ProWide - Patient Reported Outcomes Used for Weekly Internet-based DEtection of Progressive Disease in Lung Cancer; a Randomized Controlled Trial
Phase: NA
Conditions: Lung Cancer
Sponsor: Regional Hospital West Jutland

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Patient Reported Outcomes used for Weekly 
Internet-based DEtection of progressive 
disease in lung cancer;  
a randomized controlled trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 6.12, December 12, 2019 

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Study title 
ProWide 
Patient Reported Outcomes used for Weekly Internet-based DEtection 
of progressive disease in lung cancer; a randomized controlled trial 
 
Protocol committé 
Rasmus Blechingberg Friis, MD, PhD student, West Jutland Hospital, 
Herning, principal investigator 
Halla Skuladottir, MD, DMsc., Senior Consultant, West Jutland 
Hospital, Herning 
Niels Henrik Hjøllund, MD, PhD, Senior Consultant, professor, 
University Hospital Aarhus and West Jutland Hospital, Herning  
Helle Pappot, MD, PhD, Senior Consultant, Rigshospitalet 
Barbara  Malene  Fischer,  MD,  PhD,  Senior  Consultant,  Associate 
professor, Rigshospitalet 
Caroline Mejdahl, PhD, WestChronic, West Jutland Hospital, Herning 
Erik Jakobsen, MD, clinical lector, MPM, Danish Lung Cancer Registry 
Karin Holmskov Hansen, MD, Senior Consultant, University Hospital 
Odense 
Susanne Oksbjerg Dalton, MD, PhD, Research Group Head, Danish 
Cancer Society 
Marianne Ingerslev Holt, MD, Department of Oncology, Aarhus 
University Hospital 
Torben  Riis  Rasmussen,  MD,  PhD,  Senior  Consultant,  Associate 
professor, University Hospital Aarhus 
Lone Bilde, Health Economist, Senior Project Manager, Danish 
Cancer Society  
Institutions  
Oncology departments in Denmark 
Population 
Lung cancer patients who have finished induction treatment for lung 
cancer. Eligible are patients with stage III disease treated with 
palliative intent, and stage IV lung cancer, regardless of treatment 
intent. Maintenance treatment is allowed. 
Background 
According to the national Danish follow-up program for lung cancer, 
patients are followed with clinical controls and a contrast enhanced 
CT-scan of the thorax and upper abdomen, every 3 months the first 
2-3 years, then every 6 months until 5 years1. In a palliative follow-
up, CT scans are performed every 3 months after ended induction 
treatment. In case of continuous maintenance treatment, CT scans 

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are performed at prespecified intervals, usually every 8th, 9th or 12th 
week depending on treatment type. 
Recently, a study by Denis et al.2 suggested, that weekly patient-
reported (PRO) symptoms monitoring during maintenance therapy or 
follow-up of lung cancer patients, could help to early identify patients 
with relapse or progression of disease. In their randomized phase III 
trial, conducted in France, they found a median survival of 19.0 
months (12.5- non-calculable) for the PRO intervention group vs 12.0 
months (8.6-16.4) in the control arm (p=.001). HR=0.325(0.157-
0.673).   
One-year survival was 74.9% (56.6-86.4) vs 48.5% (31.9-63.2) 
(p=.05) with a benefit of 26 %. 
A significant benefit in both quality of life and survival has also been 
shown in another phase III study by Basch et al that tested weekly 
PRO monitoring of patients undergoing treatment for metastatic 
cancer, of whom approximately 25% had lung cancer3,4. The median 
overall survival was 31.2 months (24.5-39.6) in the PRO group and 
26.0 months (22.0-30.9) in the standard of care group, HR=0.83 
(0.70-0.99).  
One-year survival was 75.1% (70.7-79.0) vs 68.6% (63.2-73.6) 
(p=.05), showing a survival benefit of 6.5 %. 
Inspired by these encouraging results, we propose to test, in a 
Danish setting, whether adding weekly monitoring of patient-reported 
symptoms, can improve survival by early detection of progressive 
disease in lung cancer patients. The weekly monitoring will be added 
to the standard CT evaluation scans with clinical control and 
contrast-enhanced CT of thorax and abdomen. 
 
Endpoints 
 
Primary endpoint:  
• Overall Survival 
Secondary endpoints:  
• Performance status at the time of progressive disease 
• Progression-free survival 
• Quality of life  
• Cost-effectiveness and hospital resource use and costs 
• Type of treatment at the time of progressive disease 
 

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Evaluation criteria 
All  patients  will  have  a  baseline  CT-scan  of  the  thorax  and  upper 
abdomen performed prior to treatment and an evaluation CT scan at 
the time of enrolment. CT scan will be repeated for assessing signs of 
relapse or progression due to standard follow-up/response evaluation 
procedures.  
Health-Related Quality of life (HRQoL) will be measured using EORTC 
QOL-C305/ LC136, EQ-5D-5L7 and HADS8 every 2 months during the 
study period. 
Methodology 
Multicentre phase III trial 
Sample size 
A total of 492 patients will be included in the study with 246 patients in 
each group. The power calculation is based on a presumed 
improvement in 1-year survival on 13.2 % corresponding to half of the 
effect in the study by Denis et al. and a compliance rate at 90%. 
Intervention 
In the experimental arm, patients will fill in a web-based PRO 
questionnaire every week. If their weekly reported symptoms exceed 
a predefined threshold of severity, this results in a notification sent to 
the  hospital  and  a  nurse  will  contact  the  patient  for  verification  of 
symptoms. If progression of disease is suspected, a CT scan will be 
made.  Otherwise,  the  nurse  will  schedule  a  visit  at  the  clinic  for 
physical  examination  and  evaluation  by  a  clinician.  If  progressive 
disease  is not  suspected,  supportive  care  will  be adjusted,  and the 
patient will continue follow up/CT evaluations according to the usual 
schedule.  
Inclusion criteria 
1. Patients with lung cancer (NSCLC or SCLC) with stage III treated 
with palliative intention, or stage IV, regardless of treatment 
intention. 
2. 1st line induction treatment* started/completed prior to the current 
evaluating scan  
3. Non-progressive** disease at first CT scan evaluating 1st line 
induction treatment 
4. Diagnosis proved by cytology or histology 
5. Age ≥ 18 years 
6. Performance status (PS) ≤ 2  
7. First evaluation CT scan performed within four weeks from 
enrolment 
8. The patient has given his/her written informed consent before any 
specific procedure from protocol 
* Induction treatment includes: 
• 
Standard doublet chemotherapy 

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• 
Immunotherapy 
• 
Targeted therapy 
• 
Palliative radiotherapy 
• 
Local treatment of oligometastatic disease, including surgery and 
stereotactic radiotherapy 
• 
Any combination of the above-mentioned treatment modalities. 
Patients are eligible regardless of whether they at the time of 
inclusion continue maintenance treatment or not 
** Patients with stable disease or better response, defined by the treating 
clinician, are eligible. Patients receiving immunotherapy are eligible if 
pseudoprogression is suspected based on clinical response and treatment is 
continued.  Patients  receiving  1st  line  “treatment  beyond  progression”  are 
eligible 
Exclusion criteria 
1. No internet access  
2. No E-boks access 
3. No mobile phone 
4. Persons deprived of liberty or under guardianship or curators 
5. Dementia, mental alteration or psychiatric disease that can 
compromise informed consent from the patient and / or 
adherence to the protocol and the monitoring of the trial 
6. Pregnant or breastfeeding women 
7. Patient participating in another interventional study during the 
surveillance period. This is only relevant for studies that might 
interfere with the intervention. Participation in protocols related 
only to treatment will not preclude participation in the present 
study. Cases of doubt will be settled by the protocol committee. 
Time of Enrolment 
Patient enrolment is always at the time when the patients are informed 
of the results of their first evaluation scan after treatment induction.  
Statistical analysis 
The study will be conducted as a randomized phase III study.  First 
analyses will be conducted after 2 years of inclusion. No predefined 
criteria for termination of the trial has been determined.   

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Introduction 
 
Lung cancer is a serious disease with a dismal prognosis. The 5-year survival rate of 
Danish lung cancer patients diagnosed with loco-regional disease ranges from 43% 
for patients with stage I lung cancer, through 27% for stage II to 21% for patients with 
stage III disease. Patients with stage IIIb-IV receiving palliative treatment have an 
even worse outcome, with a 5-year survival of only 4 and 2% estimated in 2015. Of 
the more than 4500 patients who were diagnosed with lung cancer in Denmark in 
2015, 55.6% were in stage IIIb-IV9. 
 
