Radiofrequency Ablation of Primary or Metastatic Liver Tumors

Transcription

1 Medical Plicy Radifrequency Ablatin f Primary r Metastatic Liver Tumrs Sectin Surgery Subsectin Effective Date February 27, 2015 Original Plicy Date June 26, 2009 Next Review Date February 2016 Descriptin In radifrequency ablatin (RFA), a prbe is inserted int the center f a tumr and the nninsulated electrdes, which are shaped like prngs, are prjected int the tumr; heat is generated lcally by a high frequency, alternating current that flws frm the electrdes. The lcal heat treats the tissue adjacent t the prbe, resulting in a 3- t 5- cm sphere f dead tissue. The cells killed by RFA are nt remved but are gradually replaced by fibrsis and scar tissue. If there is lcal recurrence, it ccurs at the edge, and in sme cases, may be retreated. RFA may be perfrmed percutaneusly, laparscpically, r as an pen prcedure. Related Plicies Crysurgical Ablatin f Primary r Metastatic Liver Tumrs Micrwave Tumr Ablatin Radiemblizatin fr Primary and Metastatic Tumrs f the Liver Radifrequency Ablatin f Miscellaneus Slid Tumrs Excluding Liver Tumrs Transcatheter Arterial Chememblizatin (TACE) t Treat Primary r Metastatic Liver Malignancies Plicy Radifrequency ablatin and percutaneus ethanl injectin may be cnsidered medically necessary fr the treatment f patients with primary hepatcellular carcinma (HCC) with any f the fllwing cnditins: Primary HCC when the all f the fllwing criteria are met: Patient is nt a candidate fr curative resectins due t the lcatin f lesin(s) and/r cmrbid cnditins Patient is nt a candidate fr liver transplantatin* (see exceptin belw) Presence f three r fewer hepatic lesins Each lesin measures 5 centimeters (cm) r less using current technlgy Absence f extrahepatic metastatic disease All tumr fci can be adequately treated Primary HCC, as a bridge t transplantatin*, when all f the fllwing criteria are met: 1

2 Medical Plicy Patient is nt a candidate fr curative resectins due t the lcatin f lesin(s) and/r cmrbid cnditins Intent is t prevent further tumr grwth and t maintain a patient s candidacy fr liver transplant Presence f three r fewer hepatic lesins Each lesin measures 5 centimeters (cm) r less using current technlgy Nte: Criteria fr ablative therapies as a bridge t transplantatin are generally cnsistent with the United Netwrk fr Organ Sharing (UNOS) plicy n Organ Distributin: Liver Transplant Candidates with Hepatcellular Carcinma (HCC); Sectin (11/9/2010). Hepatic metastases frm clrectal cancer when all f the fllwing criteria are met: Patient is nt a candidate fr curative resectins due t the lcatin f lesin(s) and/r cmrbid cnditins Presence f fur t five r fewer hepatic lesins Each lesin measures 5 centimeters (cm) r less using current technlgy Absence f extrahepatic metastatic disease All tumr fci can be adequately treated Hepatic metastases frm neurendcrine tumrs when all f the fllwing criteria are met: Patient has symptmatic disease (e.g., wheezing, flushing f the skin, abdminal cramps, diarrhea, heart disease) Systemic therapy has failed t cntrl symptms (e.g., Octretide therapy) Patient is nt a candidate fr curative resectins due t the lcatin f lesin(s) and/r cmrbid cnditins Absence f extrahepatic metastatic disease Each lesin measures 5 centimeters (cm) r less using current technlgy Radifrequency ablatin and percutaneus ethanl injectin fr primary hepatcellular carcinma (HCC) r hepatic metastases is cnsidered investigatinal fr treatment f any f the fllwing: Primary HCC when there are either f the fllwing: Mre than three ndules When nt all sites f tumr fci can be adequately treated Primary HCC when used t dwnstage (dwnsize) HCC in patients being cnsidered fr liver transplant Hepatic metastasis frm clrectal cancer r neurendcrine tumrs nt meeting the medically necessary criteria abve Hepatic metastases frm ther types f cancer with the exceptin f clrectal cancer r neurendcrine tumrs 2

3 Medical Plicy Plicy Guidelines Explicit criteria have nt been established fr radifrequency ablatin (RFA) f hepatcellular carcinma (HCC) r cancer metastatic t the liver. Neurendcrine Tumrs Neurendcrine tumrs (NETs) may be referred t by their anatmical lcatin (e.g., pulmnary neurendcrine tumr, gastrenterpancreatic neurendcrine tumr). Neurendcrine tumrs include the fllwing: Carcinid tumrs Islet cell tumrs (r pancreatic endcrine tumrs) Neurendcrine unknwn primary Adrenal gland tumrs Phechrmcytma/paraganglima Prly differentiated (high grade r anaplastic)/small cell Multiple endcrine neplasia, Type 1 (als knwn as MEN-1 syndrme r Wermer's syndrme) Multiple endcrine neplasia, Type 2 a r b (als knwn as phechrmcytma and amylid prducing medullary thyrid carcinma, PTC syndrme, r Sipple syndrme) Symptmatic disease frm neurendcrine tumrs may include ht, red flushing f the face, severe and debilitating diarrhea, asthma attacks, palpitatins, lw bld pressure, fatigue, dizziness, and weakness. Extreme symptms may include heart disease, brnchial cnstrictin, and bwel bstructin. Systemic therapies fr neurendcrine tumrs vary depending n the lcatin and characteristics. Therapies may include, but are nt limited t: ctretide, interfern, cyttxic chemtherapy, angigenesis inhibitrs, and epidermal grwth factr inhibitrs. Cding The fllwing CPT cdes describe radifrequency ablatin specific t liver tumrs: 47370: Laparscpy, surgical, ablatin f 1 r mre liver tumr(s); radifrequency 47380: Ablatin, pen, f 1 r mre liver tumr(s); radifrequency 47382: Ablatin, 1 r mre liver tumr(s), percutaneus, radifrequency 47383: Ablatin, 1 r mre liver tumr(s), percutaneus, cryablatin 47399: Unlisted prcedure, liver CPT cde wuld be used t describe the ultrasund guidance fr, and mnitring f, parenchymal tissue ablatin. 3

