Intra-individual Patient-based Comparison of Conventional and Digital PET/CT Scanners
Phase: NA
Conditions: Breast Cancer, Lung Cancer, Esophageal Cancer, Miscellaneous Neoplasm
Sponsor: Isala

NL52329.075.15 / Intra-individual patient-based comparison of conventional and digital PET/CT 
scanners 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH PROTOCOL 
 
Intra-individual patient-based comparison of conventional and digital 
PET/CT scanners (PETPET study) 
 
 

NL52329.075.15 / Intra-individual patient-based comparison of conventional and digital PET/CT 
scanners 
 
 
 
PROTOCOL TITLE ‘Intra-individual patient-based comparison of conventional and digital 
PET/CT scanners’ 
 
Protocol ID 
15.0229 (METC Isala) 
NL 52329.075.15 
Short title 
Intra-individual comparison of conventional and 
digital PET/CT scanners (PETPET study) 
Version 
4 
Date 
31-10-2017 
Principal investigator (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
 
P. L. Jager (Isala) 
Co-investigators (in Dutch: 
medeonderzoekers) 
Isala: 
D. Koopman 
J. A. van Dalen 
J. A. C. van Osch 
A. Blaauwbroek 
S. Knollema 
Subsidizing party 
Philips Healthcare 
P. Maniawski 
Independent expert (s) 
J. P. Ottervanger, cardiologist Isala 
Contact: (038) 424 23 74 
  

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TABLE OF CONTENTS 
SUMMARY ............................................................................................................................ 7 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 8 
2. 
OBJECTIVES ................................................................................................................11 
2.1 
Primary objectives: lesion detection properties .......................................................11 
2.2 
Secondary objectives: image quality ......................................................................11 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................13 
4.1 
Population (base) ...................................................................................................13 
4.2 
Inclusion criteria .....................................................................................................13 
4.3 
Exclusion criteria ....................................................................................................13 
4.4 
Sample size calculation ..........................................................................................14 
5. 
METHODS ....................................................................................................................16 
5.1 
Study procedures ...................................................................................................16 
5.1.1 
Patient selection ..............................................................................................16 
5.1.2 
FDG injection (clinical procedure) ....................................................................16 
5.1.3 
First PET/CT acquisition ..................................................................................16 
5.1.4 
Second PET/CT acquisition (study procedure) ................................................17 
5.1.5 
PET/CT data reconstruction ............................................................................18 
5.1.6 
PET/CT diagnoses ..........................................................................................18 
5.2 
Data collection and analysis ...................................................................................19 
5.2.1 
General data collection ....................................................................................19 
5.2.2 
PET/CT evaluation ..........................................................................................20 
5.2.3 
Validation ........................................................................................................21 
5.2.4 
EANM procedure guidelines ............................................................................21 
5.3 
Main study parameters ...........................................................................................22 
5.3.1 
Primary study parameter .................................................................................22 
5.3.2 
Secondary study parameter ............................................................................22 
5.4 
Withdrawal of individual subjects ............................................................................23 
5.5 
Replacement of individual subjects after withdrawal ...............................................23 
5.6 
Follow-up of subjects withdrawn from treatment .....................................................23 
6. 
SAFETY REPORTING ..................................................................................................24 
6.1 
Section 10 WMO event ..........................................................................................24 
6.2 
AEs, SAEs and SUSARs ........................................................................................24 
6.2.1 
Adverse events (AEs) ......................................................................................24 
6.2.2 
Serious adverse events (SAEs) .......................................................................25 
6.3 
Follow-up of adverse events ...................................................................................25 
7. 
STATISTICAL ANALYSIS .............................................................................................26 
7.1 
Main study parameters ...........................................................................................26 
7.1.1 
Primary objective: diagnostic outcome of the PET/CT studies .........................26 
7.1.2 
Secondary objective: PET image quality .........................................................26 
8. 
ETHICAL CONSIDERATIONS ......................................................................................29 
8.1 
Regulation statement .............................................................................................29 

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8.2 
Recruitment and consent........................................................................................29 
8.3 
Benefits and risks assessment, group relatedness .................................................29 
8.3.1 
Additional scan time ........................................................................................30 
8.3.2 
Additional radiation dose .................................................................................30 
8.4 
Justification for the proposed study ........................................................................30 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................31 
9.1 
Handling and storage of data and documents ........................................................31 
9.2 
Monitoring and Quality Assurance ..........................................................................31 
9.3 
Amendments ..........................................................................................................32 
9.4 
Annual progress report ...........................................................................................32 
9.5 
End of study report .................................................................................................32 
9.6 
Public disclosure and publication policy ..................................................................32 
10. 
REFERENCES ..........................................................................................................33 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the 
application form that is required for submission to the 
accredited Ethics Committee (In Dutch, ABR = Algemene 
Beoordeling en Registratie) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in 
Dutch: Centrale Commissie Mensgebonden Onderzoek 
Conventional PET/CT 
 
Where the term conventional PET/CT is used, we are referring 
to te conventional system that is used in this study: the 
Ingenuity TF PET/CT scanner (Philips Healthcare). 
CT 
Computed Tomography 
ceCT 
Contrast-enhanced CT scan, used for diagnostic purposes. 
CV 
Curriculum Vitae 
Digital PET/CT 
Where the term digital PET/CT is used, we are referring to the 
digital system that is used in this study: the Vereos PET/CT 
scanner (Philips Healthcare) 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
FDG 
Fluordeoxyglucose 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
 
MRI 
Medical research ethics committee (MREC); in Dutch: medisch 
ethische toetsing commissie (METC) 
Magnetic resonance imaging 
NM 
Nuclear Medicine 
PA 
Pathology results 
PET 
Positron Emission Tomography 
(S)AE 
(Serious) Adverse Event  
Sponsor 
The sponsor is the party that commissions the organization or 

