Publications by authors named "Paul M Clement"

43 Publications

Identifying new predictive factors for survival after surgery for spinal metastases: an exploratory in-depth retrospective analysis.

Acta Clin Belg 2021 May 6:1-10. Epub 2021 May 6.

Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium.

: In selected patients with symptomatic spinal metastasis from solid tumors, surgery improves quality of life. Since selection is key, inaccurate survival prognostication may result in poor decisions and outcomes. However, most prognostic scores suffer from suboptimal external validation and subsequent mediocre performance. This warrants the ongoing search for factors that better capture the oncological status. This exploratory study aims to identify new preoperative variables that predict survival.: A retrospective analysis was conducted on 62 patients from a tertiary care referral center who underwent debulking and/or reconstruction surgery for spinal metastases between 2006 and 2018, and in whom detailed clinical, oncological, surgical and biochemical variables were collected. Univariate and multivariate analyses were performed for overall survival.: Median survival was 13.2 months. Multivariate analysis for overall survival identified that a higher number of organs with metastases, a shorter time to progression on the last line of systemic therapy before surgery (TTPbs), low serum albumin, high alkaline phosphatase, high C-reactive peptide (CRP), presence of brain metastasis and the index spinal level located in the cervical region were independently associated with shorter survival.: We confirmed previously known predictors and identified CRP and TTPbs as new variables that were strongly associated with survival. The latter variable may replace primary tumor type, as improved cancer treatments make the primary tumor type less relevant as a predictor. This study is exploratory and its findings need to be validated, preferably in large prospective multicenter studies that are aiming at improving existing models.
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http://dx.doi.org/10.1080/17843286.2021.1925028DOI Listing
May 2021

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.

Acta Neuropathol 2021 Jun 19;141(6):945-957. Epub 2021 Mar 19.

Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1 mutations. Patients harbouring IDH1 mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1 have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1 mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.
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http://dx.doi.org/10.1007/s00401-021-02291-6DOI Listing
June 2021

Impact of depatuxizumab mafodotin on health-related quality of life and neurological functioning in the phase II EORTC 1410/INTELLANCE 2 trial for EGFR-amplified recurrent glioblastoma.

Eur J Cancer 2021 Apr 15;147:1-12. Epub 2021 Feb 15.

Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address:

Background: In the EORTC 1410/INTELLANCE 2 randomised, phase II study (NCT02343406), with the antibody-drug conjugate depatuxizumab mafodotin (Depatux-M, ABT-414) in patients with recurrent EGFR-amplified glioblastoma, the primary end-point (overall survival) was not met, and the drug had ocular dose-limiting toxicity. This study reports results from the prespecified health-related quality of life (HRQoL) and neurological deterioration-free survival (NDFS) exploratory analysis.

Patients And Methods: Patients (n = 260) were randomised 1:1:1 to receive either Depatux-M 1.25 mg/kg or 1.0 mg/kg intravenously every 2 weeks with oral temozolomide (TMZ) 150 mg/m, Depatux-M alone, or TMZ or oral lomustine (CCNU) 110 mg/m (TMZ/CCNU). HRQoL outcomes were recorded using the EORTC core Quality of Life QLQ-C30, and brain cancer-specific QLQ-BN20 questionnaires. Questionnaires were completed at baseline, weeks 8 and 16, and month 6, and changes from baseline to each time point were calculated. NDFS was defined as time to first deterioration in World Health Organisation performance status.

Results: Compliance with HRQoL was 88.1% at baseline and decreased to 37.9% at month 6. Differences from baseline between Depatux-M arms and TMZ/CCNU in global health/QoL status throughout treatment did not reach clinical relevance (≥10 points). Self-reported visual disorders deteriorated to a clinically relevant extent with Depatux-M arms versus TMZ/CCNU at all timepoints (mean differences range: 24.6-35.1 points). Changes from baseline for other HRQoL scales and NDFS were generally similar between treatment arms.

Conclusions: Depatux-M had no impact on HRQoL and NDFS in patients with EGFR-amplified recurrent glioblastoma, except for more visual disorders, an expected side-effect of the study drug.

Clinical Trial Registration: NCT02343406.
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http://dx.doi.org/10.1016/j.ejca.2021.01.010DOI Listing
April 2021

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study.

ESMO Open 2020 07;5(4)

Department of Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.

Background: Glioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models.

Methods: This was a two-part, multicentre, phase Ib/II study in patients with recurrent glioblastoma pretreated with radiotherapy and temozolomide standard of care. Patients received buparlisib (80 mg or 100 mg once daily) plus carboplatin (area under the curve (AUC)=5 every 3 weeks), or buparlisib (60 mg once daily) plus lomustine (100 mg/m every 6 weeks). The primary endpoint was to determine the maximum tolerable dose (MTD) and/or recommended phase II dose of buparlisib plus carboplatin or lomustine.

Results: Between 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model.

Conclusion: The overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine.

Trial Registration Number: NCT01934361.
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http://dx.doi.org/10.1136/esmoopen-2020-000672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359195PMC
July 2020

EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand.

Neurooncol Adv 2020 Jan-Dec;2(1):vdz051. Epub 2019 Dec 9.

Departments of Neurology, Erasmus MC, Rotterdam, The Netherlands.

