EUROPEAN LUNG CANCER WORKING PARTY
PROTOCOL 01071
PROGNOSTIC ROLE OF PRIMARY NON SMALL CELL LUNG
CARCINOMA STANDARDIZED F18-FDG UPTAKE VALUES (SUV AND
TLG) MEASURED WITH F18-FLUORODEOXYGLUCOSE POSITRON
EMISSION TOMOGRAPHY (F18-FDG-PET): A NON
INTERVENTIONAL STUDY.
Writing committee: T. Berghmans, M. Dusart, M. Paesmans, S. Alard, J.J. Lafitte, C.
Hossein-Foucher, C. Garcia, B. Vanderlinden, I. Buvat, J.P. Sculier
Clinical study coordinator: T. Berghmans
Nuclear study coordinators: M. Dusart, C. Hossein-Foucher
Statistician: M. Paesmans
Data manager: N. Leclercq
Ethical committee: 18 July 2008
Activated: 24 July 2008
1
INDEX
I.
Group
II.
Background
III.
Study objectives
IV.
1
2
Study population
Criteria of eligibility
Criteria of ineligibility
V.
Study design
VI.
1
2
3
Investigations
Initial investigations
Evaluation during treatment
Follow-up after chemotherapy
VII.
Required criteria for FDG-PET scan
VIII.
Criteria of evaluation
IX.
Entry and randomisation procedures
X.
Data management and trial coordination
XI.
Ethical considerations
XII.
Statistical considerations
XIII.
Publication and authorship
Appendix I
Appendix II
Appendix III
Appendix IV
Bibliography
Performance scale
Staging classification
The World Medical Association Declaration of Helsinki
Required criteria for FDG-PET scan acquisition and interpretation
2
I. Group
Participating centres and members are the followings:
Mouscron
Belgium
Centre Hospitalier de Mouscron
Bruxelles
Institut Jules Bordet
J.P Sculier, T. Berghmans, M.
Dusart, C. Garcia, A.P. Meert,
M. Paesmans, E. Markiewicz,
C. Mascaux, P. Van Houtte,
M. Roelandts, N. Leclercq, S.
Doumit, B. Vanderlinden
Hôpital Brugmann
T. Prigogine, A. Drowart
Charleroi
CHU de Charleroi
J. Lecomte
Boussu
CHR St-Joseph – Warquignies
M. Richez, P.E Baugnee
Gilly
Clinique St-Joseph
B. Colinet
Verviers
CH Peltzer- La Tourelle
Y. Bonduelle, I. Louviaux
Mons
Hôpital Ambroise Paré
P. Wackenier, S. Holbrechts
Bouge
Clinique St Luc
O. Van Cutsem
Ath
RHMS
P. Ravez
Tourcoing
France
CHG de Tourcoing
X. Ficheroulle
Lille
CHRU de Lille – Hôpital Albert
Calmette
J.J Lafitte, A Scherpereel, B
Chahine, D. Gourcerol
Montfermeil
CHI le Raincy-Montfermeil
T. Collon
Douai
Centre Hospitalier de Douai
M.C. Florin, S. Desurmont, E.
Maetz
Valencia
Spain
Hospital de Sagunto
V Giner-Marco
CHU Pitié-Salpêtrière
CHU St Pierre
CHR de la Citadelle
Hôpital Roger Salengro
I. Buvat
S. Alard
M. Dusart
C. Hossein-Foucher
C. Tulippe
Participating experts :
Paris
Bruxelles
Liège
Lille
3
II. Background
Cancer stage is currently the most important prognostic factor for survival, also having
implications in the therapeutic strategy. The current tumour (T), node (N), metastasis (M)
staging system is based on the anatomical spread of the disease, as assessed by clinical,
imaging and pathological parameters. This TNM system was first proposed by Denoix (1). In
the years 1970, two staging systems, based on the TNM classification were developed by the
American Joint Committee on Cancer (AJCC) (2) and the Union Internationale Contre le
Cancer (UICC) (3). A new international staging system for lung cancer, proposed both by the
UICC and the AJCC and largely accepted by the international community, was published in
1986 (4). The 5th edition of the TNM Classification of Malignant Tumours, mainly based on
surgical patients, published in 1997 (5), was the last including changes with new T and N
subgroupings. This International Staging System (ISS) is nowadays used by most of the lung
cancer specialists.
The International Staging System (ISS) needs to be improved. The ISS classification is
based on a historical single-institution database including patients treated at the University of
Texas M.D. Anderson Cancer Center and those referred for confirmation of staging and
histologic features to the same institution by the National Cancer Institute Cooperative Lung
Cancer Study Group. The database was constructed during the periods 1975-1982 (4) and
1975-1988 for the last revision (5). During that period, work-up assessments did not use
modern imaging techniques, such as CT scan, nuclear magnetic resonance imaging or PET
scan. This staging system was designed and principally used by surgeons because, during the
study period, the treatment was mainly surgically based. Patients were not treated according
to the today current standards of care, which include combined modality treatment, at least in
stage III diseases. Treatment of NSCLC needs now a multidisciplinary approach based on the
clinical staging system. Most patients will be treated by initial chemotherapy, making
impossible the determination of initial pathological TNM stage.
As there was a need for improving the ISS classification, the IASLC (International
Association for the Study of Lung Cancer) Lung Cancer Staging Project searched for data
worldwide and made proposals for the forthcoming 7th edition of the TNM Classification for
Malignant Tumours based on an international database (6-10). Data were internationally
retrospectively collected from 1990 to 1999 among numerous organisations and institutions
having in charge patients with lung cancer and their treatments. Although these patients were
most treated with recent chemotherapy regimens including platinum derivatives, new imaging
4
techniques like positron emission tomography were not taken into account, mainly because
they had not been performed.
