Pol Specenier - Academia.edu (original) (raw)
Papers by Pol Specenier
Expert Review of Anticancer Therapy, Jul 16, 2018
Introduction: The majority of patients with locally advanced head and neck squamous cell carcinom... more Introduction: The majority of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) will recur. The treatment of patients with recurrent/metastatic (R/M) HNSCC) is rapidly evolving. Areas covered: This article will comprehensively review the current systemic treatment of R/M HNSCC. Expert Commentary: For the time being, the EXTREME regimen (cetuximab in combination with platinum and 5-fluorouracil) still remains standard of care in previously untreated R/M HNSCC patients who are candidates for combination chemotherapy. Single agents with well documented activity in HNSCC include methotrexate, cisplatin, 5-FU, docetaxel, and paclitaxel. The anti-PD-1 monoclonal antibody nivolumab can be considered the current standard of care in patients with R/M HNSCC progressing after platinum-based therapy based on the results of CheckMate 141 showing a survival benefit over standard of care drugs, such as single agent weekly cetuximab, methotrexate, or docetaxel. Multiple randomized phase III trials comparing anti-PD(L)-antibodies either as single agent or in combination with chemotherapy or an anti-CTLA-4 with the EXTREME as fist line treatment are ongoing or planned. The outcome of these trials might change the current treatment paradigm in previously untreated R/M HNSCC. Immunotherapeutic agents under active investigation include Toll-like receptor 8 agonists and inhibitors of IDO1.
Journal of Clinical Oncology, Jun 20, 2006
5574 Background: RT with concurrent chemotherapy is superior to RT alone as treatment for locally... more 5574 Background: RT with concurrent chemotherapy is superior to RT alone as treatment for locally advanced SCCHN. Gem is a potent radiosensitizer in vitro and in vivo and in addition has a good activity in SCCHN. Exploitation of these properties was the rationale for a single institution phase II study which evaluates the efficacy and toxicities of standard RT + weekly low dose Gem. Methods: Eligible were patients with primary inoperable or locally advanced stage III and IV SCCHN. Treatment: Planned RT was 70 Gy over 7 weeks with weekly Gem 100 mg/m2 within 2 hours prior to RT (Eisbrüch et al., ASCO, 1997, 1998). Presented endpoints are response rate (according to WHO), acute and late toxicity (according to NCICTC), disease free survival (DFS), local relapse free survival (LRFS) and overall survival (OS). Results: 26 patients (21 male, 5 female; performance status 0–2; no prior treatment) entered the study between November 1998 and September 2003. Median age was 56 years (range 48–78). Tumor sites were oropharynx (6), hypopharynx (17), glottis (1), paranasal sinus (1), unknown (1). Clinical stage was III (2) or IV (24). 7 Patients had T4N2 disease and 2 had T4N3 disease. Patients received a median of 7 Gem cycles (range 2–8) and a median of 70 Gy (66–84.75). 7 patients underwent radical neck dissection. Grade 3–4 acute toxicities included mucositis (22/26), dermatitis (18/26), pharyngitis and/or oesophagitis (21/26), pain (7/25), xerostomia (1/24), neutropenia (1/26) and anemia (1/26). 21/26 patients needed tube feeding and 21/26 needed to be hospitalized. After recovery from acute toxicity 6/23 could feed normally, 5/23 needed soft food, 5/23 were able to swallow liquid food and 2/23 required permanent tube feeding. Response was evaluable in 22 patients (11 CR, 11 PR). Intial relapse was at distant sites in 9/26 and local in 8/26. Median follow up of the patients still alive is 46 months. Median OS is 576 days, median DFS is 401 days, median LRFS is not reached. 7/26 remain free of disease more than 3 years after end of treatment. Conclusions: RT + Gem (100 mg/m2/week) is feasible but toxic. The combination is highly active in SCCHN and provides a good long term local control. [Table: see text]
Cancers, Nov 28, 2019
Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in no... more Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in non-small cell lung cancer (NSCLC) making it an interesting drug target. We examined the in vitro therapeutic effects of volasertib, a Plk1 inhibitor, in combination with irradiation in a panel of NSCLC cell lines with different p53 backgrounds. Pretreatment with volasertib efficiently sensitized p53 wild type cells to irradiation. Flow cytometric analysis revealed that significantly more cells were arrested in the G 2 /M phase of the cell cycle after the combination therapy compared to either treatment alone (p < 0.005). No significant synergistic induction of apoptotic cell death was observed, but, importantly, significantly more senescent cells were detected when cells were pretreated with volasertib before irradiation compared to both monotherapies alone (p < 0.001), especially in cells with functional p53. Consequently, while most cells with functional p53 showed permanent growth arrest, more p53 knockdown/mutant cells could re-enter the cell cycle, resulting in colony formation and cell survival. Our findings assign functional p53 as a determining factor for the observed radiosensitizing effect of volasertib in combination with radiotherapy for the treatment of NSCLC.
