The Role of PET/CT Molecular Imaging in the Diagnosis of Recurrence and Surveillance of Patients Treated for Non-Small Cell Lung Cancer

Transcription

1 dignostics Review The Role of Moleculr Imging in Dignosis of Recurrence nd Surveillnce of Ptients Treted for Non-Smll Cell Lung Cncer Julio Frncisco Jiménez-Bonill *, Remedios Quirce, I. Mrtínez-Rodríguez, Mrí De Arcoch-Torres, José Mnuel Crril nd Igncio Bnzo Nucler Medicine Deprtment, University Hospitl Mrqués de Vldecill, Moleculr Imging IDIVAL, University of Cntbri, Sntnder, Spin; (R.Q.); (I.M.-R.); (M.D.A.-T.); (J.M.C.); (I.B.) * Correspondence: jjimenez@humv.es; Tel.: ; Fx: Acdemic Editor: Andres Kjer Received: 4 My 2016; Accepted: 22 September 2016; Published: 30 September 2016 Abstrct: Non-smll cell cncer (NSCLC) is leding cuse of cncer mortlity worldwide nd its prognosis remins poor. Moleculr imging with 18 F-FDG cn metboliclly chrcterize nture of lesions s benign or mlignnt, llowing better stging t dignosis of this kind of ptient. This dvntge cn lso be pplied in re-stging due to suspicion of recurrent disese. Mny ptients hve recurrence of disese, including surgiclly treted ptients. In current context, with new personlized oncologicl tretments, surveillnce for recurrence nd its ccurte dignosis re crucil to improve ir survivl. In this pper, we revise current knowledge bout clinicl nd moleculr fctors relted to recurrent disese. In context of new, promising, vilble personlized tretments, role of moleculr imging with nd 18 F-FDG nd non- 18 F-FDG rdiotrcers in follow-up of NSCLC-treted ptients is especilly ttrctive nd interesting. Keywords: non-smll cncer; recurrence; 18 F-FDG; ; surveillnce; follow-up 1. Introduction Non-smll cell cncer (NSCLC) is neoplsm responsible for higher mortlity in Western world (27%) nd still hs poor prognosis, with n overll survivl t five yers round 15%. Unfortuntely, in most ptients (80%), disese is dignosed t n dvnced stge (III IV) nd less in erly stges (I II), when it would be potentilly curble. Erly dignosis nd ccurte stging re key to successful tretment. Moleculr imging with 18 F-FDG provides metbolic informtion, which llows better differentition of benign nd mlignnt tissue, reveling functionl bnormlities tht precede structurl dmge. Currently, it is routinely used for stging ptients nd its introduction hs n impct s high s 30% for chnge in stging mde with conventionl imging techniques. This fct contributed to better selection for cndidtes for rdicl tretments with curtive purpose, such s surgery or stereotctic rdiorpy (SSRT) [1]. Recurrence is common phenomenon in nturl history of disese, which occurs in vrible proportion of ptients (20% 80%) nd determines ir survivl [2]. The knowledge of pthophysiologic mechnisms hs been focus of growing number of works from pst decde, which is explined becuse y hve lso expnded rpeutic options. Moreover, imge hs been successfully pplied in dignosis of disese recurrence nd hs n dvntge over or imging techniques, with sme bsis s stging (restging) [3]. However, exmintion is not recommended in guidelines for monitoring nd surveillnce of NSCLC ptients. In this pper, we review current stte of knowledge of Dignostics 2016, 6, 36; doi: /dignostics

2 Dignostics 2016, 6, 36 2 of 10 fctors linked to its recurrence, recurrence ptterns nd role of moleculr imging with in er of new personlized cncer tretments nd ir potentil impct on survivl of ptients. 2. Fctors nd Ptterns of Recurrence of Non-Smll Cell Lung Cncer NSCLC recurrence is frequent in nturl history of disese. The recurrence is considered loco-regionl when it is limited to hemithorx where primry tumor ws locted nd includes ipsilterl lymph nodes, bronquil stump, pleur nd chest wll. The most common sites for distnt recurrence re reported on sme sites where metstses were found t stging [4]. Until now, most importnt group to be cured is ptients in n erly stge in whom complete surgicl resection of primry tumor cn be obtined. Unfortuntely, 30% 55% of ptients with NSCLC develop recurrence nd die of ir disese despite curtive resection [5]. Post-surgery recurrence hs been summrized by two resons: n underestimtion of true tumor stge, probbly due to occult micro-metstses cncer cells, nd, second, becuse removl of tumor during surgery itself might led to dissemintion of cncer cells [6]. However, in deeper nlysis, Boyd et l. exmined timing of locl nd distnt filure of 250 ptients who developed recurrent disese mong 975 ptients undergoing surgery [7]. They found tht 17%, 44% nd 39% of recurrences were confined to locl only, distnt only, nd both, respectively. Only 0.6% of ptients developed sequentil locl recurrence, suggesting tht crude locl recurrence rte might be underestimted if only first sites of filure re scored. Distnt metstses nd locl recurrence might rise from occult cncer cells or due to dissemintion during surgery, s hs previously been suggested. The clssic clssifiction of mlignnt tumours (TNM) stging shows severl limittions s it is only bsed on clinicl nd pthologicl findings [8], nd group of different fctors relted to recurrence following surgery re summrized in Tble 1. In new er of personlized