According to the national Danish follow-up program for lung cancer, patients are 
followed with clinical controls and a contrast enhanced CT-scan of the thorax and 
upper abdomen, every 3 months the first 2-3 years, then every 6 months until 5 
years. The purpose of follow-up is to find relapse as soon as possible to increase the 
probability of curative treatment of the relapse, or if curative treatment is not possible, 
optimal palliative treatment1. In case of treatment with palliative intent, patients are 
usually scanned every 3 months after they have finished treatment to determine the 
present status of the disease. However, during palliative treatment, patients are often 
scanned more frequently to evaluate the effect of the ongoing treatment. 
 
There have been conducted numerous studies of symptom monitoring by patient-
reported outcomes (PRO), reviewed recently10. PRO's are any measurements 
provided directly from the patients, which give information on aspects of their health 
status, often relevant to their quality of life. These studies of PRO use for symptom 
monitoring, have shown improvement in patient-caregiver communication, but have 
not been able to show improvement in clinical outcome10. Now, evidence is 
emerging, showing that a proactive approach of symptom monitoring by use of PRO 
data, might lead to a better quality of life and improved survival among patients with 
lung cancer2–4. 
 
Recently, a study by Denis et al.2 suggested, that including weekly patient-reported 
(PRO) symptom monitoring in the follow-up of lung cancer patients in all stages, 
could help identify earlier patients with progression or relapse of disease. In their 
randomized phase III trial, conducted in France, they found a survival benefit of 26% 
for the PRO intervention group, with a hazard ratio of 0,325 (0,157-0,673). In the 
study, clinicians were alerted when patients had reported detrimental changes in 
PRO symptoms, leading to earlier clinical evaluation and CT-scan, if indicated. 
Earlier detection of progression or relapse allowed for an earlier start of secondary 
treatment and patients were found in better performance status, leading to improved 
overall survival.  
 
A significant benefit in quality of life and a survival benefit has also been shown in a 
study of patients undergoing treatment for cancer, including lung cancer3,4. The 
patients were randomized between the standard of care vs. regular PRO symptom 
reporting. When detrimental changes were reported by the patients, they were 
contacted by the healthcare team for symptom management. The median overall 
survival was 31,2 months (24,5-39,6) in the PRO group and 26,0 months (22,0-30,9) 
in the standard of care group, HR=0,83 (0,70-0,99). 
 

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Aim 
 
Inspired by the impressing survival benefit found by Denis et. al.2, we propose to test, 
in a Danish setting, whether adding weekly monitoring of patient-reported symptoms, 
can improve early detection of progressive disease and improve survival for lung 
cancer patients. The weekly monitoring will be added to the standard evaluation 
program with clinical control and contrast-enhanced CT of the thorax and upper 
abdomen.  
 
We will conduct a randomized controlled trial (RCT), comparing the two arms with 
respect to overall survival, progression-free survival, performance status at relapse, 
quality of life during follow-up/ and type of treatment initiated at the time of 
progressive disease. Finally, the use of healthcare resources will be calculated and 
compared at the end of the study. 
Methods 
 
The study is divided into two consecutive phases.  
1. Defining the PRO application for symptom monitoring is inspired by a 
literature review, the Danish national lung cancer clinical guidelines11, analysis 
of historical PRO data and study group consensus. The questions have been 
adapted to a Danish setting with feasibility testing prior to trial initiation. The 
process includes the construction of an application for mobile phones, tablets 
and laptops with an algorithm for sending notifications to clinicians.  
2. Testing the PRO-tool in a randomized multicentre trial. See below for 
details. 
 
Defining the PRO application  
 
Denis et al have validated and published a list of 12 core symptoms in lung cancer 
and developed an algorithm for a web application. Certain combinations of symptoms 
and symptom-scores will send a notification to the hospital. Denis et al. found that the 
combinations and severity of the above symptoms had a high sensitivity and 
specificity for detecting relapse12–14. 
The details of the algorithm have however not been fully published, which is why the 
model could not be fully adapted to this study. 
 
We did a critical review of the symptoms published by Denis et al2 and compared 
them to the symptoms described in the official recommendations of the Danish 
national lung cancer clinical guidelines11. Based on consensus in the study group we 
decided to exclude depression, as otherwise proposed by Denis et al2, from the list of 
relevant symptoms. Already validated single items from both cancer and lung cancer-
specific EORTC QLQ-C30/LC13 questionnaires were used to describe the relevant 
symptoms for the final questionnaire. The EORTC Global Quality of Life score has in 
several studies15–18 proven to be an important prognostic factor in lung cancer. By 
another consensus decision in the study group based on the use of patient-reported 
outcomes in the clinic, we chose to incorporate self-rated overall health as a single 
item in the questionnaire. Supplementary symptoms that were not described in the 
EORTC questionnaires were formulated as questions by members of the study group 

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and added to the questionnaire. We then ended up with 12 core symptoms and a 
comment field for the following feasibility study.  
 
Individual severity thresholds for each symptom were defined for the algorithm that 
triggers the notifications to the department. 
 
A feasibility study was then conducted at the department of oncology in Herning 
(details to be published). Initial interviews that were conducted with 7 patients for 
face validity and usability revealed issues with the understanding of the 
supplementary questions, the weekly timeframe and the login procedure. The 
questions were then adjusted prior to the feasibility study where 20 patients with 
stage IV lung cancer tested the system with weekly questionnaires for 3 weeks.  
At the end of the study, patients gave a written evaluation and interviews with two 
nurses involved in the system-process were made. Additional changes based on the 
results were then made to the questionnaire and the threshold mechanism. 
 
We did, however, choose to include both items from the EORTC Global Quality of 
Life score (self-rated overall health and quality of life) in the final questionnaire. 
Though only self-rated overall health was chosen to send notifications in case of 
worsening. 
 
The definitive version of the questionnaire in Danish and the threshold algorithm for 
the RCT study can be found in the Appendix. 
 
The protocol committee holds the right to adjust the threshold algorithm during the 
study period if deemed necessary.  
 
 
The randomized clinical trial of adding weekly PRO 
 
Design and setting 
The main part of the study consists of a multicenter randomized trial in order to 
assess the effects of the weekly PRO intervention. The design follows the overall 
setup presented in the publication by Denis et al, however, adapted to a Danish 
setting, as described above, including the Danish guidelines for evaluating CT scan 
in both arms2. The randomization and baseline data collection will be made in the IT 
system (AmbuFlex) by the oncologist at the time of enrollment. 
 

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Implementation of the intervention 
The intervention is illustrated in Figure 1. In the experimental arm, patients will be 
asked to fill in the PRO questionnaire every week via an internet connection, and 
they will also be asked to fill in HRQoL questionnaires at any outpatient attendance. 
However, if their weekly reported symptoms result in a notification, the clinician will 
contact the patient, and after verification of symptoms, schedule a visit at the clinic 
for physical examination and evaluation. If relapse or progression of disease is 
suspected an extra CT scan will be made, otherwise the patient will continue 
response evaluation/follow-up according to the usual schedule. The clinicians are 
allowed to reschedule the CT scan based on the phone call alone.  
 
Both the HRQoL measurements and the web application will be administered through 
a web page that is designed for use on mobile phones, tablets and 
laptops(AmbuFlex19). The data will automatically be transferred in real time to a 
computer server, where notifications are generated and sent to clinicians if the 
prespecified symptom thresholds are exceeded. Data is automatically scored and will 
be available in easily interpretable visual reports in the AmbuFlex system. 
 
If participants do not fill in the web-based questionnaire at pre-specified times, a 
reminder will be sent using a text message to their mobile phone and a message will 
appear for the clinical staff at the daily notification list. 
 
Figure 1. Flow-chart showing the PRO-intervention in the randomized clinical trial. 
 