4 Medical Plicy Benefit Applicatin Benefit determinatins shuld be based in all cases n the applicable cntract language. T the extent there are any cnflicts between these guidelines and the cntract language, the cntract language will cntrl. Please refer t the member's cntract benefits in effect at the time f service t determine cverage r nncverage f these services as it applies t an individual member. Sme state r federal mandates (e.g., Federal Emplyee Prgram (FEP)) prhibit Plans frm denying Fd and Drug Administratin (FDA) - apprved technlgies as investigatinal. In these instances, plans may have t cnsider the cverage eligibility f FDA-apprved technlgies n the basis f medical necessity alne. Ratinale Backgrund Hepatic tumrs can arise either as primary liver cancer (hepatcellular cancer [HCC]) r by metastasis t the liver frm ther tissues. Lcal therapy fr hepatic metastasis may be indicated when there is n extrahepatic disease, which rarely ccurs fr patients with primary cancers ther than clrectal carcinma r certain neurendcrine malignancies. At present, surgical resectin with adequate margins r liver transplantatin cnstitutes the nly treatments available with demnstrated curative ptential. Hwever, mst hepatic tumrs are unresectable at diagnsis, due either t their anatmic lcatin, size, number f lesins, r underlying liver reserve. Neurendcrine tumrs are tumrs f cells that pssess secretry granules and riginate frm the neurectderm. Neurendcrine cells have rles bth in the endcrine system and the nervus system. They prduce and secrete a variety f regulatry hrmnes, r neurpeptides, which include neurtransmitters and grwth factrs. Overprductin f the specific neurpeptides prduced by the cancerus cells causes a variety f symptms depending n the hrmne prduced. They are rare, with an incidence f 2 t 4 per 100,000 per year. Treatment f liver metastases is undertaken t prlng survival and reduce endcrine-related symptms, as well as symptms related t the hepatic mass. Radifrequency ablatin (RFA) has been investigated as a treatment fr unresectable hepatic tumrs, bth as primary treatment and as a bridge t liver transplant. In the latter setting, it is hped that RFA will reduce the incidence f tumr prgressin while awaiting transplantatin and thus maintain a patient s candidacy fr liver transplant during the wait time fr a dnr rgan. This issue has becme less prblematic with additinal pririty nw assigned fr patients with stage T2 HCC. Varius lcreginal therapies fr unresectable liver tumrs have been investigated: RFA, crysurgical ablatin (crysurgery), laser ablatin, trans-hepatic artery emblizatin/chememblizatin (TACE), micrwave cagulatin, percutaneus ethanl injectin, and radiemblizatin (Yttrium-90 micrspheres). Nte: Radifrequency ablatin f extrahepatic tumrs is addressed in a separate plicy. 4

5 Medical Plicy Radifrequency Ablatin as a Primary Treatment f Unresectable Hepatcellular Liver Cancer Systematic Reviews A 2003 TEC Assessment(1) addressed radifrequency ablatin (RFA) in the treatment f unresectable primary r metastatic liver tumrs. Since that time, many systematic reviews and meta-analyses have been published n RFA fr hepatcellular cancer (HCC). In a Cchrane review, Weis et al reviewed studies n RFA fr HCC versus ther HCC interventins.(2) Mderate quality evidence demnstrated hepatic resectin had superir survival utcmes cmpared with RFA; hwever, resectin might have greater rates f cmplicatins and lnger hspital stays. Other systematic reviews and metaanalyses have als fund superir survival with hepatic resectin but higher rates f cmplicatins than RFA.(3-6) This reinfrces the use f RFA fr nly unresectable HCC. The Cchrane review als reprted finding mderate quality evidence demnstrating superir survival with RFA ver percutaneus ethanl injectin (PEI).(2) Evidence n RFA versus acetic acid injectin, micrwave ablatin, r laser ablatin was insufficient t draw cnclusins.(2) One f the first methds devised t ablate liver tumrs invlved PEI. Several nnrandmized trials in the 1990s cnfirmed that PEI culd safely achieve cmplete necrsis in small HCCs, with 5-year survival rates f 32% t 38%.(7) Hwever, the technique had several drawbacks, including the need fr multiple treatment sessins and a high lcal prgressin rate f 17% t 38%. Several randmized cntrlled trials (RCTs) have cmpared PEI and RFA in the treatment f small HCC. A systematic review f randmized trials fr HCC treated with percutaneus ablatin therapies was cnducted by Ch et al.(8) The authrs identified 4 RCTs invlving 652 patients that cmpared RFA with PEI. The review cncluded that RFA demnstrated significantly imprved 3-year survival in patients with HCC cmpared with ethanl injectins. Mst patients in these studies had 1 tumr, and mre than 75% f the tumrs were 3 cm r smaller in size. The 3-year survival with RFA ranged frm 63% t 81%. In a 2013, Shen et al reprted n a meta-analysis f 4 RCTs and quasi-rcts, ttaling 766 patients, t cmpare RFA with PEI fr treatment f HCC ndules up t 3 cm.(9) Overall survival (OS) was significantly lnger fr RFA than PEI at 3 years (hazard ratis [HR], 0.66; 95% cnfidence interval [CI]: 0.48 t 0.90; p=0.009), and lcal recurrence risk was lwer with RFA (HR=0.38; 95% CI: 0.15 t 0.96, p=0.040). Hwever, there was n difference in distant intrahepatic recurrence and RFA resulted in mre cmplicatins. In 2012, Xu et al reprted n a meta-analysis f 13 studies t cmpare RFA with surgical resectin fr early HCC.(10) Only 2 f the studies were RCTs. Surgical resectin ccurred in 1233 patients and RFA was used in 1302 patients. Surgical resectin patients had significantly lnger OS rates at 1, 3 and 5 years than RFA (dds rati [OR], 0.60; 95% CI: 0.42 t 0.86, OR=0.49; 95% CI: 0.36 t 0.65; and OR=0.60; 95% CI: 0.43 t 0.84, respectively). When nly HCC tumrs f 3 cm r less were analyzed, resectin was still significantly better in OS than RFA at 1, 3, and 5 years. Recurrence rates were als significantly lwer in the surgical resectin grup at 1, 3, and 5 years than RFA (OR=1.48; 95% CI: 1.05 t 2.08; OR=1.76; 95% CI: 1.49 t 2.08; and OR=1.68; 95% CI: 1.21 t 2.34, respectively). Lcal recurrence rates did nt differ significantly between prcedures. Cmplicatin rates were higher with resectin than RFA (OR=6.25; 95% CI: 3.12 t 12.52; p=0.000), but in a subanalysis f HCC 3 cm r less, cmplicatin rates were significantly lwer with resectin than RFA. 5