medicine, se fctors should be tken into ccount [6,9]. Tble 1. Predictors for recurrence of non-smll cell cncer fter complete resection [6,9]. Clinicl Prmeters Lymphtic permetion Pleurl Invsion Vessel invsion Intrtumorl vsculr invsion Nodl involvement Incomplete MLNs dissection High CEA MIB-1 expression MACC1 expression CK19 mrna IGF1R Biochemicl nd Moleculr Prmeters Histologicl Dedifferentition Methyltion (promoter regions p16 nd CDH13) CXCR7 expression MicroRNA expression 18 F-FDG PET or findings in primry tumour Intensity of (SUVm) Metbolic tumor volume (MTV) KRAS Ki-67 TS expression EGFR muttions NSCLC: Non smll cell cncer; MLNs:Medistinl lymph nodes; SUV: Stndrdized vlue; TS: Thymidylte synthse; CEA: Crcinoembryonic ntigen; EGFR: Epiderml growth fctor receptor; 18 F-FDG: 18 fluorine-fluoro deoxiglucose; PET: Positron emission tomogrphy; CT: Computed tomogrphy. A temporl pttern in dignosis of NSCLC recurrence hs been observed. The medin time from surgery to relpse is 13.9 months for locl filure nd 12.5 months for distnt filure [7]. Moreover, Wtnbe et l., in n interesting pper [10], note tht re re different recurrence peks during post-opertive follow-up. Indeed, structured multipek pttern of recurrence risk hs been described, with bimodl recurrence pttern similr to tht in ptients with brest cncer. One ws found t one yer fter surgery, suggesting tht surgicl invsion disrupts homeostsis, ccelerting prolifertion of dormnt cncer cells, nd nor pek ws noted t end of second yer of follow-up. A smll pek ws found even five yers fter surgery. The second nd subsequent peks of recurrence described in this study could be explined, ccording to uthors, by hyposis tht

3 Dignostics 2016, 6, 36 3 of 10 residul tumor cells proliferted nd micro-metstses developed fter entering trnsient stte of dormncy. However, underlying mechnisms remin to be fully clrified. On or hnd, recurrence dynmic of cncer with bimodl chrcteristic pttern seems to lso be sex-dependent, with differences in first pek (men t six to eight months fter surgery nd women one yer fter) nd tendency to increse t two yers in women. From histologicl point of view, recurrence due to denocrcinom seems to pper lter thn squmous cell crcinom recurrences. Finlly, severl metbolic studies ssessing intensity of glucose metbolism in primry tumors of NSCLC hve been conducted, nd high stndrdized vlue (SUV) of tumors hs been relted to n incresed risk of recurrence. However, prospective nd well-designed studies re necessry to obtin personlized prediction for ech ptient nd to pln follow-up [11]. 3. The Dignosis of NSCLC Recurrence The contribution of 18 F-FDG to stging of ptients dignosed of NSCLC is well known nd is considered current clinicl gold stndrd imging modlity for this purpose. Moreover, it ws pointed out s superior to stndrd CT nd MRI for detection of disese fter surgery nd to locl bltive rpies such s microwve bltion nd chemorpy [12]. In preopertive stging of NSCLC, s Fisher et l. hve pointed, use of PET-CT cn reduce both totl number of thorcotomies nd number of futile thorcotomies with no effect (negtive or positive) on overll survivl [13]. Furrmore, in ptients without enlrged lymph nodes nd PET-negtive medistinum, se uthors suggest tht ptient my proceed directly to surgery. However, enlrged lymph nodes on CT need confirmtion independently of PET findings nd positive finding on needs confirmtion before decision on surgery is mde [14]. 18 F-FDG is used to evlute equivocl CT findings, due to its very high ccurcy for distinguishing recurrent disese from benign post-tretment chnges ( 1). If tumor recurrence is suspected or confirmed, 18 F-FDG- for restging is indicted to differentite locl from distnt recurrence nd, thus, to pln locl or systemic tretment [15] (s 2 4). In our experience, sensitivity nd specificity of 18 F-FDG were found s high s 100% nd 78%, respectively, nd this dignostic dvntge is likely relted to its superiority in stging of NSCLC ptients [15]. In this sense, met-nlysis of 18 F-FDG- nd CT in medistinl stging of NSCLC demonstrted n ccurcy of 86% for 18 F-FDG- nd of 73% for CT. Sensitivity, specificity, positive nd negtive predictive vlues were 73%, 91%, 71%, nd 90% for 18 F-FDG- nd 74%, 73%, 52%, nd 88% for CT, respectively. The bility to detect distnt metstses with high sensitivity, specificity, nd ccurcy (94%, 97%, nd 96%, respectively) renders superior to or imging modlities. An dditionl mgnetic resonnce imging (MRI) study of brin is recommended in ptients with stge II IV disese for complete ccurte whole-body tumor stging [16]. Beyond 18 F-FDG, or rdiotrcers such s [18F]-fluoro-3 -deoxy-3 -L-fluorothymidine ( 18 F-FLT), which minly reflects cellulr prolifertion, re being evluted to ssess rel contribution to improving clinicl outcome of NSCLC ptients. Most of works hve been done to evlute tretment response in cncer ptients [17], but ir use for dignosis of recurrence remins open. In selected context of pulmonry neuroendocrine tumors, 68 G-DOTATATE PET seems to hve better results for stging nd response evlution thn 18 F-FDG nd to evlute negtive or equivocl findings on 111 In-DTPA-Octreotide scintigrphy [18].

