Axel Hinke | University of Düsseldorf (original) (raw)
Papers by Axel Hinke
Annals of Oncology, Sep 1, 2021
Clinical Chemistry, Nov 29, 2020
BACKGROUND: We assessed the usefulness of circulating tumor DNA (ctDNA) pre-or post-treatment ini... more BACKGROUND: We assessed the usefulness of circulating tumor DNA (ctDNA) pre-or post-treatment initiation for outcome prediction and treatment monitoring in metastatic colorectal cancer (mCRC).
Oncotarget, Sep 23, 2017
Background: Dermatologic toxicities, especially akne-like skin rash, are the most common side-eff... more Background: Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. Patients and methods: In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b.i.d. (standard arm) or erythromycin ointment 2% followed by doxycycline in case of insufficient activity. The primary endpoint was the percentage of patients developing no skin toxicity ≥ grade 2 at any time during the first 8 weeks of panitumumab treatment. Skin toxicity was assessed using the NCI CTCAE v 4.0. Secondary endpoints comprised the assessment of skin toxicity using a more thorough grading system (WoMo score), evaluation of skin-related (DLQI) and global quality of life (EORTC QLQ C30). Results: In total, 88 patients were included in this trial. 69% of the patients in the erythromycin arm suffered from skin toxicity of grade ≥ 2 versus 63% in the standard arm (P = n.s.). However, as per WoMo score significantly more patients www.impactjournals.com/oncotarget/
Journal of Clinical Oncology, May 20, 2021
6007 Background: Inhibition of the PD-1/PD-L1 pathway is efficient in recurrent/metastatic HNSCC.... more 6007 Background: Inhibition of the PD-1/PD-L1 pathway is efficient in recurrent/metastatic HNSCC. Targeting the immune checkpoint CTLA-4 may be synergistic to radiotherapy. This trial studies feasibility and efficacy of combined PD-L1/CTLA-4 blockade concomitant to induction chemotherapy and radiotherapy. Methods: Patients with previously untreated stage III-IVB (AJCC 8th edition) HNSCC were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30mg/m² d1-3, docetaxel 75mg/m² d1, durvalumab 1500mg fix dose d5 and tremelimumab 75mg fix dose d5. Patients with at least 20% increase of intratumoral CD8+ immune cell density or pathological complete response (pCR) in the re-biopsy (performed on d22-26) entered radio-immunotherapy (RIT) up to a total dose of 70Gy. Patients received further three cycles of durvalumab/tremelimumab (q4w, two concomitant and one subsequent) followed by eight cycles of durvalumab mono (q4w). Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80% (i.e. dose limiting toxicity/DLT ≤20%; exclusion of patients with other reasons than DLT for treatment discontinuation; feasibility unacceptable if ≤65%). The calculated sample size was 57 patients to enter RIT. Main secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between Sep 2018 and Mai 2020, 80 patients were enrolled (one excluded). Median age was 60 years, 33 patients (42%) were current smokers, 43 patients (54%) had oropharyngeal tumors (53% p16 positive), 44 patients (56%) were stage IV. Median follow up was 12.5 months. After induction chemo-immunotherapy 41 patients had pCR and 31 an intratumoral CD8+ immune cell increase. Of 60 patients entering RIT (primary endpoint cohort), 10 received DLT and 4 discontinued for other reasons. The feasibility rate of the RIT cohort until cycle 6 was 82%, meeting the primary endpoint of ≥80% (95% confidence interval (CI), one-sided (lower boundary): 72%). The RIT cohort had a PFS rate at 1 year of 79% (CI 69-90%) and at 2 years of 73% (CI 61-87%) and an OS rate at 1 year of 89% (CI 81-98%) and at 2 years of 86% (CI 77-97%). The entire study cohort had a PFS rate at 1 year of 75% (CI 65-85%) and at 2 years of 68% (CI 58-81%) and an OS rate at 1 year of 86% (CI 78-95%) and at 2 years of 80% (CI 70-91%). Toxicity (treatment-related or un-related) ≥grade 3 appeared in 75 patients (95%) and mainly consisted of dysphagia (53%), leucopenia (48%) and infections (29%). DLT mainly consisted of hepatitis (10%). Conclusions: The trial met the primary endpoint feasibility. CD8+ T cell-based pathological patient selection after induction therapy identifies patients with promising PFS rates after chemotherapy-free RIT. Clinical trial information: nct03426657.