6 Medical Plicy Ting and Maddern cnducted a systematic review f the literature frm 2000 t 2010 and a meta-analysis f survival and disease recurrence after RFA fr HCC.(11) Studies reprting n patients with HCC wh were treated with RFA, either in cmparisn r in cmbinatin with ther interventins, such as surgery r PEI, were eligible fr inclusin. Outcme data cllected were OS, disease-free survival (DFS), and disease recurrence rates. Only RCTs, quasi-rcts, and nnrandmized cmparative studies with mre than 12 mnths fllw-up were included. Frty-three articles, including 12 RCTs, were included in the review. Mst f the articles reprted the use f RFA fr unresectable HCC, ften in cmbinatin with ther treatments such as PEI, transarterial chememblizatin (TACE), and/r surgery. A meta-analysis f 5 RCTs shwed that RFA was better than PEI, with higher OS and DFS rates. Data n RFA cmpared with micrwave ablatin were incnclusive. The authrs cncluded that RFA can achieve gd clinical utcmes fr unresectable HCC. In a 2013 meta-analysis cmparing RFA with cryablatin fr HCC, Huang et al evaluated 3 prspective studies and 1 retrspective study.(12) Included in the studies were 180 RFA and 253 cryablatin patients. RFA was fund t be significantly superir t cryablatin in rates f cmplicatins (OR=2.80; 95% CI: 1.54 t 5.09), lcal recurrence f patient (OR=4.02; 95% CI: 1.93 t 8.39), and lcal recurrence f tumr (OR=1.96, 95% CI: 1.12 t 3.42). Hwever, mrtality was nt significantly different (OR=2.21; 95% CI: 0.45 t 10.8) between grups. Randmized Cntrlled Trials In 2012, Feng et al reprted n an RCT f 84 RFA patients cmpared with 84 surgical resectin patients with up t 2 HCC ndules less than 4 cm in size.(13) Patients were fllwed fr 3 years and OS and recurrence-free survival (RFS) were nt statistically different between grups, (p=0.342 and p=0.122, respectively). RFA in the Transplant Setting fr Unresectable HCC In 2002, the United Netwrk fr Organ Sharing (UNOS) intrduced a new liver allcatin system mdel fr end-stage liver disease (MELD) fr adult patients awaiting liver transplant.(14) The MELD scre is a cntinuus disease severity scale incrprating bilirubin, prthrmbin time (i.e., internatinal nrmalized [INR] rati fr prthrmbin activity), and creatinine int an equatin, prducing a number that ranges frm 1 t 40. Aside frm thse in fulminant liver failure, dnr livers are priritized t thse with the highest MELD number. This scale accurately predicts the risk f dying frm liver disease except fr thse with HCC, wh ften have lw MELD scres because bilirubin, INR, and creatinine levels are near nrmal. In cnsidering hw t allcate the scarce dnr rgans, UNOS sught t balance risk f death n the waiting list against risk f recurrence after transplant. Patients with T1 lesins (1 ndule 1.9 cm) were cnsidered at lw risk f death n the waiting list, while thse with T3 lesins (1 ndule >5.0 cm, r 2 r 3 ndules with at least 1 >3.0 cm) are at high risk f psttransplant recurrence. Patients with T2 tumrs (1 ndule 2.0 cm and 5.0 cm, r 2 r 3 ndules 1 cm and 3.0 cm) have an increased risk f dying while n the waiting list cmpared with thse having T1 lesins and an acceptable risk f psttransplant tumr recurrence. Therefre, UNOS criteria priritize T2 HCC by allcating additinal pint s equivalent t a MELD scre predicting a 15% prbability f death within 3 mnths. The definitin f T2 lesins are ften referred t as the Milan criteria, in reference t a key 1996 study that examined the recurrence rate f HCC accrding t the size f the initial tumr.(15) Nte that liver transplantatin fr thse with T3 HCC is nt prhibited, but these patients d nt receive any pririty n the waiting list. All patients with HCC 6

7 Medical Plicy awaiting transplantatin are reassessed at 3-mnth intervals. Thse whse tumrs have prgressed and are n lnger T2 tumrs will lse the additinal allcatin pints. Therefre, the UNOS allcatin system prvides incentives t use lcreginal therapies in 2 different settings: T dwnsize T3 tumrs t T2 status t meet the UNOS criteria fr additinal allcatin pints; r T prevent prgress f T2 tumrs while n the waiting list. These 2 indicatins are discussed further here. It shuld be nted that the UNOS plicy addresses the rle f lcreginal therapy in the pretransplant setting as fllws: Organ Prcurement and Transplant Netwrk (OPTN) Class 5T (Treated) ndules are defined as any OPTN Class 5 r bipsy-prven HCC lesin that was autmatically apprved upn initial applicatin r extensin and has subsequently undergne lc-reginal treatment. OPTN Class 5T ndules qualify fr cntinued pririty pints predicated n the pre-treatment classificatin f the ndule(s) and are defined as: 1. Past lc-reginal treatment fr HCC (OPTN class 5 lesin r bipsy prven prir t ablatin). 2. Evidence f persistent/recurrent HCC such as ndular r crescentic extra-znal r intra-znal enhancing tissue n late arterial imaging (relative t hepatic parenchyma) may be present. OPTN guidelines als indicate candidates whse tumrs have been ablated after previusly meeting the criteria fr additinal MELD/PELD pints (OPTN Class 5T) will cntinue t receive additinal MELD/PELD pints (equivalent t a 10-percentage pint increase in candidate mrtality) every 3 mnths withut RRB review, even if the estimated size f residual viable tumr falls belw stage T2 criteria. Candidates with HCC nt meeting transplant criteria, including thse with dwnsized tumrs whse riginal/presenting tumr was greater than a stage T2, must be referred t the applicable RRB [Reginal Review Bard] fr prspective review in rder t receive additinal pririty. (14) Lcreginal Therapy as a Technique t Prevent Tumr Prgressin While n the Waiting List Several prir studies have reprted drput rates f wait-listed patients treated with lcreginal therapy. Hwever, lacking cntrlled data, it is difficult t assess cntributins f lcreginal therapy t time n the waiting list. In additin, in 2002, as previusly discussed, UNOS revised its liver allcatin plicy, such that wait times fr patients with HCC meeting the Milan criteria have nw declined. Mst f the literature has fcused either n TACE r a variety f lcreginal therapies. Given these limitatins, the fllwing case series have been reprted. Fisher et al reprted n 33 patients wh received multimdality ablatin therapy, cnsisting primarily f RFA r TACE. Five patients (12%) were remved frm the waiting list after waits f 5 t 14 mnths.(16) In this prtcl, patients with tumrs larger than 5 cm were nt cnsidered transplant candidates until the tumr was cmpletely ablated using TACE, RFA, r anther technique. Yamashiki et al reprted n 288 patients given varius ablative therapies; the drput rate due t tumr prgressin at 1 and 3 years was 6.2% and 23%, respectively. Tumrs greater than 3 cm affected the drput rate due t tumr 7