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performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organization or 
investigator.  
SUSAR 
TNM 
Suspected Unexpected Serious Adverse Reaction 
TNM staging system; tumor (T), nodes (N) and metastasis (M) 
Sv 
The Sievert (Sv) is a derived unit of ionizing radiation, 
intended to represent the stochastic health risk. For radiation 
dose assessment, this is defined as the probability of cancer 
induction and genetic damage. 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming 
Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: 
Wet Medisch-wetenschappelijk Onderzoek met Mensen) 
 
 

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SUMMARY 
Rationale: FDG-PET/CT imaging is important for staging, response monitoring and 
prognosis prediction in patients with cancer. However, the spatial resolution of current 
PET/CT systems is relatively low, limiting the detection of small lesions and accurate staging. 
In 2017, a new state-of-the-art digital PET/CT system will be installed at the NM department 
in Isala. It is expected that this new type of scanner contributes to more accurate staging and 
possibly more effective patient management. For a period of 6-12 months, both a 
conventional and a digital PET/CT system will be available in the NM department in Isala. 
This provides the unique possibility to evaluate the performance of the digital PET/CT system 
compared with conventional PET/CT. In this study, we will analyze the impact of digital 
PET/CT on the final diagnostic conclusion of the scan in patients with lung cancer, breast 
cancer and esophageal cancer. 
Objectives: Primary objective: How does the diagnostic outcome of the digital PET/CT study 
compare to the outcome of conventional PET/CT in patients referred for (re)staging of lung 
cancer, breast cancer and esophageal cancer? 
Secondary objective: What is the image quality (in both quantitative and qualitative terms) of 
digital PET as compared to conventional PET? 
Both the primary and secondary objective are further specified in multiple detailed objectives. 
Study design: Single center diagnostic accuracy study using intra-individual comparisons of 
PET/CT scans 
Study population: 225 adults referred for a FDG-PET/CT scan in Isala to evaluate 
(suspected) lung cancer, breast cancer and esophageal cancer 
Main study parameters: Primary: diagnostic outcome of the PET/CT study (number of 
detected lesions, TNM stage, clinical performance and accidental findings) 
Secondary: image quality (rating image quality, diagnostic confidence, normal tissue 
appearance, lesion contrast and relation with EANM procedure guidelines) 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
 
Additional scan time: Immediately after acquisition of the first PET/CT study, an 
additional PET/CT study will be obtained on the second system. The additional time 
for the second PET/CT scan will typically be 25 minutes (maximum 40 minutes), in 
which patients have to lie still on a scanner bed. 
 
Additional radiation dose: In a standard clinical FDG-PET/CT scan, the average dose 
is 14 milliSievert (mSv). This consists of the dose from a low-dose CT scan for 
attenuation-correction and the dose from FDG, depending on patients’ body weight. 
The extra study-related low-dose CT scan will give an additional radiation dose of on 
average 6 mSv. 

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1. INTRODUCTION AND RATIONALE 
In 2013, more than 100.000 people were diagnosed with cancer in the Netherlands [1]. For 
an effective treatment, accurate staging of cancer is of great importance. In recent years, 
Positron Emission Tomography imaging combined with Computed Tomography (PET/CT) 
(Figure 1A) using the radioactive tracer 18F-fluorodeoxyglucose (FDG) became important for 
staging, response monitoring and prognosis prediction in patients with cancer [2-4].  
 
With FDG-PET/CT, the glucose consumption of the human body is visualised. Most tumors 
and inflammations have an increased glucose consumption (thus increased FDG uptake) as 
compared to healthy tissue. Therefore, FDG-PET/CT is able to characterize malignancies 
and lesions, find metastases and determine the reaction to treatment by visualizing the 
degree of glucose (FDG) uptake which than shows up on a PET scan as a ‘hotspot’. 
However, the spatial resolution of current PET/CT systems is relatively low. This results in an 
underestimation of the true FDG uptake of small lesions, which limits the detection of small 
lesions and accurate staging [5]. Improvements in PET detector technology may lead to 
improved image quality, which may translate into a more accurate diagnosis and ultimately 
may improve patient management. 
 
Recently, a completely new type of PET detectors has been developed. After years of 
preparatory work, this new detector  - called ‘digital’ detector -  is now ready for incorporation 
into clinical PET/CT scanners. In 2017, one of these new types of PET/CT scanners (Figure 
1B) will be installed in the Nuclear Medicine (NM) department in Isala, Zwolle, the 
Netherlands, as one of the first three systems in the world. As opposed to conventional 
scanners, this will be a digital system. The development of digital detectors for PET is 
expected to be a significant improvement in PET technology. PET scanners contain detector 
material in which a small light flash is produced when a photon strikes. In the old technology 
this small light flash was amplified using a photomultiplier. This is a glass vacuum tubes that 
finally yields a small electrical signal. The new digital PET scanner contain a silicon like 
counting device that allows direct digital photon counting of the flashes produced in the 
detector crystal, making the old-fashioned photomultiplier technique with its associated 
issues no longer necessary. This digital detector technology has the potential to improve 
PET imaging performance by providing better timing, energy and spatial resolution, higher 
count rate capabilities and linearity, increased contrast, reduced noise and lower required 
radiation dose. The CT gantry in this system is based on a commercially available CT that 
has not been modified in this device. This new type of PET scanner could potentially impact 
many clinical areas, including oncology, neurology and cardiology. 

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Figure 1: Pictures of a conventional (Fig. 1A) and a digital (Fig. 1B) PET/CT system. 
 
The present study is intended to provide an initial assessment of the digital PET technology 
as used in a clinical setting. Patient images acquired on the digital PET system will be 
directly compared to images of the same patient acquired on a commercially released clinical 
PET/CT system equipped with the conventional photomultiplier tube detectors. For a period 
of 6-12 months, both a conventional and a digital PET/CT system are available in the NM 
department in Isala. In this period, extensive comparisons will be made between the 
conventional and novel digital type of PET/CT system. We will look at technical aspects such 
as image quality and lesion contrast, as well as clinical aspects such as the final diagnostic 
outcome of the study. 
 
