- Email: [email protected]
Trial design on prophylaxis and treatment of brain metastases: Lessons learned from the EORTC Brain Metastases Strategic Meeting 2012
European Journal of Cancer (2012) 48, 3439–3447
Available at www.sciencedirect.com
journal homepage: www.ejcancer.info
Current Perspective
Trial design on prophylaxis and treatment of brain metastases: Lessons learned from the EORTC Brain Metastases Strategic Meeting 2012 Matthias Preusser a,⇑, Frank Winkler b, Laurence Collette c, Sven Haller d, Sandrine Marreaud e, Riccardo Soffietti f, Martin Klein g, Jaap C. Reijneveld h, Jo¨rg-Christian Tonn i, Brigitta G. Baumert j, Paula Mulvenna k, Dirk Schadendorf l, Renata Duchnowska m, Anna Sophie Berghoff a,n, Nancy Lin o, David A. Cameron p, Yazid Belkacemi q,r,s, Jacek Jassem t, Damien C. Weber u a
Department of Medicine I & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Neurology Clinic and National Center for Tumor Disease, University of Heidelberg, Heidelberg, Germany c Statistics Department, European Organisation for Research and Treatment of Cancer (EORTC), Data Center, Brussels, Belgium d Department of Diagnostic and Interventional Neuroradiology, DISIM, University Hospitals of Geneva, Geneva, Switzerland e European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium f Division of Neuro-oncology, Department of Neuroscience, University and San Giovanni Battista Hospital, Turin, Italy g Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands h Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands i Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany j Department of Radiation Oncology (MAASTRO), GROW (School for Oncology & Developmental Biology), Maastricht University Medical Center, Maastricht, The Netherlands k Freeman Hospital, Newcastle, UK l Department of Dermatology, Skin Cancer Center, University Hospital Essen, Essen, Germany m Oncology Department Military Institute of Medicine, Warsaw, Poland n Institute of Neurology, Medical University of Vienna, Vienna, Austria o Department of Medical Oncology, Dana-Farber Cancer Center, Boston, USA p Edinburgh Cancer Research Centre, Western General Hospital, Crewe Rd South, Edinburgh EH4 2 XU, Scotland, UK q AP-HP, Service d’Oncologie-Radiothe´rapie, Hoˆpital Henri Mondor, France r Universite´ Paris-Est Cre´teil, France s AROMEv (Association of Radiotherapy and Oncology of the Mediterranean Area), France t Medical University of Gdan´sk, Poland u Department of Radiation Oncology, Geneva University Hospital, Geneva, Switzerland b
Available online 8 August 2012
⇑ Corresponding author: Address: Department of Medicine I & Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Tel.: +43 1 40400 4457; fax: +43 1 40400 6686. E-mail address: [email protected] (M. Preusser). v www.aromecancer.org
0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.07.002
3440
KEYWORDS Brain metastases Clinical trail Prophylaxis EORTC
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
Brain metastases (BM) occur in a significant proportion of cancer patients and are associated with considerable morbidity and poor prognosis. The trial design in BM patients is particularly challenging, as many disease and patient variables, statistical issues, and the selection of appropriate end-points have to be taken into account. During a meeting organised on behalf of the European Organisation for Research and Treatment of Cancer (EORTC), methodological aspects of trial design in BM were discussed. This paper summarises the issues and potential trial strategies discussed during this meeting and may provide some guidance for the design of trials in BM patients. Ó 2012 Elsevier Ltd. All rights reserved.
Abstract
1. Introduction Brain metastases (BM) represent a substantial health care problem in cancer patients. It is estimated that approximately 20–40% of patients with malignancy will develop BM during the course of their illness.1 The most common anatomic primary sites are breast and lung.2 Melanoma has however the highest percentage of BMs relative to other primary tumours, with 75% of patients with disseminated disease developing BM.3 With best supportive care, median survival time is approximately 1–2 months.4 Radiation therapy (RT) increases the median survival to 3–5 months. Surgery, stereotactic radiotherapy, whole brain radiotherapy (WBRT) and systemic methods have been integrated in the therapeutic armamentarium, depending on the number, the site and the size of brain secondary lesions.5–7 Delivering concomitant chemo-RT may improve tumour local control but does not improve overall survival (OS) and is
thus not recommended for the routine treatment of BM patients.8 Although many patients with BM die as a result of extra-cranial disease progression, it is important to note that a substantial number suffer from the local tumour progression in the CNS.9 Optimising local control is thus of paramount importance. The development of symptomatic BM has a substantial impact on patient’s quality of life (QoL) and neuro-cognitive function. However, these metrics are difficult to assess in BM patients, as the overall compliance rates of questionnaires and neuro-psychological tests decreases as patients’ condition deteriorates over time.10–12 Treatment may also induce drowsiness, alopecia and weakness that may consequently substantially affect the overall QoL of these patients.10,12 Notwithstanding the overly optimistic estimation of the treatment’s clinical benefit of patients and referring physicians alike, palliative treatment should not be detrimental to the patients’
Fig. 1. Axial, coronal and sagittal view of whole brain radiation therapy with hippocampal sparing. Radiation dose shown in colour wash.
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
quality of life, notably when left with a limited life span.13,14 Newer radiation techniques, e.g. with hippocampal sparing (Fig. 1), and the use of novel drugs may to some extent decrease the treatment-related toxicity and preserve neuro-congition.15–17 The main prognostic factors for BM patients are age, performance status, control of primary tumour, absence of extra-cranial disease and number of brain lesions.18 It is thus possible to identify a subset of patients in the heterogeneous BM population with favourable outcome potential, who may benefit from experimental therapeutic strategies. Additionally, some primary and secondary tumours may have unique biological signatures that may respond to targeted agents and biological modulation.19 The European Organisation of Research and Treatment of Cancer (EORTC) organised in February 2012 a multidisciplinary meeting to discuss issues with and strategies for trial development in patients with BM. In this report, we discuss some of the challenges of study conception and design discussed during this meeting. We hope that our report may provide guidance for the design of future trials in BM patients. 2. Challenges to developing a brain metastases trial When developing trials for BM, there are a number of key aspects that require careful considerations like the trial organisation, the patient population, the safety assessment and the efficacy end-points. 2.1. Trial organisation The most effective method of preparing and conducting the trial is to use a multidisciplinary approach including a panel of experts in the management of primary tumour and BM, and methodologists. That will guarantee an optimal assessment of the risk and benefit for patients in a trial appropriately designed to answer the principal objective. Another critical step is the selection of participating centres. The choice should not be based only on the capacity of recruitment but also on the expertise in managing these patients and on the local infrastructure enabling an integrated multidisciplinary cancer treatment and the full evaluation of patients. The subject of the research, the multidisciplinary environment and the international context contribute markedly to the complexity of such trial. Therefore, it is essential to foster communication by developing at an early stage of the project, an effective communication plan to collect and to disseminate information amongst the participants. 2.2. Patient population Besides performance status and age, it is important to clearly define the following characteristics of the patient population, taking into account the area of investiga-
3441
tion: the primary tumour type, focusing on a specific subgroup of patients or on a broader group, the status of the systemic disease, controlled or limited and the status of BM (recurrent or not, symptomatic or not, number and size of lesions, location). 2.3. Safety assessment These patients often have a short survival and a potential high risk of toxicity related to the treatment and to the complications from the intracranial disease (haemorrhage, seizure, deterioration of cognitive function). This situation makes the assessment of the observed side-effects very challenging. Therefore, it is essential to adequately document the safety profile at baseline and during the study conduct, using an appropriate standardised scale to report toxicity data. The upfront definition of adverse events of special interest may ease a rapid reporting. In case of combined systemic therapies, the profile of drug–drug interaction should be determined ideally before initiating the trial or integrated as pre-safety phase in the trial. In phase I and II trials, patients must be closely monitored by regular medical reviews. For phase III trials, further statistical analyses may be needed to detect safety issues and it is therefore recommended to plan independent reviews by a Data and Safety Monitoring Board. 3. Trial design Two phase III randomised studies assessing cranial irradiation against appearance or recurrence of BM were recently published by EORTC (EORTC 2299308993 and EORTC 22952-26001).20–23 The following lessons can be learned from the data analysis and results of these two studies. Trials addressing prophylaxis or treatments targeting cancer metastasizing to the brain, unlike other phase III clinical trials in oncology, rarely aim to substantially increase the overall or even progression-free survival of the patients. Rather, the tested treatments aim at preventing or controlling BM, eventually improving the quality of living in patients whose primary cancer and its metastases elsewhere in the body are otherwise controlled. The nature and aggressiveness of the primary cancer severely impact the prognosis of the individual patient and in turn the end-points of any clinical trial. In phase III trials, stratification for the site of the primary cancer and tumour load at entry on study is mandatory. As the case-mix effectively recruited to a given study will directly affect the overall outcome of the randomised groups, the assumptions regarding the primary end-point that are used to build the statistical trial design, (typically assumptions regarding the expected event-free rates at a specified time in the control group) need also to be carefully monitored during the course of
