Daniëlle B.P. Eekers

Modern clinical research: How rapid learning health care and cohort multiple randomised clinical trials complement traditional evidence based medicine.

ABSTRACT Background. Trials are vital in informing routine clinical care; however, current designs have major deficiencies. An overview of the various challenges that face modern clinical research and the methods that can be exploited to solve these challenges, in the context of personalised cancer treatment in the 21st century is provided. Aim. The purpose of this manuscript, without intending to be comprehensive, is to spark thought whilst presenting and discussing two important and complementary alternatives to traditional evidence-based medicine, specifically rapid learning health care and cohort multiple randomised controlled trial design. Rapid learning health care is an approach that proposes to extract and apply knowledge from routine clinical care data rather than exclusively depending on clinical trial evidence, (please watch the animation: http://youtu.be/ZDJFOxpwqEA). The cohort multiple randomised controlled trial design is a pragmatic method which has been proposed to help overcome the weaknesses of conventional randomised trials, taking advantage of the standardised follow-up approaches more and more used in routine patient care. This approach is particularly useful when the new intervention is a priori attractive for the patient (i.e. proton therapy, patient decision aids or expensive medications), when the outcomes are easily collected, and when there is no need of a placebo arm. Discussion. Truly personalised cancer treatment is the goal in modern radiotherapy. However, personalised cancer treatment is also an immense challenge. The vast variety of both cancer patients and treatment options makes it extremely difficult to determine which decisions are optimal for the individual patient. Nevertheless, rapid learning health care and cohort multiple randomised controlled trial design are two approaches (among others) that can help meet this challenge.

Decision support systems for personalized and participative radiation oncology.

Abstract A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models ‘learn’ using advanced and innovative information technologies (ideally in a distributed fashion — please watch the animation: http://youtu.be/ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi‐faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re‐evaluated (through quality assurance procedures) in different patient datasets in order to refine and re‐optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine. Graphical abstract Figure. No caption available.

NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.

Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial.

BACKGROUND AND PURPOSE In this multicentric in silico trial we compared photon, proton, and carbon-ion radiotherapy plans for re-irradiation of patients with squamous cell carcinoma of the head and neck (HNSCC) regarding dose to tumour and doses to surrounding organs at risk (OARs). MATERIAL AND METHODS Twenty-five HNSCC patients with a second new or recurrent cancer after previous irradiation (70Gy) were included. Intensity-modulated proton therapy (IMPT) and ion therapy (IMIT) re-irradiation plans to a second subsequent dose of 70Gy were compared to photon therapy delivered with volumetric modulated arc therapy (VMAT). RESULTS When comparing IMIT and IMPT to VMAT, the mean dose to all investigated 22 OARs was significantly reduced for IMIT and to 15 out of 22 OARs (68%) using IMPT. The maximum dose to 2% volume (D2) of the brainstem and spinal cord were significantly reduced using IMPT and IMIT compared to VMAT. The data are available on www.cancerdata.org. CONCLUSIONS In this ROCOCO in silico trial, a reduction in mean dose to OARs was achieved using particle therapy compared to photons in the re-irradiation of HNSCC. There was a dosimetric benefit favouring carbon-ions above proton therapy. These dose reductions may potentially translate into lower severe complication rates related to the re-irradiation.

The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology

PURPOSE To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging. METHODS CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. RESULTS The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). CONCLUSION In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required.

The posterior cerebellum, a new organ at risk?

Eekers et al. have recently proposed a neuro-oncology atlas, which was co-authored by most centers associated in the European Proton Therapy Network (EPTN; Figure 1). With the introduction of new treatment techniques, such as integrated magnetic resonance imaging and linear accelerators (MR-linac) or particle therapy, the prediction of clinical efficacy of these more costly treatment modalities becomes more relevant. One of the side-effects of brain irradiation, being cognitive decline, is one of the toxicities most difficult to measure and predict. In order to validly compare different treatment modalities, 1) a uniform nomenclature of the organs at risk (OARs), 2) uniform atlas-based delineation [e.g., Eekers et al.], 3) long-term follow-up data with standardized cognitive tests, 4) a large patient population, and 5) (thus derived) validated normal tissue complication probability (NTCP) models are mandatory. Apart from the Gondi model, in which the role of the dose to 40% of both hippocampi (HC) proves to be significantly related to cognition in 18 patients, no similar models are available. So there is a strong need for more NTCP models, on HC, brain tissue and possible other relevant brain structures. In this review we summarize the available evidence on the role of the posterior cerebellum as a possible new organ at risk for cognition, which is deemed relevant for irradiation of brain and head and neck tumors.

Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer: Two externally validated nomograms

INTRODUCTION Commonly used clinical models for survival prediction after stereotactic radiosurgery (SRS) for brain metastases (BMs) are limited by the lack of individual risk scores and disproportionate prognostic groups. In this study, two nomograms were developed to overcome these limitations. METHODS 495 patients with BMs of NSCLC treated with SRS for a limited number of BMs in four Dutch radiation oncology centers were identified and divided in a training cohort (n=214, patients treated in one hospital) and an external validation cohort n=281, patients treated in three other hospitals). Using the training cohort, nomograms were developed for prediction of early death (<3months) and long-term survival (>12months) with prognostic factors for survival. Accuracy of prediction was defined as the area under the curve (AUC) by receiver operating characteristics analysis for prediction of early death and long term survival. The accuracy of the nomograms was also tested in the external validation cohort. RESULTS Prognostic factors for survival were: WHO performance status, presence of extracranial metastases, age, GTV largest BM, and gender. Number of brain metastases and primary tumor control were not prognostic factors for survival. In the external validation cohort, the nomogram predicted early death statistically significantly better (p<0.05) than the unfavorable groups of the RPA, DS-GPA, GGS, SIR, and Rades 2015 (AUC=0.70 versus range AUCs=0.51-0.60 respectively). With an AUC of 0.67, the other nomogram predicted 1year survival statistically significantly better (p<0.05) than the favorable groups of four models (range AUCs=0.57-0.61), except for the SIR (AUC=0.64, p=0.34). The models are available on www.predictcancer.org. CONCLUSION The nomograms predicted early death and long-term survival more accurately than commonly used prognostic scores after SRS for a limited number of BMs of NSCLC. Moreover these nomograms enable individualized probability assessment and are easy into use in routine clinical practice.

