Cryosurgical Ablation of Primary or Metastatic Liver Tumors. Next Review Date February 2016

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1 Descriptin Medical Plicy Crysurgical Ablatin f Primary r Metastatic Liver Tumrs Sectin 7.0 Surgery Subsectin Effective Date February 27, 2015 Original Plicy Date February 27, 2015 Next Review Date February 2016 Crysurgical ablatin invlves the freezing f target tissues, mst ften by inserting int the tumr a prbe thrugh which clant is circulated. Crysurgical ablatin can be perfrmed as an pen surgical technique r percutaneusly r laparscpically, typically with ultrasund guidance. Related Plicies Liver Transplant Micrwave Tumr Ablatin Radiemblizatin fr Primary and Metastatic Tumrs f the Liver Radifrequency Ablatin f Miscellaneus Slid Tumrs Excluding Liver Tumrs Radifrequency Ablatin f Primary f Metastatic Liver Tumrs Transcatheter Arterial Chememblizatin (TACE) t Treat Primary r Metastatic Liver Malignancies Plicy Crysurgical ablatin may be cnsidered medically necessary fr the treatment f patients with hepatic lesins with any f the fllwing cnditins: Primary hepatcellular carcinma (HCC) when the all f the fllwing criteria are met: Patient is nt a candidate fr curative hepatic surgical resectins due t limited hepatic reserve and/r cmrbid cnditins and/r the lcatin (e.g., adjacent t a majr vein) r number f lesins 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 in diameter using current technlgy Absence f extrahepatic metastatic disease All tumr fci can be adequately treated (cmplete ablatin determined by preperative imaging) 1

2 Medical Plicy Primary HCC, as a bridge t transplantatin*, when all f the fllwing criteria are met: Patient is nt a candidate fr curative hepatic surgical resectins due t limited hepatic reserve and/r cmrbid cnditins and/r the lcatin (e.g., adjacent t a majr vein) r number f lesins 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 in diameter using current technlgy N evidence f extrahepatic spread and/r macrvascular invlvement (i.e., prtal r hepatic veins) 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 hepatic surgical resectins due t limited hepatic reserve and/r cmrbid cnditins and/r the lcatin (e.g., adjacent t a majr vein) r number f lesins Presence f fur t five r fewer hepatic lesins Each lesin measures 5 centimeters (cm) r less in diameter using current technlgy Absence f extrahepatic metastatic disease All tumr fci can be adequately treated (cmplete ablatin determined by preperative imaging) 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 hepatic surgical resectins due t limited hepatic reserve and/r cmrbid cnditins and/r the lcatin (e.g., adjacent t a majr vein) r number f lesins Absence f extrahepatic metastatic disease Each lesin measures 5 centimeters (cm) r less in diameter using current technlgy Crysurgical ablatin fr primary 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 hepatic lesins ndules 2

3 Medical Plicy 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 r neurendcrine cancer tumrs Plicy Guidelines Dwnstaging (dwnsizing) therapy is used t reduce the tumr burden in selected patients with mre advanced HCC (withut distant metastasis) that are beynd the accepted transplant criteria. 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 crysurgical ablatin specific t liver tumrs: 47371: Laparscpy, surgical, ablatin f 1 r mre liver tumr(s); crysurgical 47381: Ablatin, pen, 1 r mre liver tumr(s); crysurgical 47383: Ablatin, 1 r mre liver tumr(s), percutaneus, cryablatin (new cde 01/01/15) 3

4 Medical Plicy CPT cde wuld be used t describe the ultrasund guidance fr, and mnitring f, parenchymal tissue ablatin. 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 r by metastasis t the liver frm ther tissues. Lcal therapy fr hepatic metastasis is indicated nly 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 tumr-free margins r liver transplantatin represent the nly treatments with curative ptential. Fr liver metastases frm clrectal cancer, pstsurgical adjuvant chemtherapy has been reprted t decrease recurrence rates and prlng time t recurrence. Hwever, mst hepatic tumrs are unresectable at diagnsis, due either t their anatmic lcatin, size, number f lesins, r underlying liver reserve. Cmbined systemic and hepatic arterial chemtherapy may increase disease-free intervals fr patients with hepatic metastases frm clrectal cancer but apparently is nt beneficial fr thse with unresectable hepatcellular carcinma. Varius lcreginal therapies fr unresectable liver tumrs are being studied: crysurgical ablatin (crysurgery), radifrequency ablatin, laser ablatin, transhepatic artery emblizatin/ chememblizatin, micrwave cagulatin, and percutaneus ethanl injectin. Ablatin ccurs in tissue that has been frzen by at least 3 mechanisms: (1) frmatin f ice crystals within cells, thereby disrupting membranes and interrupting cellular metablism amng ther prcesses; (2) cagulatin f bld, thereby interrupting bld flw t the tissue, in turn causing ischemia and cell death; and (3) inductin f apptsis (cell death). Recent studies reprt experience with crysurgical and ther ablative methds used in cmbinatin with subttal resectin and/r prcedures such as transarterial chememblizatin. Primary Hepatcellular Carcinma Primary hepatcellular carcinma (HCC) cmmnly ccurs in the cntext f chrnic liver disease and cirrhsis and is ften diagnsed in its later stages. In 2006, Brwn et al reprted that althugh patients with lcalized HCC are best managed with cmplete surgical resectin, less than 20% are viable candidates because f the extent r lcatin f the lesins, cmrbid cnditins, r disseminated disease. 1 The Natinal Cmprehensive 4

