UMC Utrecht BrainCenter A MULTIDISCIPLINARY EXPLORATION INTO THE CONSEQUENCES OF RADIOTHERAPY IN PATIENTS WITH BRAIN METASTASES Piecing the puzzle together Eva Elisabeth van Grinsven
Piecing the puzzle together A multidisciplinary exploration into the consequences of radiotherapy in patients with brain metastases Eva Elisabeth van Grinsven
Cover description Exploring the mountainous landscape of the consequences of brain radiotherapy, together. Piecing the puzzle together PhD Thesis, Utrecht University, The Netherlands Provided by thesis specialist Ridderprint, ridderprint.nl Printing: Ridderprint Layout and design: Annemarie van Amerongen, persoonlijkproefschrift.nl Artwork: Evelien Jagtman & Mariska Offerman © evelienjagtman.com ISBN: 978-94-6483-766-7 DOI: 10.33540/1053 © Eva van Grinsven, 2023. All rights reserved. No part of this thesis may be reproduced, stored or transmitted in any way or by any means without the prior permission from the author. The copyright of papers that have been published or have been accepted for publication has been transferred to the respective journals. Part of the research described in this thesis was financially supported by the Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding (KWF, grant number 11110).
TABLE OF CONTENTS Chapter 1 General introduction and thesis outline 7 Part I: Neurocognitive functioning in patients with brain metastases Chapter 2 The impact of stereotactic or whole brain radiotherapy on neurocognitive functioning in adult patients with brain metastases – A systematic review & meta-analysis 25 Chapter 3 Different profiles of neurocognitive functioning in patients with brain metastases prior to brain radiotherapy 57 Chapter 4 Individualized trajectories in post-radiotherapy neurocognitive functioning of patients with brain metastases 79 Part II: Using imaging techniques to understand neurocognitive functioning Chapter 5 The impact of etiology in lesion-symptom mapping – A direct comparison between tumor and stroke 105 Chapter 6 Hemodynamic imaging parameters in brain metastases patients – Agreement between multi-delay ASL and hypercapnic BOLD 145 Chapter 7 Evaluating physiological MRI biomarkers and cognitive performance in patients with brain metastases after stereotactic radiosurgery - a preliminary analysis and case-report 171 Summary and Discussion Chapter 8 Summary 203 Chapter 9 Discussion 211 Chapter 10 Summary in Dutch (Nederlandstalige samenvatting) 235 Appendices List of publications 246 Educational portfolio 250 Dankwoord (Acknowledgements) 252 About the author 262
1 General Introduction
8 Chapter 1 Brain metastases (BMs) are a significant neurological consequence of cancer that occurs when cancer cells from a solid tumor elsewhere in the body migrate to the brain. The most common primary tumors that metastasize to the brain are lung, breast, and melanoma.1 BMs affect a substantial proportion of adult patients with cancer with estimates ranging from 10 to 30%.2–4 Despite improvements in medical treatments, the median overall survival of patients remains limited, ranging from 3 to 47 months.5,6 Various factors influence survival, including age, Karnofsky performance status (KPS), extent of extracranial disease, number of BMs, and histological and molecular features of the primary tumor.5–9 Currently, treatment options for BMs include surgery, chemotherapy, immunotherapy, and radiotherapy, typically given in a combination. The population of patients with BMs is expected to grow in the coming years due to advancements in medical treatments improving survival of cancer patients and enhanced imaging techniques allowing for earlier detection of BMs.10–12 Consequently, patients with BMs are now living longer with cancer. In this context, patient-centered treatment is increasingly focused on not only extending the life span, but especially on maintaining or even improving quality of life (QoL). RADIOTHERAPY FOR BRAIN METASTASES Radiotherapy is a cornerstone of medical treatment for BMs. It is a non-invasive technique in which ionizing radiation is delivered to the affected areas. By damaging the DNA within cancerous cells, radiation therapy can lead to senescence and ultimately cell death. The two prominent strategies for radiotherapy in BMs are stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT; Figure 1). Traditionally, WBRT was the standard treatment for BMs. Stereotactic treatment can be delivered using either a gamma knife or a conventional linear accelerator. Both apply a steep dose gradient by allowing overdosage up to 130 percent inside the tumor. Due to advances in these techniques, SRS has now been established as an optimal option for patients with one up to ten BMs, with a total volume of ≤30 cc.13–15 With SRS, the radiation dose to the target is divided over multiple arc beams delivered from different angles to accumulate a high-precision localized dose in the BMs while reducing the dose to the surrounding healthy brain tissue. The prescribed physical dose to the BMs usually varies between 15 and 24 Gray (Gy), dependent on the size of the lesion. WBRT is typically advised to patients with more than ten BMs to ensure coverage of all brain tissue and to sterilize not-yet visible BMs.16,17 WBRT is either delivered in five fractions of 4 Gy or ten fractions of 3 Gy: a much lower biological dose to prevent immediate whole brain damage. To decrease radiation