8 Medical Plicy prgressin.(17) Mazzaferr et al reprted n 50 patients with HCC wh underwent RFA while awaiting transplantatin; n patient had t be remved frm the waiting list due t tumr prgressin ver a mean wait time f 9.5 mnths.(18) The median tumr size was 3 cm, and 80% f patients met the Milan criteria. Similarly, Lu et al reprted n 52 patients wh underwent RFA as a bridge t transplantatin, 42 f whm met the Milan criteria.(19) After a mean f 12 mnths, 5.8% had drpped ff the waiting list due t tumr prgressin. In a 2008 paper, Belghiti et al reviewed the literature reprting efficacy f lcal management appraches including resectin, TACE, RFA, and n treatment.(20) They cncluded that RFA can induce cmplete necrsis in mst small tumrs (<2.5 cm), and that there are n data demnstrating that the treatment reduces the rate f drput befre transplantatin r imprves survival after transplant. Nne f the studies included data frm U.S. centers fr patients listed after adptin f the Milan criteria. Prrett et al retrspectively cmpared 31 patients treated with RFA with 33 untreated cntrls.(21) Study end pints included patient and DFS, tumr recurrence, explant tumr viability, and the ability f magnetic resnance imaging (MRI) t detect viable tumr after therapy. Bth chrts had similar demgraphic, radigraphic, and pathlgic characteristics, althugh untreated patients waited lnger fr transplantatin (119 [untreated] vs. 54 [RFA] days after MELD assignment; p=0.05). Only 20% f treated tumrs demnstrated cmplete ablatin (necrsis) as defined by histlgic examinatin f the entire lesin. Only 55% f lesins with histlgic viable tumr were detected by MRI after pretransplant therapy. After 36 mnths f fllw-up, there was n difference between the treated and untreated grups in OS (84% vs. 91%), DFS (74% vs. 85%), cancer recurrence (23% vs. 12%), r mrtality frm cancer recurrence (57% vs. 25%, all respectively) (p>0.1). The authrs cncluded that viable tumr frequently persists after pretransplant lcreginal therapy, and neadjuvant treatment des nt appear t imprve psttransplant utcmes in the current MELD era. Current UNOS plicy n allcatin f livers indicates that candidates whse tumrs have been ablated after meeting the criteria fr additinal MELD/PELD (PELD calculatr fr persns <12 years f age) pints (OPTN class 5T) will cntinue t receive additinal pints (equivalent t a 10% increase in mrtality) every 3 mnths withut review, even if the estimated size f residual viable tumr falls belw stage T2 criteria.(14) The plicy als ntes that candidates may be remved frm the listing if they are determined t be unsuitable fr transplantatin based n prgressin f HCC. Lcreginal Therapies t Dwngrade HCC Befre Transplant RFA t Dwnstage HCC Befre Transplant Ya et al analyzed lnger term utcme data n HCC dwnstaging in a chrt f 61 patients with tumr stage exceeding T2 criteria enrlled between June 2002 and January 2007.(22) Eligibility criteria fr dwnstaging included: (1) 1 lesin larger than 5 cm and up t 8 cm; (2) 2 t 3 lesins with at least 1 lesin larger than 3 cm and nt exceeding 5 cm, with ttal tumr diameter up t 8 cm; r (3) 4 t 5 lesins with nne larger than 3 cm, with ttal tumr diameter up t 8 cm. TACE and laparscpic RFA (LRFA) either alne r in cmbinatin were the main methds used: 11 patients received LRFA alne, 14 received TACE and LRFA, and 9 received TACE and percutaneus RFA. A minimum bservatin perid f 3 mnths after dwnstaging was required befre liver transplant. Tumr dwnstaging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) received liver transplant, including 2 with live-dnr liver transplantatin. Treatment failure was bserved in 18 patients (29.5%), primarily due t tumr prgressin. In the explant f 35 patients wh underwent transplant, 13 had cmplete tumr necrsis, 17 met T2 criteria, 8

9 Medical Plicy and 5 exceeded T2 criteria. The Kaplan-Meier intentin-t-treat survival at 1 and 4 years after dwnstaging were 87.5% and 69.3%, respectively. The 1-year and 4-year psttransplantatin survival rates were 96.2% and 92.1%, respectively. N patient had HCC recurrence after a median psttransplantatin fllw-up f 25 mnths. The nly factr predicting treatment failure was pretreatment alpha-fetprtein greater than 1000 ng/ml. Frm this small series, the authrs cnclude that successful dwnstaging can be achieved with excellent psttransplant utcmes. A natinal cnference invlving transplant physicians was held t better characterize the lng-term utcmes f liver transplantatin fr patients with HCC and t discuss the plicy f assigning increased pririty fr candidates with stage T2 HCC n the transplant waiting list in the U.S. Gals f the cnference were t standardize pathlgy reprting, develp specific imaging criteria, expand the Milan criteria (the criteria used t measure tumr size t determine if a patient qualifies fr transplant), discuss lcreginal therapy, define criteria fr dwnstaging transplantatin, and review current liver allcatin system fr HCC patients. Pmfret et al summarized the cnference findings and recmmendatins.(23) The wrkgrup n lcreginal therapy fund cmpelling evidence that pretransplant lcreginal therapy decreases waitlist drput, especially fr patients wh wait lnger than 3 t 6 mnths fr transplant. They nte there is a paucity f data cmparing RFA with transarterial therapies fr the treatment f HCC prir t liver transplant and mst single-center trials have a mixture f [lcreginal therapies] included in the study ppulatin and that, while early studies suggested a high rate f tumr seeding with percutaneus RFA, it is rare in larger series frm experienced centers. The wrkgrup cnsidering evidence t supprt expansin f MELD criteria fr patients with HCC reprted wide reginal variatin in the risk f death fr patients withut HCC. The MELD scre f the nn-hcc patients was quite lw in sme regins. Psttransplant survival in HCC patients ranged frm 25% in regins with few nn-hcc patients with high MELD scres t greater than 70% in regins in which there was a greater need fr liver transplant (higher MELD scres) in the nn-hcc ppulatin. The wrkgrup bserved that there is extreme variability f the time t transplantatin f patients with HCC in the cuntry suggesting that management f patients n the waitlist and utcmes may vary. In additin, Cncern has been raised that shrt times t liver transplant may lead t an increase in psttransplant recurrence because the tumr bilgy [aggressiveness] has nt had enugh time t be expressed. The lack f natinal data n recurrence rates limits ne s ability t study this natinal experiment f nature based n the divergent waiting times fr transplantatin fr HCC. There was agreement that the allcatin plicy shuld result in similar risks f remval frm the waiting list and similar transplant rates fr HCC and nn-hcc candidates. In additin, the allcatin plicy shuld select HCC candidates s that there are similar psttransplant utcmes fr HCC and nn-hcc recipients. There was a general cnsensus fr the develpment f a calculated cntinuus HCC pririty scre fr ranking HCC candidates n the list that wuld incrprate the calculated MELD scre, alpha-fetprtein, tumr size, and rate f tumr grwth. Only candidates with at least stage T2 tumrs wuld receive additinal HCC pririty pints. The article discusses pretransplant lcal reginal therapy t allw patients t maintain transplant candidacy, as well as t dwnstage t meet MELD criteria. The wrkgrup n the rle f dwnstaging in transplant candidates with HCC nted incnsistent utcmes reprted in the literature and prpsed a definitin f dwnstaging that wuld include TACE and varius ablative techniques but nt resectin. The grup nted that nly 2 regins have adpted a dwnstaging prtcl. 9