To examine the participants quality of life during the study period and at the time of 
relapse/progressive disease, patients in both arms will be asked to fill in the health-
related quality of life (HRQoL) questionnaire every 2 months. The HRQoL 
questionnaires used are the EORTC QoL-30/LC13 and HADS questionnaire. 
EORTC-QoL-30 is a questionnaire containing 30 questions with five functional scales 
(physical function, role function, cognitive function, emotional function and social 

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function), three symptom scales (tiredness, nausea/vomiting, pain), a global health 
question and questions regarding frequent symptoms among cancer patients, such 
as dyspnea, sleep disturbances, loss of appetite, obstipation and diarrhea. The 
EORTC-QoL-30 also contains a question about financial difficulties. All scales will be 
linearly transferred to a score between 0-100. For functional scales and global health 
question, a score of 100 represents the best possible function, while a score of 100 
on a symptom scale represents the worst possible symptom. A change in the score 
by 10 or more is considered a clinically significant change20. LC13 is a 
supplementary questionnaire to the QLQ-C30 and includes 13 lung cancer-specific 
questions.  
 
The HADS (The hospital anxiety and depression scale) is a fourteen-item scale. Seven 
items  relate  to  depression  and  seven  to  anxiety.  The  tool  has  been  developed  for 
detection of anxiety and depression in patients with physical health problems. All items 
are  scored  from  0-3  with  a  possible  total  score  between  0  and  21  for  anxiety  and 
depression respectably8.  
Bjelland et al21 identified, in a systematic review, a cut-off point of 8/21 for anxiety or 
depression. For anxiety, the specificity was 0.78 and the sensitivity 0.9. For depression 
a specificity of 0.79 and a sensitivity of 0.83 was determined. 
 
The generic EQ-5D-5L7 questionnaire will be used to asses quality-adjusted life years 
(QALY) for a health economic evaluation (see statistics for details). 
 
Study design 
The study is a multicenter randomised phase III study. After signing informed 
consent, the patient will be randomized in 1:1 fashion, to the standard of care arm, 
with planned CT-scans according to a standard schedule and measurement of 
quality of life every 2 months, or to the experimental arm, adding weekly PRO 
monitoring and quality of life measurements to standard of care.  
 
Study population 
Eligible are patients with stage III lung cancer where the treatment intention is 
palliative and stage IV lung cancer regardless of treatment intent, who have received 
first-line induction treatment and have stable disease or better response after 
induction therapy. Maintenance treatment of any kind is allowed during the study 
period. Patients will be stratified by centre, stage and by main histology; small-cell 
lung cancer vs. non-small cell lung cancer.  
 
 
Inclusion Criteria 
 
 
1. Patients with lung cancer (NSCLC or SCLC) with stage III treated with palliative 
intention, or stage IV, regardless of treatment intention. 
2. 1st line induction treatment* started/completed prior to the current evaluating 
scan  
3. Non-progressive** disease at first CT scan evaluating 1st line induction 
treatment 

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4. Diagnosis proved by cytology or histology 
5. Age ≥ 18 years 
6. Performance status (PS) ≤ 2  
7. First evaluation CT scan performed within four weeks from enrolment 
8. The  patient  has  given  his/her  written  informed  consent  before  any  specific 
procedure from protocol 
 
  * Induction treatment includes: 
• Standard doublet chemotherapy 
• Immunotherapy 
• Targeted therapy 
• Palliative radiotherapy 
• Local treatment of oligometastatic disease, including surgery and 
stereotactic radiotherapy 
•  Any combination of the above-mentioned treatment modalities. Patients 
are eligible regardless of whether they at the time of inclusion continue 
maintenance treatment or not 
 
** Patients with stable disease or better response, defined by the treating clinician, are 
eligible. Patients receiving immunotherapy are eligible if pseudoprogression is 
suspected based on clinical response and treatment is continued. Patients receiving 
1st line “treatment beyond progression” are eligible 
 
Exclusion Criteria 
 
1. No internet access  
2. No E-boks access 
3. No mobile phone 
4. Persons deprived of liberty or under guardianship or curators 
5. Dementia, mental alteration or psychiatric disease that can compromise 
informed  consent  from  the patient  and/or adherence  to the protocol  and  the 
monitoring of the trial 
6. Pregnant or breastfeeding women 
7. Patient  participating  in  another  interventional  study  during  the  surveillance 
period. This is only relevant for studies that might interfere with the intervention. 
Participation in protocols related only to treatment will not preclude participation 
in the present study. Cases of doubt will be settled by the protocol committee. 
 
 
Time of enrolment 
Patient enrolment is always when the patients are informed of the results of their first 
evaluation scan after treatment induction. Patients with stable disease or better 
response, as described, are eligible.  
 
• In case of treatment end (planned or discontinued) at the time of enrolment, 
the patient will be included prior to standard follow-up  

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• In case of ongoing treatment, the patient will be included and continue 
treatment as scheduled with standard CT based response evaluations 
• In the case of local treatment of oligometastatic disease or palliative 
radiotherapy, the patient will be included if there is no sign of 
relapse/progression at first evaluation CT scan after treatment and continue 
follow-up 
 
 
Inclusion procedure 
The patient will have to sign an informed consent at enrolment. The National 
Committee on Health Research Ethics has been requested and the study does not 
require approval. Time for consideration before the submission of informed consent 
is therefore not required and the patient can be enrolled immediately at attendance.  
Information regarding the study and login procedures for the weekly PRO 
questionnaire will be provided. 
 
Evaluation criteria 
All baseline CT-scans will be evaluated at each site by usual practice. Health-related 
quality of life (HRQoL) during the observation period will be measured using EORTC 
QOL-C30/LC13 and HADS. The HRQoL questionnaires including the EQ-5D-5L will 
be filled in at baseline at randomisation and at every 2 months. The questionnaires 
will be electronically answered via the AmbuFlex system. 
 
Study plan 
The study plan for the randomized clinical trial is outlined in Table I. In the standard 
arm, all patients will be followed with CT-scan with the standard of care intervals and 
asked to fill in the web-based HRQoL questionnaires every 2 months. In the 
experimental arm, patients will additionally be asked to fill in the web-based PRO 
questionnaire on a weekly basis. If a detrimental change (See appendix) is noted in 
the patient’s weekly responses to the PRO questionnaire, the patient will be 
contacted by a study nurse for verification of symptoms. If the symptoms are verified, 
the patient will be treated by the clinical staff according to standard procedures. If 
progressive disease is suspected, the patient will have the CT scan rescheduled to 
as soon as possible. All CT-scans will be described and evaluated by standard 
practice. It will entirely be up to the treating physician to interpret the results of the CT 
scans and to define the time of progression as well as the following treatment. 
 
Evaluation at screening, prior to inclusion 
The objective of these evaluations is to identify patients, who meet the specified 
Inclusion- and exclusion criteria. The patient will be informed verbally and in writing. 
Only patients who have signed informed consent will be included. Following 
examination and data will be collected prior to inclusion: 
• Histological or cytological verification of lung cancer 
• Disease stage at treatment start 
• Prior treatment and/or maintenance treatment 

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• Baseline CT scan of the thorax and upper abdomen, showing no signs of 
progression, after completion of the first treatment for lung cancer, performed 
within 28 days of randomization. 
• Baseline performance status (according to the ECOG's scale13), estimated 
within 14 days of randomization 
 
The patient will be asked to fill in baseline health-related quality of life (EORTC QoL-
30/LC13, HADS, EQ-5D-5L) questionnaires via E-Boks immediately after inclusion 
and then every 2 months. 
 
Additional evaluation for the intervention arm, after inclusion 
• Weekly response to the PRO application 
• If detrimental changes in PRO responses, earlier evaluation, described above 
 
CT evaluation according to standard follow-up/response evaluation, all participants 
• CT-scan of the thorax and upper abdomen, to evaluate the time of progression 
(or relapse) 
 
Evaluation at relapse or progression 
• CT-scan of the thorax and upper abdomen  
• Performance status 
• Planned 2nd line treatment 
• Categorization of the performed CT scan as prescheduled as a result of a 
PRO notification 
 
Study period: 
Patients will be followed for two years after inclusion in case of non-progressive 
disease. In case of progressive disease or relapse, the patient will exit the study.  
For survival analysis and further evaluation, patients will be followed until death or up 
to 5 years from inclusion. 
 
Endpoints:  
The primary outcome measures that will be compared between the experimental and 
control arm is overall survival with an observation time of 24 months. 
 
