an excess of 80,000 individuals are diagnosed annually with tumors of the liver in the united states . less than 20% of those neoplasms are amenable to definitive surgical management due to advanced stage of local disease or comorbid medical conditions . unresectable malignant tumors of the liver carry a poor prognosis with limited nonsurgical effective treatment options . alternative modalities being used for treatment of unresectable liver tumors include trans - arterial chemoembolization ( tace ) , y90 microspheres embolization , radiofrequency ablation ( rfa ) , and transcutaneous ethanol injection ( tei ) . however , these therapies have limitations depending on size , location , number , and distribution of lesions . at this time , sorafenib is now routinely offered to patients with hcc based on the randomized results from the sharp trial . these forms of therapy have not had a significant impact on survival with a median overall survival of less than 1 year for nonsurgically removed primary tumors of the liver . stereotactic radiosurgery ( srs ) is a technique that allows precise delivery of a large ablative radiation dose to the tumor while sparing normal surrounding tissue in 1 to 5 fractions . when used to treat brain metastases , srs treatment results in extremely high local control rates in excess of 80%90% . its use in extracranial tumors had been limited due to the inherent movement of abdominal organs and associated tumor movement that occurs during the respiratory cycle . one newer device that tracks tumors during respiration and automatically adjusts during patient positioning is the cyberknife robotic radiosurgery system , which consists of three key components : ( 1 ) an advanced , lightweight linear accelerator ( linac ) , ( 2 ) a robotic arm which can point the linac from a wide variety of angles , and ( 3 ) a tumor tracking system . the system tracks a patient 's abdominal tumor during respiration using three different mechanisms : ( 1 ) an in - room kv imaging system , which is used for fiducial tracking , ( 2 ) infrared light emitting diodes ( leds ) placed on the patient 's chest ( synchrony vest ) and wall - mounted infrared detector which allows for the construction of a patient 's breathing model , and ( 3 ) a software that creates an algorithm linking the tumor movement with the chest wall movement , so that tumor position can be predicted at all stages of the breathing cycle . with the cyberknife system , sbrt is delivered in the setting of near real - time tracking of implanted fiducial markers combined with respiratory motion modeling to achieve submillimeter accuracy by continually detecting and correcting for tumor motion throughout treatment . it was reported that the average treatment delivery precision was 0.3  0.1  mm as measured at three different sbrt facilities for spinal lesions . sbrt delivered via the cyberknife and other radiosurgery systems has been used in the treatment of several abdominal tumors including pancreatic , renal , hepatic , adrenal , and pelvic malignancies among others . we report our initial experience with 17 patients who underwent sbrt for unresectable tumors of the liver . medical records of the first seventeen consecutive patients treated between october 2007 and may 2009 who underwent cyberknife sbrt for nonresectable tumors of the liver were reviewed under an irb - approved protocol . enrollment criteria for sbrt included ( 1 ) biopsy proven malignancy ; ( 2 ) nonresectable liver disease , and ( 3 ) life expectancy of at least 12 weeks . tumor pathology was represented by hcc ( n = 6 ) , ihc ( n = 3 ) , and secondary liver tumors ( lm , n = 8) . patients treated for lm were found to have primary tumors from the gi tract ( pancreas and colorectal , n = 2 and 1 , resp . ) , from the ovary ( n = 1 ) , breast ( n = 2 ) , and lung ( n = 2 ) . four patients underwent surgical resection for abdominal malignancy prior to sbrt . a patient with ihc underwent an r0 liver resection to be found to have multifocal disease 14 months after initial surgery and 13 months prior to sbrt . two patients underwent pancreatico - duodenectomy for pancreatic adenocarcinoma prior to sbrt for liver metastases . one patient with liver metastases had sequential liver resection and rfa 21 , 19 , and 4 months prior to sbrt . 76% ( 13/17 ) of all patients underwent chemotherapy and 52% of them ( 9/17 ) underwent locoregional treatments , that is , rfa , tace prior to sbrt . patients were clinically evaluated by an hpb / transplant surgeon , a medical oncologist , hepatologist , and a radiation oncologist and staged by imaging that consisted of contrast - enhanced computerized tomography ( ct scan ) , magnetic resonance imaging ( mri ) , or positron emission tomography scan ( pet ) . subsequent imaging for contouring , treatment plan development , and implementation was obtained as needed . an average of 5 , 35  mm cylindrical solid gold fiducial markers ( best medical international , springfield , va ) were placed either surgically ( n = 12 ) or percutaneously under ct guidance ( n = 5 ) within a 10  cm radius within or around the tumor tissue at a minimum distance between adjacent fiducials of 2  cm . spinal needles and , needles were placed 1 - 2  mm into the liver substance and fiducials were pushed in with the obturator . one week was provided between markers placement and sbrt treatment planning simulation to allow for fiducial settling . patients were then brought to the sbrt suite , they were immobilized using an alpha cradle and fitted with a synchrony vest during simulation and treatment . tumor definition , normal tissue constraints , and final treatment plan were approved by the attending radiation oncologist , the attending hepatobiliary surgeon , and the medical physicist . 