 2018 04 20;93:119-126. Epub 2018 Mar 20.

Department of Internal Medicine II, University Clinic, Mainz, Germany. Electronic address:

Background: Perioperative chemotherapy significantly improves survival in patients with locally advanced oesophagogastric cancer (EGC). However, as approximately 60% of patients will die from their disease, new therapeutic agents such as molecular-targeted drugs are needed.

Patients And Methods: To evaluate the role of panitumumab with perioperative chemotherapy, previously untreated patients with locally advanced EGC received, in an open-label randomised phase II study (NEOPECX), standard epirubicin, cisplatin, capecitabine (ECX) chemotherapy with or without panitumumab. The primary end-point was the histological response rate after neoadjuvant therapy. The expression status and gene copy number of EGFR, HER2, and MET were determined by immunohistochemistry and fluorescence in situ hybridization (FISH). Plasma samples were collected before the first cycle of neoadjuvant chemotherapy.

Results: Overall, 160 patients (80 versus 80) were eligible. The majority (82% versus 80%) showed lymph node involvement. Rate of R0-resection, percentage of patients with downstaging to ypT0-2 at pathohistological evaluation, and rate of major histological response was equal in both arms. Toxicity was increased by panitumumab with regard to thromboembolic events and skin toxicity. Patients with tumour EGFR, HER2 or MET expression had shorter progression-free and overall survival. FISH positivity for these markers was associated with shorter survival independent of therapy. High levels of soluble EGFR in particular predicted poor survival in the panitumumab arm.

Conclusion: The addition of panitumumab to ECX did not improve downstaging of locally advanced EGC. Low plasma levels of pathway-associated proteins such as sEGFR may identify a group of patients that benefit from EGFR-directed therapy. CLINICALTRIALS.GOV: NCT01234324.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2018.01.079DOI Listing
April 2018

New insights into frequency and contents of fear of cancer progression/recurrence (FOP/FCR) in outpatients with colorectal carcinoma (CRC) receiving oral capecitabine: a pilot study at a comprehensive cancer center.

Patient Prefer Adherence 2017 14;11:1907-1914. Epub 2017 Nov 14.

Section of Clinical Oncology, Department of Internal Medicine II, University of Wuerzburg, Bavaria, Germany.

Background: Fear of cancer progression/recurrence (FOP/FCR) is considered one of the most prevalent sources of distress in cancer survivors and associated with lower quality of life and functional impairment. Detailed measures of FOP/FCR are needed because little is known about the knowledge of FOP/FCR, its associations with the patient-doctor relationship, and the rate of adequate therapy. Colorectal cancer (CRC) is one of the most prevalent cancer entities, and oral capecitabine is widely prescribed as treatment. Therefore, we initiated a pilot study to expand the literature on FOP/FCR in CRC outpatients receiving capecitabine and to generate hypotheses for future investigations.

Methods: This study included 58 patients treated at a comprehensive cancer center. FOP/FCR was assessed with the Fear of Progression Questionnaire (FOP-Q-SF). Satisfaction with the relationships with doctors was assessed with the Patient-Doctor Relationship Questionnaire-9 (PRDQ-9). Levels of side effects were rated by the patients on a visual analog scale. Clinical data were extracted from the charts.

Results: A total of 19 out of 58 patients (36%) suffered from FOP/FCR according to our assessment. Levels of FOP/FCR seemed to be mostly moderate to high. Only four out of the 19 distressed patients (21%) were treated accordingly. Typical side effects of oncological treatment were associated with higher FOP/FCR. Satisfaction with doctor-patient relationships was not associated with FOP/FCR. Regarding single items of FOP/FCR, three out of the five most prevalent fears were associated with close relatives.

Discussion: FOP/FCR occurred frequently in more than one in three patients, but was mostly untreated in this sample of consecutive outpatients with CRC receiving oral capecitabine. In detail, most fears were related to family and friends. In addition to an unmet need of patients, our data indicate sources of distress not considered thus far. If replicated in larger studies, results may help to inform intervention development and improve patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/PPA.S142784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694194PMC
November 2017

Adherence and Coping Strategies in Outpatients With Chronic Myeloid Leukemia Receiving Oral Tyrosine Kinase Inhibitors.

Oncol Nurs Forum 2017 11;44(6):E232-E240

University of Wuerzburg.

