Improving Quality of Life and Function for Older Cancer Patients Receiving Radiotherapy. Part IC: A Prospective Observational Study
Conditions: Elderly, Cancer, Radiotherapy Side Effect
Sponsor: Sykehuset Innlandet HF

 
 
0 
 
 
COVER PAGE 
 
Title:  Improving outcomes for older cancer patients receiving 
external beam radiotherapy (EBRT): Developing and testing a 
geriatric assessment with management intervention. Part 1: A 
prospective observational study 
 
NCT03071640 
 
Date: June 9th 2021 (overall document) 
 
Dates of protocol, revisions and analysis plans are to be found on the next page 
 
 
 

 
 
1 
 
Title 
Improving outcomes for older cancer patients receiving external beam 
radiotherapy (EBRT): Developing and testing a geriatric assessment with 
management intervention. 
Part 1: A prospective observational study - NCT03071640  
 
Translation of original protocol dated 31.10.16 with minor revision 02.01.17 and 18.04.17, 
approved by the Norwegian Regional Committee for Medical and Health Research - South East. 
Revisions made 02.01.17 are marked in magenta; revisions mage 18.04.17 are marked in yellow. 
Introduction, background and some other paragraphs have been shortened, but all details 
regarding design, methods and study conduct are presented.  
A new amendment (attached) was made prior to analyses and was approved by the Norwegian 
Regional Committee for Medical and Health Research - South East on the 09.06.2021 
Detailed plans for the analyses (dated 26.05.20, 14.12.20 and 18.05.21) for the planned three first 
papers, respectively, are presented in Appendices 1-3. 
 
Project leader:  
 Marit S Jordhøy, senior consultant, MD,  professor, the Cancer Unit, Innlandet Hospital 
Trust Hamar and Institute of Clinical Medicine, University of Oslo  
Co-leader:  
 Øyvind Kirkevold, professor, Faculty of Health, Care and Nursing, NTNU Gjøvik and The 
Research Centre for Old Age Psychiatry (AFS), Innlandet Hospital Trust 
For the remaining representatives of the scientific project group, please see protocol page 21. 
 
 

 
 
2 
 
Content 
Title ................................................................................................................................................. 1 
Introduction ..................................................................................................................................... 4 
Background ..................................................................................................................................... 4 
Cancer in older adults ................................................................................................................. 4 
Geriatric assessment.................................................................................................................... 5 
Radiotherapy ............................................................................................................................... 5 
Frailty .......................................................................................................................................... 6 
Geriatric screening tools: The Edmonton Frail Scale ................................................................. 6 
Inflammation, frailty and cancer ................................................................................................. 7 
Loss of muscle mass in frailty and cancer .................................................................................. 7 
GA in the municipal health services ........................................................................................... 7 
Study aims ....................................................................................................................................... 7 
Definitions: adverse events and outcomes .................................................................................. 8 
Detailed aims and hypotheses ..................................................................................................... 8 
Primary aims and hypotheses.................................................................................................. 8 
Secondary aims and hypotheses .............................................................................................. 8 
Methods........................................................................................................................................... 8 
Design and setting ....................................................................................................................... 8 
Inclusion criteria ......................................................................................................................... 9 
Registrations, tests and forms ..................................................................................................... 9 
Overview over the study registration .................................................................................... 10 
Sociodemographic data ......................................................................................................... 11 
Medical data .......................................................................................................................... 11 
Use of municipal health services .......................................................................................... 12 
Geriatric assessment (GA) .................................................................................................... 12 
Questionnaires for self-report ............................................................................................... 13 
Feasibility of geriatric assessment in the municipal health services ..................................... 14 
Registry data ......................................................................................................................... 14 
Implementation ......................................................................................................................... 14 
Enrolment .............................................................................................................................. 14 
Follow up .............................................................................................................................. 15 

 
 
3 
 
Actions due to GA findings .................................................................................................. 16 
Patient selection and sample size .............................................................................................. 17 
Strategy for the analyses ........................................................................................................... 17 
Data storage and protection .......................................................................................................... 18 
Ethics............................................................................................................................................. 19 
Organization .................................................................................................................................. 20 
User participation .......................................................................................................................... 21 
Project group and collaboration .................................................................................................... 21 
Financial support ........................................................................................................................... 22 
Time schedule ............................................................................................................................... 22 
References ..................................................................................................................................... 22 
Amendment 1-3 ............................................................................................................................ 27 
Amendment 4: Amendments prior to data analyses. .................................................................... 28 
 
Appendices 
1. Plan for the analyses first paper 
2. Plan for the analyses second paper 
3. Plan for the analyses third paper 
 
 

 
 
4 
 
Introduction 
This prospective observational study is part of a larger project. The main aim of the overall 
project is to develop and test an intervention to improve the quality of life (QoL) and function for 
older patients with cancer who receive radiotherapy and to reduce their need for everyday 
assistance or institutional care after treatment.  
Older patients with cancer > 65 years represent the majority of all new cancer cases.1 In general, 
older patients have poorer tolerance for cancer treatment than younger patients, and they often 
have other health issues that may influence the course and treatment of cancer. To offer older 
cancer patients good and appropriate treatment including targeted supportive measures is a great 
challenge.  
Older patients with cancer represent a heterogeneous group in terms of health status, and 
treatment tolerance may vary accordingly. A systematic assessment of the older patients' 
vulnerability is therefore crucial for treatment decisions. The best established method for 
assessing vulnerability in older adults is a geriatric assessment (GA).2 In older and/or frail 
patients with other illnesses than cancer, it is well documented that GA followed by targeted 
measures (Geriatric Assessment with Management = GAM) improves survival and function. 3-5 
Although international guidelines recommend  using GA for the management of older patients 
with cancer,6-10 this is still not routinely implemented into clinical oncological practice, and the 
benefits of GAM interventions for older patients with cancer are scarcely documented.  
Radiotherapy (RT) is a main modality in cancer treatment. However, during or after RT, many 
patients experience deterioration of function and QoL. Our main hypothesis is that an 
intervention based on GAM principles will have a positive impact on these outcomes in older 
patients receiving RT. To be efficient, however, we postulate that a GAM intervention must be 
carried out before, during and after RT, and that it has to be targeted towards problems and needs 
that affect outcomes of treatment. Based on the organization of Norwegian public health care, 
this means that parts of the intervention must be carried out by the municipal health services 
(before and after RT), and that co-operation between the specialist and municipal health service 
is necessary. Furthermore, it would be crucial to know, which problems and needs are most 
likely to affect survival, function and QoL, and thereby which patients are at highest risk of 
deterioration after RT and need most attention.  
The knowledge base to develop, implement, test and evaluate such an invention is, however, 
scarce. The aim of the present prospective, observational study, is therefore to identify older 
patients receiving RT who are at risk of functional impairment, QoL deterioration and increased 
needs for health care services during and after RT, describe the prevalence of impairments that 
can be uncovered by GA, and investigate their impact on treatment outcomes and complications. 
We will also test the feasibility of GA in the municipal health services and validate a geriatric 
screening instrument for frailty. 
 
Background 
Cancer in older adults 
Older patients represent a major proportion of the cancer population.1 By the time of diagnosis, 
approximately 50% of all cancer patients are 70 years or older,11 and due to an aging population, 

 
 
5 
 
the absolute number of older cancer patients is rapidly increasing.1 Providing appropriate 
treatment to these patients represents a major challenge to our health services.6 Older age is 
followed by reduced physiological and functional reserves and increased incidence of co-existing 
health problems. In comparison to their younger counterparts, older cancer patients have more 
complex care needs, are more vulnerable and have reduced tolerance to treatment.12 Following 
cancer therapy, older patients have higher mortality and morbidity, including higher risk of 
geriatric events (e.g delirium, falls and fractures).13-17 This cannot be attributed to chronological 
age alone. Comorbidity and functional and cognitive impairments, which vary considerably 
between individuals of similar age, are important contributing factors.17,18 To avoid adverse 
outcomes that come at high personal and societal costs, it is necessary to assess the older 
patient’s vulnerability and co-existing health problems, and to provide treatment, supportive care 
and rehabilitation accordingly. Presently no such assessments are standardised and 
systematically applied in Norwegian cancer care. 
 
Geriatric assessment 
Geriatric assessment (GA) addresses problems that are frequent in older age,10,19 and includes 
assessment of comorbidity, medications, physical-, cognitive- and emotional function, nutritional 
status and social network. It is currently the most established method to identify older patients’ 
vulnerability.2 GA with management (GAM) refers to assessments followed by adequate 
management of identified vulnerabilities. GA and GAM performed as a comprehensive, multi-
professional approach has well-documented success in detecting relevant problems, maintaining 
autonomy, reducing the need for residential care, and improving mobility, cognitive function and 
survival in older patients with non-malignant diseases.3,4,20 Thus, during the last decades, GA has 
been adapted for cancer care. Using well-established geriatric assessment tools or more simple 
screening instruments, mounting evidence shows that GA may identify remediable problems, 
substantially affect oncological treatment decisions, and predict survival or adverse events from 
chemotherapy and cancer surgery.18,21,22 Despite this, and strong recommendations from current 
guidelines and proposed models for care,6,10,12,23 GA remains to be integrated into common 
oncology practice.7 It has, however, been found feasible in teaching hospital centres and 
community cancer clinics.24,25 All GA domains cover problems that may negatively affect 
outcomes of cancer and cancer treatment,19,26-30 but that may also be prevented, alleviated or 
improved. Treatment of comorbidities may be optimised and inappropriately described 
medications withdrawn.19,27 Rehabilitation, exercise and nutritional counselling may improve 
physical and nutritional deficits.31,32 Depression can be treated, and if recognized, actions can be 
taken to avoid deterioration of cognitive impairments.19 GAM interventions are therefore 
assumed to optimise treatment and care for older cancer patients.7 Evidence for the potential 
benefits is lacking,7 but a recent study suggests that such interventions may improve tolerance 
for chemotherapy.33 
 
Radiotherapy 
Radiotherapy is a main treatment modality in cancer, and external beam radiation (EBRT) is the 
most common approach. EBRT may be used with curative or palliative intent. Short and long 
term side effects occur in both settings. These may be local, i.e. related to the involved organ, or 
general, e.g. fatigue and physical deterioration.8,34 Curative EBRT is conventionally given in 

 
 
6 
 
higher total doses over a longer period of time, and has more frequent side effects compared to 
palliative treatment. Several EBRT studies have included, or specifically targeted older 
patients.8,9 Results are inconsistent, but indicate that benefits are equal to younger patients.8 
Higher toxicity rates have been noted.9 Older patients are, however, underrepresented in clinical 
trials,35 and those participating are likely to be highly selected.8 Furthermore, studies on EBRT 
rarely include assessments of problems relevant for older patients, e.g. cognitive and functional 
deficits, and outcomes such as quality of life (QoL) and functioning are either lacking or poorly 
assessed.34,36,37 A high incidence of geriatric problems in the older EBRT population is suggested 
by two smaller studies on head and neck cancer, identifying 49% (n = 35) 38 and up to 75% (n= 
100)39,40 of the patients as vulnerable. In comparison to fit patients, those who were vulnerable 
had poorer survival and QoL.39,40 To the best of our knowledge, these are the only studies 
hitherto published on GA in EBRT patients. No studies on GAM for older EBRT patients have 
been reported.7 
 
Frailty  
Frailty is widely recognized as a syndrome of increased vulnerability to adverse changes in 
health status.2 It is strongly associated with increased mortality and predisposes for a rapid 
deterioration of health status or functioning when exposed to stress factors like e.g. cancer or 
cancer treatment.2. There is, however, no general agreement on how frailty should be identified. 
Different approaches and indicators have been suggested and tested,41 and in research, Fried’s 
frailty index has been the most commonly used.42 In clinical practice, however, GA is the best 
established method.2 
In recent years, several studies have been conducted to investigate the occurrence of frailty in 
older patients with cancer. A recent review concluded that many of these studies are small and 
varying methods have been used for frailty classification, GA being the most common.43 Median 
prevalence of frailty is reportedly around 40%. 43 None of the referred studies investigated the 
occurrence of frailty in older patients referred for RT in particular. 
 