3442
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
the trial to allow the necessary adaptations to the sample size, study duration or visit schedule. Alternatively, separate trials and strategies may be needed for each specific tumour type. The primary end-point of trials testing treatments that target BM may be either ‘global’ end-points such as progression-free survival or OS, ‘brain-specific’ endpoints such as time to recurrence/progression of (symptomatic) BM or ‘quality of living’ end-points such as duration of independent living (survival with good performance status), neurological function or QoL in a broader sense. None of these end-points is exempt from methodological challenges. ‘Global’ end-points may be very insensitive to the effect of treatments of BM and thus require large studies with low chances of showing significant improvements in relation to interventions targeting BM. When using ‘brain-specific’ end-points, evolution of the disease outside the brain in absence of progression inside the brain, often results in patient’s death and acts as competing risk for the primary end-point. This must be taken into account in the sample size calculation, as these patients will not contribute events for the primary end-point. Frequency of assessment early only is also essential to a precise measure of the treatment effect. For ‘quality of living’ end-points compliance of the patients to the neurological or QoL assessments is crucial and requires specific infrastructure. Evolution of the disease outside the brain also restricts magnitude of the treatment effect that can be expected for any composite end-point (PFS, duration of independent living) (Fig. 2). Finally, blinding or partial blinding (of the staff assessing the end-points) ought to be envisaged to limit the risk of bias in reporting progression or scoring subjective end-points (QoL or
neurological function) that may be induced by knowledge of the brain treatment allocated by randomisation. 4. Study end-points Several factors influence the choice of end-points in clinical trials on BM: the patient population, as there are significant differences in terms of natural history and outcome amongst different tumour types or even molecular subtypes; the trial setting (phase I, phase II, phase III); the type of intervention (local versus systemic treatments). OS has been almost universally chosen as primary end-point in phase III trials on BM, as it is unambiguous and clinically meaningful, but, due to frequent coexistence of active extracranial disease, improved intracranial control may not necessarily translate into improved OS. Survival with functional independence or time to deterioration of performance status to WHO > 2 (EORTC 22592-26003) has been employed as alternatives in order to take into account the quality as well as the length of survival.20 Objective response has been commonly used as primary end-point for phase II trials in patients with BM, being in some studies a possible surrogate for other markers of clinical benefit, such as neurological status, neurocognitive decline, or neurological deterioration-free survival.24 Unfortunately, consistent criteria have not been adopted across the different trials, as none of the standard response criteria (RECIST, WHO, Macdonald, RANO) were designed specifically to evaluate BM. Major shortcomings are represented by the lack of standardised neuroimaging criteria (in particular MRI) regarding the type of measurement (tumour area versus volume), the shrinkage required for response and the lack
Fig. 2. Plausible effect of treatment targeting brain disease in relation to competing events affecting patient survival, illustrated by data from the control arm of European Organisation for Research and Treatment of Cancer (EORTC) trial 22952-26001.20,56
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
of inclusion of steroids and neurological symptoms in the response criteria. In the future, a uniform approach to assess response must be developed, and special situations (use of antiangiogenic agents, immunotherapy) will require specific adaptations. Future clinical studies on BM implementing brain MRI as surrogate marker for response evaluation should apply comprehensive and standardised MR imaging protocols including advance imaging techniques with the aim to (i) further validate these advance imaging techniques and (ii) provide guidelines how to combine the sometimes conflicting results of the different imaging modalities to provide a more reliable and accurate discrimination between true progression versus pseudo-progression. A recommended imaging protocol should include: axial T1w, T2w, T2*w, diffusion tensor imaging (DTI), coronal fluidattenuated inversion recovery (FLAIR) imaging, administration of gadolinium (Gd) contrast agent and dynamic susceptibility contrast (DSC) perfusion, axial T1Gd and coronal FLAIR Gd (and optionally additional T1w dynamic contrast-enhanced (DCE) perfusion). The assessment of brain progression-free survival can be challenging. First, a clear distinction between intracranial, extracranial and overall PFS is needed. Second, the assessment of intracranial progression after radiosurgery is often problematic due to the difficulties in the differential diagnosis between recurrence and radionecrosis. Third, the use of anti-vascular endothelial growth factor (VEGF) agents can delay the appearance of small enhancing lesions as initial recurrence. Neurological symptoms, whether collected by physicians or as patient-reported outcomes (PRO) still need standardisation and validation. Neurocognitive outcomes may serve as a primary end-point when a treatment (i.e. WBRT) carries a risk of neurotoxicity or as a secondary end-point to support the clinical benefit of a novel treatment (i.e. trials with motexafin gadolinium).25 Health-Related QoL (HRQoL) is a well-established secondary end-point in advanced cancer, including BM. A number of issues make HRQoL problematic as primary end-point in BM trials: differential dropout, i.e. patients who have progressed or who experience clinical deterioration are the least likely to complete all of the assessments, thus potentially making a treatment appears more favourable than it really is; confounding effect of extracranial disease and its treatment.21 QALYS (quality-adjusted life years), a key end-point in health economic evaluations, is a new end-point yet to be validated in BM trials (QUARTZ Trial, MRC UK, ongoing). 5. Neurocognitive function Since BMs are associated with poor prognosis, not only in terms of length of survival but also in terms of
3443
functioning, patient performance is of particular importance to evaluate treatment outcome. This is specifically the case for patients with BM for whom palliation of symptoms and sustained or improved QoL are equally important goals of treatment as prolonged survival and postponed metastases progression. Evaluation of treatment in patients with BM should therefore focus beyond oncological end-points, and should moreover aim at avoiding adverse treatment effects on the normal brain to ensure optimal social and professional functioning.26 Functional outcome can be considered as a construct with several dimensions. These dimensions include neurological, neurocognitive, professional, and social performance of an individual. Neurocognitive functioning is one of the critical outcome measures because subclinical neurocognitive impairment can have a large impact on the daily life of patients.27,28 Even mild neurocognitive difficulties can have functional and psychiatric consequences – especially when persistent and left untreated. Deficits in specific neurocognitive domains such as inattention, dys-executive function, and impaired processing speed may affect QoL. For example, neurocognitive impairment negatively affects professional reintegration, interpersonal relationships and leisure activities. In addition, fear of future neurocognitive decline may also negatively affect QoL. Compared to the classical oncological end-points, evaluation of neurocognitive functioning is evidently more time-consuming for the care provider and more burdensome for the patient. As is the case in patients with primary brain tumours, neurocognitive deficits in patients with BM can be caused by the metastases, by metastases-related epilepsy and its treatment (surgery, radiotherapy, antiepileptic medication, chemotherapy or corticosteroids), and by psychological distress.27 Importantly, the multifactorial processes involved need to be recognised. These factors include premorbid level of neurocognitive functioning, distant mechanical effects on the normal brain by BM, epilepsy, language and communication deficits, medication and other oncological treatments.26 Recognising these factors, it would be worth selecting a standardised neuropsychological examination covering a wide range of neurocognitive functions. Such a test battery has to meet the following criteria: (i) coverage of several domains with sufficient sensitivity to detect tumour and treatment effects; (ii) standardised multilingual materials and administration procedures; (iii) based on published normative data; (iv) moderate to high test– retest reliability and insensitivity to practice effects to be able to monitor changes in neurocognitive function over time; (v) availability of alternative forms; and (vi) an administration time not exceeding 30–40 min.29 The neurocognitive domains deemed essential to be evaluated include attention, executive functions, verbal memory and motor speed.
