Keywords
Diagnosis and imaging (inc chromoendoscopy, NBI, iSCAN, FICE, CLE) - Endoscopy Upper
GI Tract - Dilation, injection, stenting
Introduction
Curative treatment of gastric cancer generally includes surgical resection combined
with perioperative chemotherapy or postoperative chemoradiotherapy [1]
[2]. However, due to poor patient compliance during postoperative treatment regimens
and uncertainties in target definition, research interest has recently shifted toward
preoperative (chemo)radiotherapy [3]
[4]. For accurate image-guided radiotherapy (IGRT), localization of the target volume
on pretreatment computed tomography (CT) imaging and daily in-room cone-beam CT (CBCT)
imaging is essential. However, for the stomach, target localization can be challenging
because of (organ) motion and low soft-tissue contrast. The use of fiducial markers
potentially enhances target visualization during IGRT, which can aid target delineations
[5]
[6], and daily target localization and positioning [7]
[8]
[9].
The feasibility and safety of fiducial marker placement have been demonstrated for
various organs/cancers, including (upper) gastrointestinal sites [5]
[10]
[11]. Markers may improve IGRT accuracy, as demonstrated for pancreas [12]
[13], rectum [14]
[15], and esophagus [14]
[16]. For the stomach, however, marker implantation has only been investigated in a few
small (case) studies [17]
[18]
[19], with none covering visibility during IGRT courses. The stomach has distinct anatomical
characteristics (i.e., hollow, deformable and experiencing peristaltic motion), which
can affect implantation feasibility as well as marker visibility and stability on
imaging. Therefore, more research regarding gastric fiducial markers is needed.
This prospective feasibility study aims to assess the technical feasibility and safety
of endoscopic placement of (gold and liquid) fiducial markers in gastric cancer patients
and their potential benefit during a 5-week IGRT course.
Materials and methods
Patient population
From October 2018 to January 2022, gastric cancer patients were enrolled in this prospective,
non-randomized, single-arm feasibility study. Patient inclusion criteria were: histologically
proven, stage IB-IIIC (TNM 8th edition), primary gastric adenocarcinoma, and referral
for preoperative radiotherapy at our center. All eligible patients who were randomized
to preoperative chemoradiotherapy within the CRITICS-II trial (NCT02931890) at our
center were asked to participate in this fiducial study [3]. The ethics committee of the Amsterdam University Medical Center approved the protocol
(study registration number NTR7241). Seventeen patients were eligible, 14 of whom
gave written informed consent and were included. Included patients received fiducial
marker placement in the stomach wall (not tumor) and additional imaging (CTs and CBCTs)
during IGRT.
Fiducial marker placement
All patients underwent endoscopy under conscious sedation with midazolam and fentanyl
or under deep sedation with propofol. The procedures were performed by one of four
experienced gastroenterologists. Intended marker locations were determined prior to
implantation, at four to six stomach sites, taking distribution throughout the stomach
and tumor location into consideration. Two different markers were used: the flexible
10-mm-long coil-shaped gold Visicoil marker (Visicoil, Core Oncology, California,
United States; outer Ø=0.35 mm); and the liquid BioXmark marker (Nanovi A/S, Lyngby,
Denmark). The liquid marker solidifies as a three-dimensional structure after implantation,
thereby preventing diffusion. Gold markers were placed in all 14 patients; liquid
markers were placed in the final seven patients once CE mark approval was obtained.
Gold markers were individually back-loaded into a 22G fine-needle aspiration needle,
with the stylet pulled back about 2 cm; the needle tip was sealed with sterile bone
wax to prevent accidental marker loss prior to implantation. For each gold marker,
the loaded needle was placed in the gastroscope (GIF-HQ190; Olympus, Tokyo, Japan)
for implantation. Following needle placement in the gastric wall, the marker was pushed
out of the needle by pushing the stylet into the needle. For each marker, the needle
was reloaded; sometimes, two needles were used to limit procedure time.
For the liquid marker, a 23G or 25G injection needle was primed prior to the injection
procedure with 1 mL of liquid marker followed by saline solution until the injection
system
was fully filled. Next, multiple consecutive markers were placed into the gastric
wall,
using a unit dose syringe (Luer Lock, Vlow medical, Eindhoven, The Netherlands) for
controlled dosage of injected volume. For fiducial markers in the esophagus, a volume
of
>0.05mL proved sufficiently visible on CT and CBCT [16]; however, as the stomach possibly experiences more movement during imaging, we aimed
for approximately 0.1mL of injected volume per marker. The needle was maintained in
the
tissue for about 5 seconds because of slow release of the viscous liquid marker. Fluoroscopy
was sometimes used to check marker placement.