Geriatric screening tools: The Edmonton Frail Scale 
GA can be both time- and resource consuming, and because of this, several screening 
instruments have been developed, primarily to identify patients who need a full GA. The most 
frequently used tools are VES-13 and G8.44,45 Neither these nor other tested tools are found 
optimal in terms of sensitivity and specificity. 44,45 However, VES-13 and G8 in particular, are 
those most strongly recommended by the International Society of Geriatric Oncology (SIOG).10 
The Edmonton Frail Scale (EFS) is a screening tool developed for use by clinicians without 
special training in GA.83 46 Unlike VES-13, mainly focusing on functioning and G8, having a 
focus on nutritional status, EFS is a broader tool that also includes testing of cognitive function 
(clock test) and physical function (TUG). It is easy and quick to use, and therefore relevant to 
test in older patients with cancer.  

 
 
7 
 
 
Inflammation, frailty and cancer 
The etiology of frailty is not fully clarified, but several studies have linked frailty to increased 
levels of pro-inflammatory cytokines and elevated levels of C-reactive protein (CRP).2,47 Lower 
levels of serum-albumin (s-alb), higher numbers of neutrophile white blood cells and lower 
numbers of lymphocytes have also been reported.47,48 Furthermore, the association between 
systemic inflammation and cancer is well-known49. The prognostic impact of an index based on 
CRP and s-alb (Glasgow Prognostic Score = GPS) has been confirmed in several larger studies 
of patients with different types of cancer.50  Few studies have investigated whether the GPS may 
be used to identify frailty in an oncology setting. Preliminary data from an earlier study by our 
research group indicates a strong association between higher GPS scores and frailty. Since CRP 
and s-alb are routinely assessed during treatment and follow up of patients with cancer, further 
investigations on the utility of GPS in identifying frailty are relevant.  
 
Loss of muscle mass in frailty and cancer 
Severe loss of muscle mass may occur due to aging, but may also be a result of diseases, 
including cancer.30,51,52 In oncology settings, the phenomenon has often been referred to as 
sarcopenia,53 whereas in geriatric medicine, there is a broad agreement that this term should be 
used for severe muscle loss in combination with either reduced muscle strength or reduced 
physical function.52 In older adults with non-malignant illnesses, severe loss of muscle mass is 
associated with frailty, physical deterioration, falls, hospital admissions and increased 
mortality.54,55 In patients with cancer, there is evidence that loss of muscle mass is common and 
associated with poorer survival and increased toxicity of systemic cancer treatment.56,57 Thus, in 
older patients with cancer, loss of muscle mass may have several causes, but it seems relevant to 
assume that assessment of muscle mass would contribute to determine the patient’s vulnerability 
and risk of adverse treatment effects. Whether this is the case for older patients receiving EBRT 
has, as far as we know, not been investigated. 
Loss of muscle mass may also be related to an active inflammatory response.58 Neither the 
underlying mechanisms nor the correlation between clinical frailty, muscle loss and active 
inflammation is fully clarified.  
 
GA in the municipal health services  
GA for older cancer patients have been tested and found feasible both in larger university 
hospital based- and smaller oncological clinics.24,25 Whether such an assessment is feasible in the 
municipal health services is unknown. 
 
Study aims 
The overarching aim is to generate knowledge that may provide a basis for developing a targeted 
and feasible intervention to prevent adverse events during and after curative and palliative EBRT 
in patients > 65 years. 

 
 
8 
 
Definitions: adverse events and outcomes 
Adverse events are defined as reduction in QoL, physical deterioration, increased need for help 
in daily life activities and/or need for residential care.  
Primary outcomes are global QoL and physical function as measured by the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC 
QLQ-C30).79  
Secondary outcomes are the ability to maintain everyday activities as measured by the 
Nottingham Extended Activities of Daily Living (NEADL), hospital- and nursing home 
admittance.  
Detailed aims and hypotheses: 
Primary aims and hypotheses 
1. To identify patients receiving EBRT > 65 years at risk of adverse events on the defined 
outcomes and to evaluate what characterizes these patients. 
 Our hypothesis is that patients who by GA may be classified as frail will have 
increased risk of adverse events as defined compared to patients who are classified as 
non-frail, regardless of cancer type, stage, and radiotherapy procedure (localisation, 
dose, field size) 
2. To test the feasibility of GA in the municipal health services 
Secondary aims and hypotheses:  
1. To describe the prevalence of problems uncovered by GA in older patients > 65 years 
before and after EBRT, and investigate the association between specific GA domains and 
adverse events.  
 Our hypothesis is that severe comorbidity, inadequate medication, malnutrition, 
impaired physical and cognitive functioning are factors that increase the risk of 
adverse events. 
2. Validate the Edmonton Frail Scale (EFS) as a screening instrument to identify frail 
patients and patients at risk of adverse events 
3. Evaluate the potential usefulness of GA carried out in the municipal health services, for 
older patients > receiving radiotherapy 
 
Methods 
Design and setting 
The study is a prospective observational study emerging from the Radiotherapy Unit and Unit of 
Geriatric Medicine, Innlandet Hospital Trust (SI), Gjøvik and Centre for Old Age Psychiatry 
Research (AFS), SI. It will be carried out in collaboration with the municipal health services in 
the hospital's recruitment area. All municipalities in Hedmark and Oppland will be invited to 
participate. The patients will be included at the Radiotherapy Unit, SI Gjøvik and followed up 
with self-report questionnaires. Patients from the partaking municipalities will also be followed 
by study specific registrations carried out by a municipal nurse after EBRT completion. 

 
 
9 
 
To achieve the necessary co-operation with the municipal health services, the project is linked to 
the existing “Network of nurses for the severely ill” in Hedmark and Oppland County. The 
network consists of nurses working with cancer patients, both in the municipalities and in 
hospital. Most municipalities have one or more nurses attached to the network, mainly referred to 
as “cancer contacts” or “contact nurses”.  The majority of these are trained oncology nurses or 
palliative care nurses. In addition, some hold a position referred to as “cancer coordinator”, an 
assignment partly financed by The Norwegian Cancer Society. Regardless of education and 
affiliation, all these nurses are experienced, committed and dedicated, and routinely participate in 
the care for most cancer patients in their area. In all partaking municipalities, the “cancer 
contact/contact nurse” from the network will also be the project’s contact nurse.  
 
Inclusion criteria 
 Age > 65 years 
 Referred to the Radiotherapy Unit, SI Gjøvik for palliative or curative radiotherapy 
 Resident in Oppland or Hedmark County 
 Histologically verified cancer 
 Fluent in Norwegian, both oral and written 
 Able to understand and answer questionnaires 
 Provide written consent 
 
Registrations, tests and forms 
Patients who fulfil the inclusion criteria will be followed with study specific assessments from 
start of EBRT to 16 weeks after completion of treatment. With respect to survival, they will be 
followed for two years. The planned registrations include sociodemographic and medical data, 
use of municipal health care services, GAs and self-report questionnaires including physical 
function and QoL (primary outcomes) and need for assistance in daily living (secondary 
outcome). The registrations will be performed at start and end of EBRT, then 2, 8, and 16 weeks 
later. 
During follow up after EBRT, the GA will be performed by the municipal “cancer nurse/contact 
nurse” (the local nurse attached to the “Network of nurses for the severely ill”, see above), or 
another dedicated nurse in the patient`s municipality. Information that is relevant to evaluate the 
feasibility and usefulness of a GA performed by municipal home care nurses will be collected.  
The table on the next page gives an overview over the planned registrations. 
We will also collect information from the patient's hospital records (e.g. hospital admissions), the 
municipal health care services, The Norwegian Patient Registry, The Norwegian Cancer registry 
and the Norwegian Cause of Death Registry as described in detail below.  
 

 
 
10 
 
Overview over the study registration 
 
*Pasients receiving =< 10 radiation fractions; ** Patients receiving more than 10 fractions; *** Addition to the questionnaire to patients from 
municipalities not participating with follow-up GA registrations. 
 
 
A. Sociodemographic and medical data, use of health care services. Green marking: performed by project nurse. Marked red: performed by a nurse in 
the municipal health care service 
Domain 
Prior to 
EBRT 
Baseline 
At completion 
EBRT-1* 
At completion  
EBRT-1** 
weeks after 
EBRT 
Sociodemographic data 
x 
 
 
2 
8 
16 
Medical data, including former cancer treatment and planned EBRT regimen 
x 
 
 
 
 
 
Medical data, including actually received EBRT 
 
x 
x 
 
 
 
Use of home care services 
x 
x 
x 
x 
x 
x 
Medical data, including ongoing cancer treatment, hospital and nursing home admissions.  
 
