Tilburg University
Cognition and radiation study A
Verhaak, E.
Publication date:
2020
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Citation for published version (APA):
Verhaak, E. (2020). Cognition and radiation study A: Cognitive functioning, health-related quality of life, and
fatigue in patients with 1 to 10 brain metastases before and after Gamma Knife radiosurgery. Ridderprint.
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Cognition
and Radiation
Study A
Cognitive functioning,
health-related quality of life,
and fatigue in patients with 1
to 10 brain metastases before
and after Gamma Knife
radiosurgery
Eline Verhaak
Cognition and Radiation Study A
Cognitive functioning, health-related quality of life, and
fatigue in patients with 1 to 10 brain metastases before and
after Gamma Knife radiosurgery
for Health Research and Development (ZonMw, project number 842003008). Printing: Ridderprint | www.ridderprint.nl
Layout and Cover design: Elisa Calamita, www.persoonlijkproefschrift.nl ISBN: 978-94-6375-961-8
Copyright © 2020 by Eline Verhaak, The Netherlands.
All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission of the author.
Chapter 1 General introduction and aim of the dissertation 7
Chapter 2 Health-related quality of life in adult patients with brain metastases after stereotactic radiosurgery: a systematic, narrative review
21
Chapter 3 Health-related quality of life in patients with brain metastases selected for stereotactic radiosurgery
47
Chapter 4 Health-related quality of life after Gamma Knife radiosurgery in patients with 1-10 brain metastases
69
Chapter 5 Group and individual change in cognitive functioning in patients with 1-10 brain metastases following Gamma Knife radiosurgery
87
Chapter 6 Multidimensional assessment of fatigue in patients with brain metastases before and after Gamma Knife radiosurgery
107
Chapter 7 Cognitive functioning and health-related quality of life in long-term survivors with brain metastases up to 21 months after Gamma Knife radiosurgery
123
Chapter 8 General discussion and summary of the dissertation 141
Appendices Nederlandse samenvatting | Dutch summary 162
Chapter 1
CANCER
In the Netherlands, yearly, about 111,000 persons are diagnosed with cancer, and approximately 45,000 cancer patients die1. Also worldwide, cancer is a major public health
problem2. In 2018, 18 million persons were diagnosed with cancer and an estimated 9.6
million patients with cancer died3.
In the Netherlands, the most common forms of cancer are melanoma, colon cancer, breast cancer, lung cancer, and prostate cancer4. Each form of cancer can be considered as
a different disease with different treatment options. The most common cancer treatments include surgery, radiation, chemotherapy, immunotherapy, targeted therapy, and hormonal therapy5.
BRAIN METASTASES
Cancer cells of tumors that develop in an organ4 can metastasize through the body via blood
vessels or the lymphatic system6. Most brain metastases originate from primary lung cancer,
breast cancer, melanoma, and colorectal cancer6-8. Approximately 10-35% of all patients
with cancer develop brain metastases6, 9. Brain metastases are the most common tumors
in the central nervous system7, 9.
Clinical presentation of brain metastases often includes headaches, nausea, vomiting, dizziness, focal neurological deficits, epileptic seizures, and cognitive impairment6, 7, 10-12. For
most patients the signs and symptoms of brain metastases at presentation can be subtle. Brain metastases should be suspected in any patient with systemic cancer who experiences neurological symptoms6.
Life expectancy in these patients is in general poor but is increasing due to improved and new systemic treatment options of the primary tumor (e.g. targeted therapies, immunotherapies)6, 13, 14. Prognostic factors of survival time include age, histology of the
primary tumor, Karnofsky performance status (KPS), and extracranial metastases6, 15-17.
Treatment of brain metastases includes radiotherapy, surgery, and/or drugs6. Drugs can
be divided in symptomatic management (such as steroids, anti-epileptic drugs, antiemetics, and analgesics) and tumor-targeting therapies (such as chemotherapy, immunotherapy, targeted therapy, and hormonal therapy)6. Neurosurgical resection of a brain metastasis
is beneficial for selected patients: patients with KPS > 70, stable systemic disease, and a (few) symptomatic, accessible lesion(s)6. Radiotherapy is the most common and important
RADIOTHERAPY FOR BRAIN METASTASES
There are two types of radiotherapy for the treatment of brain metastases; whole brain radiation therapy and stereotactic radiosurgery or a combination of these. With whole brain radiation therapy, the entire brain, including healthy brain tissue, is irradiated multiple times, usually in 5 sessions spread over different days. With stereotactic radiotherapy, the brain metastases are targeted very precisely whereby the dose of radiation to the healthy brain tissue is limited.
A major risk of radiotherapy is radiation-induced brain injury18-20. Acute effects, such as
nausea, vomiting, drowsiness, and headache, occurring up to weeks after irradiation, and early-delayed effects, such as somnolence, fatigue, and deterioration of preexisting deficits, emerging 12 weeks to 6 months after irradiation, are mostly transient and reversible. Late-delayed effects, such as radiation-induced cognitive deficits, usually occur more than six months after radiation and are often progressive and irreversible18-20. Due to the increased
life expectancy, more patients with brain metastases may experience late-delayed side effects of radiotherapy.
In the past, most patients with brain metastases have been treated with whole brain radiation therapy, especially patients with multiple brain metastases. Whole brain radiation therapy could be initiated quickly, was widely available, and treated both visible and very small lesions that were not yet visible6. However, more recent studies have shown that
the use of whole brain radiation therapy can cause cognitive impairments6, 21-23. Due to
these possible cognitive impairments and due to the increased availability of, and the advances in, stereotactic radiosurgery, many patients are nowadays treated with stereotactic radiosurgery6, 24. With stereotactic radiosurgery, radiation is very precisely delivered to the
brain metastases only, thereby sparing healthy brain tissue and reducing the risks of long-term side effects caused by radiation25, 26. Stereotactic radiosurgery can be performed by
high-energy radiation including x-rays, gamma-rays, and protons, and can be delivered with a linear accelerator, a Gamma Knife, and a cyclotron or synchrotron, respectively27. The
median life expectancy of patients with brain metastases after stereotactic radiosurgery is approximately 6 to 12 months, depending on prognostic factors such as the primary tumor and KPS15, 28, 29.
Recently, studies showed that stereotactic radiosurgery is an effective treatment modality for patients with more than 4, and even more than 10 brain metastases28, 30-34. In
addition, multiple studies have been published that conclude that the median overall survival after stereotactic radiosurgery was similar in patients with five or more brain metastases compared to patients with four or less brain metastases28, 30, 35.
GAMMA KNIFE RADIOSURGERY
At the Gamma Knife Center Tilburg, stereotactic radiosurgery is applied with a Leksell Gamma Knife (Figure 1). With the use of cobalt 60 isotopes, radiation beams coming from 360 degrees around the head are delivered to the lesion. The point where all radiation beams come together is called the isocenter36. A high dose of radiation is produced in the
isocenter, which is targeted on the metastasis, while the radiation dose in the radiation beams outside the isocenter contain a very low dose of radiation. Gamma Knife radiosurgery has a high conformity (how adequately the radiation dose covers the target), high selectivity (how much of the surrounding healthy tissue is spared), and high gradient index (the ratio of the volume enclosed by half of the prescription isodose; an indication of dose falloff outside the target)37, 38.