The secondary outcome measures are 
• Performance status at the time of progressive disease 
• Progression-free survival 
• Health-related quality of life 
• Cost-effectiveness and hospital resource use and costs 
• Type of treatment at the time of progressive disease 
  
 
Time to progression as well as performance status at progression compared to 
performance status at enrolment into the study may be used to investigate, whether 
the intervention leads to earlier detection of and better performance status at the time 
of progression. Quality of life differences may provide insights on possible other 
patient perceived benefits to the web-mediated follow-up.  
 

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Sub-studies 
A parallel research project has been financed and will focus on benefit in terms of 
quality of life and better patient involvement through qualitative interviews with 
patients included in the study. With qualitative interviews, we aim to describe how 
participants experience the web-based PRO application and to explore the 
mechanisms of action related to PROs as a mean of patient involvement. Moreover, 
we aim at exploring how the intervention influences patients’ fear of cancer 
recurrence and their psychosocial well-being. We will apply the method of an 
interpretive description as an inductive, flexible research strategy to generate 
knowledge relevant within a clinical context22. Individual semi-structured interviews 
will be conducted with 8-10 patients from each arm. After one year, follow-up 
interviews will be conducted with the same participants in order to explore 
transformations in the patients’ experiences and give new insights in barriers and 
opportunities for patient involvement in follow up of lung cancer (For details, see 
appendix, sub-study 1). 
 
Generalizability of any study finding is important when considering future 
implementation processes. Previous trials of behavioural interventions among cancer 
patients have found that patients who choose not to participate have lower education 
and income, are more often single and have lower survival compared to 
participants23–25. In another parallel study, we will use registry data and baseline 
health-related quality of life to compare differences between participants versus non-
participant. The aim is to assess differences in their lung cancer disease, symptom- 
and comorbidity burden, and socioeconomic characteristic. By understanding these 
differences, we hope to be able to improve future planning of PRO use in lung cancer 
follow-up for all patients (See appendix for details, sub-study 2). 
 
Intervention costs, and the derived hospital resource use and costs (number of 
contacts, visits, scans etc.) can be used to estimate the difference in costs in the two 
arms. Data will be collected retrospectively upon completion of the trial (see 
Appendix, sub-study 3). Together with information on effects regarding the other 
endpoints (including health-related quality of life), this can provide a basis for a health 
economic evaluation of the intervention. 
 
Data collection and analysis 
 
Baseline information on age, gender, Charlson’s comorbidity index (extracted from 
central registry), histology (extracted from the pathology database), TNM stage and 
treatment type will be noted. During the study period, the number of CT scans will be 
recorded, as well as disease status and deaths including the cause of death.  After 
verification of progressive disease, the following cancer treatment modalities will be 
registered. Data will be filed in and stored electronically using the AmbuFlex system 
and transferred to REDCap (Research Electronic Data Capture) for further data 
management. 
 
Data on resource use and costs for the health economic evaluation will be collected 
as a retrospective study upon completion of the trial, using 1) expert assessment for 
time and material spent on the intervention and 2) individual patient cost data 

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extracted from the National Patient Registry linked to the National Cost Database 
(See appendix). 
 
 
 
Power calculation 
 
In the randomised study by Denis et al.2 the difference in 1-year survival in control vs. 
PRO arm was 49% vs. 75% with the significant hazard ratio of 0.33 in their sample of 
60 vs. 61 individuals in the two study arms. A power calculation based on a log-rank 
test for difference in survival with these anticipated survival rates and a follow-up time 
of 1-year results in for 53 patients in each arm.  Given the remarkable difference 
between the two arms, a more conservative estimate has been calculated for a 
relative improvement of approximately half this size.  
 
The crude overall 1-year survival in Denmark of 46.2%9, but given that patients 
included in the study are responders of initiated treatment and presumably have 
better survival, 50 % 1-year overall survival is assumed to be the survival rate in the 
control arm. A relative improvement of approximately half the size found by Denis et 
al2 would result in an anticipated survival rate of 63.2%. A difference of this size 
would require 221 individuals in each group (Alpha 5%, Beta-1 80%).  
 
However, the feasibility study revealed a compliance ratio of 90%, which then 
requires a total number of 492 patients. 
 
Power calculations were performed in STATA 14.2 using the procedure for two 
sample survival comparison with the log-rank test.  
 
We aim to collaborate across hospitals to get as many participants as quickly as 
possible.   
 
 
Statistics 
The study will be conducted as a randomized phase III study. A temporary analysis 
will be made after 2 years of inclusion and determine whether the study holds 
enough promise to justify the continuation of patient enrollment. No predefined 
criteria for termination of the trial have been determined.   
 
Cox proportional hazards regression will be used to estimate the hazard ratios for 
time to clinical deterioration, time or relapse, and the median time to deterioration. 
 
OS will be compared between the control arms among all randomized subjects using 
a two-sided, log-rank test. Median OS will be estimated via the Kaplan-Meier method. 
 
Health resources utilized are described in both arms. All hospital costs from the point 
in time from randomization to 1-year follow up are measured by DRGs (Diagnosis-
related groups) and inflated to the price year 2018 using the Danish Hospital PL 

16 
 
(Price and Wage) index. CIs are estimated with bias-corrected non-parametric 
bootstrapping.  
 
Cost-effectiveness of the PRO application versus standard monitoring is assessed 
with the incremental cost-effectiveness ratio (ICER), i.e. the ratio of net health care 
costs to net QALYs (Quality Adjusted Life Years). For a description of the data 
collection and the analysis, see appendix.  
 
Statistical analysis plan of the Health-Related Quality of Life data  
Health-related  quality  of  life  (HRQoL)  measures  are  secondary  endpoints  in  the 
ProWide trial and will be reported in a scientific paper published separately from the 
main paper. The primary endpoints of the HRQoL paper are Physical function (QLQ-
C30), Pain (QLQ C-30), HADS-anxiety and overall EQ-5D-5L index score. 
The statistical analyses were planned before any evaluation of the data collected in 
the trial was made.  
Data collection  
The HRQoL questionnaires are sent to the patients via the Danish public mail system 
(eBoks) every second months. All patients in the trial have access to the system. Non-
respondents receive a reminder after one week. Responses delivered > 3o days after 
the invitation is sent is categorized as “missing”. 
Specific endpoints of interest in the HRQoL analysis 
The specific HRQoL scales that will be analyzed in the ProWide study are: 
1. Physical function (QLQ-C30) 
Rationale: Physical function is considered a PRO surrogate marker for performance 
status which is an important prerequisite for both toleration effect of medical 
antineoplastic treatment.  
 
2. Pain (QLQ C-30) 
Rationale: Pain is sensitive to change toward progression in cancer and a symptom 
that can be managed with analgesics. The symptom could then be improved through 
actions that are a result of the intervention.   
 
3. HADS-anxiety 
Rationale: The intervention could improve the sense of security in the patients and 
potentially reduce anxiety. 
 
4. EQ-5D-5L index score 
Rationale: The generic score represents an overall self-assessed health status and will 
be used report the effect of the intervention on the overall health. 
The  EQ-5D-5L  score  will  be  reported  both  in  the  main  paper  as  a  mean-score 
comparison between the two groups at six months and also analyzed in the HRQoL 
paper as described below.  

17 
 
 
HRQoL hypothesis 
The HRQoL hypothesis is that the natural course of cancer-related symptom 
deteriorations can be overall reduced through actions taken on the basis continuous 
symptom monitoring throughout the study period. It is expected that the overall effect 
is larger than the effect on time to deterioration. This expectation applies to all the 
HRQoL endpoint. 
Statistical analyses 
The HRQoL data will be analyzed using a linear mixed model approach as the primary 
analysis  to  compare  longitudinal  data  between  study  arms.  Area  Under  the  Curve 
(AUC)  will  be  used  as  a  confirmatory  analysis.  These  analyses  are  based  on  the 
assumption that the scores can be considered as continuous variables26.  
Statistical significance 
The mean EQ-5D-5L score will be reported for both study groups at six months in the 
main paper as the primary HRQoL endpoint.  
The four HRQoL endpoints of primary interest will be analyzed and reported in the 
HRQoL paper.  
A p-value of <.05 will be considered statistically significant. 
Minimal Important Differences (MID) 
MID  will  be  used  to  report  the  proportion  of  patients  with  improvement,  stable  or 
deteriorating symptoms compared to baseline 
Physical function (QLQ-C30) and Pain (QLQ C-30): a 50 % reduction of the expected 
mean  deterioration  without  the  intervention  from  baseline  to  time  of  progression  is 
considered the MID. Based on clinical data from lung cancer patient treated in the 
department of oncology, Regional Hospital West Jutland, Denmark (to be published) 
the  expected  mean  deterioration  from  baseline  to  progression  is  10  points.  A  50 
percent reduction then corresponds to an MID of five point for this study.  
HADS-anxiety: A 1.5-point change in the HADS anxiety score is considered an MID27. 
EQ-5D-5L index score: A change of 6 points is considered an MID28. 
Compliance and missing data 
Reasons for missing data will be categorized as; administrative censoring (patients 
who have not reached the relevant time point at the time of the analysis), withdrawal 
and missing for participants still in the study. If the reason for non-compliance is death 
the data will not be categorized as missing. 