 
 
x 
x 
x 
ECOG performance status.  
x 
x 
x 
 
 
 
Height (only baseline) and weight.  
x 
x 
x 
x 
x 
x 
 
B. geriatric assessment  (GA). Green: performed by project nurse, red: performed by municipal cancer contact nurse 
Domain 
Method/instrument 
 
 
 
2 
8 
16 
GA domain 
 
 
 
 
 
 
 
 
Comorbidity  
Charlson Comorbidity Index 
x 
 
 
 
 
 
 
Polypharmacy 
Regular medications, ATC codes 
x 
x 
x 
x 
x 
x 
 
Physical function 
Timed up and go (TUG),  
x 
 
x 
x 
x 
x 
 
 
Number of falls 
x 
 
 
x 
x 
x 
 
 
Barthel index 
x 
 
x 
x 
x 
x 
 
Nutrtional status 
Weight loss, –MNA-SF 
x 
only weight 
x 
x 
x 
x 
 
Cognition 
Montreal Cognitive Assessment (MoCA test) 
x 
 
x 
 
x 
x 
 
Depression 
Geriatric Depression Scale (GDS) 
x 
 
x 
 
x 
x 
 
 
 
 
 
 
 
 
Frailty screening 
The Edmonton Frail Scale (EFS) 
x 
 
x 
x 
x 
x 
 
C. Patient reported outcomes  
QoL and symptoms  
EORTC QLQ-C30 
x 
x 
x 
x 
x 
x 
IADL 
NEADL 
x 
 
x 
x 
x 
x 
Activities 
Pleasurable activities 
x 
 
 
x 
x 
x 
D. GA – feasibility 
Time spent, completion rate, benefits and inconvenience (patient/nurse) 
 
 
 
x 
x 
x 

 
 
11 
 
 
Sociodemographic data  
These will be registered at patient enrolment, and will include age, gender, education, civil 
status, residence (home/residential care/nursing home) and living conditions (alone, with spouse 
or cohabitant +/- children, or others), number of children, number of children living in the same 
municipality, and smoking status. The patient will also be asked if his/her spouse/cohabitant 
(when existent) is fit and independent or in need of assistance. A project nurse will register these 
data based on information from the patient. 
Medical data  
Baseline  
Based on information from the patient, the patient’s treating physician and hospital records, the 
project nurse will register: cancer diagnosis, date of diagnosis, disease stage, localization of 
metastases, former and current cancer treatment, planned EBRT regimen (dosage, area and 
treatment target) and ECOG performance status. Diagnostic CT scans of thorax/abdomen that 
have been taken within 5 weeks prior to start of EBRT will be collected for analysis of body 
composition. 
Results of routine blood samples  (haemoglobin, white blood cell counts with differentials, 
creatinine, electrolytes, s-alb, liver function tests and CRP) taken within two weeks prior to 
EBRT will be registered. If the patient has not taken these blood samples within the last two 
weeks, he/she will be asked to so at enrolment. 
At completion of EBRT  
At this point the following will be recorded: administered radiation dose, causes of early 
treatment withdrawal (if relevant), any other cancer treatment that have been administered 
simultaneously with EBRT, plans for further cancer treatment, admission to hospital or patients’ 
hotel during treatment, residence at the end of treatment (home, nursing home or rehabilitation 
institution), ECOG status and weight. The information will obtained from the patient/hospital 
records and/or treating oncologist.  
During the follow-up 
Based on information from the patients’ general practitioner, treating oncologist and/or hospital 
records, the patients’ contact nurse in the municipality or the project nurse will prospectively 
register information on any supplementary or new cancer treatment, new comorbidities or 
hospital admissions. Detailed information on supplementary or new cancer treatment (new RT, 
medical cancer treatment or surgical interventions) will be collected from the hospital records.  
Data on hospital admissions (cause, duration and treatment received), diagnostic CT scans and 
relevant blood test will be obtained from the patients' hospital records. 
Data on survival will be obtained from the patients' hospital records and/or municipal health 
service, as well as from the Norwegian Cause of Death Registry for up to two years after 
completion of EBRT. 

 
 
12 
 
 
Use of municipal health services 
Information regarding the use of the home care services, nursing homes (number of admissions 
and their duration), and other health services from the municipalities will be registered at each 
assessment point, either by the project nurse, municipal contact nurse or by information given by 
the patient. 
 
Geriatric assessment (GA) 
GA will be performed by using well-documented, validated tests and questionnaires.  
Comorbidity will be registered by Charlson Comorbidity Index (CCI), based on information 
from the hospital record, the treating oncologist, and potentially supplemented with information 
from the general practitioner and patient. CCI categorizes comorbid conditions based on the 
International Classification of Diseases (ICD). Each comorbidity category is weighted from 1-6 
based on adjusted risk for mortality, and the scores are summarized into a total score. Originally, 
the CCI consisted of 19 categories,59 which has later been changed to 17.60 The list of specific 
ICD codes used in the categorization and the original weighting of scores have also been 
modified.61,62,63 
Medication: The project nurse will register all regular medications with name, daily dosage and 
ATC code in accordance with information from the patient/general practitioner/homecare 
nurse/hospital records. The registration will include inhalations, cremes/ointments, vitamins and 
eyedrops.  
Physical functioning will be assessed by: 
 Timed Up and Go (TUG),64 which assesses the time it takes to stand up from a chair, 
walk 3 meters, turn, walk back and sit down again. 
 Barthel ADL-indeks65 which assesses the ability to perform basic activities of daily 
living (ADL). The activities include eating, personal hygiene, getting dressed and 
undressed, bowel- and bladder control, using the toilet and mobility. The assessment 
will be done by interview. 
 Number of falls: when and where they occurred (outside or inside) and if they caused 
any injuries. 
Cognitive function will be assessed by the Montreal Cognitive Assessment (MoCA) test.66 The 
test assesses visuospatial abilities, executive functioning, attention, concentration, memory, 
language and orientation, and takes about 5-10 minutes to complete. The scores range from 0 
(worse) to 30 (best/normal) 
Depression and symptoms of depression will be assessed by the Geriatric Depression Scale 
(GDS).67 Originally, the scale consisted of 30 questions.  A modified version with 15 questions 
have been developed, and validated.68,69 This is available in a Norwegian version,70 which will 
be used in this study. GDS-15 items are answered yes/no, and the scale is scored from 0-15. 

 
 
13 
 
Score > 4 is considered an indication for depression. 71 GDS is suitable for self-reporting, but 
administration by interview has also been recommended. 72 
Nutrional status will be registered  by height, weight, body mass index (BMI) (weight/height x 
height), and the Mini Nutrional Assessment Short Form (MNA SF).73 The form has six items: 
loss of appetite, weight loss, mobility, psychological stress/acute illness, occurrence of 
neuropsychological illness (dementia or depression) and body mass index. Each item is scored 
from 0-2 or 0-3, and the scores are summarized into a total score from 0-14. Scores 12-14 
indicate normal nutritional status, 8-11 risk of malnutrition and 0-7 indicate malnutrition.74 The 
registrations will be based on observation and information given by the patient. 
Edmonton Frail Scale (EFS) is a screening instrument developed for clinicians without special 
training in frailty assessment.46 EFS includes 9 areas: cognition, health, function, social support, 
number of medications, nutritional status, continence (bladder control), balance and mobility, 
and have 11 items that are scored from 0-1 or 0-2. Item scores are summarized into a total score 
ranging from 0 (fit) to 17 (most severe level of frailty).   
As an addition to the 11 items, we will register which of the activities mentioned in the item 
“how many of the following activities do you need help with……”), the patient is not able to 
perform independently. 
Fatigue will not be assessed as part of GA, but is included in the European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30), see 
below.  
 
Questionnaires for self-report 
The EORTC QLQ-C30 75 is a 30-item questionnaire developed for QoL assessment in cancer 
patients. It is widely used and thoroughly tested. The questionnaire includes scales for physical 
function (5 items), emotional function (4 items), role function (2 items), social function (2 
items), cognitive function (2 items) and global health/QoL (2 items). In addition, there are three 
symptom scales, i.e. nausea/vomiting (2 items), fatigue (3 items) and pain (2 items), and six 
single items assessing symptoms that are common in patients with cancer and the financial 
impact of the disease . Before analysis, scale/item scores are transformed into scales ranging 
from 0 to 100.  A change of 10 points or more on each scale/item is considered clinically 
significant.76  
Nottingham Extended Activities of Daily Living (NEADL)77 assesses functional status. It 
includes 20 items covering four main areas: mobility (6 items including use of transportation), 
eating/drinking/preparing food (5 items), household activities (5 items, including laundry, 
shopping, handling money) and leisure activities (6 items). Each item is answered on a 
categorical scale ranging from 0 (activity cannot be performed) to 3 (performs without help). 
Item scores are summarized into a scale ranging from 0 to 66. The smallest change considered to 
be of clinical relevance is between 2,4 and 6,1 points.78  
Pleasurable activities. The patient's participation in pleasurable activities will be registered with 
a short questionnaire (5 items) from the DemiNor study, a study from the Norwegian National 

 
 
14 
 
Advisory Unit on Ageing and Health and the Centre for Old Age Psychiatry Research. The 
purpose is that such knowledge may be useful for the development of rehabilitation 
interventions.  
 
Feasibility of geriatric assessment in the municipal health services 
 
We will register how many of the municipalities in Hedmark and Oppland that agrees to 
participate in the study. At each assessment point (2, 8 and 16 weeks after EBRT), the contact 
nurse in the partaking municipalities will register if GA was done or not (completely or partly), 
reasons for lack of completion, if the registrations were found useful or burdensome (for the 
patient and the nurse), and if any measures were undertaken based on GA findings.  
 
Registry data 
In addition to data retrieved from patients’ hospital records, we plan to retrieve data on hospital 
admissions during follow-up from the Norwegian Patient Registry (NPR). As described, 
information regarding cancer diagnosis and treatment, survival and death will be extracted from 
patient records, but we also plan to obtain data from the Norwegian Cancer Registry (cancer 
diagnosis, stage of disease and treatment) and The Norwegian Cancer Registry (date, place and 
cause of death) to ensure data quality. Survival data will contribute to identify patients with short 
life expectancy, who potentially may benefit more from purely palliative measures than from a 
GAM intervention. 
 
Implementation 
Enrolment 
A project nurse will have the daily responsibility for all data collection.  
All patients who are 65 years or older and have been referred to the Radiotherapy Unit, SI 
Gjøvik, will receive brief information about the study together with the letter summoning them 
to their first consultation. This consultation is usually meant for information and treatment 
planning (CT dose planning), whereas the treatment itself normally starts several days, 
sometimes weeks, later. Eligible patients will be identified at the first consultation. The treating 
oncologist will ensure that the inclusion criteria are fulfilled, and that the patient is capable of 
providing informed consent. The project nurse will present the study for the patient both orally 
and in writing. If the patient consents to participation, baseline registrations will be performed on 
the same day (i.e. if the EBRT is expected to start within one week), or in connection with start 
of treatment.  
Baseline registrations (i.e. the GA) includes a test of cognitive function (MoCA test). If the 
MoCA score is below 20 (possible dementia), the patients’ treating oncologist will be consulted 
to re-evaluate the patients’ capability to give informed consent before the baseline procedures are 
completed. However, since patients with mild to moderate dementia may also have sufficient 
capability to provide an informed consent, no definite MoCA score limit is set for 
inclusion/exclusion.   
Baseline registrations include a test of cognitive function (MoCA test). If the test gives reason to 
believe that  the patient has cognitive impairment (score < 18), and the project nurse (an 

 
 
15 
 
experienced cancer nurse), based both on the MoCA score and the conversation with the patient, 
finds reasons to question the patients capability to provide informed consent despite the 
oncologist’s former evaluation, a re-in collaboration with the treating oncologist will be 
performed before completing the baseline registrations.  If the MoCA score is < 16, the patient’s 
capability to provide informed consent will in any case be re-evaluated. However, since patients 
with mild to moderate dementia may also have sufficient capability to provide informed consent, 
no definite MoCA score limit is set for inclusion/exclusion.   
Emergency referrals to EBRT is not a defined exclusion criterion. Emergency patients are 
usually managed as inpatients and may be included if they meet the inclusion criteria. It is, 
however, a prerequisite that the treating oncologist do not consider the inclusion procedure too 
burdensome for the patient.  
In addition to ask for consent to all study procedures and data collection, the patients will be 
asked for permission to inform the project contact nurse in the patient's municipality about 
his/her study inclusion and the planned schedule of his/her follow up registrations.  
Non-included patients will be registered by age, gender, diagnosis and cause of exclusion (does 
not wish to participate/does not fulfil the inclusion criteria/is considered too ill/incapable of 
participation).   
 
