FDG-PET/CT Versus Conventional CT for Response Monitoring in Metastatic Breast Cancer: A Multicenter Randomized Clinical Trial (MONITOR-RCT)
Phase: NA
Conditions: Metastatic Breast Cancer, Response Monitoring
Sponsor: Odense University Hospital

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FDG-PET/CT versus conventional CT for response monitoring 
in metastatic breast cancer: A multicenter randomized clinical 
trial (MONITOR-RCT) 
 
Sponsor: Odense University Hospital, J. B. Winsløws Vej 4, 5000 Odense, Denmark  
Delegated sponsor and authorized person: 
Malene Grubbe Hildebrandt, MD, PhD, Clinical professor,  
Department of Nuclear Medicine, Odense University Hospital, Denmark  
Involved countries and centers: 
Denmark: 
Region of Southern Denmark: 
- 
Odense University Hospital, Odense, Denmark 
- 
Hospital Lillebaelt, Vejle, Denmark 
- 
Esbjerg Hospital, Esbjerg, Denmark 
- 
Sønderborg Hospital, Sønderborg, Denmark 
 
Central Denmark Region: 
- 
Aarhus University Hospital, Aarhus, Denmark 
 
North Jutland Region: 
- 
Aalborg University Hospital, Aalborg, Denmark 
 
Capital Region of Denmark: 
- 
Rigshospitalet, Copenhagen, Denmark 
- 
Herlev og Gentofte Hospital, Copenhagen, Denmark 
 
Germany: 
- 
Technical University of Munich, Munich, Germany 
 
Italy: 
- 
IRCCS Humanitas Research Hospital, Milan, Italy 
- 
IRCCS Bologna University Hospital, Bologna, Italy 
  
Declarations: 
The clinical trial will comply with the protocol, current statutory legislation, the CTR regulation, and 
the principles of good clinical practice (GCP). 
 
 
 

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Time schedule: 
Start of trial: 01.10.2024  
Recruitment period: 12-18 months  
Individual Follow-up-period: Between 36 and 54 months 
End of trial / end of data collection: 01.04.2029  
Completion of primary analyses: 01.07.2029  
 
Table of Content 
1. List of abbreviations .................................................................................................................... 5 
2. Background information .............................................................................................................. 6 
2a) Study rationale ...................................................................................................................... 6 
2b) Current knowledge ................................................................................................................ 7 
2c) Potential benefits and risks .................................................................................................... 8 
2d) Interventions .......................................................................................................................... 8 
2e) Study population ................................................................................................................... 8 
2f) Patient involvement ................................................................................................................ 8 
2g) Relevance of the trial ............................................................................................................. 9 
3. Trial plan and trial design ............................................................................................................ 9 
3a) Study objectives .................................................................................................................... 9 
3b) Study design ......................................................................................................................... 9 
3c) Randomization .................................................................................................................... 10 
3d) Details on intervention ......................................................................................................... 10 
3e) Study procedures ................................................................................................................ 12 
3f) Authorizations ....................................................................................................................... 13 
3g) Groups and subgroups ........................................................................................................ 13 
3h) Duration of participation and trial periods ............................................................................ 13 
3i) End-of-trial ............................................................................................................................ 13 
3j) Stopping of trial .................................................................................................................... 14 
3k) Randomization code ............................................................................................................ 14 
3l) Case Report Files (CRFs) .................................................................................................... 14 
4. Selection of trial subjects and criteria for inclusion and exclusion .............................................. 15 
4a) Inclusion criteria .................................................................................................................. 15 

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4b) Exclusion criteria ................................................................................................................. 15 
4c) Leaving the trial ................................................................................................................... 16 
5. Treatment of trial subjects ......................................................................................................... 16 
5a) Interventions ........................................................................................................................ 16 
5b) Treatment definition in terms of active substance ................................................................ 17 
5c) Concomitant treatment/medication ...................................................................................... 17 
5d) Adherence ........................................................................................................................... 18 
5e) Labelling and unblinding of investigational medical product ................................................. 18 
5f) Compliance monitoring ......................................................................................................... 18 
5g) Subsequent treatment ......................................................................................................... 18 
6. Evaluation of effect.................................................................................................................... 18 
6a) Effect parameters ................................................................................................................ 18 
6b) Measurements, registration, analysis .................................................................................. 19 
7. Safety evaluation ...................................................................................................................... 19 
7a) Safety evaluation ................................................................................................................. 19 
7b) Measuring, recording and analysing the safety parameters ................................................. 21 
Patients will automatically be observed after each FDG injection for at least  one hour as part of 
the clinical routine, as the patients are waiting 60 minutes for the scan subsequent to FDG 
injection. .................................................................................................................................... 21 
7c) Reporting of adverse events ................................................................................................ 21 
7d) Notifications about adverse events ...................................................................................... 21 
7e) Arrangements for avoiding and treating complications ......................................................... 21 
7f) Monitoring in case of adverse events/adverse reactions ...................................................... 21 
8. Statistics ................................................................................................................................... 22 
8a) Statistics .............................................................................................................................. 22 
8b) Sample size considerations ................................................................................................. 23 
8c) Significance level ................................................................................................................. 23 
8d) Termination of the trial and interim analyses ........................................................................ 23 
8e) Handling of missing data ..................................................................................................... 23 
8f) Deviations from statistical analysis plan ............................................................................... 23 
8g) Analysis population .............................................................................................................. 24 
9. Charter of DSMB/DMC .............................................................................................................. 24 
9a) Charter of DSMB/DMC ........................................................................................................ 24 

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10. Source data ............................................................................................................................ 24 
10a) Description of arrangements for monitoring the conduct of the clinical trial ........................ 24 
10b) Statement of the sponsor .................................................................................................. 24 
11.Quality control and quality assurance ....................................................................................... 24 
11a) a description of measures that will be implemented in case of data security breach in order 
to mitigate the possible adverse effects ..................................................................................... 24 
12. Ethical questions ..................................................................................................................... 24 
12a) Summary and relevance .................................................................................................... 24 
12b) Exposure to radiation ........................................................................................................ 25 
12c) Risks and benefits ............................................................................................................. 25 
12d) Informed consent procedure .............................................................................................. 25 
12e) Data protection .................................................................................................................. 26 
12f) Additional ethics ................................................................................................................. 26 
13. Handling and archiving data. ................................................................................................... 26 
13a) Rules on the protection of personal data. .......................................................................... 26 
13b) Ensuring confidentiality...................................................................................................... 27 
14. Compensation trial participants, investigator and funding. ....................................................... 27 
14a) Insurance and Compensation in Denmark and Bologna (Italy) .......................................... 27 
14b) Insurance and Compensation in Germany and Milan (Italy) .............................................. 27 
15. Guidelines for publication. ....................................................................................................... 27 
15a) Publication strategy ........................................................................................................... 27 
16. Summary and appendices. ...................................................................................................... 28 
16a) Synopsis ........................................................................................................................... 28 
16b) Appendix 1: Estimated effective dose of MONITOR project patients .................................. 28 
16c) Appendix 2: Arrangements for tracing, storing, destroying and returning ........................... 29 
17. Literature references. .............................................................................................................. 29 
18. Figures and Tables. ................................................................................................................. 32 
 
  
 

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1. List of abbreviations 
FDG: Fludeoxyglucose (18F) 
CE-CT: Contrast-enhanced CT 
EMA: European Medicines Agency 
MBC: Metastatic breast cancerPERCIST: PET Response Evaluation Criteria in Solid Tumors  
RECIST: Response Evaluation Criteria in Solid Tumors 
EANM: European Association of Nuclear Medicine 
PROM: Patient-reported outcome measure 
eGFR: estimated glomerular filtration rate 
WOCBP: Women of childbearing potential 
SmPC: Summary of Product Characteristic 
PERCIST-MBC: MBC-adjusted version of PERCIST 
CRF: Case Report File 
C(M)R: Complete (metabolic) response  
P(M)R: Partial (metabolic) response 
S(M)D: Stable (metabolic) disease 
P(M)D: Progressive (metabolic) disease 
AE: Adverse event 
SAE: Severe adverse event 
SAR: Serious adverse related event 
SUSAR: Suspected Unexpected Serious Adverse Reaction 
GCP: Good clinical practice 
GDPR: General Data Protection Regulation 
PI: Principal Investigator 
Qol: Quality of life 
HRQoL: Health-related quality of life 
 
 
 
 
 

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2. Background information  
2a) Study rationale  
Investigational medicinal product 
Fludeoxyglucose (18F) 
The glucose analog —Fludeoxyglucose (18F)—FDG for PET/CT can be used to detect metabolic 
active malignant lesions from cancer and for monitoring response in cancer diseases, i.e., breast 
cancer. The isotope 18F emits radiation that is detected in the PET scanner.  FDG-PET can be 
combined with diagnostic contrast-enhanced CT (CE-CT) with iodinated contrast administered 
intravenously. Throughout this protocol, the procedure referred to as FDG-PET/CT is in fact the 
combination of FDG-PET with a contrast-enhanced diagnostic CT scan. 
The European Medicines Agency (EMA) has proposed therapeutic indications for FDG-PET/CT in 
breast cancer, which include staging locally advanced breast cancer and detecting recurrence. 
However, as of now, monitoring response in metastatic breast cancer (MBC) is not included. 
Evidence from several observational studies supports its use (see 2b), but this evidence requires 
validation through prospective randomized trials. It is worth noting that FDG-PET/CT has been 
approved for response monitoring in other types of cancers, such as malignant lymphoma and 
head-and-neck cancers, according to EMA’s Core Summary of Product Characteristics for 
Fludeoxyglucose.  
Auxillary medicinal products 
Conduct of a diagnostic contrast-enhanced CT scan in the comparator group or of the CT-part of 
the PET/CT in the intervention group will require an injection of some solution as standard iodinated 
contrast. The choice of the solution varies from center to center. In addition, medical breast cancer-
directed treatments, including standard and experimental treatments, will be applied to all patients. 
These medical treatments are not the treatments under study and do not influence the conduct of 
the study. 
Rationale for comparison  
FDG-PET/CT is increasingly used in cancer staging, and several studies have shown improved 
sensitivity of FDG-PET/CT compared with conventional imaging for diagnosing metastatic breast 
cancer (MBC). Consequently, it has to be expected that FDG-PET/CT can detect disease 
progression earlier than CT in patients treated for MBC, which a prospective study has 
corroborated.  
We hypothesize that MBC patients monitored with FDG-PET/CT will start second-line therapies 
earlier due to earlier detection of disease progression. This has the potential to increase the 
beneficial effect of second-line therapies at the individual level and result in a delayed need for 
third-line therapies, prolonged overall survival, and improved quality of life compared with patients 
monitored with conventional CT. This hypothesis aligns with the results of a retrospective, 
observational study.  

