NELSON MANAGEMENT SYSTEM

NELSON MANAGEMENT SYSTEM
To conduct this logistically complex multicenter study, the
NELSON Management System (NMS) has been developed. It is
a Web-based, interactive database application used for data collection
and management of all study-related processes with a completely
trackable data collection, study monitoring, reporting of
scan results, and scheduling of appointments for follow-up scans.
Because the system works with action dates, it provides us with a
complete overview and control of the planned actions, such as the
planning of follow-up scans, sending of invitations to participants,
test results and workup, and evaluation of suspicious nodules.
Screens The participants randomized to the screen arm
were invited by an invitation letter to one of the four screening
sites (University Hospital Groningen, University Hospital
Utrecht and Kennemer Gasthuis Haarlem in the Netherlands,
and University Hospital Gasthuisberg Leuven in Belgium). The
CT scans used were all 16-detector MSCT scanners (M 8000
IDT or Brilliance 16P, Philips Medical Systems, Cleveland,
OH, U.S.A., or Sensation-16, Siemens Medical Solutions,
Forchheim, Germany). All scans were realized in about 12 seconds
in spiral mode with 16 0.75-mm collimation and 15-
mm table feed per rotation (pitch 1.5), in a cranial–caudal
scan direction, without contrast in low-dose setting. Depending
on the body weight ( 50 kg, 50 to 80 kg, and 80 kg), the
kilovolt (peak) (kV[p]) settings were 80 to 90, 120, and 140
kV(p), respectively; and to achieve a volume computed tomography
dose index (CTDIvol) of 0.8, 1.6, and 3.2 milligrays
(mGy), respectively, the milliampere second (mAs) setting were
adjusted accordingly depending on the machine used. To minimize
breathing artefacts, scans were performed in inspiration
after appropriate instruction of the participants.
Image Reading Images have been read on Siemens workstations
using the syngo LungCARE software package (version
Somaris/5 VB 10A-W) for multidimensional image processing
and computer viewing. Lung windows were assessed at a width of
1500 and a level of 650 Hounsfield units. After a first reading
by qualified and dedicated radiologists with on average 7 years
of reading experience, the data were stored locally on the PACS
system, and sent overnight via a protected internet connection to
Groningen for second reading and central storage. The consensus
double readings were also performed by two qualified radiologists,
full time engaged with 1 and 4 years of experience after board certification,
respectively. Both the first and second readers evaluated
the CT scans independently and uploaded their results into the
central database. The nodule management system automatically
matched all nodules detected by the first and second reader based
on location and size. Subsequently, the second reader checked
this automatching for each individual nodule and made manual
adjustments in case the matching was incorrect. During this procedure
of consensus double reading, the second reader was not
blinded for the results of the first reader. This procedure provided
three groups of nodules: nodules detected by both readers, nodules
detected only by the first reader, and nodules detected only
by the second reader. The second reader also checked the consistency
of the follow-up recommendations of both readers. If there
was a discrepancy, the second reader informed the first reader and
both readers reevaluated the CT scan to reach consensus. If no
consensus was reached, an expert reader (radiologist with more
than 20 years of experience) made the final decision.
During CT evaluation, for each evaluable nodule, the surface
characteristics, distance to the pleura, and the aspect of the nodule
(i.e., solid, partial solid, or nonsolid) were entered by the radiologist
in an electronic data collection form customized for the
LungCARE Siemens workstation. Nodules were classified as peripheral
if the distance to the thoracic wall was less than one third
of the total distance to the lung hilum. Together with the calculated
sizes and volumes generated by the Siemens software, these
data were automatically uploaded in NMS immediately after
completion of the reading for an unlimited number of evaluated
nodules per scan. In case of consecutive CT scans, nodules were
matched with the same nodules documented on previous scans
to determine changes in volume and to estimate the volume doubling
time (VDT). After the second reading of the CT scan and
after reaching consensus about the screen result and the planned
actions to be taken, the NMS generated the appropriate standard
letter to inform both the participant and the general practitioner
within 3 weeks after the CT scan. Throughout the study, the definition
of growth was kept constant and was defined as a percent
volume change (PVC) of 25% or more after at least a 3-month
interval according to the following formula:
(1) PVC (%) 100 (V 2 V 1 )/V 2
was defined as an indeterminate test result that required a repeat
scan 3 to 4 months later to assess growth. If there was no
sig nificant growth on the repeat scan, the test result was called
negative, and participants were scheduled for an annual repeat
CT scan 8 to 9 months later. If there was significant growth, the
test result was positive (GROWCAT C), which means that a histological
diagnosis had to be obtained (Table 17.4). NODCAT 4
was also a positive test result, which required referral to a pulmonologist
for workup and diagnosis. In case of NODCAT 4 and
GROWCAT C, the general practitioner was first informed by
the radiologist of the screening site by phone about the test results
and its consequences, followed by a letter to the participant
and the general practitioner.