4 Dignostics 2016, 6, 36 Dignostics 2016, 6, 36 Dignostics 2016,6, 6,36 36 Dignostics 2016, 4 of 10 4 of 104 of 10 4 of Ptient with n denocrcinom ner hilum treted with chemo-rdiorpy. A 1. Ptient with n denocrcinom ner hilum treted with chemo-rdiorpy. follow up CT performed four months lter non-conclusive findings. An 18F 1. Ptient with n denocrcinom ner hilumrdiologicl treted with chemo-rdiorpy. A 1.up Ptient with n denocrcinom ner non-conclusive hilum treted with chemo-rdiorpy. A A follow CT performed four months lter rdiologicl findings. 18FFDG incresed relted to rdiorpy re (A C). Also, focl follow up CT performed four months lter non-conclusive rdiologicl findings. An 18F18 follow up CT performed four months lter non-conclusive rdiologicl findings. An Anhypermetbolism F-FDG incresed reltedconfirmed to rdiorpy re (A C); Also, in left drenl glnd ws detected (D). Surgery n drenl metstsis. FDG incresed relted to rdiorpy re (A C). Also, focl FDG inincresed relted to rdiorpy re focl focl hypermetbolism left drenl glnd ws detected (D). Surgery confirmed n(a C). drenlalso, metstsis. hypermetbolism in left drenl glnd ws detected (D). Surgery confirmed n drenl metstsis. hypermetbolism in left drenl glnd ws detected (D). Surgery confirmed n drenl metstsis. 2. This exmple illustrtes how 18F-FDG would rule out suspicion of recurrence. A resectble isolted cerebrl lesion ws dignosed in 48-yer-old femle fter tretment of NSCLC This exmplelobectomy illustrtesnd how1818 F-FDG would suspicion of recurrence. (A). She2.hd previous left drenlectomy. Tkingrule intoout ccount resectbility of 2.2.This exmple illustrtes how wouldrule ruleout out suspicion suspicionofofrecurrence. recurrence. 18F-FDG This exmple illustrtes how F-FDG would F cerebrl lesion, CT for restging solitry nodule in upper (B). An A resectble isolted cerebrl lesion ws dignosed in 48-yer-old femle fter tretment of18nsclc AA resectble isolted cerebrl lesion ws dignosed in in 48-yer-old femle fter tretment of NSCLC (A). resectble cerebrl lesion ws nodule 48-yer-old femle fter tretment of NSCLC FDG no lobectomy pthologicl (C). The ptient ws treted with (A). She hdisolted previous nd dignosed leftindrenlectomy. Tking into ccount resectbility of She hd previous lobectomy nd left drenlectomy. Tking into ccount resectbility of (A). She hdsurgery lesion, previous lobectomy nd left drenlectomy. into ccount resectbility stereotxic over lesion. Three lter,nodule shetking remined symptomtic. cerebrl CT forcerebrl restging yers solitry in upper (B). An 18F-of 18 F-FDG 18 cerebrl lesion, CT for restging solitry nodule in upper (B); An cerebrl lesion, restging solitry The upper (B). An FDG CT nofor pthologicl in nodule nodulein(c). ptient ws treted withf no pthologicl in Three nodule (C); The ptient treted with stereotxic FDG no pthologicl in nodule (C). Thews ptient ws treted with stereotxic surgery over cerebrl lesion. yers lter, she remined symptomtic. surgery oversurgery cerebrl Threelesion. yers Three lter, she remined stereotxic over lesion. cerebrl yers lter, shesymptomtic. remined symptomtic. 3. Ptient with undifferentited crcinom of surgiclly treted seven yers before followed by rdiorpy. In context of pin nd functionl impotence of shoulder, CT suspicious imge in medil spect of ner xill nd structurl chnges3.due to with previous surgery (A). 18F-FDG ruled out recurrence (B). treted seven yers Ptient undifferentited crcinom of surgiclly before followed rdiorpy. In context of pinofnd impotence of treted seven shoulder, Ptientby with undifferentited crcinom surgiclly yers 3.3. Ptient with undifferentited crcinom functionl surgiclly treted seven yers CT suspicious imge in medil spect of ner xill nd structurl beforefollowed followedby byrdiorpy. rdiorpy.in Incontext context of of pin nd functionl before functionlimpotence impotenceofof shoulder, shoulder, 18F-FDG ruled out recurrence (B). due to previous surgery (A). chnges CT suspicious suspicious imge medil spect of of ner CT imge inin medil spect ner xill xillnd ndstructurl structurl chnges due to previous surgery (A). F-FDG ruled out recurrence (B). chnges due to previous surgery (A); F-FDG ruled out recurrence (B).

