Clinical Pattern of Recurrent Disease during the Follow-Up of Rectal Carcinoma

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1 Originl Pper Received: December 20, 2016 Accepted: Februry 13, 2017 Published online: Mrch 14, 2017 Clinicl Pttern of Recurrent Disese during the Follow-Up of Rectl Crcinom Thijs Wieldrijer Pscl Bruin Lur A.M. Duineveld Pieter J. Tnis b Anke B. Smits c Henk C.P.M. vn Weert Jn Wind Deprtment of Primry Cre, Acdemic Medicl Centre, nd b Deprtment of Surgery, Acdemic Medicl Centre, Amsterdm, nd c Deprtment of Surgery, St. Antonius Hospitl Nieuwegein, Nieuwegein, The Netherlnds Keywords Rectl cncer Recurrent disese Ptients Follow-up Clinicl presenttion Abstrct Bckground/Aims: Severl inititives hve strted to trnsfer colorectl cncer follow-up (FU) from secondry to primry cre. For this purpose, it is importnt to ssess when nd how recurrences of rectl crcinom re detected fter tretment with curtive intent. Methods: Retrospective multicentre cohort study. Ptients prticipting in n FU progrmme fter curtive intended tretment for rectl cncer stges I III between 2007 nd Results: Of the 378 ptients, 64 (17%) developed recurrent disese (RD). Most were detected during scheduled FU consulttions (n = 55) by ( combintion of) rdiologicl exmintions nd crcinoembryonic ntigen levels, nd were symptomtic (n = 53); outside scheduled FU consulttions, RD ws detected during the tretment of postopertive complictions or ostomy reversl (n = 5), or due to symptoms (n = 4). Most frequent sites of recurrence were liver (50%), lung (44%), multiple (22%) or locoregionl (16%). Tretment of RD with curtive intent ws performed more frequently when detected during scheduled FU (60 vs. 22%). The only predictive fctor for developing RD ws stge III disese on initil presenttion. Conclusions: The mjority of rectl cncer ptients re dig- nosed with RD t n symptomtic stge during scheduled FU consulttions. Only few ptients presented with RD outside the FU progrmme. Argubly, generl prctitioners could order these sme dignostic tests during FU. Introduction 2017 The Author(s) Published by S. Krger AG, Bsel Colorectl cncer (CRC) is one of the most common types of cncer, with more thn 15,000 new cses in the Netherlnds in 2015 [1]. About 30% of ll cses of CRC is locted in the rectum [1]. The cornerstone of intentionlly curtive tretment of rectl crcinom is surgicl resection, preceded by (chemo) rdiotherpy if indicted. Five-yer overll survivl rte currently pproximtes 65% [1 3]. Following primry tretment, ptients re included in follow-up (FU) progrmme to provide supportive cre in the yers following tretment nd to detect recurrent disese (RD) t n symptomtic stge, since this hs been shown to improve tretment options [4 9]. Rectl cncer FU typiclly consists of periodic consulttions with lbortory nd rdiologicl exmintions. The most optiml FU schedule hs not been defined, nd FU is generlly outlined by ntionl guidelines with some inter-hospitl vribility [2]. E-Mil krger@krger.com The Author(s) Published by S. Krger AG, Bsel This rticle is licensed under the Cretive Commons Attribution- NonCommercil-NoDerivtives 4.0 Interntionl License (CC BY- NC-ND) ( Usge nd distribution for commercil purposes s well s ny distribution of modified mteril requires written permission. Thijs Wieldrijer, MD Deprtment of Primry Cre AMC-UvA Post Box NL 1100 DD Amsterdm (The Netherlnds) E-Mil mc.uv.nl