Furthermore, in the past few years procedure guidelines for FDG-PET tumor imaging were 
published by the European Association of Nuclear Medicine (EANM) to provide a minimum 
standard for the acquisition and interpretation of FDG-PET/CT scans [6]. These common 
standards are useful for quantification, valuable for response monitoring and increasingly 
used in multi-center trials. For the digital PET/CT system, acquisition- and reconstruction 
settings to fulfill these procedure guidelines yet need to be determined. Both calibration and 
validation of various system settings will be done in this study.  
 
In the current study we will focus on three specific patients groups; patients with (suspected) 
lung cancer, breast cancer and esophageal cancer. There are multiple reasons for choosing 
these three patients groups for the present study: 
1. FDG-PET/CT imaging is frequently used in these patient groups and has importance 
for diagnosis and disease staging. 
2. In many cases within these groups, invasive staging procedures are performed in our 
hospital after PET/CT acquisition. This provides validation material that can be used 
to compare the clinical performance of conventional and digital PET/CT. 

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3. The disease incidence for these three cancer types is fairly high, providing the 
opportunity to reach a large enough study population within the selected period. 
4. In these cancer types, the areas of nodal metastases are the mediastinum, the axillae 
and the upper abdomen. In this way we will obtain a fairly complete impression of 
PET staging properties in a large proportion of relevant tissue areas. 
 
With the inclusion of these three patients groups, we will be able to make a comparison of 
conventional and digital PET/CT for these specified groups. However, we expect that such 
findings can be extrapolated to obtain an impression of the general clinical impact of digital 
PET/CT in all patients with cancer. Possibly the data from this study can be used to identify 
specific clinical areas where the digital technology may outperform conventional PET 
technology. Such initial data may be used to plan specific, hypothesis-driven follow-up 
studies to support performance and clinical claims for digital PET in general. 

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2. OBJECTIVES 
2.1 Primary objectives: lesion detection properties 
 
How does the diagnostic outcome of the digital PET/CT study compare to the outcome of 
conventional PET/CT in patients referred for (re)staging of lung cancer, breast cancer and 
esophageal cancer? In other words: does digital PET detect more, the same or less 
abnormalities in patients with cancer. 
More in detail: 
1.1 What is the difference in the number of lymph node metastases? 
1.2 What is the difference in the number of involved lymph node stations? 
1.3 What is the difference in the N status? 
1.4 What is the difference in the number of distant metastases? 
1.5 What is the difference in the number of involved distant metastatic systems (e.g. bone, 
brain, adrenals, liver, lungs)? 
1.6 What is the difference in the M status? 
1.7 What is the overall difference in final TNM classification? 
1.8 Using a composite reference standard, what is the sensitivity, specificity and accuracy 
for lymph node staging, distant metastatic and overall staging of digital PET/CT as 
compared to conventional PET/CT? 
1.9 Is there a difference in unrelated accidental findings? 
2.2 Secondary objectives: image quality 
What is the image quality (in both quantitative and qualitative terms) of digital PET as 
compared to conventional PET? 
2.1 How do experienced readers rate digital PET image quality? 
2.2 How does digital PET influence diagnostic confidence for N- and M-staging? 
2.3 Are there differences in the appearance of normal tissues between digital and 
conventional PET? 
2.4 What is the lesion detectability for digital PET as compared to conventional PET? 
2.5 What is the optimal cut-off value of tumor uptake or lesion contrast to distinguish 
between benign and malignant lesions for digital PET, and how does this compare to 
conventional PET? 
2.6 What are the optimal settings for digital PET to fulfill EANM procedure guidelines? 
2.7 Do conventional and digital PET/CT studies, that both fulfill EANM procedure 
guidelines, provide comparable final PET/CT results? 
 
Both the set of primary and secondary objective research questions can be studied in a 
variety of subgroups, based on tumor type, lesion size or other clinical factors. 

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3. STUDY DESIGN 
 
We will perform a single center diagnostic accuracy study, in which patient-scans obtained 
using two types of PET/CT scanners (1 clinical study on the conventional system and 1 
clinical study on the digital system) will be intra-individually compared. 
 
Patient selection will be performed at the NM department in Isala. Patient eligibility will be 
based on the information provided by the referring specialist on the requisition for the clinical 
FDG-PET/CT study. 
 
Patients will be included during the inclusion period of 6-12 months. Patients that meet the 
inclusion criteria and have signed informed consent will undergo two PET/CT scans on both 
the conventional and the digital PET system, immediately after each other. The scan order 
will be randomized per week:  
 
Week 1: first scan on conventional PET/CT, second scan on digital PET/CT. 
 
Week 2: first scan on digital PET/CT, second scan on conventional PET/CT. Etc.  
 
For each patient, we start with a separate analysis of conventional and digital PET/CT 
images. One investigator will evaluate the PET/CT images quantitatively while two NM 
physicians will give qualitative (visual) judgments. Afterwards, we compare conventional and 
digital findings for all patients.  
 
PET/CT data will be analyzed based on three subgroups of patients with lung cancer, breast 
cancer and esophageal cancer respectively. Pathology results and follow-up imaging by 
PET, CT, echography and MRI will be used as gold standard. When validation results are not 
available, conventional and digital PET/CT results are just compared with each other. More 
information on data analysis is described in section 5.2. 
 
 
 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
During the time that the study is open, we will select consecutive patients based on the 
information provided by the referring physician on the requisition for the study. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
referred to Isala for a clinically indicated FDG-PET/CT scan  
 
suspected or proven lung cancer, esophageal cancer or breast cancer, either as a 
primary diagnosis or follow-up study 
 
signed informed consent 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
age < 18 years 
 
incapacitated adults 
 
prisoners 
 
pregnant patients 
 
unable to undergo two consecutive PET/CT scans 
 
 

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4.4 Sample size calculation 
From the detailed research questions stated in chapter 2, a rough estimate of the number 
of required subjects will be calculated, although this is difficult because the clinical 
performance parameters for digital PET are not available yet. The only qualitative 
impression from preliminary images is that image quality and detection properties are 
going to be significantly better.  
 