9 General introduction and thesis outline dose to organs at risk, like the hippocampus, and thereby reduce the risk of cognitive decline, hippocampal avoidance (HA-WBRT) is preferred over WBRT when possible. A challenge in radiotherapy treatment, as in any treatment, is achieving the optimal balance between maximizing anti-tumor effects and minimizing adverse sideeffects. This balance is constrained by the underlying physics and limitations of the radiotherapy technique employed. To ensure adequate tumor coverage with appropriate safety margins, two treatment volumes are defined for SRS: 1) gross tumor volume (GTV) and 2) planning treatment volume (PTV). The GTV represents the total volume of the BMS as seen on imaging (Figure 2). The GTV is typically identified based on the hyperintense region in a T1-weighted MRI scans after gadolinium injection. The PTV includes the volume of the GTV plus a 1-3 mm margin, depending on the radiotherapy equipment.18 This so-called error margin is necessary to achieve the desired therapeutic effect while taking into account patient set-up variation and the motion within the radiation positioning mask. Even with high dose fall-off at tumor borders, such as in SRS, some dose gradient will fall outside the tumor, possibly leading to radiation-induced brain injury in the surrounding healthy brain tissue. Figure 1. Biological dose (EQD2) distribution in stereotactic radiosurgery (SRS) and hippocampal avoidance whole-brain radiotherapy (HA-WBRT) shown on a T1-weighted MRI in axial and sagittal view (radiological orientation). Patient A was treated with 1 fraction of 15 Gy and had a single BMs in the left parietal lobe. Patient B was treated with 5 fractions of 4 Gy and had multiple BMs throughout the brain. 1
10 Chapter 1 Figure 2. Treatment volumes for SRS overlaid on a T1-weighted MRI. COGNITIVE PERFORMANCE In the context of prolonged life expectancy, potential treatment-related cognitive impairment has become an increasingly important topic. Especially since nearly 50% of patients with BMs already have cognitive deficits prior to radiotherapy.19–21 The acute radiation-induced injury that occurs in the first weeks is typically transient.22,23 However, delayed brain toxicity has been shown following radiation, leading to irreversible cognitive deterioration.22–24 Cognitive difficulties can have far-reaching impacts on various aspects of life such as work, relationships, and leisure activities.25 In fact, the impact of cognitive impairment on an individuals’ QoL has now been recognized as second only to survival in clinical trials.26 Importantly, not only severe cognitive impairment (e.g. dementia) can impact QoL, but mild cognitive changes are also perceived as a significant burden to both patients and caregivers.25 This highlights the importance of not only assessing objective cognitive functioning, but also subjective cognitive performance. Regrettably, a significant drawback of previous research is the reliance on cognitive screenings tests like the Mini-Mental Status Examination (MMSE), which cannot accurately detect these subtle, but burdensome, cognitive impairments. Additionally, studies have predominantly used group-level analyses and/or employed a focused, and thereby restricted, range of cognitive tests, thus limiting our understanding of the extent of cognitive difficulties and their full impact on individuals’ daily life. EFFECT OF BRAIN METASTASES ON THE BRAIN As briefly mentioned previously, approximately half of the patients with BMs already have cognitive problems before radiotherapy due to negative effects of
11 General introduction and thesis outline the presence of BMs themselves, and due to previous systemic treatments.27–30 The extent and type of preradiotherapy cognitive impairment can vary depending on the lesion location. Lesion studies have demonstrated the topological organization of the brain, with different areas of the brain responsible for different cognitive processes such as memory, attention, language, and executive function.31 Most of the research has focused on patients with ischemic stroke. This population has become the gold standard in this field due to the acute and focal nature of the lesions that are well-defined on imaging. Moreover, as stroke is a relatively common medical condition32, this allows for the required large patient samples in lesion-symptom mapping studies. The reliance on this population, however, raises concerns regarding the applicability of these findings to other populations, such as those with BMs. Behavioral consequences of a lesion may vary as a result of how the brain is affected by the lesion.31,33 For example, lesion distributions differ between etiologies, with certain brain areas more likely to be damaged than others, thereby affecting the spatial accuracy of lesion-symptom analyses. BMs mostly affect the cortex and subcortical white matter areas corresponding to watershed areas of large arteries34, while a stroke most often occurs in subcortical areas in the territory of the middle cerebral artery.35–37 Moreover, the mechanism of injury could vary; where an ischemic stroke leads to cell death due to a lack of oxygen and nutrients from the blood, BMs form tumors cells within the brain. MRI BIOMARKERS FOR RADIOTHERAPY-EFFECTS Although advancements have been made to limit the radiation dose to surrounding brain tissue, it is currently impossible to entirely avoid it due to the physical limitations of the photon radiotherapy technique. Consequently, cranial irradiation can potentially lead to encephalopathy, a complex phenomenon which is influenced by both the dose and time since exposure to radiation.38 The dose- and timedependency of this process is attributed to the differential radiosensitivity of the various components of the brain tissue and the blood vessels. Cranial irradiation can lead to various sequelae, including changes to the neuronal architecture, suppression of neurogenesis, neuroinflammation and autoimmune responses.23,38,39 Considering this, the underlying cause of radiation-induced cognitive decline is most likely multifaceted. In this thesis I mostly focused on the vascular component of the radiation effect. Animal experiments have revealed widespread vascular changes following cranial radiotherapy, including reduced vessel density and destabilization of the vascular endothelium.22,40–43 Microvascular damage resulting in reduced blood perfusion has already been reported in brain areas exposed to low doses of 10-15 Gy.44,45 Moreover, age-related vascular changes have been linked to cognitive 1