100 to 300 6  mv x - ray beams were used for each plan . prior to each treatment fraction , patients were premedicated with 4  mg of dexamethasone and 4  mg of ondansetron . during sbrt treatment they were continuously monitored under real - time kilovoltage cameral fiducial tracking and near real - time respiratory motion modeling using a separate synchrony camera system . patients were assessed every 3 months after completion of treatment by physical exam and imaging . total volume of the tumor was determined by multiplan treatment planning system v2.05 ( sunnyvale , ca ) . the maximum tumor diameter was measured and the tumor volume was calculated by importing the image into adac pinnacle radiotherapy planning software with 3d volume algorithms .   local response to sbrt was graded by recist ( response evaluation criteria in solid tumors ) criteria to describe change in treated tumor lesion . this grading system has four tumor response grades : progressive disease ( at least 20% increase of the lesion ) , stable disease , partial response ( at least 30% decrease of the target lesion ) , and complete response ( disappearance of all target lesions ) . to further evaluate partial tumor response to sbrt and for the purpose of these studies , we developed a grading system from i to iii and for tumor recurrence from 0 to 4 based on imaging modalities . partial response grade i was considered a decrease in tumor volume / size < 30% , but > 10% from original tumor volume / size . partial response grade ii was considered as a decrease in volume / size 30% but < 50% from original tumor volume / size . partial response grade iii was considered as a decrease in tumor volume / size 50% . in some instances in patients with ihc , the tumor size was similar to the original size but the enhancement and pet activity vanished ; we considered these particular cases as a grade iii partial response . local or distal recurrent disease was graded as well . local recurrence to treatment was defined as tumor progression within or at the periphery of the radiation field . no recurrence of the tumor was considered grade 0 ; local recurrence was considered grade 1 with two subgroups : grade 1a = 1 local tumor recurrence and grade 1b  1 local tumor recurrence . distant intraabdominal recurrence was considered grade 2 and it was defined as new tumor distant ( > 3  cms ) from the radiation field or in another organ . furthermore , distant extra - abdominal recurrence was graded as 3 . adverse events after sbrt were graded on a 15 scale according to the nci common terminology criteria for adverse events v3.0 . causes were attributed to either surgery , placement of fiducial markers , chemotherapy , radiation induced , or related to medical comorbidities . a database of clinical , imaging , and radiation variables was created and maintained in a prospective manner . statistical routines were performed using paired t - test with spss v16.0 ( chicago , il ) and they were considered significant at a probability of < .05 level . they consisted of 9 men and 8 women ( n = 17 ) with a mean age of 58.1 years ( range , 42 to 81 years ) . treated tumors received a median prescription dose of 34 grays ( 2445  gy ) in 1 to 3 ( median 3 ) fractions to a median prescription isodose line of 70% . of the 6 patients treated with srt for hcc , all of them responded to treatment with a decrease in tumor volume from 386  428  cc to 152  78  cc ( figure 1 ) . tumor volume decreased a mean of 60% three months after treatment ( p < .05 by paired t - test ) . their tumor volume decreased from 252  292  cc to 103  92  cc with a mean tumor shrinkage of 59% at 3 months after sbrt ( p < .05 by paired t - test ) . it was difficult to evaluate the response to sbrt in patients with ihc since these tumors presented in a multicentric fashion with ill - defined borders . at follow - up , tumors treated were similar in size but with no enhancement in delay films and with negative pet scans ( figure 2 ) . in the late group of patients , .   initial local control rate to sbrt was 82% ( 14/17 ) with a median follow - up of 8 months ( range 320 months ) ( table 2 ) . three patients experienced local recurrence at 1 , 4 , and 6 months after sbrt . two recurrences occurred in patients with secondary tumor of the liver and one in a patient with ihc . one patient with a liver metastasis from nonsmall cell lung cancer received a second course of sbrt ( 24  gy in 3 fractions ) 7 months after initial sbrt for a local recurrence at the superior edge of the initially treated tumor . this patient also developed distant bone metastasis and , thus , was classified as tumor recurrence grade 4 . another patient with liver metastasis from pancreatic adenocarcinoma had local tumor recurrence at 3 months follow - up imaging . this patient had 2 tumors in two distant locations within the liver , which were treated in two separate sbrt sessions and developed distant intraabdominal metastasis and was classified as tumor recurrence grade 4 . the third local failure was a patient with ihc who developed multifocal local recurrence within edges of radiosurgical field 4 months after sbrt and