With the aid of a stereotactic frame, it can be ensured that the isocenter of the radiation beams falls exactly on the brain metastasis. This frame is attached to the patients’ skull with screws under local anesthesia36. After the frame is placed, patients get a triple-dose
gadolinium MRI-scan; in 40% of the patients, more brain metastases are visible when using this high-resolution imaging compared with a diagnostic/single-dose gadolinium MRI-scan39.
Based on the triple-dose gadolinium MRI-scan, the treatment is planned by a neurosurgeon, radiation-oncologist, and physicist. Mostly, a couple of different ‘shots’, within one session, are needed to treat each brain metastasis. These shots are placed very precisely in order to follow the form of the metastasis. Gamma Knife radiosurgery is usually an outpatient procedure. At the end of the treatment-day, patients can go home36.
After treatment, patients return to the Gamma Knife Center every 6 weeks to 3 months for MRI-scan and consultation with the radiation-oncologist, as long as clinically relevant. The purpose of Gamma Knife radiosurgery is to control the brain metastases so that they stop growing. Although local progression of the brain metastasis may occur over time (local failure) and new brain metastases (distant failure) may develop36. Due to the strict
Protective shielding Collimator channels Leksell®Coordinate Frame Patient positioning system Radiation sources Isocenter/ Target in the brain
Courtesy of Elisabeth-TweeSteden Hospital Courtesy of Elekta
Figure 1. Leksell Gamma Knife Icon
OUTCOMES: FROM SURVIVAL TO WELL-BEING
In this dissertation, the goal was to evaluate the course of cognitive functioning, health-related quality of life, and fatigue after Gamma Knife radiosurgery in patients with multiple brain metastases. Thus far, most research on stereotactic radiosurgery for patients with brain metastases has focused on outcomes such as tumor control and survival. Maintaining cognitive functions and a good health-related quality of life as long as possible is an important primary objective in the management of brain metastases41, 42.
Assessment of cognitive functioning, health-related quality of life, and fatigue in cancer patients
Cognitive functioning is an umbrella term for brain functions including learning, memory, attention, problem solving, and decision making43-45. These functions can be measured with
an array of neuropsychological tests, each focusing on one or more cognitive abilities44, 46.
Patients’ cognitive abilities can be evaluated by comparing their performances to those of a normative control group, drawn from the general population, and/or with patients’ own performances at baseline (pre-treatment)47. The International Cognition and Cancer Task
Force48 recommended the following core battery of tests to measure cognitive functioning
in patients with cancer: the Hopkins Verbal Learning Test-Revised (HVLT-R), the Trail Making Test (TMT), and the Controlled Oral Word Association (COWA). In addition, tests for working memory can be included in the core test battery based on researchers’ own preferences48.
To measure potential changes in cognitive performances over time, the same tests are repeated over time. For example, to measure cognitive changes after treatment, patients can be tested before and (several times) after treatment49. Changes between test scores can
however include true changes, measurement error of the tests, and/or practice eff ects50.
Practice effects are improvements in performance due to familiarity with test stimuli and test procedures49, 51. When evaluating cognitive functioning over time, practice effects should
be taken into account. If studies do not correct for practice effects, this may lead to an underestimation of cognitive decline and an overestimation of cognitive improvement, even when using parallel/alternative versions of the same test49, 52.
Health-related quality of life is a multidimensional construct referring to a patient’s subjective perception of the effect of their disease and treatment on physical, emotional, and social functioning44, 53, 54. Health-related quality of life can be assessed with self-report
questionnaires. The most frequently used questionnaires to measure health-related quality of life in patients with brain metastases are the Functional Assessment of Cancer Therapy Brain (FACT-Br) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)55.
Fatigue is a complex symptom with physical, emotional, and mental aspects, and can be measured with a multidimensional self-report questionnaire56-58. Multidimensional fatigue
questionnaires include at least two dimensions of fatigue, such as mental fatigue (including difficulties with cognition, concentration, and speed of mental processes) and physical fatigue (including physical feelings of exhaustion, weakness, and tiredness)58.
Cognitive functioning, health-related quality of life, and fatigue in patients with brain metastases
Cognitive functioning, health-related quality of life, and fatigue are increasingly acknowledged as important outcome measures in patients with brain metastases treated with stereotactic radiosurgery41, 59, 60. Previous studies evaluating these aspects had a few limitations: the
number of brain metastases of the patients included, no corrections for practice effects, short follow-up times or small study samples at follow-up, and not analyzing the different aspects of fatigue.
One previous study on memory performance after stereotactic radiosurgery included
patients with more than 10 brain metastases61. In other previous studies on cognitive
functioning and fatigue after stereotactic radiosurgery62-65, patients with a limited number
of brain metastases (1-4) were included whereas stereotactic radiosurgery is increasingly used in patients with multiple (> 4) brain metastases66-68. Moreover, the studies on
cognitive functioning did not correct for potential practice effects due to repeated cognitive testing61-65. In addition, follow-up time was short or patient samples were small at follow-up
(ranging up to 21 patients at 12 months). Furthermore, no information regarding the effect of stereotactic radiosurgery on the various aspects of fatigue, such as physical and mental fatigue, is available in patients with brain metastases. In previous studies on health-related quality of life over time, most studies also included patients with up to 4 brain metastases62-65,
of the patients had > 4 brain metastases, respectively69, 70. One study evaluated patients
with up to 11 brain metastases, however health-related quality of life was assessed only at patients’ last follow-up73.
The limitations of previous studies regarding the effects of stereotactic radiosurgery on cognitive functioning, health-related quality of life, and fatigue hinder reliable conclusions on the (long-term) course after stereotactic radiosurgery in patients with multiple brain metastases. With Cognition And Radiation Study A (CAR-Study A) we aim to add knowledge that was missing while taking into account the limitations of previous studies.
CAR-STUDY A
Maintaining optimal well-being in patients with brain metastases as long as possible is an increasingly important treatment goal, especially since the life expectancy of these patients is increasing. To be able to evaluate cognitive functioning, health-related quality of life, and fatigue in patients with brain metastases before and after Gamma Knife radiosurgery, Cognition And Radiation Study A (CAR-Study A; ClinicalTrials.gov Identifier: NCT02953756) was initiated in the Gamma Knife Center Tilburg in collaboration with the department of Cognitive Neuropsychology of Tilburg University. CAR-Study A is a prospective study on cognitive functioning over time after Gamma Knife radiosurgery in a relatively large group of patients with 1-10 brain metastases. Secondary outcomes included the several aspects of health-related quality of life, and of fatigue. Patients completed a battery of neuropsychological tests and questionnaires concerning symptoms of anxiety and depression, health-related quality of life, and fatigue before Gamma Knife radiosurgery, and every 3 months up to 21 months thereafter.