10 Medical Plicy Ya et al reprted n a case series f 30 patients with HCC wh underwent lcreginal therapy specifically t dwnstage tumrs t meet the University f Califrnia San Francisc (UCSF) criteria.(24) Eligibility fr lcreginal therapy seeking t dwnstage patients included either (1) 1 ndule between 5 and 8 cm in diameter; (2) 2 r 3 ndules with at least 1 between 3 and 5 cm in diameter, with a sum f diameters n greater than 8 cm; r (3) 4 r 5 ndules all 3 cm r less, with a sum f diameters less than 8 cm. Amng the 30 patients, 21 (70%) met the criteria fr lcreginal therapy and 16 f these were successfully dwnstaged and underwent transplantatin. N tumrs recurred at a median fllw-up f 16 mnths. The authrs cncluded that dwnstaging can be successfully achieved in mst patients but that data regarding tumr recurrence require lnger fllw-up. Lcreginal Therapies t Reduce Risk f Recurrence in Thse With T3 tumrs An additinal indicatin fr lcreginal therapies fcuses n their use in patients with T3 tumrs, specifically t reduce the incidence f recurrence psttransplant. If the incidence f recurrence can be reduced, then advcates have argued that the UNOS allcatin criteria shuld nt discriminate against patients with larger tumrs.(25-29) Sme patients with T3 lesins apparently are cured with liver transplant, althugh mst experience recurrent tumr. Fr example, in the seminal 1996 study,(15) the 4- year RFS was 92% in thse wh met the Milan criteria cmpared with 59% in thse wh did nt; additinal studies cnfirm this difference in the RFS rate.(24) Hwever, ther institutins have reprted similar utcmes with expanded criteria. Fr example, Ya et al at UCSF reprted similar RFS after transplant in patients with T2 and a subset f thse with T3 tumrs. This T3 subset was defined as a single lesin 6.5 cm r less r 3 r fewer lesins with nne greater than 3 cm and with a sum f tumr diameters 8 cm r less. These expanded criteria are knwn as the UCSF criteria.(27) The questin is whether lcreginal therapies (including bth RFA and chememblizatin) may decrease the recurrence rate in patients meeting the UCSF criteria. Ya et al published a detailed analysis f 121 patients with HCC wh underwent transplantatin.(30) Seventy-eight patients (64%) had T2 lesins, while an additinal 27 patients (22.3%) met the expanded UCSF criteria, termed T3A lesins. The rest had T1, T3B, r T4 lesins. Individual patients received a variety f preperative lcreginal therapies, including TACE r ablative therapies, such as PEI, RFA, r cmbined therapies. A ttal f 38.7% f patients did nt receive preperative lcreginal therapy. The 1- and 5-year RFS rate was similar in thse with T2 and T3A lesins, while the crrespnding RFS rates were significantly lwer fr thse with T3B and T4 lesins. The authrs als cmpared RFS f thse wh did and did nt receive lcreginal therapy. Fr thse with T2 lesins, the recurrence rates were similar whether r nt the patient received lcreginal therapy. Hwever, fr T3 lesins (including bth T3A and T3B), the 5-year RFS was 85.9% fr thse wh received lcreginal therapy cmpared with 51.4% in thse wh did nt. When the data fr T2 and T3 lesins were gruped tgether, the 5-year RFS was 93.8% fr thse wh received lcreginal therapy cmpared with 80.6% in thse wh did nt. The authrs cncluded that preperative lcreginal therapy may cnfer a survival benefit in thse with T2 r T3 lesins. The authrs nte several limitatins t the study, including the retrspective nature f the data and the marginal statistical significance f the imprved survival given the small numbers f patients in each subgrup. Fr example, nly 19 patients were in the T3A (i.e., UCSF expanded criteria) subgrup. In additin, n prtcl specified which type f lcreginal therapy t ffer different patients. These therapies are nly ffered t thse 10

11 Medical Plicy patients with adequate liver reserve; such patients may have an imprved utcme regardless f the preperative management. RFA as a Primary Treatment f Unresectable Liver Metastases frm Clrectal Cancer Mre than half f patients with clrectal cancer (CRC) will develp liver metastases, generally with a pr prgnsis.(31) A median survival f 21 mnths has been bserved in patients with a single CRC liver metastasis; thse with several unilbar lesins have median survival f 15 mnths; and, thse with disseminated metastases have median survival f less than 1 year. A number f first-line systemic chemtherapy regimens have been used t treat metastatic CRC, with a 2-year survival rate f 25% fr thse treated with 5-flururacil (5-FU) r 5-FU plus leucvrin.(31) With the intrductin f newer agents, including irintecan and xaliplatin, and targeted drugs such as cetuximab and bevacizumab, 2- year survival rates have increased t 30% t 39%, with marked imprvement in OS duratin. As the liver is ften the nly site f metastases frm CRC, hwever, lcreginal therapies have been investigated. Surgical resectin is cnsidered the criterin standard fr treatment f CRC liver metastases, with 5-year actuarial survival rates that histrically range frm 28% t 38% but may reach 58% in apprpriately selected, resectable patients withut widely disseminated disease.(32,33) Hwever, nly 10% t 25% f patients with CRC metastases are eligible fr surgical resectin because f the extent and lcatin f the lesins within the liver r because f the presence f cmrbid cnditins r disseminated disease. Unresectable cases r thse fr whm surgery is cntraindicated typically are treated with systemic chemtherapy, with pr results and cnsiderable adverse effects. Alternatively, RFA has been prpsed as an apprach t treat metastatic CRC in the liver. Early clinical experience with RFA cmprised case series t establish feasibility, safety, tlerability, and lcal therapeutic efficacy in shrt-term fllw-up. A 2006 literature review encmpassing 6 case series (N=446) shwed that RFA f unresectable CRC metastases was assciated with 1-, 2-, and 3-year survival rates that ranged frm 87% t 99%, 69% t 77%, and 37% t 58%, respectively.(32) While these results suggest RFA may have clinical benefit in this setting, a primary caveat is the definitin f the term unresectable in the different series and that different surgens may have different pinins n this issue. Further, differences in lesin size, number, distributin, prir treatments, RFA technlgy, and physician experience may affect results, making it difficult t cmpare results f different studies. Systematic Reviews A 2012 systematic review by Circchi et al analyzed 17 nnrandmized studies and 1 abstract n a RCT frm a 2010 American Sciety f Clinical Onclgy meeting n RFA fr CRC liver metastases.(34) The RCT reprted prgressin-free survival was significantly higher in 60 patients receiving RFA plus chemtherapy cmpared with 59 patients receiving nly chemtherapy. The RCT did nt reprt OS. This Cchrane review fund different types f vulnerability in all reviewed studies. Of main cncern was the imbalance f patient characteristics in the studies reviewed, as well as hetergeneity in the interventins, cmparisns, and utcmes. Therefre the authrs cncluded the evidence was insufficient t recmmend RFA fr CRC liver metastasis. In a 2014 Health Technlgy Assessment, Lveman et al als fund insufficient evidence t draw cnclusins n the clinical effectiveness f ablative therapies, including RFA, fr liver metastases.(35) In 2013, Weng et al reprted n a systematic review and meta-analysis t cmpare RFA with liver resectin fr the treatment f CRC liver metastases.(36) One prspective study 11