Background: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.

Methods: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.

Results: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.

Conclusions: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.
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http://dx.doi.org/10.1093/noajnl/vdz051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212878PMC
December 2019

Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of Lu-DOTATATE PRRT.

Acta Oncol 2020 Jun 8;59(6):644-651. Epub 2020 Feb 8.

Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium.

Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity. Our single-center retrospective study enrolled all patients treated with Lu-DOTATATE PRRT (1-4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents ( = 41), or targeted agents (everolimus, sunitinib or both;  = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored. Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy ( = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events. In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of Lu-DOTATATE PRRT.
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http://dx.doi.org/10.1080/0284186X.2020.1723161DOI Listing
June 2020

Inflammation-Based Index and Ga-DOTATOC PET-Derived Uptake and Volumetric Parameters Predict Outcome in Neuroendocrine Tumor Patients Treated with Y-DOTATOC.

J Nucl Med 2020 07 5;61(7):1014-1020. Epub 2019 Dec 5.

Nuclear Medicine, University Hospitals Leuven, and Department of Imaging and Pathology, KU Leuven, Leuven, Belgium

We performed post hoc analyses on the utility of pretherapeutic and early interim Ga-DOTATOC PET tumor uptake and volumetric parameters and a recently proposed biomarker, the inflammation-based index (IBI), for peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumor (NET) patients treated with Y-DOTATOC in the setting of a prospective phase II trial. Forty-three NET patients received up to 4 cycles of Y-DOTATOC at 1.85 GBq/m/cycle with a maximal kidney biologic effective dose of 37 Gy. All patients underwent Ga-DOTATOC PET/CT at baseline and 7 wk after the first PRRT cycle. Ga-DOTATOC-avid tumor lesions were semiautomatically delineated using a customized SUV threshold-based approach. PRRT response was assessed on CT using RECIST 1.1. Median progression-free survival and overall survival (OS) were 13.9 and 22.3 mo, respectively. An SUV higher than 13.7 (75th percentile) was associated with better survival (hazard ratio [HR], 0.45; = 0.024), whereas a Ga-DOTATOC-avid tumor volume higher than 578 cm (75th percentile) was associated with worse OS (HR, 2.18; = 0.037). Elevated baseline IBI was associated with worse OS (HR, 3.90; = 0.001). Multivariate analysis corroborated independent associations between OS and SUV ( = 0.016) and IBI ( = 0.015). No significant correlations with progression-free survival were found. A composite score based on SUV and IBI allowed us to further stratify patients into 3 categories with significantly different survival. On early interim PET, a decrease in SUV of more than 17% (75th percentile) was associated with worse survival (HR, 2.29; = 0.024). Normal baseline IBI and high Ga-DOTATOC tumor uptake predict better outcome in NET patients treated with Y-DOTATOC. This method can be used for treatment personalization. Interim Ga-DOTATOC PET does not provide information for treatment personalization.
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http://dx.doi.org/10.2967/jnumed.119.236935DOI Listing
July 2020

INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma.

Neuro Oncol 2020 05;22(5):684-693

EORTC Headquarters, Brussels, Belgium.

Background: Depatuxizumab mafodotin (Depatux-M) is a tumor-specific antibody-drug conjugate consisting of an antibody (ABT-806) directed against activated epidermal growth factor receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as a single agent in a randomized controlled phase II trial in recurrent EGFR amplified glioblastoma.

Methods: Eligible were patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide. Patients were randomized to either Depatux-M 1.25 mg/kg every 2 weeks intravenously, or this treatment combined with temozolomide 150-200 mg/m2 day 1-5 every 4 weeks, or either lomustine or temozolomide. The primary endpoint of the study was overall survival.

Results: Two hundred sixty patients were randomized. In the primary efficacy analysis with 199 events (median follow-up 15.0 mo), the hazard ratio (HR) for the combination arm compared with the control arm was 0.71 (95% CI = 0.50, 1.02; P = 0.062). The efficacy of Depatux-M monotherapy was comparable to that of the control arm (HR = 1.04, 95% CI = 0.73, 1.48; P = 0.83). The most frequent toxicity in Depatux-M treated patients was a reversible corneal epitheliopathy, occurring as grades 3-4 adverse events in 25-30% of patients. In the long-term follow-up analysis with median follow-up of 28.7 months, the HR for the comparison of the combination arm versus the control arm was 0.66 (95% CI = 0.48, 0.93).

Conclusion: This trial suggests a possible role for the use of Depatux-M in combination with temozolomide in EGFR amplified recurrent glioblastoma, especially in patients relapsing well after the end of first-line adjuvant temozolomide treatment. (NCT02343406).
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http://dx.doi.org/10.1093/neuonc/noz222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229258PMC
May 2020

Afatinib as second-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: Subgroup analyses of treatment adherence, safety and mode of afatinib administration in the LUX-Head and Neck 1 trial.

Oral Oncol 2019 10 23;97:82-91. Epub 2019 Aug 23.

Department of Medicine, West German Cancer Center, University Hospital Essen of the University Duisburg-Essen, Essen, Germany.

Objectives: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis).

Methods: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m/week).

Results: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%).