classified as tumor recurrence grade 1b . seven patients experienced distant recurrences with mean time to distant progression of 4 months ( range 17 months ) with tumor metastases mainly to the bone ( pelvic bone , clavicle , and/or ribs ) . distant recurrence occurred in 33% ( 2/6 ) of patients with hcc at 6 and 7 months , respectively . one of these patients had intraabdominal distant metastasis , classified as tumor recurrence grade 2 . the other patient with hcc and distant metastasis had extra - abdominal metastasis and tumor recurrence grade 3 . one patient with ihc developed bone metastases 4 months after sbrt , classified as tumor recurrence grade 2 . distant recurrence occurred in 50% ( 4/8 ) of patients with secondary tumor of the liver at a mean time of 4 months . all distant extra - abdominal bone metastases were treated with conventional radiotherapy .   regarding treatment - related toxicity , two complications were observed during percutaneous placement of fiducial markers : one fiducial migration and one bleeding complication requiring angiographic coil ( table 2 ) . patient admissions to the hospital following sbrt were due to medical complications and not attributable to sbrt . one patient with liver metastasis from ovarian primary developed a fluid collection after receiving an intraabdominal cycle of chemotherapy which was drained by interventional radiology . three patients with baseline pain had pain management procedures performed after sbrt including celiac plexus block and intrathecal pump . preliminary analysis of 17 patients treated with sbrt for unresectable tumors of the liver is presented . all patients with hcc ( n = 6 ) responded to sbrt as judged by a 60% decrease in tumor volume . similar response rates were observed in patients with liver metastases treated with sbrt with a mean 59% reduction in their volume after sbrt . at 3 months follow - up one patient had local tumor recurrence on imaging after sbrt and two patients had distant intraabdominal recurrence . at six months we noted one ( 6% ) grade 3 adverse events due to fiducial placement , two grade 2 gi ulcers , and one grade 3 gi ulcer . on review , radiation doses to duodenal mucosa were below normal tolerance dose for that organ , but can be considered as a possible side effect of sbrt . there are only a few previous studies reporting on the use of sbrt for primary liver tumors . in 1998 blomgren et al . reported no local failures in 11 patients with intrahepatic primary malignancies . all tumors had either growth arrest , reduction in size , or disappearance of tumor with a mean survival of 13.4 months after a mean follow - up of 12 months . . reported on 11 hcc patients with a local control rate of 75% after 22 months . tse et al . reported a series of 41 patients with hcc ( n = 31 ) or ihc ( n = 10 ) with a 1 year local control rate of 65% and a median survival of 11.7 and 15.0 months , respectively . two patients experienced transient biliary obstruction , which was thought to be due to radiation - induced edema . this was avoided by the use of pretreatment steroids in subsequent courses of sbrt . in our study , all six patients with hcc achieved local control after a median follow - up of 9 months after sbrt . failure to achieve local control in patients with ihc may be due to the multifocal nature of this tumor 's biology . taken together with the current literature , sbrt should be considered a viable treatment option for patients with unresectable hcc , unifocal ihc , and metastasis to liver from colorectal , breast , lung , and ovarian primaries . based on the significant reduction of hcc tumor volume and size after sbrt in our study ( figure 3 ) , we have began to use sbrt as another downstaging modality , in addition to tace , for tumors over 5  cm in maximal diameter in order to make a patient eligible for liver transplantation according to milan criteria . the majority of previous reports using sbrt to treat liver tumors involve the treatment of liver metastases . reported local control rates after sbrt - treated liver metastasis range from 60%94% at 2 years [ 2 , 9 , 1117 ] . two recent phase i / ii studies reported low incidence of toxicity after sbrt with a median survival of 20.5 and 17.6 months , respectively [ 16 , 17 ] . both groups noted breast primaries had longer survival than gi ( colorectal , esophageal , hcc ) primaries . 75% ( 6/8 ) patients treated for liver metastasis in our study achieved local control . both patients who were treated with sbrt for liver metastasis after pancreaticoduodenectomy and chemoradiation ( for pancreatic adenocarcinoma ) developed distant intraabdominal metastasis rapidly within 3 months of sbrt . locoregional therapy with pei , tace , or rfa has the goal of eradicating tumor , while delaying distant progression by decreasing tumor burden . nine patients ( 33% ) in our study had prior treatment with other locoregional modalities prior to sbrt : seven patients had rfa for primary or secondary malignancy of liver and two patients with hcc had tace prior to sbrt . all nine patients developed local tumor progression with these other modalities prior to sbrt . one patient with previous rfa for lung adenocarcinoma recurred locally and distantly 6 month after sbrt . in a study by choi et al . , 20 patients were initially treated with tace , tei , or rfa with a local control rate of 80% after sbrt . this suggests a role for sbrt as salvage therapy for local recurrence