5 Dignostics 2016, 6, 36 5 of 10 Dignostics 2016, 6, 36 5 of Ptient with NSCLC in left superior lobe treted three yers before with chemordiorpy. A rdiologicl exm sclerotic bone lesions (A). FDG multiple 4. Ptient with NSCLC in left superior lobe treted three yers before with chemo-rdiorpy. A rdiologicl exm sclerotic bone lesions (A); FDG bone, left suprclviculr lymph nodes nd metstses (B). multiple bone, left suprclviculr lymph nodes nd metstses (B). Beyond 18 F-FDG, or rdiotrcers such s [ 18 F]-fluoro-3 -deoxy-3 -L-fluorothymidine ( 18 F-FLT), At which present, minly or reflects imging cellulr modlities prolifertion, hvere been being nlyzed. evluted In to this ssess context, rel promising contribution results to hve been improving reported with clinicl dynmic outcome contrst-enhncement of NSCLC ptients. CT Most (DCT-CT), of works buthve this been technique done to does evlute not seem redy fortretment clinicl response routine use in cncer yet [12]. ptients Multi-prmetric [17], but ir use mgnetic for dignosis resonnce of recurrence imging (MRI) remins is gold open. stndrd In for selected ssessment context of pulmonry of brin metstses neuroendocrine [19]. tumors, MRI hs 68 G-DOTATATE best dignostic PET seems cpbilities to hve better results for stging nd response evlution thn 18 F-FDG nd to evlute negtive to visulize medistinl nd chest wll infiltrtion due to both inherent high soft-tissue contrst nd or equivocl findings on 111 In-DTPA-Octreotide scintigrphy [18]. its bility to cquire dynmic cine-mri sequences, minimizing rtifcts from crdic nd respirtory At present, or imging modlities hve been nlyzed. In this context, promising results hve motion. been Moreover, reported with it isdynmic useful for contrst-enhncement bone metstsis, but CT its (DCT-CT), dignostic but ccurcy this technique when does compred not seem with 18 F-FDG redy for clinicl nd routine boneuse scintigrphy yet [12]. Multi-prmetric is equl or slightly mgnetic less resonnce [20]. PET/MRI imging hs (MRI) been is introduced gold nd pplied stndrd recently for ssessment in few Dignostic of brin metstses Centers. The [19]. potentil MRI hs dvntge best dignostic of this technique cpbilities isto bsed on visulize combintion medistinl of metbolic/functionl nd chest wll infiltrtion PETdue informtion, to both inherent high high soft-tissue contrst of nd MRI its nd DW-MRI; bility however, to cquire dynmic current cine-mri literture sequences, is insufficient minimizing to estblish rtifcts from clercrdic role ofnd PET/MRI respirtory for cncer motion. imging. Moreover, it is useful for bone metstsis, but its dignostic ccurcy when compred with 18 F-FDG nd bone scintigrphy is equl or slightly less [20]. PET/MRI hs been introduced 4. The nd Surveillnce pplied recently of NSCLC in few Dignostic Recurrence Centers. The potentil dvntge of this technique is bsed on combintion of metbolic/functionl PET informtion, high soft-tissue contrst of MRI nd The DW-MRI; high incidence however, of recurrence current literture of is disese insufficient during to estblish first two cler yers role of fter PET/MRI NSCLC for tretment is well cncer known imging. nd is reson specil follow-up is needed. However, re is no consensus bout wht best is strtegy for this purpose. The Americn College of Chest Physicins (ACCP) guidelines 4. The Surveillnce recommendof surveillnce NSCLC Recurrence by clinicl exmintion nd chest rdiogrphy or CT every six months The for high twoincidence yers nd of recurrence n yerly of fordisese ptients during with good first performnce two yers fter sttus NSCLC nd tretment pulmonry function is well [21]. known Thend Ntionl is reson Comprehensive specil follow-up Network is needed. Cncer However, (NCNC) re recommends is no consensus history bout nd physicl exmintion with contrst-enhnced CT every four to six months for two yers nd n physicl exmintion nd non-contrst-enhnced CT nnully; Europen Society for Medicl

6 Dignostics 2016, 6, 36 6 of 10 Oncology (ESMO) note tht re is no cler role for routine studies in symptomtic ptients nd in ptients in whom no intervention is plnned [22]. In summry, PET nd brin MRI re not currently recommended for routine follow-up. However, 18 F-FDG hs shown better dignostic ccurcy thn dignostic CT to ssess suspicion of NSCLC recurrence [15,23,24]. Recently, Mrcus et l. [25] hve pproched open question bout why re hve been mny studies demonstrting impct of 18 F-FDG on mngement pln t stging nd in ptients with suspected recurrent disese, nd re is no substntil literture evluting this clinicl question in follow-up studies. Unlike or works, se uthors noted tht identified recurrence in 44.3% of scns performed without prior clinicl suspicion of recurrence nd ruled out recurrence in 24.2% of scns performed with prior clinicl suspicion of recurrence. They conclude tht 18 F-FDG dds vlue to clinicl ssessment when it is performed in bsence of prior suspicion of recurrence nd hs clinicl impct on mngement of ptients s high s 28.1%. There re severl limittions derived from im of study, but results re interesting. The contrdictory results of or studies tht did not find significnt increment of globl survivl when 18 F-FDG ws routinely pplied in surveillnce of NSCLC ptients could be discourging for this technique. However, this fct cn indicte tht surveillnce of ech ptient should be plnned on bsis of ir individul chrcteristics nd not generlized from globl recommendtion. At this moment, two different questions could be pproched: wht new contributions on risk fctors for recurrence hve become known in lst yers to mke personlized surveillnce for ptients treted for NSCLC, nd should 18 F-FDG be pplied routinely, or only for ptients in whom recurrent disese is suspected? First, metbolism dt of primry tumor before surgicl or rdition tretment hs been relted to time free of recurrence (TFR). High vlues of SUVmx, metbolic tumor volume (MTV) nd totl lesion glycolysis (TLG) predicted higher risk of recurrence or deth in ptients treted surgiclly, s is noted in recent met-nlysis [9], suggesting tht use of 18 F-FDG my benefit selection of ptients for more ggressive tretments. Besides, clinicl tril bout n dptive neodjuvnt chemorpy guided by 18 F-FDG in resectble NSCLC [26] utility of this technique to ssess response nd n chnge chemorpy regimen in non-responding ptients. They suggest tht this dptive pproch cn be lso used to test new drugs, ttempting to optimize periopertive chemorpy to chieve better long-term outcomes. On or hnd, Ito et l. [27] hve shown correltion between SUVmx nd tumor invsiveness or post-surgicl recurrence of solid types of NSCLC, nd in prticulr, in solid-type denocrcinom, it ws correlted with recurrence. The ge of ptients does not seem to be fctor in predicting recurrence fter resection [28]. The nodl stge of surgiclly resected NSCLC hs been directly ssocited with distnt recurrence nd overll survivl but not with loco-regionl recurrence [29]. In study, cut-off SUV vlue of 4.5 ws determined by receiver operting chrcteristic (ROC) curves of ll ptients, nd sme cut-off vlue ws pplied to both denocrcinom nd squmous cell crcinom. In denocrcinom group (n = 158), PET SUV 2 ws significntly ssocited with five-yer recurrence using Kpln-Meier with log-rnk test. No one hs shown recurrence in ptients with SUV <2. However, in squmous cell crcinom group, re ws no significnt ssocition between high level of PET SUV nd tumor recurrence with cut-off vlue of 9 or 10 [30]. More relevnt is growing evidence of importnce of epiderml growth fctor receptor sttus (EGFR) s fctor for post-recurrence survivl in surgiclly treted ptients. Kudo et l. reported tht EGFR nd pthologicl stge re relted, with better survivl fter disese recurrence [31]. Glubb et l. suggested tht FLT1 genetic vrition my be prognostic fctor for recurrence in stges I III, nd should be tested in djuvnt setting of NSCLC [32]. The correltion between EGFR muttion sttus nd FDG hs not been well-estblished. A recent report from globl point of

7 Dignostics 2016, 6, 36 7 of 10 view hs pointed out tht EGFR muttion positive NSCLC ptients hve reltively lower glycolysis compred with NSCLC ptients without EGFR muttion (SUVmx 7.0 ± 3.9 vs ± 5.8) [33]. In ddition, it hs been observed tht NSCLC ptients with tumors hrboring K-RAS muttion significntly higher 18 F-FDG (SUVmen 9.5) thn wild-type K-RAS nd multivrite model bsed on ge, gender, stge nd SUVmen might be used s predictive mrker of K-RAS muttion sttus in ptients with stge III or IV NSCLC [34]. Second, or importnt question is how to design surveillnce of NSCLC ptients. Tkenk et l., in prospective work, compred ssessment of recurrence in popultion of 92 consecutive surgiclly treted ptients of NSCLC in whom follow-up ws mde with rdiologicl stndrd exmintions nd whole-body 18 F-FDG [35]. There were no sttisticlly significnt differences when ROC curves were used to compre dignostic yield of both methods of surveillnce. Sudrski et l. underlined tht this fctor might ply crucil role for n efficient workflow of lrge deprtment tht follows up lrge ptient cohorts [36] nd or uthors hve found similr results [37]. Those ppers nlyzed systemtic follow-up, including symptomtic ptients nd ptients in whom recurrence ws suspected. This question of if 18 F-FDG should be included routinely for ll ptients or only for ptients with suspicion of recurrent diseses is still debtble, but re is enough evidence to support tht when recurrence is suspected, 18 F-FDG hs better dignostic ccurcy for detection of extr-crnil recurrence [15,22]. The follow-up of non-surgiclly treted ptients is nor point of interest. Overll, SSRT hs cceptble results nd, in those ptients, surveillnce of loco-regionl recurrence is crucil. Indeed, recent study tht high 18 F-FDG on pre-rdiorpy cn identify preferentil sites of locl relpse fter chemo-rdiorpy for NSCLC [38]. The post-rpeutic chnges my mke evlution of this kind of ptient difficult, nd ssessment of imges must be creful, including potentilly delyed nd dul-point exms. The metbolic informtion provided by 18 F-FDG could resolve some difficulties inherent for conventionl CT, but more studies re needed. With regrd to rdio-frequency rpy, more evidence is still needed to determine SUVmx cut-off for dignosis of loco-regionl recurrence, where PET cn be indicted [39]. In conclusion, moleculr imging with 18 F-FDG should be considered for restging of NSCLC ptients when recurrence is suspected. Metbolic informtion provided by 18 F-FDG cn llow selection of most pproprite rpy. High qulity evidence is still necessry regrding if intensive follow-up strtegies led to improved survivl nd how my ply role in those personlized progrms of surveillnce. 5. Future Perspectives 18 F-FDG hs shown its vlue in detecting tumor-relted chnges. However, presence of inflmmtory bnormlities my reduce specificity. In such context, 18 F-FLT hs proved to be more sensitivity for erly tretment response evlution [40]. Although it is currently uncler wher se chnges predict eventul clinicl outcome, its potentil utility to clrify recurrent disese when it is strongly suspected cn be considered. According to or uthors (Yno et l., 2014), rpeutic strtegy for treting post-opertive recurrence in NSCLC ptients should be considered ccording to mode of first recurrence, tking into ccount tht limited distnt metstsis (oligo-metstsis) cn be now successfully treted, knowing bility of to detect distnt metstses nd locl recurrence [41]. All vilble resources nd knowledge should be directed to prolong post-recurrence survivl in ptients with good performnce sttus. In this sense, metbolic informtion provided by 18 F-FDG nd or rdiotrcers my ply pivotl role, nd would mke relevnt contribution in this new er of personlized medicine to get best surveillnce for NSCLC ptients. Conflicts of Interest: The uthors declre no conflict of interest.