OUTLINE OF THIS DISSERTATION
The general introduction (chapter 1) is followed by our systematic review on the
health-related quality of life in patients with brain metastases before and after stereotactic radiosurgery in chapter 2. Nine studies were included in this review. One of the conclusions
we drew was that information on the health-related quality of life in patients with brain metastases before stereotactic radiosurgery was often lacking. In the prospective study presented in chapter 3 we, therefore, specifically focused on health-related quality of life of
these patients before Gamma Knife radiosurgery. To give a detailed and in-depth overview of cognitive functioning and health-related quality of life after Gamma Knife radiosurgery, the findings with respect to these outcomes were described in separate chapters. Chapter 4 covers the course of health-related quality of life after Gamma Knife radiosurgery of 92
patients with 1-10 brain metastases up to 9 months after treatment (41 patients), and
chapter 5 covers course of cognitive functioning, with correction for practice effects, up
to 9 months after Gamma Knife radiosurgery. In chapter 6 we present our data on the
course of different aspects of fatigue of 92 patients with brain metastases before and 3
and 6 months (53 patients) after Gamma Knife radiosurgery. In chapter 7 we present our
findings on cognitive functioning and health-related quality of life of 38 long-term survivors (survival ≥ 12 months) up to 21 months (21 patients) after Gamma Knife radiosurgery. In the final chapter, chapter 8, I present an overview of the results of this dissertation, place
REFERENCES
1. NKR-IKNL. Sterfte | Alle tumoren; Landelijk;
Man & Vrouw [Internet]. 2019. [cited 2019 August 30] Available from: https://www. cijfersoverkanker.nl/selecties/dataset_2/ img5d690d2635fbb
2. WHO. Cancer [Internet]. 2018. [cited 2019
Oktober 1] Available from: https://www.who. int/news-room/fact-sheets/detail/cancer
3. WHO. International Agency for Research
on Cancer, GLOBOCAN [Internet]. 2019. [cited 2019 Oktober 1] Available from: http://gco.iarc.fr/today/data/factsheets/ populations/900-world-fact-sheets.pdf
4. KWF-IKN. Wat is kanker? [Internet].
2017. [cited 2019 August 30] Available from: https://www.kanker.nl/algemene- onderwerpen/wat-is-kanker/wat-is/wat-is-kanker#show-menu
5. NIH. Types of Cancer Treatment [Internet].
[cited 2019 October 2] Available from: https://www.cancer.gov/about-cancer/ treatment/types
6. Achrol AS, Rennert RC, Anders C, Soffietti
R, Ahluwalia MS, Nayak L, et al. Brain metastases. Nature Reviews Disease Primers. 2019;5(1):5.
7. Kaal EC, Niël CG, Vecht CJ. Therapeutic
management of brain metastasis. The Lancet
Neurology. 2005;4(5):289-98.
8. Rahmathulla G, Toms SA, Weil RJ. The
molecular biology of brain metastasis.
Journal of Oncology. 2012.
9. Arvold ND, Lee EQ, Mehta MP, Margolin K,
Alexander BM, Lin NU, et al. Updates in the management of brain metastases.
Neuro-Oncology. 2016;18(8):1043-65.
10. Lassman AB, DeAngelis LM. Brain metastases.
Neurologic Clinics. 2003;21(1):1-23.
11. Brown PD, Jaeckle K, Ballman KV, Farace
E, Cerhan JH, Anderson SK, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316(4):401-9.
12. Chang EL, Wefel JS, Hess KR, Allen PK, Lang
FF, Kornguth DG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. The
Lancet Oncology. 2009;10(11):1037-44.
13. Jensen CA, Chan MD, McCoy TP, Bourland
JD, DeGuzman AF, Ellis TL, et al. Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis. Journal
of Neurosurgery. 2011;114(6):1585-91.
14. Nayak L, Lee EQ, Wen PY. Epidemiology of
brain metastases. Current Oncology Reports. 2012;14(1):48-54.
15. Sperduto PW, Kased N, Roberge D, Xu Z,
Shanley R, Luo X, 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(4):419.
16. Nieder C, Nestle U, Motaref B, Walter K,
Niewald M, Schnabel K. Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes?
International Journal of Radiation Oncology* Biology* Physics. 2000;46(2):297-302.
17. Lu-Emerson C, Eichler AF. Brain metastases.
CONTINUUM: Lifelong Learning in Neurology.
2012;18(2):295-311.
18. Balentova S, Adamkov M. Molecular, cellular
and functional effects of radiation-induced brain injury: a review. International Journal of
Molecular Sciences. 2015;16(11):27796-815.
19. Greene-Schloesser D, Robbins M, Peiffer AM,
Shaw E, Wheeler KT, Chan MD. Radiation-induced brain injury: A review. Frontiers in
Oncology. 2012;2:73.
20. Tofilon P, Fike J. The radioresponse of the
central nervous system: a dynamic process.
Radiation Research. 2000;153(4):357-70.
21. Dhakal S, Peterson III CR, Milano MT.
Radiation therapy in the management of patients with limited brain metastases.
American Journal of Clinical Oncology.
2014;37(2):208-14.
22. Wefel JS, Parsons MW, Gondi V, Brown PD.
Neurocognitive aspects of brain metastasis. Handbook of Clinical Neurology. 149: Elsevier; 2018. p. 155-65.
23. Brown PD, Ahluwalia MS, Khan OH, Asher AL,
Wefel JS, Gondi V. Whole-brain radiotherapy for brain metastases: evolution or revolution? Journal of Clinical Oncology. 2018;36(5):483.
24. Ellis TL, Neal MT, Chan MD. The role of surgery,
radiosurgery and whole brain radiation therapy in the management of patients with metastatic brain tumors. International Journal
of Surgical Oncology. 2012.
25. Suh JH. Stereotactic radiosurgery for
the management of brain metastases.
New England Journal of Medicine.
2010;362(12):1119-27.
26. Abe E, Aoyama H. The role of whole brain
radiation therapy for the management of brain metastases in the era of stereotactic radiosurgery. Current Oncology Reports. 2012;14(1):79-84.
27. Jagannathan J, Sherman JH, Mehta GU,
Chin LS. Radiobiology of brain metastasis: applications in stereotactic radiosurgery.
Neurosurgical Focus. 2007;22(3):1-5.
28. Yamamoto M, Serizawa T, Shuto T, Akabane
A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. The Lancet
Oncology. 2014;15(4):387-95.
29. Yamamoto M, Kawabe T, Sato Y, Higuchi
Y, Nariai T, Watanabe S, et al. Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2–9 versus 10 or more tumors. Journal
of Neurosurgery. 2014;121(Suppl_2):16-25.
30. Chang WS, Kim HY, Chang JW, Park YG,
Chang JH. Analysis of radiosurgical results in patients with brain metastases according to the number of brain lesions: is stereotactic radiosurgery effective for multiple brain metastases? Journal of Neurosurgery. 2010;113(Special_Supplement):73-8.
31. Grandhi R, Kondziolka D, Panczykowski
D, Monaco EA, Kano H, Niranjan A, et al. Stereotactic radiosurgery using the Leksell Gamma Knife Perfexion unit in the management of patients with 10 or more brain metastases. Journal of Neurosurgery. 2012;117(2):237-45.
32. Kim H-S, Koh E-J, Choi H-Y. Multiple
gamma knife radiosurgery for multiple metachronous brain metastases associated with lung cancer: survival time. Journal of
Korean Neurosurgical Society. 2012;52(4):334.
