Long-term Survivors of High-grade Glioma
Conditions: Quality of Life, Brain Diseases, Depression, Physical Impairment
Sponsor: Rigshospitalet, Denmark

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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Document related to the research project: 
 
Long-term Survivors of High-grade glioma 
 
 
Review Committee of the Capital Region of Denmark 
(H-16035446) and the Danish Data Protection Agency 
(2012-58-0004). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karin Piil, BSC, Master of Health Science, Nursing, Ph.D. 
The University Hospitals Center for Health Research (UCSF) and the Center for Integrated 
Rehabilitation of Cancer Patients (CIRE) in collaboration with the Neuro-Oncology team, 
Rigshospitalet. Email: Karin.piil@regionh.dk 
 
Mary Jarden, Senior Researcher, Associate Professor, cand. cur., Ph.D. University Hospitals 
Center for Health Research (UCSF), Rigshospitalet, Center for Integrated Rehabilitation of Cancer 
Patients (CIRE) and University of Copenhagen. 
 
 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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Background 
High-grade glioma (HGG) occurs most frequently in patients 45-70 years of age (1, 2), with 
a male-to-female ratio of 1.5:1(3). Treated with optimal therapy the median survival rate for 
GBM (WHO grade IV) is approximately 15 months (4) with a two-year median survival rate 
of 30% and a five-year survival of 10% (5, 6). Standard initial treatment for HGG involves 
surgery either as diagnostic biopsy or maximal surgical resection (7). HGGs are infiltrating 
rapidly growing tumors(8), making total resection impossible and the majority recur within 
two cm of their original location(9, 10). HGGs are highly vascular and rich in a protein, 
which promotes angiogenesis(11). The Stupp regimen; i.e. concomitant 
chemoradiotherapy followed by adjuvant maintenance chemotherapy with temozolomide 
(TMZ) is currently the standard post-operative treatment for patients with newly diagnosed 
GBM(6, 12). TMZ is administrated during radiotherapy and for six maintenance cycles on 
five out of 28 days. The treatment response is evaluated by brain imaging and typically 
carried out prior to the third and sixth cycles. This regime has shown a statistically 
significant and clinically meaningful survival benefit from 12.1 to 14.6 months(13) with 
minimal additional toxicity(12). Even though multimodality treatments with neurosurgical 
resection or biopsy, radiotherapy and chemotherapy(14) have improved HGG 
prognosis(1), long-term survival is rare(15-17), however long-term survivorship (LTS) 
studies (> 5 years) have been published(17, 18). As there is currently no cure, 
progression-free survival is the primary outcome of the multimodal treatment. No standard 
treatment exists in the event of tumour progression (13) however; reoperation or treatment 
with an angiogenesis inhibitor (bevacizumab) in combination with chemotherapy 
(irinotecan) can be an option. The antiangiogenic therapy for HGG works by inhibiting new 
blood vessel formation and promotes regression of existing vessels(4). Future treatment 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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options include vaccination and treating the tumour with electric fields(19-22). Recent 
discussions regarding treatment strategies and outcomes consider the consequences of 
survival time versus quality of life (QOL), the HRQOL being suggested to influence the 
treatment decision(23). The purpose of antineoplastic treatment is to achieve progression-
free survival with delayed neurological and cognitive deterioration, and to maintain or 
increase HRQOL(11). HRQOL has become increasingly important next to more traditional 
outcome measures such as progression-free survival (24) and can guide a specific 
treatment strategy(23). The complexity of how a health-related issue interferes with QOL is 
not fully understood, mainly because HRQOL differs according to individual perspectives 
and preferences. Hence, the clinical outcome of long-term HGG survivorship and their 
caregivers´ QoL poorly understood. 
Long-term survivors of HGG 
HGG has a significant impact on the daily life of patients and their caregivers (25-27). 
Although research is emerging on patient-centered care and the psycho-social needs of 
patients with HGG and their caregivers, there is still lack of knowledge regarding long-term 
survivorship in experiences, needs and preferences for supportive care and palliation three 
years after the HGG diagnosis. LTS may face challenges as their survival permits them to 
be (re)-integrated into their previous life with deficits that make living troubling (18, 28) and 
at the same time realize that they are functioning relatively well after standard oncological 
treatment resulting in a survivorship feeling (29). Lovely et al. made one of the few existing 
studies that have included the caregivers’ perspective, and found significant changes in 
the relationships among the HGG survivors and their caregivers, a high frequency of 
depression and worsened symptoms (17).  