5 Medical Plicy Cancer Netwrk (NCCN) Guidelines fr HCC stated, All HCC patients shuld be evaluated fr ptential curative therapies (resectin, transplantatin)." 2 Lcreginal therapies are recmmended when there is n extrahepatic disease and prgressin is limited, but cure is less likely. The NCCN des nt discriminate amng the ablative therapies in the treatment f HCC. They prpse ablatin fr hepatic lesins less than r equal t 3 centimeters (cm) in size. The NCCN additinally stated unresectable r inperable lesins greater than 5 cm shuld be cnsidered fr treatment using arterial emblic appraches r systemic therapy. The NCCN principles f lcreginal therapy are as fllws: Fr ablatin (radifrequency (RFA), cryablatin (crysurgical ablatin, CSA), percutaneus ethanl r alchl injectin (PEI r PAI), and micrwave ablatin (MWA) : All tumrs shuld be amenable t ablatin such that the tumr and margin f nrmal tissue is treated. Tumrs shuld be in a lcatin accessible fr percutaneus/laparscpic/pen appraches fr ablatin Tumrs less than 3 cm are ptimally treated with ablatin. Lesins between 3 and 5 cm may be treated using a cmbinatin f emblizatin and ablatin as lng as the tumr lcatin is favrable. Unresectable r inperable lesins greater than 5 cm shuld be cnsidered fr treatment using arterial emblic appraches r systemic therapy. Cautin shuld be exercised when ablating lesins near majr vessels, majr bile ducts, diaphragm, and ther intra-abdminal rgans. The Natinal Cancer Institute's (NCI) Physician Data Query (PDQ) regarding adult primary liver cancer treatment listed PEI, CSA, RFA, and chememblizatin as standard treatment alternatives fr patients with unresectable primary HCC tumrs under 5 cm in diameter. 3 Identified cntraindicatins t emblizatin (with r withut chemtherapy) include prtal hypertensin, prtal vein thrmbsis, and clinical jaundice. New medical appraches are being researched in clinical trials including, but nt limited t, targeted therapy after chememblizatin r cmbined with chemtherapy, and cmbinatin therapy with surgery, chemtherapy, and radiatin therapy. Neurendcrine Cancer Liver Metastases Neurendcrine tumrs are relatively slw-grwing malignancies (mean survival times, 5-10 years) that cmmnly metastasize t the liver. As with ther cancers, the mst successful treatment f hepatic metastasis is resectin with tumr-free margins, but treatment benefits fr a slw-grwing tumr must be weighed against the mrbidity and mrtality f majr surgery. 4 The intent f crysurgery in these cases is t minimize r eliminate symptms caused by liver metastases while aviding the cmplicatins f pen surgery. Hepatic tumrs may als ccur as metastasis frm ther sites. Mre than half f patients with clrectal cancer (CRC) will develp liver metastases, either at the time f initial presentatin r as a result f disease recurrence, and generally with a pr prgnsis. 5 Fr ne-third, the liver is the nly site f metastases. Like primary HCC, surgical resectin is cnsidered the gld standard fr treatment f metastatic CRC in the absence f extrahepatic metastases. 5,6 Hwever, nly 10% t 25% f patients with CRC metastases are eligible fr surgical resectin due t the extent and lcatin f the lesins within the liver r because f the presence f cmrbid cnditins r disseminate disease. Unresectable cases r thse fr whm surgery is cntraindicated typically are treated 5

