surgical resection of lm is the only potentially curative modality , but it is possible in less than 20 percent of patients .
majority of patients are not suitable for surgical resection due to various clinical and technical reasons . for such patients , various non - surgical options
are three dimensional conformal radiation therapy ( 3d - crt ) , stereotactic body radiation therapy ( sbrt ) , transarterial chemoembolization ( tace ) , and various thermo - ablative procedures like radiofrequency ablation ( rfa ) and laser induced thermal therapy ( litt ) . even for operable lesions , image guided percutaneous ablative procedures are increasingly being used , because they are relatively safer , minimally invasive and equally effective .
interstitial brachytherapy ( ibt ) is relatively a new and less studied technique of treatment lm .
it is preferred over the other thermal ablative techniques for lesions larger than 3 - 5 cm in size or located in close proximity to large vessels which are less likely to be ablated due to heat sink effect [ 5 , 6 ] .
the ibt consists of insertion of single or multiple percutaneous needles in the lesion under ultrasonography ( usg ) or ct scan guidance , and connecting them to remote after loading brachytherapy machine for delivering a single high - dose - rate ( hdr ) dose of about 20 gy . as compared to external beam radiation therapy ( ebrt ) techniques like 3d - crt and sbrt , high - dose - rate interstitial brachytherapy ( hdribt ) can potentially provide better dosimetry since tumor movement due to breathing , unlike in ebrt , does not affect dose distribution .
limited experiences through small studies [ 712 ] exist in the literature regarding the role of hdribt in lm and primary hepato - cellular carcinoma , and have shown efficacy and safety .
we conducted a prospective trial to study the feasibility of hdribt in lm at our institute .
from may 2009 to june 2011 , 10 patients with 12 metastatic lesions in the liver were enrolled in this prospective trial .
all patients had either refused surgery or found ineligible for surgery due to co - morbidities , and had consented for inclusion in the study .
inclusion criteria were as follows : 1 ) age more than 18 years ; 2 ) karnofksy performance score of 70 ; 3 ) controlled primary site ; 4 ) liver function tests within normal limits .
exclusion criteria included : 1 ) patients with more than three lesions ; 2 ) pediatric patients ; 3 ) metastases from wilm 's tumor , choriocarcinoma , seminomas or other chemosensitive tumors ; 4 ) patients with metastases to multiple visceral organs ; 5 ) previous irradiation to liver including sbrt .
ct imaging was done for all patients as the baseline imaging for determining the disease extent and post treatment response assessment .
the procedure was carried out in ct scan room ( phillips large bore ct scanner , royal philips electronics , amsterdam , the netherlands ) under local anesthesia ( 2% xylocaine ) . in the breath hold position , 16 gauze blind end stainless steel or rigid plastic brachytherapy needle was inserted in the center of lesion through the percutaneous route .
the needle tip was preferably advanced 3 - 5 mm beyond the lesion since the needle tip was blind and could not dwell a source .
caution was taken not to introduce the needle during the breathing movement in order to avoid tissue tear .
usually a single ibt needle for lesions up to 3 cm and multiple needles for lesions more than 3 cm in diameter were inserted .
1 ) . if required , needles were sutured to the skin for additional securing .
ct scan images were acquired with a slice thickness of 3 mm and transferred to treatment planning system .
clinical photograph of a patient in prone position showing 4 brachytherapy needles fixed with screws brachytherapy planning was performed on plato planning system , version 14.1 ( nucletron , an elekta company , elekta ab , stockholm , sweden ) using slice thickness of 3 mm .
the clinical target volume ( ctv ) and normal liver volume were delineated on each slice .
using step size of 2.5 mm , a plan was generated for a dose of 20 gy prescribed to ptv ( fig .
the volume of normal liver ( excluding ptv ) receiving 5 gy was kept below 30% . after the plan approval , patient was taken to microselectron hdr brachytherapy unit ( nucletron , an elekta company , elekta ab , stockholm , sweden ) using ir-192 radioactive source with initial activity of 10 ci for treatment delivery .
the needle was removed in the breath hold position immediately after the completion of treatment and puncture site was sealed .
planning ct scan of a patient showing the metastatic lesion , two brachytherapy needles and dosimetry .
the red color line represents the prescription isodose line ( 20 gy ) and cyan color line represents the 200% isodose line ( 40 gy ) which covers a significant central part of the lesion acute complications were defined as those occurring within 6 months of the treatment .