Evidence on the efficacy of primary radiosurgery or stereotactic radiotherapy for drug-resistant non-neoplastic focal epilepsy in adults: A systematic review

PURPOSE Although the majority of adult epilepsy patients respond well to the current antiepileptic drug treatment, 20-40% of them are drug-resistant. In these patients, resective epilepsy surgery is a curative treatment option, for which, however, only a limited number of patients is eligible. The purpose is to summarize the outcome of radiotherapy for drug-resistant non-neoplastic focal epilepsy and to elucidate its efficacy for seizure outcome and long-term toxicity in adults. METHOD A systematic literature search was performed in Pubmed, Ovid Medline, Cochrane library, Embase and Web of Science. The methodological quality was evaluated using an adapted QUADAS checklist. RESULTS Sixteen out of 170 initially identified studies were included in this systematic literature study (n = 170 patients). Twelve of the 16 studies described a positive effect of radiotherapy on seizure frequency reduction, with 98 of the patients (on average 58%, range 25%-95%) reporting no or rare seizures (defined as radiotherapy-adapted Engel class [RAEC] I and II. In total, 20% (34 patients) of the patients needed subsequent surgery due to radionecrosis, cysts formation, edema, and intracranial hypertension or remaining seizures. A dose-effect model was fitted to the available response data in an attempt to derive a relationship between prescribed dose and RAEC frequency. CONCLUSIONS Radiotherapy is a possible non-invasive treatment option for patients with drug-resistant focal non-neoplastic epilepsy. This systematic review showed that there is only level 4 evidence of primary radiotherapy reducing seizure frequency in adult patients. Prospective randomized trials are needed to determine its exact value compared to other treatment approaches.

Impact of the revised WHO classification of diffuse low-grade glioma on clinical decision making : A case report

Background: In the 2016 update of the World Health Organization Classification of Tumors of the central nervous system, phenotypic and genotypic parameters are integrated in diffuse low-grade glioma (LGG) tumor classification. Implementation of this combined phenotypic–genotypic characterization identifies prognostic relevant subgroups. Case Description: We report a case of a 67-year-old patient with an LGG that showed molecular characteristics similar to glioblastoma multiforme (GBM). After gross total tumor resection, the patient received combination therapy (radiotherapy and chemotherapy) according to high-grade glioma treatment protocol. Conclusion: The introduction of molecular parameters to the classification of LGG will add a level of objectivity, which will yield biological homogeneous subclasses. Consequently, this will influence patient counseling and clinical decision making regarding treatment protocols.

The Prevention of Brain Metastases in Non-Small Cell Lung Cancer by Prophylactic Cranial Irradiation

Background Non-small cell lung cancer (NSCLC) patients frequently develop brain metastases (BM), even though the initial imaging with brain CT or MRI was negative. Stage III patients have the highest risk to develop BM, with an incidence of approximately 30%. BM can lead to neurocognitive disorders, loss of quality of life (QoL), and they are the most important factors influencing patient’s overall survival (OS). Although a radical local treatment of BM may be possible with primary radiosurgery or after resection, the prognosis often remains poor. Preventing the development of BM through prophylactic cranial irradiation (PCI) may improve the outcome of these patients. Methods Data from published randomized trials comparing PCI with non-PCI were sought using electronic database (PubMed) searching, hand searching, and by contacting experts. Trials were included if they considered a randomized comparison of PCI and non-PCI, enrolled NSCLC patients, excluded patients with recurrent or metastatic disease, and reported results on BM occurrence. Each randomized controlled trial (RCT) was assessed for methodological quality using the Cochrane collaboration’s tool for the assessment of risk of bias. Study estimates were pooled using a fixed effects sample-weighted meta-analysis approach to calculate an overall estimate and 95% confidence interval (CI). Results on PCI-related toxicity, QoL, and OS were only reported descriptively. Results Seven RCTs were included in the meta-analysis. In total, 1,462 patients were analyzed, including 717 patients who received PCI and 745 patients who did not. The risk of developing BM was significantly decreased through PCI (13% reduction, RR 0.33; 95% CI 0.22–0.45). PCI-related toxicity and QoL data were limited. Acute toxicity mostly included fatigue, skin-related toxicity, and nausea or vomiting. Late toxicities such as headache, dyspnea, lethargy, and low grade cognitive impairments were also reported in some of the included RCTs. Results on OS were inconclusive. Conclusion The risk of developing BM was reduced in patients who received PCI compared to patients who did not. To implement PCI as the standard treatment for patients with NSCLC, the impact of PCI-related toxicity on QoL should be further investigated, as well as long-term OS. A future individual patient data meta-analysis could produce definitive answers to this clinical question.