Background: Polo-like kinase 1 (Plk1), a master regulator of mitosis and the DNA damage response,... more Background: Polo-like kinase 1 (Plk1), a master regulator of mitosis and the DNA damage response, is overexpressed in several human malignancies, making it a promising therapeutic target. Monotherapy of Plk1 inhibition has shown only a moderate effect in clinical trials, indicating the need to combine with other therapies. Remarkably, Plk1 inhibition arrests cancer cells in mitosis, which is the most radiosensitive cell cycle phase. Hence, we are the first to investigate the effect of volasertib, the lead agent in category of Plk1 inhibitors at the moment, on the radiosensitivity of a panel of non-small cell lung cancer (NSCLC) cell lines with a different p53 background under both normal and reduced oxygen conditions. Material and methods: Three isogenic NSCLC cell lines (i.e. A549 (p53 wt); A549-NTC (non template control, p53 wt); and A549-920 (p53 deficient)) and one TP53 mutant cell line (NCI-H1975, R273H mutation) were included. Cell survival after volasertib monotherapy (0-85 nM, 24h) was assessed using the sulforhodamine B assay. The effect of volasertib (0-20 nM, 24h) on cell cycle distribution was determined flow cytometrically using the Vindelov method. The clonogenic assay (24h 0-10 nM volasertib followed by 0-8 Gy irradiation) was performed to evaluate the radiosensitizing effect of volasertib. Cells were incubated under normoxia or hypoxia (1% O2) during the treatment period. Data analysis was done using WinNonlin and FlowJo software. Results: Plk1 inhibition by volasertib established a dose-dependent growth inhibition in all cell lines under both normoxia and hypoxia. Cell survival was significantly influenced by the p53 status, with a reduced sensitivity to volasertib in p53 deficient/mutant cells compared to p53 wild type cells (p<0.001). Except for the TP53 mutant NCI-1975 cell line, IC50-values were significantly higher in hypoxic cells compared to their normoxic counterparts (p<0.001). Treatment with increasing concentrations of volasertib induced a strong G2/M phase block (p<0.001), which was most pronounced in p53 deficient A549-920 cells, accompanied by a significant decrease in the number of G1 and S phase cells (p<0.001). Under hypoxia, a mitotic arrest was only detected when high volasertib concentrations were used. Intriguingly, the radiosensitizing effect of the Plk1 inhibitor was more pronounced in p53 wild type cells than in p53 deficient cells. For example, the dose enhance factor (DEF) for volasertib treatment ranged from 1.60 to 2.13 in A549-NTC cells and from 1.18 and 1.22 in A549-920 cells, respectively. Importantly, radiosensitivity was retained when cells were treated and irradiated under hypoxia. Conclusion: Our in vitro data confirm the therapeutic potential of volasertib in NSCLC cells. Pretreatment with the Plk1 inhibitor enhanced radiosensitivity, especially in cells with functional p53, suggesting a potential role for p53 in radiosensitization by volasertib. Citation Format: Jolien Van den Bossche, Ines De Pauw, Hilde Lambrechts, Céline Merlin, Christophe Deben, Vanessa Deschoolmeester, Pol Specenier, Patrick Pauwels, Marc Peeters, Filip Lardon, An Wouters. Volasertib in combination with radiotherapy: The perfect match in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1056. doi:10.1158/1538-7445.AM2017-1056
European Journal of Cancer, Sep 1, 2015
Background: Quality of life (QOL) is important in patients with locally advanced rectal cancer (L... more Background: Quality of life (QOL) is important in patients with locally advanced rectal cancer (LARC). Recently, quality of life has been linked with biological factors in cancer studies. Their correlation in rectal cancer is unknown and here we explore the relationship between QOL and circulating tumour cells (CTCs). Aims: 1. Document QOL and treatment toxicities prior to and at week 3 of neoadjuvant long-course chemoradiation prospectively in 20 patients 2. Correlate QOL and toxicities with ethnic status and ECOG performance status 3. Isolate CTCs at same defined timepoints 4. Correlate QOL and toxicities with CTCs Methods: QOL was assessed with the EORTC QLQ-C30 and EQ-5D tools, and toxicities (diarrhoea, weight loss, pain and fatigue) were graded on Common Toxicity Criteria Version 4.0. We stratified ethnic status into Asian and Caucasian. CTC isolation was performed on a 9ml peripheral blood sample, using EpCAM-based immunomagnetic separation, with CTCs defined as cytokeratin, DAPI positive, and CD45 negative. Correlations were performed with Chi-squared test and 2-sample t-test (aim 2) and negative binomial model (aim 4). Results: The median patient age was 60, 70% male, 55% Asian and 45% Caucasian. 20% were ECOG 1 at baseline and increased to 50% at week 3 (remainder ECOG 0). Prior to treatment, 29% of patients reported moderate depression, increasing to 50% prevalence at week 3. Mean EQ score and EORTC overall health scores remained similar over time: 7.8 and 5.5 at baseline respectively, and 7.6 and 5.4 at week 3 respectively. At baseline, 35% had grade(g)1 diarrhoea, 25% g1 fatigue, 35% g1 pain, 35% g1/2/3 weight loss. At week 3, 35% had g1/2 diarrhoea, 60% g1 fatigue, 10% g1 pain and 25% g1/2 weight loss. None of the Caucasian group reported baseline fatigue while 46% of Asians did (p = 0.04). At week 3, this difference was no longer evident. Asians also reported a lower baseline EORTC overall health score of 5 vs. 6.4 in Caucasians (p = 0.023). There were similar trends in EORTC QOL and EQ health scores. Fatigue was the only toxicity that correlated with ECOG (p = 0.02), with 70% of ECOG 0 reporting no fatigue compared to 10% in the other ECOG scores. Mean baseline CTC count was 6 (range 0−45). At week 3, CTC count decreased to 2 (range 0−16). Psychological and biological correlations revealed baseline CTC count correlating with EQ-5D score (p < 0.001), with a 1 unit increase in CTC resulting in a decrease of 0.1 in EQ-5D score. Conclusion: Depression was prevalent prior to treatment and increased during treatment in LARC. Fatigue also increased while pain decreased during treatment. Ethnically diverse groups reported poorer baseline health. Baseline EQ-5D score appeared to correlate with baseline CTCs; the cause for this observation is unknown. To our knowledge, this is the first study to document a relationship between QOL and CTCs in LARC. No conflict of interest.
