although surgery is the current standard treatment for localized surgically operable lesions , many patients with liver metastases can not undergo surgical resection because of associated comorbidities , concerns about their age , the extent of the disease , or the patient 's wishes .
alternative treatment approaches for unresectable liver metastasis and primary liver cancer include chemoembolization , radiofrequency ablation , cryotherapy , and the oral multikinase inhibitor sorafenib .
treatment choice is guided by the barcelona clinic liver cancer staging system and recommended treatment strategy .
stereotactic body radiotherapy ( sbrt ) is a technique that allows the delivery of a precise dose of radiation to a tumor while sparing adjacent normal tissues .
however , the movement of intra - abdominal organs due to respiration has hampered the use of sbrt .
the insertion of a fiducial marker near to the tumor before radiotherapy allows respiratory motion to be tracked , thus enabling accurate dose delivery while the patient breathes freely .
recently , the percutaneous insertion of fiducial markers has been described [ 4 , 5 ] , but experience of such procedures is still limited .
this marker is made from gold , which makes it biocompatible and ensures it exhibits good contrast on x - ray images . in this study , we describe our initial experience with this new fiducial marker and evaluate the technical feasibility , clinical efficacy , and safety of sbrt using this marker .
this study was part of a prospective sbrt study in which the cyberknife g4 was used to treat liver tumors and was approved by the institutional review board . written informed consent was obtained from all patients .
since the patient accrual for this sbrt study was relatively slow , we report our initial experience with a gold flexible linear fiducial marker ( visicoil , radiomed corporation , barlett , tn , usa ) in this article . between july 2012 and february 2015 , 18 patients underwent percutaneous fiducial marker placement under computed tomography ( ct ) fluoroscopic guidance or ultrasonographic guidance before sbrt for liver tumors .
their median age was 68 years ( range , 4483 years ) , and all of them were inpatients .
first , all patients underwent diagnostic ct scans of their abdomen composed of 35 mm - thick contiguous axial tomographic sections . after reviewing these preliminary images , an appropriate puncture site and the optimal needle guidance method , i.e. ct fluoroscopic or ultrasound guidance , was determined in advance .
the marker placement was performed during breath - holding under ct fluoroscopic guidance in 8 cases and under ultrasound guidance in 10 cases .
the imaging parameters during ct fluoroscopy included a ct beam width collimated to 3 mm .
one patient needed contrast - enhanced ct fluoroscopy during the procedure to delineate the tumor clearly .
ultrasonography was performed with a convex probe ( 25 mhz ) . a gold flexible linear marker containing an 18-gauge coaxial needle ( 0.75 mm in diameter and 5 mm in length , fig .
local anesthesia was achieved via the subcutaneous administration of 1% lidocaine . after confirming that the needle tip had reached the target lesion ,
after the procedure , ct or cone - beam ct was performed to determine whether any complications such as pneumothorax or bleeding had occurred . 

( a ) an 18-gauge coaxial introducer needle containing the gold flexible linear fiducial marker .
( b ) ct image shows the percutaneous insertion of the gold flexible linear fiducial marker .
( c ) ct image shows the successful placement of the gold flexible linear fiducial marker ( arrow ) in the tumor . the gold flexible linear fiducial marker ( visicoil ) .
( a ) an 18-gauge coaxial introducer needle containing the gold flexible linear fiducial marker .
( b ) the gold flexible linear fiducial marker . a 73-year - old man with metastasis from carcinoma of the ampulla of vater .
( b ) ct image shows the percutaneous insertion of the gold flexible linear fiducial marker .
( c ) ct image shows the successful placement of the gold flexible linear fiducial marker ( arrow ) in the tumor .
the target site was chosen by consensus by an interventional radiologist and a radiation oncologist before the procedure .
clinical success was defined as the completion of sbrt without the marker dropping out of position .
marker position was checked by ct or cone - beam ct images taken immediately after placement and planning ct images taken before radiotherapy .
migration of a marker before radiotherapy was defined as its displacement exceeding 3 mm from the initial position on ct images ; the marker position within or relative to the tumor was evaluated . during radiotherapy , migration of a marker
was evaluated by comparing abdominal plain x - ray images at an inspiratory phase in the supine position taken after marker placement with fluoroscopy images taken at an inspiratory phase of the treatment system ; thereby the marker position was evaluated in relation to the rib bones and diaphragm .
it was difficult to evaluate subtle displacements of the marker by fluoroscopy images alone , especially once radiotherapy was started , because the size of the tumor and the surrounding tissue could change with treatment .
therefore , when migration of the marker that could influence treatment accuracy ( e.g. > 3 mm ) was suspected by fluoroscopy , ct scanning was scheduled for further evaluation to determine whether the displacement was significant or not .
first , all patients underwent diagnostic ct scans of their abdomen composed of 35 mm - thick contiguous axial tomographic sections . after reviewing these preliminary images , an appropriate puncture site and the optimal needle guidance method , i.e. ct fluoroscopic or ultrasound guidance , was determined in advance .