Image-guided radiotherapy
The target for IGRT was the entire stomach and regional lymph nodes. IGRT (45 Gy in
25
fractions) treatment planning was based on a reference CT scan. For all patients except
one,
this reference scan was acquired after implantation (0–5 days, median 1 day). During
the
IGRT course, daily CBCTs and three repeat CTs were acquired. Median time between
implantation and the first and last CBCT scan was 13 days (range 5–28) and 46 days
(range
37–60), respectively. For details on chemoradiotherapy, see Supplemental
Material 1.
Outcome measures
Technical feasibility
Following each marker implantation, the gastroenterologist assessed expected success
of placement. A marker was successfully placed when placed in the stomach wall and
present for the entire course of IGRT (i.e., at time of the reference scan, and the
first and last CBCT scan). Successful placement was assessed for all markers, per
marker type and for three sites: gastroesophageal junction (i.e., gastroesophageal
junction/cardia), corpus (i.e., corpus/antrum/fundus), and pylorus. Also, the technical
difficulty of implantation (i.e., easy, reasonable, or difficult) was scored. Finally,
the duration of the entire procedure (from first loaded needle entering the gastroscope
to final marker placed) and average time per attempted marker implantation were assessed.
Adverse events
For each marker, the gastroenterologist scored whether bleeding occurred at the implantation
location. Potential adverse events (AEs) occurring in the first 24 to 48 hours following
implantation were registered. The following AEs were potentially procedure-related:
bleeding, infection/fever, and pain.
Potential benefit
The potential benefit of markers for target delineation and position verification
during
IGRT depends upon their visibility on (CB)CT scans and positional stability throughout
radiotherapy. For each successfully placed marker, visibility was separately assessed
for
each available CT and CBCT scan. Marker visibility was defined as good (marker visible
on
≥95% of scans), moderate (on ≥75%), or poor (<75%). Marker visibility was assessed
for
the three sites: gastroesophageal junction, corpus, and pylorus. For analyses of marker
visibility on respiratory phase images, see Supplemental Material
2. Positional stability was defined as lack of observable migration within the
tissue.
Technical feasibility and potential benefit were compared between gold and liquid
markers.
Statistical analyses
Feasibility of marker implantation was assessed using descriptive statistics. Ratios
were compared with the two-sided Fisher’s exact test (α=0.05).
Results
Technical feasibility
In the 14 patients, 93 endoscopy-guided markers implantations attempts were performed
(66 gold and 27 liquid markers; [Table 1]). For each liquid marker, a volume of 0.08 to 0.20mL was injected.
Table 1 Patient, tumor and procedure characteristics, combined with the number of successful
implantations.
|
No.
|
Age (years)
|
Sex
|
Tumor location
|
No of attempts, type of markers
|
Successful implantation
|
Procedure duration (minutes)
|
Fluoroscopy used
|
|
1
|
62
|
M
|
Cardia
|
7 gold
|
4 gold
|
38
|
Yes
|
|
2
|
38
|
M
|
Antrum
|
5 gold
|
3 gold
|
25
|
Yes
|
|
3
|
48
|
M
|
Corpus and pylorus
|
6 gold
|
3 gold
|
16
|
Yes
|
|
4
|
70
|
M
|
Corpus and antrum
|
5 gold
|
4 gold
|
19
|
Yes
|
|
5
|
65
|
M
|
Antrum
|
7 gold
|
6 gold
|
19
|
Yes
|
|
6
|
71
|
M
|
Antrum and pylorus
|
6 gold
|
3 gold
|
21
|
No
|
|
7
|
58
|
F
|
Corpus
|
6 gold
|
4 gold
|
24
|
No
|
|
8
|
48
|
M
|
Cardia
|
4 gold; 4 liquid
|
1 gold; 3 liquid
|
27
|
No
|
|
9
|
45
|
M
|
Cardia
|
3 gold; 3 liquid
|
2 gold; 2 liquid
|
30
|
No
|
|
10
|
56
|
F
|
Antrum
|
4 gold; 4 liquid
|
2 gold; 4 liquid
|
20
|
No
|
|
11
|
64
|
M
|
Cardia and distal esophagus
|
5 gold; 3 liquid
|
2 gold; 3 liquid
|
24
|
No
|
|
12
|
69
|
M
|
Corpus
|
3 gold; 4 liquid
|
3 gold; 3 liquid
|
24
|
Yes
|
|
13
|
61
|
M
|
Cardia
|
3 gold; 4 liquid
|
2 liquid
|
33
|
No
|
|
14
|
60
|
M
|
Antrum and pylorus
|
2 gold; 5 liquid
|
2 gold; 3 liquid
|
21
|
No
|
|
Total
|
Median (range)
61 (38–71)
|
|
|
66 gold; 27 liquid
|
39 gold; 20 liquid
|
Mean (range)
24.4 (16−38)
|
|
Fifty-nine markers (63%; 2 to 6 per patient) were successfully placed ([Fig. 1]); this was 59% and 74% for gold and liquid markers, respectively. No significant
difference was found between success rates for gold and liquid markers (P >0.05) or when only comparing the seven patients with both marker types.