8 Dignostics 2016, 6, 36 8 of 10 References 1. Pinill, I.; Gómez León, N. The usefulness of in cncer. Rdiologi 2009, 51, [CrossRef] [PubMed] 2. Isrel, O.; Kuten, A. Erly detection of cncer recurrence: 18 F-FDG cn mke difference in dignosis nd ptient cre. J. Nucl. Med. 2007, 48 (Suppl. S1), S28 S Knzki, R.; Higshiym, M.; Fujiwr, A.; Tokung, T.; Med, J.; Okmi, J.; Nishimur, K.; Kodm, K. Long-term results of surgicl resection for pulmonry metstsis from renl cell crcinom: A 25-yer single-institution experience. Eur. J. Crdiothorc. Surg. 2011, 39, [CrossRef] [PubMed] 4. Vrlotto, J.M.; Medford-Dvis, L.N.; Recht, A.; Flickinger, J.C.; Schefer, E.; DeCmp, M.M. Filure rtes nd ptterns of recurrence in ptients with resected N 1 non-smll-cell cncer. Int. J. Rdit. Oncol. Biol. Phys. 2011, 81, [CrossRef] [PubMed] 5. Crnio, S.; Novello, S.; Ppotti, M.; Loicono, M.; Scgliotti, G.V. Prognostic nd predictive biomrkers in erly stge non-smll cell cncer: Tumor bsed pproches including gene signtures. Trnsl. Lung Cncer Res. 2013, 2, [PubMed] 6. Urmoto, H.; Tnk, F. Recurrence fter surgery in ptients with NSCLC. Trnsl. Lung Cncer Res. 2014, 3, [PubMed] 7. Boyd, J.A.; Hubbs, J.; Kim, D.W.; Hollis, D.; Mrks, L.B.; Kelsey, C.R. Timing of locl nd distnt filure in resected cncer: Implictions for reported rtes of locl filure. J. Thorc. Oncol. 2010, 5, [CrossRef] [PubMed] 8. Pollck, J.R. A perspective on DNA microrrys in pthology reserch nd prctice. Am. J. Pthol. 2007, 171, [CrossRef] [PubMed] 9. Liu, J.; Dong, M.; Sun, X.; Li, W.; Xing, L.; Yu, J. Prognostic Vlue of 18 F-FDG in Surgicl Non-Smll Cell Lung Cncer: A Met-Anlysis. PLoS ONE 2016, 11, e [CrossRef] [PubMed] 10. Wtnbe, K.; Tsuboi, M.; Skmki, K.; Nishii, T.; Ymmoto, T.; Ngshim, T.; Ando, K.; Ishikw, Y.; Woo, T.; Adchi, H.; et l. Postopertive follow-up strtegy bsed on recurrence dynmics for non-smll-cell cncer. Eur. J. Crdiothorc. Surg. 2016, 49, [CrossRef] [PubMed] 11. Urmoto, H.; Tnk, F. Prediction of recurrence fter complete resection in ptients with NSCLC. Anticncer Res. 2012, 32, [PubMed] 12. Henzler, T.; Goldstrw, P.; Wenz, F.; Pirker, R.; Weder, W.; Apfltrer, P.; Meyer, M.; Buesing, K.; Crino, L.; Fennell, D.; et l. Perspectives of novel imging techniques for stging, rpy response ssessment, nd monitoring of surveillnce in cncer: Summry of Dresden 2013 Post WCLC-IASLC Stte-of--Art Imging Workshop. J. Thorc. Oncol. 2015, 10, [CrossRef] [PubMed] 13. Fischer, B.; Lssen, U.; Mortensen, J.; Lrsen, S.; Loft, A.; Bertelsen, A.; Rvn, J.; Clementsen, P.; Høgholm, A.; Lrsen, K.; et l. Preopertive stging of cncer with combined PET-CT. N. Engl. J. Med. 2009, 361, [CrossRef] [PubMed] 14. Fischer, B.M.; Mortensen, J.; Hnsen, H.; Vilmnn, P.; Lrsen, S.S.; Loft, A.; Bertelsen, A.K.; Rvn, J.; Clementsen, P.; Høegholm, A.; et l. Multimodlity pproch to medistinl stging in non-smll cell cncer. Fults nd benefits of PET-CT: A rndomised tril. Thorx 2011, 66, [CrossRef] [PubMed] 15. Jiménez-Bonill, J.F.; Quirce, R.; Mrtínez-Rodríguez, I.; Bnzo, I.; Rubio-Vssllo, A.S.; Del Cstillo-Mtos, R.; Orteg-Nv, F.; Mrtínez-Amdor, N.; Ibáñez-Brvo, S.; Crril, J.M. Dignosis of recurrence nd ssessment of post-recurrence survivl in ptients with extrcrnil non-smll cell cncer evluted by 18 F-FDG. Lung Cncer 2013, 81, [CrossRef] [PubMed] 16. Husmnn, L.; Stolzmnn, P. Stging, Restging nd Response Evlution of Non-Smll-Cell Lung Cncer. In Diseses of Chest nd Hert; Springer: Milno, Itly, 2015; pp Bollineni, V.R.; Krmer, G.M.; Jnsm, E.P.; Liu, Y.; Oyen, W.J. A