Positron emission tomography (PET) with 2-[18F] fluoro-2-deoxy-D-glucose (F18FDG), a glucose analogue, has emerged as an useful tool for several malignancies and has
been widely studied in primary lung cancer. Two meta-analyses (11;12) established the added
value of
18
F-FDG-PET over CT and other imaging modalities for the diagnosis and the
staging of lung cancer, except for brain metastases. Studies have also explored the survival
prognostic significance of the standardised uptake value (SUV), a simplified semi-quantitative
measurement of tissue deoxyglucose metabolic rate, but most of these reports only include a
small number of patients.
In the context of the IASLC Lung Cancer Staging Project proposals for the
forthcoming 7th edition of the TNM Classification for Malignant Tumours, we performed a
systematic review of the literature and a meta-analysis of the published data in order to
determine the prognostic value of primary tumour SUV in patients with lung cancer (13). We
found 13 eligible studies dedicated to NSCLC. Most of them included patients with stages I to
III/IV and used a SUV assessment normalised for body weight. The numbers of patients
ranged from 38 to 315 per study (total: 1,474); 11 studies identified a high SUV as a poor
prognostic factor for survival although 2 studies found no significant correlation between
SUV and survival. SUV measurement and SUV threshold used to define high SUV were
study dependent. Overall, we estimated a combined hazard ratio (HR) for the 13 reports of
2.22 (95% CI : 1.83-2.70) - fixed effects model - suggesting that the primary tumour SUV
measurement has a prognostic value in NSCLC. Using a random-effects model, the combined
HR was 2.27 (95% CI : 1.70-3.02).
Despite this significant hazard ratio, more advanced analyses are required to establish the
independent prognostic role of the SUV in primary lung cancer. In fact, most of the published
studies were retrospective with all the known potential biases related to this method. SUV
estimates suffer from poor reproducibility between centres probably due to the lack of
acquisition and processing protocols standardisation leading to the assessment of the SUV.
The most important sources of variability in SUV estimates are listed below:
-
the method of tumour uptake estimate greatly impacts the SUV, which can vary by a
factor of about 2 depending on the volume of interest considered to measure the
tumour uptake
5
-
the spatial resolution in the reconstructed images: this spatial resolution depends on
the reconstruction algorithm type and on the parameters used to reconstruct the
images. All of these directly affect the blurring of the tumour in the images and hence
the tumour pixel values. The same tumour detected by two different PET imaging
systems with different spatial resolutions will have different uptakes through the bias
of the partial volume effect. This is especially true for the SUVmax, which can vary
by more than 10%, depending on the spatial resolution in the reconstructed images. In
order to limit the impact of the partial volume effect, some authors (14) have
introduced another parameter, the tumour lesion glycolysis (TLG). TLG is defined as
the product of SUVmean by the functional volume of interest where the SUVmean is
determined by the way the PET images have been corrected for systematic errors due
to physical constraints such as tissue attenuation. For instance, CT-based attenuation
correction tends to yield higher SUV (from 10% to 50%) than attenuation correction
based on a conventional PET transmission device.
-
the normalisation factor used to estimate the FDG made available to the tumour. Most
of the time, the injected activity is normalised for the patient bodyweight, but other
normalisations, using for example the lean body mass or the body surface area, have
been proposed. The lean body mass normalisation was proposed to take into account
the fact that body fat has not the same FDG uptake as the lean tissues.
-
the plasma glucose level of the patient. FDG competes with the plasma glucose and
lower SUVs are observed in fed patients compared to patients under fasting
conditions. Normalisation to take into account the plasma glucose level has been
proposed.
-
the delay between the injection time and the imaging time: the longer this delay, the
higher the SUV, as equilibrium is usually not reached at 45-60 min post-injection.
Changes in SUV between 45 min and 90 min post injection scans can be of about
20%.
In addition to these technical factors, the case-mix of the patients varying from one study to
another, including e.a. histological sub-type, lung cancer stage and some clinical
characteristics dependent of the patient, could have influenced the SUV measures. In our
meta-analysis, this variability between the different centres was partially evidenced by the
broad range of threshold values that have been used in the literature to distinguish between
patients with low and high SUV (thresholds varying from 2.5 to 20). Despite this variability,
we were able to show that SUV was correlated with patient survival. Indeed, our study design
6
used meta-analytical techniques and, therefore a HR for each study was calculated, based on
the SUV threshold used in that study (in many instances, adequately defined as the observed
median). We combined these individual HRs and therefore never compared directly a patient
with a low SUV in one study to a patient with a high SUV in another study.
In consequence, to be used as a prognostic factor in routine practice, a single SUV
threshold that would allow discriminating between long and short survival patients should be
agreed on, or the methodology to be used to determine the optimal threshold for each centre
should be established. To set a consistent threshold, most sources of variability impacting the
SUV estimates should be removed or at least controlled. Reducing the large variability
currently affecting SUV estimates would probably enhance the prognostic value of SUV.
One of the parameters to take into account is the partial volume effect on the SUV.