12 Chapter 1 performance in healthy individuals.46 Thereby, parallels have been drawn between the pathogenesis underlying vascular cognitive impairment (e.g. vascular dementia) and radiation-induced brain injury.47,48 Figure 3. Simplified illustration of brain metabolism. Oxygenated red blood cells travel from the heart through the arteries (red), to the arterioles in the brain where they deliver oxygen and nutrients to the neurons (green cells), before the deoxygenated blood returns to the heart through the veins (blue) for renewed circulation. The brain has an intricate network of blood vessels in order to meet its high oxygen and glucose demands (Figure 3). MRI is a non-invasive method that can be used to detect subtle vascular changes throughout the brain. Cerebral blood flow (CBF) indicates the amount of blood flowing to the brain through the arteries and can be measured using arterial spin labelling (ASL) MRI.49–51 To guarantee healthy functioning, CBF to the brain must remain relatively constant in response to changes in perfusion pressure or other hemodynamic events. Cerebrovascular reactivity (CVR) plays an important role in maintaining optimal CBF by regulating the diameter of cerebral vessels in response to changes in blood pressure and CO2 levels. 52–54 For example, increased CO2, a metabolic waste product, acts as a signal for heightened brain activity. In response, arterial blood vessels in these active regions dilate, facilitating increased blood flow to help remove excess CO2 and deliver oxygenrich blood to this tissue (Figure 4). This dynamic control, facilitated by smoothmuscle cells, also serves as a significant compensatory mechanism when cerebral hemodynamics are compromised by disease (e.g. narrowing of blood vessels). The CVR response can be assessed and spatially mapped using Blood Oxygenation Level-Dependent (BOLD) MRI in combination with controlled hypercapnic stimuli, like inhalation of CO2. When the brain’s metabolic demand is not (fully) met by blood flow compensation through CVR, the Oxygen Extraction Fraction (OEF) serves as an
13 General introduction and thesis outline additional regulatory mechanism. OEF reflects the amount of oxygen extracted from the brain’s arterial supply and is closely linked to oxygen usage and metabolism in the brain. Using innovative imaging techniques, OEF can be mapped by combining Quantitative Susceptibility Mapping (QSM) with quantitative BOLD (qBOLD). The cerebral metabolic rate of oxygen (CMRO2), is calculated by multiplying CBF and OEF, and thus reflects the balance between the two. As the brain heavily relies on oxygen-dependent glucose metabolism for energy production, CMRO2 serves as a key indicator for energy homeostasis and brain health.55 To illustrate, in a healthy brain CBF typically increases more than the oxygen metabolism, leading to a decrease in OEF and consequently a relatively steady CMRO2. 56 Figure 4. Illustration of vasodilation in arterial blood vessels, for example in response to increased CO2 levels in the blood. These different parameters thus reflect various aspects of the brain’s vascular reserve capacity, working together to ensure a continuous and sufficient supply of oxygen and nutrients.57,58 Disruptions to this hemodynamic balance, such as those caused by tumor growth or cranial irradiation, could result in altered blood vessel structure and function. While previous animal studies have shown radiation-induced vascular damage in surrounding healthy brain tissue, research on hemodynamic changes after cranial irradiation in humans is scarce. However, the field is continuously evolving and advances in imaging techniques now allow non-invasive MRI measurements of cerebral hemodynamics. Hypothetically, in humans vascular damage following cranial irradiation could impact the ability of blood vessels to constrict and dilate (i.e. CVR), reducing the capacity to modulate CBF to meet tissue needs. When blood flow compensation through CVR is insufficient, 1
14 Chapter 1 the brain could subsequently increase the OEF to maintain sufficient CMRO2. At the same time, previous studies have demonstrated extensive structural brain changes after radiotherapy, including cortical thinning59, grey and white matter volume loss60,61, and changes in white matter microstructure62–68. Following this research, it could be hypothesized that these structural changes lead to a decreased number of neurons and synapses and reduced neural communication, causing decreased brain metabolism and subsequently lower OEF. Interestingly, such a differential effect on OEF has already been illustrated in previous dementia research, whereby the effect on OEF varied depending on the type of dementia.69 In patients with vascular cognitive impairment, OEF was increased as a consequence of the vascular damage, while OEF was reduced in patient with Alzheimer’s Dementia most likely due to reduced brain metabolism. This underscores the importance of investigating these hemodynamic brain measures in parallel, as it provides insights into the underlying mechanism of the changes. However, these hemodynamic MRI measures have not yet been assessed in patients with BMs undergoing radiotherapy. As a result, it is still unclear whether and how these measures are influenced by either the presence of the BMs themselves or the subsequent cranial radiotherapy. THESIS OUTLINE In the pursuit of providing optimal care that considers both survival and quality of life, an integrative and multidisciplinary approach is not only essential in clinical practice, but also in research. To ensure patient-centered care, including treatmentshared decision making, thorough research is crucial to pinpoint the frequently occurring side-effects, accurately predict their occurrence in individual patients, and explore various avenues to proactively prevent them. This thesis aims to set the first steps by using a multidisciplinary approach to study radiation-induced brain injury. By simultaneously exploring neurocognitive functioning and the potential value of several potential MRI-biomarkers, this research can advance our understanding and pave the way for improved patient outcomes in the field of BMs radiotherapy. Part I: Neurocognitive functioning in patients with brain metastases The first part of this thesis will investigate neurocognitive functioning in patients with BMs both before and after radiotherapy. The aim is to provide comprehensive individual and group-level results that can deepen our understanding of this impact. By addressing these issues in detail, the hope is to offer insights that can subsequently be used in treatment-shared decision making in this population.