the marker placement was performed during breath - holding under ct fluoroscopic guidance in 8 cases and under ultrasound guidance in 10 cases .
the imaging parameters during ct fluoroscopy included a ct beam width collimated to 3 mm .
one patient needed contrast - enhanced ct fluoroscopy during the procedure to delineate the tumor clearly .
ultrasonography was performed with a convex probe ( 25 mhz ) . a gold flexible linear marker containing an 18-gauge coaxial needle ( 0.75 mm in diameter and 5 mm in length , fig .
local anesthesia was achieved via the subcutaneous administration of 1% lidocaine . after confirming that the needle tip had reached the target lesion , the fiducial marker was deployed , and then the needle was removed ( fig .
after the procedure , ct or cone - beam ct was performed to determine whether any complications such as pneumothorax or bleeding had occurred . 

( a ) an 18-gauge coaxial introducer needle containing the gold flexible linear fiducial marker .
( b ) ct image shows the percutaneous insertion of the gold flexible linear fiducial marker .
( c ) ct image shows the successful placement of the gold flexible linear fiducial marker ( arrow ) in the tumor . the gold flexible linear fiducial marker ( visicoil ) .
( a ) an 18-gauge coaxial introducer needle containing the gold flexible linear fiducial marker .
( b ) the gold flexible linear fiducial marker . a 73-year - old man with metastasis from carcinoma of the ampulla of vater .
( b ) ct image shows the percutaneous insertion of the gold flexible linear fiducial marker .
( c ) ct image shows the successful placement of the gold flexible linear fiducial marker ( arrow ) in the tumor .
the target site was chosen by consensus by an interventional radiologist and a radiation oncologist before the procedure .
clinical success was defined as the completion of sbrt without the marker dropping out of position .
marker position was checked by ct or cone - beam ct images taken immediately after placement and planning ct images taken before radiotherapy .
migration of a marker before radiotherapy was defined as its displacement exceeding 3 mm from the initial position on ct images ; the marker position within or relative to the tumor was evaluated . during radiotherapy , migration of a marker
was evaluated by comparing abdominal plain x - ray images at an inspiratory phase in the supine position taken after marker placement with fluoroscopy images taken at an inspiratory phase of the treatment system ; thereby the marker position was evaluated in relation to the rib bones and diaphragm .
it was difficult to evaluate subtle displacements of the marker by fluoroscopy images alone , especially once radiotherapy was started , because the size of the tumor and the surrounding tissue could change with treatment .
therefore , when migration of the marker that could influence treatment accuracy ( e.g. > 3 mm ) was suspected by fluoroscopy , ct scanning was scheduled for further evaluation to determine whether the displacement was significant or not .
the characteristics of patients , tumors and fiducial marker placement are summarized in table 1 .
the 18 tumors consisted of 5 hepatocellular carcinomas ( 28% ) and 13 liver metastases ( 72% ) .
the target sites for marker insertion were as follows : inside the tumor in 11 cases ( 61% ) and near the tumor in 7 cases ( 39% ) .
two patients underwent radiofrequency ablation of another lesion after fiducial marker placement ; therefore , their hospitalization period was 5 days .
sbrt was successfully performed in all 18 cases , and none of the markers was judged to have dropped out of its position .
the median period between marker implantation and sbrt was 16 days ( range : 031 ) . 

table 1.summary of patients , tumors and fiducial marker placementpatients ( n = 18 )  male / female12/6median age ( range)68 ( 4483)tumors ( n = 18 )  size ( mm )  median of maximum length ( range)35.5 ( 1188)type  hepatocellular carcinoma5  liver metastasis ( colon / gastric / others)13 ( 6/2/5)site  s1/4/6/7/8/1&8/3&4/4&8/7&81/3/1/1/7/2/1/1/1fiducial marker placement ( n = 18 )  ct fluoroscopic / us guidance8/10  inside / near the tumor11/7s1 = caudate lobe , s3 = ventrolateral segment of the left lobe , s4 = medial segment of the left lobe , s6 = posteroinferior segment of the right lobe , s7 = posterosuperior segment of the right lobe , s8 = anterosuperior segment of the right lobe
. summary of patients , tumors and fiducial marker placement s1 = caudate lobe , s3 = ventrolateral segment of the left lobe , s4 = medial segment of the left lobe , s6 = posteroinferior segment of the right lobe , s7 = posterosuperior segment of the right lobe , s8 = anterosuperior segment of the right lobe .
no major complications , such as bleeding or marker migration , occurred ( 0% , 0/18 ) .
one patient developed mild pneumothorax ; however , the sbrt was performed as planned because the pneumothorax disappeared after a few days ' observation .
in sbrt for liver lesions , techniques for controlling tumor motion are required because the bowel and stomach , which have a perforation risk , lie close to the liver .
there are two main methods for reducing the uncertainty regarding the positions of liver tumors .