12 Medical Plicy and 12 retrspective studies were included in the analysis. OS at 3 and 5 years was significantly lnger in liver resectin than RFA (risk rati [RR], 1.377; 95% CI: t 1.522; and RR=1.474; 95% CI: t 1.692, respectively). DFS was als significantly lnger in liver resectin than RFA at 3 and 5 years (RR=1.735; 95% CI: t 2.029; and RR=2.227; 95% CI: t 2.720). While pstperative mrbidity with liver resectin was significantly higher than with RFA (RR=2.495; 95% CI: t 3.308), mrtality was nt significantly different between liver resectin and RFA. Liver resectin als still perfrmed significantly better than RFA when data were analyzed in 3 subgrups: tumrs less than 3 cm, slitary tumr, and pen r laparscpic apprach. Hwever, hspital stays were significantly shrter (9.2±0.6 vs. 3.9±0.4, p<0.01) and rates f cmplicatins lwer (18.3% vs. 3.9%, p<0.01) with RFA ver liver resectin. Interpretatin f the meta-analysis is limited by the retrspective nature f mst studies. A 2011 systematic review by Pathak et al assessed the lng-term utcme and cmplicatin rates f varius ablative therapies used in the management f clrectal liver metastases.(37) The literature search was frm 1994 t 2010, and study inclusin criteria included a minimum 1-year fllw-up and mre than 10 patients. In all, 226 ptentially relevant studies were identified, 75 f which met the inclusin criteria. Mst f the studies were single-arm, single-center, retrspective and prspective. There was wide variability in patient grups, adjuvant therapies, and management appraches within individual studies. Several studies cmbined results fr clrectal and nnclrectal metastases, ften reprting cmbined utcmes. End pints were nt always reprted unifrmly, with varying definitins f survival time, recurrence time, and cmplicatin rates. Crytherapy (26 studies) had lcal recurrence rates f 12% t 39%, with mean 1-, 3-, and 5-year survival rates f 84%, 37%, and 17%, respectively. The majr cmplicatin rate ranged frm 7% t 66%. Micrwave ablatin (13 studies) had a lcal recurrence rate f 5% t 13%, with a mean 1-, 3-, and 5-year survival f 73%, 30%, and 16%, respectively, and a majr cmplicatin rate ranging frm 3% t 16%. RFA (36 studies) had a lcal recurrence rate f 10% t 31%, with a mean 1-, 3-, and 5-year survival f 85%, 36%, and 24%, respectively, with majr cmplicatin rate ranging frm 0% t 33%. The authrs cncluded that ablative therapies ffer significantly imprved survival cmpared with palliative chemtherapy alne with 5-year survival rates f 17% t 24% and that cmplicatin rates f cmmnly used techniques are lw. A review by Guenette and Dupuy in 2010 summarized the literature n the use f RFA fr clrectal hepatic metastases.(38) Apprximately 17 studies in the literature with mre than 50 patients treated with RFA fr clrectal hepatic metastases reprted survival. Average tumr size, reprted in 15 studies ranged frm 2.1 cm t 4.2 cm. Five-year OS, reprted in 12 studies, ranged frm 2% t 55.3% with a mean f 24.5%. The largest study series included in the review was by Lencini et al and cnsisted f 423 patients with average tumr size f 2.7 cm, 4 r fewer metastases, each 5 cm r less in greatest dimensin, and n extrahepatic disease.(33) OS in the Lencini et al study at 1, 3, and 5 years was 86%, 47%, and 24%, respectively. The authrs f the Guenette/Dupuy review cncluded that 5-year survival rates fllwing RFA appear t rival thse fllwing resectin but that lng-term data assciated with RFA and clrectal hepatic metastases are sparse, randmized trials have failed recruitment, and patients with resectable disease shuld underg resectin if pssible. Hwever, given the efficacy f RFA cmpared with chemtherapy alne, RFA shuld be cnsidered as a primary treatment ptin in patients with unresectable disease. 12