JAMA Oncology, Jun 23, 2022
Supportive Care in Cancer, Aug 31, 2017
Purpose This systematic review evaluates the efficacy of neurokinin-1 receptor antagonists (NK1RA... more Purpose This systematic review evaluates the efficacy of neurokinin-1 receptor antagonists (NK1RAs) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy (MEC) excluding anthracycline-cyclophosphamide-based regimens. Methods A systematic review of MEDLINE (via PubMed and OVID) and Central databases, plus major oncology conferences, identified randomized trials evaluating NK1RAs in combination with a 5-HT 3 RA plus a glucocorticoid for management of CINV. Efficacy endpoints were complete response (CR), no emesis and no nausea rates. Data were analyzed using a random effects model. Results Sixteen trials (3848 patients) were identified. Results were separately analyzed for (a) pure MEC regimens (excluding regimens containing carboplatin or oxaliplatin), (b) carboplatin-based regimens, and (c) oxaliplatin-based regimens. (a) Two trials (abstracts) enrolled 715 patients. The odds ratio for overall CR with the addition of an NK1-RA was 1.46 (95% 1.06-2.02; p = 0.02) with an absolute risk difference (RD) of 8%. (b) Nine trials (1790 patients) were identified. The OR for achieving an overall CR was 1.96 (95% CI 1.57-2.45; p < 0.00001) in favor of the NK1RA containing regimen with an RD of 15%. (c) Three trials (1190 patients) were identified. The OR for achieving an overall CR was 1.34 (95% CI 0.88-2.04; p = 0.17) not reaching statistical significance with a RD of 4%. Conclusion Clear clinically significant benefit was seen with the addition of NK1RAs in carboplatin-based chemotherapy. A global benefit of an NK1RA containing regimen for the whole MEC category cannot be attested yet and warrants more randomized trials exclusively testing pure MEC regimens without carboplatin.
![Research paper thumbnail of Reaktionen koordinierter Liganden, III [1]. Stabilisierung von Dimenthyldiphosphen und Menthylphosphiniden als Brückenliganden in Metallcarbonylkomplexen / Reaction of Coordinated Ligands, III [1]. Stabilization of Dim enthyldiphosphene and Menthylphosphinidene as Bridging Ligands in Metal Carbon...](https://attachments.academia-assets.com/119047618/thumbnails/1.jpg)
](Zeitschrift für Naturforschung B, May 1, 1986
Reduction o f M entPBr2M (C O)5 1 (M = Cr, W) with magnesium in TH F yields the diphos phene com ... more Reduction o f M entPBr2M (C O)5 1 (M = Cr, W) with magnesium in TH F yields the diphos phene com plex (C O)5M (M en t)P = P (M en t)M (C O)5 2 as the main product. In addition, a phos phinidene com plex, (C O)5M (M ent)P M (C O)5 (3) is also formed. The latter is obtained in larger am ounts, if the reaction is carried out in the presence o f M (C O)5TH F. The proposed structures are confirm ed by N M R and U V data as well as-in the case o f the chromium com pounds (2a, 3a)-by crystal structure analysis. Com pound 2a is obtained only as the frans-isomer. The P-P distance in 2a (204.0 pm) indicates a double bond which does not participate in the com plex formation. The P-Cr distance in 3a (average: 230.3 pm) is within the low est range found for this elem ent com bination. R eaction o f 2a with L iA lH 4 yields the diphosphane com plex (C O)5C rM ent(H)P-P (H)M en tC r(C O)5 4 as a mixture o f "m eso" and "rac" diastereom ers.
European Journal of Cancer, Sep 1, 2018
Background: The major prognostic relevance of primary tumour location (LPT) in advanced colorecta... more Background: The major prognostic relevance of primary tumour location (LPT) in advanced colorectal cancer was shown in large retrospective studies, but quantitative estimates are highly heterogeneous, and there is still limited information about its impact within the framework of biomarker-guided treatment strategies. Therefore, we analysed LPT in relation
Journal for ImmunoTherapy of Cancer, Jul 1, 2021
Background In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immu... more Background In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration. Methods We treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing. Results Circulating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had aboveaverage treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion. Conclusion The addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation. Trial registration number NCT03174405.
![Research paper thumbnail of Combined treatment of adenoid cystic carcinoma with cetuximab and IMRT plus C12 heavy ion boost: ACCEPT [ACC, Erbitux®and particle therapy]](https://attachments.academia-assets.com/119047591/thumbnails/1.jpg)
](BMC Cancer, Feb 15, 2011
Background: Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely ... more Background: Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent leading to the establishment of particle therapy in this indication. However, even modern techniques leave space for improvement of local control by intensification of local treatment. Radiation sensitization by exploitation of high EGFR-expression in ACC with the EGFR receptor antibody cetuximab seems promising. Methods/design: The ACCEPT trial is a prospective, mono-centric, phase I/II trial evaluating toxicity (primary endpoint: acute and late effects) and efficacy (secondary endpoint: local control, distant control, disease-free survival, overall survival) of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 49 patients with histologically proven (≥R1-resected, inoperable or Pn+) ACC. Patients receive 18 GyE carbon ions (6 fractions) and 54 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy. Discussion: The primary objective of ACCEPT is to evaluate toxicity and feasibility of cetuximab and particle therapy in adenoid cystic carcinoma.