one is to minimize tumor motion via the inhalation of oxygen , abdominal compression , learning of regular respiratory patterns , or breath - holding techniques [ 79 ] .
the other technique , which is more sophisticated , is target gating or target chasing , during which the movements of the skin surface or other markers are monitored [ 10 , 11 ] .
the placement of the gold flexible fiducial markers near or inside a tumor is considered to be the most direct version of this method . in the present study , fiducial markers were inserted before tumor - tracking sbrt ( using a cyberknife g4 ) during abdominal compression to improve the accuracy of localization .
percutaneous fiducial marker placement has been widely performed , but some complications such as marker migration ( which might cause delayed or inappropriate treatment ) have been reported [ 4 , 5 ] .
for example , a previous study described cardiac embolization due to the migration of a nester embolization coil that was used as a fiducial marker . unlike traditional cylindrical gold seed fiducial markers , for which the migration rate was reported to be 5% , the marker used in this study is flexible and has a coiled design , which might reduce the incidence of fiducial migration . in our study ,
no marker migration was observed ; thus , this gold flexible linear fiducial marker seems to be superior . however , pneumothorax occurred in one case , and a previous report found that percutaneous insertion of the gold flexible linear fiducial marker into the lungs is associated with a high risk of pneumothorax . in our experience ,
the needle included with the gold flexible linear fiducial marker is not sharp enough , and it is more difficult to penetrate the pleura and tumors with this needle than with a biopsy needle .
ohta et al .   previously reported that the transarterial placement of a fiducial marker resulted in a low complications rate ( 2% ) and a high technical success rate ( 100% ) .
however , complications such as femoral pseudoaneurysms have also been reported to occur after angiography .
in addition , some of the transarterial marker procedures failed , and the outcomes of such procedures were considered to depend on the tumor site and the anatomy of the hepatic artery .
celiac artery stenosis makes it difficult to identify the hepatic artery [ 16 , 17 ] .
therefore , the tumor site and the anatomy of the hepatic artery should be confirmed with ct and angiography . on the other hand ,
reported that the complications rate for percutaneous fiducial marker placement in the abdomen or pelvis was 4.3% ( 8/188 ) ; there were five minor complications ( small hematomas in four cases , pneumothorax in one case ) and three major complications ( bleeding in two cases , sepsis in one case ) .
the main benefit of percutaneous marker placement is that it is easy to place the marker in the target position and does not take much time .
therefore , there is a clear need for additional research to address this issue . at this time
, the fiducial marker placement method should be decided based upon a consensus being reached between radiation oncologists and interventional radiologists after consideration of the tumor location and the anatomy of the hepatic artery , which should be confirmed with ct and angiography .
however , the deep part of the liver can not be clearly observed using ultrasound .
furthermore , the skill of the operator and the efficiency of the ultrasound machine vary among hospitals . therefore , the implantation method should be discussed on an individual basis .
three or more fiducial markers were used in the cases described in the literature . in our study , however , only one marker was used based on the consensus of an interventional radiologist and a radiation oncologist .
complications such as pneumothorax might occur more frequently when multiple fiducial markers are inserted percutaneously .
one marker is considered to be sufficient because the gold flexible linear fiducial marker is less likely to migrate . in this study ,
no signs of migration were observed , and all patients underwent radiotherapy without any problems . in future , the complications rate and the frequency of recurrence after radiotherapy should be analyzed with respect to the number of markers employed . in conclusion ,
the new gold flexible linear fiducial marker is useful for percutaneous insertion because of its good stability . in this study , we were unable to determine the local control rate of patients undergoing sbrt with this fiducial marker due to the short follow - up periods involved .
it is therefore necessary to observe our patients for a longer period to evaluate the clinical usefulness of this marker .
funding to pay the open access publication charges for this article was provided by each of the co - authors in this search .
 the aim of this study was to describe our initial experience with a gold flexible linear fiducial marker and to evaluate the safety and technical and clinical efficacy of stereotactic body radiotherapy using this marker for malignant liver tumors . between july 2012 and february 2015 , 18 patients underwent percutaneous fiducial marker placement before stereotactic body radiotherapy for malignant liver tumors . 
 we evaluated the technical and clinical success rates of the procedure and the associated complications . 
 technical success was defined as successful placement of the fiducial marker at the target site , and clinical success was defined as the completion of stereotactic body radiotherapy without the marker dropping out of position . 
 all 18 fiducial markers were placed successfully , so the technical success rate was 100% ( 18/18 ) . 
 all 18 patients were able to undergo stereotactic body radiotherapy without marker migration . 
 thus , the clinical success rate was 100% ( 18/18 ) . 
 slight pneumothorax occurred as a minor complication in one case . 
 no major complications such as coil migration or bleeding were observed . the examined percutaneous fiducial marker 
 was safely placed in the liver and appeared to be useful for stereotactic body radiotherapy for malignant liver tumors . 