Annals of Oncology, Sep 1, 2014
Translational cancer research, Jun 1, 2016
Concurrent high-dose cisplatin-based chemoradiation (CCRT) is the preferred standard of care for ... more Concurrent high-dose cisplatin-based chemoradiation (CCRT) is the preferred standard of care for patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-HNSCC) (1,2). The addition of cetuximab to irradiation (RT) improves locoregional control and prolongs progression-free survival (PFS) and overall survival (OS) (3,4). The combination of an EGFR-directed monoclonal antibody and cisplatin-based CCRT is not superior to cisplatin-based CCRT alone, but adds toxicity, and is therefore not recommended (5,6). Until recently, there were no direct comparisons between cisplatin-based CCRT and RT + cetuximab. Nevertheless, RT + cetuximab are widely rumored to be less toxic than cisplatin-based CCRT and is commonly advocated in patients unsuitable for cisplatin-based CCRT (7).
BMC Geriatrics
Background Falls and fall-related injuries are a major public health problem. Data on falls in ol... more Background Falls and fall-related injuries are a major public health problem. Data on falls in older persons with cancer is limited and robust data on falls within those with a frailty profile are missing. The aim of this study is to investigate the incidence and predictive factors for falls and fall-related injuries in frail older persons with cancer. Methods This study is a secondary data analysis from data previously collected in a large prospective multicenter observational cohort study in older persons with cancer in 22 Belgian hospitals (November 2012–February 2015). Patients ≥70 years with a malignant tumor and a frailty profile based on an abnormal G8 score were included upon treatment decision and evaluated with a Geriatric Assessment (GA). At follow-up, data on falls and fall-related injuries were documented. Results At baseline 2141 (37.2%) of 5759 included patients reported at least one fall in the past 12 months, 1427 patients (66.7%) sustained an injury. Fall-related d...
Journal of Geriatric Oncology
EJNMMI Research
Background FDG-PET/CT has a high negative predictive value to detect residual nodal disease in pa... more Background FDG-PET/CT has a high negative predictive value to detect residual nodal disease in patients with locally advanced squamous cell head and neck cancer after completing concurrent chemoradiotherapy (CCRT). However, the positive predictive value remains suboptimal due to inflammation after radiotherapy, generating unnecessary further investigations and possibly even surgery. We report the results of a preplanned secondary end point of the ECLYPS study regarding the potential advantages of dual time point FDG-PET/CT imaging (DTPI) in this setting. Standardized dedicated head and neck FDG-PET/CT images were obtained 12 weeks after CCRT at 60 and 120 min after tracer administration. We performed a semiquantitative assessment of lymph nodes, and the retention index (RI) was explored to optimize diagnostic performance. The reference standard was histology, negative FDG-PET/CT at 1 year, or > 2 years of clinical follow-up. The time-dependent area under the receiver operator cha...