2 Tble 1. Rectl cncer follow-up schedule 1 Yer 1 Yer 2 Yer 3 Yer 4 5 Consulttion Every 6 months Every 6 months Every 6 months Yerly Physicl exmintion On indiction CEA blood test (cut-off point 5.5 µg/l) Every 3 6 months Every 3 6 months Every 3 6 months Every 6 months Imging of liver (ultrsound or CT bdomen 2 ) Every 6 months Every 6 months Yerly Yerly Imging of chest optionl (rdiogrph or CT thorx 3 ) Every 6 months Every 6 months Yerly Yerly Colonoscopy After 1 yer 4 Depending on previous colonoscopy: fter 3 5 yers 1 In pt1n0 tumours, CEA nd imging re optionl. 2 If ultrsound is unrelible or ptient hs high risk of recurrence. 3 If ptient hs high risk of recurrence. 4 If there ws no (complete) preopertive colonoscopy it should be performed 3 months fter surgery. Incresing incidence, improved tretment, nd the recently strted ntionl screening progrmme to detect CRC in the Netherlnds will led to rise in the number of ptients in FU [1, 2, 10]. This rise might further congest hospitl outptient clinics, compromising the bility to offer comprehensive FU cre, including ttention to psychosocil effects of cncer nd its tretment, nd frequent comorbid conditions [10 12]. Becuse generl prctitioners (GPs) re more ccustomed to offering such comprehensive cre, severl inititives hve proposed to trnsfer FU from secondry to primry cre [2, 10, 11]. While few studies ssessed the fesibility of trnsferring colon cncer FU to primry cre [13, 14], no such reserch hs been performed for rectl cncer. The first step towrds trnsfer of FU to primry cre, nd the purpose of this study, ws to ssess when nd how RD ws detected whether this ws during scheduled FU consulttions, by mens of dditionl dignostic exmintions, nd whether or not ptients presented with symptoms. Methods Study Design nd Outcome We performed retrospective cohort study to determine when RD of rectl crcinom ws discovered, which tests identified RD, whether RD ws detected during scheduled FU visit or n intervl consulttion nd if there were symptoms present suggestive for RD. Ptients Ptients were selected from 2 hospitls in the Netherlnds: the Acdemic Medicl Centre (AMC) in Amsterdm, nd the St. Antonius Hospitl in Nieuwegein. Using surgery record lists for the AMC from 2007 until 2009 nd the ntionl colorectl registrtion dtbse (the Dutch surgicl colorectl udit) for both hospitls from 2009 until 2014, ll ptients who underwent surgery for rectl cncer were selected. Inclusion criteri were tretment with curtive intent for primry rectl crcinom stge I, II or III, defined s tumour locted within 15 centimetres of the nl verge. Exclusion criteri were: stge IV disese, locl excision (trnsnl endoscopic microsurgery), hereditry colorectl crcinom, colorectl crcinom in the presence of inflmmtory bowel disese, or synchronous mlignncies other thn rectl crcinom. Additionlly, in-hospitl deths following surgery, or ptients not eligible for scheduled FU were excluded from nlysis. FU Schedule FU in both hospitls is performed ccording to the Dutch ntionl guideline [2, 3], which is depicted in Tble 1. FU is generlly coordinted by surgeons. In the St. Antonius Hospitl, it is commonly n oncologist who coordintes FU fter djuvnt therpy. Dt Extrction Dt ws retrieved by studying the electronic ptient records of ll included ptients in both hospitls. Bseline chrcteristics were documented: tumour stge, site of tumour, therpy, rdicl extent of surgery, FU consulttions nd exmintions, nd whether ptients developed RD during the FU period. An FU exmintion ws coded s missing if it did not tke plce, or ws crried out more thn 3 months lter thn the period tht the guideline suggests. When ptient ws dignosed with locoregionl recurrence, metchronous colorectl crcinom or distnt metstses, dditionl informtion ws extrcted; whether ptients were dignosed by exmintions performed s prt of scheduled FU or not, which dignostic test(s) resulted in the discovery of RD, nd the site of 36 Wieldrijer/Bruin/Duineveld/Tnis/ Smits/vn Weert/Wind