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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Caregivers of persons with HGG 
An increasing number of relatives provide care at home as hospitalization is only offered to 
those in need of treatment or specialized care. In order to support best practice based on 
evidence, there is a need for an understanding of daily live experiences and how they can 
be met. A research group from Pittsburgh, USA studied the predictors of distress in 
caregivers of persons with primary malignant brain tumor (30, 31), lost working hours (32), 
perceptions of economic hardship (33) and sleep characteristics (34). Most of these 
studies recruit caregivers in the early stage of the HGG trajectory. Caregivers of patients 
with HGG are known to experience a caregiver burden resulting in negative health status 
as hypertension, altered immune function and overall poor physical health. Yet, research 
has also found that being a caregiver can add value as they experience satisfaction from  
completing tasks and assisting their love ones (the patient)(35). Limited research 
describes the emotional and physical stress response of caregivers of LTS of a HGG(17). 
 
Rationale for the study protocol 
This study builds on the limited body of existing literature combined with the results from 
our previous research conducted with 30 newly diagnosed patients with HGG and 33 of 
their caregivers. We established an overview of the daily life experiences when diagnosed 
with a HGG or being a caregiver. Descriptions of needs and preferences from time of 
diagnosis to one year exist (36, 37). However, such data are still lacking the representation 
from LTS and their caregivers. We identified that newly diagnosed patients and their 
caregivers used an individual strategy for acquiring prognostic information (PI) and this 
revealed two different strategies for obtaining additional PI that involved either seeking or 
limiting the amount and content of PI. How and whether these or other strategies are 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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applied as long-term survivors of HGG is unknown.  Patients and caregivers shared hope, 
and it concerns a strong sense of solidarity between the patient and their caregiver. 
However, at the same time our findings also revealed that the caregivers experienced a 
burden due to the changed role from relative to becoming a caregiver. Hence, the 
relationship between the patients and their caregiver was often challenged by lack of 
energy and difficulties in managing the patients’ limitations, e.g. the cognitive changes. 
How this might be expressed for caregivers to LTS has not been described before. Finally, 
the newly diagnosed patients were found to be engaged in health promotion activities, 
involved the joining forces of patients and caregivers towards a healthier lifestyle, 
facilitated by shared hope reflecting that being involved and taking responsibility were 
highly valued. For the 12-month survivors who participated in our former study we 
identified a decrease in this engagement. Therefore it is of great interest to explore the 
level of such engagement among the 3 years survivors and their caregivers. Moreover, it is 
of great interest to explore their preferences for involvement in treatment decisions and 
thereby be able to discuss its implication for clinical practice. 
 
Aim 
This mixed methods study aims to address perspectives on daily life experiences of long-
term survivors with HGG and their caregivers as well as the needs and preferences for 
support, rehabilitation and palliation. 
 
Methods 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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This mixed-method study applies separate telephone interviews with patients and their 
caregivers and self-reported questionnaires for patients. The mixed methods design is a 
convergent sequential design using an identical sampling.  
 
Study participants and sampling 
The inclusion criteria are participants ≥18 years of age, diagnosed with HGG for a 
minimum of 3 years with the ability to speak and understand Danish. Caregivers are 
eligible if they are named by the patient as being one of the closest relative(s) providing 
care at home on a regular basis. 
  