this included complications encountered during and within one week of the procedure ( perioperative complications ) .
major complications were defined as those resulting in life threatening condition ( like intra - abdominal hemorrhage ) requiring emergency therapies like blood transfusion and endotracheal intubation .
minor complications included the nausea / vomiting , pain requiring analgesics , minor bleeding which did not require any active or resuscitative measures .
patients were followed up every month till a period of 6 months and then every 3 months .
response evaluation was done using the criteria   defined by response evaluation criteria in solid tumors ( recist ) .
first assessment ct scan was performed at 3 months post procedure in view of the post treatment edema and slow regression following large single dose of 20 gy .
local control was defined as absence of more than 20% increase in the size of treated lesion compared with baseline .
appearance of any new lesion outside the treated area was not taken as local recurrence . local progression free survival ( lpfs )
was defined as the period from date of enrollment until the date of local disease progression ( more than 20% increase in the size of treated lesion ) , or death , or last follow up whichever came first .
the procedure was carried out in ct scan room ( phillips large bore ct scanner , royal philips electronics , amsterdam , the netherlands ) under local anesthesia ( 2% xylocaine ) . in the breath hold position , 16 gauze blind end stainless steel or rigid plastic brachytherapy needle was inserted in the center of lesion through the percutaneous route .
the needle tip was preferably advanced 3 - 5 mm beyond the lesion since the needle tip was blind and could not dwell a source .
caution was taken not to introduce the needle during the breathing movement in order to avoid tissue tear .
usually a single ibt needle for lesions up to 3 cm and multiple needles for lesions more than 3 cm in diameter were inserted .
1 ) . if required , needles were sutured to the skin for additional securing .
ct scan images were acquired with a slice thickness of 3 mm and transferred to treatment planning system . clinical photograph of a patient in prone position showing 4 brachytherapy needles fixed with screws
brachytherapy planning was performed on plato planning system , version 14.1 ( nucletron , an elekta company , elekta ab , stockholm , sweden ) using slice thickness of 3 mm .
the clinical target volume ( ctv ) and normal liver volume were delineated on each slice .
using step size of 2.5 mm , a plan was generated for a dose of 20 gy prescribed to ptv ( fig .
the volume of normal liver ( excluding ptv ) receiving 5 gy was kept below 30% . after the plan approval , patient was taken to microselectron hdr brachytherapy unit ( nucletron , an elekta company , elekta ab , stockholm , sweden ) using ir-192 radioactive source with initial activity of 10 ci for treatment delivery .
the needle was removed in the breath hold position immediately after the completion of treatment and puncture site was sealed .
planning ct scan of a patient showing the metastatic lesion , two brachytherapy needles and dosimetry .
the red color line represents the prescription isodose line ( 20 gy ) and cyan color line represents the 200% isodose line ( 40 gy ) which covers a significant central part of the lesion
this included complications encountered during and within one week of the procedure ( perioperative complications ) .
major complications were defined as those resulting in life threatening condition ( like intra - abdominal hemorrhage ) requiring emergency therapies like blood transfusion and endotracheal intubation .
minor complications included the nausea / vomiting , pain requiring analgesics , minor bleeding which did not require any active or resuscitative measures .
patients were followed up every month till a period of 6 months and then every 3 months .
response evaluation was done using the criteria   defined by response evaluation criteria in solid tumors ( recist ) .
first assessment ct scan was performed at 3 months post procedure in view of the post treatment edema and slow regression following large single dose of 20 gy .
local control was defined as absence of more than 20% increase in the size of treated lesion compared with baseline .
appearance of any new lesion outside the treated area was not taken as local recurrence . local progression free survival ( lpfs )
was defined as the period from date of enrollment until the date of local disease progression ( more than 20% increase in the size of treated lesion ) , or death , or last follow up whichever came first .
there were 5 males and 5 females with a median age 54 years ( range 40 - 72 ) .
the median size of the lesion was 3.8 cm ( range 2.7 - 7.0 cm ) .
single needle was used in 5 patients while multiple needles were used in 5 patients . in one patient ,
the average time for the entire ibt procedure ( needle insertion to needle removal ) was 65 minutes ( range of 50 - 105 minutes ) .
the volume of normal liver ( excluding the target volume ) receiving more than 5 gy did not exceed 19% in any of the patient .