3444
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
Table 1 Core neurocognitive testing battery. Test
Domain measured
Outcome
Trail Making Test A Trail Making Test B Controlled Oral Word Association Hopkins Verbal Learning Test
Visual scanning speed Divided attention Verbal fluency
Number of seconds to complete (0–300) Number of seconds to complete (0–300) Age and sex-adjusted raw score (range 0–no upper limit)
Verbal memory
Digit Symbol Subtest of the WAIS-III Grooved Pegboard Test
Psychomotor speed
Immediate memory of word list rehearsed three times (maximum score = 36). After 20–30 min delay, number of words correctly recalled (maximum score = 12). Recognition is number of words recognised from a longer list (maximum score = 12) Age-corrected subtest score (0–20)
Fine motor control for dominant and non-dominant hands
Number of seconds to complete (0–300)
A standardised neuropsychological examination that meets these criteria is currently in use in a number of EORTC Brain Tumor Group, North Central Cancer Treatment Group (NCCTG), National Cancer Institute of Canada (NCI-C), Radiation Therapy Oncology Group (RTOG) and Medical Research Council (MRC) multisite clinical trials (Table 1). This battery has been shown to be quick and easy to administer by non-physicians with very good compliance and motivation of patients.29 Evidently, local modifications of this battery can be made by adding tests depending on the goal of the neuropsychological assessment. 6. Quality of life During the last decades, QoL has become an increasingly important outcome measure in clinical cancer trials. It has been recognised that duration of survival is not the only goal of treatment, and that maintaining QoL is an important outcome as well. QoL of brain tumour patients is dependent on both tumour- and treatment-related factors.30 It is pivotal to avoid negative impact of treatment on QoL, but there always is a trade-off: a temporary drop in QoL might be acceptable when treatment considerably prolongs survival. From studies in primary brain tumour patients, particularly glioma, we have learned that treatment can prolong survival without long-lasting negative effects on QoL, particularly for patients with a favourable prognosis, but also for patients with a limited prognosis.31–35 Information on QoL during treatment of BM patients, who on average have a poorer prognosis than primary brain tumour patients, is limited. The only phase III trial including adequate QoL-measurements did not show a decrease in global QoL over the first year after addition of whole-brain radiotherapy (WBRT) to patients who underwent radiosurgery or resection for 1-3 metastases.20,21 In an earlier review on QoL measurements in BM studies applying WBRT, Wong et al. concluded that many different (and sometimes inadequate) QoL instruments were used and that, generally speaking, aspects of QoL might improve after treatment
in patients with a favourable prognosis, and worsen in patients with a poor prognosis.36 Proper selection of patients seems therefore important; for patients with a favourable prognostic profile, experimental treatment might prolong survival substantially, and QoL should be a secondary outcome in order to monitor whether treatment does not lead to unacceptable negative impact on QoL. On the other hand, for BM patients with a poor prognosis, QoL might even be regarded as the primary outcome measure as the main goal of treatment is to maintain acceptable QoL for as long as possible. Problems and pitfalls in measuring QoL during future experimental trials in BM patients are decreasing compliance rates during follow-up, resulting in a bias towards patients with a better prognosis, and too liberal time windows for subsequent measurements, resulting in inadequate comparisons as patients that fill in questionnaires representing the same time point in fact are in different treatment phases.21,31,32 Furthermore, patients’ cognitive deficits may render QoL patient-reported outcomes through questionnaires to be unreliable.37 Exclusion of these patients from analysis obviously introduces undesirable bias in the evaluation of QoL. These problems and pitfalls might be tackled by the incorporation of shorter questionnaires, for example the EORTC QLQ-C15 PAL instead of the EORTC QLQ-C30, the application of strict time slots for QoL measurements and adequate monitoring by study nurses, and the incorporation of proxy-measurements.38,39 Previous reports indicate that in high-grade glioma patients, patientand proxy-reported HRQoL have a high level of concordance as long as the patient shows no signs of cognitive decline, but differences, particularly in mood-related issues, increase when cognitive performance decreases.40,41 When differences between patient and proxy-reported HRQoL ratings develop in the course of the disease (presumably at the time cognitive decline becomes an issue) proxy-reported instead of patientreported HRQoL ratings might be the more reliable source of information on a patient’s HRQoL from that point. The results of two ongoing EORTC phase II (EORTC 26091 and EORTC 26101) studies in brain
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
tumour patients, measuring both patient- and proxyreported QoL as a secondary outcome measure, will provide further insight into the value of using proxy assessments in this population. 7. Biology of brain metastases: opportunities for targeted agents and translational research BM is in principle a multifocal disease for which metastasizing cancer cells have to successfully master distinct mandatory steps to eventually grow to a clinically significant macrometastasis.42,43 BM formation may be prevented by interfering with distinct steps of the brain-metastatic process, as demonstrated for inhibition of brain colonisation of NSCLC cell lines in a mouse model using bevacizumab.43 The following biological hallmarks of BM make it likely that judicious addition of systemic targeted therapies will substantially add to the therapeutic armamentarium in the future: First, one of the greatest challenges of systemic brain tumour therapy is the blood-brain/blood-tumour barrier (BBB/BTB). This consists of additional layers of thickened basement membrane, irregular pericyte coverage, and occasionally astrocyte foot processes in the brain.44–46 Furthermore, drug penetration to the cancer cell is also hindered by the aberrant and highly heterogeneous blood flow in brain tumour vessels lacking the normal hierarchical structure of normal brain vasculature and increased interstitial fluid pressure.47 Overall, most drugs available today do not or only inefficiently overcome these barriers between the blood stream and the brain tumour cell, at least in meaningful concentrations. In contrast, some antiangiogenic agents have to reach only the endothelial cell without needing to cross the entire blood-tumour barrier. Similarly, immunomodulators targeting cells responsible for anti-tumour immunity (e.g. ipilimumab) do not need to reach the cancer cell by themselves to exert their action. Second, targeted small molecule and even antibody inhibitors can be designed to efficiently cross the BBB, or linked to an agent that is actively transported over it.48 Third, it is proven that metastatic outgrowth in the brain can be effectively prevented – by prophylactic WBRT which targets the whole organ (without being hindered by the BBB). Applied during a short time frame (2–3 weeks) early in the beginning of the disease, prophylactic WBRT decreases the incidence of (macro)metastasis formation by more than 50%, an effect that continues over the next 24 months in patients.49 Since targeted agents can be applied over long periods of time, are active in the whole body, and do not show the neurotoxicity of WBRT, they seem to be perfect future candidates for BM prevention. Some of these do not have to cross the BBB to be active, e.g. anti-VEGF antibodies exert their main function
3445
on the luminal side of the vascular wall. An interesting retrospective analysis from the clinic has shown that patients with renal cell carcinoma who received sorafenib had lower incidence of symptomatic BM than those patients who did not receive sorafenib (3% versus 12%).50 This effect stayed statistically significant over 2 years.50 Inhibition of the angiogenic switch might be indeed a very effective way to prevent tumour outgrowth, which has been shown for BM, too.43,51 Moreover, a recent study documented lower rates of CNS progression in EGFR mutant advanced NSCLC initially treated with EGFR tyrosine kinase inhibitors (gefitinib or erlotinib) compared with upfront chemotherapy, further underlining that chemoprevention of CNS metastases is a feasible approach.52 In the era of successful therapeutic targeting of distinct molecular pathways in more and more systemic tumours, the incidence and relevance of BM are rising. It is mandatory to test the efficacy of established agents in randomised BM trials, and desirable to promote the development of inhibitors of potential BM specific pathways.53,54 It is likely that inhibitor classes will significantly differ regarding their ability to influence control of macrometastases versus outgrowth of micrometastases versus the prevention of initial micrometastatic spread to the CNS. This has to be taken into consideration in the design of future clinical trials. Presurgical treatment of patients scheduled for resection of BM with novel drugs offers the possibility for translational trials to investigate the drug penetration and efficacy of the drug to exert its biological action in the tumour tissue. The feasibility of such a study concept has been shown in a recent trial analysing the intratumoural concentration and the effect on its target pathway of the EGFR tyrosine kinase inhibitor gefitinib in glioblastoma.55 8. Summary and conclusions Based on the discussion held at the EORTC Brain Metastases Strategic Meeting 2012, the following conclusions were made: – There is a strong need for well conducted trials on prophylaxis and treatment of BM. – New study initiatives should focus on specific tumour types/molecular subtypes instead of enrolling unselected BM patients with tumours of all histological types. – New trials should investigate the prophylaxis of BM based on insights into the pathogenesis of CNS involvement, e.g. by targeted therapies that inhibit early stages of BM formation. One example could be the prevention of BM formation in NSCLC patients by antiangiogenic drugs as recently exemplified in the experimental setting.43
3446
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
– The trial design is particularly challenging, as many disease and patient variables, statistical issues and the selection of appropriate end-points have to be taken into account. These facts make dedicated multidisciplinary and multinational efforts including involvement of high bio-statistical expertise in the study planning and conduct necessary. Conflict of interest statement Matthias Preusser has received travel support (scientific meetings), research support (unrestricted grants) and lecture honoraria by Roche. Frank Winkler has received lecture honoraria by Roche, and research support restricted grants) by Roche and Genentech. Sven Haller has received travel support (scientific meetings) and research support (unrelated to the current manuscript). Riccardo Soffietti has received honoraria for Advisory Boards from Roche, Merck and MSD. Jaap Reijneveld received funding from EU Framework Program 7, the Dutch Epilepsy Foundation (NEF), the Dutch Cancer Society (KWF Kankerbestrijding), Foundation “NutsOhra”, Foundation “STOPhersentumoren.nl”, and the National Brain Tumor Foundation/ Tug McGraw Foundation, and received unrestricted grants from UCB and Sanofi-Aventis. Brigitta G. Baumert has received travel support by Roche. Jacek Jassem has received travel support (scientific meetings) from Roche, Boehringer Ingelheim and Astra Zeneca, research support (unrestricted grants) from Roche and GSK and lecture or advisory board honoraria from Roche, GSK, Pfizer, Saladax and Amgen. Dirk Schadendorf has attended compensated advisory boards and received honoraria as part of its speaker´s bureau from Roche, Genentech, Amgen, Novartis, BMS, GSK and Merck. None of the other authors have reported conflicts of interest. Acknowledgements The Meeting was kindly supported by Roche, Novocure, Merck Serono and the Comprehensive Cancer Center Vienna. The sponsors had no role or influence in the content of the meeting or this manuscript. References 1. Mehta MP, Tsao MN, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 2005;63(1):37–46. 2. Villa S, Weber DC, Moretones C, et al. Validation of the new Graded Prognostic Assessment scale for brain metastases: a multicenter prospective study. Radiat Oncol 2011;6:23. 3. Amer MH, Al-Sarraf M, Baker LH, Vaitkevicius VK. Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer 1978;42(2):660–8.