Conclusion: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.
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http://dx.doi.org/10.1016/j.oraloncology.2019.08.004DOI Listing
October 2019

Defining EGFR amplification status for clinical trial inclusion.

Neuro Oncol 2019 10;21(10):1263-1272

Department of Neurology, Erasmus Medical Center Cancer Institute, Rotterdam, Netherlands.

Background: Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no gold standard in determining the amplification status of EGFR or variant III (EGFRvIII) expression. Here, we aimed to determine which technique and which cutoffs are suitable to determine EGFR amplification status.

Methods: We compared fluorescence in-situ hybridization (FISH) and real-time quantitative (RT-q)PCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA).

Results: By using data from >1000 samples, we show that at least 50% of EGFR amplified nuclei should be present to define EGFR gene amplification by FISH. Gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with receiver operating characteristics analysis showing an area under the curve of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data show that EGFR copy numbers can strongly vary between tumors, with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level, FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII.

Conclusion: Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help define the optimal cutoff for various techniques to determine EGFR amplification for diagnostic purposes.
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http://dx.doi.org/10.1093/neuonc/noz096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784284PMC
October 2019

Clinically Relevant Response to Cisplatin-5-Fluorouracyl in Intestinal-Type Sinonasal Adenocarcinoma with Loss of Vision: A Case Report.

Case Rep Oncol 2019 Jan-Apr;12(1):277-281. Epub 2019 Mar 29.

Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium.

A 68-year-old man presented with rapid progressive visual loss caused by a progressive local invasive sinonasal intestinal-type adenocarcinoma (ITAC) with intracranial invasion. The local relapse of ITAC in the ethmoid sinus was previously treated with palliative radiotherapy and carboplatin-paclitaxel, without response, hence disease progression was seen. Ophthalmological examination revealed irreversible blindness of the left eye and a dramatic progressive visual loss of the right eye. Due to important visual loss caused by optic nerve invasion, a palliative treatment with cisplatin-5-fluorouracyl was started. This therapy resulted in a good clinical response with a regression of the local mass and a partial recovery of the vision.
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http://dx.doi.org/10.1159/000499602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489020PMC
March 2019

Repeatability and reproducibility of relative cerebral blood volume measurement of recurrent glioma in a multicentre trial setting.

Eur J Cancer 2019 06 9;114:89-96. Epub 2019 May 9.

University of Heidelberg, Germany.

Background: Measurement of relative cerebral blood volume (rCBV) with dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) is used extensively for brain tumour diagnosis and follow-up. The aim of this pilot study was to assess the robustness of rCBV measurement in patients with enhancing recurrent glioma in a European multicentre trial setting.

Methods: We included pre-treatment postcontrast T1 weighted (T1w) and DSC scans of 20 patients with recurrent glioma from 2 European Organisation for Research and Treatment of Cancer trials (26101 and 26091). Three reviewers independently placed a fixed circular region of interest of 70 mm in the tumour area of highest rCBV (rCBV). To calculate the normalised rCBV (nrCBV), three ROIs were placed in the anterior, middle and posterior centrum semiovale normal-appearing white matter of the contralateral hemisphere. After several months, each observer repeated the assessments blinded for initial findings. Repeatability and reproducibility were estimated with a mixed model. Each measurement was also classified according to 4 clinically meaningful categories.

Results: Three patients were post hoc excluded from analysis because of lack of enhancing tumour. The mean nrCBV repeatability was 49.5%, and reproducibility was 5.5%. In 14 of 17 patients, at least 2 reviewers classified the patient into the same category.

Conclusions: Our results indicate that a well-established review process needs to be applied upfront to assess perfusion in a multicentre trial setting. While awaiting further validation, we propose as a strategy to measure rCBV in the context of recurrent glioma trials to use two central reviewers and an adjudicator in case of disagreement.
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http://dx.doi.org/10.1016/j.ejca.2019.03.007DOI Listing
June 2019

Imaging necrosis during treatment is associated with worse survival in EORTC 26101 study.

Neurology 2019 06 10;92(24):e2754-e2763. Epub 2019 May 10.

From the University Medical Center & German Cancer Research Center (M.N., F.S., I.H., P.K., M.P., M.B., W.W.), Heidelberg, Germany; EORTC Headquarters (T.G., V.G.), Brussels, Belgium; Brain Tumor Center at Erasmus MC Cancer Institute (J.E.C.B., W.T., M.J.v.d.B.), Rotterdam, the Netherlands; Medical Oncology Department (A.A.B.), AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italy; Haaglanden Medical Center (M.J.B.T.), the Hague; Leiden University Medical Center (M.J.B.T.), the Netherlands; Institut Gustave Roussy (J.D.), Villejuif; Sorbonne Université (A.I.), Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris; Institut de Cancerologie de l'Ouest (ICO)-Centre Rene Gauducheau (M.C.), Saint-Herblain, France; Leuven Cancer Institute-KU Leuven (P.M.C.), Belgium; Department of Neurology and Brain Tumor Center (M.W.), University Hospital and University of Zurich, Switzerland; Institut Régional du Cancer Montpellier (M.F.); University of Lille (E.L.R.), U-1192, Inserm; CHU Lille (E.L.R.), General and Stereotaxic Neurosurgery Service; Oscar Lambret Center (E.L.R.), Neurology, Lille, France; Department of Neurology (M.P.), Medical Faculty Mannheim, Heidelberg University, Germany; and Department of Neurology (M.N.), Medical University Innsbruck, Austria.