Recruitment  
Patients were identified via a database at the Department of Oncology, Rigshospitalet, 
University of Copenhagen. A nurse coordinator contacted the patients diagnosed with 
GBM for more than 3 years. The identification of patients was given to the principal 
investigator (KP) in case they accepted to be contacted for further information. Patients 
were also asked to name their closest caregivers, and these were contacted regardless 
the patients´ acceptability.  The participant flow is scheduled at Figure 1. 
 
Design  
The dominant status relies on the qualitative data as the interviews are emphasized as the 
best suited method to address the primary aim of this study(38). The interviews follow a 
semi-structured interview guide for patients and for caregivers (Tables 1 and 1).   
 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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Long-term Survivors of HGG – Study Protocol 20 august 2016 
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Table 1: Interview topics for patients 
 
Research questions 
 
Examples of interview questions 
What happened and how did 
the patient experience the time 
between the first symptoms and 
the operation? 
 
Please describe your overall disease- and treatment trajectory - what 
happened and how did you experienced the episodes?  
Does the patient experience any 
symptoms/side effects, and 
what are the consequences and 
how are they managed? 
Do you have any complaints/symptoms/side effects? Does it have any effect 
on the way that you manage your life? Is there anything that has helped you 
to overcome symptoms / side effects? Have you noticed difficulties in 
remembering, reading, or in attention?  Have you noticed whether you have 
changed your way of behaving? How do you cope/manage with this? How is 
your mood? Do you receive medical treatment for depression?  Do you feel 
depressed? 
 
How are everyday life, work, 
network and support 
experienced? 
Are there any changes in 
lifestyle? 
Can you describe a typical day? Has it changed from earlier? What do you 
usually do in your spare time? Do you/can you enjoy yourself now? How 
would you describe your network? Do you have children? How are they 
affected? What attitudes / reactions have you experienced to your disease? 
How is your working situation? Have you changed anything in the way you 
live your life (e.g. diet, sleep quality, exercise, everyday activities,  social 
contacts) 
 
How does the patient 
experience the communication 
and information with the health 
professionals? 
What have the health professionals told you about your disease? 
What do you think about that information? Do you lack any information? 
Have you looked for information - of what kind and where? How do you think 
about the way the health professionals address you?  
 
Does the patient experience 
challenges during everyday 
activities? What are the needs 
for rehabilitation? 
Is there anything you find difficult to do? What is your need for rehabilitation? 
Do you have any experience with rehabilitation services, at hospitals or 
within the municipality? 
Is the patient motivated to meet 
her/his needs? Any 
preferences?  
What would be the best thing that anyone could do for you these days? 
Do you need any advice on how to handle your situation/condition/symptoms 
or everyday activities? Are you getting the support you need from the family / 
hospital / general practitioner? 
What are the preferences of the 
patient in relation to support and 
rehabilitation & palliation? 
 
Can you imagine being physically active now, and how do you prefer to be 
active? 
How many hours a week are you physically active now? 
Can you imagine accepting psychological support to handle your situation? 
Can you imagine getting help to exercise your memory and attention?  
What do you do to help yourself? Would you like to participate in physical 
exercise, cognitive training and/or psychosocial support? (think about 
preferences, type, location, frequency, duration, supervised or not 
supervised). What you are hoping for? Have you ever discussed the notion of 
hope with anyone? Have you been introduced for palliative care? 
 
Does the patient seek help from 
alternative therapy as a 
supplement to standard 
treatment? 
 
Have you considered any alternative treatment to relieve your 
situation/condition?  Please tell me about your considerations. Have you 
discussed this with someone?  
Are there financial worries and 
how important are they? 
 
Are you worried about your financial situation? 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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How does the patient prioritize 
her/his needs? 
Is the patient offered help and 
by whom? 
What needs are the most important for you to be met? Have you done 
anything to solve an unmet need? Do you have suggestions to how we could 
improve the situation/condition for future patients? Is there any advice you 
would give other patients being diagnosed with this type of brain tumor? Is 
there anything else you would like to tell me/or ask me about? 
 