Indeed, in a recently published study, Vesselle et al (15) did not report a significant
relationship between a poor survival and a high SUV if this one was corrected for the partial
volume effect. In their multivariate analysis, tumour size but not SUV was an independent
prognostic factor for survival. Tumour size has been considered by other authors as a
prognostic factor, mainly in surgical stages (16;17) and in patients with NSCLC receiving
thoracic radiotherapy (18). Recently, the IASLC reported on the importance of the tumoural
size in NSCLC leading to some new proposals for the next International Staging System
(6;10). However, tumour size measurement could be inconsistent, leading to incorrect
interpretations of tumour evolution (19). For the smaller tumours (less than 3 cm), SUV
contains information about the size and about the aggressiveness of the tumour. In the study
by Vesselle et al, the way used to correct the SUV could have introduced other biases than
those previously existing as pointed out by Weber and al in their editorial (20).
In the retrospective studies included in our meta-analysis, tumour size was also
assessed in addition to the SUV in 7 studies (21-27) but only five were looking for a
correlation between these two variables and survival (21-23;26;27). Moreover, the size of the
tumour was measured either on the pathological specimen or on CT or conventional X-ray.
According to the different studies, tumour size thresholds were variable when this parameter
was dichotomised. In only one study, the tumour volume was considered for prognostic
significance.
We aim to determine the role of the degree of
18
F-FDG uptake (SUV and TLG)
measured by 18F-FDG-PET scan as prognostic factor for survival in lung cancer patients. We
want to try standardising the measurement techniques of SUV and TLG to avoid all the biases
that we have previously described. The independent value of these parameters will be
7
determined by a multivariate analysis taking into account reproducible factors as stage, age,
weight loss, gender, performance status and some routine biological variables.
8
III. Study objectives
3.1. Primary endpoint
The primary aim of this non interventional study is to assess the independent prognostic role
on overall survival of primary tumour
18
18
F-FDG uptake value (SUVmax) measured on
fluorodeoxyglucose positron emission tomography (18F-FDG-PET) in patients with non-
metastatic non-small cell lung cancers treated with curative intent, taking into account the
other conventional prognostic factors (performance status, age, sex, disease stage).
3.2. Secondary endpoints
- to determine the best discriminant value of
18
F-FDG uptake for survival and for
progression-free survival: SUVmax, SUV mean (volume defined by a percentage of
SUVmax [75%, 80%, 90%]), TLG, SUVmax corrected for the partial volume effect (volume
defined on CT or on PET)
- to determine the best discriminant value of CT measurements for survival and for
progression-free survival, measurement performed on the CT associated to PET for the cases
where the PET is performed by a combined PET-CT scan for size, area and volume
determinations
IV. Study population
4.1 Criteria of eligibility include :
- Pathologically demonstrated NSCLC
- Stage I-III (6) (see appendix 2) treated by curative treatment by surgery with or without
chemotherapy (induction or adjuvant) or by chemoradiotherapy
- Inoperable patients treated by exclusive radiotherapy
- A whole-body (skull base to mid tighs) FDG-PET or a combined FDG-PET/CT on a
dedicated machine, performed before any anticancer treatment
- FDG-PET or combined FDG-PET/CT has to be previously standardised according to the
procedure described in appendix IV
- Written informed consent
- Accessibility to follow-up
- Age  18 years
4.2 Criteria of ineligibility include:
- Prior anticancer treatment (surgery, radiotherapy or chemotherapy)
- Stage IV NSCLC
9
- A history of prior malignant tumour, except non-melanoma skin cancer or in situ carcinoma
of the cervix and cured malignant tumour (more than 5-year disease free interval)
- Uncontrolled diabetes mellitus (fast glycaemia above 130 mg/dl)
- Pregnancy and lactating woman
- Unavailibilty to send a copy of the PET or PET-CT (DICOM format) to the data centre
V. Study design
After registration, eligible patients will be treated according to the ELCWP guidelines
(28;29) (available online at www.elcwp.org).
VI. Investigations
Patients will be assessed conventionally before, during and after treatment.
The initial following examinations are recommended:
a.
Clinical examination completed by record of performance status, body weight and
height
b.
Standard biological tests including glycaemia just before
18
F-FDG injection,
haemoglobin, LDH, white blood cells, neutrophils, platelets, sodium, creatinine,
alkaline phosphatase, calcium, albumin
c.
Chest CT scan
d.
18
e.
Brain CT scan or MRI
F-FDG-PET scan or 18F-FDG-PET-CT.
VII. Required criteria for FDG-PET scan
The main following criteria requested in order to obtain correct primary tumour
18
F-FDG
uptake measurements as well as comparison among participating centres (see appendix IV
about the physic prerequisites) are:
- Patient has to fast at least 6 hours before injection
- Injected 18F-FDG activity must be optimised by each centre according to the phantom
acquisition (see appendix IV)
- Patient has to rest in a relaxing chair for one hour after the injection
- Images must be acquired 60 +/- 5 min post-injection with patient in supine position with
hand upright and breathing normally.
- Acquisition must be done from the mid-tighs to the base of the skull
10
- Data must be reconstructed with the preliminary defined algorithm (see appendix IV) and
engraved on a CD Rom in DICOM format that has to be transferred to the data centre
- The delay between the PET scan and the first line of treatment has to be as short as possible,
with a maximum of 4 weeks and if possible less than 2 weeks.
VIII. Criteria of evaluation
8.1. SUV measurements (18F-FDG-PET scan)(see appendix IV):
SUV and TLG measurements will be done by at least two experienced ELCWP nuclear
medicine physicians blinded to the CT results
The following SUVs will be measured on the primary tumour:
- SUV max
- SUV mean (volume defined by a percentage of SUVmax [75%, 80%, 90%])
- TLG (volume defined by a percentage of SUVmax [75%, 80%, 90%])
- SUVmax corrected for the partial volume effect (volume defined on CT or on PET)
The body weight, the lean body mass and the glycaemia will be used to normalise the data.