3 RD. If symptoms led to the discovery of RD, or if ptients hd symptoms tht could be relted to RD t the time of dignosis, they were lbelled symptomtic. Furthermore, proceedings fter dignosis with RD were documented: tretment with curtive intent, pllitive tretment with chemotherpy or rdiotherpy (RT), or supportive cre. All dt of ptients with RD were checked by 2 reserchers (T.W. nd P.B.). In cse of disgreement, third resercher (J.W.) ws consulted. Sttistics Sttisticl clcultions were performed using SPSS version 23.0 pckge (SPSS, Chicgo, IL, USA). χ 2 nd Fisher s exct test were used to compre group mens nd predictive fctors for RD. The Kpln Meier nlysis ws used to clculte the 5-yer overll survivl nd recurrence-free survivl for ll ptients, nd for survivl fter detection of RD. The dte of the surgicl resection of the primry rectl cncer ws used s the strting point for survivl nlysis. The log-rnk test ws used for comprison of recurrences detected during regulr FU nd in between consulttions. Ptients who were lost to FU were censored in the nlysis. Tble 2. Excluded ptients (n = 172) Reson Number Percentge of resons for exclusion Stge IV disese IBD Other primry crcinom No scheduled follow-up In-hospitl deth Hereditry rectl crcinom Other primry crcinom 6 3 Recurrence of rectl crcinom 3 2 TEM 3 2 IBD, inflmmtory bowel disese; TEM, trnsnl endoscopic microsurgery. 1 Synchronous tumour(s) other thn rectl crcinom. 2 Becuse of return to hospitl close to ptient s residence (n = 8), ge (n = 6), without reson (n = 5), comorbidity (n = 2), nursing home (n = 2), ptient s request (n = 1). Results Ptients During the studied period, 550 ptients underwent surgery for rectl cncer of whom 172 were excluded (Tble 2). The remining 378 ptients hd medin FU of 30 months (interqurtile rnge [IQR] 15 49). Neodjuvnt therpy ws given in 317 (84%) ptients; this therpy consisted of chemordiotherpy in 143 (45%). Chrcteristics re shown in Tble 3. At the time of dt extrction, 62 ptients hd completed 5 yers of FU, 227 ptients were still prticipting in FU, 13 ptients were lost to FU nd 76 ptients stopped premturely with scheduled FU: becuse of RD (n = 64), ptient s request for termintion (n = 4), ge (n = 4), comorbidity (n = 3) or trnsfer of FU to nother hospitl (n = 1). In totl, 218 ptients (58%) hd received ll exmintions recommended by the ntionl guideline: 249 ptients (66%) received ll crcinoembryonic ntigen (CEA) blood tests ccording to the plnned FU schedule, 63 ptients (17%) missed 1 test, nd 66 ptients (17%) missed 2 or more tests. Three hundred nd eight ptients (82%) received ll plnned rdiologicl exmintions (ultrsound, CT or MRI), 53 ptients (14%) missed 1 test, nd 17 ptients (4%) missed 2 or more tests. Of the 165 ptients with over 3 yers of FU nd no RD, colonoscopy within 3 yers fter primry surgery ws performed in 111 ptients (67%). Whether there ws specific reson for not performing surveillnce colonoscopy, for exmple, t the ptient s request, ws not lwys cler from the hospitl records. Tble 3. Chrcteristics of included ptients (n = 378) n (%) Age, medin (IQR) 66 (58 72) Mle 260 (69) Neodjuvnt RT (84) Short 174 (46) Chemordiotherpy (short) 5 (1) Chemordiotherpy (long) 138 (37) Site of cncer 2 Distl (0 5 cm) 186 (49) Mid (6 10 cm) 138 (37) Proximl (11 15 cm) 54 (14) Stge(p) 3 pcr 20 (5) I 134 (35) II 87 (23) III 137 (36) Type of surgery 4 54 (14) Open LAR Lp LAR 169 (45) Open APR 53 (14) Lp APR 102 (27) Rdicl surgicl resection (96) Adjuvnt CHT 6 42 (11) PCR, pthologicl complete response. 1 Rdiotherpy short course (5 5 Gy) or long course (25 2 or Gy). 2 Distnce from nl verge. 3 Pthologicl stge. 4 Open or lproscopic (Lp), low nterior resection (LAR) or bdominoperinel resection (APR). 5 Missing dt (n = 6). 6 Adjuvnt chemotherpy frequently until 2010, not prt of tretment since Clinicl Pttern of RD during FU of Rectl Crcinom 37

4 Recurrences of Rectl Crcinom Sixty-four ptients (17%) were dignosed with RD, of whom 55 (86%) were detected during scheduled FU visit. In the remining 9 ptients (14%), RD ws detected during non-scheduled (intervl) consulttions. Five were isolted locoregionl recurrences nd 5 included locoregionl recurrences. The medin time till detection of RD ws 15 months (IQR 9 25). Confirmtion of recurrence ws done with imging or biopsy. Of ll recurrences, 43% were detected within the first yer fter surgery, 77% within 2 yers, nd 97% within 3 yers. Two ptients were dignosed with RD fter more thn 3 yers of FU. A