Journal of Geriatric Oncology, 2015
Peer reviewe
Journal of Geriatric Oncology, 2021
Background: This study aims to investigate the occurrence of unplanned hospitalizations in older ... more Background: This study aims to investigate the occurrence of unplanned hospitalizations in older patients with cancer and to determine predictive factors. Methods: A prospective Belgian multicentre (n = 22), observational cohort study was performed. Patients ≥70 years with a malignant tumor were included. Patients underwent G8 screening followed by geriatric assessment (GA) if abnormal at baseline and were followed for unplanned hospitalizations at approximately three months. Uni-and multivariable regression models were performed to determine predictive factors associated with unplanned hospitalizations in older patients with an abnormal G8. Results: In total, 7763 patients were included in the current analysis of which 2409 (31%) patients with a normal G8 score and 5354 (69%) with an abnormal G8 score. Patients with an abnormal G8 were hospitalized more frequently than patients with a normal G8 (22.9% versus 12.4%; p < 0.0001). Reasons for unplanned hospitalizations were most frequently cancer related (25.7%) or cancer therapy related (28%). In multivariable analysis, predictive factors for unplanned hospitalizations in older patients with cancer and an abnormal G8 were female gender, absence of surgery, chemotherapy, ADL dependency, malnutrition and presence of comorbidities. Conclusion: Older patients with cancer and an abnormal G8 screening present a higher risk (23%) for unplanned hospitalizations. Predictive factors for these patients were identified and include not only patient and treatment related factors but also GA related factors.
Journal of Clinical Oncology, 2009
6017 Background: CRT is considered a standard approach for LA-LxHxSCC. TPF IC regimen seems to im... more 6017 Background: CRT is considered a standard approach for LA-LxHxSCC. TPF IC regimen seems to improve outcome in locally advanced head and neck SCC. The addition of LAP was investigated in combination with a sequential therapeutic approach (IC→ CRT). Methods: Eligible tumors were SCCHN: T3-T4 larynx (Lx), T2-T4 hypopharynx (Hx) N0–3 M0. The objective of this trial is to determine MTD, DLT and recommended dose of LAP when administered with TPF IC (docetaxel (T) 75mg/m2 (60 mg/m2 for the first cycle) d1, CDDP 75mg/m2 d1, 5FU 750mg/m2/d continuous infusion d1-d5 q3weeks) followed by CRT (weekly carboplatin AUC 1.5 and RT 70Gy in 7 weeks; 2Gy/fx). LAP is administered concomitantly with IC (escalating dose 500–1500mg po daily) and during CRT (1,500 mg daily). Results: Seven male patients were included; tumor sites: LX (n = 3) / Hx: (n = 4), median age 59 years (range: 47–79), WHO PS 0–1, no severe or uncontrolled comorbidity. Three pts were included in the first cohort, at dose level 1 ...
Journal of Clinical Oncology, 2017
e18208 Background: Health Information Technology (HIT) is increasingly integrated in clinical can... more e18208 Background: Health Information Technology (HIT) is increasingly integrated in clinical cancer care. Simultaneous routine assessment of patient reported outcomes (PROs) reliably improve symptom management, patient-provider communication and ultimately survival. Methods: his pilot study is a single center experience with the development and validation of an I-PRO tool (AMOCT). After obtaining informed consent, outpatients, using oral anticancer treatment, recorded their medication intake and 17 PRO measures (PROM) using this I-PRO tool. The device allowed real time data collection via a central platform. The registered data were processed by an algorithm, which stratifies the data into different grades according to international standards of care (CTCAE v4.0). In response to registration of data, patients received either automated symptom management suggestions or were referred to their caregivers. Patient clinical and demographic information is collected from medical records a...
Journal of Clinical Oncology, 2016
6076Background: To test the safety of BCRT with P and C after TPF-E. Methods: Stage III/IV unrese... more 6076Background: To test the safety of BCRT with P and C after TPF-E. Methods: Stage III/IV unresectable, HNSCC pts received up to 4 cycles (cy) of TPF-E (P and docetaxel [D] 75 mg/m² d 1, 5-FU 750 mg/m²/d d1-5, cetuximab [E, 400/250 mg/m²/wk]), with prophylactic antibiotics, no G-CSF. Pts with no PD after 4 cy were randomly assigned to BCRT (70 Gy/7 weeks/2 Gy fractions), weekly E, with either P 40 mg/m²/wk or C AUC 1.5/wk. Primary endpoint: feasibility of BCRT ( > 80% dose intensity (DI) of RT, P or C, and E). Results: 46 patients started TPF-E, 30 started BCRT. Median age: 57 (48-72), 41 male. WHO 0/1: 29/17. Stage III/IV: 4/42. 4 oral cavity, 24 oropharynx, 12 hypopharynx, 4 larynx, 2 unknown. 34, 4, 6, 2 pts received 4,3,2, and 1 TPF-E cy. Median DI (mg/m²/wk): D: 24.4, P: 24.4, 5-FU: 1220.9, E: 255.4. ICT was discontinued in 12 pts (6 toxicity [1 grade 5], 1 protocol violation, 2 medical decision, 1 pt refusal, 1 death [cause unknown], 1 cerebrovascular accident). 3 were not randomized: 1 PD under IC...
Journal of Clinical Oncology, 2016
6021Background: FDG-PET/CT surveillance after CRT in LAHNSCC results in non-inferior overall surv... more 6021Background: FDG-PET/CT surveillance after CRT in LAHNSCC results in non-inferior overall survival (OS) compared to routine neck dissection (ND) (Mehanna H, ASCO 2015). However, optimal imaging ...