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2b) Current knowledge 
Extensive literature has shown the high accuracy of FDG-PET/CT for detecting distant metastases 
from primary and recurrent breast cancer in most molecular subtypes (1-3). Consequently, FDG-
PET/CT has recently been introduced in European clinical guidelines for metastatic staging in 
breast cancer patients (4). Most molecular subtypes of breast cancer appear FDG-avid with higher 
FDG-uptake in tumours with more aggressive characteristics (Triple-negative breast cancer, high 
Ki67, and high-grade tumours) (5-7). Lobular carcinomas remain the most challenging type to 
diagnose since these tumours and corresponding metastatic lesions tend to have lower FDG 
uptake and a less typical dissemination pattern (6, 8). 
Some observational studies have directly addressed the question of the value of FDG-PET/CT in 
monitoring MBC patients compared to CT and are briefly described below. 
1) Riedl et al. (2017) reported on 65 MBC patients who had both FDG-PET/CT and CT before 
initiation of therapy (baseline scan) and 90 days afterwards. The prediction of outcome was 
compared between the modalities. They concluded that PET Response Evaluation Criteria 
in Solid Tumors (PERCIST) was superior to Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 in predicting progression-free and disease-specific survival (9). 
2) Naghavi-Behzad et al. (2021) analyzed the clinical impact of CT or FDG-PET/CT for 
response monitoring. In 286 CT scans and 189 FDG-PET/CT scans, it was shown that FDG-
PET/CT classified scans as a regressive disease more often than CT (46.0% vs 12.2%) and 
classified scans as stable disease less often than CT (31.2% vs 70.6%) (10).  
3) Vogsen et al. (2021) performed a feasibility study of PERCIST for monitoring patients with 
MBC. In this study, the one-lesion SULpeak was used and along with the nadir scan, 
PERCIST one-lesion was found as a feasible tool to apply for monitoring response in MBC 
patients (11).  
4) Vogsen et al. (2023) reported the results of a prospective study in 87 MBC patients 
monitored by CT scans every 3rd month and a median follow-up time of 16 months. PET/CT 
was applied in a blinded manner in addition to CT, which was used for routine clinical 
evaluation. The median time from detection of progression by FDG-PET/CT to detection by 
CT was six months. CT detected progression earlier than FDG-PET/CT only in one patient 
(12). 
5) Naghavi-Behzad et al. (2022) reported the results of a retrospective analysis of all MBC 
patients diagnosed with MBC at Odense University Hospital between 2007 and 2018. 
During this time, the treating clinician made the monitoring modality choice and reflected 
mainly personal preferences. Consequently, the two groups monitored only with CT (n=144) 
or FDG-PET/CT, respectively (n=83), were comparable in their patient characteristics. The 
median survival was 44 months in the FDG-PET/CT group compared to 30 months in the 
CT group. A multivariable Cox regression analysis indicated an HR of 0.44 (95%CI: 0.29-
0.68, p=0.001). The patients monitored with PET/CT had, on average, a larger time from 
detection of the first progression to detection of the second progression and received, on 
average fewer treatment lines (13).  
6) Vogsen et al. (2023) analysed FDG-PET/CT compared with CT and found that tumour 
response was significantly associated with progression-free and disease-specific survival, 
while no association was found for tumour response on CT (14). 

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In summary, the existing clinical knowledge suggests that patients with MBC may benefit from being 
monitored by FDG-PET/CT instead of CT with respect to prolonged survival and reduced treatment 
burden. The reduced treatment burden may result in improved quality of life. 
2c) Potential benefits and risks 
FDG-PET/CT is a frequently used modality in daily clinical practice, with no reported toxicities 
following injection of FDG.  
The use of FDG-PET/CT instead of CT for response monitoring implies an increase in radiation 
dose from 9 mSv to 13 mSv, which results in an increase in 4 mSv per scan, thus ranging from a 
minimum of 4 mSv (one scan) to 92 mSv (23 scans) with a long-term risk of secondary radiation-
induced cancers (cf. Appendix 1).  
The interventional arm examinations will last up to two hours, while conventional examinations in 
the CT arm last less than 30 min. The physical exposure (placement in a tube) is comparable across 
the two modalities.  
Participation in the trial implies a minimal additional burden for the patients. The additional 
procedures are limited to being informed about the study, deciding on participation, signing the 
informed consent form, and filling out questionnaires at home every three months during the first 
year and every six months later. Questionnaires can be filled out electronically or on paper, 
depending on patient preferences.  
2d) Interventions  
Response monitoring based on FDG-PET/CT (intervention) will be compared with response 
monitoring based on CT (standard).  
The FDG dose depends on the PET scanner system, but it is usually between 3-4 mBq per kilo 
bodyweight, following local guidelines adhering to the European Association of Nuclear Medicine 
(EANM) guidelines (15). The FDG dose will be registered for each scan. The exact FDG dose will 
be registered for each scan. FDG will be administered in nuclear medicine departments as a single 
intravenous injection, 45-75 minutes before the examination begins. The image acquisition takes 
20-60 minutes. 
The schedule for response monitoring scans will adhere to international clinical guidelines. As such, 
scans are expected to be performed every 8-16 weeks, depending on the type of systemic 
treatment given. Medical treatment will be given according to local guidelines or as part of 
experimental trials and is not considered an intervention in the study.  
2e) Study population  
The study population will consist of patients with newly diagnosed metastatic breast cancer initiating 
first-line treatment at one of the participating sites.  
2f) Patient involvement 
Two patient representatives with prior breast cancer and two with metastatic breast cancer are 
currently involved in designing the MONITOR-RCT study. They contribute to developing patient 

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information material, deciding on ethical issues, and communicating the project objectives and, 
later, the results to patients and citizens in layman terms.  
2g) Relevance of the trial 
Breast cancer is the most commonly diagnosed cancer in Europe, and it is widely anticipated that 
30% of patients diagnosed with primary breast cancer will eventually develop MBC (16). Exact 
numbers for MBC patients are unavailable at the European level, but about 120,000 patients per 
year are suggested to reach this state. Due to in the improvement in survival rates among MBC 
patients, the number of patients living with MBC will increase in the future. 
There has been substantial progress in the treatment of MBC patients over the last decades, 
allowing to select today from a variety of (individualized) treatment choices in the case of a need 
for a second or third-line therapy. However, MBC patients can only benefit from these advantages 
if the need for treatment is detected in good time. The current response monitoring with CT cannot 
be regarded as optimal in this situation, as it only allows the detection of morphological changes. 
Molecular imaging  such as FDG-PET/CT can be a game changer, as it relies on changes in 
metabolic activity. Consequently, FDG-PET/CT can detect disease progression earlier than CT in 
patients treated for MBC, which a prospective study has corroborated (12).  
The MONITOR-RCT is hence addressing a highly relevant question, and in case of demonstrating 
the expected benefit, it may substantially impact care in MBC patients. It is designed to target the 
population expected to benefit from FDG/PET-CT and to compare the interventions of interest.  
3. Trial plan and trial design  
3a) Study objectives 
The primary objective of the MONITOR-RCT is to demonstrate that in patients with MBC, response 
monitoring based on FDG-PET/CT is superior to response monitoring based on CT with respect to 
overall survival. The objective will be based on applying standardized response evaluation criteria, 
using an appropriate adaptation of the PERCIST criteria for FDG-PET/CT and the RECIST1.1 
criteria for CT.  
Secondary objectives of the MONITOR-RCT are to demonstrate superiority with respect to the 
quality of life and exposure to oncologic treatment and to investigate the cost-effectiveness.  
Consequently, the primary endpoint of the study is overall survival. Secondary endpoints are quality 
of life, exposure to oncologic treatment, and cost-effectiveness.  
3b) Study design 
The MONITOR-RCT study will be an international multicenter study. The design will be a parallel 
group comparative randomized trial comparing an experimental monitoring strategy based on 
FDG-PET/CT with a standard monitoring strategy based on CT.  
A flowchart depicting the trial design is seen in Figure 1.  