15 General introduction and thesis outline To provide a thorough overview of the current knowledge in the field, Chapter 2 summarizes and compares the available literature on the effect of either SRS or WBRT on neurocognitive performance in patients with BMs. Since SRS is increasingly being favored over WBRT in current practice, this review aimed to gain insight on whether current evidence regarding cognitive side-effects substantiate contemporary shifts in treatment preference. Moreover, this chapter offers insights into potential gaps in knowledge, which can serve as a foundation for future studies. Chapter 3 offers a detailed description of the cognitive performance, both subjectively and objectively, of patients with BMs before they begin radiotherapy. Examination of clusters of cognitive deficits enabled a deeper understanding of how different aspects of cognitive function may relate to one another. This chapter provides a thorough understanding of the patients who will be the topic of investigation in this thesis and their presentation to the radiotherapy clinic. It thereby provides important context within which the post-radiotherapy cognitive changes should be evaluated. Chapter 4 evaluates the short- and long-term changes in both subjective and objective cognitive performance in patients with BMs after radiotherapy. It provides insight into the multifaceted nature of changes and highlights opportunities for interventions (e.g. patient-tailored psycho-education, cognitive strategy training) in this specific group of patients. Individual trajectories of cognitive function are assessed to gain a clearer understanding of the cognitive impact of radiotherapy on the individuals comprising this patient group. Part II: Using imaging techniques to understand neurocognitive functioning To aid in understanding of the pathophysiology underlying the cognitive difficulties described in part I, the second part of this thesis focuses on the use of various imaging techniques. The aim is two-fold. First, I determined the generalizability of insights from other imaging studies to different patient populations. Next, the use of physiological MRI biomarkers within the BMs population was assessed. As researching lesion-behavior patterns in large populations of patients with BMs is challenging due to their limited life expectancy and diversity of lesion locations, we sought to gain insights from other diseases affecting the central nervous system, like ischemic stroke. In Chapter 5 we examined whether damage to the same brain regions cause by either a stroke or primary brain tumor resulted in similar or different sets of cognitive outcomes. This aids in understanding the generalizability of findings from one patient population to others. 1
16 Chapter 1 It is crucial to not only capture, but also comprehend the nature of post-radiotherapy changes on physiological imaging. Chapter 6 describes how imaging parameters derived from BOLD imaging and ASL measures were compared in patients with BMs before undergoing cranial radiotherapy. The study aimed to improve our understanding of the relationship between these two imaging techniques and their respective value in the BMs population. Building on the findings from the previous chapters, Chapter 7 provides preliminary evidence for the added value of several physiological MRI biomarkers in detecting changes after radiotherapy. Through a case-report the potential of these MRI biomarkers and their link to cognitive performance are described. A summary of the main findings and implications of all chapters within this doctoral thesis are discussed in Chapter 8 and 9, respectively.
17 General introduction and thesis outline REFERENCES 1. Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol 2017; 19: 1511–1521. 2. Barnholtz-Sloan JS, Yu C, Sloan AE, et al. A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro Oncol 2012; 14: 910–918. 3. Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. Journal of Clinical Oncology 2004; 22: 2865–2872. 4. Achrol AS, Rennert RC, Anders C, et al. Brain metastases. Nat Rev Dis Primers; 5. Epub ahead of print 2019. DOI: 10.1038/s41572-018-0055-y. 5. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745–751. 6. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010; 77: 655–661. 7. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology: Cancer Clinical Trials 1982; 5: 649–656. 8. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: An accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. Journal of Clinical Oncology 2012; 30: 419–425. 9. Gilbride L, Siker M, Bovi J, et al. Current predictive indices and nomograms to enable personalization of radiation therapy for patients with secondary malignant neoplasms of the central nervous system: A review. Neurosurgery 2018; 82: 595–603. 10. Nieder C, Spanne O, Mehta MP, et al. Presentation, patterns of care, and survival in patients with brain metastases: What has changed in the last 20 years? Cancer 2011; 117: 2505–2512. 11. Lanier CM, Hughes R, Ahmed T, et al. Immunotherapy is associated with improved survival and decreased neurologic death after SRS for brain metastases from lung and melanoma primaries. Neurooncol Pract 2019; 6: 402–409. 12. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep 2012; 14: 48–54. 13. Pinkham MB, Whitfield GA, Brada M. New developments in intracranial stereotactic radiotherapy for metastases. Clin Oncol 2015; 27: 316–323. 14. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): A multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–395. 15. Soliman H, Das S, Larson DA, et al. Stereotactic radiosurgery (SRS) in the modern management of patients with brain metastases. Oncotarget 2016; 7: 12318– 12330. 1
18 Chapter 1 16. Khuntia D, Brown P, Li J, et al. Whole-brain radiotherapy in the management of brain metastasis. Journal of Clinical Oncology 2006; 24: 1295–1304. 17. Mehta MP. The controversy surrounding the use of whole-brain radiotherapy in brain metastases patients. Neuro Oncol 2015; 17: 919–923. 18. Wilke L, Andratschke N, Blanck O, et al. ICRU report 91 on prescribing, recording, and reporting of stereotactic treatments with small photon beams. Strahlentherapie und Onkologie 2019; 195: 193–198. 19. Grosshans DR, Meyers CA, Allen PK, et al. Neurocognitive function in patients with small cell lung cancer: effect of prophylactic cranial irradiation. Cancer 2008; 112: 589–595. 20. Vardy J, Dhillon HM, Pond GR, et al. Cognitive function and fatigue after diagnosis of colorectal cancer. Annals of Oncology 2014; 25: 2404–2412. 21. Mitchell T, Turton P. ‘Chemobrain’: Concentration and memory effects in people receiving chemotherapy - a descriptive phenomenological study. Eur J Cancer Care (Engl) 2011; 20: 539–548. 22. Makale MT, McDonald CR, Hattangadi-Gluth JA, et al. Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours. Nat Rev Neurol 2017; 13: 52–64. 23. Greene-Schloesser D, Robbins ME, Peiffer AM, et al. Radiation-induced brain injury: A review. Front Oncol 2012; 2 JUL: 1–18. 24. Duffau H. Why brain radiation therapy should take account of the individual structural and functional connectivity: Toward an irradiation “à la carte”. Crit Rev Oncol Hematol; 154. Epub ahead of print 2020. DOI: 10.1016/j. critrevonc.2020.103073. 25. Mitchell AJ, Kemp S, Benito-León J, et al. The influence of cognitive impairment on health-related quality of life in neurological disease. Acta Neuropsychiatr 2010; 22: 2–13. 26. Frost MH, Sloan JA. Quality of life measurements: A soft outcome - Or is it? American Journal of Managed Care 2002; 8: 574–579. 27. Hodgson KD, Hutchinson AD, Wilson CJ, et al. A meta-analysis of the effects of chemotherapy on cognition in patients with cancer. Cancer Treat Rev 2013; 39: 297–304. 28. Joly F, Castel H, Tron L, et al. Potential effect of immunotherapy agents on cognitive function in cancer patients. J Natl Cancer Inst 2020; 112: 123–127. 29. Wefel JS, Schagen SB. Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep 2012; 12: 267–275. 30. Schagen SB, Tsvetkov AS, Compter A, et al. Cognitive adverse effects of chemotherapy and immunotherapy: are interventions within reach? Nat Rev Neurol 2022; 18: 173–185. 31. Karnath HO, Sperber C, Rorden C. Mapping human brain lesions and their functional consequences. Neuroimage 2018; 165: 180–189. 32. Vaartjes I, Reitsma JB, De Bruin A, et al. Nationwide incidence of first stroke and TIA in the Netherlands. Eur J Neurol 2008; 15: 1315–1323. 33. Karnath HO, Berger MF, Küker W, et al. The anatomy of spatial neglect based on voxelwise statistical analysis: A study of 140 patients. Cerebral Cortex 2004; 14: 1164–1172. 34. Akeret K, Staartjes VE, Vasella F, et al. Distinct topographic-anatomical patterns in primary and secondary brain tumors and their therapeutic potential. J Neurooncol 2020; 149: 73–85.