INCIDENCE SCREEN PROTOCOL
At annual repeat screening, there are two possibilities: either an
NCN already exists, and comparison with baseline screening
is possible, or the NCN is new. For the new nodules, the same
classification according to size was made as for the baseline
screening round. Follow-up was different, however, because at
incidence screen, new nodules are supposed to have a relatively
higher growth rate (Table 17.5). 9
For all existing nodules, except for NODCAT 1, always
a comparison with the baseline screening round was made. If
in solid nodules or solid components of partial solid nodules
the PVC was 25% or more (Table 17.5), the VDT based on
changes in calculated volumes over time (VDT v ) was determined
according to formula (2): 11
(2) VDT v (days) [ln 2     t]/[ln(V 2 /V 1 )]
In situations in which a reliable volume estimate could not
be made because of software limitations and/or manual measurement
was preferred in either one of the two evaluations,
changes in volumes based on changes in estimated diameter
over time (VDT d ) was determined according to formula (3):
(3) VDT d (days) [ln 2     t]/[3ln (MaxDiamXY2/
MaxDiamXY1]
where MaxDiamXY is equal to maximum diameter in X/Y-axis.
However, if both scans had to be evaluated by manual measurements,
such as for pleural-based solid nodules or nonsolid
nodules, the following formula for growth determination was
applicable:
(4) VDTd [ln2     t]/[ln((MaxDiamXY2
PerpDiamXY2 MaxDiamZ2)/
(MaxDiamXY1 PerpDiamXY1
MaxDiamZ1)]
where MaxDiamXY is equal to maximum diameter in X/Y-axis,
PerpdiamXY is equal to maximum diameter perpendicular to
MaxDiamXY, and MaxDiamZ is equal to maximum diameter
in Z-axis. If MaxDiamZ was missing, then MaxDiamZ equalled
0.7 |Caudal slice number Cranial slice number|.
According to the VDT, growing NCNs were classified
in three growth categories: GROWCAT A with a VDT more
than 600 days, GROWCAT B with a VDT between 400 to
600 days, and GROWCAT C with a VDT less than 400 days.
Nonsolid nodules in which a new solid component appeared
were also classified GROWCAT C (Table 17.6). 9
During incidence screening, the test result (negative, indeterminate,
positive) was based on the highest GROWCAT or
the highest NODCAT in case of a new nodule. Subjects with
no growth or GROWCAT A received a negative test result,
and they were rescheduled for a CT scan in year 4. For subjects
with GROWCAT B or a new NODCAT 2, the test result was
indeterminate, and a repeat scan was made 1 year later (year 3)
(Table 17.4). A new NODCAT 3 was also an indeterminate
test result, which however, required a repeat scan 6 to 8 weeks
later. Participants with GROWCAT C or a new NODCAT 4
had a positive test result and were referred to a chest physician
for workup and diagnostic evaluation. 9
Management of NODCAT 4
and GROWCAT C Nodules
Baseline NODCAT 4 If the highest category was a NODCAT
4, the participant was referred to the chest physician of choice
via the general practitioner, usually the chest physician associated
with the screening center. Primary objective was to confirm the
presence of malignancy by performing routine physical examinations,
routine laboratory tests, and a bronchoscopy (bronchial
washing for cytology and culture and transbronchial biopsy or
brushing on indication). A percutaneous CT-guided fine-needle
aspiration (FNA) to obtain histology or cytology of the lesion is
not a routine procedure in the Netherlands and Belgium, and
if the FNA technique was used, it was only for large peripheral
nodules with good access. The FNA result can be malignant,
specific benign, or nonspecific benign. Specific benign diagnoses
include tuberculosis, mycoses, nocardia, hamartoma, or a benign
lymph node. If a malignancy was proven, the patient was further
staged and followed by surgical resection. A definitively specified
benign diagnosis required treatment or just observation, but if
no diagnosis or a nonspecific benign diagnosis was obtained, the
follow-up strategy was based on the assessment of nodule growth
similar as to NODCAT 3 (i.e., a repeat scan after 3 to 4 months).
If at that time there was no growth, the test result was negative,
and participants were scheduled for an annual repeat CT scan 8
to 9 months later. If there was growth, the test result was positive
(GROWCAT C), which meant that a definitive histological diagnosis
had to be obtained. Actually, this workup was according to
our national CBO guidelines for the diagnosis and treatment of
non–small cell lung cancer, 12 with the exception that a 18F-fluorodeoxyglucose
(FDG)-positron emission tomography (PET)
scan was not routinely included in the workup of a NODCAT 4,
primarily because our NELSON trial is a CT-screening trial, in
which the presence or absence of growth of the nodule is leading,
and not the outcome of the PET scan. Furthermore, the
pretest probability of malignancy in this population of current
and former smokers is very high, and a substantial proportion
of the PET scan is false negative because of bronchioloalveolar
cell carcinomas (BAC) or adenocarcinomas with BAC features,
limiting the diagnostic value of the PET in the context of this
CT-screening trial. 13–15
Baseline or Incidence: GROWCAT C The workup for
participants with growing lesions (GROWCAT C) was essentially
the same as for NODCAT 4, except that for these nodules
a final histological diagnosis had to be obtained either by
FNA, video-assisted thoracoscopic surgery (VATS), or wedge
resection and examination on frozen section, and that further
observation by follow-up CT scans was no longer allowed. If
malignant, the nodule had to be surgically removed after appropriate
staging. If the outcome of the investigation was that
the lesion was benign, the participant was rescheduled for the
next regular annual CT scan.