Purpose/objectives: To assess adherence and coping strategies in outpatients with chronic myeloid leukemia (CML) on oral tyrosine kinase inhibitors (TKIs).
.

Design: Prospective, descriptive.
.

Setting: An interdisciplinary oncology outpatient clinic in Germany.
.

Sample: 35 outpatients with CML on oral TKIs.
.

Methods: Adherence and coping strategies were assessed with questionnaires. Clinical data were extracted from medical charts.
.

Main Research Variables: Adherence rates, main coping strategies, and frequency and contents of single coping strategies.
.

Findings: 18 patients showed adherence according to the applied screening instrument. Main coping strategies were spirituality and search for meaning. The two single items most frequently specified were adhering to medical instructions and trusting in the medical personnel involved.
.

Conclusions: The low adherence rate of 51% most likely resulted from using the Basel Assessment of Adherence Scale as the questionnaire of choice. The relevance of spirituality and search for meaning as main coping strategies has not been shown previously in outpatients with CML. Most patients wish to obey medical instructions accurately and put trust in their oncologists; this introduces a resource that should gain relevance considering the increasing number of oral anticancer drugs.
.

Implications For Nursing: Nurses are encouraged to routinely assess adherence and spiritual needs in outpatients with CML. Spirituality and search for meaning represent pivotal coping strategies in this group, which has an excellent prognosis. Oncology nurses may help provide tailored support, thereby ameliorating care for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1188/17.ONF.E232-E240DOI Listing
November 2017

Impact of adjuvant chemotherapy after neoadjuvant radio- or radiochemotherapy for patients with locally advanced rectal cancer.

J Cancer Res Clin Oncol 2017 Nov 29;143(11):2363-2373. Epub 2017 Jul 29.

Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital, Julius-Maximilians-University, University of Wuerzburg, Oberduerrbacherstr.6, 97080, Wuerzburg, Germany.

Background: Due to its primarily extraperitoneal location, potential affection of the anorectal continence and different metastatic behavior the rectal carcinoma (RC) is classified and treated as an independent disease. Over the past few decades various trials have led to improved multimodal therapies (including radiation, chemotherapy and surgery) for locally advanced rectal cancer and significant changes in the management of this disease whereas the benefit of adjuvant chemotherapy remains unclear.

Methods: Based on a prospective tumor register of the University Hospital of Wuerzburg data of 263 patients having undergone neoadjuvant therapy and surgical resection for locally advanced rectal cancer were retrieved from the Wuerzburg International database (WID) between October 1992 and September 2013 analyzing the overall survival according to the application of an adjuvant therapy.

Results: The cohort consisted of 263 patients with a median age of 65 years (27-89 years), mostly male gender (n = 191; 72.6%) and an ASA performance score of II or III. 143 patients (54.3%) received an adjuvant therapy. Those patients have been significant younger (median 10 years; p < 0.05) and in a better general condition (ASA-score; p < 0.05). The tumor specific overall survival of adjuvant treated patients was significant better (5-years overall-survival 87.4%; p = 0.025) than the surveillance group. In the performed subgroup analysis no significant differences in overall survival according to the kind of neoadjuvant therapy (radiation vs. radiochemotherapy) have been found whereas patients in lower UICC-stages (ypUICC 0 + I) had a significant benefit by receiving a postoperative chemotherapy (p = 0.035).

Conclusion: We considered patients with locally advanced rectal cancer have a significant benefit in overall survival by receiving an adjuvant chemotherapy especially in lower pathological tumor stage (ypUICC 0 + I). Especially because of the heterogeneity of our study population prospective randomized trials are necessary to determine the impact of adjuvant chemotherapy for locally advanced rectal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-017-2483-6DOI Listing
November 2017

Butyrophilin 3A (BTN3A, CD277)-specific antibody 20.1 differentially activates Vγ9Vδ2 TCR clonotypes and interferes with phosphoantigen activation.

Eur J Immunol 2017 06 27;47(6):982-992. Epub 2017 Apr 27.

Institute for Virology and Immunbiology, University of Würzburg, Würzburg, Germany.