Expert Review of Anticancer Therapy, Jul 16, 2018
Introduction: The majority of patients with locally advanced head and neck squamous cell carcinom... more Introduction: The majority of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) will recur. The treatment of patients with recurrent/metastatic (R/M) HNSCC) is rapidly evolving. Areas covered: This article will comprehensively review the current systemic treatment of R/M HNSCC. Expert Commentary: For the time being, the EXTREME regimen (cetuximab in combination with platinum and 5-fluorouracil) still remains standard of care in previously untreated R/M HNSCC patients who are candidates for combination chemotherapy. Single agents with well documented activity in HNSCC include methotrexate, cisplatin, 5-FU, docetaxel, and paclitaxel. The anti-PD-1 monoclonal antibody nivolumab can be considered the current standard of care in patients with R/M HNSCC progressing after platinum-based therapy based on the results of CheckMate 141 showing a survival benefit over standard of care drugs, such as single agent weekly cetuximab, methotrexate, or docetaxel. Multiple randomized phase III trials comparing anti-PD(L)-antibodies either as single agent or in combination with chemotherapy or an anti-CTLA-4 with the EXTREME as fist line treatment are ongoing or planned. The outcome of these trials might change the current treatment paradigm in previously untreated R/M HNSCC. Immunotherapeutic agents under active investigation include Toll-like receptor 8 agonists and inhibitors of IDO1.
Journal of Clinical Oncology, Jun 20, 2006
5574 Background: RT with concurrent chemotherapy is superior to RT alone as treatment for locally... more 5574 Background: RT with concurrent chemotherapy is superior to RT alone as treatment for locally advanced SCCHN. Gem is a potent radiosensitizer in vitro and in vivo and in addition has a good activity in SCCHN. Exploitation of these properties was the rationale for a single institution phase II study which evaluates the efficacy and toxicities of standard RT + weekly low dose Gem. Methods: Eligible were patients with primary inoperable or locally advanced stage III and IV SCCHN. Treatment: Planned RT was 70 Gy over 7 weeks with weekly Gem 100 mg/m2 within 2 hours prior to RT (Eisbrüch et al., ASCO, 1997, 1998). Presented endpoints are response rate (according to WHO), acute and late toxicity (according to NCICTC), disease free survival (DFS), local relapse free survival (LRFS) and overall survival (OS). Results: 26 patients (21 male, 5 female; performance status 0–2; no prior treatment) entered the study between November 1998 and September 2003. Median age was 56 years (range 48–78). Tumor sites were oropharynx (6), hypopharynx (17), glottis (1), paranasal sinus (1), unknown (1). Clinical stage was III (2) or IV (24). 7 Patients had T4N2 disease and 2 had T4N3 disease. Patients received a median of 7 Gem cycles (range 2–8) and a median of 70 Gy (66–84.75). 7 patients underwent radical neck dissection. Grade 3–4 acute toxicities included mucositis (22/26), dermatitis (18/26), pharyngitis and/or oesophagitis (21/26), pain (7/25), xerostomia (1/24), neutropenia (1/26) and anemia (1/26). 21/26 patients needed tube feeding and 21/26 needed to be hospitalized. After recovery from acute toxicity 6/23 could feed normally, 5/23 needed soft food, 5/23 were able to swallow liquid food and 2/23 required permanent tube feeding. Response was evaluable in 22 patients (11 CR, 11 PR). Intial relapse was at distant sites in 9/26 and local in 8/26. Median follow up of the patients still alive is 46 months. Median OS is 576 days, median DFS is 401 days, median LRFS is not reached. 7/26 remain free of disease more than 3 years after end of treatment. Conclusions: RT + Gem (100 mg/m2/week) is feasible but toxic. The combination is highly active in SCCHN and provides a good long term local control. [Table: see text]
Cancers, Nov 28, 2019
Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in no... more Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in non-small cell lung cancer (NSCLC) making it an interesting drug target. We examined the in vitro therapeutic effects of volasertib, a Plk1 inhibitor, in combination with irradiation in a panel of NSCLC cell lines with different p53 backgrounds. Pretreatment with volasertib efficiently sensitized p53 wild type cells to irradiation. Flow cytometric analysis revealed that significantly more cells were arrested in the G 2 /M phase of the cell cycle after the combination therapy compared to either treatment alone (p < 0.005). No significant synergistic induction of apoptotic cell death was observed, but, importantly, significantly more senescent cells were detected when cells were pretreated with volasertib before irradiation compared to both monotherapies alone (p < 0.001), especially in cells with functional p53. Consequently, while most cells with functional p53 showed permanent growth arrest, more p53 knockdown/mutant cells could re-enter the cell cycle, resulting in colony formation and cell survival. Our findings assign functional p53 as a determining factor for the observed radiosensitizing effect of volasertib in combination with radiotherapy for the treatment of NSCLC.