19 General introduction and thesis outline 35. Sperber C, Karnath HO. Topography of acute stroke in a sample of 439 right brain damaged patients. Neuroimage Clin 2016; 10: 124–128. 36. Corbetta M, Ramsey L, Callejas A, et al. Common behavioral clusters and subcortical anatomy in stroke. Neuron 2015; 85: 927–941. 37. Phan TG, Donnan GA, Wright PM, et al. A digital map of middle cerebral artery infarcts associated with middle cerebral artery trunk and branch occlusion. Stroke 2005; 36: 986–991. 38. Gorbunov N V., Kiang JG. Brain Damage and Patterns of Neurovascular Disorder after Ionizing Irradiation. Complications in Radiotherapy and Radiation Combined Injury. Radiat Res 2021; 196: 1–16. 39. Katsura M, Sato J, Akahane M, et al. Recognizing radiation-induced changes in the central nervous system: Where to look and what to look for. Radiographics 2021; 41: 224–248. 40. Brown WR, Blair RM, Moody DM, et al. Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: A potential rat model of vascular dementia. J Neurol Sci 2007; 257: 67–71. 41. Price RE, Langford LA, Jackson EF, et al. Radiation-induced morphologic changes in the rhesus monkey (Macaca mulatta) brain. J Med Primatol 2001; 30: 81–87. 42. Peña LA, Fuks Z, Kolesnick RN. Radiation-induced apoptosis of endothelial cells in the murine central nervous system: Protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res 2000; 60: 321–327. 43. Li YQ, Chen P, Haimovitz-Friedman A, et al. Endothelial apoptosis initiates acute blood-brain barrier disruption after ionizing radiation. Cancer Res 2003; 63: 5950–5956. 44. Park HJ, Griffin RJ, Hui S, et al. Radiation-induced vascular damage in tumors: Implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res 2012; 177: 311–327. 45. Hou C, Gong G, Wang L, et al. The Study of Cerebral Blood Flow Variations during Brain Metastases Radiotherapy. Oncol Res Treat 2022; 45: 130–137. 46. Peng SL, Chen X, Li Y, et al. Age-related changes in cerebrovascular reactivity and their relationship to cognition: A four-year longitudinal study. Neuroimage 2018; 174: 257–262. 47. Román GC. Vascular dementia revisited: Diagnosis, pathogenesis, treatment, and prevention. Medical Clinics of North America 2002; 86: 477–499. 48. Jellinger KA. Pathology and pathogenesis of vascular cognitive impairment-a critical update. Front Aging Neurosci 2013; 5: 1–19. 49. Alsop DC, Detre JA, Golay X, et al. Recommended Implementation of Arterial Spin Labeled Perfusion MRI for Clinical Applications: A consensus of the ISMRM Perfusion Study Group and the European Consortium for ASL in Dementia. Magn Reson Med 2015; 73: 102–116. 50. Detre JA, Rao H, Wang DJJ, et al. Applications of arterial spin labeled MRI in the brain. Journal of Magnetic Resonance Imaging 2012; 35: 1026–1037. 51. Telischak NA, Detre JA, Zaharchuk G. Arterial spin labeling MRI: Clinical applications in the brain. Journal of Magnetic Resonance Imaging 2015; 41: 1165– 1180. 52. Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry 2004; 75: 353–361. 53. Sebök M, Niftrik CHB Van, Wegener S, et al. Agreement of Novel Hemodynamic Imaging Parameters for the Acute and Chronic Stages of Ischemic Stroke: A Matched-pair Cohort Study. Neurosurg Focus 2021; 51: 1–8. 1
20 Chapter 1 54. Václavů L, Meynart BN, Mutsaerts HJMM, et al. Hemodynamic provocation with acetazolamide shows impaired cerebrovascular reserve in adults with sickle cell disease. Haematologica 2019; 104: 690–699. 55. Rodgers ZB, Detre JA, Wehrli FW. MRI-based methods for quantification of the cerebral metabolic rate of oxygen. Journal of Cerebral Blood Flow and Metabolism 2016; 36: 1165–1185. 56. Angleys H, Jespersen SN, Østergaard L. The effects of capillary transit time heterogeneity on the BOLD signal. Hum Brain Mapp 2018; 39: 2329–2352. 57. Fantini S, Sassaroli A, Tgavalekos KT, et al. Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods. Neurophotonics 2016; 3: 031411. 58. Murkin JM. Cerebral autoregulation: The role of CO2 in metabolic homeostasis. Semin Cardiothorac Vasc Anesth 2007; 11: 269–273. 