one patient who had minimal pleural effusion without any symptom was managed with observation alone and no active intervention was required .
at 12 months , 3 out of 12 lesions showed local progression and thus local control rate was 75% . all these 3 patients developed metastases to other visceral organs as well ( lung 2 , brain 1 ) . of the 7 patients ( with 9 lesions under control ) , 2 patients developed metastases to bones , lung and liver .
the kaplan meier curve showing local progression free survival patient characteristics cm  centimeter , rfa  radiofrequency ablation details of brachytherapy dosimetry c.c .
 cubic centimeter , v100  volume receiving 100% of prescription dose , v150  volume receiving 150% of prescription dose , v200  volume receiving 200% of prescription dose number of patients showing major and minor complications ( n = 10 patients )
among non surgical options for patients with lm , rfa is relatively more popular method of ablation .
however , it has limitations concerning the number , localization , as well as size and shape of the lm , with the risk of complications ranging from 8 - 35% [ 15 , 16 ] .
ct guided hdribt is a new treatment for lm with only limited studies [ 712 ] in the literature reporting local control rates of 87 - 93% ; similar to other ablative therapies . unlike rfa
compared to ebrt treatment methods like sbrt , hdribt dosimetry remains unaffected by respiratory movements , because the implanted needle moves with target .
therefore , it precisely delivers a large single dose of radiation to the target lesion and minimal dose to the surrounding liver parenchyma which has limited radiation tolerance .
this makes it a highly conformal treatment with good therapeutic potential , while experience is limited . to the best of our knowledge ,
ours is the first such study being reported from india so far , and our results have shown that hdribt is a safe and feasible non surgical option for lm in our setup . the largest experience in the literature has been reported by ricke et al . 
 [ 79 ] .
in their first study ,   19 patients of lm were treated by hdribt dose of 17 gy ( range 12 - 25 gy ) .
two patients ( 10% ) experienced severe side effects , one had obstructive jaundice due to irradiation edema , and the other had intra - abdominal hemorrhage . in their second study ,
ricke et al . 
  treated 35 patients with mean tumor size of 4.6 cm ( range , 2.5 - 11 cm ) with either hdribt alone using median dose of 17 gy ( range , 10 - 20 gy ) or in combination with thermal ablation .
the local control rate after 6 months was 87% and 73% for ibt alone and combined treatment , respectively . in their third study , they used three different dose levels ( 15 , 20 and 25 gy ) , and observed a statistically significant better local control with 25 gy as compared to 20 gy or 15 gy . 

table 4 summaries the results of various studies [ 712 ] published so far relating to use of hdribt in lm .
the results of our study may not be strictly compared with others in the literature due to small sample size and short follow up .
although local control rates in our study were slightly inferior to other studies , possibly due to small sample size and heterogeneous population of patients having different primary sites ; but our severe complication rate of 0% has been least of all the studies .
the 1-year lpfs in our study is consistent with other studies by ricke et al .   and ricke et al . 
 
studies published regarding the use of hdribt for liver metastases lm  liver metastasis , pts  patients , ibt- interstitial brachytherapy , lc- local control , pfs- progression free survival , hdr- high - dose - rate ; fu- follow up although most studies have used large single dose of hdr , but recently , tselis et al . 
 
reported their results of 31 patients using a fractionated schedule of hdribt ( twice a day ) with total dose ranging from 7 - 32 gy .
the dose per fraction varied from 4 - 14 gy . in their series , 23 patients had lm from different primary sites .
they observed local control rates of 79% at 1 year and 59% at 2 year with 4.7% severe complication rate .
most series including ours ( table 4 ) have included patients with heterogeneous primary sites and therefore results vary across these studies
. however , two studies by ricke et al .   and steffen et al .  
have included patients with lm from colorectum only , and one study by wieners et al . 