Moreover, success rates differed between sites as it was 63% (10 successfully placed
of 16
attempts) for markers in the gastroesophageal junction, 60% (37/62) in the corpus,
and 80%
(12/15) in the pylorus. Of the unsuccessful implantations, 17 markers that were expected
to
be successfully placed were either not visible on the reference scan (N=10; lost in
the
first 0 to 5 days following implantation) or not placed in the stomach wall (N=7;
5 gold and
2 liquid markers); of these latter seven, three were placed outside the stomach wall
(<1cm), one in the spleen, one in the diaphragm, and two in surrounding fat. All seven
markers placed outside the stomach wall were present for the entire radiotherapy course.
In
addition, five markers were lost between the reference scan (on days 0–3 following
implantation) and the start of IGRT delivery (i.e., first CBCT; on days 9–14 following
implantation), and two were lost during IGRT delivery (on days 15 and 22 post-implantation).
Of the 93 attempts, 14 were not expected to be successfully placed during implantation
(13
gold and 1 liquid) because, for instance, the marker was partially sticking out of
the
mucosa into the lumen, the marker could not be pushed out of the needle, or liquid
marker
that leaked intraluminally from the tissue. Of the 14 markers expected not to be
successfully placed, four were visible on the reference scan; three of these four
were lost
prior to the end of IGRT.
Fig. 1 Sankey plot showing the number of implantation attempts (N=93), the number of marker
implantations expected to be successful (N=79), the number of markers placed in the
stomach wall and present on the reference scan (N=66), the first CBCT (N=61), and
the last CBCT (N=59). Seventeen markers expected to be successfully placed were either
not visible on the reference scan (N=10) or not placed in the stomach wall (N=7).
*For one patient, the reference scan was acquired prior to marker implantation; for
this patient, we regarded the first CBCT also as reference scan.
The average procedure duration was 24.4 minutes (range 16–38 minutes), with time per
marker attempt 2.5 to 5.4 minutes (average 3.7 minutes). The technical feasibility
was rated easy for 77 markers, reasonable for nine, and difficult for seven. All difficult
implantations were unsuccessful. Reasons for difficult marker implantation included
challenges with pushing the gold or liquid marker out of the needle; causes included
sharp angulation of the gastroscope or changes in bone wax type/brand.
Adverse events
Only mild bleeding occurred (N=15, all gold), indicating that the bleeding stopped
immediately. No procedure-related complications were reported afterwards.
Potential benefit
For each patient, three to four CTs (total=53) and 19 to 25 CBCTs (total=339) were
used
to score marker visibility ([Fig. 2]). The visibility of all successfully placed markers was good on CT scans ([Fig. 3]). On CBCTs, most markers (81%) had good visibility. For only five markers (four
patients), visibility was poor on CBCT. All five were liquid markers (significantly
more
often than gold marker; P=0.003) located in the corpus (not
significant compared to the other locations); three were visually assessed as small.
Fig. 2 Typical example of gold (orange arrows) and liquid (blue arrows) fiducial markers
on CT and CBCT. On the CTs, two liquid markers are visible; one of the two was, although
present, not visible on the CBCTs.
Fig. 3 Boxplots of the visibility of successfully placed markers (N=59) on CT and CBCT scans
for liquid (blue) and gold markers (orange). Symbols indicate marker location: square
= gastroesophageal junction (i.e., junction), circle = corpus, triangle = pylorus).
Boxplots: box = interquartile range (IQR), whiskers = lowest and highest data point
within 1.5×IQR.
Besides marker loss between the first and last acquired scan, no apparent migration
within the tissue was observed.
Discussion
Currently, there is limited research on fiducial marker implantations in the stomach.
Hence, in this prospective feasibility study, we demonstrated that endoscopic fiducial
marker placement in the stomach is technically feasible and safe. In addition, the
successfully implanted fiducial markers are positionally stable and sufficiently visible
on acquired imaging, thereby showing their potential benefit.
Implantation was successful in 63% of implantation attempts, with no significant difference
in success rates between gold and liquid markers. Every patient had at least two markers
(range 2 to 6) successfully implanted in the stomach wall that remained present for
the entire IGRT course (i.e., 37 to 60 days post-implantation). In similar studies
for gastrointestinal cancers [11]
[12]
[13]
[17]
[20]
[21], technical success is often measured by the ability to successfully place at least
two markers in the target. With this measure, our technical success rate per patient
is 100%, which is similar to or higher than previous studies that include gastric
cancer [17]
[21]. The characteristics of the stomach (e.g., hollow and flexible with peristaltic
motion) may complicate implantations, as reflected in the success rate of 60% in the
corpus.