Sample size calculations are performed for primary objectives 1.1 and 1.3. We do not 
formally calculate estimates for the remaining objectives, but estimate that there will be 
ample scans to answer these objectives, once the first questions have been answered. 
Furthermore in general, we expect that around 10% of the patients that are included in 
this study show a negative PET/CT scan, without the presence of malignant disease. 
Therefore, we will increase the required number of patients with 10%, to reach the 
required number of patients with malignancies for this study.  
 
The sample size calculation is performed for the three subgroups of cancer types 
separately. However, the sample size calculation for patients with lung cancer and 
patients with breast cancer is identical, due to a roughly comparable disease incidence 
(and thus a comparable amount of FDG-PET/CT scans acquired) and a comparable 
expected performance. For esophageal cancer, a separate sample size calculation is 
provided, due to a lower disease incidence. 
 
Sample size calculation for patients with lung cancer and patients with breast cancer: 
Objective 1.1 What is the difference in the number of lymph node metastases? 
For power-calculations we translated this question into: does digital PET detect more, fewer or identical 
numbers of lymph node metastasis? We would like to be able to detect a 20% difference, if present. This level 
is generally considered relevant in obtaining a new type of scanner. Using the two-tailed sign-test, assuming a 
power of 80% and a p value of 0.05, this requires the inclusion of 49 subjects. After applying the 10%-
correction for the inclusion of negative PET/CT scans, the number of required subjects is 54. 
 
Objective 1.3 What is the difference in the N status? 
For power-calculations we translated this question into: is the N-status on digital PET equal, lower or higher as 
compared to conventional PET? We would like to be able to detect a 16% difference, if present. Using the 
two-tailed sign-test, assuming a power of 80% and a p value of 0.05, this requires the inclusion of 79 subjects. 
After applying the correction for negative PET/CT scans, the number of required subjects is 87. 
 
Sample size calculation for patients with esophageal cancer: 
The incidence of esophageal cancer is much lower as compared to lung and breast 
cancer. As a consequence, the number of FDG-PET/CT scans that is acquired for this 

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patient group is much lower. Therefore, we accept a lower level of power (65%) and a 
lower significance level (p < 0.10) for the sample size calculation for this specific tumor 
type.  
 
Objective 1.1 What is the difference in the number of lymph node metastases? 
For power-calculations we translated this question into: does digital PET detect more, fewer or identical 
numbers of lymph node metastasis? We would like to be able to detect a 20% difference, if present. This level 
is generally considered relevant in obtaining a new type of scanner. Using the two-tailed sign-test, assuming a 
power of 65% and a p value of 0.10, this requires the inclusion of 28 subjects. After applying the correction for 
negative PET/CT scans, the number of required subjects is 31. 
 
Objective 1.3 What is the difference in the N status? 
For power-calculations we translated this question into: is the N-status on digital PET equal, lower or higher as 
compared to conventional PET? We would like to be able to detect a 16% difference, if present. Using the 
two-tailed sign-test, assuming a power of 65% and a p value of 0.10, this requires the inclusion of 42 subjects. 
After applying the correction for negative PET/CT scans, the number of required subjects is 46. 
 
From all above calculations, we aim to include 90 patients with lung cancer, 90 patients 
with breast cancer and 45 esophageal cancer patients, for a total of 225 patients. 
 
 
 
 
  
 
 
 
 

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5. METHODS 
5.1 Study procedures 
5.1.1 
Patient selection 
During the study period, all referrals for FDG-PET/CT scans in the NM department 
in Isala will be evaluated by one of the investigators. Based on inclusion and 
exclusion criteria, the investigator makes an initial selection of patients suitable for 
this study. Each referral that meets the inclusion criteria will be listed. For these 
selected patients, we plan a informed consent talk of around 15 minutes with a NM 
physician, physician assistant or one of the investigators. This talk takes place prior 
to the first clinical FDG-PET/CT scan. More details on the informed-consent 
procedure are described in section 8.2 Recruitment and consent. 
5.1.2 
FDG injection (clinical procedure) 
All FDG-PET/CT scans for this study will be acquired on the NM department in Isala 
(Zwolle). Before acquisition, patients have to be at least 6 hours sober. Before 
intravenous injection of the radiotracer FDG (GE Healthcare, radiopharmacy, 
Zwolle), blood glucose levels will be measured to ensure a value below 15 
millimol/L. Depending on patients’ body weight, 185-500 megabecquerel (MBq) of 
FDG will be administered (Figure 4).  
 
Figure 4: Dose-scan time protocol for the conventional PET/CT system, based on patients’ body 
weight (in kilogram). For patients with a body weight up to 80 kilogram, PET acquisition time is 1 
minute per bed position. PET acquisition time is 2 minutes per bed position for patients with a body 
weight from 81 kilogram. On average 11 bed positions are required to cover the whole-body region. 
5.1.3 
First PET/CT acquisition  
Sixty minutes after FDG tracer injection, a standard clinical whole-body PET/CT 
scan is performed on the conventional or digital PET/CT scanner. (As mentioned in 
the study design, the PET scan order is randomized per week). For the first scan, 
the acquisition times are 1 and 2 minutes per bed position for patients with body 
weight up to 80 kilogram and from 81 kilogram respectively. To cover the whole-
body region, on average 11 bed positions are required. This results in total PET 