 
the best local control rates ( 93% ) have been observed in series having breast primary , but the 1-year pfs of 40% is apparently same compared to rest of the studies . in terms of toxicity , hdribt seems to be safe as the procedure or radiation related severe complications rate has been found to be within acceptable limits ( 1.5 - 10% ) in the published literature so far .
several possible factors namely target volume , irradiation time , number of needle / catheters has been theoretically associated with toxicity , but none has been proved in the literature so far .
occurring 12 to 24 hours after treatment have been reported in about 10% of patients .
sbrt re - fers to the delivery of large doses of highly conformal radiation with steep dose gradients toward the surrounding normal tissue over a limited number of fractions ( 1 to 6 fractions ) to extra cranial tumor sites .
it is a simple , convenient and non - invasive method of treatment , and therefore rapidly becoming popular . though metastatic lesions up to 6 cm in liver have been treated , but lesion size between 3 - 5 cm is the ideal one . unlike hdribt
, lesions located in close proximity to bowel lumen or chest wall / ribs are avoided .
although uncertainty related to breathing movements is minimal with the use of immobilization devices , abdominal compression and gating techniques ; the dosimetric variation can not be ruled out during treatment delivery .
shift in liver position relative to the vertebral bodies can be as large as 1 cm from fraction to fraction . in hdribt ,
breathing motion is not a limiting factor since the catheter has a constant position relative to the target without further specific preparations . due to sharp dose gradient within and outside the target ,
normal liver receives minimal doses and the center of the tumor receives 2 - 3 times higher dose than the prescription dose ( fig .
although there are no studies comparing sbrt and hdribt in lm , local control rates seem to be comparable .
severe toxicity related to sbrt is uncommon , but likely to be more in patients receiving higher doses to bowel or large volumes of liver .
major complications in the form of hemorrhagic gastritis , rib fracture or chest wall necrosis have been rarely observed . as per the paris system   of dosimetry
, multiple needles should be inserted for adequate coverage of lesions larger than 1.5 cm in diameter .
we used single needle for lesions up to 3 cm in diameter and accepted the inhomogeneous dosimetry in the tumor .
such inhomogeneity , which is not usually acceptable in routine hdribt procedures like breast and prostate brachytherapy , actually proves advantageous in liver tumors .
firstly , the central hypoxic area of the tumor , which is closure to needle , definitely receives much higher dose ( > 50 gy for ) as compared to the peripheral portion ( 20 gy ) , and therefore may result in higher tumor control .
secondly , multiple needle insertion will definitely enhance the risk of trauma and associated complications .
we realize the limitations of our study : 1 ) small sample size and 2 ) short follow up duration . yet
, our results consolidate the safety aspect of hdribt in patients of lm and should encourage the readers to further study this topic .
ours is the first study being reported from india so far on the use of hdribt in patients with lm .
although limited by small sample size , the results of our study suggest that hdribt is a safe and effective non surgical option for lm in our setup .
addition of our results to the existing literature would consolidate the practice of hdribt , a technique with excellent therapeutic potential , but relatively under - utilized in lm , and encourage us and the readers to design future multi - centric randomized controlled trials with larger sample size and longer follow up .
 purposeto study the safety and efficacy of high - dose - rate interstitial brachytherapy ( hdribt ) in patients with liver metastases ( lm).material and methodsbetween 2009 and 2011 , 10 patients with 12 metastatic lesions in the liver were enrolled in this prospective trial . 
 all patients had either refused surgery or found ineligible for surgery due to various factors . under ct guidance , 
 16 gauze blind end stainless steel or rigid plastic brachytherapy needle was inserted in the center of lesion through the percutaneous route . 
 generally , a single interstitial brachytherapy ( ibt ) needle for lesions up to 3 cm and multiple needles for lesions more than 3 cm in diameter were inserted . 
 treatment was delivered with a single high - dose - rate ( hdr ) dose of 20 gy prescribed to the target . 
 the needles were removed immediately after the treatment . 
 the endpoints of study were acute complications and local control of the disease.resultsthe median size of the lesion was 3.8 cm ( 2.7 - 7.0 cm ) . 
 the average time for the entire ibt procedure was 65 minutes ( 50 - 105 minutes ) . 
 median follow up was 9 months ( 3 - 17 months ) . 
 none of the patients had fatal complications . 
 minor complications like pain , nausea / vomiting , and asymptomatic pleural effusion were observed in 3 , 2 and 1 patients , respectively 
 . local control rate at 12 months was 75% . 
 the 1-year local progression free survival ( lpfs ) was 33%.conclusionalthough limited by small sample size , the results of our first study from india suggest that hdribt is a safe and effective non surgical option for lm . 
Purpose
Material and methods
Brachytherapy implant procedure
Brachytherapy planning and treatment delivery
Assessment of complications
Follow up and response assessment
Results
Discussion
Conclusions