18 
 
Compliance is defined as the ratio between the number of responses and expected 
responses (death and administrative censoring as the reason for non-compliance are 
excluded at the specific time points). 
A first look on the data before doing the HRQoL analysis will define the cut of point of 
the  analysis  according  to  the  following  rule.  Data  obtained  from  baseline  up  to  12 
months will be analyzed as long as the compliance is at least 50 % in both study arms.   
A  supplementary  analysis  will  explore  potential  differences  in  the  HRQoL  endpoint 
between patient with high or low compliance and the dropout rates will be compared 
between study arms.  
Imputation 
EORTC QLQ C30/L13 
If at least half the items used in a scale are available, the mean scores of these items 
are imputed to the remaining missing items to calculate the specific scale. If more than 
half of the items in a scale are missing, this whole scale will be considered missing for 
the individual patient. This approach (the half rule) is recommended in the EORTC 
QLQ scoring manual5,6. 
Multiple imputation will not be used to adjust for missing data. 
 
Ethics 
All patients must give their written consent prior to the study according to local ethical 
standards and all data will be treated with confidentiality. The study has been 
approved by the Danish Data Protection Agency. Permissions to withdraw data from 
DLCR will be obtained. 
 
Both study arms will be offered the CT-scans and clinical evaluations according to 
standard procedures. In the study presented by Denis et al.2, patients in the 
experimental arm were offered less regular prescheduled CT-scans than control arm, 
which is not the case in the present study.  
 
Perspectives 
The French randomized trial of incorporating PRO data in the follow up of lung 
cancer patients has shown compelling evidence of a substantial improvement in 
median and overall survival by using a web-application mediated follow-up5. If this 
Danish adaption of the study shows similar positive results it holds great promise for 
the future strategy for lung cancer follow-up/response evaluation – and possibly also 
perspectives for improving follow-up for other cancer patients. 
 
In Denmark there is a unique chance to conduct clinical trials of follow up due to the 
free and equal access to health care, and the possibility of complete follow up by use 
of the civil registration number, allowing for linkage between registries, a very low 
rate of patients lost to follow up and often high completeness of data, leading to good 
data quality. 

19 
 
 
The previous Danish findings of the collection of PRO from lung cancer patients 
across several regions in Denmark29 indicated that lung cancer patients generally 
had positive feedback about their participation in the project. They felt they made a 
contribution to their own treatment and follow up, and that the PRO data facilitated 
their communication with their clinician. The patient felt better prepared for the 
consultation and that the clinician also had a better idea about their complaints and 
symptoms. Supported by these data, application of systematically collected PRO 
data in clinical practice might contribute to better clinical care of Danish patients. If 
we find similar results as our French colleagues, we might even find a survival 
benefit. Thus, our hope is to both improve clinical care and survival with the use of 
PRO data. 
 
The planning of this study is coordinated with the group behind the SUPE-R trial, 
assessing the benefit of adding PET/CT scans and liquid biopsies in the follow up of 
patients with stage I-III lung cancer, enabling a comprehensive assessment, 
standardization and improvement of surveillance of all patients treated for lung 
cancer in Denmark. 
 
 
 
 
 
 
Timetable 
The study is expected to begin in January 2018 and end in December 2021. Below is 
the detailed description of each phase is presented. 
 
January-May 2018 
Construction of application 
May-July 2018 
Feasibility testing 
May-July 2018 
Data collection plan, including the establishment of a database 
for data from the study 
September 2018 
Recruitment of patients begins in Herning 
November-December 2018 
Recruitment of patients begins in Aarhus and Hillerød  
January 2019 
Recruitment of patients begins in Aalborg 
February-April 2019 
Recruitment of patients begins in Herlev and Copenhagen 
(Rigshospitalet) 
Summer/Autumn 2019 
Recruitment of patients begins in Sønderborg and Odense 
Autumn 2019 
Enrollment is competitive and continues until all patients are 
included. 
July-December 2020 
Follow up and publication of PhD dissertation and analyses of 
preliminary findings 
December-July 2021 
End of study, analyses and publications 
2022 
Health economic evaluation of the intervention  
 
The final publication with full 24 months follow-up will be expected in the final half of 
the year 2022. 

20 
 
 
Feasibility of the project 
The project is based in the Regional Hospital in Herning, but the intention is a wide 
collaboration across hospitals to recruit as many participants as quickly as possible 
which is also reflected in the broad collaboration of the project group (see organization 
below). 
 
Implementation  of  PRO  data  for  clinical  practice  is  complex,  both  in  terms  of 
organization and technology. PRO data system AmbuFlex has already been 
incorporated  in  every  day  clinical  practice  in  the  oncology  department  in  Herning, 
based in the Central Region of Denmark, and is already available in many oncology 
departments in Denmark, facilitating rapid recruitment and increasing the possibility of 
successful completion of the project19. 
 
PRO data collection in oncology departments, where PRO data is not incorporated in 
everyday practice, will be implemented by using the experience gathered by the 
collaboration between WestChronic /AmbuFlex and the Danish Cancer Society, 
where PRO data were collected from lung cancer patients from seven hospitals from 
different regions in Denmark in 2013-201529. This project also demonstrated large 
differences between hospitals, which could be due to differences in regional health-it 
resources. To ensure fast and reliable implementation, the project will be started 
stepwise in phases in regions with actual access to AmbuFlex. The pilot phase will 
be conducted in the oncology department of the Regional Hospital in Herning. The 
first phase will be started in oncology departments of Central Denmark Region (in 
Herning and Aarhus), the second phase includes the North Denmark Region (in 
Aalborg). The third phase will include Region Zealand, and if technically possible, 
other regions. 
 
Publications 
 
The study will be published after completion, when the final analyses have been 
performed, in international peer-reviewed journals. The protocol committee writes the 
first draft and the Vancouver declaration will be followed in all publications based on 
this study. The names on the author list will be given according to the active 
participation in the design of the protocol, in the recruitment of patients.  
 
Project organization 
The project is intended for a PhD thesis. 
 
Following are members of the protocol committee: 
 
Rasmus Blechingberg Friis, MD, PhD student, West Jutland Hospital, Herning 
Halla Skuladottir, MD, DMsc., Senior Consultant, West Jutland Hospital, Herning 

21 
 
Niels  Henrik  Hjøllund,  MD,  PhD,  Senior  Consultant,  Professor,  University  Hospital 
Aarhus and West Jutland Hospital, Herning  
Helle Pappot, MD, PhD, Senior Consultant, Rigshospitalet 
Barbara Malene Fischer, MD, PhD, Senior Consultant, Associate professor, 
Rigshospitalet 
Caroline Mejdahl, PhD, WestChronic, West Jutland Hospital, Herning 
Erik Jakobsen, MD, clinical lector, MPM, Danish Lung Cancer Registry 
Karin Holmskov Hansen, MD, Senior Consultant, University Hospital Odense 
Susanne Oksbjerg Dalton, MD, PhD, Research Group Head, Danish Cancer Society 
Marianne Ingerslev Holt, MD, Department of Oncology, Aarhus University Hospital 
Torben Riis Rasmussen, MD, PhD, Senior Consultant, Associate professor, University 
Hospital Aarhus 
Lone Bilde, health economist, Senior Project Manager, Danish Cancer Society 
 
Budget  
The project is intended as a 3-year Ph.D. study. Additional expenses include 
expenses for developing the web application, fees for using the web application 
system (including technical support) and storing the PRO data. Further, a 
biostatistician will be required to aid in the data analyses following the data collection 
and study nurses to aid the data collection coordination in the multiple sites. A health 
economic evaluation will also be conducted at the end of the study period. 
 