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3c) Randomization 
Randomization will be based on electronic randomization within a REDCap database. It will be 
stratified by site and and an prognostic index based on blocks with a randomized block length of 4 
or 6. The prognostic index will be based on the same variables as used for adjustment in the 
primary analysis (cf. Section 8a ). The prognostic index will describe the estimated 42-months-
survival-probability when monitored by PET/CT and will be dichotomized at a threshold of 0.5. 
Blinding of patients and health care professionals involved is not intended. However, data 
collection of quality-of-life questionnaires will be based on a centralized procedure, minimizing the 
risk of assessment bias.  
3d) Details on intervention 
Scan techniques 
Imaging will be performed with the standard equipment of the Department of Radiology and the 
Department of Nuclear Medicine at each site, which will be in accordance with international and 
national guidelines of CT and FDG-PET/CT (15).  
CT scans will be performed in diagnostic quality, using iodinated contrast (CE-CT). In cases of 
allergy to the iv contrast or compromised kidney function, diagnostic CT scans will be performed 
without iodinated contrast. 
FDG-PET/CT scans will be performed with at least 4 hours faste before the FDG injection and 
serum glucose level (no correction) must be less than 200 mg/dL. Additionally, the estimated 
glomerular filtration rate (eGFR) needs to be a minimum of over 30 ml/min/m², while adhering to 
local guidelines. FDG is injected intravenously (iv) one hour before imaging, and patients must rest 
between the injection and the scan. The FDG dose depends on the PET scanner system, but it is 
usually between 3-4 MBq per kilo bodyweight, following local guidelines adhering to the EANM 
guidelines (15). CT scans as part of FDG-PET/CT will be performed in diagnostic quality, using 
iodinated contrast (CE-CT). 
All CT and FDG-PET/CT scans for individual patients will be intentionally performed on the same 
type of scanner, with any deviations documented during the study. Each local site will establish and 
apply scan protocols that are comparable, though not identical, between hospital sites. Scan 
protocols will be regularly monitored, and any necessary updates will be registered. 
Precautionary measures  
The guidelines for FDG-PET/CT scans include several precautionary measures to ensure the 
safety of the patients. Consequently,  various parameters will be considered, including the patient's 
latest chemotherapy, weight, height, blood sugar levels, eGFR, FDG dose, injection-scan time, 
fasting duration, scan type, acquisition protocol, reconstruction method, software version, and CT 
contrast. Additionally, we will adhere to local guidelines to determine an acceptable delay between 
the latest received treatment (including chemotherapy) and the scanning as one of the 
precautionary measures before conducting the scan. 
Furthermore, as a precautionary measure, a pregnancy test is required for women of childbearing 
potential (WOCBP), defined as those who have not undergone surgical sterilization or who have 
not been postmenopausal for at least 12 consecutive months, if they have missed periods. The test 

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used for pregnancy confirmation will be a standard blood test, such as the serum beta-hCG test. 
It's important to note that according to the Summary of Product Characteristic (SmPC), no special 
recommendations are needed for patients regarding the use of contraceptives. 
Each patient will receive a daily weight-adapted FDG-dose for each scan, and the dose will be 
registered for each scan for reference and analysis.  
Similarly, the guidelines for CE-CT scans include several precautionary measures. Consequently, 
factors such as the patient's latest chemotherapy, eGFR, CT contrast usage, and any other relevant 
scans and results will be taken into account. Additionally, as a precautionary measure, pregnancy 
status will be assessed in accordance with local guidelines. 
Number of response monitoring scans 
At the level of a single patient, a maximum of one baseline scan and about 23 follow-up scans will 
be performed in MONITOR-RCT. Additional scans, i.e., bone scans or brain MRI, can be used at 
the discretion of the oncologists and will be an option in both the CT and FDG-PET/CT arm.  
A baseline scan should be performed according to randomization, i.e., CE-CT in Arm A and FDG-
PET with diagnostic contrast-enhanced CT in Arm B. In case a corresponding scan already exists, 
a new baseline scan can be omitted. However, the time between the baseline scan and treatment 
initiation may not exceed 28 days (Table 1). 
Assessment of treatment response 
The assessment of treatment response will be locally performed by specialists in radiology or 
nuclear medicine at each patient-recruiting center using standard response evaluation criteria for 
both modalities. In the CT arm, a radiologist will prepare a report which directly refers to RECIST 
1.1. (17) or allows the oncologists to apply RECIST 1.1. In the FDG-PET/CT, a nuclear medicine 
physician will prepare a report which directly refers to an MBC-adjusted version of PERCIST 
(PERCIST-MBC) (18). The diagnostic CT part of the FDG-PET/CT will be visually assessed and 
reported by a radiologist. 
In cases of equivocal findings, we seek confirmation by consulting with another specialist. This 
typically involves reaching a consensus on the report or conducting a review of the initial evaluation 
before communicating the findings to the oncologists. This process applies to both types of scans. 
In both groups, radiologists or nuclear medicine specialists will report incidental/unsolicited findings 
considered relevant for clinical reporting. This process will ensure that all relevant findings are 
communicated to the treating oncologists, who will then take care of any issues from the imaging 
reports. Additionally, participants will be notified directly if there is certainty or a high probability of 
a serious illness that can be treated, prevented, or alleviated. This decision is made by the treating 
oncologists – as it is already today clinical practice. This direct communication ensures that 
participants are promptly informed about relevant health information concerning their well-being. 
This information on incidental findings and their related consequences is integral to the 
implementation of FDG-PET/CT and is part of the overall study outcomes, such as quality-of-life 
and cost-effectiveness analyses. 
Deviations from the intended modality 
Monitoring by a specific modality means the intention to consider this modality as the first choice 
at any scan visit. However, if there are temporary clinical indications against this modality (e.g. 
entering pharmaceutical clinical studies requiring a specific modality for response monitoring), an 

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alternative modality should be used. Corresponding modality-specific guidelines should be 
followed.  
In cases of a new incidence of allergy to FDG during the study, patients in the FDG-PET arm will 
be monitored using CT.   
In case of a patient becoming pregnant during the study, monitoring will proceed according to local 
standards.  
In case it is clinically indicated that monitoring is no longer necessary, monitoring should be 
stopped.  
In all these cases, the patient will remain in the study. 
3e) Study procedures  
The informed consent for the trial will be obtained according to applicable national legislation. 
Quality of life questionnaires  
Quality of life questionnaires will be completed at home every three months during the first year 
and every six months later. Depending on patient preferences, these questionnaires can be filled 
out electronically or on paper. The sponsor will contact the patient directly. In the case of using 
paper forms, the patient will send back the questionnaire directly by ordinary mail to the sponsor 
(at the sponsor's cost).  
Only at baseline, the patients will be offered to fill out the questionnaire at the clinic, either on paper 
or a tablet. In case of using a paper form, the local site will send the form to the sponsor.  
In case of missing questionnaires, the sponsor will automatically send reminders to the patient 
either electronically or per ordinary mail in accordance with the preference chosen by the patient. 
In case of lacking response in spite of a reminder, the local investigator will be informed and local 
staff will remind  the patients at their next visit or directly by telephone or SMS.  
Information from the questionnaires will only be used for research purposes, not for daily clinical 
management.  
Two questionnaires will be used: 
 
EQ-5D-5L  
 
FACT-B  
In addition, patients can report complaints related to the conduct of scans in a final open question 
at the end of the questionnaires. 
All questionnaires will be available in English, Danish, German, and Italian.  
Variables collected  
A list of all variables collected as part of the study is seen in Table 3. It also informs about how the 
data is collected.  
In addition, data on healthcare utilization and costs will be extracted from national registries at the 
end of the trial period.  
Data Registration  

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Data will be collected in a secure and central REDCap database. All sites will be able to use the 
REDCap database for data entry. The local investigator will manage the extraction of data from the 
hospital records. 
If patients do not show up for a follow-up scan or oncology visit, the the patient and/or relatives will 
be contacted to check the reason and to plan another day for the scan/visit. These follow-
up/reminders will be performed in accordance with applicable national requirements. 
At the end of the data collection phase, patients with unclear living status will be checked by contact 
with local authorities/local registries. 
3f) Authorizations 
Fludeoxyglucose (18F) follows the specifications set by the European Pharmacopeia and is an 
authorized medicinal compound (Marketing Authorization). Fludeoxyglucose (18F) is produced 
according to the standards laid out in the EU-GMP legislation for sterile and radioactive compounds. 
The production facilities are controlled via inspections from the Danish Medicines Agency; 
approximately every 2 years. Fludeoxyglucose (18F) can be distributed to other hospital facilities 
following the EU-GDP legislation.  
3g) Groups and subgroups 
Participating patients should have newly diagnosed metastatic breast cancer and be considered 
eligible for initiating first-line medicinal treatment and subsequent regular response monitoring.  
This is the patient population for whom a benefit from FDG-PET/CT-based response monitoring is 
expected. They are very similar to the criteria defining the populations investigated in Vogsen et al. 
(2023) and Naghavi-Behzad et al. (2022) (12, 13). 
3h) Duration of participation and trial periods 
In MONITOR-RCT, patients will be followed for a maximum of 4 years and 6 months, encompassing 
a maximum of about 23 monitoring scans for each patient following the initial baseline scan. 
Recruitment is planned to begin uniformly across centers between October and December 2024. 
The recruitment period will last between 12 and 18 months, aiming to enroll a total sample size of 
420 patients. The last follow-up assessment will be conducted no later than April 1, 2029. 
3i) End-of-trial 
Data collection will cease latest April 1st, 2029, with statistical reporting completed by July 1st, 2029 
and the main publication finalized by October, 1st 2029. The trial will end together with the end of 
data collection.  
This plan is based on the assumptions that recruitment can be finished within 18 months after start 
of the trial. In this case the intended follow up times between 36 and 54 months will be sufficient for 
evaluation of the primary endpoint according to the sample size considerations in Section 8b). In 
case of delays in the recruitment phase, the trial period will be extended to ensure an average 
follow-up time of 45 months.   