33. Xue J, Kubicek GJ, Grimm J, LaCouture T,
Chen Y, Goldman HW, et al. Biological implications of whole-brain radiotherapy versus stereotactic radiosurgery of multiple brain metastases. Journal of Neurosurgery. 2014;121(Suppl_2):60-8.
34. Bhatnagar AK, Flickinger JC, Kondziolka D,
Lunsford LD. Stereotactic radiosurgery for four or more intracranial metastases.
International Journal of Radiation Oncology* Biology* Physics. 2006;64(3):898-903.
35. Karlsson B, Hanssens P, Wolff R, Söderman
M, Lindquist C, Beute G. Thirty years’ experience with Gamma Knife surgery for metastases to the brain. Journal of
Neurosurgery. 2009;111(3):449-57.
36. Elekta. Gamma Knife Treatment Process
[Internet]. [cited 2020 January 12] Available from: https://www.elekta.com/patients/ gammaknife-treatment-process/
37. Torrens M, Chung C, Chung H-T, Hanssens
P, Jaffray D, Kemeny A, et al. Standardization of terminology in stereotactic radiosurgery: Report from the Standardization Committee of the International Leksell Gamma Knife Society: special topic. Journal of Neurosurgery. 2014;121(Suppl_2):2-15.
38. Paddick I, Lippitz B. A simple dose gradient
measurement tool to complement the conformity index. Journal of Neurosurgery. 2006;105(Supplement):194-201.
39. Hanssens P, Karlsson B, Yeo TT, Chou N,
Beute G. Detection of brain micrometastases by high-resolution stereotactic magnetic resonance imaging and its impact on the timing of and risk for distant recurrences.
Journal of Neurosurgery. 2011;115(3):499-504.
40. Noh T, Walbert T. Brain metastasis: clinical
manifestations, symptom management, and palliative care. Handbook of Clinical Neurology. 149: Elsevier; 2018. p. 75-88.
41. Pham A, Lo SS, Sahgal A, Chang EL.
Neurocognition and quality-of-life in brain metastasis patients who have been irradiated focally or comprehensively.
Expert Review of Quality of Life in Cancer Care.
2016;1(1):45-60.
42. Soffietti R, Kocher M, Abacioglu UM, Villa S,
Fauchon F, Baumert BG, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. Journal
of Clinical Oncology. 2012;31(1):65-72.
43. Fisher GG, Chacon M, Chaffee DS. Theories
of Cognitive Aging and Work. Work Across the Lifespan: Elsevier; 2019. p. 17-45.
44. Coomans MB, Dirven L, Taphoorn MJ. Quality
45. Kolb B, Whishaw IQ. Fundamentals of human
neuropsychology: Macmillan; 2009.
46. Lezak MD, Howieson DB, Loring DW, Fischer
JS. Neuropsychological assessment: Oxford University Press, USA; 2004.
47. Noll KR, Bradshaw ME, Parsons MW,
Dawson EL, Rexer J, Wefel JS. Monitoring of neurocognitive function in the care of patients with brain tumors. Current Treatment
Options in Neurology. 2019;21(7):33.
48. Wefel JS, Vardy J, Ahles T, Schagen SB.
International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. The Lancet Oncology. 2011;12(7):703-8.
49. Calamia M, Markon K, Tranel D. Scoring
higher the second time around: meta-analyses of practice effects in neuropsychological assessment. The Clinical
Neuropsychologist. 2012;26(4):543-70.
50. Maassen GH, Bossema E, Brand N. Reliable
change and practice effects: Outcomes of various indices compared. Journal of
Clinical and Experimental Neuropsychology.
2009;31(3):339-52.
51. McCaffrey RJ, Duff KE, Westervelt HJE.
Practitioner’s guide to evaluating change with intellectual assessment instruments: Kluwer Academic Publishers; 2000.
52. McCaffrey RJ, Duff K, Westervelt HJ.
Practitioner’s guide to evaluating change with neuropsychological assessment instruments: Springer Science & Business Media; 2000.
53. CHMP. Guideline on the evaluation of
anticancer medicinal products in man.
London: European Medicines Agency (EMA).
2016.
54. Chen E, Nguyen J, Zhang L, Zeng L, Holden L,
Lauzon N, et al. Quality of life in patients with brain metastases using the EORTC QLQ-BN20 and QLQ-C30. Journal of Radiation
Oncology. 2012;1(2):179-86.
55. Verhaak E, Gehring K, Hanssens PE,
Aaronson NK, Sitskoorn MM. Health-related quality of life in adult patients with brain metastases after stereotactic radiosurgery: a systematic, narrative review. Supportive
Care in Cancer. 2020;28(2):473-84.
56. Ahlberg K, Ekman T, Gaston-Johansson F,
Mock V. Assessment and management of cancer-related fatigue in adults. The Lancet. 2003;362(9384):640-50.
57. Jacobsen PB. Assessment of fatigue
in cancer patients. JNCI Monographs. 2004;2004(32):93-7.
58. Stone PC, Minton O. Cancer-related fatigue.
European Journal of Cancer.
2008;44(8):1097-104.
59. Witgert ME, Meyers CA. Neurocognitive
and quality of life measures in patients with metastatic brain disease. Neurosurgery
Clinics. 2011;22(1):79-85.
60. Wong J, Hird A, Kirou–Mauro A, Napolskikh
J, Chow E. Quality of life in brain metastases radiation trials: a literature review. Current
Oncology. 2008;15(5):25.
61. Giuseppe M, Luca C, Barbara N, Giorgio R,
Claudia S, Federico B, et al. Neurological outcome and memory performance in patients with 10 or more brain metastases treated with frameless linear accelerator (LINAC)-based stereotactic radiosurgery.
Journal of Neuro-Oncology. 2020:1-9.
62. Habets EJ, Dirven L, Wiggenraad RG,
Verbeek-de Kanter A, Lycklama à Nijeholt GJ, Zwinkels H, et al. Neurocognitive functioning and health-related quality of life in patients treated with stereotactic radiotherapy for brain metastases: a prospective study.
Neuro-Oncology. 2016;18(3):435-44.
63. Van Der Meer PB, Habets EJ, Wiggenraad
RG, Verbeek-de Kanter A, à Nijeholt GJL, Zwinkels H, et al. Individual changes in neurocognitive functioning and health-related quality of life in patients with brain oligometastases treated with stereotactic radiotherapy. Journal of Neuro-Oncology. 2018;139(2):359-68.
64. Chang EL, Wefel JS, Maor MH, Hassenbusch
III SJ, Mahajan A, Lang FF, et al. A pilot study of neurocognitive function in patients with one to three new brain metastases initially treated with stereotactic radiosurgery alone. Neurosurgery. 2007;60(2):277-84.
65. Kirkpatrick JP, Wang Z, Sampson JH,
McSherry F, Herndon JE, Allen KJ, et al. Defining the optimal planning target volume in image-guided stereotactic radiosurgery of brain metastases: results of a randomized trial. International Journal of Radiation
Oncology* Biology* Physics. 2015;91(1):100-8.
66. Hunter GK, Suh JH, Reuther AM, Vogelbaum
MA, Barnett GH, Angelov L, et al. Treatment of five or more brain metastases with stereotactic radiosurgery. International
Journal of Radiation Oncology• Biology• Physics. 2012;83(5):1394-8.