6 Medical Plicy with systemic chemtherapy, with pr results and cnsiderable adverse effects. 7 The NCCN Clinical Practice Guidelines fr Cln Cancer and Rectal Cancers indicated ablative techniques may be cnsidered either "alne r in cnjunctin with resectin" fr the treatment f CRC metastasis and the best utcmes are achieved with small single lesins. 8 Additinally; all riginal sites f the disease need t be amenable t ablatin. Similarly, the NCI recmmended lcal ablative techniques such as RFA and CSA fr CRC patients wh are nt viable surgical candidates. 3 Neurendcrine tumrs are tumrs f cells that pssess secretry granules and riginate frm the neurectderm. The varius types f neurendcrine tumrs include carcinid, islet cell, medullary thyrid carcinmas, phechrmcytmas, and neurendcrine carcinmas f the skin. 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 tw t fur per 100,000 persns per year and presentatin with metastatic disease accunts fr 12% t 22%. 9 The liver is als a cmmn site f metastases frm neurendcrine cancers. Treatment f liver metastases is undertaken t prlng survival and reduce endcrine-related symptms, as well as symptms related t the hepatic mass. The NCCN Guidelines and NCI PDQ fr neurendcrine tumrs advised the management f unresectable liver metastases may include, hepatic reginal therapy (arterial emblizatin, chememblizatin, radiemblizatin), r ablative therapies such as RFA, crytherapy, r MWA. 10,11 Fr pancreatic islet cell tumrs, the NCI PDQ database stated patients with hepatic-dminant disease and intractable symptms due t tumr bulk r aberrant hrmne release "may benefit frm prcedures that reduce hepatic arterial bld flw t metastases (hepatic arterial cclusin with emblizatin r with chememblizatin)." 11 Fr select patients, lcreginal treatment in cmbinatin with chemtherapy may be apprpriate. The NCI PDQ fr cular melanma, als called uveal melanma, is the secnd mst cmmn frm f melanma; striking abut 2,000 adults in the United States (U.S.) each year. 12 It is the mst cmmn primary eye cular malignancy in adults and shws a strng predilectin fr liver metastases. Even with successful treatment f the primary tumr, up t 50% f patients will subsequently develp systemic metastases, with liver invlvement in up t 90% f these patients, which is universally fatal. Metastatic uveal melanma is resistant t systemic chemtherapy, leading t the evaluatin f lcreginal treatment mdalities t cntrl tumr prgressin in the liver, including TACE. It can affect patients at any age but is mst cmmn in patients ver 50. There were n NCCN Clinical Practice Guidelines identified fr cular melanma. The NCI PDQ database made n specific recmmendatins regarding lcreginal therapies in the treatment f hepatic metastases frm intracular melanma. 12 Liver Metastases frm ther Cancers Including Clrectal Cancer Ablative therapy as a primary treatment f metastatic tumrs in the liver ther than CRC and neurendcrine tumrs has als been investigated. Hwever, evidence is absent r limited t small case series and retrspective reviews. Breast Cancer A number f case series reprted n RFA f breast cancer liver metastases. A series f 19 patients was described by Lawes et al. 13 Eight patients had disease cnfined t the liver, with 11 als having stable extrahepatic disease. At the time f the reprt, seven patients 6

7 Medical Plicy with disease cnfined t the liver at presentatin, were alive, as were six with extrahepatic disease; median fllw-up after RFA was 15 mnths (range: 0 t 77 mnths). Survival at 30 mnths was 41.6%. Radifrequency ablatin failed t cntrl hepatic disease in three patients. A case series f 66 patients with breast cancer liver metastases wh underwent hepatic resectin (n = 35), resectin and RFA (n = 18), r RFA alne (n = 13) was reprted by Pawlik et al. 14 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 ne-, three-, and five-year verall survival rates were 91.5%, 65.4%, and 27.1%, respectively. The authrs recmmended patients with metastatic disease wh can be rendered surgically free f disease be cnsidered fr ptential hepatic resectin. In a retrspective review, Melni et al assessed lcal cntrl as well as intermediate- and lng-term survival in 52 patients. 15 Inclusin criteria were fewer than five 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 five-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 cncluded these survival rates were cmparable t thse reprted in the literature fr surgery r laser ablatin. In anther series f 43 breast cancer patients with 111 liver metastases, Jakbs et al reprted that technical success was achieved in 107 metastases (96%). 16 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. While many f the authrs reprted RFA f breast cancer liver metastases was technically feasible and may prvide a survival benefit in wman withut extrahepatic r stable extrahepatic disease (excluding bne metastases); there are nt clinical practice guidelines r psitin statements frm U.S. prfessinal assciatins recmmending RFA fr breast cancer liver metastases. Sarcma Jnes et al evaluated RFA in a series f patients with sarcma. 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 ne achieved stable disease. 17 Tw GIST patients received RFA n tw ccasins t separate lesins within the liver and bth respnded t the secnd RFA prcedure. Of the ther subtypes; seven underwent RFA t liver lesins, five f these respnded t RFA, ne prgressed, and ne was nt assessable fr respnse at the time f analysis. Radifrequency ablatin was well-tlerated in this series f sarcma patients and may have a rle in patients with GIST wh have prgressin in a single metastasis but stable disease elsewhere. The authrs advised larger studies were required t better define the rle f this technique in this patient ppulatin. Other Tumrs Other retrspective studies and case series perfrming ablative therapy fr hepatic metastases frm ther primary tumr sites have been published by Martin et al and Lrentzen et al; hwever, the studies nly reprt the feasibility f the prcedures and prpse imprved prgressin-free survival. 18,19 Additinally, studies were small, and 7