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3j) Stopping of trial  
The coordinating investigators can stop the trial if external evidence or feedback from the local 
investigators indicates potential harm to patients or in case of practical issues such as insufficient 
inclusion of patients.   
3k) Randomization code 
The randomization code will be stored in the REDCap database. Code breaking is not relevant in 
MONITOR-RCT.  
3l) Case Report Files (CRFs) 
Data to be extracted from the hospital records (cf. Table 3) will be directly typed into the central 
REDCap data base.  
Questionnaires filled out by the patient electronically at home or on a tablet at the first visit will 
directly be stored in the central REDCap data base. Questionnaires filled out by the patient on 
paper will be sent to the sponsor and typed into the data base by the sponsor.  
All variables collected by the local investigator at randomization, at the Department of Radiology, 
or the Department of Nuclear Medicine (cf. Table 3),will be directly typed into the central REDCap 
data base. 
Paper CRFs will be used to collect data on deaths and reasons for stopping before end-of-study. 
They will be typed into the REDCap data base by the local investigator.  
3m) Embedding of MONITOR RCT in the Horizon Europe project "PREMIO COLLAB"  
The MONITOR-RCT will be part of the PREMIO COLLAB project funded by the European 
Commision as part of the HORIZON-MISS-2023-CANCER-01 call. It constitutes one of ten work 
packages. The MONITOR-RCT will interact with the other work packages in various forms:  
1. All participating patients in MONITOR RCT will be offered participation in a research cohort, 
aiming at including at least 100 patients. Participants of this cohort will be asked for blood 
samples at each scan visit. These will be used to analyze the value of ctDNA analysis and 
deeper genome sequencing for early detection of non-response and identification of 
treatment targets (WP8). In addition, a low-dose CT will be performed in these patients and 
evaluated with respect to the ability of non-response detection (WP7).  
2. Participating patients (and their family members) will be offered to participate in a one-point 
survey.  The survey aims to investigate family health in the diagnostic period, covering 
aspects such as family social and emotional health processes, family healthy lifestyle, family 
health resources, and family external social supports. In addition, patients will be asked 
about their experience with being monitored (WP4).  
3. The FDG-PET/CT scans, data on the clinical evaluation, and clinical outcomes will be used 
to develop next-generation response criteria (WP6).  
4. The CT and FDG-PET/CT scans and the result of the evaluation of the RECIST and 
PERCIST-MBC response evaluation criteria will be used to develop tools for improved 

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image analysis (WP2), for automatic reporting generation and writing, for early detection of 
non-reponse, and for assessment of heterogeneity (WP7).  
5. To ensure ethical and legal requirements for human subjects in research, an ethical work 
package (WP9) is established to support and better understand patients' and carers' 
diagnostic needs as health needs, with the goal of developing guidelines for ethical 
decision-making for diagnostic imaging in cancer care in the context of monitoring.  
For all these activities, we will seek approval separately.  
4. Selection of trial subjects and criteria for inclusion and exclusion  
4a) Inclusion criteria 
Criteria for inclusion will be: 
1) Women and men aged ≥18 years  
2) Diagnosis of distant relapsed MBC (biopsy-verified) or de novo breast cancer. In patients 
with distant relapsed MBC, biopsy verification from a distant metastasis is required.  In 
patients with de novo MBC, biopsy verification of primary tumor and diagnostic imaging with 
distant metastasis with a typical pattern of MBC is required.  
3) Considered eligible for first-line systemic treatment 
4) Considered eligible for continuous treatment monitoring by scans.  
5) Signed informed consent 
6) Participants must have the ability to read and understand the following languages based on 
their country of participation: in Denmark, patients must be able to read and understand 
Danish; in Italy, they must be able to read and understand Italian or English; and in 
Germany, they must be able to read and understand German or English. 
In case of patients for whom it is necessary to start first-line systemic treatment while still waiting 
for the evaluation of the biopsy, it is allowed to include the patients, as long as the other criteria are 
fulfilled and the biopsy is made or planned. In case verification by biopsy fails, the patients will leave 
the trial (cf. 4c). We expect that up to 3% of the patients included will start first-line systemic 
treatment prior to evaluation of the biopsy. 
4b) Exclusion criteria 
Criteria for exclusion will be: 
1) Pregnant or lactating women 
2) Ongoing oncological treatment for another cancer 
3) Exclusively brain metastasis 
4) Allergy to FDG 
The following arguments justify the exclusion criteria: Any radiation exposure should be avoided in 
pregnant women. Oncological treatment for another cancer type is associated with a high risk of 
dying for reasons the intervention cannot influence. For patients with exclusively cerebral 
metastases, a diagnostic modality (typically magnetic resonance imaging) other than those 
currently under study will be indicated. 
Pregnancy status and lactation status will be assessed based on a self-reporting by the patient as 
part of the performing all scans. Necessary precautions will be implemented in adherence to local 

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guidelines to ensure patient safety regarding pregnancy. A more detailed assessment will be 
performed at each scan (cf. Section “Scan techniques”). 
Other criteria of interest 
Allergy to iodinated CT contrast will not be an exclusion criterion, but patients will be monitored 
using diagnostic CT without iv contrast or will obtain corresponding premedication (both groups).  
Diminished renal function, typically characterized by an eGFR below 30 mL/min, will not serve as 
an exclusion criterion, but patients will be monitored using diagnostic CT without iv contrast (both 
groups). Patients can enter oncological treatment trials while being monitored in this study.  
Scans would typically not be clinically indicated for patients who are unable to consent to study 
participation or for patients with a short expected lifetime. 
4c) Leaving the trial  
Patients can stop participating in the trial at any time point without explanation. The local 
investigators can withdraw patients from the trial if further participation constitutes a risk for the 
patient. Participants may be withdrawn if they exhibit serious anxiety or reluctance towards being 
monitored or completing questionnaires that remind them of the situation. 
Patients who are withdrawn or withdraw themselves will be offered to continue monitoring at the 
participating center according to local standards. The statistical analyses will include the data 
collected from these patients until withdrawal. 
Patients, who have been included while still waiting for the evaluation of the biopsy, will leave the 
trial in case of failure of verification. The data of these patients will not be included in any analysis. 
 
4d) Inclusion of subjects who are incapable of giving informed consent  
Informed written consent will be required from all participating patients.  
4e) Exclusion of gender or age groups explanation 
There are no restrictions on age and gender except for restricting the participation to adults. MBC 
is extremely rare below the age of 18.  
As MBC is rare in males, we expect only a few males to be recruited. As the oncology department 
typically handles MBC in males, we do not expect males to be underrepresented.  
5. Treatment of trial subjects  
5a) Interventions  
The intervention of interest is the use of FDG-PET/CT for response monitoring compared with CT 
for response monitoring. The use of CT as a monitoring modality represents the usual care in 
patients with MBC. 
FDG-PET/CT scans will be evaluated using the PERCIST-MBC criteria, whereas the CT scan will 
be evaluated using the RECIST 1.1 criteria (17, 18). Both criteria aim at classifying the patient as 

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having complete (metabolic) response (CR/CMR), partial (metabolic) response (PR/PMR), stable 
(metabolic) disease (SD/SMD), or progressive (metabolic) disease (PD).  
PERCIST-MBC is an adaptation of PERCIST (18, 24) for monitoring patients with MBC. PERCIST-
MBC is defined based on data from the MESTAR study and previous studies (11, 12). It introduces 
the nadir scan for comparison in cases where the disease has regressed compared with the 
baseline scan. PERCIST-MBC constrains, in particular, the criteria for progression by detecting new 
lesions and aims to cover a broader group of MBC patients, hence covering also the patients with 
initially low metabolic disease.  
Clinical decision-making: For patients in the intervention group, clinical decision-making will be 
supported by FDG-PET/CT and PERCIST-MBC, while the conventional group will be supported by 
the CE-CT and RECIST 1.1. The decision-making will be in both groups following the current 
standard according to the local practice and following international guidelines. The decision-making 
may include a request for further imaging procedures. Parameters such as toxicity profile and the 
patient’s general condition will also influence treatment decisions. Major components of patient 
management and the main reasons for treatment decisions will be registered throughout the study.  
Scan procedure and interpretation: All patients will have baseline scans performed before treatment 
and according to the randomization group. Treatment and follow-up scans will be approximated at 
regular intervals of 9-12 weeks or according to local guidelines. The choice of the diagnostic 
modality does not influence the monitoring intervals or time points.   
Contrast-enhanced CT of at least the thorax and abdomen will be performed using diagnostic scan 
quality. Pelvic CT may be added based on clinical need. The scan reports will be made by 
specialists in radiology with an assessment according to the RECIST 1.1 criteria (17). FDG-PET/CT 
will follow standard guidelines from the European Association of Nuclear Medicine and the 
PERCIST guidelines (15, 18). The CT performed along with the PET scan will also be of diagnostic 
quality and will have contrast enhancement. The scans will be assessed by specialists in nuclear 
medicine according to the suggested PERCIST-MBC criteria. 
According to RECIST 1.1 and PERCIST, disease measurability will be evaluated at the baseline 
scan in each study group. In cases of no measurable disease according to the respective criteria 
applied, the patient’s scans will be assessed qualitatively with a parallel response categorization. 
This categorization slightly differs from the one used in the case of measurable disease, but it still 
allows for the distinction of progressive disease from all other states.   
CT and FDG-PET/CT scans will be viewed based on the existing standard software. Viewing of 
FDG-PET/CT scans will be further supported by software developed as part of the establishment 
of the PERCIST-MBC criteria. Application of the criteria remains a task for radiologists or nuclear 
medicine specialists.   
5b) Treatment definition in terms of active substance  
Not applicable.  
5c) Concomitant treatment/medication 
Not applicable.  