Phosphoantigens (PAgs)-like HMBPP ((E)-4-hydroxy-3-methyl-but-2-enyl diphosphate) and butyrophilin 3 (BTN3A, CD277)-specific monoclonal antibody 20.1 induce TCR-mediated activation of Vγ9Vδ2 T cells. Here, we compared murine reporter cells transduced with Vγ9Vδ2 TCRs G115, D1C55, and MOP for the activation in culture with human RAJI cells and PAgs or mAb 20.1 and its single-chain (sc) derivative. All transductants responded readily to PAg but only TCR MOP γ-chain-expressing cells responded to mAb/sc 20.1. Furthermore, both antagonist and agonist mAb and sc of the agonist mAb inhibited the PAg response of TCR-transduced murine reporter cells. These findings suggest that, in contrast to stimulation by physiological stimulators (PAg), the responsiveness to mAb 20.1 depends strongly on CDR3 sequences of the TCR, and that mAb 20.1 can interfere with the PAg-response. Mouse or human origin of reporter cells might affect the mAb 20.1 response since all three TCR-mediated mAb 20.1-induced activation of TCR-transduced Jurkat cells. The pronounced differences between PAg and mAb 20.1-induced activation observed here help to understand the often contradictory published data. This study provides novel perspectives on the physiological mechanism of Vγ9Vδ2 T-cell activation, and highlights the complex mode of action of BTN3A-specific antibodies as agents in cancer immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201646818DOI Listing
June 2017

The impact of pulmonary metastasectomy in patients with previously resected colorectal cancer liver metastases.

PLoS One 2017 22;12(3):e0173933. Epub 2017 Mar 22.

Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital, University of Wuerzburg, Oberduerrbacherstr. Wuerzburg, Germany.

Background: 40-50% of patients with colorectal cancer (CRC) will develop liver metastases (CRLM) during the course of the disease. One third of these patients will additionally develop pulmonary metastases.

Methods: 137 consecutive patients with CRLM, were analyzed regarding survival data, clinical, histological data and treatment. Results were stratified according to the occurrence of pulmonary metastases and metastases resection.

Results: 39% of all patients with liver resection due to CRLM developed additional lung metastases. 44% of these patients underwent subsequent pulmonary resection. Patients undergoing pulmonary metastasectomy showed a significantly better five-year survival compared to patients not qualified for curative resection (5-year survival 71.2% vs. 28.0%; p = 0.001). Interestingly, the 5-year survival of these patients was even superior to all patients with CRLM, who did not develop pulmonary metastases (77.5% vs. 63.5%; p = 0.015). Patients, whose pulmonary metastases were not resected, were more likely to redevelop liver metastases (50.0% vs 78.6%; p = 0.034). However, the rate of distant metastases did not differ between both groups (54.5 vs.53.6; p = 0.945).

Conclusion: The occurrence of colorectal lung metastases after curative liver resection does not impact patient survival if pulmonary metastasectomy is feasible. Those patients clearly benefit from repeated resections of the liver and the lung metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173933PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362054PMC
August 2017

-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: a subgroup analysis of the Western European cohort of the MPACT trial.

Onco Targets Ther 2017 2;10:591-596. Epub 2017 Feb 2.

Celgene Corporation, Paris, France.

Purpose: The global Phase III MPACT trial demonstrated superior efficacy of -paclitaxel plus gemcitabine over gemcitabine alone as first-line treatment for metastatic pancreatic cancer. Region was a randomization stratification factor in the MPACT trial. This subgroup analysis of MPACT examined efficacy and safety of patients treated in Western Europe.

Patients And Methods: Patients received -paclitaxel plus gemcitabine or gemcitabine alone as first-line treatment for metastatic pancreatic cancer as previously described. A total of 76 patients were included in this analysis (n=38 for each arm).

Results: Differences between the overall Western European cohort and the intention-to-treat population included lower percentages of male patients (46% and 58%, respectively) and patients with biliary stents (8% and 17%), and higher percentages of patients with Karnofsky performance status of 90-100 (78% and 60%) and primary tumors in the body of the pancreas (48% and 31%). The median overall survival was 10.7 months with -paclitaxel plus gemcitabine vs 6.9 months with gemcitabine alone (hazard ratio [HR]: 0.82 [95% confidence interval (CI): 0.48-1.40]; =0.471). Median progression-free survival was 5.3 vs 3.7 months, respectively (HR: 0.70 [95% CI: 0.37-1.33]; =0.277). The independently assessed overall response rate was 18% vs 5% (response rate ratio, 3.50 [95% CI: 0.78-15.78]; =0.076). The most common grade ≥3 adverse events with -paclitaxel plus gemcitabine and gemcitabine alone were neutropenia (46% vs 33%, respectively), leukopenia (35% vs 19%), anemia (22% vs 0%), asthenia (21% vs 6%), thrombocytopenia (14% vs 3%), and peripheral neuropathy (13% vs 3%).