4. Weissman DE. Glucocorticoid treatment for brain metastases and epidural spinal cord compression: a review. J Clin Oncol 1988;6(3):543–51. 5. Gaspar LE, Mehta MP, Patchell RA, et al. The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96(1):17–32. 6. Kalkanis SN, Kondziolka D, Gaspar LE, et al. The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96(1):33–43. 7. Linskey ME, Andrews DW, Asher AL, et al. The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96(1):45–68. 8. Mehta MP, Paleologos NA, Mikkelsen T, et al. The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96(1):71–83. 9. Khuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 2006;24(8):1295–304. 10. Weber DC, Caparrotti F, Laouiti M, Malek K. Simultaneous infield boost for patients with 1 to 4 brain metastasis/es treated with volumetric modulated arc therapy: a prospective study on qualityof-life. Radiat Oncol 2011;6:79. 11. Regine WF, Schmitt FA, Scott CB, et al. Feasibility of neurocognitive outcome evaluations in patients with brain metastases in a multi-institutional cooperative group setting: results of Radiation Therapy Oncology Group trial BR-0018. Int J Radiat Oncol Biol Phys 2004;58(5):1346–52. 12. Steinmann D, Schafer C, van Oorschot B, et al. Effects of radiotherapy for brain metastases on quality of life (QoL). Prospective pilot study of the DEGRO QoL working party. Strahlenther Onkol 2009;185(3):190–7. 13. Mitera G, Zhang L, Sahgal A, et al. A survey of expectations and understanding of palliative radiotherapy from patients with advanced cancer. Clin Oncol (R Coll Radiol) 2012;24(2):134–8. 14. Barnes E, Chow E, Tsao M, et al. Physician expectations of treatment outcomes for patients with brain metastases referred for whole brain radiotherapy. Int J Radiat Oncol Biol Phys 2010;76(1):187–92. 15. Gondi V, Tolakanahalli R, Mehta MP, et al. Hippocampalsparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2010;78(4):1244–52. 16. Gutierrez AN, Westerly DC, Tome WA, et al. Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study. Int J Radiat Oncol Biol Phys 2007;69(2):589–97. 17. Hsu F, Carolan H, Nichol A, et al. Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for 1–3 brain metastases: a feasibility study using volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys 2010;76(5):1480–5. 18. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosisspecific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012;30(4):419–25. 19. Preusser M, Capper D, Ilhan-Mutlu A, et al. Brain metastases: pathobiology and emerging targeted therapies. Acta Neuropathol 2012;123(2):205–22. 20. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011;29(2):134–41.
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447 21. Soffietti R, Mueller R, Abacioglu U, et al. Quality of life results of an EORTC phase III randomized trial of adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of 1–3 cerebral metastases of solid tumors. Neuro Oncol 2010;12(Suppl. 4):Ql-08. 22. Slotman BJ, Mauer ME, Bottomley A, et al. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol 2009;27(1):78–84. 23. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357(7):664–72. 24. Lin NU, Dieras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 2009;15(4):1452–9. 25. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10(11):1037–44. 26. Witgert ME, Meyers CA. Neurocognitive and quality of life measures in patients with metastatic brain disease. Neurosurg Clin N Am 2011;22(1):79–85, vii. 27. Taphoorn MJB, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol 2004;3(3):159–68. 28. Mitchell AJ, Kemp S, Benito-Leon J, Reuber M. The influence of cognitive impairment on health-related quality of life in neurological disease. Acta Neuropsychiatr 2010;22(1):2–13. 29. Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol 2004;22(1):157–65. 30. Taphoorn MJ, Sizoo EM, Bottomley A. Review on quality of life issues in patients with primary brain tumors. Oncologist 2010;15(6):618–26. 31. Taphoorn MJ, van den Bent MJ, Mauer ME, et al. Health-related quality of life in patients treated for anaplastic oligodendroglioma with adjuvant chemotherapy: results of a European Organisation for Research and Treatment of Cancer randomized clinical trial. J Clin Oncol 2007;25(36):5723–30. 32. Taphoorn MJ, Stupp R, Coens C, et al. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 2005;6(12):937–44. 33. Bosma I, Reijneveld JC, Douw L, et al. Health-related quality of life of long-term high-grade glioma survivors. Neuro Oncol 2009;11(1):51–8. 34. Brown PD, Maurer MJ, Rummans TA, et al. A prospective study of quality of life in adults with newly diagnosed high-grade gliomas: the impact of the extent of resection on quality of life and survival. Neurosurgery 2005;57(3):495–504, discussion 495–504. 35. Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med 2007;356(15):1527–35. 36. Wong J, Hird A, Kirou-Mauro A, Napolskikh J, Chow E. Quality of life in brain metastases radiation trials: a literature review. Curr Oncol 2008;15(5):25–45. 37. Sizoo EM, Braam L, Postma TJ, et al. Symptoms and problems in the end-of-life phase of high-grade glioma patients. Neuro Oncol 2010;12(11):1162–6.
3447
38. Groenvold M, Petersen MA, Aaronson NK, et al. The development of the EORTC QLQ-C15-PAL: a shortened questionnaire for cancer patients in palliative care. Eur J Cancer 2006;42(1):55–64. 39. Sneeuw KC, Aaronson NK, Sprangers MA, et al. Value of caregiver ratings in evaluating the quality of life of patients with cancer. J Clin Oncol 1997;15(3):1206–17. 40. Giesinger JM, Golser M, Erharter A, et al. Do neurooncological patients and their significant others agree on quality of life ratings? Health Qual Life Outcomes 2009;7:87. 41. Brown PD, Decker PA, Rummans TA, et al. A prospective study of quality of life in adults with newly diagnosed high-grade gliomas: comparison of patient and caregiver ratings of quality of life. Am J Clin Oncol 2008;31(2):163–8. 42. Steeg PS, Camphausen KA, Smith QR. Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 2011;11(5):352–63. 43. Kienast Y, von Baumgarten L, Fuhrmann M, et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 2010;16(1):116–22. 44. Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004;6(6):553–63. 45. Plate KH, Mennel HD. Vascular morphology and angiogenesis in glial tumors. ExpToxicolPathol 1995;47(2–3):89–94. 46. Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 2002;3(1):53–7. 47. Jain RK, Di TE, Duda DG, et al. Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8(8):610–22. 48. Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 2002;1(2):131–9. 49. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357(7):664–72. 50. Massard C, Zonierek J, Gross-Goupil M, et al. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol 2010;21(5):1027–31. 51. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86(3):353–64. 52. Heon S, Yeap BY, Lindeman N, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res, 2012 (in press). 53. Bos PD, Zhang XH, Nadal C, et al. Genes that mediate breast cancer metastasis to the brain. Nature 2009;459(7249):1005–9. 54. Nguyen DX, Chiang AC, Zhang XH, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 2009;138(1):51–62. 55. Hegi ME, Diserens AC, Bady P, et al. Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib – a phase II trial. Mol Cancer Ther 2011;10(6):1102–12. 56. Soffietti R, Mueller R, Abacioglu M. Quality of life results of an EORTC phase III randomized trial of adjuvant whole brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases of solid tumors. J Clin Oncol 2010;28(Suppl.):9036.