Objective: Imaging necrosis on MRI scans was assessed and compared to outcome measures of the European Organisation for Research and Treatment of Cancer 26101 phase III trial that compared single-agent lomustine with lomustine plus bevacizumab in patients with progressive glioblastoma.

Methods: MRI in this post hoc analysis was available for 359 patients (lomustine = 127, lomustine + bevacizumab = 232). First, imaging necrosis at baseline being formally measurable (>10 × 10 mm, given 2 slices) was assessed. At weeks 6 and 12 of treatment, it was analyzed whether this necrosis remained stable or increased >25% calculated by 2 perpendicular diameters or whether necrosis developed de novo. Univariate and multivariate associations of baseline necrosis with overall survival (OS) and progression-free survival (PFS) were tested by log-rank test. Hazard ratios (HR) with 95% confidence interval were calculated by Cox model.

Results: Imaging necrosis at baseline was detected in 191 patients (53.2%) and was associated with worse OS and PFS in univariate, but not in multivariate analysis. Baseline necrosis was predictive for OS in the lomustine-only group (HR 1.46, = 0.018). At weeks 6 and 12 of treatment, increase of baseline necrosis and de novo necrosis were strongly associated with worse OS and PFS in univariate and multivariate analysis (PFS both < 0.001, OS univariate < 0.001, multivariate = 0.0046).

Conclusion: Increase of and new development of imaging necrosis during treatment is a negative prognostic factor for patients with progressive glioblastoma. These data call for consideration of integrating the assessment of imaging necrosis as a separate item into the MRI response assessment criteria.
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http://dx.doi.org/10.1212/WNL.0000000000007643DOI Listing
June 2019

Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy.

Eur J Cancer 2019 01 18;107:142-152. Epub 2018 Dec 18.

Medical Oncology Department, Catalan Institute of Oncology, University of Barcelona, IDIBELL, Barcelona, Spain.

Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC.

Patients And Methods: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS).

Results: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up.

Conclusion: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.
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http://dx.doi.org/10.1016/j.ejca.2018.11.015DOI Listing
January 2019

Lomustine and Bevacizumab in Progressive Glioblastoma.

N Engl J Med 2017 11;377(20):1954-1963

From the University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W., M.B., F.S., I.H., A.D., M.P.); the European Organization for Research and Treatment of Cancer, Brussels (T.G., V.G.), and Leuven Cancer Institute-KU Leuven, Leuven (P.M.C.) - both in Belgium; Haaglanden Medical Center, The Hague (M.T.), Erasmus MC Cancer Institute, Rotterdam (W.T., J.C.B., M.J.B.), and VU University Medical Center, Amsterdam (M.K.) - all in the Netherlands; the Medical Oncology Department, Azienda Unità Sanitaria Locale di Bologna-IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy (A.A.B.); Institut Gustave Roussy, Villejuif (J.D.), Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, INSERM Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, University Pierre and Marie Curie 06 UMR S1127, and Institut du Cerveau et de la Moelle Épinière, Paris (A.I.), Institut de Cancerologie de l'Ouest-Centre Rene Gauducheau, Saint-Herblain (M.C.), Institut Régional du Cancer Montpellier, Montpellier (M.F.), and Centre Hospitalier Régional Universitaire de Lille, Lille (E.L.R., F.D.) - all in France; and the Departments of Oncology and Neurology, University Hospital and University of Zurich, Zurich, Switzerland (R.S., M.W.).

Background: Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma.

Methods: We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O-methylguanine-DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival.

Results: A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P<0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to lomustine affected neither health-related quality of life nor neurocognitive function. The MGMT status was prognostic.

Conclusions: Despite somewhat prolonged progression-free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann-La Roche and by the EORTC Cancer Research Fund; EORTC 26101 ClinicalTrials.gov number, NCT01290939 ; Eudra-CT number, 2010-023218-30 .).
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http://dx.doi.org/10.1056/NEJMoa1707358DOI Listing
November 2017

Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study.

Lancet 2017 Oct 8;390(10103):1645-1653. Epub 2017 Aug 8.

Neuro-Oncology Unit, Brain Tumour Centre at Erasmus MC Cancer Institute, Rotterdam, Netherlands.

Background: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas.

Methods: This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990.

Findings: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45-0·93). Overall survival at 5 years was 55·9% (95% CI 47·2-63·8) with and 44·1% (36·3-51·6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible.

Interpretation: Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed.

Funding: Schering Plough and MSD.
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http://dx.doi.org/10.1016/S0140-6736(17)31442-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806535PMC
October 2017

Incidence of osteonecrosis of the jaw in patients with bone metastases treated sequentially with bisphosphonates and denosumab.

Acta Clin Belg 2018 Apr 10;73(2):100-109. Epub 2017 Jul 10.

a Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute , Leuven , Belgium.