Journal of Clinical Oncology, Feb 1, 2020
96 Background: Single agent PD-1/L1 inhibition is efficacious in MCRC patients (pts) with high mi... more 96 Background: Single agent PD-1/L1 inhibition is efficacious in MCRC patients (pts) with high microsatellite instability (MSI-H). For the vast majority of MCRC pts with MS stable (MSS) phenotype the role of immunotherapy remains undetermined. Methods: The single arm phase II AVETUX trial combined mFOLFOX6 and cetuximab with avelumab (10mg/kg day 1 from cycle 2 onwards) in RAS/BRAF wildtype (local lab) MCRC pts. Primary endpoint was 12 month progression-free survival rate. Secondary endpoints included overall response rate (ORR), tolerability, overall survival and translational research evaluating tissue including PD-L1 expression (tumour/immune cells) and serial ctDNA. Efficacy analyses were done by intention to treat (ITT). Results: Overall 43 pts were enrolled. Median age was 61 (range 29-82), 14 pts (33%) were female and 39 (91%) left sided. 30 pts (70%) had liver mets and 17 (40%) liver mets only. 2 pts were MSI-H, one MSI-low and 40 MSS. Besides immediate and otherwise unexplained fever in 4 pts treatment was well tolerated and avelumab was not associated with unexpected adverse events to standard FOLFOX/cetuximab. Central tissue review found 4 pts to be ineligible due to low frequent KRAS or BRAF mutation (15-31%). Thus, ITT included 39 pts. The ORR was 79.5%, including 6 complete (CR) and 25 partial responses (PR). Further 5 stable diseases were noted, thus disease control rate was 92.3%; 2 pts had progression and 1 was not evaluable. Early tumor shrinkage (ETS) rate (≥20% after 8 weeks) was 79.5% (1 CR, 27 PR and 3 SD with ≥20% - < 30%). In MSI-H pts 1 PR and 1 SD and in the 3 low RAS mut pts 2 PR were noted. Panel sequencing was feasible with 153 mutations detected, showing an immediate ctDNA drop within 4 weeks of treatment, mirroring the high rate of early tumor response. Notably, the 4 pts with fever had a high T cell infiltration in the tumor. Final data including the primary endpoint and translational data will be presented at the meeting. Conclusions: The AVETUX regimen was feasible producing a high rate of responses in MSS pts mainly occurring within the first 8 weeks. The noted ORR/ETS of 79.5% warrants further evaluation in a randomized trial. Clinical trial information: NCT03174405.
Journal of Clinical Oncology, Jun 1, 2005
5060 Background: Adjuvant RT for pT3 R1 or R0 patients (pts.) after RP remains controversial. Res... more 5060 Background: Adjuvant RT for pT3 R1 or R0 patients (pts.) after RP remains controversial. Results of an EORTC-phase-III- study (with unknown PSA-status after RP) suggested a 20% better biochemical control (bNED) after 5 years for RT. Methods: 385 men with prostate cancer were randomized to either 60 Gy RT (arm A; n=193) or WS (arm B; n=192) before achieving an undetectable PSA. Pts. were stratified for Gleason-score, margin status, neoadjuvant hormonal treatment and stage (pT3A+B vs. C). When the undetectable PSA-level after RP was not achieved, the pts. were stated as progressive disease and left arm A/B and were irradiated. PSA-progression for pts. with undetectable PSA was stated after two consecutive increasing PSA out of the undetectable range. Primary endpoint was bNED. Study was powered to demonstrate a 15% increase in bNED for RT. Results: 78 pts. (20%) did not achieve an undetectable PSA and were stated as progressive disease (arm A: 45 pts., arm B: 33 pts.). Additionally, 34 pts. (23%) from the RT-arm did not receive RT. Therefore, 114 pts. had RT (arm A) and 159 pts. WS (arm B). Median follow up was 53.6 months for arm A and 53.7 months for arm B. BNED at 5 years increased to 72% for arm A (RT) compared with 54% for arm B (WS) (p=0.0015, hazard ratio 0.53). Pts. with a preop. PSA > 10 ng/ml, tumor stage =pT3b, Gleason score =8 as well as positive margins profited significantly from adjuvant RT. The rate of late grade II side effects for the rectum was 1%. Conclusions: Adjuvant radiotherapy for pT3 prostate cancer significantly reduces the risk of biochemical progression after radical prostatectomy. The rate of side effects is very low. No significant financial relationships to disclose.
PubMed, Mar 1, 1996
Background: The value of megestrol acetate in treating tumor anorexia and cachexia of terminal pa... more Background: The value of megestrol acetate in treating tumor anorexia and cachexia of terminal patients is well known. However, the supportive effect of megestrol acetate during intensive radio-(chemo-)therapy was not investigated up to now. Therefore a randomized trial was performed including patients with advanced tumors in the head and neck region. Patients and methods: From June 1991 to December 1993 a total of 64 patients were admitted to a randomized, double-blind placebo-controlled study. During and up to 6 weeks following radiotherapy patients received 160 mg/d megestrol acetate or placebo. The nutritional status (anthropometric and laboratory parameters) and the quality-of-life index according to Padilla et al. [24] were determined prior to therapy, 1, 4, 6 weeks later during radiotherapy and 12, 18 weeks after completion. Results: Sixty-one out of 64 patients were evaluable (control group: n = 30; megestrol acetate patients: n = 31). One patient refused further participation after randomization. One patient in each arm was excluded due to side effects (impotence, diarrhoea). Further side effects were not observed. In the control group the nutritional parameters (body weight, triceps skinfold) and the subjective feeling of the patients deteriorated during radiotherapy and did not restore following radiotherapy. By contrast, the patients of the megestrol acetate group were able to stabilize these parameters. This difference was most prominent in the orally nourished patients (weight loss during therapy: control group: -4.1 kg; megestrol acetate group: -0.8 kg; p = 0.004); but not in the patients fed by percutaneous endoscopically guided gastrostomy (weight loss control group: -2.4 kg; megestrol acetate group: -0.8 kg; p = 0.14). Conclusion: In patients on radiochemotherapy megestrol acetate prevents patients from further deterioration of the nutritional status and quality of life.