8 Medical Plicy selectin criteria were nt identified r unifrmly adpted. Several authrs advised larger prspective trials were needed t cnfirm results. Gervais et al reprted that the Sciety f Interventinal Radilgy published a psitin statement n percutaneus RFA fr the treatment f liver tumrs in 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 the current literature was insufficient t supprt any recmmendatins supprting r refuting the use f RFA in ther diseases. The published evidence fr demnstrating imprved health utcmes with ablative therapies f ther hepatic metastatic tumrs is lacking. Cmparative trials are needed fr these malignancies that may have assciated systemic disease. While lcreginal ablative therapy is included in the NCCN Guidelines fr CRC and neurendcrine tumrs, ablative therapy is nt recmmended fr all ther metastatic tumrs t the liver. Lcreginal Ablative Therapies There is research available fr each f the ablative therapies. Hwever, many f the studies cmbine multiple ablative prcedures r utilize ablative techniques as an adjunct t surgical resectin r chemtherapy. Studies als include patients with a brad range f tumr size and etilgy. As a result, it is smetimes difficult t draw specific cnclusins regarding the efficacy f an ablative technique. Careful selectin f candidates fr each treatment ptin and expert applicatin f these treatments are required t achieve best utcmes. Crysurgical Ablatin Crysurgical ablatin, als knwn as cryablatin, invlves the destructin f targeted abnrmal tissue thrugh freezing. The prcedure is typically perfrmed by inserting a cryprbe int the tumr thrugh which clant is circulated. The freezing prcess is mnitred t limit damage t surrunding healthy liver tissue. Crysurgical ablatin is usually perfrmed as an pen surgical technique, but may als be percutaneus r laparscpic with imaging guidance. Crysurgical ablatin may be a stand-alne interventin r perfrmed in cnjunctin with surgical resectin r in cmbinatin with ther ablative techniques. Ptential advantages f CSA include lcal cntrl f tumr prgressin and preservatin f parenchymal tissue. In 1999, Seifert & Mris reprted that ptential cmplicatins include hypthermic damage t surrunding nrmal tissue, structural damage alng the prbe track and secndary tumrs frm seeding during prbe remval. 21 Seifert et al reprted n a series f patients with clrectal liver metastases treated frm 1996 t In this series, 168 patients underwent resectin and 55 had CSA (in 25 f these patients it was cmbined with resectin). Twenty-nine percent f the ablatin grup had prir liver resectin cmpared with nly 5% in the resectin grup. Twenty percent f bth grups had extrahepatic disease at the time f surgery. With a median fllw-up f 23 mnths, median and five-year survival rates fllwing resectin and CSA were cmparable at 29 mnths; 23% and 26%, respectively. While median disease-free survival times and five-year disease-free survival rates fllwing resectin were superir fr resectin (10 mnths and 19%) cmpared t CSA (six mnths and 12%), 29% f the patients in the CSA grup had undergne prir resectin, suggesting mre advanced disease. Jsten et al evaluated the efficacy f CSA and RFA in a mixed grup f resected and unresected patients. 23 There was n significant difference in survival between patients treated with CSA r RFA alne versus thse treated by lcal ablatin cmbined with 8

9 Medical Plicy resectin (p =0.55). Overall cmplicatin rates were higher fr the CSA grup (30%) than fr the RFA grup (11%). It was cncluded that CSA and RFA can be used either alne r as an adjunct t resectin in patients with unresectable clrectal liver metastases. The authrs nted additinal cmparative study in randmized trials were indicated. Ruers et al reprted n a cnsecutive series f 201 CRC patients, withut extrahepatic disease, treated between 1995 and 2004 that underwent lapartmy fr surgical treatment f liver metastases. 24 These patients were prspectively fllwed up fr survival and quality f life. At lapartmy, three grups were identified: patients in whm radical resectin f metastases prved feasible, patients in whm resectin was nt feasible wh received lcal ablative therapy (CSA r RFA), and patients in whm resectin r lcal ablatin was nt feasible fr technical reasns wh received systemic chemtherapy. The study reprted patients in the chemtherapy and lcal ablatin grups were cmparable fr all prgnstic variables tested. Fr the RFA and CSA grup, verall survival at tw and five years was 56% and 27%, respectively (median 31 mnths, n = 45), fr the chemtherapy grup 51% and 15%, respectively (median 26 mnths, n = 39) (p = 0.252). The median disease-free survival after lcal ablatin was nine mnths. The authrs cncluded althugh verall survival f lcal ablatin versus chemtherapy did nt reach statistical significance, the median disease-free survival f nine mnths suggested a beneficial effect f lcal tumr ablatin. Crysurgical ablatin is included as ne f the ablative techniques in the treatment f hepatic tumrs by the NCCN guidelines; althugh, the literature cited in the guideline reprted predminantly n RFA and PEI. The majrity f literature regarding CSA cnsists f uncntrlled case series that did nt reprt survival data, r papers describing technical aspects f this technique. Based n the literature, RFA appears t be the mst cmmn ablatin technique used in the United States; hwever, the chice f ablative technique is mst ften based n individual clinician and the institutin's experience and preference. The evidence indicates lcally ablative techniques, including CSA, are a viable treatment ptin when resectin is nt feasible, r in sme cases, as an adjunct t resectin. In additin, ablative prcedures such as CSA may ffer a survival benefit ver chemtherapy. Unresectable Hepatcellular Carcinma Tumrs in the Transplant Setting As nted earlier, liver transplantatin is the nly curative alternative fr unresectable HCC. Lcreginal therapies (e.g., ablatin, TACE) have been explred in varius settings including as a technique t prevent tumr prgressin in patients n the liver transplant waiting list, dwnstaging tumrs such that the patient will be cnsidered a better candidate fr liver transplantatin, and decreasing the incidence f pst-transplant recurrence in patients with larger (T3) tumrs. All f these indicatins are in part related t the United Netwrk fr Organ Sharing (UNOS) liver allcatin plicy, which priritizes patients fr receiving dnr livers. 25 The UNOS plicy recgnized pretransplant lcreginal therapies including chememblizatin f lesin, radifrequency, cry, r chemical ablatin f the lesin, as a cmpnent f patient management during the waiting perid. In 2002, UNOS intrduced a new liver allcatin system, mdel fr endstage liver disease (referred t as MELD) fr adult patients awaiting liver transplant. 26 The MELD scre is a cntinuus disease severity scale incrprating bilirubin, prthrmbin time (i.e., internatinal nrmalized rati [INR]), and creatinine int an equatin, prducing a number that ranges frm 6 (less ill) t 40 (gravely ill). Aside frm thse in fulminant liver failure, dnr livers are priritized t thse with the highest MELD number. This scale 9