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acquisition times of approximately 11 and 22 minutes for patients with body weight ≤ 
80 kg and > 80 kg respectively. Furthermore, attenuation CT acquisition takes 
around 5 minutes in all patients. Moreover, for many patients an additional 
diagnostic contrast-enhanced CT scan is acquired on the clinical PET/CT system 
with a total procedure time of approximately 15 minutes. 
5.1.4 
Second PET/CT acquisition (study procedure) 
Consecutively after the first PET/CT scan, an additional PET/CT scan is acquired on 
the second PET/CT system. To minimize the decrease in FDG present in the human 
body when performing the second PET/CT scan, the time between first and second 
PET/CT scan should be kept as short as possible. However, the amount of FDG 
present in the human body during the second PET/CT scan will be less as 
compared to the first PET/CT scan. Therefore, the acquisition time for second 
PET/CT scanning will equal to first PET/CT scan, plus a compensation for the 
radioactive decay. Due to differences in PET acquisition times and the acquisition of 
a diagnostic CT scan, there will be differences in delay time between patients. In 
general, patients can be divided in four groups for expected delay: 
1. 
Patient bodyweight ≤ 80 kg and no diagnostic ceCT: delay ≈ 21 minutes 
2. 
Patient bodyweight > 80 kg and no diagnostic ceCT: delay ≈ 32 minutes 
3. 
Patient bodyweight ≤ 80 kg and a diagnostic ceCT: delay ≈ 36 minutes 
4. 
Patient bodyweight > 80 kg and a diagnostic ceCT: delay ≈ 47 minutes 
 
FDG has a half-life of 110 minutes. Using the formula for radioactive decay N(t) = 
N(0)*0.5T/T0.5, the percentage of FDG after the delay can be calculated. The 
correction factor is determined by calculating the inverse of the percentage of FDG, 
present after the delay. Based on this correction factor, the total acquisition time for 
the second PET/CT system can be calculated. Table 2 provides an indication of the 
scan times required for digital PET/CT scanning. As can be seen in this table, 
patients’ bodyweight (≤80 kg or >80kg) is the main predicting factor whether the 
acquisition time on second PET takes approximately 20 minutes or approximately 
35 minutes. Based on this estimation, we expect that the additional time for patients 
participating in this study will typically be 25 minutes but will not take more than 40 
minutes.  
 
 

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Table 2: Indications of total scan time on second PET/CT system, based on expected delays in 
four groups of patients. The total scan time on second PET/CT includes the time for PET acquisition 
(with 11 bed positions (bp)) and attenuation CT acquisition. 
Patient 
group 
Delay in  
minutes (≈) 
Amount of FDG  
after delay (%) 
Correction 
 factor 
Second PET, 
scan time per 
bp (s) 
Second 
PET/CT scan 
time (min) 
1 
21 
88% 
1.14 
60*1.14 = 68 
18 
2 
32 
82% 
1.22 
120*1.22 = 147 
32 
3 
36 
80% 
1.25 
60*1.25 = 75 
19 
4 
47 
74% 
1.34 
120*1.34 = 161 
35 
 
To provide an optimal comparison between conventional and digital PET/CT, we will 
use a patient-specific protocol for the second PET scan, based on the exact delay 
for each patient. This delay will be determined once the patient arrives in the room 
for the second PET/CT scan and will be used to set the final PET scan time per bed 
position for the second PET scan, for each patient separately.  
5.1.5 
PET/CT data reconstruction 
For both conventional and digital PET/CT, the attenuation correction of PET images 
is based on CT attenuation maps. For the conventional PET/CT study, images will 
be reconstructed using standard clinical Isala protocol. This protocol includes two 
types of reconstructions: one reconstruction method fulfilling EANM guidelines for 
FDG-PET tumor imaging and one reconstruction method for optimal lesion detection 
using small 2x2x2 mm3 voxels [7]. 
 
Digital PET/CT images will initially be reconstructed using a protocol advised by the 
vendor. 
However, 
in 
retrospective 
we 
may 
perform 
several 
additional 
reconstructions on the PET/CT scans obtained during this study. This will be done to 
determine and evaluate for example optimal settings for image quality, lesion 
detectability and clinical performance. This will also include the reconstruction 
fulfilling EANM guidelines for FDG-PET tumor imaging. 
5.1.6 
PET/CT diagnoses 
Diagnoses will be made from images acquired on both the conventional and digital 
PET/CT system. The images acquired from the digital PET/CT scan will be included 
in the patients’ medical record. The nuclear medicine physician will mention 
differences between the analog and digital PET in the PET/CT report, and the 
referring physician can discuss this with the patient.  

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5.2 Data collection and analysis 
5.2.1 
General data collection 
For each patient, we will collect several patient- and scan characteristics as 
presented in Figure 5.  
Figure 5: Description of patient- and scan characteristics that will be collected for this study. 
For each patient, we will start with an analysis of both conventional and digital 
PET/CT images separately. One investigator will evaluate the PET/CT images 
quantitatively while two NM physicians will give qualitative (visual) judgments. When 
both conventional and digital PET/CT images from a patient are evaluated 
separately, the results will be compared and differences between the image 
datasets will be identified.  
 
We will focus on PET/CT based TNM staging, which includes evaluation of the 
primary tumor, regional lymph nodes and distant metastasis. This means that for 
patients with (suspected) lung cancer, we will focus on the evaluation of primary 
lung tumor(s), mediastinal and hilair lymph nodes and distant metastases (in 
particular adrenal glands). For patient with (suspected) breast cancer, we will focus 
on the analysis of primary breast tumors, regional lymph nodes (axillary, 
subclaviculair, internal mammary and supraclavicular) and distant metastases. In 
patients suspicious for esophageal cancer, we will focus on the primary esophageal 
tumor, regional lymph nodes in the thorax and lower abdomen, and distant 
metastasis. Furthermore, other (rather unexpected) findings and differences 
between conventional and digital PET imaging will be studied and documented. 

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5.2.2 
PET/CT evaluation 
Quantitative evaluation 
The following general measurements will be performed on all PET images: 
 Liver noise level 
 Lung noise level 
 Normal tissue uptake (SUVmean and SUVmax) in both lungs, blood pool, liver, 
both adrenal glands, spleen, bones and bone marrow. 
 
For all lesions, the following measurements will be performed on PET images: 
 SUVmax 
 SUVmean (based on 50% SUVmax) 
 Volume om mL (based on 50%SUVmax) 
 Lesion contrast 
 Lesion contrast-to-noise 
 Lesion-to-liver ratio 
 Lesion-to-aorta ratio 
Furthermore, the lesion diameter as measured on the attenuation CT scan will be 
collected to make stratifications based on lesion diameter. 
 