67. Limon D, McSherry F, Herndon J, Sampson
J, Fecci P, Adamson J, et al. Single fraction stereotactic radiosurgery for multiple brain metastases. Advances in Radiation Oncology. 2017;2(4):555-63.
68. Lam T-C, Sahgal A, Chang EL, Lo SS.
Stereotactic radiosurgery for multiple brain metastases. Expert Review of Anticancer
Therapy. 2014;14(10):1153-72.
69. Bragstad S, Flatebø M, Natvig GK, Eide GE,
Skeie GO, Behbahani M, et al. Predictors of quality of life and survival following Gamma Knife surgery for lung cancer brain metastases: a prospective study. Journal of
Neurosurgery. 2017;129(1):71-83.
70. Skeie BS, Eide GE, Flatebø M, Heggdal
JI, Larsen E, Bragstad S, et al. Quality of life is maintained using Gamma Knife radiosurgery: a prospective study of a brain metastases patient cohort. Journal of
Neurosurgery. 2017;126(3):708-25.
71. Miller JA, Kotecha R, Barnett GH, Suh JH,
Angelov L, Murphy ES, et al. Quality of Life following Stereotactic Radiosurgery for Single and Multiple Brain Metastases.
Neurosurgery. 2017;81(1):147-55.
72. Randolph DM, McTyre E, Klepin H, Peiffer
AM, Ayala-Peacock D, Lester S, et al. Impact of radiosurgical management of geriatric patients with brain metastases: Clinical and quality of life outcomes. Journal of
Radiosurgery and SBRT. 2017;5(1):35-42.
73. Kotecha R, Damico N, Miller JA, Suh JH,
Chapter 2
Health-related quality of life
in adult patients with brain metastases
after stereotactic radiosurgery:
a systematic, narrative review
Supportive Care in Cancer, 2020; 28: 473–484Eline Verhaak1,2,3
Karin Gehring1,2,3
Patrick E. J. Hanssens1,2
Neil K. Aaronson4
Margriet M. Sitskoorn2,3
1 Gamma Knife Center, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands 2 Department of Neurosurgery, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands 3 Department of Cognitive Neuropsychology, Tilburg University, Tilburg, The Netherlands
ABSTRACT
Background
A growing number of patients with brain metastases (BM) are being treated with stereotactic radiosurgery (SRS), and the importance of evaluating the impact of SRS on the health-related quality of life (HRQoL) in these patients has been increasingly acknowledged. This systematic review summarizes the current knowledge about HRQoL in patients with BM after SRS.
Methods
We searched EMBASE, Medline Ovid, Web-of-Science, the Cochrane Database, PsycINFO Ovid, and Google Scholar up to November 15, 2018. Studies in patients with BM in which HRQoL was assessed before and after SRS and analyzed over time were included. Studies including populations of several types of brain cancer and/or several types of treatments were included if the results for patients with BM and treatment with SRS alone were described separately.
Results
Out of 3638 published articles, nine studies met the eligibility criteria and were included. In four out of seven studies on group results, overall HRQoL in patients with BM remained stable after SRS. In small study samples of longer-term survivors, overall HRQoL remained stable up to 12 months post-SRS. Contradictory results were reported for physical and general/global HRQoL, which might be explained by the different questionnaires that were used.
Conclusions
INTRODUCTION
Brain metastases (BM) originate from a malignancy outside the central nervous system.
Most patients diagnosed with BM have primary lung cancer, breast cancer, or melanoma1,
2. Partly due to improved imaging such as MRI and improved systemic treatment of the
primary cancer, the number of patients with BM is increasing3-7.
Traditionally, most patients with BM have been treated with whole brain radiation therapy (WBRT)3, 8, 9. However, due to advances in the technology, and the increased availability, of
stereotactic radiosurgery (SRS) and concerns about the long-term side effects of WBRT, radiation treatment is shifting toward SRS3, 10-12. The high precision of SRS spares healthy
brain tissue, reducing the risks of long-term side effects13, 14. Although SRS is usually delivered
in one fraction, it can be delivered in up to five fractions using a linear accelerator, particle beam accelerator or multisource Cobalt-60 unit15.
Although the prognosis still remains poor16-18, life expectancy in patients with BM is increasing
due to improvements in systemic treatments of the primary tumor6, 19. Therefore, maintaining a
good health-related quality of life (HRQoL) as long as possible is an important20 primary objective
in this patient group21. Consequently, management of BM is no longer focused solely on survival,
but also on HRQoL and cognitive functioning in patients with BM after treatment22-24.
Authors of previous clinical studies and reviews concluded that future trials that include patients with BM should assess HRQoL as outcome measure, to inform clinical practice (e.g., make informed treatment decisions, assess the efficacy of treatment, and inform patients about HRQoL over time)21, 23-26. In addition, HRQoL is important to evaluate as patients with
BM rated HRQoL as the most important factor to be considered in choosing among available treatment options27, as results from standard assessment of HRQoL in clinical practice may
help communication between patients and clinicians28, and as HRQoL appears to be an
independent prognostic factor for survival29-32.
To our knowledge, no systematic review has been conducted that focuses primarily on HRQoL outcomes after treatment with SRS alone in patients with BM. A synthesis of the available research findings can help to better understand patients’ HRQoL over time after SRS and can provide directions for future clinical trials. Ultimately, patients and physicians can be better informed on what to expect after SRS in terms of HRQoL. This systematic review summarizes the current knowledge on (changes in) the HRQoL of this patient group after SRS.
METHODS
Literature search
A systematic literature search was conducted to identify studies in which adult patients with BM were treated with SRS, and HRQoL was assessed by means of a self-report questionnaire.
EMBASE, Medline Ovid, Web-of-Science, the Cochrane Database, PsycINFO Ovid, and Google Scholar were searched up to November 15, 2018. Search terms were verified, and search strategies were built and performed by a biomedical information specialist of the library service of the Erasmus Medical Center, the Netherlands. Studies had to be published as empirical research articles in peer-reviewed journals and written in English, German, or Dutch. Case-report studies were excluded. Studies with an HRQoL assessment before and at least one HRQoL assessment after SRS alone were included. Within-group analyses had to be performed on HRQoL data. Studies that included a heterogeneous sample of patients in terms of type of brain-involved malignancies and/or studies in which different types of treatment were evaluated, were included only if the results for patients with BM treated with SRS alone were reported separately. Inclusion and exclusion criteria in terms of PICOs (patient, intervention, comparison, outcome) and search strategies are presented in supplementary Table 1 and supplementary Table 2, respectively.
Study selection
All studies were screened by the first author (E.V.) based on title and abstract. If eligibility was not clear from the title and abstract, the full text was screened. Papers that potentially met the eligibility criteria after full text screening were also reviewed by the second author (K.G.). Consensus was reached in all cases. This review is a qualitative synthesis of empirical studies. The same two authors extracted data from the included studies and results were compared; there were no disagreements. Reference lists of eligible articles were screened for additional articles.