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5d) Adherence  
The data from each scan visit will be collected from the PI or a research technician at each 
participating site. The oncologist will refer patients to response monitoring scans according to 
randomization.  
Batch number, accounts, and disposal of FDG will performed as part of daily standard in the 
Departments of Nuclear Medicine.  
5e) Labelling and unblinding of investigational medical product 
Not applicable.  
5f) Compliance monitoring  
The modality used initially at each scan visit, and all subsequently used modalities will be 
documented.  
The weight-adjusted FDG dose will be registered for each scan. 
5g) Subsequent treatment 
There is no need for additional care for patients who leave/terminate the trial. They will be offered 
continuous response monitoring at the local site if indicated.  
6. Evaluation of effect  
6a) Outcome variables 
The primary endpoint “Overall survival” will be addressed based on the primary outcome variable 
“Time from randomization until death”.  
The secondary endpoint “Quality of life” will be addressed by two outcome variables. The first is 
the overall summary score of the FACT-B, the second the complaints related to the conduct of 
scans reported by the patients.  
The secondary endpoint “Exposure to oncologic treatment” will be addressed by the following 
outcome variables describing different aspects of oncological treatment:  
1) Experience of progression 
2) Start of a new treatment line because of progression 
3) Time to first progression 
4) Time from first to second progression 
5) Time from second to third progression 
6) Experiencing other diagnostic procedures 
7) Hospitalization  
 
The secondary endpoint “Cost-effectiveness” will be adressed based on relating the outcome 
variable “Overall survival” to the outcome variable “Costs”.  

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These outcome variables correspond to the expected benefits described above.  
6b) Measurements, registration, analysis 
Measurement  
Information on exposure to diagnostic procedures and treatment will be extracted from the hospital 
records at baseline and regularly during follow-up.  
Assessement of Quality of life and survival is described in Section 3e).  
Information on healthcare utilization and/or cost will be extracted from national registries.   
Definition of efficacy parameters  
Patients cannot immediately benefit from using FDG-PET/CT for response monitoring. They can 
only benefit after detecting their first progression from the earlier start of efficient second-line 
therapy. According to Vogsen et al. (12) (2023), the median time until detection of the first 
progression is about 15 months in this population. It also has to be expected that the benefit 
increases with increasing survival time due to the opportunity to benefit from the adequate time to 
start a third-line therapy. This is corroborated by the results of Naghavi-Behzad et al. (13) (2022), 
reporting a hazard ratio of 0.75 after 24 months, 0.4 after 36 months, and 0.2 after 60 months.  
Due to the expected non-proportionality of the hazard ratio, the effect on survival will not be 
assessed by a hazard ratio. Instead, the effect of survival will directly be quantified by differences 
in survival probabilities at 36, 42, and 48 months.  
The quality of life data collected will be used to compute the instrument-specific summary scores. 
Efficacy parameters are the expected quality of life difference between the two intervention groups 
for each score. 
The data on management and treatment will be used to assess the difference between the two 
intervention groups with respect to the following parameters:  
1) Risk of experiencing a progression 
2) Risk of starting a new treatment line because of progression 
3) Time to first progression 
4) Time from first to second progression 
5) Time from second to third progression 
6) Risk of experiencing other diagnostic procedures 
7) Risk of hospitalization 
The healthcare utilization and cost data will be used to compute the incremental cost-effectiveness 
ratio, which relaties the difference in survival to the difference in costs.  
7. Safety evaluation  
7a) Safety evaluation 
Definitions 
 
Adverse event (AE) 

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Any untoward medical occurrence in a subject to whom a medicinal product is administered 
and which does not necessarily have a causal relationship with this treatment.  
 
Adverse reaction (AR) 
Any response to a medicinal product which is noxious and unintended. 
 
Serious adverse event (SAE)  
Any untoward medical occurrence that at any dose requires inpatient hospitalisation or 
prolongation of existing hospitalisation, results in persistent or significant disability or 
incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in 
death.  
 
Serious adverse reaction (SAR) 
An SAE in which there is a reasonable possibility of establishing a causal relationship 
between the event and the investigational medicinal product based on an analysis of 
available evidence.  
Causality assessment given by the investigator must not be downgraded by the sponsor.  
A planned hospitalization will not be considered an SAE. 
 
Suspected unexpected serious adverse reaction (SUSAR) 
A serious adverse reaction where the nature, severity or outcome is not consistent with the 
reference safety information and is therefore considered unexpected based on the 
reference safety information. 
 
Reference safety information (RSI) 
Section 4.8 in Guideline on core SmPC and package leaflet for fludeoxyglucose (18F) 
EMA/CHMP/448228/2012 https://www.ema.europa.eu/en/core-summary-product-characteristics-
smpc-package-leaflet-fludeoxyglucose-18f-scientific-guideline (current version 19 July 2012) 
Any change in RSI will only be done when the Annual Safety Report (ASR) is prepared unless 
new safety information makes it necessary. In that case, a Substantial Modification will be 
submitted for CTIS.   
 
Risk adaption 
With reference to  
 
Article 41 of regulation (EU) No 536/2014 of 16 April 2014 on clinical trials on medicinal 
products for human use  
 
Risk proportionate approaches in clinical trials. Recommendations of the expert group on 
clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on 
medicinal products for human use 25 April 2017 
 
The Danish Medicines Agency’s guidance on risk-based recording and reporting of adverse 
events in clinical trials on medicinal products under Regulation (EU) no. 536/2014, Version 
1.0, October 2023 
and risk assessment  
 
IMP is authorized and used for diagnostic purposes according to authorization  
 
The intervention is comparable to standard treatment  
 
IMP is used and well-known in all centers and SmPC will be followed by all investigators 
 
Population is comparable to the population mentioned in SmPC, e.g. recurrence of breast 
cancer and monitoring of other malignancies 
 
FDG dose will be weight-adjusted according to authorization 

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 
No unknown adverse reactions are expected 
the trial is evaluated as a low-risk trial, and the approach is adjusted according to this risk 
assessment and references mentioned above. 
7b) Measuring, recording and analysing the safety parameters 
Patients will automatically be observed after each FDG injection for at least  one hour as part of the 
clinical routine, as the patients are waiting 60 minutes for the scan subsequent to FDG injection.   
As no AEs or ARs are expected, only SUSARs will be registered. However, the investigator always 
has the option to report any event to the sponsor via email if deemed relevant. 
7c) Reporting of adverse events  
SUSAR 
Only SUSARs will be reported to the sponsor. The investigator must assess the expectedness of 
the event and report it to the sponsor by the investigator through the eCRF within 24 hours. 
With assistance from The GCP Unit at Odense University Hospital, the sponsor will report SUSARs 
in the EudraVigilance database within 7 days for fatal or life-threatening SUSARs and within 15 
days for other SUSARs. 
Annual Safety Report (ASR) 
The sponsor will report the annual safety report, including a list of all investigator reported events 
and SUSARs, for the entire trial to CTIS. The ASR will describe the risk-adapted approaches as 
provided in the protocol and include an assessment of whether the benefit-risk balance is changed 
or unchanged. 
The first ASR will be reported no later than 60 days after the first approval of the trial in a member 
state. Subsequently, ASR will be reported annually. 
All investigators will receive a copy of the ASR, and if there are any changes in the risk-benefit 
balance or the RSI, this will be specified in the communication with investigators. 
7d) Notifications about adverse events  
When the investigator has completed the SUSAR report in the eCRF, the sponsor will automatically 
be informed about the SUSAR by e-mail. This procedure is incorporated into the eCRF system 
(REDCap) and validated. 
7e) Arrangements for avoiding and treating complications 
Complications are not expected, and hence, no special arrangements are made. See section 7f) 
7f) Monitoring in case of adverse events/adverse reactions  
If a study participant reports any adverse events or reactions, the investigator will offer additional 
consultations on a case-by-case basis according to local procedures. Within these consultations, a 
decision will be made with respect to future scan applications.  