Follow up 
The patients will be followed with study specific registrations for 16 weeks after completion of 
EBRT. As the length of the treatment period may vary from one day (single fraction) to 5-7 (8) 
weeks for some patients receiving curative treatment, the length of the period from baseline to 16 
weeks after treatment will also vary from 16 to 22-23 (24) weeks. With respect to survival, the 
patients will be followed for two years after completion of EBRT.  
 
At completion of EBRT 
At completion of EBRT, the project nurse will perform a repeated GA and hand out the 
scheduled self-report questionnaire. If the patient prefers to fill in the questionnaire at home, 
he/she will be given the questionnaire along with a pre-paid return envelope.  
Patients who have received less than six radiation fractions (about one week of treatment), will 
only fill in the questionnaire since a new GA after such a short period is likely to add little new 
information 
Patients who have received less than 10 radiation fractions (treatment duration two weeks or 
less), will only fill in the self-report questionnaire since a new GA after such a short period is 
likely to add little new information.  
 
Further follow-up 
The self-report questionnaires, scheduled at 2, 8 and 16 weeks after completion of EBRT, will be 
administered by post to all patients with a prepaid return envelope attached. If no answer is 
received within 2 weeks, a reminder will be sent. 

 
 
16 
 
Apart from this, the follow-up will vary somewhat depending on whether the health services in 
the patients' municipality have consented to participate with GA or not.  
1. For patients from non-consenting municipalities who does not have any contact with the 
municipal home care services, the project nurse will offer to contact them (or the 
municipal cancer contact nurse) by the end of EBRT. The purpose is to ensure that the 
patient receives a follow up according to the municipality’s routine.   
Moreover, for these patients, a few questions will be added to the self-report follow-up 
questionnaires. The patients will be asked if they have any questions or needs that makes 
a phone call from the project nurse or a cancer nurse at the Radiotherapy Unit warranted, 
and about their use of municipal health care services. If the information about the latter is 
lacking or incomplete, the project nurse will take contact with the municipality services 
directly.  
2. For patients from municipalities participating in the project with GA, the project nurse 
will inform the municipal cancer /contact nurse when the patients’ EBRT is completed. 
The contact nurse will get in touch with the patient to make an appointment for the next 
registration procedure, 2 weeks after completion of EBRT. The GA performed at this 
point will be limited to registration of medications, nutritional status, physical 
functioning (TUG, Barthel Index and falls) and the Edmonton Frail Scale. For the next 
registrations at 8 and 16 weeks, all parts of GA will be included except comorbidity. The 
contact nurse is encouraged to make the appointments for subsequent registrations in 
advance. All registrations will preferably take place at the patients’ current residence (at 
home or in a nursing home), but if the patient wishes to meet at another suitable place, 
this can be arranged. The patients should, however, not be summoned to any particular 
location (e.g. family physician’s or a nurses’ office) specifically for the registrations. 
After each registration, the nurse will fill in a special form to evaluate feasibility (see 
“Feasibility of a geriatric assessment in the municipal health services, page 14). She/he 
will also register any measures or interventions undertaken due to GA findings.  
 
Actions due to GA findings 
The study is an observational study, but if the GA uncovers problems or needs requiring 
management, actions should be undertaken in collaboration/consultation with the patient. No 
measure can, however, be initiated without the patient's consent. Furthermore, the information 
acquired during the GA cannot be passed on to the health professionals who normally take care 
of the patient without the patient’s informed consent. A general instruction has been attached to 
GA registration forms to ensure that this information reaches all contact nurses performing GA 
in the municipalities.  
GA findings indicating that actions are required may vary from patient to patient, dependent on 
established support, care and treatment from the involved health care services. Simple, general 
guidelines have been developed, stating when actions should be considered and/or undertaken.  
 

 
 
17 
 
Patient selection and sample size 
The Radiotherapy Unit, SI Gjøvik offers EBRT to patients with cancer from Oppland and 
Hedmark Counties (approximately 380 000 inhabitants) and treats about 700 patients each year. 
About 2/3 of these are 65 years or older. Palliative treatment represents about 60% of all 
treatment, and is offered regardless of cancer type. Curative treatment is administered only to 
patients with breast-, prostate-, lung- or skin cancer. Patients with other types of cancer in need 
of EBRT with curative intent, or patients who need stereotactic or internal radiotherapy are 
referred to Oslo University Hospital 
Sample size estimates: The prevalence and impact of problems uncovered by GA in older 
Norwegian patients receiving EBRT are not known. Neither is the frequency of the defined 
adverse outcomes. Thus, estimates of the sample size needed to reliably define characteristics of 
patients at risk for adverse outcomes cannot be made. Furthermore, our sample will be 
heterogeneous and several demographic, medical and GA characteristics will have to be taken 
into account.  
Based on these considerations, we will extend the inclusion period to one year and aim at 
including 325 patients. This cohort, we believe, will be a representative sample, large enough to 
ensure that all participating municipalities are represented for the evaluation of the feasibility of 
GA. To achieve 325 enrolled patients within one year, we presume that 70% of the patients 65 
years or older who are treated at the RTU will consent to participation.  
Our hypothesis is that patients, who are classified as frail, will have increased risk of 
deterioration in global QoL and physical functioning (PF), assessed by the corresponding 
EORTC QLQ-C30 scales ranging from 0-100. A difference of 10 points on these scales is 
considered a clinically significant difference.76 Based on the reported prevalence of frailty in 
studies of other cohorts of older patients with cancer,18,43 one may assume that about 40% will be 
frail and 60% non-frail. To detect a difference of 10 points in global QoL and PF between the 
two groups at 8 weeks follow up,  standard deviation (SD) = 30 (a conservative estimate), power 
80% and significance level 5%, 119 patients will be needed in the frail group and 178 patients in 
the non-frail group, in total 297 patients. To document a difference of 11 points, 247 patients are 
needed. Based on these estimates, and taking into account that some drop out will occur, we find 
that including 325 patients will be satisfactory. 
 
Strategy for the analyses 
Adverse events are defined as described under Study aims, page 7-8. The patients will be 
classified as frail or non-frail based on GA at baseline. Primary and secondary outcomes will be 
compared between the non-frail and frail using bivariate regression analyses. Since the study 
cohort will be heterogeneous and several factors most likely will affect the outcomes, we will 
also estimate multivariate regression models, adjusted for these factors. The most important 
factors will be type of cancer, stage of disease, gender and radiotherapy regimen. Time trend 
models will be estimated in order to assess the development in the primary outcomes for non-
frail/frail patients during the follow up period. We will also estimate bi- and multivariate 
regression models to assess the impact of each individual factor in GA (i.e. comorbidity, physical 
function, nutritional status) on the defined outcomes. Furthermore, we will use descriptive 
statistics to compare sociodemographic and medical data and GA findings between patients 
experiencing and not experiencing adverse events. 

 
 
18 
 
The sensitivity and specificity of EFS in identifying frail patients will be tested against the full 
GA. EFS ability to predict adverse events on the defined outcomes will be assessed with uni- and 
multivariate regression analysis, controlled for relevant co-variates (e.g. type of cancer, stage of 
disease, and radiotherapy regimen).  
To assess the feasibility of GA for the municipal health care service, we will partly lean on the 
RE-AIM Framework,79 and evaluate the proportion of consenting and participating 
municipalities and explore potential difference between them. We will also evaluate the number 
and completeness of the GAs that are actually performed in relation to those planned. For each 
assessment, the municipal contact nurse, who performs the assessment, will answer a short 
questionnaire addressing time spent, obstacles, facilitators, patients’ opinion on relevance and 
convenience, and actions taken due to identified problems. These data will be linked to the 
individual patients and thereby contribute to identify patients who may benefit the most from 
GA. For analyses, we will use descriptive statistics.   
Analysis of muscle mass and inflammation markers: Muscle mass will be quantified by 
analyses of diagnostic CT scans taken within five weeks prior to start of EBRT. The analyses 
will be performed with special soft-ware developed for this purpose (Slice-O-Matic software 
V4.3 - Tomovision, Montreal, QC, Canada).30,51,53,80 As an indicator of inflammation, we will use 
the Glasgow Prognostic Score (GPS) which is based on C-reactive protein (CRP) and serum-
albumin (s-alb) and is scored on a scale from 0 to 2 (0 = CRP < 10 + s-alb> 35, 1 = CRP> 10, 
any s-alb value, 2 = CRP > 10 + s-alb< 35). 50 The association between frailty defined by GA, 
GPS and muscle mass will be assessed using descriptive statistics and correlation analyses. 
Regression analyses will be used to assess the association with survival.  
 
Comparison with outcomes in a subsequent pilot study: The plan is that an intervention 
targeting patients at risk of adverse events will be developed based on the results from the 
present study, and that this intervention will be tested in a pilot study before embarking on a 
larger randomised trial. The pilot study will have a cluster-randomized design, randomising 
municipalities to either control or intervention to avoid that the same staff treats both control and 
intervention patients. In a smaller pilot study, a cluster-randomised design may results in an 
imbalance in characteristics between control and intervention patients. Although this may partly 
be adjusted for in the analyses, it may be relevant to draw comparisons to a matched control 
group from the present cohort. This potential use of study data is explicitly stated in the patient 
information and consent form.  
 
Data storage and protection 
Data storage and management are described in detail in the Norwegian protocol with the purpose 
of informing the Ethical Review Board and the Data Protection Officials. In short, data storage 
and use will follow Norwegian laws and regulations and be approved by both the Norwegian 
Ethical Review Board, Health Region South-East, and the Privacy Protection Official at 
Innlandet Hospital Trust before study start. According to Norwegian regulations, data sharing is 
not possible before data are anonymised, i.e. unless the patients are specifically informed through 
the patient information and consent form.  