Assessment of included studies
Factors that were cross-checked and critically evaluated among the studies included the following: type of cohorts/study samples included (e.g., different histologies of primary cancers), prior BM treatment, compliance or reasons for dropout reported, primary endpoints, HRQoL questionnaire used, timing of baseline HRQoL assessment, and timing and place of post-measurements.
RESULTS
Selected studies
Sc reen in g In cl ud ed Eligib ility Id en tif ic atio n Records excluded (n = 2348)
Full text articles excluded, with reasons (n = 1281): No (self-report) HRQoL measure (n = 558)
No full text published (n = 365)
No empirical article, e.g., review, protocol, editorial (n = 184) No SRS (alone) treatment group (n = 106) No English, German, or Dutch language (n = 29)
No BM (n = 18) Case report (n = 9)
No within-group analyses on HRQoL data (n = 5) No (pre- and/or post-treatment) HRQoL data reported (n = 4)
No pretreatment HRQoL measurement (n = 3) Studies included in qualitative
synthesis (n = 9) Records identified through
database searching (n = 5244) Records after duplicates
removed (n = 3638)
Full text articles assessed for eligibility (n = 1290)
Records screened (n = 3638)
Figure 1. PRISMA flowchart of the study selection
BM: brain metastases, n: number of studies, HRQoL: health-related quality of life.
Characteristics of studies
All studies included a heterogeneous group of patients with different primary histologies, except for one study32, in which only patients with primary lung cancer were included. In one
study33, only geriatric patients (age ≥ 70) were included. In one other study34, patients were
included who already received 3 courses of SRS, whereas in most studies, patients were included before their first course of SRS. Baseline characteristics of patients with baseline HRQoL scores were not reported in two studies33, 34. For two studies35, 36, a proportion of
patients were also included in a subsequent study (respectively32, 37). Sample sizes in the nine
selected studies ranged from 15 to 97 patients. In most studies, patients were female (range 43.2 to 67.3%), had primary lung cancer (range 37.3 to 100%), and had a median Karnofsky Performance Status (KPS) score of 80 (range < 70 to 100) (Table 1). In four studies36-39,
patients with newly diagnosed BM were included; in four other studies32, 34, 35, 40, patients
received prior BM treatment; and in one study33, it was not reported if patients received
prior BM treatment. Reasons for dropout were not reported in six studies32-34, 38-40, and in two
studies36, 37, reasons of dropout were reported, but without the numbers of patients (Table 1).
HRQoL assessments
Results on HRQoL over time of all reviewed studies are presented in Table 1. In three32,
35, 40 out of nine studies, HRQoL was the primary outcome measure. Four studies32, 34, 35,
40 evaluated HRQoL both at the group level and at the individual level, two studies36, 39
evaluated HRQoL at the group level only, and two studies37, 38 evaluated HRQoL at the
individual level only. In the studies reviewed, HRQoL was measured with five different self-report questionnaires. The most frequently used questionnaire was the brain cancer-specific Functional Assessment of Cancer Therapy Brain (FACT-Br), used in four studies (Table 2). The most commonly investigated aspects of HRQoL at the group level were physical, general/ global, social, and emotional aspects. In six studies32, 35-39, cancer-specific HRQoL self-report
questionnaires were used to measure HRQoL, and in three studies33, 34, 40, generic HRQoL
self-report questionnaires were used to measure HRQoL. In two studies38, 40, an unknown
number of patients completed the “pretreatment”/baseline HRQoL measurement after SRS. Follow-up questionnaires were sent by mail in two studies32, 35, and in the other studies,
administration was scheduled to coincide with hospital visits after SRS. In five studies34, 36-38, 40, mean HRQoL scores during follow-up were not reported, although in two of them34, 40,
mean HRQoL at patients’ last follow-up were reported (this point is not the same for each patient).
DISCUSSION
The aim of this review was to summarize findings of studies on (changes in) the HRQoL in patients with BM after SRS. Nine studies were included. Conclusions on HRQoL after SRS however should be drawn with caution, as several (methodological) limitations (discussed below) complicate the interpretation of findings. In two studies on individual scores only, stable overall HRQoL was demonstrated in most patients37, 38. In four out of seven studies
evaluating group scores, overall HRQoL remained stable in patients with BM after SRS32, 35,
36, 39, even up to 12 months after SRS in small groups of long-term survivors32, 35. However,
the three other studies found a decline in overall HRQoL after SRS. One of these studies reported a decline in overall HRQoL 6 and 12 months after treatment in an otherwise undefined small subgroup of geriatric patients (age ≥ 70)33, and two other studies reported
a statistically significant decline in overall HRQoL at patients’ last follow-up34, 40.
These last two studies34, 40 most likely assessed HRQoL at the point of progressive
disease for many patients, as no further follow-up assessments could be completed. As several studies report a decline in HRQoL after progressive disease31, 35, 36, 51, 52, the occurrence
of progressive disease might explain why these two studies found a decline in HRQoL while other studies reported stable HRQoL during multiple follow-up assessments. Differences in negative and stable outcomes might also be due to different patient or treatment
characteristics. In one of these studies34, patients underwent a minimum of three SRS
courses before inclusion and patient characteristics were not reported. However, baseline patient and treatment characteristics in the other study40 were comparable with the baseline
characteristics in the studies reporting stable HRQoL after SRS32, 35, 36, 39.
Although HRQoL scores on the group level appear to remain stable over time, they may mask individual changes in HRQoL. Habets et al.36 reported stable HRQoL over time on the
group level, while analysis of individual results from a portion of the same study sample on a selection of the scales by van der Meer et al.37 showed that most patients demonstrated
both improvements as well as deterioration in different aspects of HRQoL over time. Four other studies32, 34, 35, 40 evaluated both group and individual changes in HRQoL after SRS.
Two studies found stable mean group scores on additional concerns over time, while on the individual level, the majority of patients (60%) reported less additional concerns32 and small
groups of patients (23 to 36%) reported more additional concerns 1 month after SRS32, 35. Two
between both studies may be explained by chance due to the small sample size (n = 27) in one of these studies34; in addition, patients in this study had already undergone a minimum
of three SRS courses before inclusion in the study.
Similarly, combining the multidimensional aspects of HRQoL, including physical, social, and emotional functioning53, into a single overall HRQoL score may also lead to a loss of
information or mask potential improvements and declines in more specific aspects of HRQoL. One study38 evaluated an overall HRQoL score only, limiting conclusions about the full range
of potentially different HRQoL effects. However, preselecting certain HRQoL subscales based on existing literature and/or clinical insights is a more conservative approach than assessing a wide range of HRQoL outcomes which might lead to potential problems with type I errors in statistical testing due to multiple comparisons.