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The duration and type of follow-up will be determined by the severity and nature of the adverse 
event, ensuring appropriate monitoring and management of patient safety throughout the trial 
period according to local procedures. 
8. Statistics  
8a) Statistics 
The difference in survival will be visualized by model-based Kaplan-Meier-curves. These model-
based Kaplan-Meier-estimate will also be used to compute the difference in survival rates at 36, 
42, and 48 months together with 95% confidence intervals. The statistical significance of the 
difference in survival will be assessed using a statistical test procedure not relying on the 
assumption of proportional hazards.  
The model-based approach will be used to adjust for variables which are expected to be of strong 
prognostic value in the rather heterogenous populations of MBC patients.  
The analysis of the longitudinal quality of life scores will take into account the expected systematic 
difference in exposure time between the two groups due to the expected difference in survival and 
a potential general decline over time. Consequently, a model-based approach will be used. 
Differences in the risk of progression, in the risk of starting a new treatment line because of 
progression, in the risk of experiencing diagnostic procedures, and the risk of hospitalization will be 
assessed by a Poisson regression with the risk time as offset. The first two analyses will be adjusted 
for the same variables as in the analysis for survival.  
Time until progression and time between progressions will be analyzed by a Cox model with 
adjustment for the same variables as in the analysis for survival.  
Patients complaints related to the conduct of scans will be categorized and the frequencies reported 
for each arm.  
Cost-effective analyses will be based on computing an incremental cost effectiveness ratio (ICER). 
Effectiveness will be assessed by the gain in quality adjusted life years (QUAL) based on the data 
from the EQ-5D-5L and survival. Costs will be assessedby two different approaches:  A)  Difference 
in costs related to the scans and subsequent oncological treatment. B) Difference in cost of using 
of health care as documented in registry data.  
A detailed statistical analysis plan will be finalized prior to recruiting the first patient. The plan will 
included specifications of the models and test procedures used. In particular the plan will include 
the following details:  
 
The selection of variables with a strong prognostic value. 
 
The prognostic index used for stratification in randomization.  
 
The model specifications to be used for computing model-based Kaplan-Meier-curves and 
subsequent inference.  
 
A choice of a powerful statistical test procedure based on simulation studies similar to those 
reported by Klingmüller et al (2023). [Florian Klinglmüller, Tobias Fellinger, Franz König, Tim 
Friede, Andrew C. Hooker, Harald Heinzl, Martina Mittlböck, Jonas Brugger, Maximilian 
Bardo, Cynthia Huber, Norbert Benda, Martin Posch, Robin Ristl (2023): A neutral 

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comparison of statistical methods for time-to-event analyses under non-proportional 
hazards. Preprint available at https://doi.org/10.48550/arXiv.2310.05622.]  
 
The model specifications to be used for a longitudinal analysis of the quality of life scores, 
including the handling of missing data.  
 
Planned sensitivity and subgroup analyses.  
 
8b) Sample size considerations  
Sample size considerations are based on using a direct comparison of the survival rates at 42 
months. The statistical test finally used will be more powerful due to summarizing the information 
from all time points and adjustment for prognostic covariates.  
In the study of Naghavi-Behzad et al. (13) (2022), the survival rate after 42 months was 34% in the 
CT group and 51% in the FDG-PET/CT group. Due to the introduction of new, more effective 
treatment lines in the last decade, we expect higher survival rates in this RCT. Sample size 
calculations are based on the assumption that true survival probabilities will be 39% and 56%, 
respectively. Under this assumption, we have to include overall 420 patients to reach a power of 
87% (based on two-sided testing at the 5% level).  
According to the timeline of the study, the minimal (planned) follow-up time of the patients will be 
36 months, and the maximal follow-up time will be 54 months. In the above calculations, a uniform 
distribution of the follow-up time was assumed. 
With respect to the primary outcome (survival), we do not expect drop outs, as we can rely also on national 
registries. Hence drop-outs are not accounted for in the sample size calculation. 
8c) Significance level  
A significance level of 5% (two-sided) will be applied.  
8d) Termination of the trial and interim analyses 
Interim analyses involving the outcomes of survival and quality of life are not planned.  
The choice of treatment lines and diagnostic procedures will be continuously monitored to detect 
early potential differences between the participating centers with respect to the management and 
treatment of the patients. Such differences will be discussed with and across the participating 
centers.  
8e) Handling of missing data  
Missing data in the outcome variables are only to be expected with respect to the time-point-specific 
quality of life measurements. Details of the handling of these missing values will be described in 
the statistical analysis plan.  
8f) Deviations from statistical analysis plan  
Deviations from the statistical analysis plan will be reported in the final publications.  

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8g) Analysis population 
All analyses will be based on all randomized patients. Sensitivtiy analyses may include the analysis 
of subpopulations.  
9. Charter of DSMB/DMC  
9a) Charter of DSMB/DMC 
There are no plans to establish a Data Safety Monitoring Committee. 
10. Source data  
10a) Description of arrangements for monitoring the conduct of the clinical trial  
Risk-based monitoring of MONITOR-RCT will be performed at the participating Danish centers by 
the GCP Unit at Odense University Hospital, while it will be performed locally in non-Danish centers.  
10b) Statement of the sponsor  
The sponsor of MONITOR-RCT confirms that the investigator and all institutions involved in the 
clinical trial will permit clinical trial-related monitoring, audits and regulatory inspections, including 
provision of direct access to source data and documents.  
11.Quality control and quality assurance 
11a) a description of measures that will be implemented in case of data security 
breach in order to mitigate the possible adverse effects  
MONITOR-RCT will be conducted following the study protocol, the declaration of Helsinki, and the 
principles of good clinical practice (ICH-GCP).  
12. Ethical questions  
12a) Summary and relevance 
The study will be a parallel group comparative randomized trial comparing an experimental 
monitoring strategy based on FDG-PET/CT with a standard monitoring strategy based on CT. 
Participating patients should have newly diagnosed metastatic breast cancer and be considered 
eligible for initiating first-line medicinal treatment and subsequent regular response monitoring.  
Current knowledge about the potential benefit of PET/CT comes from observational 
studies.Consequently, current evidence is only hypothesis generating and prospective, randomized 
trial  studies such as the intended MONITOR-RCT are needed to corroborate these findings (cf. 
section 2b). 

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12b) Exposure to radiation 
The radiation dose is an issue of consideration. The average radiation dose per patient per scan 
procedure is estimated, in conventional diagnostic CT, to be 9 mSv and in conventional 18F-FDG-
PET/CT to an additional 4 mSv, respectively (see Appendix 1).  
12c) Risks and benefits 
The iodinated contrast agent of the CE-CT is applied both in the standard and interventional group. 
Iodinatied contrast is known to cause the following AEs and ARs in a substantial number of patients: 
allergic reactions, warmth, flushing, metallic taste, vomiting, and nausea. With a risk-adjusted 
approach, we avoid registration of these known AEs and ARs.  
Taking into account the potential long-term benefit of patients with MBC (section 2b) and the 
potential direct benefit of patients randomized to monitoring with FDG-PET/CT, there is a fair 
balance between benefits and risks.  
Patients will be fully informed about the potential benefits and risks of FDG-PET/CT. This includes 
understanding that while FDG-PET/CT may provide more accurate detection of metastases and 
potentially lead to improved survival and reduced treatment burden, it also exposes them to 
additional radiation and a higher detection rate of incidental findings. 
12d) Informed consent procedure 
Patients potentially eligible for the trial (based on inclusion criteria 1-4) will be identified by the 
oncologists and related clinical/research staff at the participating sites prior to a regular patient visit. 
A qualified medical doctor, who may be the Principal Investigator (PI) or another doctor at the 
Department of Oncology or Gynecology involved in the project with a written agreement from the 
PI, will check further in- and exclusion criteria and provide the information during oral information 
sessions at initial visit (Visit 1 in Table 1, providing a detailed description of the inclusion period), 
ensuring privacy. Additionally, participants receive handout information material and a link in case 
they consider giving or denying the consent electronically. Subsequently, participants are given a 
minimum of 24 hours to review the reading material at home and make decisions privately. 
Following this period, a responsible research technician/assistant will contact those patients who 
have not expressed their decision electronically via phone or video to inquire about their decision. 
In case the patient wishes to discuss her or his decision, the technician/assistant will inform 
qualified medical personnel at the Department of Oncology or Nuclear Medicine about this wish. 
After a phone or video contact between the qualified medical personnel and the patient, the 
research technician/assistant will repeat the inquiry, except if the patient has, in between, 
expressed her or his decision electronically or has denied participation during the contact with the 
qualified medical personnel.  
If, in the inquiry by the research technician/assistant, the patient expresses the wish to participate, 
the patient is asked to sign the consent form which will be provided in English and the local 
language immediately and to confirm this signing verbally or show the signature in case of a video 
call.  
If consent has been confirmed electronically or as part of the contact with the research 
technician/assistant, the patient will be randomized. Based on the result of the randomization, the 

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potential need for a baseline scan is determined. In case of this need, a corresponding visit (Visit 
2) is arranged prior to the treatment initiation visit (Visit 3). The patient is informed by the research 
technician/assistant about the results of the randomization and the arrangements for a potential 
baseline scan, which would take place in Department of Radiology or Nuclear Medicine. This 
information is conveyed both verbally during the phone or video call and in written form. At the first 
in-person visit after the patient has consented via the phone or video call, a responsible research 
technician/assistant verifies the written informed consent. 
Included patients can withdraw from the trial at any time point during the study as described in 
section 4c) 
All participating centers will have handout information and the informed consent form in English, 
Danish, German, and Italian.  
12e) Data protection  
The study will adhere to the General Data Protection Regulation (GDPR) [EU] 2016/679 and the 
Declaration of Helsinki.  
Data will be stored and managed securely as described in section 3k) 
12f) Additional ethics  
No data will be registered before signed informed consent, except for an anonymous registration 
of reasons for exclusion or non-participation.  
13. Handling and archiving data.  
13a) Rules on the protection of personal data. 
All data from the different sources will be stored in a REDCap database maintained by the Open 
Patient Data Explorative Network (OPEN) and stored securely according to GDPR, the Danish data 
protection law, and the health law.  
The database and the REDCap software are fully GCP compliant, and all input and modifications 
are logged.   
A master data set with pseudonymized data will be created for the statistical analyses. 
The REDCap database and the trial master file will be archived for 25 years.  
The trial staff will ensure that the subjects' anonymity is maintained and that their data is fully 
protected. All data and documents will be stored in a secure REDCap database hosted by the 
Region of Southern Denmark. User privileges are utilized within the software, and access to the 
database is controlled by the coordinating investigator. All connections are fully encrypted and 
protected by multi-factor authentication. The system maintains a built-in audit trail that logs all user 
activity and pages viewed by every user, including contextual information (e.g., the project or record 
being accessed). The system in use is GCP-compliant and complies with the EU General Data 
Protection Regulation 2016/679. 