 
 
19 
 
 
Ethics 
Study approval and data storage will be applied for to The Regional Committee for Medical 
Research Ethics, Health Region South-East (REK HSØ) and the Data Protection Official at 
Innlandet Hospital Trust before start of study. The study will be performed according to the rules 
of the Helsinki-declaration, and registered in the ClinicalTrials.gov database. Participation will not 
inflict upon the patients’ cancer treatment and will not imply any health risks or deviation from 
good clinical practice. The patients will receive treatment and care according to routine practice, 
and all participants will provide written informed consent.  
Besides the inconvenience of providing potential sensitive information and spending time to fill 
in questionnaires and to perform the study test, study participation inflicts little burden on the 
patients. The registrations are kept as simple as possible, and represent no health risks. Even so, 
certain ethical aspects are still relevant to discuss. Being an observational study, it is from a 
methodological point of view important that study participation and registrations inflict as little 
as possible upon the patients’ routine care. However, thorough evaluations like  GA will 
potentially uncover problems and needs that it will be ethically unacceptable not to act upon. As 
formerly stated, we have therefore prepared general guidelines for the project nurse and our 
contact nurses in the municipalities stating when actions should be considered or carried out 
(with patients’ informed consent). These actions and the undertaken measures will be registered, 
both to clarify the needs for GA in older patients with cancer receiving EBRT, and also in order 
to interpret the results.  
It is possible that the extra attention the structured assessments entails, may benefit the 
participating patient. Hence it might be seen as problematic that patients from non-participating 
municipalities do not receive the same follow up as those from municipalities agreeing to 
perform GA during follow-up.  We find, however, no reason to believe that these GA 
registrations will have a significant clinical impact. Firstly, all patients will be registered and 
tested in the same way prior to and at completion of EBRT. Secondly, there is currently no 
documentation indicating that GA without management provides significant benefits for the 
patients. On the contrary, a recently published study81of lung cancer patients randomized for GA 
or not did not report any impact of GA, except for a little less toxicity from chemotherapy. This 
latter finding may be explained by the fact that fewer patients in the GA group received such 
treatment. Thirdly, patients from non-participating municipalities will be given the opportunity 
to keep in touch with the project nurse or cancer nurse at the Radiotherapy Unit if they report any 
need for it through the questionnaire especially added for these patients. Overall, we believe that 
participating in this study will have the same impact on all patients.  
The knowledge generated by this study will be beneficial for future patients, and we find that the 
possible inconvenience for the participants is exceeded by the potential benefit for the 
participants and for the overall group of older patients with cancer receiving EBRT. 

 
 
20 
 
 
Organization 
The project is organized with a project leader, an assistant project leader, a scientific (main) and a 
local project group, a reference group, and user representatives. Participants and details appear in 
section “Project group and collaboration” below. The study will provide the basis for a doctoral 
thesis, completed by a PhD student, financed by the Research Department, Innlandet Hospital 
Trust and connected to The Research Centre for Old Age Psychiatry (AFS). AFS will also serve 
as the project office. 
A project nurse in a full-time position, financed by the Research Department, Innlandet hospital 
trust will be employed before the study starts in February 2017. He/she will be a professional 
cancer nurse and will have the daily responsibility for the data collection. Furthermore, he/she 
will be a key person in the collaboration with the municipal health services, and will have a co-
responsibility for training of the municipal contact nurses who will perform the follow-up GA 
registrations. The project nurse will continuously be available for the municipal health services 
for guidance, and will have all necessary access to academic expertise from local geriatrists, 
geriatric nurses, cancer nurses and oncologists, all represented in the scientific and the local 
project group. If the project nurse is intermittently absent (holidays etc.), the PhD student (a 
physician) will be responsible for patient inclusion, registrations and data collecting. The PhD 
student will receive the necessary training from the project nurse and participants in the project 
group.  
The study conduct will depend on a good collaboration with the municipal health services in 
Hedmark and Oppland counties. To achieve this, the project is linked to the existing “Network of 
nurses for the severely ill”, as formerly explained (page 9). Four nurses from this network have 
collaborated with the scientific project group in the study design (including the scheduled 
registrations), and will continue to participate in the further study conduct. There is also 
established a larger reference group comprising municipal cancer contact nurses and cancer 
coordinators. Before the study commences, a cancer contact nurse, preferably a cancer nurse, 
from each participating municipality will be assigned to the project and the reference group. 
Additionally, participants in the reference group from general practitioners (GPs) in the area 
arewarranted. To achieve this, the plan is to contact the local GPs union in the two counties.    
Participation in the study must be anchored to the health care management in each municipality. 
Thus, all 46 municipalities in Hedmark and Oppland have received written information about the 
study, and a final confirmation or rejection of their participation will be retrieved before study 
start.  
Future contact with the municipal health care service will be maintained through email, phone, 
video conferences, and established meeting points. For those nurses who will participate in GA 
registrations, meetings/seminars for training will be arranged. Participation will not be charged, 
and travel expenses will be covered.  
 

 
 
21 
 
User participation 
A group of four user representatives has been established. So far, they have participated in the 
planning of the study, and also evaluated and approved the scheduled registrations. These 
representatives will continue their collaboration throughout the study conduct, and will also 
participate in interpreting and dissemination of results.  
 
Project group and collaboration 
The project emerges from Innlandet Hospital Trust (SI) and will be performed in collaboration 
with the municipalities in Hedmark and Oppland counties and several internal and external 
partners, including the Norwegian University of Science and Technology (NTNU) Campus 
Gjøvik. Marit S Jordhøy (prof., MD, oncologist), SI will lead the project. Co-leader is Øyvind 
Kirkevold (prof, ass. research director), Faculty of Health, Care and Nursing, NTNU Gjøvik and 
The Research Centre for Old Age Psychiatry (AFS), SI.  
The scientific project group: Anne Hjelstuen (MD, PhD), Unit of Geriatric Medicine, SI Gjøvik 
contribuing with expertise in internal and geriatric medicine. Katharina Lederer (MD), leading 
radiation oncologist, The Radiotherapy Unit, SI Gjøvik contributing with expertise in radiation 
oncology. Sverre Bergh (MD, PhD, leader of research) and Lene Kirkhus (MD, PhD student), 
AFS, SI contributing with broad experience from large studies involving health resources, 
depression and dementia, and from the ongoing SI study on older cancer patients receiving 
chemotherapy, respectively. Aud Obstfelder (prof. leader of Centre for Care Research) and Øyvind 
Kirkevold (prof), The Faculty of Health, Care and Nursing, NTNU Gjøvik provide expertise on 
health organisation research, technology and quantitative methodology, and broad experience from 
research involving community health care, including large national and international cohort 
studies, respectively. The following additional members all contribute with expertise from their 
area of work, in which they all have long lasting clinical and research experience and are also 
frontline experts: Ingvild Saltvedt (geriatrician, PhD), Dept. of Geriatric Medicine (Head of Dept.), 
St Olav’s Hospital and Dept. of Neuroscience, NTNU; Bjørn Henning Grønberg (oncologist, 
PhD), Dept of Cancer Research and Molecular Medicine, NTNU and Clinic of Oncology, St. 
Olav’s Hospital; Line Oldervoll (prof., rehabilitation medicine), Dept. of Social Work and Health 
Science, NTNU and Norwegian Heart and Lung Patient Organization (NHL) (leader of research); 
Asta Bye (PhD, nutritionist) Oslo and Akershus University College (HiOA), Astrid Bergland (prof, 
PhD, physiotherapist) (HiOA) and Siri Rostoft (MD, PhD, geriatric oncology), Dept. of Geriatric 
Medicine, Oslo University Hospital. The project’s statistician is senior researcher, PhD, Jūratė 
Šaltytė Benth, University of Oslo and Akershus University Hospital.  
The local project group provides local clinical and organizational expertise, ensures the co-
operation with the involved health services and thereby the project implementation and conduct. 
The group includes a geriatrician and specialized geriatric nurse from the Unit of Geriatric 
Medicine, SI Gjøvik, a radiation technologist, RTU Gjøvik, a nutritionist, four cancer contact 
nurses representing SI, and Gjøvik, Stange and Valdres municipalities.  
International collaboration is established with the University of Alberta, Edmonton, Canada 
including the developer of the Edmonton Frail Scale, Darryl Rolfson (prof, geriatrician), Dept. of 
Geriatric Medicine. 

 
 
22 
 
User representatives: Our aim is to establish a group of 6 members (3 of each gender) > 65 years 
of age with experience from EBRT. Currently 4 members have been assigned from the local Breast 
Cancer Society and the local Prostate Society, respectively.  
Reference group: Presently the group includes 11 cancer nurses and cancer co-ordinators 
representing 16 municipalities. We are aiming at including the remaining cancer coordinators (6-
8) in the SI catchment area as well as representatives for the GPs.  
 
Financial support 
The study is fully financed by the Research Department at Innlandet Hospital Trust. No other 
financial partner is involved. 
Time schedule 
Start of enrolment is planned for February 2017 and will continue for 12 months or until the 
planned number of participants are included. The patients will be followed with study specific 
registrations for 16 weeks after the end of EBRT. Data on survival will be retrieved for up to 2 
years  after completion of EBRT.  Furthermore, a PhD student and a project nurse will be 
contracted from the time of study start.  
 
References 
 
1. Syse A VM, Aagnes B, Tretli S: Cancer incidence, prevalence and survival in an aging Norwegian 
population. Norsk epidemiologi 22:109-120, 2012 
2. Clegg A, Young J, Iliffe S, et al: Frailty in elderly people. Lancet 381:752-62, 2013 
3. Prestmo A, Hagen G, Sletvold O, et al: Comprehensive geriatric care for patients with hip fractures: 
a prospective, randomised, controlled trial. Lancet 385:1623-33, 2015 
4. Saltvedt I, Jordhoy M, Opdahl Mo ES, et al: Randomised trial of in-hospital geriatric intervention: 
impact on function and morale. Gerontology 52:223-30, 2006 
5. Ellis G, Whitehead MA, Robinson D, et al: Comprehensive geriatric assessment for older adults 
admitted to hospital: meta-analysis of randomised controlled trials. Bmj 343:d6553, 2011 
6.  (IOM) IoM: Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis.  
7. Magnuson A, Allore H, Cohen HJ, et al: Geriatric assessment with management in cancer care: 
Current evidence and potential mechanisms for future research. J Geriatr Oncol, 2016 
8. Bayman N, Alam N, Faivre-Finn C: Radiotherapy for lung cancer in the elderly. Lung Cancer 
68:129-36, 2010 
9. VanderWalde NA, Fleming M, Weiss J, et al: Treatment of older patients with head and neck 
cancer: a review. Oncologist 18:568-78, 2013 
10. O'Donovan A, Mohile SG, Leech M: Expert consensus panel guidelines on geriatric assessment in 
oncology. Eur J Cancer Care (Engl) 24:574-89, 2015 
11. The Norwegian Cancer Registry: Cancer in Norway 2014. 
http://www.kreftregisteret.no/no/Registrene/Kreftstatistikk/, The Norwegian Cancer registry, 
2015 
12. Wildiers H, Heeren P, Puts M, et al: International Society of Geriatric Oncology consensus on 
geriatric assessment in older patients with cancer. J Clin Oncol 32:2595-603, 2014 

 
 