British Journal of Cancer, Nov 9, 2017
Background: The CAIRO3 and AIO 0207 trials demonstrated the efficacy of fluoropyrimidine plus bev... more Background: The CAIRO3 and AIO 0207 trials demonstrated the efficacy of fluoropyrimidine plus bevacizumab (FP þ Bev) maintenance treatment in metastatic colorectal cancer (mCRC) patients. In this individual patient data meta-analysis with updated follow-up, we aim to provide more precise estimates of treatment effects and to identify subgroups that benefit most from maintenance treatment or observation. Methods: In 871 patients, randomised to FP þ Bev maintenance treatment or observation, we investigated whether treatment effect was modified by sex, age, performance status, response to induction treatment, primary tumour location, number of metastatic sites, disease stage and primary tumour resection, serum LDH, platelet count, CEA, and RAS/BRAF mutation status. Primary end point was time to second progression after reintroduction of the induction regimen (PFS2). Secondary end points were first progression-free survival (PFS1) and overall survival (OS). Results: At a median follow-up of 68.5 months (IQR 54.6-87.0 months), maintenance treatment was more effective compared with observation in PFS1 (HR 0.40(95% CI 0.34-0.47)) and PFS2 (HR 0.70(0.60-0.81)). No subgroups were identified that did not benefit from maintenance treatment in PFS1 and PFS2; no clinically relevant subgroup effects were observed. Regarding OS, pooled results were not significant (HR 0.91(0.78-1.05)), and the trials showed marked heterogeneity in overall treatment effect and subgroup effects. Conclusions: FP þ Bev maintenance treatment is effective in all patients, regardless of the investigated subgroups.
Social Science Research Network, 2022
Blood, Dec 7, 2017
Keywords: quality of life, multiple myeloma, ixazomib, thalidomide, dexamethasone Introduction: H... more Keywords: quality of life, multiple myeloma, ixazomib, thalidomide, dexamethasone Introduction: Health-related quality of life in patients with multiple myeloma may be affected by the disease itself and by myeloma therapy. Ixazomib is a novel oral proteasome inhibitor with significant activity even in patients with high-risk cytogenetics featuring a favorable toxicity profile. In this phase II study we used ixazomib in combination with thalidomide and dexamethasone (IxaThalDex) in patients with relapsed/refractory multiple myeloma (RRMM). Interim treatment results showed an overall response rate of 49.3% in the ITT group, a median PFS of 9.3 months, median overall survival has not been reached yet (EHA 2017, abstract 336). Here, we analyze patient-reported outcomes regarding health-related quality of life in the induction and maintenance phase. Patients and Methods: At time of analysis, 77 patients with relapsed/refractory MM had been enrolled (median age: 67 years, ISS stage I: 39%, II: 33%, III: 26%, ECOG status 0-1: 95%, 2: 5%). Treatment consisted of 8 cycles of ixazomib, 4mg, d 1, 8 and 15, q 28 days, thalidomide, 100mg/d, and dexamethasone: 40mg d 1, 8, 15. Patients aged ≥75 years had a 50% dose reduction of thalidomide to 50mg/d and of dexamethasone to 20mg. Maintenance treatment consisted of ixazomib, 4mg, days 1, 8, 15 of a 28 day cycle and 3mg in patients aged ≥75 years, and was given for one year. Health-related quality of life was assessed by the EORTC questionnaires EORTC QOL-C30 and the Myeloma subscale QOL-MY20. Health-related quality of life assessments were done at baseline and before each cycle during induction and maintenance treatment. Here, results of global health-related QOL, physical functioning and of 2 symptom subscales that are of major importance for patients, namely pain and fatigue are shown. An increase in score points reflects an improvement for the functional scores global health-related quality of life and physical functioning, while the opposite applies to the symptom scores pain and fatigue. Results: QOLdata at baseline were available in 77 patients before induction and in 31 patients at start of maintenance therapy. Median follow-up was 11.4 months. Mean global health-related QOL score at baseline (Figure 1A) was 57.9, which is lower than that of a normal population of similar age (65.5, Waldmann A et al., Plos 1, 2013). Among patients staying on protocol therapy, QOL scores remained stable during the entire induction therapy, and were similar at start of maintenance treatment but increased distinctly by more than 10 points after the first months of maintenance and remained stable during the entire maintenance period Figure 1 A. A similar pattern was noted for physical functioning (Figure 1B), with a clinical meaningful improvement (more than 10 points). Patients presented with significant fatigue (mean score 42.6 versus 29.2 in a normal population of similar age) at start of therapy that remained stable during the 8 cycles of IxaThalDex induction therapy. During maintenance treatment, a tendency towards improvement was noted but this showed substantial variation between cycles probably because of the still limited number of patients who completed the entire maintenance protocol. The mean pain score was 46.1 (versus 31.6 in a normal population of similar age) and improved already during induction therapy. A further relevant improvement was noted during the maintenance phase, which showed a marked improvement which was maintained over the one-year treatment period. Conclusion: This study is the first to report the impact of Ixazomib maintenance therapy on several dimensions of QOL and provides QOL data during IxaThalDex induction therapy in patients with RRMM. Results show impaired, but stable health-related QOL and physical functioning during IxaThalDex therapy with relevant improvement of health-related QOL and a tendency for better physical functioning during maintenance therapy. Similar findings were obtained for fatigue, while for pain a marked improvement was noted already during the induction phase, which improved further during the maintenance period. Updated results will be presented at the meeting. Disclosures Ludwig: Takeda: Consultancy, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Bristol-Meyers: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Knop: Takeda: Consultancy. Hajek: Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory…
Beiträge zur Onkologie, 1989
Oncology Research and Treatment, 1990
Annals of Oncology, Sep 1, 2021
Clinical Chemistry, Nov 29, 2020
BACKGROUND: We assessed the usefulness of circulating tumor DNA (ctDNA) pre-or post-treatment ini... more BACKGROUND: We assessed the usefulness of circulating tumor DNA (ctDNA) pre-or post-treatment initiation for outcome prediction and treatment monitoring in metastatic colorectal cancer (mCRC).