10 Medical Plicy accurately predicts the risk f dying frm liver disease except fr thse with HCC, wh ften have lw MELD scres since bilirubin, INR, and creatinine levels are near nrmal. Therefre, patients with HCC are assigned additinal allcatin pints accrding t the size and number (T stage) f tumr ndules as fllws: T1: One ndule, 1.9 cm r smaller T2: One ndule between 2.0 t 5.0 cm, r tw r three ndules each smaller than 3.0 cm T3: One ndule larger than 5.0 cm, r tw r three ndules with at least ne larger than 3.0 cm 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 were cnsidered at lw risk f death n the waiting list, while thse with T3 lesins are at high risk f pst-transplant recurrence, and are generally nt cnsidered transplant candidates. Patients with T2 tumrs have an increased risk f dying while n the waiting list cmpared t thse with T1 lesins and an acceptable risk f pst-transplant 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 three mnths. This definitin f T2 lesins is ften referred t as the Milan criteria, in reference t a key study reprted by Mazzaferr et al that examined the recurrence rate f HCC accrding t the size f the initial tumr. 27 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 awaiting transplantatin are reassessed at three-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 strng incentives t use lcreginal therapies t dwnsize tumrs t T2 status and t prevent prgressin while n the waiting list. Prmfet et al reprt f a natinal cnference n liver allcatin in patients with HCC in the U.S. addressed the need t better characterize the lng-term utcmes f liver transplantatin fr patients with HCC and t assess whether it is justified t cntinue the plicy f assigning increased pririty fr candidates with early stage HCC n the transplant waiting list in the U.S.. 28 At the cmpletin f the meeting, 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, alphafetprtein, tumr size, and rate f tumr grwth and that nly candidates with at least stage T2 tumrs wuld receive additinal HCC pririty pints. Lcreginal Therapies as a Bridge t Transplant Several 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 discussed abve, UNOS revised its liver allcatin plicy, such that wait times fr patients with HCC meeting the Milan criteria have nw declined. 26 The majrity f the literature has fcused either n TACE r a variety f lcreginal therapies. Given these limitatins the fllwing case series have been reprted: Graziadei et al reprted n 48 patients with HCC awaiting transplantatin; all underwent TACE every six t eight weeks until a cmplete respnse r a dnr rgan became available. 29 N patients were remved frm the list due t tumr prgressin and mean waiting time was 178 (+/- 105) days. Maddala et al studied the drput rates f 54 patients receiving TACE while awaiting transplantatin. 30 During a median waiting time f 211 days (range: 28 t 1,099 days), the drput rate was 15%. Obed et al reprted n 20 10

11 Medical Plicy patients with nn-prgressin f lesins after TACE wh had liver transplantatin; median survival in this grup was 92.3 mnths. 31 Fisher et al reprted n 33 patients wh received multimdality ablatin therapy, cnsisting primarily f RFA r TACE. 32 Five patients (12%) were remved frm the waiting list after waits f five t 14 mnths. 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 ne and three years was 6.25 and 23%, respectively. 33 Tumrs larger than 3 cm affected the drput rate due t tumr prgressin. 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. 34 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. 35 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. 36 They cncluded RFA can induce cmplete necrsis in the majrity f small tumrs (<2.5 cm) and there was n data demnstrating that the treatment reduced the rate f drp ut befre transplantatin r imprved 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. 37 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 verall survival (84 versus 91%), disease-free survival (74% versus 85%), cancer recurrence (23% versus 12%), r mrtality frm cancer recurrence (57% versus 25% - all respectively) (p > 0.1). The authrs cncluded viable tumr frequently persisted after pretransplant lcreginal therapy and neadjuvant treatment did nt appear t imprve pst- transplant utcmes in the current MELD era. The UNOS plicy n allcatin f livers indicated candidates whse tumrs have been ablated after meeting the criteria fr additinal MELD/PELD (PELD- calculatr fr persns under age 12 years) pints will cntinue t receive additinal pints (equivalent t a 10% increase in mrtality) every three mnths withut review, even if the estimated size f residual viable tumr falls belw stage T2 criteria. 38 The plicy als nted candidates may be remved frm the listing if they are determined t be unsuitable fr transplantatin based n prgressin f HCC. Lcreginal Therapies t Dwnstage HCC Prir t 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 Eligibility criteria fr dwnstaging included: 1) ne lesin larger than 5 cm and up t 8 cm; 2) tw t three lesins with at least ne lesin larger than 3 cm and nt exceeding 5 cm, with ttal tumr diameter up t 8 cm; r 3) fur t five lesins with nne larger than 3 cm, with ttal tumr diameter up t 8 cm. Transcatheter arterial chemablatin 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 nine received TACE and percutaneus RFA. A minimum bservatin perid f three mnths after dwnstaging was required befre liver transplant. 11