23 
 
13. Lal A, Bhurgri Y, Rizvi N, et al: Factors influencing in-hospital length of stay and mortality in 
cancer patients suffering from febrile neutropenia. Asian Pac J Cancer Prev 9:303-8, 2008 
14. Chrischilles E, Delgado DJ, Stolshek BS, et al: Impact of age and colony-stimulating factor use on 
hospital length of stay for febrile neutropenia in CHOP-treated non-Hodgkin's lymphoma. Cancer 
Control 9:203-11, 2002 
15. Shayne M, Culakova E, Poniewierski MS, et al: Risk factors for in-hospital mortality and prolonged 
length of stay in older patients with solid tumor malignancies. J Geriatr Oncol 4:310-8, 2013 
16. Surgery for colorectal cancer in elderly patients: a systematic review. Colorectal Cancer 
Collaborative Group. Lancet 356:968-74, 2000 
17. Tan HJ, Saliba D, Kwan L, et al: Burden of Geriatric Events Among Older Adults Undergoing 
Major Cancer Surgery. J Clin Oncol 34:1231-8, 2016 
18. Kristjansson SR, Nesbakken A, Jordhoy MS, et al: Comprehensive geriatric assessment can predict 
complications in elderly patients after elective surgery for colorectal cancer: a prospective 
observational cohort study. Crit Rev Oncol Hematol 76:208-17, 2010 
19. Pal SK, Katheria V, Hurria A: Evaluating the older patient with cancer: understanding frailty and 
the geriatric assessment. CA Cancer J Clin 60:120-32, 2010 
20. Ellis G, Whitehead MA, O'Neill D, et al: Comprehensive geriatric assessment for older adults 
admitted to hospital. Cochrane Database Syst Rev:Cd006211, 2011 
21. Hamaker ME, Schiphorst AH, ten Bokkel Huinink D, et al: The effect of a geriatric evaluation on 
treatment decisions for older cancer patients--a systematic review. Acta Oncol 53:289-96, 2014 
22. Puts MT, Santos B, Hardt J, et al: An update on a systematic review of the use of geriatric 
assessment for older adults in oncology. Ann Oncol 25:307-15, 2014 
23. Hurria A, Wildes T, Blair SL, et al: Senior adult oncology, version 2.2014: clinical practice 
guidelines in oncology. J Natl Compr Canc Netw 12:82-126, 2014 
24. Hurria A, Gupta S, Zauderer M, et al: Developing a cancer-specific geriatric assessment: a 
feasibility study. Cancer 104:1998-2005, 2005 
25. Williams GR, Deal AM, Jolly TA, et al: Feasibility of geriatric assessment in community oncology 
clinics. J Geriatr Oncol 5:245-51, 2014 
26. Wedding U, Rohrig B, Klippstein A, et al: Age, severe comorbidity and functional impairment 
independently contribute to poor survival in cancer patients. J Cancer Res Clin Oncol 133:945-50, 
2007 
27. Scott IA, Hilmer SN, Reeve E, et al: Reducing inappropriate polypharmacy: the process of 
deprescribing. JAMA Intern Med 175:827-34, 2015 
28. Sorensen JB, Klee M, Palshof T, et al: Performance status assessment in cancer patients. An inter-
observer variability study. Br J Cancer 67:773-5, 1993 
29. Muscaritoli M, Anker SD, Argiles J, et al: Consensus definition of sarcopenia, cachexia and pre-
cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in 
chronic wasting diseases" and "nutrition in geriatrics". Clin Nutr 29:154-9, 2010 
30. Kazemi-Bajestani SM, Mazurak VC, Baracos V: Computed tomography-defined muscle and fat 
wasting are associated with cancer clinical outcomes. Semin Cell Dev Biol, 2015 
31. Salakari MR, Surakka T, Nurminen R, et al: Effects of rehabilitation among patients with advances 
cancer: a systematic review. Acta Oncol 54:618-28, 2015 
32. Paccagnella A, Morassutti I, Rosti G: Nutritional intervention for improving treatment tolerance in 
cancer patients. Curr Opin Oncol 23:322-30, 2011 
33. Kalsi T, Babic-Illman G, Ross PJ, et al: The impact of comprehensive geriatric assessment 
interventions on tolerance to chemotherapy in older people. Br J Cancer 112:1435-44, 2015 
34. Cleeland CS, Allen JD, Roberts SA, et al: Reducing the toxicity of cancer therapy: recognizing 
needs, taking action. Nat Rev Clin Oncol 9:471-8, 2012 
35. Lewis JH, Kilgore ML, Goldman DP, et al: Participation of patients 65 years of age or older in 
cancer clinical trials. J Clin Oncol 21:1383-9, 2003 

 
 
24 
 
36. Cameron MG, Kersten C, Guren MG, et al: Palliative pelvic radiotherapy of symptomatic incurable 
prostate cancer - a systematic review. Radiother Oncol 110:55-60, 2014 
37. Cameron MG, Kersten C, Vistad I, et al: Palliative pelvic radiotherapy of symptomatic incurable 
rectal cancer - a systematic review. Acta Oncol 53:164-73, 2014 
38. Neve M, Jameson MB, Govender S, et al: Impact of geriatric assessment on the management of 
older adults with head and neck cancer: A pilot study. J Geriatr Oncol, 2016 
39. Pottel L, Lycke M, Boterberg T, et al: G-8 indicates overall and quality-adjusted survival in older 
head and neck cancer patients treated with curative radiochemotherapy. BMC Cancer 15:875, 2015 
40. Pottel L, Lycke M, Boterberg T, et al: Serial comprehensive geriatric assessment in elderly head 
and neck cancer patients undergoing curative radiotherapy identifies evolution of multidimensional 
health problems and is indicative of quality of life. Eur J Cancer Care (Engl) 23:401-12, 2014 
41. Sternberg SA, Wershof Schwartz A, Karunananthan S, et al: The identification of frailty: a 
systematic literature review. J Am Geriatr Soc 59:2129-38, 2011 
42. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype. J Gerontol 
A Biol Sci Med Sci 56:M146-56, 2001 
43. Handforth C, Clegg A, Young C, et al: The prevalence and outcomes of frailty in older cancer 
patients: a systematic review. Ann Oncol 26:1091-101, 2015 
44. Hamaker ME, Jonker JM, de Rooij SE, et al: Frailty screening methods for predicting outcome of 
a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet 
Oncol 13:e437-44, 2012 
45. Decoster L, Van Puyvelde K, Mohile S, et al: Screening tools for multidimensional health problems 
warranting a geriatric assessment in older cancer patients: an update on SIOG 
recommendationsdagger. Ann Oncol 26:288-300, 2015 
46. Rolfson DB, Majumdar SR, Tsuyuki RT, et al: Validity and reliability of the Edmonton Frail Scale. 
Age Ageing 35:526-9, 2006 
47. Hubbard JM, Jatoi A: Incorporating biomarkers of frailty and senescence in cancer therapeutic 
trials. J Gerontol A Biol Sci Med Sci 70:722-8, 2015 
48. Fernandez-Garrido J, Navarro-Martinez R, Buigues-Gonzalez C, et al: The value of neutrophil and 
lymphocyte count in frail older women. Exp Gerontol 54:35-41, 2014 
49. Clarke SJ, Chua W, Moore M, et al: Use of inflammatory markers to guide cancer treatment. Clin 
Pharmacol Ther 90:475-8, 2011 
50. McMillan DC: The systemic inflammation-based Glasgow Prognostic Score: a decade of 
experience in patients with cancer. Cancer Treat Rev 39:534-40, 2013 
51. Baracos V, Kazemi-Bajestani SM: Clinical outcomes related to muscle mass in humans with cancer 
and catabolic illnesses. Int J Biochem Cell Biol 45:2302-8, 2013 
52. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al: Sarcopenia: European consensus on definition and 
diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 
39:412-23, 2010 
53. Prado CM, Baracos VE, McCargar LJ, et al: Sarcopenia as a determinant of chemotherapy toxicity 
and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment. 
Clin Cancer Res 15:2920-6, 2009 
54. Muhlberg W, Sieber C: Sarcopenia and frailty in geriatric patients: implications for training and 
prevention. Z Gerontol Geriatr 37:2-8, 2004 
55. Landi F, Cruz-Jentoft AJ, Liperoti R, et al: Sarcopenia and mortality risk in frail older persons aged 
80 years and older: results from ilSIRENTE study. Age Ageing 42:203-9, 2013 
56. Sjoblom B, Gronberg BH, Benth JS, et al: Low muscle mass is associated with chemotherapy-
induced haematological toxicity in advanced non-small cell lung cancer. Lung Cancer 90:85-91, 
2015 
57. Sjoblom B, Gronberg BH, Wentzel-Larsen T, et al: Skeletal muscle radiodensity is prognostic for 
survival in patients with advanced non-small cell lung cancer. Clin Nutr, 2016 

 
 
25 
 
58. Cesari M, Fielding RA, Pahor M, et al: Biomarkers of sarcopenia in clinical trials-recommendations 
from the International Working Group on Sarcopenia. J Cachexia Sarcopenia Muscle 3:181-90, 
2012 
59. Charlson ME, Pompei P, Ales KL, et al: A new method of classifying prognostic comorbidity in 
longitudinal studies: development and validation. J Chronic Dis 40:373-83, 1987 
60. Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9-CM 
administrative databases. J Clin Epidemiol 45:613-9, 1992 
61. Romano PS, Roos LL, Jollis JG: Adapting a clinical comorbidity index for use with ICD-9-CM 
administrative data: differing perspectives. J Clin Epidemiol 46:1075-9; discussion 1081-90, 1993 
62. Schneeweiss S, Wang PS, Avorn J, et al: Improved comorbidity adjustment for predicting mortality 
in Medicare populations. Health Serv Res 38:1103-20, 2003 
63. Quan H, Li B, Couris CM, et al: Updating and validating the Charlson comorbidity index and score 
for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol 
173:676-82, 2011 
64. Podsiadlo D, Richardson S: The timed "Up & Go": a test of basic functional mobility for frail 
elderly persons. J Am Geriatr Soc 39:142-8, 1991 
65. Mahoney FI, Barthel DW: FUNCTIONAL EVALUATION: THE BARTHEL INDEX. Md State 
Med J 14:61-5, 1965 
66. Nasreddine ZS, Phillips NA, Bedirian V, et al: The Montreal Cognitive Assessment, MoCA: a brief 
screening tool for mild cognitive impairment. J Am Geriatr Soc 53:695-9, 2005 
67. Yesavage JA BT, Rose TL, Lum O, Huang V, Adey M, et al: Development and validation of a 
geriatric depression screening scale: a preliminary report. Journal of Psychiatric Research 17:12, 
1982 
68. Incalzi RA, Cesari M, Pedone C, et al: Construct validity of the 15-item geriatric depression scale 
in older medical inpatients. J Geriatr Psychiatry Neurol 16:23-8, 2003 
69. Nyunt MS, Fones C, Niti M, et al: Criterion-based validity and reliability of the Geriatric 
Depression Screening Scale (GDS-15) in a large validation sample of community-living Asian 
older adults. Aging Ment Health 13:376-82, 2009 
70. Halvorsrud L, Kalfoss M: Exploring the quality of life of depressed and nondepressed, home-
dwelling, Norwegian adults. Br J Community Nurs 21:170, 172-7, 2016 
71. Weintraub D, Oehlberg KA, Katz IR, et al: Test characteristics of the 15-item geriatric depression 
scale and Hamilton depression rating scale in Parkinson disease. Am J Geriatr Psychiatry 14:169-
75, 2006 
72. Geriatrisk Depresjonsskala, in forening NG (ed), Norsk Geriatrisk Forening 
73. Rubenstein LZ, Harker JO, Salva A, et al: Screening for undernutrition in geriatric practice: 
developing the short-form mini-nutritional assessment (MNA-SF). J Gerontol A Biol Sci Med Sci 
56:M366-72, 2001 
74. Kaiser MJ, Bauer JM, Ramsch C, et al: Validation of the Mini Nutritional Assessment short-form 
(MNA-SF): a practical tool for identification of nutritional status. J Nutr Health Aging 13:782-8, 
2009 
75. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst 85:365-76, 1993 
76. Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in health-related 
quality-of-life scores. J Clin Oncol 16:139-44, 1998 
77. Gladman JR, Lincoln NB, Adams SA: Use of the extended ADL scale with stroke patients. Age 
Ageing 22:419-24, 1993 
78. Wu CY, Chuang LL, Lin KC, et al: Responsiveness, minimal detectable change, and minimal 
clinically important difference of the Nottingham Extended Activities of Daily Living Scale in 
patients with improved performance after stroke rehabilitation. Arch Phys Med Rehabil 92:1281-
7, 2011 