Background: Polo-like kinase 1 (Plk1), a master regulator of mitosis and the DNA damage response,... more Background: Polo-like kinase 1 (Plk1), a master regulator of mitosis and the DNA damage response, is overexpressed in several human malignancies, making it a promising therapeutic target. Monotherapy of Plk1 inhibition has shown only a moderate effect in clinical trials, indicating the need to combine with other therapies. Remarkably, Plk1 inhibition arrests cancer cells in mitosis, which is the most radiosensitive cell cycle phase. Hence, we are the first to investigate the effect of volasertib, the lead agent in category of Plk1 inhibitors at the moment, on the radiosensitivity of a panel of non-small cell lung cancer (NSCLC) cell lines with a different p53 background under both normal and reduced oxygen conditions. Material and methods: Three isogenic NSCLC cell lines (i.e. A549 (p53 wt); A549-NTC (non template control, p53 wt); and A549-920 (p53 deficient)) and one TP53 mutant cell line (NCI-H1975, R273H mutation) were included. Cell survival after volasertib monotherapy (0-85 nM, 24h) was assessed using the sulforhodamine B assay. The effect of volasertib (0-20 nM, 24h) on cell cycle distribution was determined flow cytometrically using the Vindelov method. The clonogenic assay (24h 0-10 nM volasertib followed by 0-8 Gy irradiation) was performed to evaluate the radiosensitizing effect of volasertib. Cells were incubated under normoxia or hypoxia (1% O2) during the treatment period. Data analysis was done using WinNonlin and FlowJo software. Results: Plk1 inhibition by volasertib established a dose-dependent growth inhibition in all cell lines under both normoxia and hypoxia. Cell survival was significantly influenced by the p53 status, with a reduced sensitivity to volasertib in p53 deficient/mutant cells compared to p53 wild type cells (p<0.001). Except for the TP53 mutant NCI-1975 cell line, IC50-values were significantly higher in hypoxic cells compared to their normoxic counterparts (p<0.001). Treatment with increasing concentrations of volasertib induced a strong G2/M phase block (p<0.001), which was most pronounced in p53 deficient A549-920 cells, accompanied by a significant decrease in the number of G1 and S phase cells (p<0.001). Under hypoxia, a mitotic arrest was only detected when high volasertib concentrations were used. Intriguingly, the radiosensitizing effect of the Plk1 inhibitor was more pronounced in p53 wild type cells than in p53 deficient cells. For example, the dose enhance factor (DEF) for volasertib treatment ranged from 1.60 to 2.13 in A549-NTC cells and from 1.18 and 1.22 in A549-920 cells, respectively. Importantly, radiosensitivity was retained when cells were treated and irradiated under hypoxia. Conclusion: Our in vitro data confirm the therapeutic potential of volasertib in NSCLC cells. Pretreatment with the Plk1 inhibitor enhanced radiosensitivity, especially in cells with functional p53, suggesting a potential role for p53 in radiosensitization by volasertib. Citation Format: Jolien Van den Bossche, Ines De Pauw, Hilde Lambrechts, Céline Merlin, Christophe Deben, Vanessa Deschoolmeester, Pol Specenier, Patrick Pauwels, Marc Peeters, Filip Lardon, An Wouters. Volasertib in combination with radiotherapy: The perfect match in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1056. doi:10.1158/1538-7445.AM2017-1056
European Journal of Cancer, Sep 1, 2015
Background: Quality of life (QOL) is important in patients with locally advanced rectal cancer (L... more Background: Quality of life (QOL) is important in patients with locally advanced rectal cancer (LARC). Recently, quality of life has been linked with biological factors in cancer studies. Their correlation in rectal cancer is unknown and here we explore the relationship between QOL and circulating tumour cells (CTCs). Aims: 1. Document QOL and treatment toxicities prior to and at week 3 of neoadjuvant long-course chemoradiation prospectively in 20 patients 2. Correlate QOL and toxicities with ethnic status and ECOG performance status 3. Isolate CTCs at same defined timepoints 4. Correlate QOL and toxicities with CTCs Methods: QOL was assessed with the EORTC QLQ-C30 and EQ-5D tools, and toxicities (diarrhoea, weight loss, pain and fatigue) were graded on Common Toxicity Criteria Version 4.0. We stratified ethnic status into Asian and Caucasian. CTC isolation was performed on a 9ml peripheral blood sample, using EpCAM-based immunomagnetic separation, with CTCs defined as cytokeratin, DAPI positive, and CD45 negative. Correlations were performed with Chi-squared test and 2-sample t-test (aim 2) and negative binomial model (aim 4). Results: The median patient age was 60, 70% male, 55% Asian and 45% Caucasian. 20% were ECOG 1 at baseline and increased to 50% at week 3 (remainder ECOG 0). Prior to treatment, 29% of patients reported moderate depression, increasing to 50% prevalence at week 3. Mean EQ score and EORTC overall health scores remained similar over time: 7.8 and 5.5 at baseline respectively, and 7.6 and 5.4 at week 3 respectively. At baseline, 35% had grade(g)1 diarrhoea, 25% g1 fatigue, 35% g1 pain, 35% g1/2/3 weight loss. At week 3, 35% had g1/2 diarrhoea, 60% g1 fatigue, 10% g1 pain and 25% g1/2 weight loss. None of the Caucasian group reported baseline fatigue while 46% of Asians did (p = 0.04). At week 3, this difference was no longer evident. Asians also reported a lower baseline EORTC overall health score of 5 vs. 6.4 in Caucasians (p = 0.023). There were similar trends in EORTC QOL and EQ health scores. Fatigue was the only toxicity that correlated with ECOG (p = 0.02), with 70% of ECOG 0 reporting no fatigue compared to 10% in the other ECOG scores. Mean baseline CTC count was 6 (range 0−45). At week 3, CTC count decreased to 2 (range 0−16). Psychological and biological correlations revealed baseline CTC count correlating with EQ-5D score (p < 0.001), with a 1 unit increase in CTC resulting in a decrease of 0.1 in EQ-5D score. Conclusion: Depression was prevalent prior to treatment and increased during treatment in LARC. Fatigue also increased while pain decreased during treatment. Ethnically diverse groups reported poorer baseline health. Baseline EQ-5D score appeared to correlate with baseline CTCs; the cause for this observation is unknown. To our knowledge, this is the first study to document a relationship between QOL and CTCs in LARC. No conflict of interest.