Oncotarget, Sep 23, 2017
Background: Dermatologic toxicities, especially akne-like skin rash, are the most common side-eff... more Background: Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. Patients and methods: In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b.i.d. (standard arm) or erythromycin ointment 2% followed by doxycycline in case of insufficient activity. The primary endpoint was the percentage of patients developing no skin toxicity ≥ grade 2 at any time during the first 8 weeks of panitumumab treatment. Skin toxicity was assessed using the NCI CTCAE v 4.0. Secondary endpoints comprised the assessment of skin toxicity using a more thorough grading system (WoMo score), evaluation of skin-related (DLQI) and global quality of life (EORTC QLQ C30). Results: In total, 88 patients were included in this trial. 69% of the patients in the erythromycin arm suffered from skin toxicity of grade ≥ 2 versus 63% in the standard arm (P = n.s.). However, as per WoMo score significantly more patients www.impactjournals.com/oncotarget/
Journal of Clinical Oncology, May 20, 2021
6007 Background: Inhibition of the PD-1/PD-L1 pathway is efficient in recurrent/metastatic HNSCC.... more 6007 Background: Inhibition of the PD-1/PD-L1 pathway is efficient in recurrent/metastatic HNSCC. Targeting the immune checkpoint CTLA-4 may be synergistic to radiotherapy. This trial studies feasibility and efficacy of combined PD-L1/CTLA-4 blockade concomitant to induction chemotherapy and radiotherapy. Methods: Patients with previously untreated stage III-IVB (AJCC 8th edition) HNSCC were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30mg/m² d1-3, docetaxel 75mg/m² d1, durvalumab 1500mg fix dose d5 and tremelimumab 75mg fix dose d5. Patients with at least 20% increase of intratumoral CD8+ immune cell density or pathological complete response (pCR) in the re-biopsy (performed on d22-26) entered radio-immunotherapy (RIT) up to a total dose of 70Gy. Patients received further three cycles of durvalumab/tremelimumab (q4w, two concomitant and one subsequent) followed by eight cycles of durvalumab mono (q4w). Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80% (i.e. dose limiting toxicity/DLT ≤20%; exclusion of patients with other reasons than DLT for treatment discontinuation; feasibility unacceptable if ≤65%). The calculated sample size was 57 patients to enter RIT. Main secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between Sep 2018 and Mai 2020, 80 patients were enrolled (one excluded). Median age was 60 years, 33 patients (42%) were current smokers, 43 patients (54%) had oropharyngeal tumors (53% p16 positive), 44 patients (56%) were stage IV. Median follow up was 12.5 months. After induction chemo-immunotherapy 41 patients had pCR and 31 an intratumoral CD8+ immune cell increase. Of 60 patients entering RIT (primary endpoint cohort), 10 received DLT and 4 discontinued for other reasons. The feasibility rate of the RIT cohort until cycle 6 was 82%, meeting the primary endpoint of ≥80% (95% confidence interval (CI), one-sided (lower boundary): 72%). The RIT cohort had a PFS rate at 1 year of 79% (CI 69-90%) and at 2 years of 73% (CI 61-87%) and an OS rate at 1 year of 89% (CI 81-98%) and at 2 years of 86% (CI 77-97%). The entire study cohort had a PFS rate at 1 year of 75% (CI 65-85%) and at 2 years of 68% (CI 58-81%) and an OS rate at 1 year of 86% (CI 78-95%) and at 2 years of 80% (CI 70-91%). Toxicity (treatment-related or un-related) ≥grade 3 appeared in 75 patients (95%) and mainly consisted of dysphagia (53%), leucopenia (48%) and infections (29%). DLT mainly consisted of hepatitis (10%). Conclusions: The trial met the primary endpoint feasibility. CD8+ T cell-based pathological patient selection after induction therapy identifies patients with promising PFS rates after chemotherapy-free RIT. Clinical trial information: nct03426657.