Conclusion: Although a statistically significant difference between the treatment arms was not reached for efficacy endpoints, this study does report treatment benefit and a manageable safety profile associated with -paclitaxel plus gemcitabine in patients treated in Western Europe with metastatic pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S124097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295788PMC
February 2017

Tumor Reduction in Primary and Metastatic Pancreatic Cancer Lesions With nab-Paclitaxel and Gemcitabine: An Exploratory Analysis From a Phase 3 Study.

Pancreas 2017 02;46(2):203-208

From the *Medizinische Klinik und Poliklinik II, University of Würzburg, Würzburg, Germany; †Mayo Clinic, Scottsdale, AZ; ‡Prince of Wales Hospital, Sydney, New South Wales, Australia; §Celgene Corporation, Summit, NJ; and ∥Translational German Research Institute and Honor Health Research Institute, Scottsdale, AZ.

Objectives: Results from the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) led to approval of nab-paclitaxel plus gemcitabine for first-line treatment of metastatic pancreatic cancer. The current analysis evaluated the effects of nab-paclitaxel plus gemcitabine versus gemcitabine on primary pancreatic and metastatic lesions.

Methods: In this analysis of the previously described MPACT trial, changes in pancreatic and metastatic tumor burden were assessed using independently measured diameters of lesions on computed tomography or magnetic resonance imaging scans. Changes in the sums of longest tumor diameters were summarized using descriptive statistics and were included in a multivariate analysis of overall survival.

Results: Primary pancreatic lesion measurement was feasible. Reductions in primary pancreatic tumor burden and metastatic burden from baseline to nadir were significantly greater with nab-paclitaxel plus gemcitabine versus gemcitabine. Baseline pancreatic tumor burden was independently predictive of survival. Both regimens elicited linear reductions in primary pancreatic and metastatic tumor burden through time. There was a high within-patient concordance of tumor changes between primary pancreatic lesions and metastatic lesions.

Conclusions: This analysis of MPACT demonstrated significant tumor shrinkage benefit for nab-paclitaxel plus gemcitabine in both primary pancreatic and metastatic lesions, supporting ongoing evaluation of this regimen in locally advanced disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPA.0000000000000742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266413PMC
February 2017

Original article: role of adjuvant chemotherapy in a perioperative chemotherapy regimen for gastric cancer.

BMC Cancer 2016 08 18;16:650. Epub 2016 Aug 18.

Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital, University of Wuerzburg, Oberduerrbacherstr.6, 97080, Wuerzburg, Germany.

Background: Multimodal treatment strategies - perioperative chemotherapy (CTx) and radical surgery - are currently accepted as treatment standard for locally advanced gastric cancer. However, the role of adjuvant postoperative CTx (postCTx) in addition to neoadjuvant preoperative CTx (preCTx) in this setting remains controversial.

Methods: Between 4/2006 and 12/2013, 116 patients with locally advanced gastric cancer were treated with preCTx. 72 patients (62 %), in whom complete tumor resection (R0, subtotal/total gastrectomy with D2-lymphadenectomy) was achieved, were divided into two groups, one of which receiving adjuvant therapy (n = 52) and one without (n = 20). These groups were analyzed with regard to survival and exclusion criteria for adjuvant therapy.

Results: Postoperative complications, as well as their severity grade, did not correlate with fewer postCTx cycles administered (p = n.s.). Long-term survival was shorter in patients receiving postCTx in comparison to patients without postCTx, but did not show statistical significance. In per protocol analysis by excluding two patients with perioperative death, a shorter 3-year survival rate was observed in patients receiving postCTx compared to patients without postCTx (3-year survival: 71.2 % postCTx group vs. 90.0 % non-postCTx group; p = 0.038).

Conclusion: These results appear contradicting to the anticipated outcome. While speculative, they question the value of post-CTx. Prospectively randomized studies are needed to elucidate the role of postCTx.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-016-2708-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991066PMC
August 2016

Dose modification and efficacy of nab-paclitaxel plus gemcitabine vs. gemcitabine for patients with metastatic pancreatic cancer: phase III MPACT trial.