Similarly, implantations in the gastroesophageal junction were occasionally challenging
due to the retroflexed position of the gastroscope (success rate 63%). In contrast,
implantations in the pylorus, with a success rate of 80%, were generally more straightforward.
However, although some implantations were unsuccessful, these were regularly expected
to be unsuccessful during the procedure (N=14; e.g., gold markers partially sticking
out of the tissue), and additional markers could still be placed at the same location.
Hence, the clinical impact of these unsuccessful implantations on IGRT was minimal.
During this study, the implantation procedures were found to be generally efficacious.
A large number of implantation attempts (5–8) and successful implantations (2–6) per
patient were performed within a relatively short implantation procedure duration (24.4
minutes). Furthermore, few technical difficulties were encountered and four different
gastroenterologists performed the implantations, thereby showing broad applicability.
In addition, similarly to other studies in which these gold (Visicoil) and/or liquid
markers (BioXmark) were implanted, we found no procedure-related complications [11]
[16]
[21]. Hence, we demonstrated that fiducial marker implantations in the stomach are technically
feasible and safe.
Most successfully placed markers had good visibility on both CT and CBCT imaging.
Poor visibility on CBCT was likely primarily caused by marker location (i.e., corpus
has largest peristaltic motion) and/or type (i.e., small-volume liquid marker). Migration
within the tissue was not observed but is also difficult to assess because of the
large day-to-day stomach shape changes. In this feasibility study, markers were placed
distributed throughout the stomach and frequently also near the tumor borders. Even
though in this study the target for IGRT included the entire stomach, these markers
can evidently also assist in tumor demarcation when the tumor is the intended target.
Hence, with good overall marker visibility and no marker migration, fiducial markers
in the stomach show great potential to improve target delineations, and daily target
localization and positioning during gastric cancer IGRT. Consequently, by implanting
fiducial markers, radiotherapy accuracy may be enhanced, thereby potentially contributing
to reduced toxicity and improved treatment outcomes for patients with gastric cancer.
Including patients with both marker types, although only seven, enabled fair comparisons
of the implantation procedure, the number of successful implantations, and marker
visibility, unlike other studies with multiple marker types [13]
[20]
[21]. For liquid markers, multiple markers could be placed without retraction and reloading
of the needle. Therefore, in addition to being user-friendly, liquid markers have
the potential to reduce procedure time and associated costs. Moreover, when multiple
markers are required, the cost of liquid marker implantations may be further reduced
compared to gold markers as multiple markers can be implanted from a single purchased
1-mL ampoule. Conversely, despite the use of a unit dose syringe to regulate the injected
liquid marker volume, various marker volumes were observed (e.g., very large and too
small volumes). By comparison, gold markers always contain the same amount of gold
and have a higher contrast due to the higher density. Gold markers are thus more consistently
visible in imaging and easier to locate. However, the visibility of liquid markers
may be enhanced by clinical implementation of advanced CBCT reconstruction methods
[22] or by ensuring that an adequate volume of the liquid marker is injected [16]. Hence, each marker has its benefits, and the type of marker should be selected
based on the intended use.
Strengths of this study include the clear focus on the stomach, the relatively large
number of implanted fiducial markers, and the extensive evaluation of marker visibility
on imaging data. As a result, we were able to show the evident clinical applicability
of fiducial markers during IGRT, despite the relatively small patient cohort in this
feasibility study. Because liquid markers were placed only in the final seven patients
due to the absence of CE mark approval at the start of patient inclusion, this study
contained unequal sample sizes of gold and liquid markers. Moreover, because each
patient had multiple markers, the statistical tests included non-independent observations.
Hence, statistical comparisons between marker types and locations should be cautiously
interpreted. Furthermore, marker implantations were performed in this study without
endoscopic ultrasound (EUS) guidance, unlike similar studies. Limiting factors of
EUS guidance can be its technical characteristics (e.g., less flexible scope) and
lack of widespread availability [17]. Although implantations outside the stomach wall occurred for only a small number
of markers (N=7), EUS guidance may prove beneficial in preventing such unsuccessful
implantations. A greater positive impact on the success rate in general may be expected
from more clinical experience by the gastroenterologist in both needle loading/sealing
and marker injection or consistent use of fluoroscopy.
Conclusions
In conclusion, fiducial marker implantations, both gold (Visicoil) and liquid (BioXmark),
were feasible and safe in gastric cancer patients. Furthermore, because they have
good overall visibility on the acquired images during 5-week IGRT, gastric fiducial
markers have potential benefit for radiotherapy.