JAMA Oncology, Jun 23, 2022
Supportive Care in Cancer, Aug 31, 2017
Purpose This systematic review evaluates the efficacy of neurokinin-1 receptor antagonists (NK1RA... more Purpose This systematic review evaluates the efficacy of neurokinin-1 receptor antagonists (NK1RAs) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy (MEC) excluding anthracycline-cyclophosphamide-based regimens. Methods A systematic review of MEDLINE (via PubMed and OVID) and Central databases, plus major oncology conferences, identified randomized trials evaluating NK1RAs in combination with a 5-HT 3 RA plus a glucocorticoid for management of CINV. Efficacy endpoints were complete response (CR), no emesis and no nausea rates. Data were analyzed using a random effects model. Results Sixteen trials (3848 patients) were identified. Results were separately analyzed for (a) pure MEC regimens (excluding regimens containing carboplatin or oxaliplatin), (b) carboplatin-based regimens, and (c) oxaliplatin-based regimens. (a) Two trials (abstracts) enrolled 715 patients. The odds ratio for overall CR with the addition of an NK1-RA was 1.46 (95% 1.06-2.02; p = 0.02) with an absolute risk difference (RD) of 8%. (b) Nine trials (1790 patients) were identified. The OR for achieving an overall CR was 1.96 (95% CI 1.57-2.45; p < 0.00001) in favor of the NK1RA containing regimen with an RD of 15%. (c) Three trials (1190 patients) were identified. The OR for achieving an overall CR was 1.34 (95% CI 0.88-2.04; p = 0.17) not reaching statistical significance with a RD of 4%. Conclusion Clear clinically significant benefit was seen with the addition of NK1RAs in carboplatin-based chemotherapy. A global benefit of an NK1RA containing regimen for the whole MEC category cannot be attested yet and warrants more randomized trials exclusively testing pure MEC regimens without carboplatin.
Zeitschrift für Naturforschung B, May 1, 1986
Reduction o f M entPBr2M (C O)5 1 (M = Cr, W) with magnesium in TH F yields the diphos phene com ... more Reduction o f M entPBr2M (C O)5 1 (M = Cr, W) with magnesium in TH F yields the diphos phene com plex (C O)5M (M en t)P = P (M en t)M (C O)5 2 as the main product. In addition, a phos phinidene com plex, (C O)5M (M ent)P M (C O)5 (3) is also formed. The latter is obtained in larger am ounts, if the reaction is carried out in the presence o f M (C O)5TH F. The proposed structures are confirm ed by N M R and U V data as well as-in the case o f the chromium com pounds (2a, 3a)-by crystal structure analysis. Com pound 2a is obtained only as the frans-isomer. The P-P distance in 2a (204.0 pm) indicates a double bond which does not participate in the com plex formation. The P-Cr distance in 3a (average: 230.3 pm) is within the low est range found for this elem ent com bination. R eaction o f 2a with L iA lH 4 yields the diphosphane com plex (C O)5C rM ent(H)P-P (H)M en tC r(C O)5 4 as a mixture o f "m eso" and "rac" diastereom ers.
European Journal of Cancer, Sep 1, 2018
Background: The major prognostic relevance of primary tumour location (LPT) in advanced colorecta... more Background: The major prognostic relevance of primary tumour location (LPT) in advanced colorectal cancer was shown in large retrospective studies, but quantitative estimates are highly heterogeneous, and there is still limited information about its impact within the framework of biomarker-guided treatment strategies. Therefore, we analysed LPT in relation
Journal for ImmunoTherapy of Cancer, Jul 1, 2021
Background In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immu... more Background In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration. Methods We treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing. Results Circulating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had aboveaverage treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion. Conclusion The addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation. Trial registration number NCT03174405.
BMC Cancer, Feb 15, 2011
Background: Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely ... more Background: Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent leading to the establishment of particle therapy in this indication. However, even modern techniques leave space for improvement of local control by intensification of local treatment. Radiation sensitization by exploitation of high EGFR-expression in ACC with the EGFR receptor antibody cetuximab seems promising. Methods/design: The ACCEPT trial is a prospective, mono-centric, phase I/II trial evaluating toxicity (primary endpoint: acute and late effects) and efficacy (secondary endpoint: local control, distant control, disease-free survival, overall survival) of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 49 patients with histologically proven (≥R1-resected, inoperable or Pn+) ACC. Patients receive 18 GyE carbon ions (6 fractions) and 54 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy. Discussion: The primary objective of ACCEPT is to evaluate toxicity and feasibility of cetuximab and particle therapy in adenoid cystic carcinoma.
Journal of Clinical Oncology, Feb 1, 2020
96 Background: Single agent PD-1/L1 inhibition is efficacious in MCRC patients (pts) with high mi... more 96 Background: Single agent PD-1/L1 inhibition is efficacious in MCRC patients (pts) with high microsatellite instability (MSI-H). For the vast majority of MCRC pts with MS stable (MSS) phenotype the role of immunotherapy remains undetermined. Methods: The single arm phase II AVETUX trial combined mFOLFOX6 and cetuximab with avelumab (10mg/kg day 1 from cycle 2 onwards) in RAS/BRAF wildtype (local lab) MCRC pts. Primary endpoint was 12 month progression-free survival rate. Secondary endpoints included overall response rate (ORR), tolerability, overall survival and translational research evaluating tissue including PD-L1 expression (tumour/immune cells) and serial ctDNA. Efficacy analyses were done by intention to treat (ITT). Results: Overall 43 pts were enrolled. Median age was 61 (range 29-82), 14 pts (33%) were female and 39 (91%) left sided. 30 pts (70%) had liver mets and 17 (40%) liver mets only. 2 pts were MSI-H, one MSI-low and 40 MSS. Besides immediate and otherwise unexplained fever in 4 pts treatment was well tolerated and avelumab was not associated with unexpected adverse events to standard FOLFOX/cetuximab. Central tissue review found 4 pts to be ineligible due to low frequent KRAS or BRAF mutation (15-31%). Thus, ITT included 39 pts. The ORR was 79.5%, including 6 complete (CR) and 25 partial responses (PR). Further 5 stable diseases were noted, thus disease control rate was 92.3%; 2 pts had progression and 1 was not evaluable. Early tumor shrinkage (ETS) rate (≥20% after 8 weeks) was 79.5% (1 CR, 27 PR and 3 SD with ≥20% - < 30%). In MSI-H pts 1 PR and 1 SD and in the 3 low RAS mut pts 2 PR were noted. Panel sequencing was feasible with 153 mutations detected, showing an immediate ctDNA drop within 4 weeks of treatment, mirroring the high rate of early tumor response. Notably, the 4 pts with fever had a high T cell infiltration in the tumor. Final data including the primary endpoint and translational data will be presented at the meeting. Conclusions: The AVETUX regimen was feasible producing a high rate of responses in MSS pts mainly occurring within the first 8 weeks. The noted ORR/ETS of 79.5% warrants further evaluation in a randomized trial. Clinical trial information: NCT03174405.