 
 

22 
 
References 
1. 
Danish 
Lung 
Cancer 
Recommendations. 
(2016). 
Available 
at: 
https://www.sst.dk/da/nyheder/2016/opfoelgningsprogram-for-lungekraeft. 
Accessed 3/5/2019. (Accessed: 6th October 2017) 
2. 
Denis, F. et al. Randomized Trial Comparing a Web-Mediated Follow-up With 
Routine  Surveillance  in  Lung  Cancer Patients.  J.  Natl.  Cancer Inst.  109,  1–8 
(2017). 
3. 
Basch,  E.  et  al.  Symptom  monitoring  with  patient-reported  outcomes  during 
routine cancer treatment: A randomized controlled trial. J. Clin. Oncol. 34, 557–
565 (2016). 
4. 
Basch, E. et al. Overall Survival Results of a Trial Assessing Patient-Reported 
Outcomes  for  Symptom  Monitoring  During  Routine  Cancer  Treatment.  Jama 
318, 197 (2017). 
5. 
EORTC  Quality  of  Life  Group.  EORTC  QLQ-C30  Scoring  Manual.  (2001). 
Available  at:  http://www.eortc.be/qol/files/SCManualQLQ-C30.pdf.  (Accessed: 
28th February 2018) 
6. 
EORTC  Quality  of  Life  Group.  EORTC  QLQ-LC13  Scoring  Manual.  (2001). 
Available 
at: 
http://www.eortc.be/qol/files/ScoringInstructions/LC13_summary.pdf. 
(Accessed: 28th February 2018) 
7. 
Herdman, M. et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual. Life Res. 20, 1727–36 (2011). 
8. 
Zigmond, A. S. & Snaith, R. P. The hospital anxiety and depression scale. Acta 
Psychiatr. Scand. 67, 361–70 (1983). 
9. 
Danish Lung Cancer Group (DLCG). Annual Report 2015,. (2015). 
10. 
Kotronoulas, G. et al. What is the value of the routine use of patient-reported 
outcome measures toward improvement of patient outcomes, processes of care, 
and health service outcomes in cancer care? A systematic review of controlled 
trials. J. Clin. Oncol. 32, 1480–1501 (2014). 
11. 
Danish Lung Cancer Group (DLCG). Lungecancer – Visitation, Diagnose, Stadie 
- Kliniske Retningslinjer, version 1.0. (2018). 
12. 
Denis, F. et al. Detection of lung cancer relapse using self-reported symptoms 
transmitted via an internet web-application: pilot study of the sentinel follow-up. 
Support. Care Cancer 22, 1467–73 (2014). 
13. 
Denis,  F.  et  al.  Overall  survival  in  patients  with  lung  cancer  using  a  web-
application-guided follow-up compared to standard modalities: Results of phase 
III randomized trial. J. Clin. Oncol. 34, LBA9006–LBA9006 (2016). 
14. 
Denis, F., Viger, L., Charron, A., Voog, E. & Letellier, C. Detecting lung cancer 
relapse using self-evaluation forms weekly filled at home: the sentinel follow-up. 
Support. Care Cancer 22, 79–85 (2014). 
15. 
Steel, J. L. et al. Health-related quality of life as a prognostic factor in patients 
with advanced cancer. Cancer 120, 3717–3721 (2014). 
16. 
Montazeri, A. Quality of life data as prognostic indicators of survival in cancer 
patients:  an  overview  of  the  literature  from  1982  to  2008.  Health  Qual.  Life 
Outcomes 7, 102 (2009). 
17. 
Coates,  A.,  Porzsolt,  F.  &  Osoba,  D.  Quality  of  life  in  oncology  practice: 
Prognostic value of EORTC QLQ-C30 scores in patients with advanced 
malignancy. Eur. J. Cancer 33, 1025–1030 (1997). 
18. 
Movsas, B. et al. Quality of life supersedes the classic prognosticators for long-

23 
 
term  survival  in  locally  advanced  non-small-cell  lung  cancer:  an  analysis  of 
RTOG 9801. J. Clin. Oncol. 27, 5816–22 (2009). 
19. 
Schougaard, L. M. V. et al. AmbuFlex: tele-patient-reported outcomes (telePRO) 
as the basis for follow-up in chronic and malignant diseases. Qual. Life Res. 25, 
525–534 (2016). 
20. 
Snyder,  C.  F.  et  al.  Identifying  Changes  in  Scores  on  the  EORTC-QLQ-C30 
Representing a Change in Patients’ Supportive Care Needs HHS Public Access. 
Qual Life Res 24, 1207–1216 (2015). 
21. 
Bjelland, I., Dahl, A. A., Haug, T. T. & Neckelmann, D. The validity of the Hospital 
Anxiety and Depression Scale. An updated literature review. J. Psychosom. Res. 
52, 69–77 (2002). 
22. 
Fitzpatrick1, R. & Davies2, L. Health economics and quality of life in cancer trials: 
report based on a UKCCCR workshop. Br. J. Cancer 77, 1543–1548 (1998). 
23. 
Kjaer, T. et al. Do we reach the patients with the most problems? Baseline data 
from the WebCan study among survivors of head-and-neck cancer, Denmark. J. 
Cancer Surviv. 10, 251–260 (2016). 
24. 
Boesen, E. H. et al. Survival after a psychoeducational intervention for patients 
with  cutaneous  malignant  melanoma:  a  replication  study.  J.  Clin.  Oncol.  25, 
5698–703 (2007). 
25. 
Dalton,  S.  O.  et  al.  Socioeconomic  position  and  survival  after  lung  cancer: 
Influence of stage, treatment and comorbidity among Danish patients with lung 
cancer diagnosed in 2004–2010. Acta Oncol. (Madr). 54, 797–804 (2015). 
26. 
Donneau, A. F., Mauer, M., Coens, C., Bottomley, A. & Albert, A. Longitudinal 
quality of life data: a comparison of continuous and ordinal approaches. Qual. 
Life Res. 23, 2873–81 (2014). 
27. 
Puhan, M. A., Frey, M., Büchi, S. & Schünemann, H. J. The minimal important 
difference of the hospital anxiety and depression scale in patients with chronic 
obstructive pulmonary disease. Health Qual. Life Outcomes 6, 46 (2008). 
28. 
Pickard,  A.  S.,  Neary,  M.  P.  &  Cella,  D.  Estimation  of  minimally  important 
differences  in  EQ-5D  utility  and  VAS  scores  in  cancer.  Health  Qual.  Life 
Outcomes 5, 70 (2007). 
29. 
Kræftens Bekæmpelse. Klinisk anvendelse af Patient Reported Outcome 
Measures (PROM) – en evalueringsrapport. 
 
 
 
 
 
 
 
 
 
 

24 
 
APPENDIX 
 
 
 
 
Table 1. Study plan for the randomized clinical trial testing weekly PRO responses 
 
 
 
At baseline 
At every CT eval. 
At progression* 
Histology 
(x) 
 
 
Disease stage 
x 
 
 
Charlson's comorbidity index 
(x) 
 
 
Prior treatment 
x 
 
 
Maintenance treatment 
x 
 
 
Clinical examination 
x 
x 
x 
Performance status 
x 
 
x 
Quality of life (every 2 months) 
x 
 
 
CT-scan 
x 
- 
- 
Treatment type after 
progression 
 
 
x 
Weekly PRO (only the 
intervention group) 
x 
- 
- 
 
* Patients exit the study when progressive disease has been determined 
(x) data is extracted from central registry  

25 
 
 
 
 
 
 
 
 
EORTC QLQ-C30 (version 3.0)  
 
Vi er interesserede i at vide noget om Dem og Deres helbred. Vær venlig at besvare alle 
spørgsmålene selv ved at sætte en ring omkring det svar (tal), som passer bedst på Dem. Der er 
ingen "rigtige" eller "forkerte" svar. De oplysninger, som De giver os, vil forblive strengt fortrolige. 
 