Annals of Oncology, Sep 1, 2014
Translational cancer research, Jun 1, 2016
Concurrent high-dose cisplatin-based chemoradiation (CCRT) is the preferred standard of care for ... more Concurrent high-dose cisplatin-based chemoradiation (CCRT) is the preferred standard of care for patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-HNSCC) (1,2). The addition of cetuximab to irradiation (RT) improves locoregional control and prolongs progression-free survival (PFS) and overall survival (OS) (3,4). The combination of an EGFR-directed monoclonal antibody and cisplatin-based CCRT is not superior to cisplatin-based CCRT alone, but adds toxicity, and is therefore not recommended (5,6). Until recently, there were no direct comparisons between cisplatin-based CCRT and RT + cetuximab. Nevertheless, RT + cetuximab are widely rumored to be less toxic than cisplatin-based CCRT and is commonly advocated in patients unsuitable for cisplatin-based CCRT (7).
BMC Geriatrics
Background Falls and fall-related injuries are a major public health problem. Data on falls in ol... more Background Falls and fall-related injuries are a major public health problem. Data on falls in older persons with cancer is limited and robust data on falls within those with a frailty profile are missing. The aim of this study is to investigate the incidence and predictive factors for falls and fall-related injuries in frail older persons with cancer. Methods This study is a secondary data analysis from data previously collected in a large prospective multicenter observational cohort study in older persons with cancer in 22 Belgian hospitals (November 2012–February 2015). Patients ≥70 years with a malignant tumor and a frailty profile based on an abnormal G8 score were included upon treatment decision and evaluated with a Geriatric Assessment (GA). At follow-up, data on falls and fall-related injuries were documented. Results At baseline 2141 (37.2%) of 5759 included patients reported at least one fall in the past 12 months, 1427 patients (66.7%) sustained an injury. Fall-related d...
Journal of Geriatric Oncology
EJNMMI Research
Background FDG-PET/CT has a high negative predictive value to detect residual nodal disease in pa... more Background FDG-PET/CT has a high negative predictive value to detect residual nodal disease in patients with locally advanced squamous cell head and neck cancer after completing concurrent chemoradiotherapy (CCRT). However, the positive predictive value remains suboptimal due to inflammation after radiotherapy, generating unnecessary further investigations and possibly even surgery. We report the results of a preplanned secondary end point of the ECLYPS study regarding the potential advantages of dual time point FDG-PET/CT imaging (DTPI) in this setting. Standardized dedicated head and neck FDG-PET/CT images were obtained 12 weeks after CCRT at 60 and 120 min after tracer administration. We performed a semiquantitative assessment of lymph nodes, and the retention index (RI) was explored to optimize diagnostic performance. The reference standard was histology, negative FDG-PET/CT at 1 year, or > 2 years of clinical follow-up. The time-dependent area under the receiver operator cha...