At the group level, the most frequently evaluated aspects of HRQoL were physical, general/global, social, and emotional aspects. Mean scores of these aspects remained stable over time32, 35, 36, 39, except for physical well-being/functioning and general/global
HRQoL. On these aspects, contradictory results were reported. Three studies using the EORTC-QLQ-C30 or EQ-5D reported a decline in the physical aspect of HRQoL34, 36, 40, while
three other studies using the FACT-Br reported stable scores over time32, 35, 39. This can be
explained by the different questionnaires that were used. For example, the subscale physical functioning of the EORTC-QLQ-C30 and the subscales mobility, self-care, and usual-activities of the EQ-5D are more focused on physical activities, while the subscale physical well-being of the FACT-Br is more focused on physical symptoms. It should be noted in addition that declines were reported by the two studies in which HRQoL was assessed at a patients’ last follow-up. This might also explain the difference in findings among studies on general/global HRQoL; the two studies measuring HRQoL at patients’ last follow-up reported a decline34, 40, while four other studies reported stable scores32, 35, 36, 39. However, the different setup in
questionnaires might also play a role. Since there is no standard assessment tool for HRQoL in patients with BM, comparing results from studies using different HRQoL measurements remains a challenge23, 24.
It should be noted that in two studies38, 40 an unknown number of patients completed
the pretreatment HRQoL measurement after SRS, which may have affected conclusions on HRQoL over time. In addition, in five studies33, 36-39, previous treatments directed at the
BM could have negatively affected the HRQoL of the patients. In two studies32, 35,
follow-up questionnaires were sent by mail; consequently, it was not known whether patients completed the self-report questionnaire themselves without the influence of significant others. On the other hand, patients could fill out these questionnaires at home, which may cause less stress or anxiety compared with the other studies, in which questionnaires were administered in the hospital at control visits, and thus provide a more realistic representation of HRQoL in daily life.
Among the other methodological limitations of studies on HRQoL after SRS was the lack of (reporting of) group analyses. To investigate changes in HRQoL after SRS, within-group analyses are needed to be able to draw conclusions on the effect of SRS on HRQoL over time. Unfortunately, several studies did not perform such analyses or did not report the results31, 52, 54-56, and were therefore not included in this review.
When interpreting results from longitudinal studies on HRQoL after SRS, it is important to be aware that a range of other factors, besides the treatment of interest, may influence HRQoL over time, including medication use (e.g., steroids), effects of treatment for the primary tumor (including chemotherapy, immunotherapy, radiation, surgery), pseudo-progression or pseudo-progression of disease, HRQoL before treatment, cognitive symptoms, and the mere passage of time. For example, low mood after the diagnosis of BM may be alleviated by the use of an antidepressant or just passage of time. In four of the included studies, factors that affected (changes in) HRQoL after SRS were evaluated. These studies suggested that HRQoL after SRS was associated with KPS, total tumor volume in the brain, symptomatic BM, time since SRS, and disease progression (e.g., intra- and extracranial tumor activity)32, 35, 36, 40, while the number of BM, sex, and age did not appear to influence
HRQoL32, 35, 36. However, due to differences between these studies in statistical techniques
employed (univariate and multivariate), differences in the choice as to which predictors were investigated and at which time points, it was not possible to draw reliable conclusions.
In addition, a potential effect of “response shift” should be considered. A response shift refers to changes in patients’ internal standards, values, and conceptualization of HRQoL that may occur during the course of their disease57-60. Studies have shown that although
the clinical health status of patients with cancer might deteriorate considerably over time, HRQoL scores often remain stable57. Most of the studies reviewed did not find considerable
deterioration of HRQoL, which may be (partly) explained by the response shift phenomenon. However, although patients might have shifted their response pattern over time, their self-reported HRQoL may still reflect their actual personal interpretation of their HRQoL at a given point in time61.
High attrition and low response rates are very common in studies that include patients whose life expectancy is short24, 58, 62. In many of the studies reviewed, the number of patients
completing (long-term) follow-up assessments dropped substantially. In most studies, reasons for dropout (e.g., decease, disease progression, personal motivation) were not or only partly described32-34, 36-40. As a result, interpretation of results is complicated58, and
results might not be generalizable to the whole population of patients63. However, if the
The timing of follow-up measurements varied across the studies reviewed and only three studies32, 33, 35 had follow-up periods longer than 6 months; in two other studies34, 40, HRQoL
was assessed at last follow-up, which differed for each patient.
Several limitations of the review process should be noted as well. Abstract screening was carried out by only one author, and thus, we cannot rule out the possibility that one or more additional relevant articles might have been identified if another author had been involved in this screening process. However, we believe that the screening process as carried out was very thorough. It is also possible that relevant studies were excluded due to language constraints. A risk of publication bias cannot be ruled out, since, for example, gray literature was not included in this review.
Future research
The synthesis of the findings of the nine relevant studies revealed that future clinical trials on the effects of SRS on HRQoL in patients with BM are needed to further investigate the multiple aspects of HRQoL over time, individual changes in HRQoL after treatment, and factors that influence HRQoL. Studies should report within-group changes and clearly describe statistical analyses and reasons for dropout. For the assessment of HRQoL in this patient population, brain cancer-specific self-report HRQoL questionnaires, evaluating the different aspects of HRQoL, should be used. To minimize patient burden and therefore prevent high dropout rates, dedicated personnel should be available to administer HRQoL questionnaires, and follow-up HRQoL assessments should be scheduled to coincide with and take place before, instead of after, standard hospital visits after SRS58, 64. In addition, more
studies with adequate sample sizes at long-term follow-ups (e.g., > 6 months) are needed to analyze different aspects of HRQoL at these time points, especially because irreversible and progressive radiation-induced brain injury, including cognitive impairment, usually emerges > 6 months after treatment65, 66. There are many methodological and logistical challenges in
performing serial HRQoL assessments in these patients, but the payoff in terms of increased understanding of the effect of both the disease and its treatment on the functional health, symptom burden, and well-being of our patients justifies the additional investment required.
Relevance for clinical practice
HRQoL appears to be an independent prognostic factor for survival in cancer patients with and without BM29-32, and in a recent study27, HRQoL was rated by patients with BM as the
most important factor to be considered in choosing among available treatment options. Since more patients with multiple BM are treated with SRS, it is important to know how this treatment may affect HRQoL in patients over time. In general, results of the studies reviewed here suggest that SRS does not have a significant negative effect on patients’ overall HRQoL over time (even up to 12 months after SRS). This indicates that, in terms of HRQoL, SRS
can be safely used in the management of patients with BM. Although more research is needed on factors influencing HRQoL in patients with BM, the current evidence suggests that clinicians should pay additional attention to patients with low KPS, large tumor volumes, symptomatic BM, and disease progression. In addition, assessment of HRQoL in clinical practice may improve communication between patients and clinicians, is helpful to identify patients’ concerns28, and helps clinicians to provide patients with personalized information.
SUPPLEMENTARY TABLES
Supplementary Table 1. Inclusion and exclusion criteria in terms of PICOs Patients Adult patients with BMAny primary cancer
No restriction for prognosis, country or clinical setting
Intervention Stereotactic radiosurgery (only)
Comparison Change in HRQoL after stereotactic radiosurgery (within-group analyses)
Outcomes Self-report HRQoL questionnaire
BM: brain metastases, HRQoL: health-related quality of life, PICO: patient, intervention, comparison, outcome.