 
 
26 
 
79. Glasgow RE, Vogt TM, Boles SM: Evaluating the public health impact of health promotion 
interventions: the RE-AIM framework. Am J Public Health 89:1322-7, 1999 
80. Martin L, Birdsell L, Macdonald N, et al: Cancer cachexia in the age of obesity: skeletal muscle 
depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol 31:1539-
47, 2013 
81. Corre R, Greillier L, Le Caer H, et al: Use of a Comprehensive Geriatric Assessment for the 
Management of Elderly Patients With Advanced Non-Small-Cell Lung Cancer: The Phase III 
Randomized ESOGIA-GFPC-GECP 08-02 Study. J Clin Oncol 34:1476-83, 2016 
 
 
 

 
 
27 
 
Amendment 1-3 
These amendments have not been translated from Norwegian. Amendments 1-2 were added due 
to the revision of the protocol on the 18.04.17 and concerns evaluation of the patients’ capability 
of providing informed consent, and MoCA score cut-offs for when a re-evaluation of the patients 
capability should be performed. The resulting changes in the protocol are marked in yellow.  
Amendment 3 was written as some additional data collection was planned, but this was never 
carried out due to practical problems with the planned registrations.  
 
 

 
 
28 
 
Amendment 4: Amendments prior to data analyses. 
Several years have passed since the original protocol was written, and during this time, the field 
of geriatric oncology has evolved considerably. Thus, before embarking on the analyses, the 
analytic strategy has been discussed in the scientific group, and some amendments have been 
made. 
1. We have decided to report overall survival (OS) among palliative versus curative patients, 
and investigate the association between GA domains and OS in the first paper emerging from 
this study.  
This first paper will fulfil the secondary aim of our study reading as follows: “To define the 
prevalence of problems uncovered by GA in older patients > 65 years before and after 
EBRT, and investigate the association between GA domains and adverse events”, except that 
OS and not deterioration in QoL and physical function (PF) will be the main outcome and 
only GA findings at baseline will be included.  
 
Explanation for changes: 
Although the study includes a two-year follow-up with respect to survival, OS was not a pre-
defined outcome in this observational study. The exception was a plan to investigate the 
association between CT based muscle measure, inflammation and survival (protocol, page 
18: “Analysis of muscle mass and inflammation markers “).  One reason for this omission 
was that the association between GA defined frailty and OS was relatively well-documented 
in 2016, and thereby assumed to be of less interest than the outcomes QoL and PF.   
The association between frailty/GA impairments and survival in older patients receiving 
EBRT is, however, currently still scarcely investigated, and therefore of interest. 
Furthermore, the overarching aim of the present study was to “generate knowledge that may 
provide a basis for developing a targeted and feasible intervention to prevent adverse events 
during and after curative and palliative EBRT in patients > 65 years”. Although not pre-
defined as such in our study, death is the ultimate adverse event, and a gold standard 
endpoint in cancer studies. Hence, we found that investigating whether GA impairments are 
associated with mortality risk is both appropriate and pertinent, and well in line with the 
study purpose.  Several of the impairments that may be identified by GA, are remediable. If 
any of these could have an impact on OS in patients with cancer receiving curative or 
palliative EBRT, developing and/or implementing interventions that specifically target these 
impairments would be highly important, i.e. in hope of improving an endpoint of major 
importance for the patients. Finally, when investigating the impact of GA impairments on 
global QoL, physical function and need for daily life assistance, it is crucial to know, whether 
the same impairments also affect OS.  
Before any analysis for the first paper was conducted, a detailed analysis plan was 
prepared(Appendix 1). Subsequently, however, the definition of OS was corrected from 
“time from end of EBRT to death or last observation” to “time from inclusion to death or last 

 
 
29 
 
observation”, and we also decided to explore the association between number of GA 
impairments and OS.  
 
2. OS will also be used as an outcome in the validation of the Edmonton Frail Scale, i.e. the 
planned second paper 
The second secondary aim of our study is to “Validate the Edmonton Frail Scale (EFS) as a 
screening instrument to identify frail patients and patients at risk of adverse events” (see 
page 8).  
The plan for the analyses was: “The sensitivity and specificity of EFS in identifying frail 
patients will be tested against the full GA. EFS’ ability to predict adverse events on the 
defined outcomes will be assessed with uni- and multivariable regression analyses, 
controlled for relevant co-variates (e.g. type of cancer, stage of disease, and radiotherapy 
regimen”(see page 17) 
Partly based on the considerations stated under point 1, we have now decided to perform the 
validation by investigating the association between the instrument’s scores and OS in 
addition to association with GA findings. Another strong argument for this is that other well-
known and widely used frailty screening instruments, e.g. the G8, have been widely tested 
against patients’ survival.1-5 Thus, for comparison, which is important, we will do likewise.  
Before embarking on these analyses, a detailed plan has also been prepared (Appendix 2). 
 
3. We have decided not to use the term “frailty” when classifying the patients according to GA. 
Hence, we will not define the patients as frail or non-frail, but instead classify them 
according to their number of identified GA impairments. 
Our primary hypothesis (page 8) has been revised accordingly, now reading: “Our 
hypothesis is that increasing number of GA impairments is associated with increased risk of 
adverse events as defined, regardless of cancer type, stage, and radiotherapy procedure 
(localisation, dose, field size) 
This hypothesis and the primary aim of our study will be addressed in paper 3, for which a 
detailed plan for the analyses has also been prepared (Appendix 3) 
This amendment also affects paper 2 as the sensitivity and specificity of Edmonton Frail 
Scale will be evaluated against number of geriatric deficits, not against a classification of 
frail vs. non-frail patients.  
 
Explanation: 
The concept of frailty has received increasing attention in oncology research since the start of 
the present study, and the understanding of the syndrome has also increased considerably. 
There is, however, still no consensus on how frailty should be defined based on GA. Former 
studies have used various numbers of GA impairments (from one to four) to identify patients 
as frail.6 Thus choosing a more or less arbitrary number to define frailty, we have realised, 
makes little sense. Furthermore, it is increasingly clear that frailty is developed as a 

 
 
30 
 
continuum from vulnerability to severe frailty.7 A classification as frail vs. non-frail therefore 
gives a poor description of the patients’ vulnerability status, whereas this is reflected more 
correctly by number of geriatric deficits. 
 
4. The fourth paper so far being planned is a description of the MoCA test results at baseline 
and during follow-up, and simultaneously an evaluation of the feasibility of this test for older 
patients with cancer. A detailed plan for the analyses has not yet been prepared.  
This fourth paper will partly contribute to fulfil our primary aim 2 (evaluating the feasibility 
of GA performed in the municipalities) and secondary aim (describing the prevalence of 
geriatric problems after EBRT). 
The reasons why we have chosen to look specifically on cognitive function and MOCA 
scores before evaluating the feasibility of the remaining GA registrations are: 
 The MoCA test was assessment reported to cause most inconvenience for both 
patients and nurses. Patients with cancer, when consulting health care professionals, 
are not used to being cognitively evaluated, and some patients objected to this. For 
the same reason, some of the nurses also found it difficult to repeat the test after 
EBRT. 
 Whether the MoCA test is relevant and appropriate for patients with cancer referred 
for new treatment, is poorly assessed. It is important to investigate if there might be a 
trend towards improvement from baseline through follow-up at home after EBRT, i.e. 
indicating that scores obtained before start of new treatment may not appropriately 
reflect the patients’ cognitive function. According to some of the testing nurses, the 
scores seemed to be significantly affected by distress related to start of new treatment 
or other cancer-related problems. 
 Overall, the trajectory of MoCA scores obtained from older patients with cancer 
receiving EBRT is scarcely described. 
  
The overall feasibility of GA performed in the municipality, after EBRT, in this patient 
cohort will be evaluated in a subsequent paper. 
5. We have decided not to assess the patients’ muscle mass from available CT scans (as stated 
in the protocol page 17), hence these scans have not been retrieved.  
The reason for this is our experience from a former study8 in another cohort of older patients 
with cancer. From that study, it was clear that as long as a baseline CT scan is not an 
obligatory part of the study design, or the procedures for such scans are not clearly defined, a 
large number of patients will not have scans taken within a reasonable time frame or at the 
appropriate body level including the overall body circumference. Hence, it is highly likely 
that the number of patients having non-available CT scans would be just as high in the 
present cohort as in our former study. Hence, the sample size for the planned analyses would 
most likely be too small. Furthermore, our former study, as well as another one recently 

 
 
31 
 
published,9 have found no association between muscle mass and frailty as defined by GA. 
Further investigations on the issue therefore seems futile. 
 