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In case of a data security breach, the sponsor will be immediately notified. The sponsor will promptly 
analyze the case and notify the relevant regulatory bodies, including the Danish Data Protection 
Agency and the Data Protection Officer of the Region of Southern Denmark, as necessary. 
13b) Ensuring confidentiality 
Data extraction from the medical records will be performed by authorized staff at the participating 
centers and typed directly into the REDCap database or imported. Collection of questionnaire data 
will be organized centrally by the Sponsor. Electronic collection of questionnaire data will be 
performed directly within REDCap.  
14. Compensation trial participants, investigator and funding.  
The MONITOR-RCT is fully financed by grants from the Danish Cancer Society (€282,000) and the 
Region of Southern Denmark (€242,000), and Horizon Europe Grant from the European 
Commission (€3,307,000),  with a total fixed amount of €3,831,000. The financial agreement 
between the sponsor and participating sites encompasses the coverage of agreed costs related to 
various aspects of the trial, including setup, patient recruitment, scans, and data collection and 
imaging analysis. This compensation will be in accordance with fair market value and will comply 
with all applicable laws and regulations. 
14a) Insurance and Compensation in Denmark and Bologna (Italy) 
Patients under study are financially covered by the public insurance program for all patients. If A 
patient experienceS unpredictable adverse events or other damages caused by the study, the 
patient has the right to complain and ask for compensation according to the patient insurance 
system in Denmark and Bologna (Italy). 
14b) Insurance and Compensation in Germany and Milan (Italy) 
Patients participating in the study in Germany and Milan (Italy) will be covered by the sponsor for 
all costs related to the study, including the scans, as these are not covered by the national insurance 
system. Additionally, the sponsor will provide necessary insurance coverage for patients in case of 
unpredictable adverse events or damages caused by the study. Patients will have the right to seek 
compensation through the sponsor's insurance system in Germany and Milan (Italy) if needed. 
15. Guidelines for publication.  
15a) Publication strategy 
The MONITOR-RCT results are intended for publication in peer-reviewed scientific journals. The 
sponsor is responsible for ensuring corresponding submissions. 
A writing committee will be selected 3 months prior to the end of the data collection. Each 
participating site is invited to suggest between one and three members. In addition, all other 
scientists who have made an intellectual contribution to the planning or conduct of the RCT will be 
offered participation. The writing committee will select a subgroup to prepare a first draft of the main 
publication. This draft will then be discussed with the writing committee. 

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A second publication to be prepared by the writing committee will be a report about the practical 
experience of implementing and conducting this study in order to encourage other researchers to 
conduct RCTs on diagnostic modalities. 
As soon as possible and no later than one year after the trial has ended, the summary of the results will be 
submitted to the CTIS portal.  
16. Summary and appendices.  
16a) Synopsis 
A synopsis has been uploaded to CTIS.  
16b) Appendix 1: Estimated effective dose of MONITOR project patients 
In order to estimate the effective dose given to the MONITOR project patients, effective doses from 
457 PET/CT scans from representative patients were collected. The representative patients were 
chosen as adult non-pregnant females, weighing between 50 to 90 kg, with a scan length not longer 
than 100 cm.All 457 patient scans were performed within the last 6 months at the Department of 
Nuclear Medicine at Odense University Hospital. The CT scans were standard diagnostic CT scans. 
In our protocol, we have meticulously calculated the average radiation dose per patient per scan 
procedure for Fludeoxyglucose (18F) PET/CT based on our specific dosing regimen. Utilizing a 
dose of 3 MBq/kg, we have estimated the average radiation dose to be 4 mSv for patients with an 
average weight of 70 kg. Even for patients with higher weights, our protocol specifies a maximal 
dose of 300 MBq, resulting in lower radiation doses compared to those mentioned in the SmPC. In 
the two tables below, the effective patient doses are plotted, for the diagnostic CT (following ICRP 
103) and from the 18F-FDG-PET (following ICRP 128), respectively, the mean effective patient 
dose for the two modalities are: 
𝑀𝑒𝑎𝑛 𝑒𝑓𝑓𝑒𝑐𝑡𝑖𝑣𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑑𝑜𝑠𝑒 𝑓𝑟𝑜𝑚 𝑑𝑖𝑎𝑔𝑛𝑜𝑠𝑡𝑖𝑐 𝐶𝑇= 8.84 𝑚𝑆𝑣≈9 𝑚𝑆𝑣 
𝑀𝑒𝑎𝑛 𝑒𝑓𝑓𝑒𝑐𝑡𝑖𝑣𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑑𝑜𝑠𝑒 𝑓𝑟𝑜𝑚 
𝐹−𝐹𝐷𝐺−𝑃𝐸𝑇=
18
3.92 𝑚𝑆𝑣≈4 𝑚𝑆𝑣 
 
 
 

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16c) Appendix 2: Arrangements for tracing, storing, destroying and returning the 
investigational medicinal product in accordance with Article 51 of the regulation. 
The MONITOR-RCT protocol meticulously addresses the tracing, storing, destroying, and returning 
processes for the investigational medicinal product, Fludeoxyglucose (18F), in adherence with 
regulatory standards and safety guidelines. Regarding storage, it will be ensured to maintain 
Fludeoxyglucose (18F) below 25°C, as per national regulations governing radioactive materials. 
Each unit of the product is delivered in either a 30 ml or 15 ml glass container, meticulously sealed 
with silicone elastomer or chlorobutyl rubber stoppers, and further safeguarded within a 35 mm 
thick lead container during transportation. These measures ensure the product's stability and 
integrity throughout handling and transit. 
Special precautions are outlined for handling and disposal to mitigate risks associated with 
radioactive materials. Only authorized personnel in designated clinical settings are permitted to 
handle Fludeoxyglucose (18F), and preparation must adhere to stringent radiation safety and 
pharmaceutical quality requirements. Aseptic precautions are emphasized to prevent 
contamination and ensure patient safety during administration. 
Additionally, comprehensive measures are in place to address the risks posed by external radiation 
exposure or contamination from spills, such as urine or vomiting. Adherence to national regulations 
for radiation protection is mandatory to mitigate these risks effectively. 
Furthermore, disposal procedures are strictly governed by local regulations to ensure the safe and 
proper handling of any unused product or waste material. This includes adherence to specific 
guidelines for the disposal of radioactive waste, emphasizing our commitment to safety and 
regulatory compliance throughout all stages of the clinical trial process. It should be noted that our 
protocol ensures thorough monitoring of materials from receipt, manufacturing, dispensing, and the 
product's journey to customers/consumers, allowing for recall if necessary due to quality issues. 
 
17. Literature references. 
1. 
Groheux D. FDG-PET/CT for systemic staging of patients with newly diagnosed 
breast cancer. European journal of nuclear medicine and molecular imaging. 2017;44(9):1417-9. 