Available at www.sciencedirect.com
journal homepage: www.ejcancer.info
Current Perspective
Trial design on prophylaxis and treatment of brain metastases: Lessons learned from the EORTC Brain Metastases Strategic Meeting 2012 Matthias Preusser a,⇑, Frank Winkler b, Laurence Collette c, Sven Haller d, Sandrine Marreaud e, Riccardo Soffietti f, Martin Klein g, Jaap C. Reijneveld h, Jo¨rg-Christian Tonn i, Brigitta G. Baumert j, Paula Mulvenna k, Dirk Schadendorf l, Renata Duchnowska m, Anna Sophie Berghoff a,n, Nancy Lin o, David A. Cameron p, Yazid Belkacemi q,r,s, Jacek Jassem t, Damien C. Weber u a
Department of Medicine I & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Neurology Clinic and National Center for Tumor Disease, University of Heidelberg, Heidelberg, Germany c Statistics Department, European Organisation for Research and Treatment of Cancer (EORTC), Data Center, Brussels, Belgium d Department of Diagnostic and Interventional Neuroradiology, DISIM, University Hospitals of Geneva, Geneva, Switzerland e European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium f Division of Neuro-oncology, Department of Neuroscience, University and San Giovanni Battista Hospital, Turin, Italy g Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands h Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands i Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany j Department of Radiation Oncology (MAASTRO), GROW (School for Oncology & Developmental Biology), Maastricht University Medical Center, Maastricht, The Netherlands k Freeman Hospital, Newcastle, UK l Department of Dermatology, Skin Cancer Center, University Hospital Essen, Essen, Germany m Oncology Department Military Institute of Medicine, Warsaw, Poland n Institute of Neurology, Medical University of Vienna, Vienna, Austria o Department of Medical Oncology, Dana-Farber Cancer Center, Boston, USA p Edinburgh Cancer Research Centre, Western General Hospital, Crewe Rd South, Edinburgh EH4 2 XU, Scotland, UK q AP-HP, Service d’Oncologie-Radiothe´rapie, Hoˆpital Henri Mondor, France r Universite´ Paris-Est Cre´teil, France s AROMEv (Association of Radiotherapy and Oncology of the Mediterranean Area), France t Medical University of Gdan´sk, Poland u Department of Radiation Oncology, Geneva University Hospital, Geneva, Switzerland b
Available online 8 August 2012
⇑ Corresponding author: Address: Department of Medicine I & Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Tel.: +43 1 40400 4457; fax: +43 1 40400 6686. E-mail address: [email protected] (M. Preusser). v www.aromecancer.org
0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.07.002
3440
KEYWORDS Brain metastases Clinical trail Prophylaxis EORTC
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
Brain metastases (BM) occur in a significant proportion of cancer patients and are associated with considerable morbidity and poor prognosis. The trial design in BM patients is particularly challenging, as many disease and patient variables, statistical issues, and the selection of appropriate end-points have to be taken into account. During a meeting organised on behalf of the European Organisation for Research and Treatment of Cancer (EORTC), methodological aspects of trial design in BM were discussed. This paper summarises the issues and potential trial strategies discussed during this meeting and may provide some guidance for the design of trials in BM patients. Ó 2012 Elsevier Ltd. All rights reserved.
Abstract
1. Introduction Brain metastases (BM) represent a substantial health care problem in cancer patients. It is estimated that approximately 20–40% of patients with malignancy will develop BM during the course of their illness.1 The most common anatomic primary sites are breast and lung.2 Melanoma has however the highest percentage of BMs relative to other primary tumours, with 75% of patients with disseminated disease developing BM.3 With best supportive care, median survival time is approximately 1–2 months.4 Radiation therapy (RT) increases the median survival to 3–5 months. Surgery, stereotactic radiotherapy, whole brain radiotherapy (WBRT) and systemic methods have been integrated in the therapeutic armamentarium, depending on the number, the site and the size of brain secondary lesions.5–7 Delivering concomitant chemo-RT may improve tumour local control but does not improve overall survival (OS) and is
thus not recommended for the routine treatment of BM patients.8 Although many patients with BM die as a result of extra-cranial disease progression, it is important to note that a substantial number suffer from the local tumour progression in the CNS.9 Optimising local control is thus of paramount importance. The development of symptomatic BM has a substantial impact on patient’s quality of life (QoL) and neuro-cognitive function. However, these metrics are difficult to assess in BM patients, as the overall compliance rates of questionnaires and neuro-psychological tests decreases as patients’ condition deteriorates over time.10–12 Treatment may also induce drowsiness, alopecia and weakness that may consequently substantially affect the overall QoL of these patients.10,12 Notwithstanding the overly optimistic estimation of the treatment’s clinical benefit of patients and referring physicians alike, palliative treatment should not be detrimental to the patients’
Fig. 1. Axial, coronal and sagittal view of whole brain radiation therapy with hippocampal sparing. Radiation dose shown in colour wash.
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
quality of life, notably when left with a limited life span.13,14 Newer radiation techniques, e.g. with hippocampal sparing (Fig. 1), and the use of novel drugs may to some extent decrease the treatment-related toxicity and preserve neuro-congition.15–17 The main prognostic factors for BM patients are age, performance status, control of primary tumour, absence of extra-cranial disease and number of brain lesions.18 It is thus possible to identify a subset of patients in the heterogeneous BM population with favourable outcome potential, who may benefit from experimental therapeutic strategies. Additionally, some primary and secondary tumours may have unique biological signatures that may respond to targeted agents and biological modulation.19 The European Organisation of Research and Treatment of Cancer (EORTC) organised in February 2012 a multidisciplinary meeting to discuss issues with and strategies for trial development in patients with BM. In this report, we discuss some of the challenges of study conception and design discussed during this meeting. We hope that our report may provide guidance for the design of future trials in BM patients. 2. Challenges to developing a brain metastases trial When developing trials for BM, there are a number of key aspects that require careful considerations like the trial organisation, the patient population, the safety assessment and the efficacy end-points. 2.1. Trial organisation The most effective method of preparing and conducting the trial is to use a multidisciplinary approach including a panel of experts in the management of primary tumour and BM, and methodologists. That will guarantee an optimal assessment of the risk and benefit for patients in a trial appropriately designed to answer the principal objective. Another critical step is the selection of participating centres. The choice should not be based only on the capacity of recruitment but also on the expertise in managing these patients and on the local infrastructure enabling an integrated multidisciplinary cancer treatment and the full evaluation of patients. The subject of the research, the multidisciplinary environment and the international context contribute markedly to the complexity of such trial. Therefore, it is essential to foster communication by developing at an early stage of the project, an effective communication plan to collect and to disseminate information amongst the participants. 2.2. Patient population Besides performance status and age, it is important to clearly define the following characteristics of the patient population, taking into account the area of investiga-
3441
tion: the primary tumour type, focusing on a specific subgroup of patients or on a broader group, the status of the systemic disease, controlled or limited and the status of BM (recurrent or not, symptomatic or not, number and size of lesions, location). 2.3. Safety assessment These patients often have a short survival and a potential high risk of toxicity related to the treatment and to the complications from the intracranial disease (haemorrhage, seizure, deterioration of cognitive function). This situation makes the assessment of the observed side-effects very challenging. Therefore, it is essential to adequately document the safety profile at baseline and during the study conduct, using an appropriate standardised scale to report toxicity data. The upfront definition of adverse events of special interest may ease a rapid reporting. In case of combined systemic therapies, the profile of drug–drug interaction should be determined ideally before initiating the trial or integrated as pre-safety phase in the trial. In phase I and II trials, patients must be closely monitored by regular medical reviews. For phase III trials, further statistical analyses may be needed to detect safety issues and it is therefore recommended to plan independent reviews by a Data and Safety Monitoring Board. 3. Trial design Two phase III randomised studies assessing cranial irradiation against appearance or recurrence of BM were recently published by EORTC (EORTC 2299308993 and EORTC 22952-26001).20–23 The following lessons can be learned from the data analysis and results of these two studies. Trials addressing prophylaxis or treatments targeting cancer metastasizing to the brain, unlike other phase III clinical trials in oncology, rarely aim to substantially increase the overall or even progression-free survival of the patients. Rather, the tested treatments aim at preventing or controlling BM, eventually improving the quality of living in patients whose primary cancer and its metastases elsewhere in the body are otherwise controlled. The nature and aggressiveness of the primary cancer severely impact the prognosis of the individual patient and in turn the end-points of any clinical trial. In phase III trials, stratification for the site of the primary cancer and tumour load at entry on study is mandatory. As the case-mix effectively recruited to a given study will directly affect the overall outcome of the randomised groups, the assumptions regarding the primary end-point that are used to build the statistical trial design, (typically assumptions regarding the expected event-free rates at a specified time in the control group) need also to be carefully monitored during the course of