systemtic review on [(18)F]FLT-PET s mesure of tretment response in cncer ptients. Eur. J. Cncer 2016, 55, [CrossRef] [PubMed] 18. Srirjsknthn, R.; Kyni, I.; Quigley, A.M.; Soh, J.; Cplin, M.E.; Bomnji, J. The role of 68 G-DOTATATE PET in ptients with neuroendocrine tumors nd negtive or equivocl findings on 111 In-DTPA-octreotide scintigrphy. J. Nucl. Med. 2010, 51, [CrossRef] [PubMed] 19. D Addrio, G.; Früh, M.; Reck, M.; Bumnn, P.; Klepetko, W.; Felip, E.; ESMO Guidelines Working Group. Metsttic non-smll-cell cncer: ESMO Clinicl Prctice Guidelines for dignosis, tretment nd follow-up. Ann. Oncol. 2010, 21 (Suppl. S5), v116 v119. [CrossRef] [PubMed]

9 Dignostics 2016, 6, 36 9 of Tkenk, D.; Ohno, Y.; Mtsumoto, K.; Aoym, N.; Onishi, Y.; Koym, H.; Nogmi, M.; Yoshikw, T.; Mtsumoto, S.; Sugimur, K. Detection of bone metstses in non-smll cell cncer ptients: Comprison of whole-body diffusion-weighted imging (DWI), whole-body MR imging without nd with DWI, whole-body FDG-, nd bone scintigrphy. J. Mgn. Reson. Imging 2009, 30, [CrossRef] [PubMed] 21. Colt, H.G.; Murgu, S.D.; Korst, R.J.; Sltore, C.G.; Unger, M.; Qudrelli, S. Follow-up nd surveillnce of ptient with cncer fter curtive-intent rpy: Dignosis nd mngement of cncer, 3rd ed.: Americn College of Chest Physicins evidence-bsed clinicl prctice guidelines. Chest 2013, 143 (Suppl. 5), e437s e454s. [CrossRef] [PubMed] 22. Vnsteenkiste, J.; De Ruysscher, D.; Eberhrdt, W.E.; Lim, E.; Senn, S.; Felip, E.; Peters, S.; ESMO Guidelines Working Group. Erly nd loclly dvnced non-smll-cell cncer (NSCLC): ESMO Clinicl Prctice Guidelines for dignosis, tretment nd follow-up. Ann. Oncol. 2013, 24 (Suppl. S6), vi89 vi98. [CrossRef] [PubMed] 23. Hicks, R.J.; Klff, V.; McMnus, M.P.; Wre, R.E.; McKenzie, A.F.; Mtws, J.P.; Bll, D.L. The utility of 18 F-FDG PET for suspected recurrent non-smll cell cncer fter potentilly curtive rpy: Impct on mngement nd prognostic strtifiction. J. Nucl. Med. 2001, 42, [PubMed] 24. Keidr, Z.; Him, N.; Gurlnik, L.; Wollner, M.; Br-Shlom, R.; Ben-Nun, A.; Isrel, O. using 18 F-FDG in suspected cncer recurrence: Dignostic vlue nd impct on ptient mngement. J. Nucl. Med. 2004, 45, [PubMed] 25. Mrcus, C.; Pidplly, V.; Antoniou, A.; Zheer, A.; Whl, R.L.; Subrmnim, R.M. 18 F-FDG nd cncer: Vlue of fourth nd subsequent postrpy follow-up scns for ptient mngement. J. Nucl. Med. 2015, 56, [CrossRef] [PubMed] 26. Chft, J.E.; Dunphy, M.; Nidoo, J.; Trvis, W.D.; Hellmnn, M.; Woo, K.; Downey, R.; Rusch, V.; Ginsberg, M.S.; Azzoli, C.G. Adptive Neodjuvnt Chemorpy Guided by 18 F-FDG PET in Resectble Non-Smll Cell Lung Cncers: The NEOSCAN Tril. J. Thorc. Oncol. 2016, 11, [CrossRef] [PubMed] 27. Ito, R.; Iwno, S.; Kishimoto, M.; Ito, S.; Kto, K.; Ngnw, S. Correltion between FDG- findings nd solid type non-smll cell cncer prognostic fctors: Are re differences between denocrcinom nd squmous cell crcinom? Ann. Nucl. Med. 2015, 29, [CrossRef] [PubMed] 28. Goodgme, B.; Viswnthn, A.; Zoole, J.; Go, F.; Miller, C.R.; Subrmnin, J.; Meyers, B.F.; Ptterson, A.G.; Govindn, R. Risk of recurrence of resected stge I non-smll cell cncer in elderly ptients s compred with younger ptients. J. Thorc. 