 
 
 
 
Slet 
 
 
ikke 
Lidt 
En del Meget 
1. Har De nogen vanskeligheder ved at udføre anstrengende  
 
aktiviteter, som f.eks. at bære en tung indkøbstaske  
 
eller en kuffert? 
1 
2 
3 
4 
 
2. Har De nogen vanskeligheder ved at gå en lang tur? 
1 
2 
3 
4 
 
3.     Har De nogen vanskeligheder ved at gå en 
  
kort tur udendørs? 
1 
2 
3 
4 
 
4. Er De nødt til at ligge i sengen eller at sidde i  
 
en stol om dagen? 
1 
2 
3 
4 
 
5. Har De brug for hjælp til at spise, tage tøj på,  
 
vaske Dem eller gå på toilettet? 
1 
2 
3 
4 
 
 
I den forløbne uge: 
Slet 
 
 
ikke 
Lidt 
En del Meget 
6. Var De begrænset i udførelsen af enten Deres arbejde 
 
eller andre daglige aktiviteter? 
1 
2 
3 
4 
 
7. Var De begrænset i at dyrke Deres hobbyer eller 
 
andre fritidsaktiviteter? 
1 
2 
3 
4 
 
8. Havde De åndenød? 
1 
2 
3 
4 
 
9. Har De haft smerter? 
1 
2 
3 
4 
 
10.  Havde De brug for at hvile Dem? 
1 
2 
3 
4 
 
11.  Har De haft besvær med at sove? 
1 
2 
3 
4 
 
12.  Har De følt Dem svag? 
1 
2 
3 
4 
 
13.  Har De savnet appetit? 
1 
2 
3 
4 
 
14.  Har De haft kvalme? 
1 
2 
3 
4 
 
15.  Har De kastet op? 
1 
2 
3 
4 
 
 

26 
 
 
 
 
I den forløbne uge: 
Slet 
 
 
ikke 
Lidt 
En del Meget
 
 
16.  Har De haft forstoppelse? 
1 
2 
3 
4 
 
17.  Har De haft diarré (tynd mave)? 
1 
2 
3 
4 
 
18.  Var De træt? 
1 
2 
3 
4 
 
19.  Vanskeliggjorde smerter Deres daglige gøremål? 
1 
2 
3 
4 
 
20.  Har De haft svært ved at koncentrere Dem om ting som 
 
f.eks. at læse avis eller se fjernsyn? 
1 
2 
3 
4 
 
21.  Følte De Dem anspændt? 
1 
2 
3 
4 
 
22.  Var De bekymret? 
1 
2 
3 
4 
 
23.  Følte De Dem irritabel? 
1 
2 
3 
4 
 
24.  Følte De Dem deprimeret? 
1 
2 
3 
4 
 
25.  Har De haft svært ved at huske?  
1 
2 
3 
4 
 
26.  Har Deres fysiske tilstand eller medicinske behandling 
 
vanskeliggjort Deres familieliv? 
1 
2 
3 
4 
 
27.  Har Deres fysiske tilstand eller medicinske behandling 
 
vanskeliggjort Deres omgang med andre mennesker? 
1 
2 
3 
4 
 
28.  Har Deres fysiske tilstand eller medicinske behandling 
 
medført økonomiske vanskeligheder for Dem? 
1 
2 
3 
4 
 
 
 
Ved de næste 2 spørgsmål bedes De sætte en ring omkring det tal mellem  
1 og 7, som passer bedst på Dem 
 
 
29. Hvordan vil De vurdere Deres samlede helbred i den forløbne uge? 
 
 
1 
2 
3 
4 
5 
6 
7 
 
 Meget dårligt 
 
 
 
 
Særdeles godt    
 
 
30. Hvordan vil De vurdere Deres samlede livskvalitet i den forløbne uge? 
 
 
1 
2 
3 
4 
5 
6 
7 
 
 Meget dårlig 
 
 
 
 
Særdeles god 
 
 
©  Copyright 1995 EORTC Study Group on Quality of Life. All rights reserved.    Version 3.0 
 

27 
 
 
 
 

28 
 
 
HADS – The Hospital Anxiety and Depression Scale 
(Danish version) 
 

29 
 
 

30 
 
 

31 
 
 
 

32 
 
ProWide:   Symptoms and PRO-notification thresholds  
(Danish version) 
1. Hvordan vil du vurdere dit samlede helbred i den forløbne uge? 
1                2               3              4              5             6             7        
Meget dårligt 
 Særdeles godt       
2. Hvordan vil du vurdere din samlede livskvalitet i den forløbne uge? 
1                2               3              4              5             6             7        
Meget dårligt 
 Særdeles godt       
I den forløbne uge:  
Slet ikke 
Lidt 
En del         Meget 
3. Havde du åndenød? 
1 
2 
3 
4  
4. Har du haft smerter? 
1 
2 
3 
4 
5. Var du træt? 
1 
2 
3 
4        
6. Har du savnet appetit? 
1 
2 
3 
4 
7. Hvor meget har du hostet? 
1 
2 
3 
4 
8. Har du hostet blod op? 
1 
2 
3 
4 
 
(OBS: 1 = ingen symptomer) 
PRO-underretning sendes til afdelingen ved rødt markeret svar. Sender kun første gang med 
mindre der sker en yderligere forværring ift. seneste uge eller der i mellemtiden har været en 
bedring. Hoste med blod sender Pro-underretning hver gang. 
9. Har du feberfornemmelse?   
Nej / Ja 
(Hvis ”Ja”) Du bedes måle din temperatur og skrive svaret her (f.eks 38,5)  
 
 
< 38,2           ≥38,2  
(I tilfælde af ”forhøjet temperatur” vil en pop-up meddelelse gøre opmærksom på at 
man skal henvende sig på afdelingen akut med følgende tekst) 
Du har oplyst, at du har feberfornemmelse og forhøjet temperatur. 
Der kan være tale om en akut tilstand, og du skal derfor kontakte 
den læge eller afdeling, der lige nu er ansvarlig for dit forløb! 
10. Har du hæs stemme?   
Nej        Ja  
(Hvis ”Ja”) Er din hæse stemme blevet forværret i den forløbne uge? Nej / Ja  
 

33 
 
11. Har du hævelse af ansigtet? 
 
Nej         Ja 
(Hvis ”Ja”) Er din hævelse af ansigtet blevet forværret i den forløbne uge? Nej / Ja  
 
12. Kan du mærke en knude der vokser?     Nej / ved ikke / Ja  
 
 
13. Hvor mange kilo vejer du? _____ 
 
                 ≥ 3 kg vægttab fra baseline 
 
 
14. Har du, i den forløbne uge, fået andre symptomer, som du tror kan have forbindelse med 
din kræftsygdom? 
_____Tekst________________________________________________________ 
Skriv kun i feltet, hvis du ønsker at det bliver læst af personalet på afdelingen 
Disclaimer;  
Spørgeskemaet kan ikke opspore alle de problemer, der kan opstå, når man har lungekræft.  
Vi vil kun kontakte dig, hvis vi ud fra dine besvarelser finder det nødvendigt. 
Du skal selv kontakter afdelingen, hvis du har det dårligt eller har brug for at tale med en læge eller 
sygeplejerske. 
Hvis du har det akut dårligt af for eksempel feber eller åndenød, skal du kontakte afdelingen med det 
samme.  
 
 
 
 

34 
 
Appendix, sub-study 1:  
A study of the non-participating candidates for the full ProWide study 
 
Patients who do not wish to participate in the full ProWide study or were not able to, 
because they did not have access to the necessary technology (internet, mobile phone 
or E-Boks - a Danish public online digital mailbox) are candidates to this sub-study. 
Aim:  To  explore  and  identify  differences  in  HRQoL,  socioeconomics  and  family 
structures between  participants and non-participants in a Danish Lung Cancer 
population. 
Hypothesis:  The  hypothesis  is  that  study  participants  have  higher  income  and 
education, and worse HRQoL than the participants.  
Methods:  All  patients  who  meet  the  inclusion  criteria  will  be  asked  to  give  written 
consent and fill in a single questionnaire containing questions about reasons for non-
participation, their family structure and the same HRQoL measures as participant fill in 
during the study period (EORTC QLQ-C30/LC13, HADS and EQ-5D-5L). 
Additional  data  for  the  analysis  will  be  retrieved  from  central  public  registries  (The 
National  Board  of  Health  Data  (Sundhedsdatastyrelsen)  and  Statistics  Denmark 
(Danmarks statistik). 
Perspectives: The introduction of new health technology in the health care system 
can  be  of  potential  great  advantage.  However,  detailed  knowledge  of  the  non-
participants is needed to describe and address the risk of an increased inequity in the 
health care system when new health technology is implemented. Future work should 
consider  other  possible  health  care  services  that  could  be  offered  to  this  group  of 
patients. 
Publication: The results will be published in a scientific journal paper  
 
 

35 
 
Appendix, sub-study 2:  
An  interpretive  description  of  the  patient  and  clinician  perspective  in  the 
ProWide study.  
 