References 
1. Hamaker ME, Mitrovic M, Stauder R: The G8 screening tool detects relevant geriatric impairments 
and predicts survival in elderly patients with a haematological malignancy. Ann Hematol 93:1031-
40, 2014 
2. Martinez-Tapia C, Paillaud E, Liuu E, et al: Prognostic value of the G8 and modified-G8 screening 
tools for multidimensional health problems in older patients with cancer. Eur J Cancer 83:211-219, 
2017 
3. Agemi Y, Shimokawa T, Sasaki J, et al: Prospective evaluation of the G8 screening tool for 
prognostication of survival in elderly patients with lung cancer: A single-institution study. PLoS 
One 14:e0210499, 2019 
4. Takahashi M, Takahashi M, Komine K, et al: The G8 screening tool enhances prognostic value to 
ECOG performance status in elderly cancer patients: A retrospective, single institutional study. 
PLoS One 12:e0179694, 2017 
5. van Walree IC, Scheepers E, van Huis-Tanja L, et al: A systematic review on the association of the 
G8 with geriatric assessment, prognosis and course of treatment in older patients with cancer. J 
Geriatr Oncol, 2019 
6. Handforth C, Clegg A, Young C, et al: The prevalence and outcomes of frailty in older cancer 
patients: a systematic review. Annals of Oncology 26:1091-1101, 2015 
7. Gobbens RJJ, van Assen M: Associations between multidimensional frailty and quality of life 
among Dutch older people. Arch Gerontol Geriatr 73:69-76, 2017 
8. Harneshaug M, Benth JS, Kirkhus L, et al: CT Derived Muscle Measures, Inflammation, and Frailty 
in a Cohort of Older Cancer Patients. In Vivo 34:3565-3572, 2020 
9. Williams GR, Deal AM, Muss HB, et al: Frailty and skeletal muscle in older adults with cancer. J 
Geriatr Oncol 9:68-73, 2018 
 
 
 

 
 
32 
 
Appendix 1  
Dated 26-05-20 
Statistical analysis plan for the first paper from the study: Improved quality of life and 
function for older cancer patients receiving radiotherapy – a prospective observational 
study  
A total of 301 patients were included, 165 (54.8%) patients received radiotherapy (RT) with 
curative intent, and 136 (45.2%) received palliative RT. 
The aims of this first paper are to:  
1) describe the characteristics of this older population referred for RT in terms of 
demographics, cancer diagnosis, stage, former and planned treatment, and deficits/needs 
identified by a geriatric assessment (GA), 
2) compare the overall and 1-, 3- and 6-month survival of the patients treated with curative 
versus palliative intent 
3) investigate if frailty indicators assessed as part of the GA can predict overall survival in 
the curative and palliative group, respectively. 
 
The GA includes the following factors 
Cognition assessed by MoCA test 
Physical function 
 Activites of daily living assessed by Barthel Index 
 Instrumental activities of daily living (IADL) assessed by the Nottingham Extended 
Activities of Daily (NEADL) 
 Mobility assessed by the Timed Up and Go (TUG) 
 Number of falls the last 6 months 
Comorbidity assessed by Charlson Comorbidity Index (CCI) 
Depressive symptoms assessed by the Geriatric Depression Scale-15 (GDS-15) 
Medications: Number of regular, prescribed medications 
Nutritional status assessed by the Mini Nutritional Assessmennt MNA 
 
Statistics 
Patient characteristics will be presented as means, standard deviations (SD), minimum and 
maximum values for continuous variables, and frequencies and percentages for categorical 
variables. Survival time, defined as time from end of radiotherapy (last fraction) to death or 
censoring (last observation) will be assessed by Kaplan-Meier plot and compared between 
groups using log-rank test. Bivariate and multiple Cox regression models will be used to 
investigate if frailty indicators specified above may predict the overall survival. The estimates 
will be adjusted for age, gender, type of cancer (lung cancer/breast cancer/prostate 
cancer/others), ECOG performance status and treatment intent (palliative versus curative intent). 

 
 
33 
 
To assess whether the predictors act differently in two treatment groups, the interactions between 
treatment intent variable and all other variables will be included. The Akaike’s Information 
Criterion will be used to reduce the multiple model for excessive interactions. A significant 
interaction would imply that certain predictor predicts the overall survival differently in two 
treatment groups. 
 
 

 
 
34 
 
Appendix 2  
Dated 14-12-20 
Paper 2 from the study: Improving Quality of Life and Function for Older Cancer Patients 
Receiving Radiotherapy: an observational study 
Paper investigating the relationship between Edmonton Frail Scale (EFS) scores and 
overall survival and the construct validity of EFS in relation to a geriatric assessment (GA) 
 
Part 1: EFS in relation to survival in older patients receiving radiotherapy 
The aims are to 
A) investigate if the Edmonton Frail Scale (continuous, scores 1-17) assessed at baseline is 
predictive of survival independent of age, gender and major cancer-related prognostic 
factors (treatment intent (curative vs. palliative), diagnostic groups and ECOG status) 
B) assess the survival of groups of patients classified according  to proposed cut-off points 
for EFS scores (see below), and explore the data to find cut-off point(s) (potentially new) 
that best divide our cohort into groups with respect to survival 
 
Proposed cut-off points and categories for the EFS scores 
o 0-3 Fit 
o 4-5 Vulnerable 
o 6-7 Mild Frailty  
o 8-9 Moderate Frailty 
o 10+ Severe Frailty 
 
Hypotheses 
A) EFS scores are independently predictive of survival in older patients referred for curative 
or palliative radiotherapy 
B) The survival of older patients with cancer referred for curative or palliative radiotherapy 
differ between the groups defined by formerly used/suggested cut-off points 
 
Methods 
A) Cox proportional hazards regression model will be estimated 
B) Receiver Operating Characteristics curve analysis, Akaike’s Information Criterion 
 
Part  II: Evaluate the concurrent validity of the EFS in a cohort of patients receiving 
radiotherapy 

 
 
35 
 
The aims are to 
A) describe the number and type of GA deficits within each of the formerly  proposed 
categories of EFS  (see above) 
B) assess the association between the formerly proposed EFS categories and number of GA 
deficits, and explore the data to find the  cut-off point of EFS score that is most relevant 
to use in a screening procedure to ensure that the majority of patients in need of a full 
geriatric assessment are captured 
Hypotheses 
A) the number of GA deficits increases according to the formerly proposed EFS categories 
(fit, vulnerable, mild frailty, moderate frailty and severe frailty) with patients with 
moderate/severe frailty having the highest number of GA deficits 
B) there is a significant association between EFS categories and number of GA deficits, and 
the proposed cut point EFS>=6  for frailty is the appropriate cut-off point to ensure that a 
full GA is applied in patients where this is needed (based on number of GA deficits) 
Methods 
A) Descriptive statistics 
B) ANOVA 
Baseline data for EFS scores and the geriatric assessment will be used. 
 
 

 
 
36 
 
Appendix 3 
Dated 18-05-21 
Plan for analyses, paper no.3  
Preliminary title: 
Is the presence of geriatric impairments associated with quality of life and physical 
function after radiotherapy in older cancer patients? - A prospective observational study. 
Main objectives:  
In a cohort of older patients with cancer, referred for curative or palliative RT, we will: 
1. assess the trend in quality of life (QoL) and physical function prior to and after RT for 
palliative and curative patients, and investigate if there is a significant difference in trend 
between the two groups  
2. assess the trend in QoL and physical function prior to and after  RT stratified on number 
of geriatric impairments present at baseline, and investigate if there is a significant 
difference in trend depending on the number of geriatric impairments  
Predefined outcomes:  
Primary: Global quality of life (QoL) and physical function as assessed by the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC 
QLQ-C30) global QoL (glQoL) and physical functioning (PF) scale. 
Secondary:  
 Instrumental Activities of Daily Living (ADL)-function assessed by Nottingham 
Extended Index of Activities of Daily Living (NEADL) based on patients’ self-report.  
 Role function as assessed by the  EORTC QLQ-C30 role function (RF) scale 
 Fatigue and pain as assessed by the EORTC QLQ-C30 corresponding symptom scales 
(FA = fatigue)(PA = Pain) 
Exploratory: Functioning and symptom scales/items of the EORTC QLQ-C30 that are not 
defined as primary or secondary outcomes will be assessed for explorative purposes 
Hypotheses:  
1. Patients referred for palliative RT have poorer scores for all primary and secondary 
outcomes prior to and after RT compared to patients referred for curative treatment  
2. There is a significant  difference in trend in outcomes for palliative and curative patients: 
a. patients referred for palliative RT will experience an improvement in the primary 
outcomes global QoL and PF, and the secondary outcomes RF, NEADL and pain 
(PA) within 8 weeks after RT.  
b. patients referred for curative RT will experience a deterioration in the primary 
outcomes global QoL and PF and the secondary outcomes RF, NEADL and 

 
 
37 
 
fatigue (FA)  scores from baseline to 2 weeks after RT. Thereafter the scores will 
return to baseline values within 16 weeks.   
3. There is a significant difference in trend in outcomes depending on number of geriatric  
impairments 
a. scores for the primary outcomes global QoL and PF, and the secondary outcome 
RF decreases with increasing number of geriatric impairments 
b. there is a significant association between number of geriatric impairments and the 
primary outcomes global QoL and PF as well as the secondary outcome RF scores  
 
Timeline for the assessments: Patients answered EORTC QLQ-C30 and NEADL at five 
different time points: baseline, when completing RT (except palliative patients who received 
only a single fraction were per protocol test schedule not asked to answer EORTC QLQ-C30, 
and patients who received ˂10 fractions were not asked to answer NEADL), and 2, 8 and 16 
weeks after RT. We will exclude the assessment of NEADL at the end of RT from our analyses 
because patients with short courses of RT did not fill in this questionnaire. 
 
Statistical approach 
Categorical baseline characteristics of curative and palliative patients will be described with 
frequencies and percentages, while continuous with means and standard deviations (SD) or 
median and min-max values. 
Raw scores for all QLQ-C30 scales/items will be transformed into scales ranging from 0-100 in 
accordance with the official manual for this questionnaire. NEADL item scores will be 
summarized into a scale ranging from 0-66.  Missing NEADL items scores will be imputed as 
follows: 
The missing values are assumed to be missing at random (MAR), and will be imputed if at least 
half of the items of the scale had been answered. The imputation will be performed by generating 
an empirical distribution for each item based on non-missing values, and a random number 
drawn from it was used to replace the missing value. 
To answer Study aim 1 and test our first  hypothesis, the primary outcomes, global QoL and PF 
will be assessed by linear mixed model with fixed effects for (non-linear) time, treatment group 
(curative vs. palliative) and the interaction between the two. Random effects for patients will be 
included. The models will be adjusted for age, gender, performances status (ECOG PS) and 
cancer type. The secondary outcomes RF, NEADL and pain scores will be evaluated by similar 
models. 
To answer Study aim 2 and test our second hypothesis, similar models to those describe for aim 
1 will be performed for the primary outcomes global QoL and the secondary outcome RF. 
However, these models will use number of geriatric impairments as a stratification variable 
instead of treatment intent (palliative vs curative). The models will be adjusted for age, gender, 
cancer type, treatment intent (curative vs palliative) and ECOG PS.  
Sensitivity analyses to estimate models for non-imputed variables for NEADL will be also be 
performed.  

 
 
38 
 
For explorative purposes linear mixed model with fixed effects for (non-linear) time, treatment 
group (curative vs. palliative) and the interaction between the two will be estimated to assess 
differences in trend between palliative and curative patients for emotional function (EF, 
insomnia, appetite loss). Similar models will also be estimated to assess possible differences in 
trend in pain, fatigue, insomnia, and appetite loss between groups defined according to number 
of geriatric impairments. For these models number of geriatric impairments will be used for 
stratification instead of treatment intent. No adjustments will be made in any of the explorative 
models.