Qualitative (visual) evaluation 
Visual assessment of conventional and digital PET images will be performed by two 
NM physicians, blinded for patient characteristics and patient history. They perform 
a general evaluation for: 
 PET image quality (4-point scale: poor, fair, good, excellent) 
 Liver noise (4-point scale: low, mild, moderate, high)  
 Lung noise (4-point scale: low, mild, moderate, high) 
 Assessment of any visible artifacts, occurrence of distortion or any other visual 
impressions 
Moreover, each selected lesion will be visually evaluated on both PET datasets 
using a 4-point scale: 
1. No visualization 
2. Mild intensity 
3. Moderate intensity 
4. High intensity 
Moreover, the NM physicians will both judge each lesion on a 4-point scale 
(definitely benign, likely benign, likely malignant, definitely malignant) on both 

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datasets separately. This is used for performance evaluation in lesion 
characterization, and to compare the diagnostic confidence. 
Finally, the adrenal glands are visually assessed using the following 4-point scale: 
1. Uptake below liver uptake 
2. Uptake equal to liver 
3. Uptake slightly greater than liver uptake 
4. Uptake much greater than liver uptake 
To reduce the impact of a potential learning effect for reading digital PET images, 
we will randomize the reading order for both NM physicians. 
5.2.3 
Validation 
For each patient, the results of the PET/CT studies will be compared with available 
validation results. It is preferred that this regards invasive staging with pathology 
(PA) evaluation, although it may also include follow-up or information from other 
imaging modalities such as MRI and contrast-enhanced CT. Validation shall be 
performed based on findings from both conventional and digital PET/CT.  
5.2.4 
EANM procedure guidelines 
In the present study, we will calibrate and validate the EANM procedure guidelines 
for FDG-PET tumor imaging on a digital PET/CT system. Calibration of the required 
acquisition and reconstruction settings will be done by performing a phantom study. 
Afterwards, the digital PET/CT scans are reconstructed using the predefined 
acquisition and reconstruction settings. 
 
For each patient, the conventional and digital PET/CT scans that fulfill EANM 
procedure guidelines will be visually compared by two NM physicians. For both 
datasets, they will provide a final diagnostic outcome which will be compared. These 
EANM-fulfilled scans will also be compared quantitatively, but we will be cautious to 
use those measurements for finite conclusions on EANM-validation due to the time 
delay between conventional and digital PET/CT. 
 
 

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5.3 Main study parameters 
5.3.1 
Primary study parameter 
Diagnostic outcome of the PET/CT study 
In more detail: 
 
Number of lymph node metastasis 
 
Involved lymph node stations 
 
N-status 
 
Number of distant metastasis 
 
Involved distant metastatic systems (e.g. bone, brain, adrenals, liver, lungs) 
 
M-status 
 
Final TNM classification 
 
Sensitivity, specificity and accuracy for lymph node staging, distant metastatic 
and overall staging 
 
Unrelated accidental findings 
5.3.2 
Secondary study parameter 
PET image quality 
In more detail: 
 
General PET image quality  
o Subjective: whole-body, liver and lung 
o Objective: liver and lung noise 
 
Diagnostic confidence for N- and M-staging 
 
Normal tissue appearance 
 
Lesion detectability (SUVmax, SUVmean (based on 50% SUVmax), lesion 
volume, lesion contrast, lesion contrast-to-noise ratio, lesion-to-liver ratio, 
lesion-to-aorta ratio as compared to lesion diameter measured on the 
attenuation CT) 
 
Optimal cut-off values of tumor uptake or lesion contrast to distinguish 
between benign and malignant lesions 
 
Optimal settings for digital PET to fulfill EANM procedure guidelines 
 
Comparison of conventional and digital PET fulfilling EANM procedure 
guidelines, based on: 
o Subjective opinion from NM physicians (lesion-based and patient-based) 
o Quantitative measurements (lesion-based) 
 
 

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5.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for 
urgent medical reasons. 
 
5.5 Replacement of individual subjects after withdrawal 
If an included individual subject withdraws from the study, another subject can be included 
and replaces this subject. 
 
5.6 Follow-up of subjects withdrawn from treatment 
There will be no follow up of subjects, withdrawn from this study. 

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6. SAFETY REPORTING 
6.1 Section 10 WMO event 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the 
subjects and the reviewing accredited METC if anything occurs, on the basis of which it 
appears that the disadvantages of participation may be significantly greater than was 
foreseen in the research proposal. The study will be suspended pending further review by 
the accredited METC, except insofar as suspension would jeopardize the subjects’ 
health. The investigator will take care that all subjects are kept informed. 
 
6.2 AEs, SAEs and SUSARs 
6.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the investigational product. All 
adverse events reported spontaneously by the subject or observed by the investigator 
or his staff will be recorded. 
 
The occurrence of any adverse events due to the conduct of the study is not 
foreseen. Risks associated with the digital PET/CT system have been evaluated and 
are mitigated according to industry safety standards for radiation, mechanical, 
thermal, and electric hazards. Foreseeable adverse events associated with this 
investigation linked to the device would be considered very rare and would be the 
same type of physical events that could occur in any normal PET/CT scan. These 
would include pinching of skin, minor falls or bumps.   
 
Normal risks of NM scans from the injection of a radiopharmaceutical include allergic 
reactions, swelling, infections, intravenous injuries, bruising, pain and discomfort. 
These hazards, if encountered, would likely occur as the result of the scheduled 
clinical PET/CT scan. Clinical guidelines for the PET and CT scan will be followed 
according to hospital policy.  
 
The following adverse changes from baseline require reporting as Adverse Events: 
• Any adverse change that has either of the following relations to the investigational 
device or study procedures: ‘possibly related’ or ‘related’ 
• Any event that is an Unanticipated Adverse Device Effect  

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An adverse change that does not meet any of the above does not require reporting to 
the Sponsor (or the METC). 
6.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that at any 
dose:  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; 
- 
Any other important medical event that may not result in death, be life threatening, 
or require hospitalization, may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the subject 
or may require an intervention to prevent one of the outcomes listed above. 
 