8.2. CT scan measurements
The following parameters will be measured on the CT associated to PET in case of PET-CT:
- Size : largest diameter of the tumour any axis (T)
- Volume : assessed by automatic segmentation corrected by two experimented ELCWP
radiologists
8.3. Survival
Will be dated from the date of PET scan. All patients have to be followed until death.
8.4. Progression-free survival.
Period between the date of PET scan and the date of first progression or death.
IX. Entry and registration procedures
All patients who will be treated according to this protocol must be registered before
beginning the treatment (or after pathological diagnosis for surgically treated patients whose
histology has been only obtained at thoracotomy, in the 30 days following thoracotomy) at
the ELCWP data centre (data manager Mrs N. Leclercq) by phone (32/2/539.04.96 between 9
a.m. and 12 a.m), by fax (32/2/534.37.56) or by e-mail (nathalie.leclercq@bordet.be).
The following information will be required at registration:
11
- Trial number
- Treatment centre
- PET centre
- Patient's name or code
- Birthday (month/year)
- Performance status
- Histology sub-type
- TNM Stage
- Therapeutic strategy (surgery, radiotherapy, combined treatment)
X. Data management and trial coordination
Study coordinator and data manager
The clinical study coordinator is Dr. Thierry Berghmans (tel. : 32/2/539.04.96) and the
nuclear study coordinators are Drs C. Hossein-Foucher (tel 33/320446161) and M. Dusart
(tel 32/42256003) The data manager is Mrs Nathalie Leclercq (Institut Jules Bordet, rue
Héger-Bordet 1, 1000 Bruxelles, tél. : 32/2/539.04.96 or fax : 32/2/534.37.56 or e-mail:
nathalie.leclercq@bordet.be).
Case records revision
After completion of treatment, each patient case record and eligibility will be reviewed
during ELCWP regular meetings.
Forms to be submitted
The following forms have to be submitted:
Form Role
Indication
2B
Registration report
at the time of initial allocation together with form A1
A1
Current tumour status
at the registration and at each evaluation
2C
Comorbidity
at the time of initial allocation together with form A1
C
Chemotherapy summary
In case of chemotherapy
4
Radiotherapy report
In case of radiotherapy
13
Surgical report
In case of surgery
12
PET(-CT) report
at the time of initial allocation together with form A1
5
Post-treatment follow-up
every 3 months following the end of treatment or at
or failure report
progression of the disease
12
7
Final report
on death of the patient
14
cTNM report
during evaluation meeting
15
pTNM report
during evaluation meeting
13B
Final report
during evaluation meeting
The forms 2B, A1, 2C, C, 4, 13, 12, 5 and 7 have to be submitted by the local investigator.
The forms 14, 15 and 13B will be completed during the evaluation meeting.
XI. Ethical considerations
1.
The protocol will be approved by the ethical committees according to the local
national legislation.
2.
Patients will be asked to agree that their data will be used for the study. The patient
will be informed that the study will comply with the principles present in the Declaration of
Helsinki.
3.
Patient consent will be noted in the hospital file and a signed informed consent must
be conserved by the local investigator.
4.
The patient’s confidentiality has to be respected.
5. As the study is non interventional, there is no adverse event submission form required for
clinical research.
XII. Statistical considerations
Sample size evaluation has been done considering as primary endpoint the prognostic role on
survival of primary tumour standardised uptake value (SUVmax) measured on
18
fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with non-
metastatic non-small cell lung cancer treated with curative intent.
The sample size has been evaluated to be able to detect a HR of 1.7 between two groups of
patients who will be defined as low SUV or high SUV. This value of 1.7 has been chosen as
being the lower bound of the 95% CI for the combined HR in the ELCWP meta-analysis
(random-effects model) (13). Low or high SUVmax will be defined according to the
observed median value of the whole sample population in the primary analysis. However, as
it is known in the literature that SUV is associated to histology which does not have a strong
prognostic value at least among subtypes of non small cell lung cancer, a sensitivity analysis
will be done on the impact of the results of the use of different thresholds for patients with
adenocarcinoma, squamous cell carcinoma and other non small cell lung cancer. Association
13
between SUV and stage will also be assessed and might lead to defining different thresholds
according to disease stage in a sensitivity analysis.
With these assumptions, we need to observe 211 events (power of 90% and significance level
of 1%).
We further estimate the number of patients needed to observe this number of events. Using
the recent papers published in JTO about the TNM classification (results obtained by the
IASLC Staging Project with the current classification) (6) and with hypotheses on the
distributions of stage in the surgically treated and in the non surgically treated non small cell
lung cancer patients, we estimate that the 5 years survival rates would be 41% in the first
group and 17% in the second group.
We also considered that 40% of the patients would belong to the first group and 60% of
patients to the second group and those patients would be included during a four years period
followed by a further two years follow-up.
In these circumstances, we need to recruit in the study 320 patients in total. The sample size
will be extended to 340 patients to take possible drop-outs into account.
An interim analysis will be performed after the first 100 registered patients in order to
confirm the correct distribution of the patients according to stage (surgical versus non
surgical stages), a second interim analysis with the same objective will be done after 250
patients. The results of these interim analyses could lead us to change the number of patients
included or the length of follow-up but will not change the number of events required. It is
not known whether TLG might be a better parameter than SUV max. At the end of the study,
the prognostic impact of SUV max and of TLG adjusted for stage and for administered
treatment (including or not including surgery) will be investigated. If the model including
TLG has a better discrimination than the one with SUV and if this is validated by bootstrap
samples, TLG instead of SUV max will be used as the primary covariate of interest.