Objectives: Osteonecrosis of the jaw (ONJ) is a serious adverse event of bone resorption inhibitors (BRIs), such as bisphosphonates and denosumab. Bisphosphonates and denosumab inhibit osteoclast function through different pharmacological effects and bisphosphonates are retained in bone for several months to years. Sequential treatment with bisphosphonates and denosumab might lead to an overlapping treatment effect, due to the addition of the effect of denosumab on the residual bisphosphonate effect. Therefore, the aim of our study was to investigate if switching from denosumab to bisphosphonates is associated with a higher incidence of ONJ.

Methods: We retrospectively reviewed records of patients with solid tumors and bone metastases treated with denosumab after prior treatment with bisphosphonates at the University Hospitals Leuven (sequential group). Patients treated with denosumab or bisphosphonates alone were used as control groups.

Results: We identified 110 patients sequentially treated with bisphosphonates and denosumab with a median total BRI exposure of 36 months (sequential group). Median bisphosphonates exposure was 16 months and median denosumab exposure was 13 months. About 299 patients were included in the bisphosphonates control group with a median bisphosphonate exposure 19 months. About 6.7% (20/299) of patients developed ONJ. About 240 patients were included in the denosumab control group with a median denosumab exposure 17.5 months. About 10.0% of patients (24/240) developed ONJ. In the sequential group, 15.5% of patients (17/110) developed ONJ. The incidence of ONJ was 1.8% (2/110), 6.3% (6/99), 4.9% (4/82), 5.6% (3/54), and 3.4% (1/29), respectively in the first, second, third, fourth, and fifth year of BRI exposure, an ONJ-incidence similar to ONJ-incidence in the denosumab control group. In a time-to-ONJ-analysis, the curves of the sequential group and the denosumab control group were overlapping. In the sequential group, most of the ONJs occurred in the first year of denosumab exposure and in a matched control group analysis, with correction for median BRI-exposure, ONJ cases tend to occur earlier in the sequential group compared to ONJ cases in the bisphosphonates group.

Conclusion: Cancer patients with bone metastases treated with BRIs seem to have a slightly higher risk of ONJ early after switching from bisphosphonates to denosumab compared to patients remaining on bisphosphonates. Nevertheless, based on the global ONJ-incidence, the switch from bisphosphonates to denosumab can be considered as safe as an equivalent exposure to denosumab from the start on.
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http://dx.doi.org/10.1080/17843286.2017.1348001DOI Listing
April 2018

Up-front and Salvage Transoral Robotic Surgery for Head and Neck Cancer: A Belgian Multicenter Retrospective Case Series.

Front Oncol 2017 9;7:15. Epub 2017 Feb 9.

Otorhinolaryngology-Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, Section Head and Neck Oncology, KU Leuven, Leuven, Belgium.

Introduction/aim: We analyzed the functional and oncologic outcomes of primary and salvage transoral robotic surgery (TORS) procedures, performed in three Belgian institutions with a similar philosophy.

Patients And Methods: A total of 86 patients who underwent TORS between 24-12-2009 and 25-09-2015 were retrospectively reviewed. Descriptive statistics, overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS; Kaplan-Meier), and the variation of these outcomes according to whether patients had primary or salvage TORS were evaluated (univariate log-rank analysis).

Results: Of 86 patients, 56 (65.1%) underwent TORS as a primary treatment and 30 (34.9%) as a salvage procedure for recurrent or second primary cancer. Tumor location was mainly oropharynx ( = 63; 73.3%) followed by supraglottic larynx ( = 11; 12.8%), hypopharynx ( = 11; 12.8%), and glottic larynx ( = 1; 1.2%). In the up-front TORS group, most tumors were classified as cT1 ( = 23; 41.1%)/pT1 ( = 24; 42.9%) or cT2 ( = 27; 48.2%)/pT2 ( = 27; 48.2%) and cN0 ( = 18; 32.1%), cN1 ( = 13; 23.2%), or cN2 ( = 25; 44.6%). In the salvage TORS group, most tumors were cT1-rT1 ( = 18; 60.0%)/pT1-rpT1 ( = 18; 60.0%) or cT2-rT2 ( = 12; 40.0%)/pT2-rpT2 ( = 7; 23.3%) and cN0 ( = 25; 83.3%). Neck dissection was performed in 87.5% of primary cases and 30.0% of salvage cases. In the up-front TORS group, patients were postoperatively submitted to follow-up ( = 13; 23.2%) or received adjuvant radiotherapy, either as single modality ( = 26; 46.4%) or with concomitant cisplatin ( = 15; 26.8%). On the other hand, most salvage TORS patients did not receive any adjuvant therapy ( = 19; 63.3%). Mean and median follow-up was 23.1 and 21.2 months, respectively. Functional results were excellent (no definitive tracheostomy, long-term tube feeding in 1.8% of primary cases, and 20% of salvage cases). In the up-front TORS group, estimated 2-year OS was 88.5% (SE = 5.0%), 2-year DSS was 91.8% (SE = 4.6%) and 2-year DFS was 86.1% (SE = 5.3%). In the salvage TORS group, estimated 2-year OS was 73.5% (SE = 10.9%), 2-year DSS was 93.3% (SE = 6.4%), and 2-year DFS was 75.8% (SE = 9.7%). Comparing outcome of primarily treated patients to salvage patients, a non-statistically significant trend toward better OS ( = 0.262) and DFS ( = 0.139) was observed.