12 Medical Plicy Tumr dwnstaging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) received liver transplant, including tw 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, and five exceeded T2 criteria. The Kaplan-Meier intentin-t-treat survival analysis at ne and fur years after dwnstaging was 87.5% and 69.3%, respectively. The ne-year and fur-year pst- transplantatin survival rates were 96.2% and 92.1%, respectively. N patient had HCC recurrence after a median pst-transplantatin fllwup f 25 mnths. The nly factr predicting treatment failure was pretreatment alphafetprtein greater than 1,000 ng/ml. Frm this small series, the authrs cncluded successful dwnstaging can be achieved with excellent pst-transplant utcmes. Lewandwski et al cmpared radiemblizatin with chememblizatin (TACE) in the efficacy f dwnstaging 86 patients with HCC frm stage T3 t T2. 40 Patients were treated with either 90-yttrium micrspheres (n = 43) r TACE (n = 43). Median tumr size was similar between the tw treatment grups (5.7 and 5.6 cm, fr TACE versus radiemblizatin, respectively). Partial respnse rates were 61% versus 37% fr radiemblizatin versus TACE, respectively with dwnstaging frm T3 t T2 in 58% f patients treated with radiemblizatin versus 31% with TACE (p < 0.05). As part f a natinal cnference invlving transplant physicians, wrkgrups were frmed t discuss the plicy f assigning increased pririty fr candidates with stage T2 HCC n the transplant list in the U.S. The wrkgrup assigned t 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. Prmfet et al nted that nly tw regins have adpted a dwnstaging prtcl. 28 The results and efficacy f dwnstaging with TACE t achieve a reductin in tumr burden t a T2 lesin remain cntrversial. There are retrspective data shwing the ability t dwnstage patients with TACE, hwever, there is n randmized evidence that tumr dwnstaging prir t liver transplant cnfers a survival advantage Lcreginal Therapies t Reduce Risk f Recurrence f T3 Tumrs Published literature by Pmfret et al reflects an nging discussin as t whether the UNOS allcatin criteria shuld expand t include patients with larger tumrs. 28 An additinal indicatin fr lcreginal therapies fcused n their use in patients with T3 tumrs, specifically t reduce the incidence f recurrence pst-transplant. If the incidence f recurrence can be reduced, then Ya et al, Ya et al, Fernandez et al, Merli et al, and Sauer et al reprted that advcates have argued the UNOS allcatin criteria shuld nt discriminate against patients with larger tumrs 41,42,43,44,45 Sme patients with T3 lesins apparently are cured with liver transplant, althugh mst experience recurrent tumr. Fr example, in the seminal 1996 study by Mazzaferr et al, the fur-year recurrence-free survival was 92% in thse wh met the Milan criteria (T2 lesin) cmpared t 59% in thse wh did nt; Sauer et al reprted additinal studies cnfirmed this difference in recurrence-free survival rate. 27,45 Hwever, ther institutins have reprted similar utcmes with expanded criteria. Fr example, Ya and clleagues at University f Califrnia at San Francisc (UCSF) reprted similar recurrence-free survival 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 < three lesins with nne greater than 3 cm and with a sum f tumr diameters <8 cm. These expanded criteria are knwn as the UCSF criteria reprted by Ya et al. 42 The questin is whether lcreginal therapies (including bth RFA and TACE) may 12

13 Medical Plicy decrease the recurrence rate in patients meeting the UCSF criteria. Ya and clleagues published a detailed analysis f 121 patients with HCC wh underwent transplantatin. 46 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 ne- and five-year recurrence-free survival was similar in thse with T2 and T3A lesins, while the crrespnding recurrence-free rates were significantly lwer fr thse with T3B and T4 lesins. The authrs als cmpared recurrence-free survival 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 five-year recurrence-free survival was 85.9% fr thse wh received lcreginal therapy cmpared t 51.4% in thse wh did nt. When the data fr T2 and T3 lesins were gruped tgether, the five-year recurrence-free survival was 93.8% fr thse wh received lcreginal therapy cmpared t 80.6% in thse wh did nt. The authrs cncluded preperative lcreginal therapy may cnfer a survival benefit in thse with T2 r T3 lesins. The authrs nted 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 patients with adequate liver reserve; such patients may have an imprved utcme regardless f the preperative management. Summary In cnclusin, althugh cmparisns amng the varius lcreginal therapies are difficult due t factrs such as interstudy patient and treatment hetergeneity, differences in patient management prtcls and multimdality treatment prtcls, the bdy f data illustrates the likely verall benefit f certain lcreginal therapies fr specific patient ppulatins. U.S. Preventive Services Task Frce Recmmendatins The U.S. Preventive Services Task Frce has nt addressed cryablatin f liver tumrs. Medicare Natinal Cverage There is n natinal cverage determinatin (NCD). In the absence f an NCD, cverage decisins are left t the discretin f lcal Medicare carriers. References 1. Brwn DB, Geschwing J-FH, Sulen MC et al. Sciety f Interventinal Radilgy Psitin Statement n Chememblizatin f Hepatic Malignancies. J Vasc Interv Radil. 2006; 17: Natinal Cmprehesive Cancer Netwrk (NCCN) Guidelines. Hepatbiliary Cancers: Hepatcellular Carcinma (HCC) (Versin ). Retrieved n February 11, 2015 frm 3. Natinal Cancer Institute. Adult Primary Liver Cancer Treatment (PDQ ). Health Prfessinal Versin. Updated 2011, Oct 31. Retrieved n February 11, 2015 frm 4. Xu KC, Niu LZ, Zhu Q, et al. Sequential use f transarterial chememblizatin 13