The ProWide study encompasses a complex intervention involving the interactions and 
interpretations of several individuals. The randomized controlled trial (RCT) is 
designed to uncover specific outcomes and will, therefore, provide valuable knowledge 
about  whether  the  ProWide  intervention  has  an  effect.  However,  the  RCT  cannot 
evaluate the processes that lead to those outcomes and the RCT cannot explain how 
the context of this complex intervention influences its effectiveness. There is much 
going on within and around the intervention, and it can be difficult to tell which aspects 
of the social and cultural context among the participants that are supporting the desired 
outcome, and which are inhibiting it. In order to gain nuanced knowledge about the 
web-based surveillance of lung cancer patients, we will conduct two qualitative studies 
concurrently with the RCT study. 
Aim 
The aim is to explore experiences of patients with lung cancer and clinicians working 
with the ProWide system that can inform our understanding of the complex 
mechanisms in web-based surveillance in lung cancer care. This qualitative project 
consists of two additional sub-studies: 
Qualitative sub-study 1: An interpretive description of patients’ experiences with web-
based surveillance. The aim is to explore how web-based surveillance can support 
patient  involvement  and  individualized  patient  care  in  patients  with  lung  cancer. 
Moreover, we aim to explore how the intervention influences patients’ fear of cancer 
recurrence and their psychosocial wellbeing.  
Qualitative  sub-study  2:  An  interpretive  description  of  clinicians’  experiences  with 
web-based surveillance. The aim is to explore the perspectives and experiences of 
nurses and physicians working with web-based surveillance. The intention is to widen 
our understanding of the clinician’s interpretation of the answers given by the patients 
and the following clinical decisions. The study will provide important knowledge and 
possible explanations for the outcomes of the ProWide study. 

36 
 
Methods 
Interpretive Description (ID) will be the overriding research strategy. ID is an applied 
inductive research strategy stressing the importance of conducting  research arising 
from and with the aim of improving clinical practice. 
Multiple  data  collection  techniques  are  applied  to  obtain  a  comprehensive  and 
substantial amount of data. Individual semi-structured interviews will be conducted with 
15-20 patients from the experimental arm. After 6-12 months, follow-up interviews will 
be  conducted  with  the  same participants  in order to  explore  transformations  in  the 
patients' experiences.  Individual  semi-structured  interviews  with  10-15  clinicians 
(nurses and physicians) working with web-based surveillance in the different oncology 
departments will also be conducted. Furthermore, field studies will be performed in the 
oncology departments comprising participant observations during nurses' and 
physicians' management and assessment of the patients' PRO responses and informal 
interviews with these clinicians.  
Plan for dissemination of the Results 
The results will be published in international scientific peer-reviewed journals. The final 
results will be presented for all relevant parties including all participating departments 
and patient organizations. 
Perspectives 
The intentions of the studies are to provide complementary explanations of the findings 
from the RCT and to generate knowledge and directions for ways to reframe or to 
optimize the future management of lung cancer patient care. In addition, if this Danish 
version of intensified frequent symptom reporting in lung cancer shows positive results, 
it  holds  great  promise  for  the  future  strategy,  not  just  for  lung  cancer,  but  also 
perspectives  for  a  possible  improvement  in  disease  surveillance  for  other  cancer 
diagnoses. Thus, the results from the qualitative studies will contribute with important 
insights  into  barriers  and  opportunities  for  patient  involvement  and  individualized 
patient care across cancer diagnosis.  
 
 

37 
 
Appendix, sub-study 3:  
Health economic evaluation alongside the ProWide clinical trial 
 
This document describes the data collection, outcome measures, and analysis for a 
health  economic  evaluation  of  the  weekly  internet-based  detection  of  progressive 
disease in lung cancer.  
 
The health economic evaluation will be conducted after the completion of the ProWide 
trial. The evaluation will use the trial efficacy data supplemented by a cost assessment 
based on data collected outside the trial and be conducted in accordance with the 
recommended practice for health economic evaluation (1). 
 
Aims  
The study will assess the incremental cost per quality-adjusted life year gained (QALY) 
for patients with lung cancer (corresponding to the inclusion criteria) of using a weekly 
internet-based tool for systematic self-reporting of symptoms compared with standard 
care, that is, not-systematic reporting of symptoms of progressive disease.  
 
The assessment will take a 1-year perspective and a 5-year perspective 
 
Study perspective: 
The evaluation will use a hospital perspective only 
 
Data 
Data  for  the  assessment  of  patient  unit  costs  (intervention  costs;  derived  hospital 
costs) will be collected outside the trial: 
 
Intervention costs will be assessed using structured interviews with study nurses, 
doctors and other relevant personnel at 3-4 of the participating hospitals. The purpose 
of  these  interviews  is  to  describe  and  quantify  the  resource  use  relating  to  the 
intervention  (e.g.  the number of  telephone calls,  clinical  staff  time  spent on  patient 
contacts, IT support etc.) and relating to patient telephone contact in the control arm. 
The resource used will be valued using average net salary information for the relevant 

38 
 
type of personnel plus social costs in accordance with the recommendations for cost 
assessment in health care. 
 
Derived hospital costs will be assessed in a research project based at the National 
Board  of  Health  Data  (Sundhedsdatastyrelsen)  or  Statistics  Denmark.  Data  on 
resource  use  –  eg.  Procedures,  admissions  and  dates,  ambulatory  contacts,  and 
hospital costs for each of the participating patients will be collected from the National 
Patient Registry and linked with patient data from the National Cost Database. The 
research project is subject to approval from the Danish Data Protection Agency.  
 
Mortality data are collected in the trial and survival analysis for the accumulation of 
life years will be undertaken as part of the statistical analysis plan. 
 
Health-related quality of life data based on the utility weights from the EQ-5D-5L 
questionnaires is collected as part of the trial at baseline and every second month. The 
EQ-5D-5L derived utility weights will be used to calculate the QALYs.  
 
EQ 5D-5L is a generic questionnaire, consisting of five domains and a VAS scale and 
it  is  commonly  used for estimating the  generic  health  status,  with  high  validity and 
reliability in various health conditions (3,4) and should be more sensitive at eliciting 
changes in the health status than the previous EQ-5D-3L questionnaire.  
 
Analysis 
Health resources used are described and compared for both arms (intervention and 
derived hospital costs) and are inflated to the price year 2018 using the Danish Hospital 
PL index (price and wage). Confidence intervals will be estimated using bias-corrected 
non-parametric bootstrapping. 
 
In the five-year scenario, both costs and QALYs will be discounted to present value 
using an annual discount rate of 3%. 
 
Furthermore, subgroup analysis will be undertaken to investigate explanatory factors 
for cost differences not related to the trial intervention. Finally, a number of sensitivity 
analyses will be run for the assessment of the robustness of the study assumptions. 

39 
 
 
Publications 
The  health  economic  evaluation  will  be  described  in  a  paper  and  submitted  for  a 
scientific  journal  in  accordance  with  good  reporting  practice  for  health  economic 
studies (4). 
 
 
References 
 
1)  Drummond, M.; Schulper, MJ; Claxton, C; Stoddard, GL; Torrance GW.: 
“Methods for the economic evaluation of health care programmes”. 4th Edition, 
Oxford University Press, 2015 
2)  Herdman, M. et al. Development and preliminary testing of the new five-level 
version of EQ5D (EQ5D-5L). Qual.Life.Res.20, 1727-36 ( 2011) 
3)  Janssen MF et al. Measurement properties of the EQ-5D-5L compared to the 
EQ5D-3L across eight patient groups: a multi-country study. Qual.Life.Res. 22, 
1717-27. (2013) 
4)  Husereau D; Drummond, M; Petrou, S; Carswell, C; Moher, D, Greenberg D; 
Augustovski, F; Briggs AH; Mauskop J; Loder E. and on behalf of the 
Consolidated Health Economic Evaluation, Reporting Standards (CHEERS) 
statement CHEERS Task Force. Cost-effectiveness and Resource Allocation 
2013, 11:6 
Downloaded from http://www.resource-allocation.com/content/11/1/6