Exploratory analyses will be conducted to look at the PET measure as a continuous variable
and to analyze the impact of the choice of the threshold. Theses analyses will be adjusted for
multiplicity and done on a derivation set (two thirds of the patients) and validated on a
validation set (the remaining third of patients). Multivariate analyses including age, sex,
stage, histology, treatment and routine laboratory parameters (leucocytosis, neutrophils and
platelets counts, haemoglobinemia, creatininemia, sodium and calcium levels, bilirubinemia,
LDH, alkaline phosphatase, albuminemia) found significant will also be conducted as
exploratory analyses.
14
XIII. Publication and authorship
Authors on publication include the study coordinators, the authors of the protocol, the
statistician and a member of each institution entering at least 10% of evaluable patients for
abstracts and 5% of evaluable patients for full papers. Authorship will also include the data
manager for full papers. All information generated by the study is full property of the
European Lung Cancer Working Party. No information may be used for publication or
presentation without written approval of the study coordinators and the chairman of the
Group.
15
Appendix I : Performance scale (Karnofsky)
Able to carry on normal activity;
no special care is needed
100
Normal; no complaints, no evidence
of disease
90
Able to carry on normal activity;
minor signs or symptoms of disease
80
Normal activity with effort; some
signs or symptoms of disease
_________________________________________________________________________
Unable to work, able to live at
home, care for most personal needs;
a varying amount of assistance is
needed
70
Care for self, unable to carry on
normal activity or do active work
60
Requires occasional assistance,
but is able to care for most of his needs
50
Requires considerable assistance, and
frequent medical care
_________________________________________________________________________
Unable to care for self; requires
equivalent of institutional or
hospital care; disease may be
progressing rapidly
40
30
Disabled; required special care and
assistance
Severely disabled; hospitalisation is
indicated, although death not imminent
20
Very sick; hospitalisation necessary,
active supportive treatment necessary
10
Moribund; fatal process progressing
rapidly
0 Dead
___________________________________________________________________________
(Cancer 1 : 634 (1948) )
16
Appendix II. Staging classification (6)
A TNM Clinical Classification
T – Primary Tumour
-
TX Primary tumour cannot be assessed, or tumour proven by the presence of
malignant cells in sputum or bronchial washings but not visualized by imaging or
bronchoscopy
-
T0 No evidence of primary tumour
-
Tis Carcinoma in situ
-
T1 Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura,
without bronchoscopic evidence of invasion more proximal than the lobar bronchus
(i.e., not in the main bronchus)
o T1a Tumour 2 cm or less in greatest dimension
o T1b Tumour more than 2 cm but not more than 3 cm in greatest dimension
-
T2 Tumour more than 3 cm but not more than 7 cm; or tumour with any of the
following features*:
 Involves main bronchus, 2 cm or more distal to the carina
 Invades visceral pleura
 Associated with atelectasis or obstructive pneumonitis that extends to
the hilar region but does not involve the entire lung
o T2a Tumour more than 3 cm but not more than 5 cm in greatest dimension
o T2b Tumour more than 5 cm but not more than 7 cm in greatest dimension
 *T2 tumours with these features are classified T2a if 5 cm or less
-
T3 Tumour more than 7 cm or one that directly invades any of the following: chest
wall (including superior sulcus tumours), diaphragm, phrenic nerve, mediastinal
pleura, parietal pericardium; or tumour in the main bronchus less than 2 cm distal to
the carina1 but without involvement of the carina; or associated atelectasis or
obstructive pneumonitis of the entire lung or separate tumour nodule(s) in the same
lobe
-
T4 Tumour of any size that invades any of the following: mediastinum, heart, great
vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina;
separate tumour nodule(s) in a different ipsilateral lobe
N – Regional Lymph Nodes
-
NX Regional lymph nodes cannot be assessed
-
N0 No regional lymph node metastasis
-
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and
intrapulmonary nodes, including involvement by direct extension
17
-
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
-
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or
contralateral scalene, or supraclavicular lymph node(s)
M – Distant Metastasis
-
MX Distant metastasis cannot be assessed
-
M0 No distant metastasis
-
M1 Distant metastasis
o M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleural
nodules or malignant pleural (or pericardial) effusion2
o M1b Distant metastasis
pTNM Pathological Classification
The pT, pN, and pM categories correspond to the T, N, and M categories.
pN0 Histological examination of hilar and mediastinal lymphadenectomy specimen(s) will
ordinarily include 6 or more lymph nodes. If the lymph nodes are negative, but the number
ordinarily examined is not met, classify as pN0.
Stage Grouping#
Stage
Occult carcinoma
0
IA
IB
IIA
IIB
IIIA
IIIB
IV
T
N
M
x
0
0
0
0
1
0
1
0
2
1-2
0-1
2
3
any
0
0
0
0
0
0
0
0
0
0
0
0
0
1a, 1b
IS
1a, 1b
2a
1a, 1b, 2a
2b
2b
3
1-2
3
4
4
any
any
18
Appendix III: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by
the 29th WMA General Assembly, Tokyo, Japan, October 1975, 35th WMA General
Assembly, Venice, Italy, October 1983, 41st WMA General Assembly, Hong Kong,
September 1989, 48th WMA General Assembly, Somerset West, Republic of South Africa,
October 1996, and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000
Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington
2002
Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 2004
A. INTRODUCTION
1. The World Medical Association has developed the Declaration of Helsinki as a statement
of ethical principles to provide guidance to physicians and other participants in medical
research involving human subjects. Medical research involving human subjects includes
research on identifiable human material or identifiable data.