after tace , tei , or rfa . due to high recurrence rates after tace and rfa in patients with primary or secondary liver malignancies , a complementary local therapy with sbrt in tumors greater than 3  cm may be in order to decrease risk of local recurrence . the role of sbrt as primary form of therapy deserves further study . for patients with hcc , sorafenib , a creatine - kinase inhibitor is now routinely offered based on results from the randomized results from the sharp trial . this study demonstrated an increase in survival from 10.7 months in sorafenib group compared to 7.9 months in the placebo group ( p < .001 ) . we acknowledge that many of these patients with locally advanced cancer have other medical comorbidities or poor performance status that may preclude chemotherapy . it is our practice , all patients with unresectable hepatobiliary malignancies are offered multimodal treatment including chemotherapy when medically feasible in addition to the locally ablative treatment of sbrt . the oncology community should be aware that sbrt is a different treatment approach than conventional radiotherapy because the radiation dose in radiosurgery is ablative . thus , using sbrt earlier in the natural history of cancer progression ( before second - line chemotherapy ) may lead to improved outcomes . sbrt for unresectable hepatobiliary tumors achieved excellent local control rates with low adverse events from radiotherapy or fiducial marker placement [ 2 , 819 ] . in our study of the five patients with percutaneous fiducial placement , we noted one grade i fiducial migration and one grade iii bleeding complication requiring angiographic coil placement . surgical placement of fiducial markers is enhanced by use of the intraoperative ultrasound to detect tumor(s ) . recist is most commonly used method to report response based on measurement of maximal diameter in the abdominal tumor(s ) . however , this grading system is not the optimal way to assess the entire tumor 's response to therapy . measurement of largest two dimensional diameters is a single snapshot view into tumor effect that can occur after chemotherapy or locoregional therapy compared to a three - dimensional assessment of effect based on tumor volume . gross tumor volume ( gtv ) the same process can be used after locoregional therapy including sbrt to assess tumor volume . we report the change in tumor volume after sbrt based on measuring gtv using the multiplan system ( table 2 ) . amongst the current literature , there are vague and inconsistent definitions of tumor response and recurrence . without a precise and uniform classification system we have developed a grading system for abdominal tumor response and recurrence using change in tumor volume after sbrt . we encourage its use in similar cohorts in an attempt to standardize comparisons among centers and among different treatment modalities . it has been suggested that radiographic response analysis should be set no earlier than 46 months after sbrt to assess tumor response in clinical trials . future long - term data from randomized clinical trials are needed to determine the role of sbrt in the treatment of tumors of the liver . it appears that sbrt can play a primary role in the local control of these malignancies . the sample size and follow - up of this study are similar to other reported sbrt studies and add to the existing literature pertaining to sbrt for hepatobiliary malignancies . within the limitations of a small sample size and short follow - up we have demonstrated that sbrt is a safe form of therapy for unresectable tumors of the liver with an 89% local response rate with six months mean follow - up . future studies should focus on the development of strategies to define the role of sbrt in the treatment of liver tumors . cyberknife radiosurgery is a safe and effective local treatment option for unresectable primary and secondary liver tumors . in the multidisciplinary management of malignant maladies of the liver , sbrt adds to our armamentarium of local treatment modalities as complementary or salvage therapy . further prospective studies are ongoing to determine long - term response and survival after sbrt for hepatobiliary malignancies .
purpose . 
 stereotactic body radiation therapy ( sbrt ) has emerged as a treatment option for local tumor control of primary and secondary malignancies of the liver . 
 we report on our updated experience with sbrt in patients with non - resectable tumors of the liver 
 . methods . 
 our first 17 consecutive patients ( mean age 58.1 years ) receiving sbrt for hcc ( n = 6 ) , ihc ( 
 n = 3 ) , and lm ( n = 8) are presented . 
 mean radiation dose was 34gy delivered over 13 fractions . 
 results . treated patients had a mean decrease in maximum pretreatment tumor diameter from 6.9  4.6  cm to 5.0  2.1  cm at three months after treatment ( p < .05 ) . 
 the mean total tumor volume reduction was 44% at six months ( p < .05 ) . 
 82% of all patients ( 14/17 ) achieved local control with a median follow - up of 8 months . 
 100% of patients with hcc ( n = 6 ) achieved local control . 
 patients with surgically placed fiducial markers had no complications related to marker placement . conclusion . 
 our preliminary results showed that sbrt is a safe and effective local treatment modality in selected patients with liver malignancies with minimal adverse events . 
 further studies are needed to define its role in the management of these malignancies .