Conclusion: This retrospective study confirms favorable oncologic and functional outcomes of TORS for selected head and neck malignancies, both in the primary and in the salvage setting.
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http://dx.doi.org/10.3389/fonc.2017.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298968PMC
February 2017

Single-Centre Experience of Systemic Treatment with Vincristine, Ifosfamide, and Doxorubicin Alternating with Etoposide, Ifosfamide, and Cisplatin in Adult Patients with Ewing Sarcoma.

Sarcoma 2017 28;2017:1781087. Epub 2017 Dec 28.

Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.

The treatment of Ewing sarcoma (ES) in adult patients requires a multidisciplinary approach. Systemic therapy remains an important component of clinical management of this disease. ES is extremely rare in adult patients. Due to the rarity of the disease, no standard of care in terms of chemotherapy for the adult population exists, and the level of evidence for individual agents or some multidrug combinations is limited. Most regimens that are used in both adults and children include anthracyclines, etoposide, vincristine, cyclophosphamide, and ifosfamide. In this report, we describe our experience with the alternating use of triple combination therapies based on vincristine, ifosfamide, and doxorubicin (VIA) and an etoposide, ifosfamide, and cisplatin combination (VIP). We retrospectively evaluated the response rates, outcome, and tolerance of adult patients ( = 64) treated with VIA/VIP between 1990 and 2014. The patients included were treated with perioperative chemotherapy (53.1% neoadjuvant therapy and 17.2% adjuvant therapy) or had synchronous metastases at diagnosis (29.7%). Five-year overall survival rate was 52.2% for all patients, 72.2% for patients with localized disease, and 5.3% in patients with synchronous metastases. Overall response rate (ORR) was 37% after 2 cycles of VIA and 2 cycles of VIP. There were no patients with progressive disease (PD).
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http://dx.doi.org/10.1155/2017/1781087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763128PMC
December 2017

Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.

Lancet Oncol 2016 Nov 27;17(11):1521-1532. Epub 2016 Sep 27.

KU Leuven, Department of Oncology, Leuven, Belgium.

Background: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors.

Methods: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819.

Findings: Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9-1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21-2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group.

Interpretation: Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices.

Funding: Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
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http://dx.doi.org/10.1016/S1470-2045(16)30313-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124485PMC
November 2016

Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck.

Cancer 2016 Dec 15;122(24):3803-3811. Epub 2016 Aug 15.

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.

Background: This open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual-action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck.

Methods: On day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m and 5-fluorouracil at a dose of 1000 mg/m /day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6 mg/mL/min) and paclitaxel (at a dose of 200 mg/m ) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred.

Results: Nine patients in arm A and 15 patients in arm B received a median of 6 cycles of chemotherapy, and a median of 11 cycles (arm A) and 9 cycles (arm B) of duligotuzumab. Dose-limiting toxicities occurred in 3 patients in arm A and 1 patient in arm B. Grade ≥ 3 treatment-related adverse events (graded according to graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) in ≥ 3 patients were neutropenia (5 patients), hypokalemia (4 patients), dehydration (3 patients), anemia (3 patients), and diarrhea (3 patients) in arm A, and neutropenia (8 patients), anemia (5 patients), febrile neutropenia (4 patients), leukopenia (3 patients), thrombocytopenia (3 patients), and hypomagnesemia (3 patients) in arm B. The chemotherapy dose was reduced in 19 of 24 patients. Sixteen patients (67%) demonstrated objective responses regardless of human papillomavirus status or neuregulin 1 (NRG1) mRNA expression (arm A: 2 confirmed complete responses and 4 confirmed partial responses; arm B: 2 confirmed complete responses and 8 confirmed partial responses).

Conclusions: Duligotuzumab in combination with cisplatin/5-fluorouracil or carboplatin/paclitaxel demonstrated encouraging activity in patients with recurrent/metastatic squamous cell cancer of the head and neck; an association with increased frequency and severity of select adverse events relative to historical data was suggestive of the potentiation of chemotherapy-related adverse events. Cancer 2016;122:3803-3811. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30256DOI Listing
December 2016

Metastatic HER-2-positive salivary gland carcinoma treated with trastuzumab and a taxane: a series of six patients.

Acta Clin Belg 2016 Dec 30;71(6):383-388. Epub 2016 May 30.

a Departments of General Medical Oncology , University Hospitals Leuven and KU Leuven , Leuven , Belgium.

Metastatic salivary gland carcinoma is a rare malignancy. A subset of these tumors overexpresses the human epidermal growth factor receptor 2 (HER-2), which is considered a poor prognostic marker. Targeted therapy with the monoclonal antibody trastuzumab can be a treatment option in these patients. We describe six cases of metastatic salivary gland carcinoma treated with trastuzumab in combination with a taxane. Three of these patients had salivary duct cancer, two had mucoepidermoid carcinoma and one patient was treated for acinic cell carcinoma. The therapy was well tolerated. We observed five partial responses and a median progression free survival of 10.8 months, which compares favorably with the reported outcome of combination chemotherapy. One patient achieved a complete and durable remission. When HER-2 and androgen receptor were co-expressed, trastuzumab-based treatment appeared to be more active than androgen deprivation in our experience.
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http://dx.doi.org/10.1080/17843286.2016.1173940DOI Listing
December 2016

Dynamic 68Ga-DOTATOC PET/CT and static image in NET patients. Correlation of parameters during PRRT.