59. Nagtegaal SHJ, David S, Snijders TJ, et al. Effect of radiation therapy on cerebral cortical thickness in glioma patients: Treatment-induced thinning of the healthy cortex. Neuro-Oncology Advances; 2. Epub ahead of print 2020. DOI: 10.1093/ noajnl/vdaa060. 60. Nagtegaal SHJ, David S, Philippens MEP, et al. Dose-dependent volume loss in subcortical deep grey matter structures after cranial radiotherapy. Clin Transl Radiat Oncol 2021; 26: 35–41. 61. Nagtegaal SHJ, David S, van Grinsven EE, et al. Morphological changes after cranial fractionated photon radiotherapy: Localized loss of white matter and grey matter volume with increasing dose. Clin Transl Radiat Oncol 2021; 31: 14–20. 62. Nazem-Zadeh MR, Chapman CH, Lawrence TL, et al. Radiation therapy effects on white matter fiber tracts of the limbic circuit. Med Phys 2012; 39: 5603–5613. 63. Zhu T, Chapman CH, Tsien C, et al. Effect of the Maximum Dose on White Matter Fiber Bundles Using Longitudinal Diffusion Tensor Imaging. Int J Radiat Oncol Biol Phys 2016; 96: 696–705. 64. Connor M, Karunamuni R, McDonald C, et al. Regional susceptibility to dosedependent white matter damage after brain radiotherapy. Radiotherapy and Oncology 2017; 123: 209–217. 65. Tibbs MD, Huynh-Le MP, Karunamuni R, et al. Microstructural Injury to LeftSided Perisylvian White Matter Predicts Language Decline After Brain Radiation Therapy. Int J Radiat Oncol Biol Phys 2020; 108: 1218–1228. 66. Chapman CH, Zhu T, Nazem-Zadeh M, et al. Diffusion tensor imaging predicts cognitive function change following partial brain radiotherapy for low-grade and benign tumors. Radiotherapy and Oncology 2016; 120: 234–240. 67. Chapman CH, Nagesh V, Sundgren PC, et al. Diffusion tensor imaging of normalappearing white matter as biomarker for radiation-induced late delayed cognitive decline. Int J Radiat Oncol Biol Phys 2012; 82: 2033–2040. 68. Huynh-Le MP, Tibbs MD, Karunamuni R, et al. Microstructural Injury to Corpus Callosum and Intrahemispheric White Matter Tracts Correlate With Attention and Processing Speed Decline After Brain Radiation. Int J Radiat Oncol Biol Phys 2021; 110: 337–347. 69. Jiang D, Lin Z, Liu P, et al. Brain Oxygen Extraction Is Differentially Altered by Alzheimer’s and Vascular Diseases. Journal of Magnetic Resonance Imaging 2020; 52: 1829–1837.
21 General introduction and thesis outline 1
Part I Neurocognitive functioning in patients with brain metastases
2 The impact of stereotactic or whole brain radiotherapy on neurocognitive functioning in adult patients with brain metastases – A systematic review & meta-analysis Eva E. van Grinsven, Steven H. J. Nagtegaal, Joost J. C. Verhoeff, & Martine J. E. van Zandvoort Oncology Research and Treatment (2021)
26 Chapter 2 ABSTRACT Background & Objectives Radiotherapy is standard treatment for patients with brain metastases (BMs), although it may lead to radiation-induced cognitive impairment. This review explores the impact of whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) on cognition. Methods The PRISMA-guidelines were used to identify manuscripts on PubMed and EmBase reporting on objective assessment of cognition before, and at least once after radiotherapy, in adult patients with non-resected BMs. Results Of the 867 records screened, twenty manuscripts (14 unique studies) were included. WBRT lead to decline in cognitive performance, which stabilized or returned to baseline in patients with survival of at least 9-15 months. For SRS, a decline in cognitive performance was sometimes observed shortly after treatment, but the majority of patients returned to or remained at baseline until a year after treatment. Conclusions These findings suggest that after WBRT patients can experience deterioration over a longer period of time. The cognitive side-effects of SRS are transient. Therefore this review advices to choose SRS, as this will result in lowest risks for cognitive adverse side-effects, irrespective of predicted survival. In an already cognitively vulnerable patient population with limited survival, this information can be used in communicating risks and aid in making educated decisions.