J Gastrointest Oncol 2016 Jun;7(3):469-78

1 Medizinische Universität Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hôpital Beaujon, Clichy, France ; 7 Universitätsklinikum Würzburg, Würzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA.

Background: Dose modifications following adverse events (AEs) are an important part of the management of patients with pancreatic cancer treated with chemotherapy. While dose modifications are utilized to ensure patient safety, the subsequent influence of dose adjustments on treatment exposure and efficacy have not been reported in detail. This exploratory analysis examined the influence of dose modifications on treatment exposure and efficacy in the phase III MPACT trial, which demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) to Gem alone for the treatment of metastatic pancreatic cancer.

Methods: Patients received either nab-P 125 mg/m(2) + Gem 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1,000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥2). The protocol allowed up to 2 dose reductions per agent. Dose delays were also used to manage toxicities.

Results: Toxicities that most commonly led to dose modifications were neutropenia, peripheral neuropathy, thrombocytopenia, and fatigue for nab-P and neutropenia, thrombocytopenia, and fatigue for Gem alone. Baseline characteristics were similar in patients with dose modifications and the intent-to-treat (ITT) population. Among the 421 treated patients in the nab-P + Gem arm, all patients initiated treatment at the per-protocol nab-P starting dose of 125 mg/m(2); 172 (41%) had a nab-P dose reduction, and 300 (71%) had a nab-P dose delay during the study. Most dose modifications occurred after the first 3 months (2 cycles) of treatment. The majority of patients (104/172, 60%) required only 1 nab-P dose reduction, and over half of patients (163/300) had either 1 or 2 dose delays. Patients who underwent dose modifications of nab-P had greater treatment exposure than those who did not in terms of treatment duration, number of cycles administered, and cumulative dose of nab-P delivered. Overall survival (OS) was shorter in the nab-P + Gem arm for patients who did not vs. did undergo dose reduction [median, 6.9 vs. 11.4 months; hazard ratio (HR), 1.93; 95% CI, 1.53-2.44; P<0.0001] and for those who did not vs. did undergo a dose delay (median, 6.2 vs. 10.1, HR, 2.05; 95% CI, 1.60-2.63; P<0.0001). Progression-free survival (PFS) and overall response rate (ORR) were also improved in patients with dose modifications. Similar trends were observed in the Gem-alone arm. Multivariate analyses confirmed that both dose delay and dose reduction were significantly associated with OS.

Conclusions: This analysis suggests that although most doses of nab-P were given at the starting dose of 125 mg/m(2) the first 3 of 4 weeks, dose reductions and delays were effective when necessary to ameliorate toxicity allowing greater treatment exposure without compromising efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo.2016.01.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880765PMC
June 2016

Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice.

Clin Colorectal Cancer 2016 12 7;15(4):381-388. Epub 2016 May 7.

Pharmaceutical Institute, University Bonn, Bonn, Germany.

Background: Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice.

Patients And Methods: A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data.

Results: The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU-related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses.

Conclusion: Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU-related toxicities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2016.04.001DOI Listing
December 2016

Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial.

Br J Haematol 2016 06 17;173(5):731-41. Epub 2016 Mar 17.

Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany.

The prospective, randomized phase III trial GMMG-HD2 aimed at demonstrating non-inferiority of single (Arm A) versus tandem (Arm B) high-dose melphalan followed by autologous transplantation (HDM/ASCT) with regard to 2-year event-free survival (EFS) in newly-diagnosed multiple myeloma (MM) and included 358 evaluable patients [Intention-to-treat population, (ITT), single/tandem HDM/ASCT: n = 177/181]. After a median follow-up of more than 11 years, non-inferiority of single versus tandem HDM/ASCT was demonstrated using the planned non-inferiority threshold of 15% of the 2-year EFS rate. Neither EFS (P = 0·53) nor overall survival (OS) (P = 0·33) differences were observed in the ITT population. In the tandem arm, 26% (n = 47/181) of patients refused a second HDM/ASCT due to non-medical reasons. A per-protocol (PP) analysis, including patients who received the intervention (single/tandem HDM/ASCT: n = 156/93) and patients who did not receive a second HDM/ASCT due to medical reasons (12%, n = 22/181), did not yield differences in EFS (P = 0·61) or OS (P = 0·16). In the ITT and PP set of the tandem arm, the rates of complete responses increased from first to second HDM/ASCT (both P = 0·04). Ten-year OS for the entire ITT was 34% (95% confidence interval: 29-40%). OS after first relapse was significantly shortened in the tandem arm (P = 0·04). In this study single HDM/ASCT was non-inferior to tandem HDM/ASCT in MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.13994DOI Listing
June 2016

Exceptional Response to Nanoparticle Albumin-Bound Paclitaxel and Gemcitabine in a Patient with a Refractory Adenocarcinoma of the Ampulla of Vater.