14 Medical Plicy and percutaneus crysurgery fr hepatcellular carcinma. Wrld J Gastrenterl. 2009;15(29): Kemeny N. Management f liver metastases frm clrectal cancer. Onclgy (Willistn Park) Sep; 20(10): , 1179; discussin , Lencini R, Crcetti L, Cini D et al. Percutaneus radifrequency ablatin f hepatic clrectal metastases: Technique, indicatins, results, and new prmises. Invest Radil. 2005; 39(11): McKay A, Dixn E, Taylr M. Current rle f radifrequency ablatin fr the treatment f clrectal liver metastases. Br J Surg. 2006; 93(10): Natinal Cmprehensive Cancer Netwrk (NCCN) Guidelines. Cln Cancer (Versin ). Retrieved n February 11, 2015 frm 9. Taal BG, Visser O. Epidemilgy f neurendcrine tumurs. Neurendcrinlgy. 2004; 80 Suppl 1: Natinal Cmprehensive Cancer Netwrk (NCCN) Guidelines. Neurendcrine Tumrs (Versin ). Retrieved n February 11, 2015 frm Natinal Cancer Institute. Pancreatic Neurendcrine Tumrs (Islet Cell Tumrs) Treatment (PDQ ). Health Prfessinal Versin. Updated 2011, Nv 11. Retrieved n February 11, 2015 frm Natinal Cancer Institute. Intracular (Eye) Melanma Treatment (PDQ ). Health Prfessinal Versin. Updated 2007, Dec 5. Retrieved Retrieved n February 11, 2015 frm althprfessi nal. 13. Lawes D, Chpada A, Gillams A et al. Radifrequency ablatin (RFA) as a cytreductive strategy fr hepatic metastasis frm breast cancer. Ann R Cll Surg Engl. 2006;88(7): Pawlik TM, Vauthey JN, Abdalla EK et al. Results f a single-center experience with resectin and ablatin fr sarcma metastatic t the liver. Arch Surg. 2006; 141(6): Melni MF, Andrean A, Laeseke PF et al. Breast cancer liver metastases: USguided percutaneus radifrequency ablatin intermediate and lng-term survival rates. Radilgy. 2009; 253(3): Jakbs TF, Hffmann RT, Schrader A et al. CT-guided radifrequency ablatin in patients with hepatic metastases frm breast cancer. Cardivasc Intervent Radil. 2009;32(1): Jnes RL, McCall J, Adam A et al. Radifrequency ablatin is a feasible therapeutic ptin in the multi mdality management f sarcma. Eur J Surg Oncl. 2010; 36(5): Martin RC, Scggins CR, McMasters KM. Safety and efficacy f micrwave ablatin f hepatic tumrs: A prspective review f a 5-year experience. Ann Surg Oncl. 2010;17(1): Lrentzen T, Skjldbye BO, Nlse CP. Micrwave ablatin f liver metastases guided by cntrast-enhanced ultrasund: Experience with 125 metastases in 39 patients. Ultraschall Med. 2011; 32(5): Gervais DA, Gldberg SN, Brwn DB et al. Sciety f Interventinal Radilgy psitin statement n percutaneus radifrequency ablatin fr the treatment f liver tumrs. J Vasc Interv Radil. 2009; 20(7 Suppl):S342-S