27 Cognitive Impact of SRS vs. WBRT: Systematic Review & Meta-analysis INTRODUCTION Local and systemic treatment for extracranial cancers is improving, leading to longer life expectancy. New challenges arise due to increased survival rates including the development of brain metastases (BMs). BMs occur in at least 10% of patients diagnosed with cancer and this incidence continues to rise.1,2 BMs are difficult to treat systemically because chemotherapeutic agents barely pass the blood-brain barrier. Median overall survival, despite systemic and focal treatment, is limited spanning months to several years, depending on factors such as lesion number, Karnofsky performance status and the primary cancer as reflected in GPA calculators.3,4 Treatment (shared) decisions in this vulnerable patient population are tailored towards gaining the best disease control while maintaining adequate quality of life (QoL) during the remaining life span. Treatment for BMs consists of different (palliative) options, including surgery, chemotherapy, immunotherapy and radiotherapy.5 One of the concerns with radiotherapy treatment is how to achieve the optimal balance between maximizing anti-tumor effects and minimizing possible adverse side-effects. The two prominent strategies for radiotherapy in BMs are whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS). WBRT is typically advised for patients with more than three BMs since treatment covers all brain tissue and has the advantage of sterilizing not-yet visible BMs.6,7 The main disadvantage is that WBRT can lead to radiation-induced tissue damage across the entire brain. SRS has mainly been applied in selected patients with one to three BMs and a favorable prognosis.8 During SRS, high precision localized irradiation is delivered to the BMs in a single fraction to maximize local tumor control and minimize the dose to the surrounding, healthy brain tissue. Patients with BMs compose a vulnerable patient group, since a high percentage of patients already experience cognitive impairment before starting radiotherapy, as a direct result of BMs but also due to previous cancer treatments.9–11 Deteriorated cognitive functions have been related to impaired financial, work and social activities, which are all important in maintaining good QoL and autonomy.12,13 Although literature on the cognitive changes after radiotherapy has been reviewed both for WBRT and SRS separately14,15, to date no publication exists comparing WBRT with SRS in relation to the cognitive outcome after treatment. Since SRS is increasingly being favored over WBRT in current practice16, we performed a systematic review on changes in cognitive functioning provoked by either WBRT or SRS in adult patients 2
28 Chapter 2 with non-resected BMs to gain insight on whether current evidence regarding cognitive side-effects substantiate contemporary shifts in treatment preference. METHODS Search Strategy The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used in conducting and reporting this systematic review.17 We reviewed all published manuscripts on the neurocognitive effects of WBRT or SRS in adult patients with BMs from 1-1-1950 until 4-1-2021. The search strategy combined terms for BMs, radiotherapy and cognition, and was developed for PubMed and adapted for Embase. The complete search strings can be found in the Supplementary Materials. Additionally, reference lists were manually screened for potentially relevant studies. Manuscripts were screened by two researchers (EEvG & SHJN) and disagreement was resolved through consensus meetings. The screening of the studies was facilitated by Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). Reasons for exclusion were documented for each paper. Eligibility The search was confined to manuscripts in English and Dutch. Studies were selected in which objective neurocognitive assessment was performed at baseline (defined as any time point between presentation of the BMs and start of radiotherapy), and at least once after radiotherapy, in adult patients with BMs. Only objective cognitive measurements were included since self-reports may be biased due to impairments caused by the BMs and (previous) cancer treatments.18 Moreover, subjective cognitive complaints do not represent underlying cognitive deficits per se and may be more indicative of psychological distress than actual cognitive impairment.19,20 Studies solely utilizing short neurocognitive-screening tools, such as the Mini-Mental Status Examination (MMSE), were excluded since these tests lack the sensitivity to detect subtle changes in cognitive functioning expected to be present after radiotherapy.21–23 Furthermore, all papers including patients with resected BMs were excluded since co-acting cortical tissue damage adjacent to the resection site can influence cognitive performance. Studies investigating the influence of treatments concurrent to radiotherapy (e.g. memantine) that did not report on a radiotherapy-only control group were also excluded. Case reports, reviews, commentaries, editorials and protocols were excluded. If multiple papers reported on the same dataset, the results were combined and reviewed as one cohort.
29 Cognitive Impact of SRS vs. WBRT: Systematic Review & Meta-analysis Data extraction and analysis The follow-up time points were converted to units of ‘months after radiotherapy’. To aid comparability across studies and following the classification used in previous studies, time points were clustered: short-term follow-up 1 to 4 months after radiotherapy, mid-term follow-up 5 to 8 months after radiotherapy, and longterm follow-up 9 to 15 months after radiotherapy. Baseline measurements always refer to the assessment before start of radiotherapy treatment. Additionally, neuropsychological tests were attributed to cognitive constructs in a data-driven classification, based on the subdivision as reported in the majority of the included studies (Supplementary Materials). Data was collected from text, tables and figures from the manuscripts and then tabulated. Missing data points were excluded from analyses and changes in sample size due to attrition were considered. For metaanalysis of the incidence of cognitive decline compared to baseline performance, we used the inverse variance method in a DerSimonian-Laird random effects model. For individual studies Clopper-Pearson confidence intervals were calculated. Heterogeneity between studies was assessed using Cochran’s Q test and the I2 statistic. Statistical analyses were performed with R 3.5.1 open-source software with the ‘meta’ package (http://www.R-project.org). Data quality A critical appraisal of the included studies was performed to assess data quality as reported in the manuscripts, for which a checklist consisting of 7 criteria was constructed (shown in Table 1). One point was awarded if the criterion was met and zero points if not, or if it was unclear based on the available information. A maximum score of 7 points could be obtained. A score between 5 and 7 indicates good to high quality, 3 and 4 medium quality and scores below 2 indicate low quality. RESULTS Study inclusion The initial search yielded 867 unique manuscripts. After applying the in- and exclusion criteria, 20 manuscripts reporting on 14 original datasets were included in this review (Figure 1). The majority of these studies were rated a good to high quality (Table 2). The one study rated as low quality was excluded from further analysis.24 Study and baseline patient characteristics and the main conclusions of the selected papers are shown in Table 3 and Table 4 respectively. Patient numbers varied considerably across studies with a median sample size of 81 (range: 20-208) and 35 (range: 7-111) at baseline for the WBRT and SRS studies, respectively. In total, 751 WBRT patients were included and 300 SRS patients. Since data on the incidence 2