2. It is the duty of the physician to promote and safeguard the health of the people. The
physician's knowledge and conscience are dedicated to the fulfillment of this duty.
3. The Declaration of Geneva of the World Medical Association binds the physician with the
words, "The health of my patient will be my first consideration," and the International Code
of Medical Ethics declares that, "A physician shall act only in the patient's interest when
providing medical care which might have the effect of weakening the physical and mental
condition of the patient."
4. Medical progress is based on research which ultimately must rest in part on
experimentation involving human subjects.
5. In medical research on human subjects, considerations related to the well-being of the
human subject should take precedence over the interests of science and society.
6. The primary purpose of medical research involving human subjects is to improve
prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology
and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic
methods must continuously be challenged through research for their effectiveness, efficiency,
accessibility and quality.
7. In current medical practice and in medical research, most prophylactic, diagnostic and
therapeutic procedures involve risks and burdens.
8. Medical research is subject to ethical standards that promote respect for all human beings
and protect their health and rights. Some research populations are vulnerable and need special
protection. The particular needs of the economically and medically disadvantaged must be
recognized. Special attention is also required for those who cannot give or refuse consent for
themselves, for those who may be subject to giving consent under duress, for those who will
not benefit personally from the research and for those for whom the research is combined with
care.
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9. Research Investigators should be aware of the ethical, legal and regulatory requirements for
research on human subjects in their own countries as well as applicable international
requirements. No national ethical, legal or regulatory requirement should be allowed to reduce
or eliminate any of the protections for human subjects set forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
10. It is the duty of the physician in medical research to protect the life, health, privacy, and
dignity of the human subject.
11. Medical research involving human subjects must conform to generally accepted scientific
principles, be based on a thorough knowledge of the scientific literature, other relevant
sources of information, and on adequate laboratory and, where appropriate, animal
experimentation.
12. Appropriate caution must be exercised in the conduct of research which may affect the
environment, and the welfare of animals used for research must be respected.
13. The design and performance of each experimental procedure involving human subjects
should be clearly formulated in an experimental protocol. This protocol should be submitted
for consideration, comment, guidance, and where appropriate, approval to a specially
appointed ethical review committee, which must be independent of the investigator, the
sponsor or any other kind of undue influence. This independent committee should be in
conformity with the laws and regulations of the country in which the research experiment is
performed. The committee has the right to monitor ongoing trials. The researcher has the
obligation to provide monitoring information to the committee, especially any serious adverse
events. The researcher should also submit to the committee, for review, information regarding
funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives
for subjects.
14. The research protocol should always contain a statement of the ethical considerations
involved and should indicate that there is compliance with the principles enunciated in this
Declaration.
15. Medical research involving human subjects should be conducted only by scientifically
qualified persons and under the supervision of a clinically competent medical person. The
responsibility for the human subject must always rest with a medically qualified person and
never rest on the subject of the research, even though the subject has given consent.
16. Every medical research project involving human subjects should be preceded by careful
assessment of predictable risks and burdens in comparison with foreseeable benefits to the
subject or to others. This does not preclude the participation of healthy volunteers in medical
research. The design of all studies should be publicly available.
17. Physicians should abstain from engaging in research projects involving human subjects
unless they are confident that the risks involved have been adequately assessed and can be
satisfactorily managed. Physicians should cease any investigation if the risks are found to
outweigh the potential benefits or if there is conclusive proof of positive and beneficial
results.
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18. Medical research involving human subjects should only be conducted if the importance of
the objective outweighs the inherent risks and burdens to the subject. This is especially
important when the human subjects are healthy volunteers.
19. Medical research is only justified if there is a reasonable likelihood that the populations in
which the research is carried out stand to benefit from the results of the research.
20. The subjects must be volunteers and informed participants in the research project.
21. The right of research subjects to safeguard their integrity must always be respected. Every
precaution should be taken to respect the privacy of the subject, the confidentiality of the
patient's information and to minimize the impact of the study on the subject's physical and
mental integrity and on the personality of the subject.
22. In any research on human beings, each potential subject must be adequately informed of
the aims, methods, sources of funding, any possible conflicts of interest, institutional
affiliations of the researcher, the anticipated benefits and potential risks of the study and the
discomfort it may entail. The subject should be informed of the right to abstain from
participation in the study or to withdraw consent to participate at any time without reprisal.
After ensuring that the subject has understood the information, the physician should then
obtain the subject's freely-given informed consent, preferably in writing. If the consent cannot
be obtained in writing, the non-written consent must be formally documented and
witnessed.
23. When obtaining informed consent for the research project the physician should be
particularly cautious if the subject is in a dependent relationship with the physician or may
consent under duress. In that case the informed consent should be obtained by a wellinformed physician who is not engaged in the investigation and who is completely
independent of this relationship.
24. For a research subject who is legally incompetent, physically or mentally incapable of
giving consent or is a legally incompetent minor, the investigator must obtain informed
consent from the legally authorized representative in accordance with applicable law. These
groups should not be included in research unless the research is necessary to promote the
health of the population represented and this research cannot instead be performed on legally
competent persons.