2009, 4, [CrossRef] [PubMed] 29. Vrlotto, J.M.; Yo, A.N.; DeCmp, M.M.; Rmkrishn, S.; Recht, A.; Flickinger, J.; Andrei, A.; Reed, M.F.; Toth, J.W.; Fizgerld, T.J.; et l. Nodl stge of surgiclly resected non-smll cell cncer nd its effect on recurrence ptterns nd overll survivl. Int. J. Rdit. Oncol. Biol. Phys. 2015, 91, [CrossRef] [PubMed] 30. Lee, S.H.; Jo, E.J.; Eom, J.S.; Mok, J.H.; Kim, M.H.; Lee, K.; Kim, K.U.; Prk, H.K.; Lee, C.H.; Kim, Y.D.; et l. Predictors of Recurrence fter Curtive Resection in Ptients with Erly-Stge Non-Smll Cell Lung Cncer. Tuberc. Respir. Dis. 2015, 78, [CrossRef] [PubMed] 31. Kudo, Y.; Shimd, Y.; Sji, H.; Kto, Y.; Yoshid, K.; Mtsubyshi, J.; Ngse, S.; Kkihn, M.; Kjiwr, N.; Ohir, T.; et l. Prognostic Fctors for Survivl fter Recurrence in Ptients With Completely Resected Lung Adenocrcinom: Importnt Roles of Epiderml Growth Fctor Receptor Muttion Sttus nd Current Stging System. Clin. Lung Cncer 2015, 16, e213 e221. [CrossRef] [PubMed] 32. Glubb, D.M.; Pré-Brunet, L.; Jntus-Lewintre, E.; Jing, C.; Cron, D.; Eridge, A.S.; Mirz, O.; Zhng, W.; Seiser, E.L.; Rzymn, W.; et l. Functionl FLT1 Genetic Vrition is Prognostic Fctor for Recurrence in Stge I III Non-Smll-Cell Lung Cncer. J. Thorc. Oncol. 2015, 10, [CrossRef] [PubMed] 33. Cho, A.; Hur, J.; Moon, Y.W.; Hong, S.R.; Suh, Y.J.; Kim, Y.J.; Im, D.J.; Hong, Y.J.; Lee, H.J.; Kim, Y.J.; et l. Correltion between EGFR gene muttion, cytologic tumor mrkers, 18 F-FDG in non-smll cell cncer. BMC Cncer 2016, 16, 224. [CrossRef] [PubMed] 34. Cicedo, C.; Grci-Velloso, M.J.; Lozno, M.D.; Lbino, T.; Vigil Diz, C.; Lopez-Piczo, J.M.; Gurpide, A.; Zuluet, J.J.; Richter Echevrri, J.A.; Perez Grci, J.L. Role of [ 18 F]FDG PET in prediction of KRAS nd EGFR muttion sttus in ptients with dvnced non-smll-cell cncer. Eur. J. Nucl. Med. Mol. Imging 2014, 41, [CrossRef] [PubMed]

10 Dignostics 2016, 6, of Tkenk, D.; Ohno, Y.; Koym, H.; Nogmi, M.; Onishi, Y.; Mtsumoto, K.; Mtsumoto, S.; Yoshikw, T.; Sugimur, K. Integrted FDG- vs. stndrd rdiologicl exmintions: Comprison of cpbility for ssessment of postopertive recurrence in non-smll cell cncer ptients. Eur. J. Rdiol. 2010, 74, [CrossRef] [PubMed] 36. Sudrski, S.; Henzler, T.; Schoenberg, S.O. Post-rpeutic positron emission tomogrphy/computed tomogrphy for erly detection of non-smll cell cncer recurrence. Trnsl. Lung Cncer Res. 2013, 2, [PubMed] 37. Onishi, Y.; Ohno, Y.; Koym, H.; Nogmi, M.; Tkenk, D.; Mtsumoto, K.; Yoshikw, T.; Mtsumoto, S.; Mniw, Y.; Nishimur, Y.; et l. Non-smll cell crcinom: Comprison of postopertive intr- nd extrthorcic recurrence ssessment cpbility of qulittively nd/or quntittively ssessed FDG- nd stndrd rdiologicl exmintions. Eur. J. Rdiol. 2011, 79, [CrossRef] [PubMed] 38. Clis, J.; Thureu, S.; Dubry, B.; Modzelewski, R.; Thiberville, L.; Grdin, I.; Ver, P. Ares of high 18 F-FDG on prerdiorpy identify preferentil sites of locl relpse fter chemordiorpy for non-smll cell cncer. J. Nucl. Med. 2015, 56, [CrossRef] [PubMed] 39. Wng, Y.; Li, G.; Li, W.; He, X.; Xu, L. Rdiofrequency bltion of dvnced tumors: Imging fetures, locl control, nd follow-up protocol. Int. J. Clin. Exp. Med. 2015, 8, [PubMed] 40. Everitt, S.J.; Bll, D.L.; Hicks, R.J.; Cllhn, J.; Plumridge, N.; Collins, M.; Herschtl, A.; Binns, D.; Kron, T.; Schneider, M.; et l. Differentil 18 F-FDG nd 18 F-FLT Uptke on Seril Imging Before nd During Definitive Chemordition for Non-Smll Cell Lung Cncer. J. Nucl. Med. 2014, 55, [CrossRef] [PubMed] 41. Yno, T.; Okmoto, T.; Fukuym, S.; Mehr, Y. Therpeutic strtegy for postopertive recurrence in ptients with non-smll cell cncer. World J. Clin. Oncol. 2014, 5, [CrossRef] [PubMed] 2016 by uthors; licensee MDPI, Bsel, Switzerlnd. This rticle is n open ccess rticle distributed under terms nd conditions of Cretive Commons Attribution (CC-BY) license (