30 Chapter 2 of cognitive decline was absent in some manuscripts, the meta-analysis could only be performed for those studies that reported on this data. Table 1. Criteria for assessing the quality of the data of the manuscripts for the review, including reasons for assessing these criteria. Criteria Reason Inclusion of >20 patients at baseline (avoid type II errors for baseline data) ≥50% of patients available for first followup measurements (avoid type II errors for follow-up data) Neurocognitive performance scores corrected to norms for age, sex and education when appropriate (bias by demographical variables) Definition of change in cognitive performance was provided (bias by definition of change) Cognitive performance at follow-up time points were adjusted for baseline performance (bias by differences in baseline performance) Use of parallel versions of neuropsychological tests for retesting procedures was stated in the manuscript (bias by learning effects due to repeated administration) Diversity of neurocognitive assessment, assessed by fulfilling (1/2 point each): ≥3 different neuropsychological tests used AND ≥3 cognitive constructs assessed with test battery (quality of cognitive testing procedures) Baseline cognitive performance Data on baseline cognitive performance before WBRT was solely explicitly reported for the Mehta et al. study (N = 208).18 The other included studies reported relative scores to an unreported baseline. Before starting WBRT 91% of the patients displayed cognitive impairment (Z-score <1.5) on ≥1 neuropsychological test and 42% on ≥4 neuropsychological tests. Fine motor coordination was impaired in 6365%, learning and memory (L&M) in 21-60%, executive function (EF) in 44% and verbal fluency in 33%. Lower baseline cognitive performance correlated with higher total BMs volume at baseline, but not with number of BMs.18,25 On the contrary, in another study neither the volume of BMs nor volume of white matter injury correlated with L&M performance before radiotherapy in a subset of patients.26,27 Patients with a KPS of ≥80 and patients ≤65 years performed better at baseline on subtests of L&M.28
31 Cognitive Impact of SRS vs. WBRT: Systematic Review & Meta-analysis Data on the incidence of baseline cognitive impairment before SRS was explicitly reported for the pilot-study by Chang et al. (N = 15) and by Habets et al. (N = 77).29,30 Pre-radiotherapy 53-67% of patients had cognitive impairment (Z-score <1.5 SD) on ≥1 neuropsychological test. At baseline, EF was impaired in 47% of the patients, fine motor coordination in 40%, L&M in 31%, visual memory and visuoconstruction in 22%, information processing speed in 10% and verbal fluency in 7%. Before SRS the mean z-scores of both the Chang et al. (N = 30) and the Brown et al. cohort (N = 111) were impaired.31,32 Worst group performance was observed on tasks for EF and information processing speed. Patients with a baseline BMs volume of >3 cc performed worse on attention than those with smaller lesion volumes.29 Similarly, Onodera et al. reported higher total lesion volume, but not number of BMs at baseline corresponded with worse cognitive performance, while Habets et al. reported no significant association with BMs volume.25,30 Post-radiotherapy cognitive performance At short-term follow-up (1-4 months) the majority of the WBRT studies (N = 455 patients) found consistent declines in cognitive performance on most cognitive constructs.18,25,26,28,33–40 Overall, between 19-37% of the patients deteriorated regarding L&M performance. Gondi et al. found that patients treated with hippocampal avoidance WBRT (HA-WBRT) had significantly less mean relative decline in L&M performance compared to the patients of Mehta et al. who received conventional WBRT (7% vs 30%, respectively).18,26 The change in L&M performance was correlated to pre-treatment BMs volume, age and the volume of white matter injuries.27 Other impaired cognitive constructs in the WBRT studies were EF (29-38%), fine motor coordination (31%), information processing speed (28%) and verbal fluency (7-32%). Even though Westover et al. observed a decline in 17% of their patients (N = 18) regarding L&M performance, on the group level no significant changes from baseline were found for the other cognitive constructs.41 Nevertheless, large variations in mean relative change were found for all cognitive constructs (L&M, information processing speed, EF, verbal fluency). At mid-term follow-up (5-8 months) the results were more variable. The 29 patients who received HA-WBRT had a mere relative decline of 0-3% on multiple tests for L&M at mid-term follow-up compared to baseline.26,33 Similarly, patients who survived more than 6 months after HA-WBRT with simultaneous integrated boost recovered to baseline scores regarding L&M performance.42 On the contrary, performance on most cognitive tasks declined in at least 114 patients who received conventional WBRT.35,39,40 L&M performance was most often affect, with 53% of the patients showing decline.35 Moreover, the percentage of patients with declined performance 2
32 Chapter 2 increased from 19% at short-term to 35% at mid-term follow-up.39 Although group performance declined compared to both baseline and short-term follow-up when considering all 17 patients in the Onodera et al. cohort, improvements were observed in a subgroup of patients with a baseline BMs volume of <4.0 cc and in BMs patients surviving at least 12 months.25 A similar trend was reported by Saito et al., where the subgroup surviving at least 8 months (N = 19) had stable L&M performance over time.28 Thus, most patients further decreased in cognitive performance at mid-term follow-up, but in a subgroup of patients stable or improved cognitive performance was observed over time. Figure 1. PRISMA flow chart illustrating the systematic proves conducted to identify the article in this review. *14 original datasets
33 Cognitive Impact of SRS vs. WBRT: Systematic Review & Meta-analysis Table 2. Assessment of data quality for each included study listed from highest to lowest quality. + indicates 1 point awarded for that criterion, - indicates no points and +/- 0.5 points. Authors ≥20 patients ≥50% at first follow-up Corrected to norms Definition provided Adjusted for baseline Parallel tests Diversity NCA Overall quality WBRT Mehta et al., 2003 18,36–38 + + + + + - + 6 good Gondi et al., 2014 26,27,33 + + - + + + +/- 5.5 good Westover et al., 2020 41 + + - +/- + + + 5.5 good Saito et al., 2016 28 + + - + + + - 5 good Deng et al., 2017 35 + + - + + - + 5 good Zhu et al., 2018 40 + + - + + - + 5 good Zhan et al., 2018 39 + + - + + - 4 medium Onodera et al., 2014 25 + + + - - - + 4 medium Cheng et al., 2018 34 + + - - - - + 3 medium SRS Chang et al., 2007 29 - + + + + + + 6 good Brown et al., 2016 32 + + + + + - + 6 good Chang et al., 2009 31 + + - + + - + 5 good Habets et al., 2016 30,43 + - + + + - + 5 good Minniti et al., 2020 44 + + - + + + - 5 good Onodera et al., 2014 25 - + + - - - + 3 medium Kirkpatrick et al., 2015 24 + - - - - - +/- 1.5 low Abbreviations: NCA, neurocognitive assessment; RT, radiotherapy; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy. 2
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