Case Rep Oncol 2016 Jan-Apr;9(1):15-24. Epub 2016 Jan 8.

Division of Medical Oncology, Department of Internal Medicine II, Würzburg, Germany.

Ampullary carcinoma is a rare tumor and evidence on the treatment of recurrent metastatic disease is scarce. We report the case of a 60-year-old patient with an R0-resected node-positive adenocarcinoma of the papilla of Vater of an initially diagnosed intestinal subtype who developed pulmonary metastases 2 months after adjuvant gemcitabine chemotherapy and, subsequently, liver metastases. Palliative combination chemotherapy with standard regimens for intestinal-type adenocarcinoma (FOLFOX and FOLFIRI) failed. However, subsequent combination chemotherapy with nanoparticle albumin-bound paclitaxel and gemcitabine, a regimen with proven efficacy in metastatic adenocarcinoma of the pancreas, resulted in a durable, very good partial remission. Treatment was manageable and well tolerated. Primary tumor and metastatic tissue were reassessed by immunohistochemistry and had to be reclassified to a mixed phenotype containing predominant elements of the pancreatobiliary subtype. Our case suggests that combination chemotherapy with nanoparticle albumin-bound paclitaxel and gemcitabine could represent a promising option for the treatment of this rare disease and warrants further investigation within controlled clinical trials. Moreover, thorough characterization of ampullary carcinomas by histomorphology and additional immunohistochemistry should become mandatory in order to start a chemotherapeutic regimen tailored for the definitive subtype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000443304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748796PMC
March 2016

Fear of Progression in Outpatients With Chronic Myeloid Leukemia on Oral Tyrosine Kinase Inhibitors.

Oncol Nurs Forum 2016 Mar;43(2):190-7

University of Wuerzburg.

Purpose/objectives: To assess fear of progression (FoP) in outpatients with chronic myeloid leukemia (CML) on oral tyrosine kinase inhibitors (TKIs).


Design: Prospective and descriptive.


Setting: A university-based outpatient cancer clinic in Wuerzburg, Germany. 


Sample: 37 outpatients with CML on oral TKIs. 
.

Methods: FoP was assessed with a questionnaire. Clinical data were extracted from the medical charts.
.

Main Research Variables: Frequency and contents of FoP.


Findings: Sum scores and levels of FoP in the sample population (N = 37) were as high as in cancer populations with more unfavorable life expectancies. Regarding single items, fear that medication may harm the body was most prevalent, regardless of group affiliation. The actual fear of disease progression was only ranked sixth out of 12 items for the total sample and was ranked second by the second-generation TKI group. 


Conclusions: In a sample of outpatients with CML, FoP was frequent and most often generated by fears of treatment side effects.


Implications For Nursing: Nurses should be vigilant about FoP in this population. Established questionnaires may help to identify and evaluate this frequent source of distress. Specific communication could reveal unmet informational needs and may help to initiate interventions. Additional studies are needed to confirm the numbers in a larger cohort of patients, to examine the prevalence during the course of disease, to search for potential influences on the outcome (i.e., via adherence), and to extract the best interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1188/16.ONF.190-197DOI Listing
March 2016

Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine.

Oncol Res Treat 2015 20;38(11):596-603. Epub 2015 Oct 20.

Klinik fx00FC;r Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Germany.

In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years, new treatment options such as the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in patients with good performance status. Unfortunately, patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients, have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical treatment of this patient group is limited. In a meeting of German medical oncology experts, the available clinical evidence and own clinical experience regarding the management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present publication summarises the discussion outcomes with regard to appropriate management of these patients, including consensus-based recommendations for nab-paclitaxel/gemcitabine treatment, according to the best available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the experts provide advice for an initial dose reduction of chemotherapy with nab-paclitaxel/gemcitabine based on the total bilirubin level in patients with biliary obstruction or extensive liver metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000441310DOI Listing
September 2016