Table 2 Interview topics for caregivers 
Research questions 
Examples of interview questions 
How did you experience the 
period between the first 
symptoms and the 
operation? 
How did you find out that X was sick? 
Describe what you observed, what happened and how you did experience that 
period? How was it to be a caregiver while X was admitted to hospital? What has 
happened since the last interview? 
 
 
Does the caregiver 
experience the patient has 
any symptoms/side effects, 
what are the consequences 
and how are they managed? 
How would you describe what X experiences these days? Do you observe any 
symptoms/side effects? Does it have any effect on the way you live your life? Is 
there anything that has helped you to manage X´s symptoms / side effects?  
Have you observed any difficulties in remembering, reading or attending for X? 
Has he/she changed personality/ way of behaving? How does that affect you?  
Have you ever thought that brain cancer differs from other types of cancer? 
Please tell me about this.  
How is everyday life, network 
and support? 
What norms and attitudes do 
the caregivers experience? 
Are there any changes in 
behaviour? 
Can you describe a typical day? Has that changed from earlier? What do you 
usually do during your spare time? Do you enjoy yourself now? Are there family / 
friends that have special meaning to you after X got sick? How? Do you have 
children? How are they affected? How would you describe your network? What 
attitudes / reactions to the disease, do you meet? 
How is your working situation right now? Have you changed anything in the way 
you live your life (e.g. diet, every day activities)? 
 
How does the caregiver 
experience the 
communication and 
information with the health 
professionals? 
What have the health professionals told you about X´s disease? 
Did you receive the right amount of information? How did you find the written 
information? Do you lack any information? Have you looked for information, of 
what kind and where?  How do you find the way the health professionals address 
you? 
 
Does the caregiver 
experience any challenges in 
the physical environment? 
What are the needs of 
rehabilitation? 
 
Do you experience practical problems in your life after X became diseased? Have 
you taken on another role since X became sick? How does it affect you? 
 
Is the caregiver motivated to 
meet her/his own needs?  
Any preferences? 
 
What would be the best thing someone can do for you right now? Do you need 
any advice on how to handle your situation? Are you getting the support you need 
from family / hospital / general practitioner? What does hop mean to you? Have 
you discussed this with anyone? Is this a stressful period for you? Do you 
experience any symptoms, physical problems? Have you received help to 
manage your changed responsibilities? Have you been involved in decisions 
regarding X´s treatment plan? 
 
What are the preferences of 
the caregivers in relation to 
support and rehabilitation & 
palliation? 
 
What do you do to help yourself (physical, social and psychological activities)? 
Would you like to participate in a support group/information group? Think about 
preferences, type, location, frequency, duration, supervised or not supervised 
support. Have you been introduced to palliative care? 
 
Does the caregiver seek help 
from alternative methods as 
a supplement to standard 
treatment? 
 
Have you considered any alternative treatment to relieve your or X´s 
situation/condition?  

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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Are there financial worries 
and how important are they? 
Are you worried about your financial situation now that X is sick? 
How does the caregiver 
prioritize her/his own needs? 
 
 
What needs are most important for you to be meet? Have you done anything to 
solve an unmet need? Do you have suggestions on how we could improve the 
situation/condition in the future for caregivers and for patients with a brain tumor? 
Is there any advice you would give to other caregivers?  Is there anything else 
you would like to tell me/or ask me about? 
 
Quantitative Data 
Information about socio-economic conditions, disease and treatment variables will be 
obtained by the investigator at baseline. Disease, treatment and clinical variables will be 
collected including the WHO performance scale (PS) which will be obtained by medical 
chart review. The self-reported questionnaires (quantitative data) are viewed as a useful 
supplemental data source, and embrace the topics as distress, anxiety and depressive 
symptoms: 
• Anxiety/depression – The Hospital Anxiety and Depression Scale (HADS)  
• HRQOL - The Functional Assessment of Cancer Therapy, General and Brain 
(FACT-G and FACT-Br)  
• Physical Activity - Questionnaire on leisure time physical activity level 
The qualitative and quantitative data will be integrated during the interpretation and 
findings will draw inferences using both approaches. 
 