13 Medical Plicy Chrt Studies Prspective studies in which RFA was cmpared with resectin r systemic chemtherapy in well-defined cnsecutive chrts f patients with lcalized CRC metastases and n evidence f additinal metastatic disease have been cnducted. In the first study, Abdalla et al examined recurrence and survival rates fr clinically similar patients treated with hepatic resectin nly (n=190), resectin plus RFA (n=101), RFA nly (n=57, pen lapartmy by hepatbiliary surgen), and systemic chemtherapy alne (n=70).(39) In the key relevant cmparisn, RFA versus chemtherapy in chemtherapynaive patients with nn-resectable CRC metastases (median 1 lesin per patient; range, 1-8; median tumr size, 2.5 cm), OS at 4 years was 22% in the RFA grup cmpared with 10% in the chemtherapy grup (p=0.005). Median survival was estimated at 25 mnths in the RFA grup and 17 mnths in the chemtherapy grup (p nt reprted). Recurrence anywhere in the liver at median fllw-up f 21 mnths was 44% in the RFA grup and 11% in the resectin-nly grup (p<0.001), althugh the prprtin f patients with distant recurrence as a cmpnent f failure was similar (41% resectin, 40% RFA, p nt significant). In a secnd trial, a cnsecutive series f well-defined, previusly untreated patients (n=201) withut extrahepatic disease underwent lapartmy t determine therapeutic apprach.(40) Three grups were identified: thse amenable t hepatic resectin (n=117); thse fr whm resectin plus lcal ablatin were indicated (RFA, n=27; cryablatin, n=18); and thse deemed unresectable and unsuitable fr lcal ablatin (n=39) wh received systemic chemtherapy. Median OS was 61 mnths (95% CI: 41 t 81 mnths) in resected patients (median 1 tumr per patient; range, 1-9, median diameter; 3.8 cm), 31 mnths (95% CI: 20 t 42 mnths) in lcally ablated patients (median 4 tumrs per patient; range, 1-19; median diameter, 3 cm per lesin), and 26 mnths (95% CI: 17 t 35 mnths) in the chemtherapy patients (median 4 tumrs per patient; range, 1-17; median diameter, 4 cm per lesin; p=ns, ablated vs. chemtherapy). Results frm 2 validated quality-f-life instruments (EurQl-5D, EORTC QLQ C-30) shwed that patients treated by lcal ablatin returned t baseline values within 3 mnths, whereas thse treated with chemtherapy remained significantly lwer (i.e., wrse quality f life) than baseline ver 12 mnths psttreatment (p<0.05). 2011, van Tilbrg et al reprted lng-term results in 100 patients with unresectable clrectal liver metastases wh underwent a ttal f 126 RFA sessins (237 lesins).(41) Lesin size ranged frm 0.2 t 8.3 cm (mean 2.4 cm). The mean fllw-up time was 29 mnths (range, 6-93 mnths). Majr cmplicatins (including abscess, hemrrhage, grunding pad burns, and diaphragm perfratin) ccurred in 8 patients. Factrs that determined the success f the prcedure included lesin size and the number and lcatin f the lesins. Lcal tumr site recurrence was 5.6% fr tumrs less than 3 cm, 19.5% fr tumrs 3 t 5 cm, and 41.2% fr thse greater than 5 cm. Centrally lcated lesins recurred mre ften than peripheral nes, at 21.4% versus 6.5%, respectively (p=0.009). Mean survival time frm the time f RFA was 56 mnths (95% CI: 45 t 67 mnths). RFA as a Treatment f Unresectable Liver Metastases frm Neurendcrine Tumrs Mst reprts f RF treatment f neurendcrine liver metastases include small numbers f patients r subsets f patients in reprts f mre than 1 ablative methd r very small subsets f larger case series f patients with varius diagnses. Berber and Siperstein analyzed a large series f liver tumrs treated with RFA.(42) Of 1032 tumrs in the study, 295 were neurendcrine tumr metastases. The mean number f lesins treated was 5.6 (range, 1-16) and mean size was 2.3 cm (range, cm). Lcal recurrence rates were lwer in patients with neurendcrine tumrs than in 13

14 Medical Plicy patients with ther tumr types; neurendcrine tumrs (19/295 [6%]), clrectal metastases (161/480 [24%]), nnclrectal, nnneurendcrine metastases (28/126 [22%]), and HCC (23/131 [18%]). In patients with neurendcrine tumrs, 58% f the recurrences were evident at 1 year and 100% at 2 years versus 83% at 1 year and 97% at 2 years fr clrectal metastases. Eight neurendcrine tumrs were eligible fr repeat RFA; 7 were retreated, and 1 was nt. Symptm cntrl and survival were nt reprted in this study. Mazzaglia et al reprt n a series gathered ver 10 years f 63 patients with neurendcrine metastases wh were treated with 80 sessins f LRFA.(43) Tumr types were 36 carcinid, 18 pancreatic islet cell, and 9 medullary thyrid cancer. Indicatins fr enrllment in the study were liver metastases frm neurendcrine tumrs, enlarging liver lesins, wrsening f symptms, and/r failure t respnd t ther treatment mdalities, and predminance f disease in the liver; hwever, patients with additinal minr extrahepatic disease were nt excluded frm the study. RFA was perfrmed 1.6 years (range, years) after diagnsis f liver metastases. Furteen patients had repeat sessins fr disease prgressin. The mean number f lesins treated at the first RFA sessin was 6 and the mean tumr size was 2.3 cm. One week after surgery, 92% f patients had at least partial symptm relief and 70% had cmplete relief. Symptm cntrl lasted 11±2.3 mnths. Median survival times were 11 years pstdiagnsis f primary tumr, 5.5 years pstdiagnsis f neurendcrine hepatic metastases, and 3.9 years pst first RFA treatment. Elias et al reprt n 16 patients wh underwent a 1-step prcedure cmprising a cmbinatin f hepatectmy and RFA fr treatment f gastrenterpancreatic endcrine tumrs.(44) A mean f 15± 9 liver tumrs per patient were surgically remved, and a mean f 12±8 were ablated using RFA. Three-year survival and DFS rates were similar t thse bserved in the authrs preliminary series f 47 patients wh had hepatectmy with a median f 7 liver tumrs per patient. Venkatesan et al reprt n 6 patients treated fr phechrmcytma metastases.(45) Cmplete ablatin was achieved in 6 f 7 metastases. Mean fllw-up was 12.3 mnths (range, mnths). RFA as a Primary Treatment f Unresectable Liver Metastases Frm Tumrs Other Than Clrectal Cancer and Neurendrcrine Tumrs Breast Cancer A number f case series reprt RFA f breast cancer liver metastases. In 2014, Veltri et al analyzed 45 wmen treated with RFA fr 87 breast cancer liver metastases f a mean size f 23 mm.(46) Cmplete ablatin was seen n initial fllw-up in 90% f tumrs, but tumr recurrence ccurred in 19.7% within 8 mnths. RFA did nt impact OS, which at 1 year was 90% and at 3 years was 44%. In a retrspective review, Melni et al assessed lcal cntrl and intermediate- and lngterm survival in 52 patients.(47) Inclusin criteria were fewer than 5 tumrs, maximum tumr diameter f 5 cm r smaller, and disease cnfined t the liver r stable with medical therapy. Cmplete tumr necrsis was achieved in 97% f tumrs. Median time t fllw-up frm diagnsis f liver metastasis and frm RFA was 37.2 and 19.1 mnths, respectively. Lcal tumr prgressin ccurred in 25% f patients, and new intrahepatic metastases develped in 53%. Overall median survival time, frm the time the first liver metastasis was diagnsed, was 42 mnths, and 5-year survival was 32%. Patients with tumrs 2.5 cm in diameter r larger had a wrse prgnsis than thse with smaller tumrs. The authrs cnclude that these survival rates are cmparable with thse reprted in the literature fr surgery r laser ablatin. In anther series f 43 breast cancer patients with 14