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2. 
Han S, Choi JY. Impact of 18F-FDG PET, PET/CT, and PET/MRI on Staging and 
Management as an Initial Staging Modality in Breast Cancer: A Systematic Review and Meta-
analysis. Clin Nucl Med. 2021;46(4):271-82. 
3. 
Hildebrandt MG, Gerke O, Baun C, Falch K, Hansen JA, Farahani ZA, et al. 
[18F]Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) 
in suspected recurrent breast cancer: a prospective comparative study of dual-time-point FDG-
PET/CT, contrast-enhanced CT, and bone scintigraphy. J Clin Oncol. 2016;34(16):1889-97. 
4. 
Gennari A, André F, Barrios CH, Cortés J, de Azambuja E, DeMichele A, et al. ESMO 
Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic 
breast cancer. Annals of oncology : official journal of the European Society for Medical Oncology. 
2021. 
5. 
Groheux D, Giacchetti S, Moretti JL, Porcher R, Espie M, Lehmann-Che J, et al. 
Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in 
breast cancer. Eur J Nucl Med Mol Imaging. 2011;38(3):426-35. 
6. 
Koolen BB, Vrancken Peeters MJ, Wesseling J, Lips EH, Vogel WV, Aukema TS, et 
al. Association of primary tumour FDG uptake with clinical, histopathological and molecular 
characteristics in breast cancer patients scheduled for neoadjuvant chemotherapy. Eur J Nucl Med 
Mol Imaging. 2012;39(12):1830-8. 
7. 
Ulaner GA, Castillo R, Wills J, Gönen M, Goldman DA. (18)F-FDG-PET/CT for 
systemic staging of patients with newly diagnosed ER-positive and HER2-positive breast cancer. 
Eur J Nucl Med Mol Imaging. 2017;44(9):1420-7. 
8. 
Jung NY, Kim SH, Choi BB, Kim SH, Sung MS. Associations between the 
standardized uptake value of (18)F-FDG PET/CT and the prognostic factors of invasive lobular 
carcinoma: in comparison with invasive ductal carcinoma. World J Surg Oncol. 2015;13:113. 
9. 
Riedl CC, Pinker K, Ulaner GA, Ong LT, Baltzer P, Jochelson MS, et al. Comparison 
of FDG-PET/CT and contrast-enhanced CT for monitoring therapy response in patients with 
metastatic breast cancer. Eur J Nucl Med Mol Imaging. 2017;44(9):1428-37. 
10. 
Naghavi-Behzad M, Oltmann HR, Alamdari TA, Bülow JL, Ljungstrøm L, Braad PE, et 
al. Clinical Impact of FDG-PET/CT Compared with CE-CT in Response Monitoring of Metastatic 
Breast Cancer. Cancers (Basel). 2021;13(16). 
11. 
Vogsen M, Bulow JL, Ljungstrom L, Oltmann HR, Alamdari TA, Naghavi-Behzad M, 
et al. FDG-PET/CT for Response Monitoring in Metastatic Breast Cancer: The Feasibility and 
Benefits of Applying PERCIST. Diagnostics (Basel). 2021;11(4). 
12. 
Vogsen M, Harbo F, Jakobsen NM, Nissen HJ, Dahlsgaard-Wallenius SE, Gerke O, 
et al. Response Monitoring in Metastatic Breast Cancer: A Prospective Study Comparing (18)F-
FDG PET/CT with Conventional CT. Journal of nuclear medicine : official publication, Society of 
Nuclear Medicine. 2023;64(3):355-61. 
13. 
Naghavi-Behzad M, Vogsen M, Vester RM, Olsen MMB, Oltmann H, Braad PE, et al. 
Response monitoring in metastatic breast cancer: a comparison of survival times between FDG-
PET/CT and CE-CT. British journal of cancer. 2022;126(9):1271-9. 
14. 
Vogsen M, Naghavi-Behzad M, Harbo FG, Jakobsen NM, Gerke O, Asmussen JT, et 
al. 2-[(18)F]FDG-PET/CT is a better predictor of survival than conventional CT: a prospective study 
of response monitoring in metastatic breast cancer. Scientific reports. 2023;13(1):5552. 
15. 
Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, et al. 
FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol 
Imaging. 2015;42(2):328-54. 

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16. 
Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. 
Breast cancer. Nat Rev Dis Primers. 2019;5(1):66. 
17. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European 
journal of cancer (Oxford, England : 1990). 2009;45(2):228-47. 
18. 
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving 
considerations for PET response criteria in solid tumors. Journal of nuclear medicine : official 
publication, Society of Nuclear Medicine. 2009;50 Suppl 1:122s-50s. 
19. 
Clarijs ME, Thurell J, Kühn F, Uyl-de Groot CA, Hedayati E, Karsten MM, et al. 
Measuring Quality of Life Using Patient-Reported Outcomes in Real-World Metastatic Breast 
Cancer Patients: The Need for a Standardized Approach. Cancers (Basel). 2021;13(10). 
20. 
EORTC questionnaire for assessing the HRQOL in metastatic breast cancer  
[Available from: https://qol.eortc.org/questionnaire/metastatic-breast-cancer/. 
21. 
Nguyen J, Popovic M, Chow E, Cella D, Beaumont JL, Chu D, et al. EORTC QLQ-
BR23 and FACT-B for the assessment of quality of life in patients with breast cancer: a literature 
review. J Comp Eff Res. 2015;4(2):157-66. 
22. 
Bjelic-Radisic V, Cardoso F, Cameron D, Brain E, Kuljanic K, da Costa RA, et al. An 
international update of the EORTC questionnaire for assessing quality of life in breast cancer 
patients: EORTC QLQ-BR45. Annals of oncology : official journal of the European Society for 
Medical Oncology. 2020;31(2):283-8. 
23. 
EORTC 
QLQ 
BR-45 questionnaire 
in 
breast 
cancer  [Available from: 
https://qol.eortc.org/questionnaire/update-qlq-br23/  
24. 
O JH, Lodge MA, Wahl RL. Practical PERCIST: a simplified guide to PET response 
criteria in solid tumors 1.0. Radiology. 2016;280(2):576-84. 
 
 
 

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18. Figures and Tables.  
Figure 1: Patient flowchart for MONITOR-RCT. 
 

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Table 1: Timeline and data collection for the inclusion period for MONITOR-RCT  
Task 
Before 
visit 1 
Visit 1 
Between visit 
1 and 2/3 
Visit 2 
Visit 3 
Where 
Who 
Identification of potential candidates for MONITOR protocol 
X 
 
 
 
 
Department of Oncology 
Oncologists of the Department 
Information on diagnosis and treatment options 
 
X 
 
 
 
Department of Oncology 
Qualified medical doctor (Oncologist) 
Information on MONITOR project 
 
 
X 
 
 
 
Department of Oncology 
Qualified medical doctor (Oncologist) 
Reading information material on medical treatment and on 
the MONITOR project 
 
 
X 
 
 
At home 
The patient and relatives 
 
Finishing informed consent process$ 
 
 
X 
 
 
At home 
The patient and relatives 
Qualified medical doctor (Oncologist) 
Randomization 
 
 
 
X 
 
 
At home 
Oncologist/Study coordinator/ Research staff 
Baseline scan (Only in patients with no scan within 28 days 
of randomization)  
 
 
 
X 
 
Department of Nuclear 
Medicine or Radiology 
Study coordinator/ Research staff/ 
Radiology/Nuclear medicine staff 
Treatment initiation 
 
 
 
 
 
X 
Department of Oncology 
Oncology nurse 
Baseline quality of life questionnaire* 
 
 
 
 
 
X 
Department of Oncology 
Oncology nurse/ Study coordinator 
Black: standard tasks 
Red: study-related tasks 
$ In case of no consent, relevant clinical scans will be arranged  
*Quality of life questionnaires can be filled out on paper or tablet 
 

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Table 2: Timeline and data collection for the response monitoring period for MONITOR- RCT 
 
Quality of life assessment 
Follow-up scan visits  
Follow-up oncology visits  
When 
Every 3rd month in year 1. 
Every 6th month afterwards.  
Every 9.-12. weeks*   
Every 9.-12. weeks*  
What 
Quality of life questionnaire# 
Scan 
Scan result 
Where 
At home 
Department of Nuclear Medicine ¤ 
Department of Radiology ¤ 
Department of Oncology 
Who  
Patient and relatives  
Research technical staff /  Scan technicians 
Oncology doctor 
Details 
Quality of life questionnaires 
are filled out electronically or 
on paper by the patients.  
Conduct of scan 
 
1) Information on the scan result and planning of further treatment  
2) Referral for the next follow-up scan ¤ 
3) Documentation of final scan interpretation and treatment change. 
Data collection 
Quality of life questionnaire 
Information on  
1) FDG-PET/CT scan (patient weight, blood glucose, FDG dose, 
injection-to-scan time, reconstruction, CT contrast) 
2) CE-CT scan (CT contrast) 
3) Information on potential SUSARs adverse events since the last 
visit within 1 hour after injection of FDG in the current scan ¥  
  
Black: standard tasks 
Red: study-related tasks 
* scan intervals depend on the choice of systemic treatment,  
¤ according to randomization 
# quality of life questionnaires can be filled out on paper 
¥ For patients followed with FDG-PET/CT 

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Table 3: List of variables for MONITOR-RCT¤ 
Baseline characteristics 
Randomization 
CT 
FDG-PET/CT 
QoL 
Patient management 
End-of-study 
Extracted from hospital 
records 
Local investigator 
Department of 
Radiology  
Department of Nuclear 
Medicine 
Patient 
Extracted from patient 
records  
Local investigator  
 
Age 
Performance status 
De novo or recurrent MBC 
ER status 
HER2 status 
Histological type 
Location of confirmatory 
biopsy 
Burden of disease 
Date 
CT 
FDG-PET/CT 
QoL 
Inclusion- and exclusion 
criteria 
Reasons for non-
participation 
Patient contact 
preferences 
Patient contact information 
Latest chemotherapy 
eGFR 
CT contrast 
Other scans and results 
Response (RECIST 1.1) 
Measurability 
Reasons for progression 
Assessment system 
Latest chemotherapy 
Weight 
Height  
Blood sugar 
eGFR 
FDG-dose  
Injection-scan time  
Faste time  
Scan type  
Acquisition protocol  
Reconstruction method  
Version of software  
CT contrast  
Adverse events  
Other scans 
Response (PERCIST-MBC)  
Measurability 
Reasons for progression 
Assessment system 
 
EQ-5D-5L  
 
A subset of  
EORTC QLQ-C30 
EORTC QLQ-BR42 
FACT-B 
Patient complaints 
related to the conduct 
of scans 
Type of treatment 
Reasons for changes 
Hospitalization 
Further diagnostics 
 
Death 
Reasons for stopping 
before end-of-study 
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth receptor 2; FDG-PET/CT, 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomografi CT; RECIST, response evaluation criteria in solid tumors; PERCIST, PET response evauation criteria in solid 
tumors; MBC, metastatic breast cancer; QoL, quality of life; QALY, quality adjusted life year; eGFR, estimated glomerular filtration rate 
¤: Interview data and patient questionnaire after first scan and after 6 months are not listed here.