3442
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
the trial to allow the necessary adaptations to the sample size, study duration or visit schedule. Alternatively, separate trials and strategies may be needed for each specific tumour type. The primary end-point of trials testing treatments that target BM may be either ‘global’ end-points such as progression-free survival or OS, ‘brain-specific’ endpoints such as time to recurrence/progression of (symptomatic) BM or ‘quality of living’ end-points such as duration of independent living (survival with good performance status), neurological function or QoL in a broader sense. None of these end-points is exempt from methodological challenges. ‘Global’ end-points may be very insensitive to the effect of treatments of BM and thus require large studies with low chances of showing significant improvements in relation to interventions targeting BM. When using ‘brain-specific’ end-points, evolution of the disease outside the brain in absence of progression inside the brain, often results in patient’s death and acts as competing risk for the primary end-point. This must be taken into account in the sample size calculation, as these patients will not contribute events for the primary end-point. Frequency of assessment early only is also essential to a precise measure of the treatment effect. For ‘quality of living’ end-points compliance of the patients to the neurological or QoL assessments is crucial and requires specific infrastructure. Evolution of the disease outside the brain also restricts magnitude of the treatment effect that can be expected for any composite end-point (PFS, duration of independent living) (Fig. 2). Finally, blinding or partial blinding (of the staff assessing the end-points) ought to be envisaged to limit the risk of bias in reporting progression or scoring subjective end-points (QoL or
neurological function) that may be induced by knowledge of the brain treatment allocated by randomisation. 4. Study end-points Several factors influence the choice of end-points in clinical trials on BM: the patient population, as there are significant differences in terms of natural history and outcome amongst different tumour types or even molecular subtypes; the trial setting (phase I, phase II, phase III); the type of intervention (local versus systemic treatments). OS has been almost universally chosen as primary end-point in phase III trials on BM, as it is unambiguous and clinically meaningful, but, due to frequent coexistence of active extracranial disease, improved intracranial control may not necessarily translate into improved OS. Survival with functional independence or time to deterioration of performance status to WHO > 2 (EORTC 22592-26003) has been employed as alternatives in order to take into account the quality as well as the length of survival.20 Objective response has been commonly used as primary end-point for phase II trials in patients with BM, being in some studies a possible surrogate for other markers of clinical benefit, such as neurological status, neurocognitive decline, or neurological deterioration-free survival.24 Unfortunately, consistent criteria have not been adopted across the different trials, as none of the standard response criteria (RECIST, WHO, Macdonald, RANO) were designed specifically to evaluate BM. Major shortcomings are represented by the lack of standardised neuroimaging criteria (in particular MRI) regarding the type of measurement (tumour area versus volume), the shrinkage required for response and the lack
Fig. 2. Plausible effect of treatment targeting brain disease in relation to competing events affecting patient survival, illustrated by data from the control arm of European Organisation for Research and Treatment of Cancer (EORTC) trial 22952-26001.20,56
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
of inclusion of steroids and neurological symptoms in the response criteria. In the future, a uniform approach to assess response must be developed, and special situations (use of antiangiogenic agents, immunotherapy) will require specific adaptations. Future clinical studies on BM implementing brain MRI as surrogate marker for response evaluation should apply comprehensive and standardised MR imaging protocols including advance imaging techniques with the aim to (i) further validate these advance imaging techniques and (ii) provide guidelines how to combine the sometimes conflicting results of the different imaging modalities to provide a more reliable and accurate discrimination between true progression versus pseudo-progression. A recommended imaging protocol should include: axial T1w, T2w, T2*w, diffusion tensor imaging (DTI), coronal fluidattenuated inversion recovery (FLAIR) imaging, administration of gadolinium (Gd) contrast agent and dynamic susceptibility contrast (DSC) perfusion, axial T1Gd and coronal FLAIR Gd (and optionally additional T1w dynamic contrast-enhanced (DCE) perfusion). The assessment of brain progression-free survival can be challenging. First, a clear distinction between intracranial, extracranial and overall PFS is needed. Second, the assessment of intracranial progression after radiosurgery is often problematic due to the difficulties in the differential diagnosis between recurrence and radionecrosis. Third, the use of anti-vascular endothelial growth factor (VEGF) agents can delay the appearance of small enhancing lesions as initial recurrence. Neurological symptoms, whether collected by physicians or as patient-reported outcomes (PRO) still need standardisation and validation. Neurocognitive outcomes may serve as a primary end-point when a treatment (i.e. WBRT) carries a risk of neurotoxicity or as a secondary end-point to support the clinical benefit of a novel treatment (i.e. trials with motexafin gadolinium).25 Health-Related QoL (HRQoL) is a well-established secondary end-point in advanced cancer, including BM. A number of issues make HRQoL problematic as primary end-point in BM trials: differential dropout, i.e. patients who have progressed or who experience clinical deterioration are the least likely to complete all of the assessments, thus potentially making a treatment appears more favourable than it really is; confounding effect of extracranial disease and its treatment.21 QALYS (quality-adjusted life years), a key end-point in health economic evaluations, is a new end-point yet to be validated in BM trials (QUARTZ Trial, MRC UK, ongoing). 5. Neurocognitive function Since BMs are associated with poor prognosis, not only in terms of length of survival but also in terms of
3443
functioning, patient performance is of particular importance to evaluate treatment outcome. This is specifically the case for patients with BM for whom palliation of symptoms and sustained or improved QoL are equally important goals of treatment as prolonged survival and postponed metastases progression. Evaluation of treatment in patients with BM should therefore focus beyond oncological end-points, and should moreover aim at avoiding adverse treatment effects on the normal brain to ensure optimal social and professional functioning.26 Functional outcome can be considered as a construct with several dimensions. These dimensions include neurological, neurocognitive, professional, and social performance of an individual. Neurocognitive functioning is one of the critical outcome measures because subclinical neurocognitive impairment can have a large impact on the daily life of patients.27,28 Even mild neurocognitive difficulties can have functional and psychiatric consequences – especially when persistent and left untreated. Deficits in specific neurocognitive domains such as inattention, dys-executive function, and impaired processing speed may affect QoL. For example, neurocognitive impairment negatively affects professional reintegration, interpersonal relationships and leisure activities. In addition, fear of future neurocognitive decline may also negatively affect QoL. Compared to the classical oncological end-points, evaluation of neurocognitive functioning is evidently more time-consuming for the care provider and more burdensome for the patient. As is the case in patients with primary brain tumours, neurocognitive deficits in patients with BM can be caused by the metastases, by metastases-related epilepsy and its treatment (surgery, radiotherapy, antiepileptic medication, chemotherapy or corticosteroids), and by psychological distress.27 Importantly, the multifactorial processes involved need to be recognised. These factors include premorbid level of neurocognitive functioning, distant mechanical effects on the normal brain by BM, epilepsy, language and communication deficits, medication and other oncological treatments.26 Recognising these factors, it would be worth selecting a standardised neuropsychological examination covering a wide range of neurocognitive functions. Such a test battery has to meet the following criteria: (i) coverage of several domains with sufficient sensitivity to detect tumour and treatment effects; (ii) standardised multilingual materials and administration procedures; (iii) based on published normative data; (iv) moderate to high test– retest reliability and insensitivity to practice effects to be able to monitor changes in neurocognitive function over time; (v) availability of alternative forms; and (vi) an administration time not exceeding 30–40 min.29 The neurocognitive domains deemed essential to be evaluated include attention, executive functions, verbal memory and motor speed.