The PI will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 15 days after the PI has first knowledge of 
the serious adverse events. 
 
SAEs that result in death or are life threatening should be reported expedited. The 
expedited reporting will occur not later than 7 days after the responsible investigator 
has first knowledge of the adverse event. This is for a preliminary report with another 
8 days for completion of the report.  
 
6.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol. 
 

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7. STATISTICAL ANALYSIS 
7.1 Main study parameters 
Differences are specified as follows: generally when performing the lesion-based or 
patient-based comparison between conventional and digital PET, all disagreements in 
measured scales, numbers of lesions and quantitative data will be regarded as 
differences. Furthermore, all disagreements in T, N and M stage between conventional 
and digital PET will be regarded as differences.  
7.1.1 
Primary objective: diagnostic outcome of the PET/CT studies 
For each patient separately, the diagnostic outcome for the conventional and digital 
PET/CT study will be compared. Measured ordinal differences in for example the N-
status or the TNM classification will be assessed based on two methods. The first 
method is based on the sign test, in which the comparison results in an agreement 
or a disagreement. The second method is based on the Wilcoxon signed-ranked 
test, in which the amount of disagreement is also taken into account. Moreover, we 
will calculate agreement percentages on the diagnostic outcome between both 
systems. Furthermore, using validation results as a reference, we will determine the 
sensitivity, specificity and accuracy for both NM physicians based on the following 
formulas: 
𝑆𝑒𝑛𝑠𝑖𝑡𝑖𝑣𝑖𝑡𝑦=  𝑁𝑃𝐸𝑇 𝑝𝑜𝑠𝑖𝑡𝑖𝑣𝑒  𝑁 𝑡𝑟𝑢𝑒 𝑝𝑜𝑠𝑖𝑡𝑖𝑣𝑒
⁄
 
𝑆𝑝𝑒𝑐𝑖𝑓𝑖𝑐𝑡𝑦=  𝑁𝑃𝐸𝑇 𝑛𝑒𝑔𝑎𝑡𝑖𝑣𝑒  𝑁 𝑡𝑟𝑢𝑒 𝑛𝑒𝑔𝑎𝑡𝑖𝑣𝑒
⁄
 
𝐴𝑐𝑐𝑢𝑟𝑎𝑐𝑦=  𝑁𝑃𝐸𝑇 𝑝𝑜𝑠𝑖𝑡𝑖𝑣𝑒+ 𝑁 𝑃𝐸𝑇 𝑛𝑒𝑔𝑎𝑡𝑖𝑣𝑒  𝑁 𝑡𝑟𝑢𝑒 𝑝𝑜𝑠𝑖𝑡𝑖𝑣𝑒+ 𝑁 𝑡𝑟𝑢𝑒 𝑛𝑒𝑔𝑎𝑡𝑖𝑣𝑒
⁄
 
To test whether differences in sensitivity, specificity and accuracy between 
conventional and digital PET/CT are significant, we will apply the McNemar paired 
proportion test. A p value of less than 0.05 will be considered to indicate statistical 
significance. 
7.1.2 
Secondary objective: PET image quality 
General PET image quality 
We will perform a population-based comparison between conventional and digital 
PET for general PET image quality and noise levels in the liver and lung. 
Differences in scores will be assessed using the sign test and the Wilcoxon signed-
rank test. Furthermore, to evaluate the inter-observer variation between the 
subjective opinions from both NM physicians, we will calculate the kappa and 
compare the percentage agreement of PET image quality and noise levels in the 
liver and lung. 
 

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Diagnostic confidence 
Differences in diagnostic confidence between conventional and digital PET are 
assessed using the sign test and the Wilcoxon signed-rank test.  
 
Normal tissue appearance 
When looking at the normal tissue appearance, we will perform a population-based 
comparison of average values in normal tissue uptake between conventional and 
digital PET/CT. Differences will be assessed using the Wilcoxon signed-rank test. It 
is expected that patient delay may influence normal tissue FDG-uptake. Therefore, 
we will study the presence of correlations between the amount of time-delay and 
differences in normal tissue uptake between conventional- and digital scans.  
 
Lesion detectability 
For all lesions that are detected on both scans, we will compare all parameters 
(such as lesion SUVmean, SUVmax and contrast) measured on conventional and 
digital PET. Differences between conventional and digital PET will be assessed 
using the Wilcoxon signed-rank test. 
 
Optimal cut-off values 
To compare the performance of various quantitative PET evaluation parameters 
(such as lesion SUVmean, SUVmax and contrast), we will create receiver operating 
characteristic (ROC) curves and calculate sensitivity, specificity and accuracy values 
using validation results as a reference. Again, to test whether differences in 
sensitivity, specificity and accuracy between conventional and digital PET/CT are 
significant, we will apply the McNemar paired proportion test. A p value of less than 
0.05 will be considered to indicate statistical significance. Finally, for each 
quantitative evaluation parameter, we will determine the optimal cut-off value to 
distinguish benign from malignant lesions on both conventional and digital PET/CT. 
This will be based on the value with optimal sensitivity and specificity (highest sum). 
 
 
EANM procedure guidelines 
It is expected that both conventional and digital PET/CT studies, which fulfill EANM 
procedure guidelines, provide a comparable PET/CT diagnostic outcome. These 
results will be evaluated for all patients. Differences in diagnostic outcome will be 
assessed using the sign-test and the Wilcoxon signed-rank test.   
 
 
 

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Inter-observer agreements 
Two NM physicians will evaluate conventional and digital PET/CT images on final 
diagnostic outcome, general image quality and diagnostic confidence. To evaluate 
the inter-observer variation between these two operators, we will compare 
percentage agreements and calculate a kappa. 
 
Both the set of primary and secondary study parameters will be studied in a variety 
of subgroups, based on tumor type, lesion size and other clinical factors. 
 
 
 
 

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8. ETHICAL CONSIDERATIONS 
8.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (64th 
WMA General Assembly, October 2013) and in accordance with the Medical Research 
Involving Human Subjects Act (a Dutch act called the ‘WMO’). 
 