Nuklearmedizin 2016 Jun 8;55(3):104-14. Epub 2016 Apr 8.

Christophe Deroose, MD, PhD, Nuclear Medicine, University Hospitals Leuven and Department of Imaging & Pathology, KU Leuven, Tel. +32/(0)16/34 37 15; Fax +32/(0)16/34 37 59.

Purpose: To investigate the relationship between the dynamic parameters (Ki) and static image-derived parameters of 68Ga-DOTATOC-PET, to determine which static parameter best reflects underlying somatostatin-receptor-expression (SSR) levels on neuroendocrine tumours (NETs).

Patients, Methods: 20 patients with metastasized NETs underwent a dynamic and static 68Ga-DOTATOC-PET before PRRT and at 7 and 40 weeks after the first administration of 90Y-DOTATOC (in total 4 cycles were planned); 175 lesions were defined and analyzed on the dynamic as well as static scans. Quantitative analysis was performed using the software PMOD. One to five target lesions per patient were chosen and delineated manually on the baseline dynamic scan and further, on the corresponding static 68Ga-DOTATOC-PET and the dynamic and static 68Ga-DOTATOC-PET at the other time-points; SUVmax and SUVmean of the lesions was assessed on the other six scans. The input function was retrieved from the abdominal aorta on the images. Further on, Ki was calculated using the Patlak-Plot. At last, 5 reference regions for normalization of SUVtumour were delineated on the static scans resulting in 5 ratios (SUVratio).

Results: SUVmax and SUVmean of the tumoural lesions on the dynamic 68Ga-DOTATOC-PET had a very strong correlation with the corresponding parameters in the static scan (R²: 0.94 and 0.95 respectively). SUVmax, SUVmean and Ki of the lesions showed a good linear correlation; the SUVratios correlated poorly with Ki. A significantly better correlation was noticed between Ki and SUVtumour(max and mean) (p < 0.0001).

Conclusions: As the dynamic parameter Ki correlates best with the absolute SUVtumour, SUVtumour best reflects underlying SSR-levels in NETs.
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http://dx.doi.org/10.3413/Nukmed-0742-15-05DOI Listing
June 2016

First evidence of treatment efficacy in metastatic carcinoma of the parotid gland with BRD4/NUT translocation.

J Chemother 2016 Jun;28(3):242-6

b Department of General Medical Oncology , UZ Leuven , Belgium.

Background: Nuclear protein in testis (NUT) midline carcinomas (NMC) are characterized by rearrangements of the gene NUT. In the majority of NMCs, a translocation t(15;19), resulting in a BRD4/NUT fusion gene, is present. Nuclear protein in testis midline carcinomas is a rare, but probably underdiagnosed entity due to misdiagnosis. Most cases have been reported in the mediastinum and upper aero-digestive tract. The clinical course of a NMC is extremely aggressive, in spite of intensive chemotherapy and radiotherapy, with an average survival < 1 year.

Methods And Results: A 32-year-old man presented with a pre-auricular swelling on the left side. After partial parotidectomy, the diagnosis of a NMC was made based on the presence of t(15;19)(q14;p13.1) and BRD4/NUT fusion gene demonstrated by fluorescence in situ hybridization (FISH). During postoperative radiotherapy, the patient developed bone metastases for which chemotherapy consisting of cisplatine, doxorubicine and ifosfamide (PAI) was initiated with remarkable clinical and radiological improvement. Nevertheless, the response was not durable.

Conclusion: This case illustrates that responses to chemotherapy in the palliative treatment of a t(15;19)-translocated salivary gland carcinoma are possible but not durable.
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http://dx.doi.org/10.1179/1973947815Y.0000000046DOI Listing
June 2016

Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.

Lancet Oncol 2015 May 16;16(5):583-94. Epub 2015 Apr 16.

University of California San Diego Moores Cancer Center, La Jolla, CA, USA.

Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy.

Methods: In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682.

Findings: Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients.

Interpretation: Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC.

Funding: Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S1470-2045(15)70124-5DOI Listing
May 2015

Patient outcome in the Belgian medical need program on bevacizumab for recurrent glioblastoma.

J Neurol 2015 Mar 9;262(3):742-51. Epub 2015 Jan 9.