3444
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
Table 1 Core neurocognitive testing battery. Test
Domain measured
Outcome
Trail Making Test A Trail Making Test B Controlled Oral Word Association Hopkins Verbal Learning Test
Visual scanning speed Divided attention Verbal fluency
Number of seconds to complete (0–300) Number of seconds to complete (0–300) Age and sex-adjusted raw score (range 0–no upper limit)
Verbal memory
Digit Symbol Subtest of the WAIS-III Grooved Pegboard Test
Psychomotor speed
Immediate memory of word list rehearsed three times (maximum score = 36). After 20–30 min delay, number of words correctly recalled (maximum score = 12). Recognition is number of words recognised from a longer list (maximum score = 12) Age-corrected subtest score (0–20)
Fine motor control for dominant and non-dominant hands
Number of seconds to complete (0–300)
A standardised neuropsychological examination that meets these criteria is currently in use in a number of EORTC Brain Tumor Group, North Central Cancer Treatment Group (NCCTG), National Cancer Institute of Canada (NCI-C), Radiation Therapy Oncology Group (RTOG) and Medical Research Council (MRC) multisite clinical trials (Table 1). This battery has been shown to be quick and easy to administer by non-physicians with very good compliance and motivation of patients.29 Evidently, local modifications of this battery can be made by adding tests depending on the goal of the neuropsychological assessment. 6. Quality of life During the last decades, QoL has become an increasingly important outcome measure in clinical cancer trials. It has been recognised that duration of survival is not the only goal of treatment, and that maintaining QoL is an important outcome as well. QoL of brain tumour patients is dependent on both tumour- and treatment-related factors.30 It is pivotal to avoid negative impact of treatment on QoL, but there always is a trade-off: a temporary drop in QoL might be acceptable when treatment considerably prolongs survival. From studies in primary brain tumour patients, particularly glioma, we have learned that treatment can prolong survival without long-lasting negative effects on QoL, particularly for patients with a favourable prognosis, but also for patients with a limited prognosis.31–35 Information on QoL during treatment of BM patients, who on average have a poorer prognosis than primary brain tumour patients, is limited. The only phase III trial including adequate QoL-measurements did not show a decrease in global QoL over the first year after addition of whole-brain radiotherapy (WBRT) to patients who underwent radiosurgery or resection for 1-3 metastases.20,21 In an earlier review on QoL measurements in BM studies applying WBRT, Wong et al. concluded that many different (and sometimes inadequate) QoL instruments were used and that, generally speaking, aspects of QoL might improve after treatment
in patients with a favourable prognosis, and worsen in patients with a poor prognosis.36 Proper selection of patients seems therefore important; for patients with a favourable prognostic profile, experimental treatment might prolong survival substantially, and QoL should be a secondary outcome in order to monitor whether treatment does not lead to unacceptable negative impact on QoL. On the other hand, for BM patients with a poor prognosis, QoL might even be regarded as the primary outcome measure as the main goal of treatment is to maintain acceptable QoL for as long as possible. Problems and pitfalls in measuring QoL during future experimental trials in BM patients are decreasing compliance rates during follow-up, resulting in a bias towards patients with a better prognosis, and too liberal time windows for subsequent measurements, resulting in inadequate comparisons as patients that fill in questionnaires representing the same time point in fact are in different treatment phases.21,31,32 Furthermore, patients’ cognitive deficits may render QoL patient-reported outcomes through questionnaires to be unreliable.37 Exclusion of these patients from analysis obviously introduces undesirable bias in the evaluation of QoL. These problems and pitfalls might be tackled by the incorporation of shorter questionnaires, for example the EORTC QLQ-C15 PAL instead of the EORTC QLQ-C30, the application of strict time slots for QoL measurements and adequate monitoring by study nurses, and the incorporation of proxy-measurements.38,39 Previous reports indicate that in high-grade glioma patients, patientand proxy-reported HRQoL have a high level of concordance as long as the patient shows no signs of cognitive decline, but differences, particularly in mood-related issues, increase when cognitive performance decreases.40,41 When differences between patient and proxy-reported HRQoL ratings develop in the course of the disease (presumably at the time cognitive decline becomes an issue) proxy-reported instead of patientreported HRQoL ratings might be the more reliable source of information on a patient’s HRQoL from that point. The results of two ongoing EORTC phase II (EORTC 26091 and EORTC 26101) studies in brain
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
tumour patients, measuring both patient- and proxyreported QoL as a secondary outcome measure, will provide further insight into the value of using proxy assessments in this population. 7. Biology of brain metastases: opportunities for targeted agents and translational research BM is in principle a multifocal disease for which metastasizing cancer cells have to successfully master distinct mandatory steps to eventually grow to a clinically significant macrometastasis.42,43 BM formation may be prevented by interfering with distinct steps of the brain-metastatic process, as demonstrated for inhibition of brain colonisation of NSCLC cell lines in a mouse model using bevacizumab.43 The following biological hallmarks of BM make it likely that judicious addition of systemic targeted therapies will substantially add to the therapeutic armamentarium in the future: First, one of the greatest challenges of systemic brain tumour therapy is the blood-brain/blood-tumour barrier (BBB/BTB). This consists of additional layers of thickened basement membrane, irregular pericyte coverage, and occasionally astrocyte foot processes in the brain.44–46 Furthermore, drug penetration to the cancer cell is also hindered by the aberrant and highly heterogeneous blood flow in brain tumour vessels lacking the normal hierarchical structure of normal brain vasculature and increased interstitial fluid pressure.47 Overall, most drugs available today do not or only inefficiently overcome these barriers between the blood stream and the brain tumour cell, at least in meaningful concentrations. In contrast, some antiangiogenic agents have to reach only the endothelial cell without needing to cross the entire blood-tumour barrier. Similarly, immunomodulators targeting cells responsible for anti-tumour immunity (e.g. ipilimumab) do not need to reach the cancer cell by themselves to exert their action. Second, targeted small molecule and even antibody inhibitors can be designed to efficiently cross the BBB, or linked to an agent that is actively transported over it.48 Third, it is proven that metastatic outgrowth in the brain can be effectively prevented – by prophylactic WBRT which targets the whole organ (without being hindered by the BBB). Applied during a short time frame (2–3 weeks) early in the beginning of the disease, prophylactic WBRT decreases the incidence of (macro)metastasis formation by more than 50%, an effect that continues over the next 24 months in patients.49 Since targeted agents can be applied over long periods of time, are active in the whole body, and do not show the neurotoxicity of WBRT, they seem to be perfect future candidates for BM prevention. Some of these do not have to cross the BBB to be active, e.g. anti-VEGF antibodies exert their main function
3445
on the luminal side of the vascular wall. An interesting retrospective analysis from the clinic has shown that patients with renal cell carcinoma who received sorafenib had lower incidence of symptomatic BM than those patients who did not receive sorafenib (3% versus 12%).50 This effect stayed statistically significant over 2 years.50 Inhibition of the angiogenic switch might be indeed a very effective way to prevent tumour outgrowth, which has been shown for BM, too.43,51 Moreover, a recent study documented lower rates of CNS progression in EGFR mutant advanced NSCLC initially treated with EGFR tyrosine kinase inhibitors (gefitinib or erlotinib) compared with upfront chemotherapy, further underlining that chemoprevention of CNS metastases is a feasible approach.52 In the era of successful therapeutic targeting of distinct molecular pathways in more and more systemic tumours, the incidence and relevance of BM are rising. It is mandatory to test the efficacy of established agents in randomised BM trials, and desirable to promote the development of inhibitors of potential BM specific pathways.53,54 It is likely that inhibitor classes will significantly differ regarding their ability to influence control of macrometastases versus outgrowth of micrometastases versus the prevention of initial micrometastatic spread to the CNS. This has to be taken into consideration in the design of future clinical trials. Presurgical treatment of patients scheduled for resection of BM with novel drugs offers the possibility for translational trials to investigate the drug penetration and efficacy of the drug to exert its biological action in the tumour tissue. The feasibility of such a study concept has been shown in a recent trial analysing the intratumoural concentration and the effect on its target pathway of the EGFR tyrosine kinase inhibitor gefitinib in glioblastoma.55 8. Summary and conclusions Based on the discussion held at the EORTC Brain Metastases Strategic Meeting 2012, the following conclusions were made: – There is a strong need for well conducted trials on prophylaxis and treatment of BM. – New study initiatives should focus on specific tumour types/molecular subtypes instead of enrolling unselected BM patients with tumours of all histological types. – New trials should investigate the prophylaxis of BM based on insights into the pathogenesis of CNS involvement, e.g. by targeted therapies that inhibit early stages of BM formation. One example could be the prevention of BM formation in NSCLC patients by antiangiogenic drugs as recently exemplified in the experimental setting.43
3446
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447
– The trial design is particularly challenging, as many disease and patient variables, statistical issues and the selection of appropriate end-points have to be taken into account. These facts make dedicated multidisciplinary and multinational efforts including involvement of high bio-statistical expertise in the study planning and conduct necessary. Conflict of interest statement Matthias Preusser has received travel support (scientific meetings), research support (unrestricted grants) and lecture honoraria by Roche. Frank Winkler has received lecture honoraria by Roche, and research support restricted grants) by Roche and Genentech. Sven Haller has received travel support (scientific meetings) and research support (unrelated to the current manuscript). Riccardo Soffietti has received honoraria for Advisory Boards from Roche, Merck and MSD. Jaap Reijneveld received funding from EU Framework Program 7, the Dutch Epilepsy Foundation (NEF), the Dutch Cancer Society (KWF Kankerbestrijding), Foundation “NutsOhra”, Foundation “STOPhersentumoren.nl”, and the National Brain Tumor Foundation/ Tug McGraw Foundation, and received unrestricted grants from UCB and Sanofi-Aventis. Brigitta G. Baumert has received travel support by Roche. Jacek Jassem has received travel support (scientific meetings) from Roche, Boehringer Ingelheim and Astra Zeneca, research support (unrestricted grants) from Roche and GSK and lecture or advisory board honoraria from Roche, GSK, Pfizer, Saladax and Amgen. Dirk Schadendorf has attended compensated advisory boards and received honoraria as part of its speaker´s bureau from Roche, Genentech, Amgen, Novartis, BMS, GSK and Merck. None of the other authors have reported conflicts of interest. Acknowledgements The Meeting was kindly supported by Roche, Novocure, Merck Serono and the Comprehensive Cancer Center Vienna. The sponsors had no role or influence in the content of the meeting or this manuscript. References 1. Mehta MP, Tsao MN, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 2005;63(1):37–46. 2. Villa S, Weber DC, Moretones C, et al. Validation of the new Graded Prognostic Assessment scale for brain metastases: a multicenter prospective study. Radiat Oncol 2011;6:23. 3. Amer MH, Al-Sarraf M, Baker LH, Vaitkevicius VK. Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer 1978;42(2):660–8.