Journal of Clinical Oncology, Jun 1, 2005
5060 Background: Adjuvant RT for pT3 R1 or R0 patients (pts.) after RP remains controversial. Res... more 5060 Background: Adjuvant RT for pT3 R1 or R0 patients (pts.) after RP remains controversial. Results of an EORTC-phase-III- study (with unknown PSA-status after RP) suggested a 20% better biochemical control (bNED) after 5 years for RT. Methods: 385 men with prostate cancer were randomized to either 60 Gy RT (arm A; n=193) or WS (arm B; n=192) before achieving an undetectable PSA. Pts. were stratified for Gleason-score, margin status, neoadjuvant hormonal treatment and stage (pT3A+B vs. C). When the undetectable PSA-level after RP was not achieved, the pts. were stated as progressive disease and left arm A/B and were irradiated. PSA-progression for pts. with undetectable PSA was stated after two consecutive increasing PSA out of the undetectable range. Primary endpoint was bNED. Study was powered to demonstrate a 15% increase in bNED for RT. Results: 78 pts. (20%) did not achieve an undetectable PSA and were stated as progressive disease (arm A: 45 pts., arm B: 33 pts.). Additionally, 34 pts. (23%) from the RT-arm did not receive RT. Therefore, 114 pts. had RT (arm A) and 159 pts. WS (arm B). Median follow up was 53.6 months for arm A and 53.7 months for arm B. BNED at 5 years increased to 72% for arm A (RT) compared with 54% for arm B (WS) (p=0.0015, hazard ratio 0.53). Pts. with a preop. PSA > 10 ng/ml, tumor stage =pT3b, Gleason score =8 as well as positive margins profited significantly from adjuvant RT. The rate of late grade II side effects for the rectum was 1%. Conclusions: Adjuvant radiotherapy for pT3 prostate cancer significantly reduces the risk of biochemical progression after radical prostatectomy. The rate of side effects is very low. No significant financial relationships to disclose.
PubMed, Mar 1, 1996
Background: The value of megestrol acetate in treating tumor anorexia and cachexia of terminal pa... more Background: The value of megestrol acetate in treating tumor anorexia and cachexia of terminal patients is well known. However, the supportive effect of megestrol acetate during intensive radio-(chemo-)therapy was not investigated up to now. Therefore a randomized trial was performed including patients with advanced tumors in the head and neck region. Patients and methods: From June 1991 to December 1993 a total of 64 patients were admitted to a randomized, double-blind placebo-controlled study. During and up to 6 weeks following radiotherapy patients received 160 mg/d megestrol acetate or placebo. The nutritional status (anthropometric and laboratory parameters) and the quality-of-life index according to Padilla et al. [24] were determined prior to therapy, 1, 4, 6 weeks later during radiotherapy and 12, 18 weeks after completion. Results: Sixty-one out of 64 patients were evaluable (control group: n = 30; megestrol acetate patients: n = 31). One patient refused further participation after randomization. One patient in each arm was excluded due to side effects (impotence, diarrhoea). Further side effects were not observed. In the control group the nutritional parameters (body weight, triceps skinfold) and the subjective feeling of the patients deteriorated during radiotherapy and did not restore following radiotherapy. By contrast, the patients of the megestrol acetate group were able to stabilize these parameters. This difference was most prominent in the orally nourished patients (weight loss during therapy: control group: -4.1 kg; megestrol acetate group: -0.8 kg; p = 0.004); but not in the patients fed by percutaneous endoscopically guided gastrostomy (weight loss control group: -2.4 kg; megestrol acetate group: -0.8 kg; p = 0.14). Conclusion: In patients on radiochemotherapy megestrol acetate prevents patients from further deterioration of the nutritional status and quality of life.