25. When a subject deemed legally incompetent, such as a minor child, is able to give assent
to decisions about participation in research, the investigator must obtain that assent in addition
to the consent of the legally authorized representative.
26. Research on individuals from whom it is not possible to obtain consent, including proxy
or advance consent, should be done only if the physical/mental condition that prevents
obtaining informed consent is a necessary characteristic of the research population. The
specific reasons for involving research subjects with a condition that renders them unable to
give informed consent should be stated in the experimental protocol for consideration and
approval of the review committee. The protocol should state that consent to remain in the
research should be obtained as soon as possible from the individual or a legally
authorized surrogate.
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27. Both authors and publishers have ethical obligations. In publication of the results of
research, the investigators are obliged to preserve the accuracy of the results. Negative as well
as positive results should be published or otherwise publicly available. Sources of funding,
institutional affiliations and any possible conflicts of interest should be declared in the
publication. Reports of experimentation not in accordance with the principles laid down in
this Declaration should not be accepted for publication.
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH
MEDICAL CARE
28. The physician may combine medical research with medical care, only to the extent that
the research is justified by its potential prophylactic, diagnostic or therapeutic value. When
medical research is combined with medical care, additional standards apply to protect the
patients who are research subjects.
29. The benefits, risks, burdens and effectiveness of a new method should be tested against
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not
exclude the use of placebo, or no treatment, in studies where no proven prophylactic,
diagnostic or therapeutic method exists.1
30. At the conclusion of the study, every patient entered into the study should be assured of
access to the best proven prophylactic, diagnostic and therapeutic methods identified by the
study.2
31. The physician should fully inform the patient which aspects of the care are related to the
research. The refusal of a patient to participate in a study must never interfere with the
patient-physician relationship.
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic
methods do not exist or have been ineffective, the physician, with informed consent from the
patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic
measures, if in the physician's judgement it offers hope of saving life, re-establishing health or
alleviating suffering. Where possible, these measures should be made the object of research,
designed to evaluate their safety and efficacy. In all cases, new information should be
recorded and, where appropriate, published. The other relevant guidelines of this Declaration
should be followed.
1 Note
of clarification on paragraph 29 of the WMA Declaration of Helsinki
The WMA hereby reaffirms its position that extreme care must be taken in making use of a
placebo-controlled trial and that in general this methodology should only be used in the
absence of existing proven therapy. However, a placebo-controlled trial may be ethically
acceptable, even if proven therapy is available, under the following circumstances:
- Where for compelling and scientifically sound methodological reasons its use is necessary to
determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
- Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor
condition and the patients who receive placebo will not be subject to any additional risk of
serious or irreversible harm.
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for
appropriate ethical and scientific review.
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2 Note
of clarification on paragraph 30 of the WMA Declaration of Helsinki
The WMA hereby reaffirms its position that it is necessary during the study planning process
to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic
procedures identified as beneficial in the study or access to other appropriate care. Post-trial
access arrangements or other care must be described in the study protocol so the ethical
review committee may consider such arrangements during its review.
9.10.2004
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Appendix IV. Required criteria for 18F-FDG -PET scan acquisition and interpretation
Standardization procedure across PET departments
1. Introduction
SUV are known to suffer from a large variability between institutions, due to the different
performance of the PET scanners and the lack of standardization regarding the imaging
procedure (e.g. time post-injection) and data processing protocols (reconstruction algorithm,
corrections, filtering, methods of measurements).
To facilitate consistent pooling of data between PET departments, attempts should be made to
control and decrease this variability. This document proposes a procedure aiming at
characterizing the variability of SUV between imaging centers. Once this variability is
characterized, actions can be taken to reduce it to an acceptable level. Specific methods (e.g.,
compensation for differences in spatial resolution) can also be used to account for the
variability when pooling the data.
The procedure will be based on two phantom measurements. A first phantom experiment
(phantom 1) will aim at characterizing the existing variability between centers. Following the
analysis of the results of this first experiment, strategies (like modifying the image processing
protocols used in the different centers) will be agreed on to try reducing this variability. The
data from phantom 1 will be reprocessed to check that the variability between centers is
effectively reduced with this strategy. Because results from phantom 1 will be used to
optimize processing strategies in different centers as diminishing the variability of SUV
estimates, a different phantom experiment (phantom 2) will be considered to independently
assess the efficiency of the first attempt to reduce variability between centers.
For each phantom (phantom 1 and phantom 2), a strict phantom preparation and imaging
protocol has to be used (as when performing NEMA experiments). Data has to be
reconstructed in 2 ways: 1) as in the clinics, 2) using a standard protocol provided to the
center.
Reconstructed images will be sent to a unique center (called reference center hereafter) where
they will be further processed (estimation of SUV in different structures).
Feedback will be provided to each department, together with instructions to help the
department reaching specific image quality and accuracy.
The department may be asked to reprocess (but not re-acquire) the original phantom data as a
function of these instructions so as to better match the standard image quality. For each
phantom, each participating department will have to archive the raw emission data, the
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attenuation map, and all correction files needed for the reconstruction (i.e. normalization…).
The reprocessed data will be sent back to the reference center.
A final report regarding the variability of image quantification across departments will be sent
to all departments. This report will include: 1) the initial performance estimated using
phantom 1 and the clinical imaging and processing protocol; 2) the performance with
phantom 1 when using the recommended processing protocol; 3) the performance with
phantom 2 when using the clinical imaging and processing protocol; 4) the performance with
phantom 2 when using the recommended processing protocol.
At that point and based on the phantom 2 results, it will be checked that the recommended
processing protocols reduce the SUV variability among centers.