Journal of Geriatric Oncology, 2015
Peer reviewe
Journal of Geriatric Oncology, 2021
Background: This study aims to investigate the occurrence of unplanned hospitalizations in older ... more Background: This study aims to investigate the occurrence of unplanned hospitalizations in older patients with cancer and to determine predictive factors. Methods: A prospective Belgian multicentre (n = 22), observational cohort study was performed. Patients ≥70 years with a malignant tumor were included. Patients underwent G8 screening followed by geriatric assessment (GA) if abnormal at baseline and were followed for unplanned hospitalizations at approximately three months. Uni-and multivariable regression models were performed to determine predictive factors associated with unplanned hospitalizations in older patients with an abnormal G8. Results: In total, 7763 patients were included in the current analysis of which 2409 (31%) patients with a normal G8 score and 5354 (69%) with an abnormal G8 score. Patients with an abnormal G8 were hospitalized more frequently than patients with a normal G8 (22.9% versus 12.4%; p < 0.0001). Reasons for unplanned hospitalizations were most frequently cancer related (25.7%) or cancer therapy related (28%). In multivariable analysis, predictive factors for unplanned hospitalizations in older patients with cancer and an abnormal G8 were female gender, absence of surgery, chemotherapy, ADL dependency, malnutrition and presence of comorbidities. Conclusion: Older patients with cancer and an abnormal G8 screening present a higher risk (23%) for unplanned hospitalizations. Predictive factors for these patients were identified and include not only patient and treatment related factors but also GA related factors.
Journal of Clinical Oncology, 2009
6017 Background: CRT is considered a standard approach for LA-LxHxSCC. TPF IC regimen seems to im... more 6017 Background: CRT is considered a standard approach for LA-LxHxSCC. TPF IC regimen seems to improve outcome in locally advanced head and neck SCC. The addition of LAP was investigated in combination with a sequential therapeutic approach (IC→ CRT). Methods: Eligible tumors were SCCHN: T3-T4 larynx (Lx), T2-T4 hypopharynx (Hx) N0–3 M0. The objective of this trial is to determine MTD, DLT and recommended dose of LAP when administered with TPF IC (docetaxel (T) 75mg/m2 (60 mg/m2 for the first cycle) d1, CDDP 75mg/m2 d1, 5FU 750mg/m2/d continuous infusion d1-d5 q3weeks) followed by CRT (weekly carboplatin AUC 1.5 and RT 70Gy in 7 weeks; 2Gy/fx). LAP is administered concomitantly with IC (escalating dose 500–1500mg po daily) and during CRT (1,500 mg daily). Results: Seven male patients were included; tumor sites: LX (n = 3) / Hx: (n = 4), median age 59 years (range: 47–79), WHO PS 0–1, no severe or uncontrolled comorbidity. Three pts were included in the first cohort, at dose level 1 ...
Journal of Clinical Oncology, 2017
e18208 Background: Health Information Technology (HIT) is increasingly integrated in clinical can... more e18208 Background: Health Information Technology (HIT) is increasingly integrated in clinical cancer care. Simultaneous routine assessment of patient reported outcomes (PROs) reliably improve symptom management, patient-provider communication and ultimately survival. Methods: his pilot study is a single center experience with the development and validation of an I-PRO tool (AMOCT). After obtaining informed consent, outpatients, using oral anticancer treatment, recorded their medication intake and 17 PRO measures (PROM) using this I-PRO tool. The device allowed real time data collection via a central platform. The registered data were processed by an algorithm, which stratifies the data into different grades according to international standards of care (CTCAE v4.0). In response to registration of data, patients received either automated symptom management suggestions or were referred to their caregivers. Patient clinical and demographic information is collected from medical records a...
Journal of Clinical Oncology, 2016
6076Background: To test the safety of BCRT with P and C after TPF-E. Methods: Stage III/IV unrese... more 6076Background: To test the safety of BCRT with P and C after TPF-E. Methods: Stage III/IV unresectable, HNSCC pts received up to 4 cycles (cy) of TPF-E (P and docetaxel [D] 75 mg/m² d 1, 5-FU 750 mg/m²/d d1-5, cetuximab [E, 400/250 mg/m²/wk]), with prophylactic antibiotics, no G-CSF. Pts with no PD after 4 cy were randomly assigned to BCRT (70 Gy/7 weeks/2 Gy fractions), weekly E, with either P 40 mg/m²/wk or C AUC 1.5/wk. Primary endpoint: feasibility of BCRT ( > 80% dose intensity (DI) of RT, P or C, and E). Results: 46 patients started TPF-E, 30 started BCRT. Median age: 57 (48-72), 41 male. WHO 0/1: 29/17. Stage III/IV: 4/42. 4 oral cavity, 24 oropharynx, 12 hypopharynx, 4 larynx, 2 unknown. 34, 4, 6, 2 pts received 4,3,2, and 1 TPF-E cy. Median DI (mg/m²/wk): D: 24.4, P: 24.4, 5-FU: 1220.9, E: 255.4. ICT was discontinued in 12 pts (6 toxicity [1 grade 5], 1 protocol violation, 2 medical decision, 1 pt refusal, 1 death [cause unknown], 1 cerebrovascular accident). 3 were not randomized: 1 PD under IC...
Journal of Clinical Oncology, 2016
6021Background: FDG-PET/CT surveillance after CRT in LAHNSCC results in non-inferior overall surv... more 6021Background: FDG-PET/CT surveillance after CRT in LAHNSCC results in non-inferior overall survival (OS) compared to routine neck dissection (ND) (Mehanna H, ASCO 2015). However, optimal imaging ...