British Journal of Cancer, Nov 9, 2017
Background: The CAIRO3 and AIO 0207 trials demonstrated the efficacy of fluoropyrimidine plus bev... more Background: The CAIRO3 and AIO 0207 trials demonstrated the efficacy of fluoropyrimidine plus bevacizumab (FP þ Bev) maintenance treatment in metastatic colorectal cancer (mCRC) patients. In this individual patient data meta-analysis with updated follow-up, we aim to provide more precise estimates of treatment effects and to identify subgroups that benefit most from maintenance treatment or observation. Methods: In 871 patients, randomised to FP þ Bev maintenance treatment or observation, we investigated whether treatment effect was modified by sex, age, performance status, response to induction treatment, primary tumour location, number of metastatic sites, disease stage and primary tumour resection, serum LDH, platelet count, CEA, and RAS/BRAF mutation status. Primary end point was time to second progression after reintroduction of the induction regimen (PFS2). Secondary end points were first progression-free survival (PFS1) and overall survival (OS). Results: At a median follow-up of 68.5 months (IQR 54.6-87.0 months), maintenance treatment was more effective compared with observation in PFS1 (HR 0.40(95% CI 0.34-0.47)) and PFS2 (HR 0.70(0.60-0.81)). No subgroups were identified that did not benefit from maintenance treatment in PFS1 and PFS2; no clinically relevant subgroup effects were observed. Regarding OS, pooled results were not significant (HR 0.91(0.78-1.05)), and the trials showed marked heterogeneity in overall treatment effect and subgroup effects. Conclusions: FP þ Bev maintenance treatment is effective in all patients, regardless of the investigated subgroups.
Social Science Research Network, 2022
Blood, Dec 7, 2017
Keywords: quality of life, multiple myeloma, ixazomib, thalidomide, dexamethasone Introduction: H... more Keywords: quality of life, multiple myeloma, ixazomib, thalidomide, dexamethasone Introduction: Health-related quality of life in patients with multiple myeloma may be affected by the disease itself and by myeloma therapy. Ixazomib is a novel oral proteasome inhibitor with significant activity even in patients with high-risk cytogenetics featuring a favorable toxicity profile. In this phase II study we used ixazomib in combination with thalidomide and dexamethasone (IxaThalDex) in patients with relapsed/refractory multiple myeloma (RRMM). Interim treatment results showed an overall response rate of 49.3% in the ITT group, a median PFS of 9.3 months, median overall survival has not been reached yet (EHA 2017, abstract 336). Here, we analyze patient-reported outcomes regarding health-related quality of life in the induction and maintenance phase. Patients and Methods: At time of analysis, 77 patients with relapsed/refractory MM had been enrolled (median age: 67 years, ISS stage I: 39%, II: 33%, III: 26%, ECOG status 0-1: 95%, 2: 5%). Treatment consisted of 8 cycles of ixazomib, 4mg, d 1, 8 and 15, q 28 days, thalidomide, 100mg/d, and dexamethasone: 40mg d 1, 8, 15. Patients aged ≥75 years had a 50% dose reduction of thalidomide to 50mg/d and of dexamethasone to 20mg. Maintenance treatment consisted of ixazomib, 4mg, days 1, 8, 15 of a 28 day cycle and 3mg in patients aged ≥75 years, and was given for one year. Health-related quality of life was assessed by the EORTC questionnaires EORTC QOL-C30 and the Myeloma subscale QOL-MY20. Health-related quality of life assessments were done at baseline and before each cycle during induction and maintenance treatment. Here, results of global health-related QOL, physical functioning and of 2 symptom subscales that are of major importance for patients, namely pain and fatigue are shown. An increase in score points reflects an improvement for the functional scores global health-related quality of life and physical functioning, while the opposite applies to the symptom scores pain and fatigue. Results: QOLdata at baseline were available in 77 patients before induction and in 31 patients at start of maintenance therapy. Median follow-up was 11.4 months. Mean global health-related QOL score at baseline (Figure 1A) was 57.9, which is lower than that of a normal population of similar age (65.5, Waldmann A et al., Plos 1, 2013). Among patients staying on protocol therapy, QOL scores remained stable during the entire induction therapy, and were similar at start of maintenance treatment but increased distinctly by more than 10 points after the first months of maintenance and remained stable during the entire maintenance period Figure 1 A. A similar pattern was noted for physical functioning (Figure 1B), with a clinical meaningful improvement (more than 10 points). Patients presented with significant fatigue (mean score 42.6 versus 29.2 in a normal population of similar age) at start of therapy that remained stable during the 8 cycles of IxaThalDex induction therapy. During maintenance treatment, a tendency towards improvement was noted but this showed substantial variation between cycles probably because of the still limited number of patients who completed the entire maintenance protocol. The mean pain score was 46.1 (versus 31.6 in a normal population of similar age) and improved already during induction therapy. A further relevant improvement was noted during the maintenance phase, which showed a marked improvement which was maintained over the one-year treatment period. Conclusion: This study is the first to report the impact of Ixazomib maintenance therapy on several dimensions of QOL and provides QOL data during IxaThalDex induction therapy in patients with RRMM. Results show impaired, but stable health-related QOL and physical functioning during IxaThalDex therapy with relevant improvement of health-related QOL and a tendency for better physical functioning during maintenance therapy. Similar findings were obtained for fatigue, while for pain a marked improvement was noted already during the induction phase, which improved further during the maintenance period. Updated results will be presented at the meeting. Disclosures Ludwig: Takeda: Consultancy, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Bristol-Meyers: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Knop: Takeda: Consultancy. Hajek: Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory…
Beiträge zur Onkologie, 1989
Oncology Research and Treatment, 1990