15 Medical Plicy 111 liver metastases, technical success was achieved in 107 metastases (96%).(48) During fllw-up, lcal tumr prgressin was bserved in 15 metastases. The estimated verall median survival was 58.6 mnths. Survival was significantly lwer amng patients with extrahepatic disease, with the exceptin f skeletal metastases. A series f 19 patients was reprted by Lawes et al.(49) Eight patients had disease cnfined t the liver, with 11 als having stable extrahepatic disease. At the time f the reprt, 7 patients, with disease cnfined t the liver at presentatin, were alive, as were 6 with extrahepatic disease; median fllw-up after RFA was 15 mnths (range, 0-77 mnths). Survival at 30 mnths was 41.6%. RFA failed t cntrl hepatic disease in 3 patients. Other reprts include few subjects. Authrs reprt that RFA f breast cancer liver metastases is technically feasible and may prvide a survival benefit in wman withut extrahepatic r stable extrahepatic disease (excluding bne metastases). Sarcma Jnes et al evaluated RFA in a series f patients with sarcma.(50) Thirteen gastrintestinal strmal tumr (GIST) patients and 12 with ther histlgical subtypes received RFA fr metastatic disease in the liver: 12 f these respnded t the first RFA prcedure and 1 achieved stable disease. Tw GIST patients received RFA n 2 ccasins t separate lesins within the liver, and bth respnded t the secnd RFA prcedure. Of the ther subtypes: 7 underwent RFA t liver lesins, 5 f these respnded t RFA, 1 prgressed and 1 was nt assessable fr respnse at the time f analysis. RFA was well-tlerated in this series f sarcma patients. RFA may have a rle in patients with GIST wh have prgressin in a single metastasis but stable disease elsewhere. The authrs advise that further larger studies are required t better define the rle f this technique in this patient ppulatin. A case series f 66 patients wh underwent hepatic resectin (n=35), resectin and RFA (n=18), r RFA alne (n=13) was reprted by Pawlik et al.(51) After a median fllw-up f 35.8 mnths, 44 patients had recurrence (intrahepatic nly, n=16; extrahepatic nly, n=11; bth, n=17). The 1-, 3-, and 5-year OS rates were 91.5%, 65.4%, and 27.1%, respectively. The authrs recmmend that patients with metastatic disease wh can be rendered surgically free f disease be cnsidered fr ptential hepatic resectin. Onging and Unpublished Clinical Trials A search f nline site ClinicalTrials.gv n June 20, 2014 identified 7 nging phase 3 and 4 trials n RFA f the liver fr HCC and CRC liver metastases. Summary In radifrequency ablatin (RFA), a prbe that generates heat is inserted int the center f a tumr resulting in a 3- t 5-cm sphere f dead tissue. The cells killed by RFA are nt remved but are gradually replaced by fibrsis and scar tissue. If there is lcal recurrence, it ccurs at the edge, and in sme cases may be retreated. RFA may be perfrmed percutaneusly, laparscpically, r as an pen prcedure. Fr treating patients with unresectable hepatcellular cancer (HCC), numerus studies including randmized trials demnstrate that in patients with small fci f HCC (n mre than 3 lesins), RFA appears t be better than ethanl injectin in achieving cmplete ablatin and preventing lcal recurrence. Three-year survival rates f 80% have been reprted. Thus, the plicy statement ntes that this indicatin fr RFA in patients with HCC wh are nt candidates fr resectin r transplant may be cnsidered medically necessary. 15

16 Medical Plicy A substantial bdy f literature has been published n the use f RFA t treat clrectal cancer (CRC) metastases in the liver. Tw prspective studies cmprise gd evidence that verall survival (OS) fllwing RFA is at least equivalent and likely better than that btained with currently accepted systemic chemtherapy in well-matched patients with unresectable hepatic metastatic CRC wh d nt have extrahepatic disease. Additinal evidence frm 1 cmparative study suggests RFA has a lesser deleterius effect n quality f life than chemtherapy and that RFA patients recver quality f life significantly faster than chemtherapy recipients. Quicker recvery f quality f life may be viewed as a net health benefit when viewed in the cntext f expected survival duratins f patients with metastatic cancer. In additin, results frm a number f uncntrlled case series als suggest RFA f hepatic CRC metastases prduces lngterm survival that is at minimal equivalent and likely superir t histrical utcmes achieved with systemic chemtherapy. Althugh indirect cmparisns f series results are difficult, the bdy f data shws cnsistent change in directin and magnitude f effect that suggests an RFA benefit. It shuld be recgnized, hwever, that patients treated with RFA in different series may have better prgnsis than thse wh underg chemtherapy, suggesting patient selectin bias may at least partially explain the apparent better utcmes bserved fllwing RFA. Given the caveats just utlined, the available bdy f clinical evidence is sufficient t cnclude that RFA f unresectable CRC metastases t the liver, absent extrahepatic metastatic disease, may be cnsidered medically necessary accrding t the Plicy Guidelines nted earlier. Evidence shws that durable tumr and symptm cntrl f neurendcrine liver metastases can be achieved by RFA. This evidence is based n case series; neurendcrine tumrs are uncmmn. Thus, a statement indicating that RFA f hepatic metastases f neurendcrine tumrs may be cnsidered medically necessary in patients whse symptms are nt cntrlled by systemic therapy has been added. Transplant clinicians find the evidence cmpelling that use f lcreginal therapy reduces the drput rate f patients with HCC awaiting a liver transplant. After listing fr transplant, UNOS des nt reassign status based n tumr shrinkage frm lcreginal therapy. A number f appraches are accepted fr use in this situatin, including TACE and RFA. Small case series cnclude that patients managed n the transplant list with lcreginal therapy have utcmes cmparable with patients wh d nt receive pretransplant treatment. Hwever, earlier liver transplant fr HCC patients may reduce the need fr RFA in this situatin. Thus, given the strng clinical supprt, UNOS psitin, and clinical studies, the plicy statement has been changed t indicate that RFA may be cnsidered medically necessary as a bridge t liver transplant. Currently, there is less evidence available fr patients treated with RFA t specifically dwnsize (dwnstage) tumrs (tumrs f stage >T2) t meet pririty transplant criteria, and its use fr this applicatin is cnsidered investigatinal. The published evidence fr demnstrating imprved health utcmes with RFA f ther hepatic metastatic tumrs (e.g., breast cancer and sarcma) is lacking. Cmparative trials are needed fr these malignancies that may have assciated systemic disease. Use f RFA in these tumrs is cnsidered investigatinal under this plicy; the data are insufficient t change this plicy statement. Practice Guidelines and Psitin Statements The Sciety f Interventinal Radilgy published a psitin statement n percutaneus radifrequency ablatin fr the treatment f liver tumrs in 2009.(52) It is the psitin f the Sciety that percutaneus RF ablatin f hepatic tumrs is a safe and effective treatment fr selected patients with HCC and clrectal carcinma metastases and 16