At the end of this preliminary study, each department will receive a specific processing
protocol (image reconstruction, corrections) to be used for clinical data acquisition (possibly
in addition to their routine processing protocol). All departments willing to enter the clinical
study will have to commit themselves to provide the clinical data obtained using this specific
protocol.
2. Outline of the normalization procedure
2.1. Phantoms
Phantom 1: a specific phantom PETQC designed by the “Lille center” shall be used. This
phantom is provided with a program that automatically measures some characteristics (SUV,
resolution…) from the phantom images. Using this phantom, the same image characteristics
will be exactly measured in the same way across centers. The only difference between centers
might come from different ways of filling the phantom, but strict instructions will be provided
to minimize this source of variability.
Phantom1 can be easily and quickly scanned (30 minutes for preparation and acquisition). A
scan can be performed every week in order to provide statistical data on the investigated
parameters. Each image characteristics will be given as a mean and associated standard
deviation, in order to facilitate comparisons between centers.
Phantom 2: a NEMA-like phantom (cylinder or thoracic phantom including spheres of
different sizes) will be considered to assess the final variability of SUV estimates after tuning
between centers has been performed. Note that it would be desirable for this phantom to
include different types of tissues (lung, bone, and soft tissues), to make it more realistic than
the PETQC phantom.
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The phantom will have to be filled with specific activity concentrations in the different
compartments. The activity values set in each compartment will have to be carefully
controlled and the controlled procedure will have to be reported.
2.2. Acquisition protocol
2.2.1. PET scanners
Specify the manufacturer, the model and the acquisition protocol (acquisition time after
phantom preparation, transmission scan (time and duration), emission scan duration, mode
(2D versus 3D).
2.2.2. PET/CT scanners
Specify the acquisition protocol: acquisition time after phantom preparation, CT scan (time
and parameters, slice thickness), emission scan duration, mode (2D versus 3D).
2.3. Reconstruction protocol
Two reconstruction procedures will be considered: a first corresponding to the one used for
the clinical data, and a second based on the recommendations aiming at reducing the intercenter variability.
For each reconstruction procedure, the following data will be carefully recorded:
- Reconstruction algorithm, sampling, parameters of the reconstruction algorithm, no or postfiltering
- Attenuation correction (specify a protocol for conventional transmission scans and for CT
scans, checking PET/CT or PET/Transmission registration, dealing with noise for
transmission scans)
- Scatter correction
- Decay correction
2.4. Data storage
For all phantom acquisitions, the raw data and the entire files needed for additional
reconstructions must be archived.
The following data should be stored in DICOM to be sent to the reference center:
-
CT scan aligned with the PET scan if available
-
Conventional transmission scan (reconstructed) aligned with the PET scan if available
-
Reconstructed images (in Bq/ml units)
2.5. Data transmission to the reference center
Data should be transmitted using: CD or DVD
3. Data analysis
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The analysis of the PETQC phantom can be performed by each center. The results or the
DICOM images must be sent to the reference center. All data will first be analyzed to
determine the best processing parameters for each scanner.
The analysis of these results and of the images will tell us what has to be changed to improve
the consistency of results between departments.
Following the analysis, a feedback will be given to the different departments, suggesting if
needed to repeat the image reconstruction and corrections with different parameters.
The analysis of these new results and of the images will tell us whether the new protocols (the
protocol will certainly be different in the different departments, as the software are different
across PET companies) are able to reduce the variability of SUV measurements between
centers.
A final analysis using phantom 2 will check the consistency of results between centers in a
configuration different from that used for optimizing the protocols.
All analysis reports will be sent to the departments participating in the study.
Definitions:
SUVbw = tumour uptake (kBq/mL) / [injected dose (kBq) / patient weight (g)]
SUVlean body mass = tumour uptake (kBq/mL) / [injected dose (kBq) / lean body mass]
(where lean body mass will be calculated with the formula of James:
- lean body mass (man) expressed in kg = 1.10 x weight (kg) - 128
[weight(kg)2/height(cm)2]
- lean body mass (women) expressed in kg = 1.07 x weight (kg) - 148
[weight(kg)2/height(cm)2]
SUVbody surface area = tumour uptake (kBq/mL) / [injected dose (kBq) / patient body
surface area] (where body surface area is obtained by Dubois formula: 0,007184 x weight
(kg)0,425 x height (cm)0,725)
SUVglycaemia= SUV x (100/plasma glucose level)
SUVpartial vol effect CT = SUV corrected by a coefficient obtained by a recovery curve
estimated on a phantom acquisition
SUVpartial vol effet functional = SUV corrected by the metabolic volume.
- Considering the tumour uptake is given by the maximum pixel value in the tumour,
SUVbwmax = max pixel value in the tumour (kBq/mL) / [injected dose (kBq) / patient weight
(g)]
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- Measuring the tumour uptake as the mean pixel value in a volume of interest (VOI)
around the tumour yields SUVmean.
SUVbwmean = mean pixel value in a tumour VOI (kBq/mL) / [injected dose (kBq) / patient
weight (g)]
SUVmean 75%, 80% and 90% signifies that the VOI encompassed all the pixel values above
75%, 80% and 90% of the maximum pixel value.
Indeed, unlike SUVmax, SUVmean depends on the way the VOI around the tumour is drawn.
To avoid manual drawing that makes the result dependent on the operator, an isocontour,
defined as a percentage of the maximum pixel value in the tumour (typically between 50%
and 80%) will be used.
TLG = SUVmean x volume
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