Theoretical Framework 
The qualitative and quantitative research components represent different paradigmatic 
traditions including diverse ontological, epistemological and methodological assumptions. 
However, these paradigms are not necessarily incompatible (39). This study applied a 
pragmatic paradigm, reflecting a pluralistic view using both inductive and deductive 
reasoning. Applying a qualitative perspective, the present interviews seek to capture the 
subjective experiences of the study participants related to their life situation.  
 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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Ethical issues 
This study poses no serious ethical problems. The study is registered at The Research 
Ethics Committees at the Regional capital (file No. xxx) and  the Danish Data Protection 
Agency (file No. xxx) and carried out in accordance with the Declaration of Helsinki (40). 
Written consent will be obtained from each participant, including permission to record the 
interviews and to use anonymized quotes in future presentations. Participants will not be 
identifiable and the authors will disseminate the findings in peer reviewed publications and 
at relevant conferences. 
Data collection  
This study involves individual semi-structured telephone interviews with LTS of HGG and 
their caregivers. Socio-economic conditions, PS, disease and treatment variables are 
obtained from the medical records. Participants receive a questionnaire by mail with 
written instructions on how to complete and return their responses in an enclosed, 
addressed envelope.   
 
Analysis 
The semi-structured interviews will be recorded and transcribed in full length by either the 
interviewer or a research assistant. Interview data will be transferred to NVivo 10 software 
program(41). A thematic analysis will be conducted for the analysis of the semi-structured 
interviews. Thematic analysis is a basic method for qualitative analysis as it identifies, 
analyzes and reports themes and patterns within data(42). The findings will be presented 
in themes and subthemes. A theme is an expression or context being defined as important 
by the researchers. In this study a theme is not necessarily dependent on quantifiable 
measures, but rather captures an important meaning in relation to the research questions 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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and aims(42). Data from the interviews are descriptive in nature and reflect the subjective 
experience of the life situation of patients with HGG and their caregivers. The steps for 
thematic analysis are inspired by Braun and Clarke and as follows(42); Step 1) Data are 
transcribed immediately after an interview by the investigator or a research assistant. 
Transcriptions are read several times until the investigators are familiar with the depth and 
extent of the content. This process guides the investigators to the next level of analysis. 
Step 2) The text is read and divided into units of meanings, which are identified by the 
investigators. Some meaning units are sentences, others a whole paragraph. In this 
process data are coded in order to organize them into meaningful groups. This process 
assures that the whole dataset is systematically worked through by the investigators. Step 
3) Then, the codes are analyzed in order to consider if different codes can be combined 
into mutual themes. This three step process will result in a collection of themes and sub-
themes.  
 
Statistical analysis 
The KPS, the HADS sub-scales, the FACT-Br sub-scales and the responses to the ordinal 
items of the leisure time physical activity scale were analysed separately. Socio-economic 
information and data from questionnaires will be entered into a database. The 
questionnaires will be analyzed according to their manuals. Categorical variables are 
reported as frequencies and percentages, while continuous variables are reported as 
mean and standard deviations (s.d.) using a significance level of p\0.05. HADS and FACT-
Br data refer to the normative values. The statistical analysis was performed with SAS 
statistical software, version 9.3. 

Long-term Survivors of HGG – Study Protocol 20 august 2016 
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Perspectives 
This study will add new evidence to the existing knowledge in regard to the needs and 
preferences of the LTS and their caregivers and could be incorporated into future clinical 
guidelines for rehabilitation and supportive care. Discussion of implication for clinical 
practice will be included in future publications. 
 
Publication plan 
Patient and caregiver perspective on long-term survivorship of HGG – a mixed methods 
study  
 
 
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