Department of Neurosurgery, UZ Brussel, Brussels, Belgium,

Bevacizumab (BEV) has demonstrated anti-tumor activity in patients with recurrent glioblastoma (rGB). Given the unmet need for active therapeutic options in rGB patients, a medical need program was initiated by the Belgian competent authorities. Between November 2010 and February 2013, a total of 313 patients with rGB initiated treatment with BEV administered at a dose of 10 mg/kg every 2 weeks. All patients had failed prior treatment with at least radiation therapy and temozolomide and the majority of patients (70 %) were treated with corticosteroids at baseline. Patients received a median of 6 BEV administrations (range 1-53). Overall, BEV was well tolerated. During BEV treatment the WHO-Performance Score (WHO-PS) improved in 59 patients (19 %) and stabilized for at least 6 weeks in an additional 139 (44 %) patients. Corticosteroid treatment could be stopped in 16 % or reduced in dose in 32 % of patients. The best objective tumor response rate using RANO criteria (investigator's assessment) was 3.5 % CR, 22 % PR, 38 % SD and 37 % PD. The median and 6-month PFS were 13 weeks (95 % CI 12.7-14) and 27.3 % (95 % CI 22.3-32.5), median and 6-month OS rates were 26 weeks (23-29) and 52 % (46.4-58.6), respectively. WHO-PS (0-1 vs. 2-3) and baseline steroid use were significantly correlated with PFS and OS. Our observations support the use of BEV as a monotherapy for patients with rGB who have no alternative treatment options. Optimal benefit from BEV treatment is likely to be obtained when treatment is initiated before the performance status deteriorates to two or less.
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http://dx.doi.org/10.1007/s00415-014-7633-zDOI Listing
March 2015

Individualized dosimetry-based activity reduction of ⁹⁰Y-DOTATOC prevents severe and rapid kidney function deterioration from peptide receptor radionuclide therapy.

Eur J Nucl Med Mol Imaging 2014 Jun 26;41(6):1141-57. Epub 2014 Mar 26.

Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium,

Purpose: Assessment of kidney function evolution after (90)Y-DOTATOC peptide receptor radionuclide therapy (PRRT) with capped activity administration based on a 37-Gy threshold of biological effective dose (BED) to the kidney.

Methods: In a prospective phase II study, patients with metastasized neuroendocrine tumours were evaluated for therapy using 185 MBq (111)In-pentetreotide with amino acid coinfusion. Planar whole-body images were acquired at four time-points after injection and kidney volumes were measured using CT/MRI. BED to the kidneys was estimated using an extended BED formula and biexponential renal clearance. Based on published BED dose-toxicity relationships, we allowed a maximal kidney BED of 37 Gy; if the calculated BED exceeded 37 Gy, treatment activity was reduced accordingly. Kidney function was assessed at baseline and at 18 months, predominantly using (51)Cr-EDTA. The rate of renal function decline was expressed as annual glomerular filtration rate loss (aGFRL).

Results: Only 22 of 50 patients reached the 18-months time-point, with most missing patients having died due to disease progression. In the 22 patients who reached 18 months, no rapid kidney function deterioration was observed over the 18 months, aGFRL >33% was not seen, and only three patients showed an increase of one toxicity grade and one patient an increase of two grades. No significant correlations between kidney volume (p = 0.35), baseline GFR (p = 0.18), risk factors for renal function loss (p = 0.74) and aGFRL were observed. Among the 28 patients who did not reach 18 months, one developed grade 4 kidney toxicity at 15 months after PRRT.

Conclusion: Prospective dosimetry using a 37 Gy BED as the threshold for kidney toxicity is a good guide for (90)Y-DOTATOC PRRT and is associated with a low risk of rapid renal function deterioration and evolution to severe nephrotoxicity.
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http://dx.doi.org/10.1007/s00259-013-2670-xDOI Listing
June 2014

Primary brain tumours, meningiomas and brain metastases in pregnancy: report on 27 cases and review of literature.

Eur J Cancer 2014 May 14;50(8):1462-71. Epub 2014 Mar 14.

Gynecologic Oncology, University Hospitals Leuven, Herestraat, 49, 3000 Leuven, Belgium; Division of Oncology, KULeuven, Herestraat, 49, 3000 Leuven, Belgium. Electronic address:

Background: The concurrence of intracranial tumours with pregnancy is rare. The purpose of this study was to describe all reported patients registered in the international Cancer in Pregnancy registration study (CIP study; http://www.cancerinpregnancy.org), and to review the literature in order to obtain better insight into outcome and possibilities of treatment in pregnancy.

Methods: We collected all intracranial tumours (primary brain tumour, cerebral metastasis, or meningioma) diagnosed during pregnancy, registered prospectively and retrospectively by international collaboration since 1973. Patients diagnosed postpartum were excluded. We summarised the demographic features, treatment decisions, obstetrical and neonatal outcomes.

Results: The mean age of the 27 eligible patients was 31years (range 23-41years), of which 13 and 12 patients were diagnosed in the second and third trimesters, respectively. Eight patients (30%) underwent brain surgery, seven patients (26%) had radiotherapy and in three patients (11%) chemotherapy was administered during gestation. Two patients died during pregnancy and four pregnancies were terminated. In 16 (59%) patients elective caesarean section was performed of which 14 (52%) were still preterm (range 30-36weeks, mean 33weeks). Five patients had a vaginal delivery (range 36-40weeks). Of the 21 ongoing pregnancies all children were born alive without visible congenital malformations and the available long-term follow-up data (range 2-25years) of six children were reassuring.

Conclusion: Adherence to standard protocol for the treatment of brain tumours during pregnancy appears to allow a term delivery and a higher probability of a vaginal delivery.
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http://dx.doi.org/10.1016/j.ejca.2014.02.018DOI Listing
May 2014

Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression.

J Neurooncol 2014 Mar 19;117(1):141-5. Epub 2014 Jan 19.

Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland,

The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT → TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT → TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.
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http://dx.doi.org/10.1007/s11060-014-1365-xDOI Listing
March 2014