8.2 Recruitment and consent 
During the study period, all referrals for FDG-PET/CT scans in the NM department in Isala 
will be evaluated by one of the investigators. Based on inclusion and exclusion criteria, the 
investigator makes an initial selection of patients suitable for this study. Because the time 
period between PET/CT referral and PET/CT acquisition is very short (only a few days), 
we will approach the patients when they arrive at the NM department for their clinical 
PET/CT scan. 
 
During a personal talk with a NM physician, physician assistant or one of the investigators, 
an adequate explanation of the aims, methods, anticipated benefits, and potential hazards 
of the study will be provided. Furthermore, the patient receives the study information 
letter. The patient will be given the opportunity to discuss the participation with family and 
friends (if they desire) or to further review on their own prior to signing the informed-
consent form. After the personal talk, the radioactive tracer FDG is injected and the 
patient has to wait for  60 minutes (exposure time). After this waiting period, we ask the 
patient to sign the informed-consent form. Subsequently the first and eventually second 
PET/CT scan are acquired. The patient will have at least one hour to consider his 
decision. 
 
The written consent form will be revised if new information becomes available during the 
study that may be relevant to the subject. Any revision(s) will be submitted to the METC 
for review and approval in advance of use. 
8.3 Benefits and risks assessment, group relatedness 
For patients participating in this study, there are two main disadvantages that should be 
mentioned: the additional scan time and the additional radiation dose. Furthermore, 
patients may benefit from participation in this study, as the digital PET/CT images may 
reveal more diagnostic information compared with the conventional PET/CT scan.  

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8.3.1 
Additional scan time 
The second PET/CT study will be obtained immediately after the first PET study 
employing the same FDG injection. Study-participants will therefore remain 
averagely 30-40 minutes longer in the NM department than non-participants. In this 
time period, the additional scan will be acquired on the second PET/CT scanner. 
The additional time in the scanner will typically be 25 minutes (maximum 40 
minutes), in which patients have to lie still on a scanner bed.   
8.3.2 
Additional radiation dose 
The extra study-related low-dose CT scan will give an additional radiation dose of on 
average 6 milliSievert (mSv). In comparison: in a standard clinical FDG-PET/CT 
scan, the average dose is 14 mSv which constitutes the dose from a low-dose CT 
scan for attenuation-correction and the dose from FDG, depending on patients’ body 
weight. When the standard clinical PET/CT scan is combined with a diagnostic CT 
scan using intravenous contrast, the average dose is approximately 22 mSv. 
Furthermore, a large amount of patients from our study population will be treated 
with radiotherapy, where patients receive up to 100 times higher doses as compared 
to the dose that patients receive with diagnostic imaging. Moreover, participating in 
this study does not influence the ability to acquire other diagnostic imaging scans. 
8.4 Justification for the proposed study 
Before a novel PET/CT system that is based on a completely new detector 
technique can enter clinical practice, extensive clinical research is required. The 
proposed study will provide detailed information on the technical and clinical 
performance of the novel digital PET/CT system. The extra burden for the patient 
participating in this study is relative low and furthermore there is a relative low risk 
for side effects and other issues for patients participating in this study. 

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9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
9.1 Handling and storage of data and documents 
The handling of personal data complies with the Dutch Personal Data Protection Act. 
Research data will be stored in a research database (Research manager). Data is added 
to the database by two investigators. One investigator has the key to access the source 
data. This document is protected by an account name and password.  
 
On request, the coded anonymized raw data and processed images, will be provided to 
Philips for analysis and post-processing. A secure point to point data transfer with an 
existing capability will be used, or if the data sets are too large for practical transmission, 
we will use encrypted hard drives.   
 
Each dataset will be coded with an unique study identifier assigned by the principal 
investigator (PI) or designee. The PI will maintain a document with the name of the patient 
and their associated study identification number. Additionally, Isala will provide Philips 
with coded medical record information (i.e., patient medical history), diagnostic reports (as 
relevant for the study), etc.) when it is determined to aid in the evaluation of the digital 
PET images. The patients personal health information, such as name, medical record 
number etc., will not be divulged to Philips. Isala will maintain all research related 
documents and dataset on secured servers with password protection or in a locked area 
with limited access. 
 
9.2 Monitoring and Quality Assurance  
A study binder will be maintained at the site that will include the protocol, METC 
documents, Case Report Forms, and other study logs and records. The site study 
coordinator and investigator will be responsible for keeping the information up-to-date.  All 
records pertaining to the conduct of the clinical study, including case report forms, 
informed consent forms, source documents, METC correspondence and other study 
documentation will be retained at the site. 
 
The records will be maintained for a period of at least 15 years, including 2 years after the 
latter of the following two dates: the date on which the investigation is terminated or 
completed, or the date that the records are no longer required for purposes of supporting 
a Pre-market Notification Clearance.  

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9.3 Amendments  
Amendments are changes made to the research after a favorable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favorable opinion.  
9.4 Annual progress report 
The investigator will submit a summary of the progress of the trial to the accredited METC 
once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, 
serious adverse events/ serious adverse reactions, other problems, and amendments.  
9.5 End of study report 
The investigator will notify the accredited METC of the end of the study within a period of 
8 weeks. The end of the study is defined as the moment that 225 patients are included. 
In case the study is ended prematurely, the investigator will notify the accredited METC 
within 15 days, including the reasons for the premature termination.  Within one year after 
the end of the study, the investigator will submit a final study report with the results of the 
study, including any publications/abstracts of the study, to the accredited METC.  
9.6 Public disclosure and publication policy 
Results provided by this study will be submitted for publication in peer-reviewed scientific 
journals, but may also be used to support marketing and regulatory claims. Both negative, 
indifferent and positive results can be considered for publication. 
 
For the remaining arrangements regarding data sharing between the site (Isala) and 
Philips Healthcare, we refer to the mutually agreed document “Data sharing plan”, version 
3  
 
 
 

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