4. Weissman DE. Glucocorticoid treatment for brain metastases and epidural spinal cord compression: a review. J Clin Oncol 1988;6(3):543–51. 5. Gaspar LE, Mehta MP, Patchell RA, et al. The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96(1):17–32. 6. Kalkanis SN, Kondziolka D, Gaspar LE, et al. The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96(1):33–43. 7. Linskey ME, Andrews DW, Asher AL, et al. The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96(1):45–68. 8. Mehta MP, Paleologos NA, Mikkelsen T, et al. The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96(1):71–83. 9. Khuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 2006;24(8):1295–304. 10. Weber DC, Caparrotti F, Laouiti M, Malek K. Simultaneous infield boost for patients with 1 to 4 brain metastasis/es treated with volumetric modulated arc therapy: a prospective study on qualityof-life. Radiat Oncol 2011;6:79. 11. Regine WF, Schmitt FA, Scott CB, et al. Feasibility of neurocognitive outcome evaluations in patients with brain metastases in a multi-institutional cooperative group setting: results of Radiation Therapy Oncology Group trial BR-0018. Int J Radiat Oncol Biol Phys 2004;58(5):1346–52. 12. Steinmann D, Schafer C, van Oorschot B, et al. Effects of radiotherapy for brain metastases on quality of life (QoL). Prospective pilot study of the DEGRO QoL working party. Strahlenther Onkol 2009;185(3):190–7. 13. Mitera G, Zhang L, Sahgal A, et al. A survey of expectations and understanding of palliative radiotherapy from patients with advanced cancer. Clin Oncol (R Coll Radiol) 2012;24(2):134–8. 14. Barnes E, Chow E, Tsao M, et al. Physician expectations of treatment outcomes for patients with brain metastases referred for whole brain radiotherapy. Int J Radiat Oncol Biol Phys 2010;76(1):187–92. 15. Gondi V, Tolakanahalli R, Mehta MP, et al. Hippocampalsparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2010;78(4):1244–52. 16. Gutierrez AN, Westerly DC, Tome WA, et al. Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study. Int J Radiat Oncol Biol Phys 2007;69(2):589–97. 17. Hsu F, Carolan H, Nichol A, et al. Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for 1–3 brain metastases: a feasibility study using volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys 2010;76(5):1480–5. 18. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosisspecific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012;30(4):419–25. 19. Preusser M, Capper D, Ilhan-Mutlu A, et al. Brain metastases: pathobiology and emerging targeted therapies. Acta Neuropathol 2012;123(2):205–22. 20. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011;29(2):134–41.
M. Preusser et al. / European Journal of Cancer 48 (2012) 3439–3447 21. Soffietti R, Mueller R, Abacioglu U, et al. Quality of life results of an EORTC phase III randomized trial of adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of 1–3 cerebral metastases of solid tumors. Neuro Oncol 2010;12(Suppl. 4):Ql-08. 22. Slotman BJ, Mauer ME, Bottomley A, et al. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol 2009;27(1):78–84. 23. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357(7):664–72. 24. Lin NU, Dieras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 2009;15(4):1452–9. 25. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10(11):1037–44. 26. Witgert ME, Meyers CA. Neurocognitive and quality of life measures in patients with metastatic brain disease. Neurosurg Clin N Am 2011;22(1):79–85, vii. 27. Taphoorn MJB, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol 2004;3(3):159–68. 28. Mitchell AJ, Kemp S, Benito-Leon J, Reuber M. The influence of cognitive impairment on health-related quality of life in neurological disease. Acta Neuropsychiatr 2010;22(1):2–13. 29. Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol 2004;22(1):157–65. 30. Taphoorn MJ, Sizoo EM, Bottomley A. Review on quality of life issues in patients with primary brain tumors. Oncologist 2010;15(6):618–26. 31. Taphoorn MJ, van den Bent MJ, Mauer ME, et al. Health-related quality of life in patients treated for anaplastic oligodendroglioma with adjuvant chemotherapy: results of a European Organisation for Research and Treatment of Cancer randomized clinical trial. J Clin Oncol 2007;25(36):5723–30. 32. Taphoorn MJ, Stupp R, Coens C, et al. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 2005;6(12):937–44. 33. Bosma I, Reijneveld JC, Douw L, et al. Health-related quality of life of long-term high-grade glioma survivors. Neuro Oncol 2009;11(1):51–8. 34. Brown PD, Maurer MJ, Rummans TA, et al. A prospective study of quality of life in adults with newly diagnosed high-grade gliomas: the impact of the extent of resection on quality of life and survival. Neurosurgery 2005;57(3):495–504, discussion 495–504. 35. Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med 2007;356(15):1527–35. 36. Wong J, Hird A, Kirou-Mauro A, Napolskikh J, Chow E. Quality of life in brain metastases radiation trials: a literature review. Curr Oncol 2008;15(5):25–45. 37. Sizoo EM, Braam L, Postma TJ, et al. Symptoms and problems in the end-of-life phase of high-grade glioma patients. Neuro Oncol 2010;12(11):1162–6.
3447
38. Groenvold M, Petersen MA, Aaronson NK, et al. The development of the EORTC QLQ-C15-PAL: a shortened questionnaire for cancer patients in palliative care. Eur J Cancer 2006;42(1):55–64. 39. Sneeuw KC, Aaronson NK, Sprangers MA, et al. Value of caregiver ratings in evaluating the quality of life of patients with cancer. J Clin Oncol 1997;15(3):1206–17. 40. Giesinger JM, Golser M, Erharter A, et al. Do neurooncological patients and their significant others agree on quality of life ratings? Health Qual Life Outcomes 2009;7:87. 41. Brown PD, Decker PA, Rummans TA, et al. A prospective study of quality of life in adults with newly diagnosed high-grade gliomas: comparison of patient and caregiver ratings of quality of life. Am J Clin Oncol 2008;31(2):163–8. 42. Steeg PS, Camphausen KA, Smith QR. Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 2011;11(5):352–63. 43. Kienast Y, von Baumgarten L, Fuhrmann M, et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 2010;16(1):116–22. 44. Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004;6(6):553–63. 45. Plate KH, Mennel HD. Vascular morphology and angiogenesis in glial tumors. ExpToxicolPathol 1995;47(2–3):89–94. 46. Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 2002;3(1):53–7. 47. Jain RK, Di TE, Duda DG, et al. Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8(8):610–22. 48. Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 2002;1(2):131–9. 49. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357(7):664–72. 50. Massard C, Zonierek J, Gross-Goupil M, et al. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol 2010;21(5):1027–31. 51. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86(3):353–64. 52. Heon S, Yeap BY, Lindeman N, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res, 2012 (in press). 53. Bos PD, Zhang XH, Nadal C, et al. Genes that mediate breast cancer metastasis to the brain. Nature 2009;459(7249):1005–9. 54. Nguyen DX, Chiang AC, Zhang XH, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 2009;138(1):51–62. 55. Hegi ME, Diserens AC, Bady P, et al. Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib – a phase II trial. Mol Cancer Ther 2011;10(6):1102–12. 56. Soffietti R, Mueller R, Abacioglu M. Quality of life results of an EORTC phase III randomized trial of adjuvant whole brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases of solid tumors. J Clin Oncol 2010;28(Suppl.):9036.