15 Medical Plicy 21. Seifert JK, Mris DL. Wrld survey n the cmplicatins f hepatic and prstate crytherapy. Wrld J Surg. 1999; 23(2): Seifert JK, Springer A, Baier P et al. Liver resectin r crytherapy fr clrectal liver metastases: A prspective case cntrl study. Int J Clrectal Dis. 2005; 20(6): Jsten J, Jager G, Oyen W et al. Crysurgery and radifrequency ablatin fr unresectable clrectal liver metastases. Eur J Surg Oncl. 2005; 31(10): Ruers TJ, Jsten JJ, Wiering B et al. Cmparisn between lcal ablative therapy and chemtherapy fr nn-resectable clrectal liver metastases: A prspective study. Ann Surg Oncl. 2007; 14(3): United Netwrk fr Organ Sharing (UNOS). Plicy management. Organ distributin: Allcatin f livers. Revised 2010, Nv 9. Retrieved n February 11, 2015 frm United Netwrk fr Organ Sharing (UNOS). Talking Abut Transplantatin. Questins & Answers fr Transplant Candidates abut Liver Allcatin Plicy May. Retrieved n February 11, 2015 frm Mazzaferr V, Regalia E, Dci R et al. Liver transplantatin fr the treatment f small hepatcellular carcinmas in patients with cirrhsis. N Engl J Med Mar 14;334(11): Pmfret EA, Washburn K, Wald C et al. Reprt f a natinal cnference n liver allcatin in patients with hepatcellular carcinma in the United States. Liver Transpl. 2010; 16(3): Graziadei IW, Sandmueller H, Waldenberger P et al. Chememblizatin fllwed by liver transplantatin fr hepatcellular carcinma impedes tumr prgressin while n the waiting list and leads t excellent utcme. Liver Transpl. 2003; 9(6): Maddala YK, Stadheim L, Andrews JC et al. Drp-ut rates f patients with hepatcellular cancer listed fr liver transplantatin: Outcme with chememblizatin. Liver Transpl. 2004; 10(3): Obed A, Beham A, Pullmann K et al. Patients withut hepatcellular carcinma prgressin after transarterial chememblizatin benefit frm liver transplantatin. Wrld J Gastrenterl. 2007; 13(5): Fisher RA, Maluf D, Ctterell AH et al. Nn-resective ablatin therapy fr hepatcellular carcinma: Effectiveness measured by intentin t treat and drput frm liver transplant waiting list. Clin Transplant. 2004; 18(5): Yamashiki N, Tateishi R, Yshida H et al. Ablatin therapy in cntaining extensin f hepatcellular carcinma: A simulative analysis f drput frm the waiting list fr liver transplantatin. Liver Transpl. 2005; 11(5): Mazzaferr V, Battistn C, Perrne S et al. Radifrequency ablatin f small hepatcellular carcinma in cirrhtic patients awaiting liver transplantatin:a prspective study. Ann Surg 2004; 240(5): Lu DS, Yu NC, Raman SS et al. Percutaneus radifrequency ablatin f hepatcellular carcinma as a bridge t liver transplantatin. Hepatlgy. 2005; 41(5): Belghiti J, Carr BI, Greig PD et al. Treatment befre liver transplantatin fr HCC. Ann Surg Oncl. 2008; 15(4): Prrett PM, Peterman H, Rsen M et al. Lack f benefit f pretransplant lcreginal hepatic therapy fr hepatcellular cancer in the current MELD era. Liver Transpl. 2006;12(4): United Netwrk fr Organ Sharing (UNOS). Plicy management. Organ distributin: Allcatin f livers. Revised 2010, Nv 9. Retrieved n February 11, 2015 frm 15

16 Medical Plicy Ya FY, Kerlan RK Jr, Hirse R. Excellent utcme fllwing dwn-staging f hepatcellular carcinma prir t liver transplantatin: An intentin-t-treat analysis. Hepatlgy. 2008; 48(3): Lewandwski RJ, Kulik LM, Riaz A et al. A cmparative analysis f transarterial dwnstaging fr hepatcellular carcinma: Chememblizatin versus radiemblizatin. Am J Transplant Aug; 9(8): Ya FY, Ferrell L, Bass NM et al. Liver transplantatin fr hepatcellular carcinma: Expansin f the tumr size limits des nt adversely impact survival. Hepatlgy. 2001;33(6): Ya FY, Ferrell L, Bass NM et al. Liver transplantatin fr hepatcellular carcinma: cmparisn f the prpsed UCSF criteria with the Milan criteria and the Pittsburgh mdified TNM criteria. Liver Transpl. 2002; 8(9): Fernandez JA, Rbles R, Marin C et al. Can we expand the indicatins fr liver transplantatin amng hepatcellular carcinma patients with increased tumr size? Transplant Prc. 2003; 35(5): Merli M, Niclini G, Gentili F et al. Predictive factrs f utcme after liver transplantatin in patients with cirrhsis and hepatcellular carcinma. Transplant Prc.2005; 37(6): Sauer P, Kraus TW, Schemmer P et al. Liver transplantatin fr hepatcellular carcinma: is there evidence fr expanding the selectin criteria? Transplantatin. 2005;80(1 suppl): S Ya FY, Hirse R, LaBerge JM et al. A prspective study n dwnstaging f hepatcellular carcinma prir t liver transplantatin. Liver Transpl. 2005; 11(12): Blue Crss Blue Shield Assciatin. Medical Plicy Reference Manual, N (February 2015). Dcumentatin Required fr Clinical Review Please prvide the fllwing dcumentatin: Histry and physical, and/r cnsultatin reprts and prgress ntes including: Clinical indicatins/justificatin f prcedure Clinical indicatins/justificatin f prcedure Eastern Cperative Onclgy Grup functinal status (if applicable) Previus treatment(s), duratin, and respnse(s) Treatment plan Tumr type and descriptin (i.e., resectable r unresectable, primary r metastatic, tumr burden [e.g., liver dminant]) Pertinent radilgical imaging results (i.e., abdminal CT and/r MRI and/r PET) Pathlgy reprt including tumr nde metastatis (TNM) classificatin Current serum chemistry, liver functin tests, and tumr marker results Pst Service Prcedure reprt(s) 16