Supplementary Table 2. Search strategies
Database Search
Embase.com (‘brain tumor’/exp OR (brain/exp AND metastasis/exp) OR (((brain OR intracereb*
OR cerebr* OR intracrani* OR Infratentor* OR skull) NEAR/3 (tumor* OR tumour* OR neoplas* OR metasta* OR malign*))):ab,ti) AND (Radiosurgery/exp OR ‘stereotactic procedure’/de OR ‘stereotactic radiosurgery’/de OR ‘gamma knife’/ exp OR (Radiosurg* OR (Radio NEXT/1 surg*) OR ‘gamma knife’ OR gammaknife OR CyberKnife OR (Fractionat* NEAR/3 radiotherap*) OR GKSR OR stereotactic* OR stereotaxic*):ab,ti) AND (‘quality of life’/exp OR ‘mood disorder’/exp OR ‘emotion’/ exp OR ‘fatigue’/exp OR ‘mental health’/exp OR ‘psychological aspect’/de OR ‘functional assessment’/exp OR ‘functional status assessment’/exp OR ‘functional status’/exp OR ‘stress’/exp OR ((qualit* NEAR/3 life) OR hrql OR hrqol OR qol OR depressi* OR (mood NEAR/3 disorder*) OR affect* OR emotion* OR fatigue* OR (mental* NEAR/3 health*) OR well-being* OR wellbeing* OR Anxi* OR psycholog* OR ((functional* OR mental*) NEAR/3 (assess* OR status OR state)) OR EORTC OR ‘Rotterdam Symptom* Checklist*’ OR rscl OR stress OR distress OR ((‘Short Form’ OR sf) NEXT/1 (36 OR 20 OR 12 OR 8)) OR sf36 OR sf20 OR sf12 OR sf8 OR ‘Anderson Symptom* Inventor*’ OR MDASI OR hads OR BCM20 OR ‘Brain Cancer Module’):ab,ti)
Medline Ovid (exp “Brain Neoplasms”/ OR (brain/ AND “Neoplasm Metastasis”/) OR (((brain
OR intracereb* OR cerebr* OR intracrani* OR Infratentor* OR skull) ADJ3 (tumor* OR tumour* OR neoplas* OR metasta* OR malign*))).ab,ti.) AND (exp “Stereotaxic Techniques”/ OR (Radiosurg* OR (Radio ADJ surg*) OR “gamma knife” OR gammaknife OR CyberKnife OR (Fractionat* ADJ3 radiotherap*) OR GKSR OR stereotactic* OR stereotaxic*).ab,ti.) AND (“quality of life”/ OR exp “Mood Disorders”/ OR exp “emotions”/ OR exp “fatigue”/ OR “mental health”/ OR psychology.xs. OR “Stress, Psychological”/ OR ((qualit* ADJ3 life) OR hrql OR hrqol OR qol OR depressi* OR (mood ADJ3 disorder*) OR affect* OR emotion* OR fatigue* OR (mental* ADJ3 health*) OR well-being* OR wellbeing* OR Anxi* OR psycholog* OR ((functional* OR mental*) ADJ3 (assess* OR status OR state)) OR EORTC OR “Rotterdam Symptom* Checklist*” OR rscl OR stress OR distress OR ((“Short Form” OR sf) ADJ (36 OR 20 OR 12 OR 8)) OR sf36 OR sf20 OR sf12 OR sf8 OR “Anderson Symptom* Inventor*” OR MDASI OR hads OR BCM20 OR “Brain Cancer Module”).ab,ti.)
Supplementary Table 2. Search strategies (continued)
Database Search
psycINFO Ovid (exp “Brain Neoplasms”/ OR (((brain OR intracereb* OR cerebr* OR intracrani*
OR Infratentor* OR skull) ADJ3 (tumor* OR tumour* OR neoplas* OR metasta* OR malign*))).ab,ti.) AND (“Stereotaxic Techniques”/ OR (Radiosurg* OR (Radio ADJ surg*) OR “gamma knife” OR gammaknife OR CyberKnife OR (Fractionat* ADJ3 radiotherap*) OR GKSR OR stereotactic* OR stereotaxic*).ab,ti.) AND (“quality of life”/ OR exp “Affective Disorders”/ OR exp “emotions”/ OR exp “fatigue”/ OR “mental health”/ OR “Stress”/ OR ((qualit* ADJ3 life) OR hrql OR hrqol OR qol OR depressi* OR (mood ADJ3 disorder*) OR affect* OR emotion* OR fatigue* OR (mental* ADJ3 health*) OR well-being* OR wellbeing* OR Anxi* OR psycholog* OR ((functional* OR mental*) ADJ3 (assess* OR status OR state)) OR EORTC OR “Rotterdam Symptom* Checklist*” OR rscl OR stress OR distress OR ((“Short Form” OR sf) ADJ (36 OR 20 OR 12 OR 8)) OR sf36 OR sf20 OR sf12 OR sf8 OR “Anderson Symptom* Inventor*” OR MDASI OR hads OR BCM20 OR “Brain Cancer Module”).ab,ti.)
Cochrane ((((brain OR intracereb* OR cerebr* OR intracrani* OR Infratentor* OR skull)
NEAR/3 (tumor* OR tumour* OR neoplas* OR metasta* OR malign*))):ab,ti) AND ((Radiosurg* OR (Radio NEXT/1 surg*) OR ‘gamma knife’ OR gammaknife OR CyberKnife OR (Fractionat* NEAR/3 radiotherap*) OR GKSR OR stereotactic* OR stereotaxic*):ab,ti) AND (((qualit* NEAR/3 life) OR hrql OR hrqol OR qol OR depressi* OR (mood NEAR/3 disorder*) OR affect* OR emotion* OR fatigue* OR (mental* NEAR/3 health*) OR well-being* OR wellbeing* OR Anxi* OR psycholog* OR ((functional* OR mental*) NEAR/3 (assess* OR status OR state)) OR EORTC OR ‘Rotterdam Symptom* Checklist*’ OR rscl OR stress OR distress OR ((‘Short Form’ OR sf) NEXT/1 (36 OR 20 OR 12 OR 8)) OR sf36 OR sf20 OR sf12 OR sf8 OR ‘Anderson Symptom* Inventor*’ OR MDASI OR hads OR BCM20 OR ‘Brain Cancer Module’):ab,ti)
Web-of-Science TS=(((((brain OR intracereb* OR cerebr* OR intracrani* OR Infratentor* OR skull) NEAR/2 (tumor* OR tumour* OR neoplas* OR metasta* OR malign*)))) AND ((Radiosurg* OR (Radio NEAR/1 surg*) OR “gamma knife” OR gammaknife OR CyberKnife OR (Fractionat* NEAR/2 radiotherap*) OR GKSR OR stereotactic* OR stereotaxic*)) AND (((qualit* NEAR/2 life) OR hrql OR hrqol OR qol OR depressi* OR (mood NEAR/2 disorder*) OR affect* OR emotion* OR fatigue* OR (mental* NEAR/2 health*) OR well-being* OR wellbeing* OR Anxi* OR psycholog* OR ((functional* OR mental*) NEAR/2 (assess* OR status OR state)) OR EORTC OR “Rotterdam Symptom* Checklist*” OR rscl OR stress OR distress OR ((“Short Form” OR sf) NEAR/1 (36 OR 20 OR 12 OR 8)) OR sf36 OR sf20 OR sf12 OR sf8 OR “Anderson Symptom* Inventor*” OR MDASI OR hads OR BCM20 OR “Brain Cancer Module”)) )
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