comprison of ptients tht developed RD with those tht did not is shown in Tble 4. The only independent predictive fctor for developing RD ws stge III crcinom (p < 0.001). There ws no ssocition between missing FU consulttions or exmintions nd detection of RD. Sites of recurrence were most frequently the liver (n = 32; 50%) nd lungs (n = 28; 44%). RD hd multiple loclistions in 14 ptients (22%; Tble 5). Re-opertion with curtive intent ws performed in 35 ptients (55%) with RD, while 23 ptients (36%) strted pllitive tretment soon fter dignosis. RD ws detected t symptomtic stge in 6 ptients (9%): 4 ptients with locoregionl recurrences nd 2 with distnt metstses. None of the symptomtic ptients were treted with curtive intent becuse of dvnced disese, nd 5 ptients strted pllitive tretment shortly fter RD ws detected. RD Detected during Scheduled FU In 55 ptients, RD ws detected during scheduled FU, with 53 ptients (96%) being symptomtic. Imging rised suspicion of RD in 26 ptients (49%): by mens of CT-scn (n = 10), ultrsonogrphy (n = 8) or chest rdiogrphy (n = 8). Elevted CEA levels rised the suspicion of the presence of RD in 18 ptients (34%) with medin vlue of 11.3 µg/l (medin increse: 5.5 µg/l). Both rdiologicl nd CEA levels simultneously rised suspicion in 8 ptients (15%). RD ws detected by colonoscopy in 1 ptient. Two symptomtic ptients presented themselves on scheduled FU consulttions with 1 ptient hving plpble tumour during pinful digitl rectl exmintion nd the other ptient hving lymphedem of the left leg. Of the ptients with RD detected during scheduled FU, 33 ptients (60%) were re-operted with curtive intent, wheres 16 (29%) strted pllitive tretment soon fter dignosis. Tble 4. Comprison of ptient chrcteristics: recurrences versus no recurrences No recurrences Recurrences p vlue Ptients, n (%) 314 (83) 64 (17) Age, medin (IQR) 66 (58 73) 65 (57 70) Gender, mle, n (%) 216 (69) 44 (69) Site of cncer 1, n (%) Distl (0 5 cm) 153 (49) 33 (52) Mid (6 10 cm) 114 (36) 24 (38) Proximl (11 15 cm) 47 (15) 7 (11) Stge(p) 2, n (%) <0.001 pcr 3 19 (6) 1 (2) I 125 (40) 9 (14) II 79 (25) 8 (13) III 91 (29) 46 (72) Type of surgery 4, n (%) Open LAR 44 (14) 10 (16) Lp LAR 140 (45) 29 (45) Open APR 45 (14) 8 (13) Lp APR 85 (27) 17 (27) Rdicl surgicl resection 5, n (%) 298 (95) 59 (92) Distnce from nl verge. 2 Pthologicl stge. 3 Pthologicl complete response. 4 Open or lproscopic (Lp), low nterior resection (LAR) or bdominoperinel resection (APR). 5 Missing dt (n = 6). Tble 5. Loclistion recurrence/metstsis (n = 64) Site n (%) Multiple 1 14 (22) Liver (isolted) 32 (50) Lung (isolted) 28 (44) Locoregionl 10 (16) Anstomosis 3 (5) Pelvic 7 (11) Lymph nodes 9 (14) Peritonel 3 (5) Other 2 2 (3) 1 A combintion of sites listed in this tble. 2 Pncres, skeletl, subcutneous nd drenl glnd. RD Detected Outside Scheduled FU Visits In 9 ptients, RD ws detected outside the scheduled FU visits; of the 9, 4 hd symptoms. Symptoms tht led to detection of recurrence were jundice, weight loss, bdominl pin with fever nd 38 Wieldrijer/Bruin/Duineveld/Tnis/ Smits/vn Weert/Wind

5 strngury. Three of the 5 symptomtic recurrences were identified during the tretment of postopertive bdominl bscess (with metstses observed in liver or lung); the other 2 were peritonel deposits biopsied during the reversl of temporry ostomy. Ptients with RD detected outside scheduled FU did not miss more FU consulttions or exmintions thn those with RD detected during scheduled FU visits (p = 0.16). Two ptients in whom RD ws detected outside of scheduled FU were treted with curtive intent (22%) for solitry liver nd lung metstsis, respectively. Pllitive cre ws strted in the other 7 ptients (78%). Survivl During the FU period, 22 ptients died: 17 ptients fter being dignosed with RD nd 5 ptients without RD due to other cuses. Recurrence of rectl crcinom ws the direct cuse of deth in 14 ptients. The estimted 5-yer overll survivl rte ws 85%. The estimted recurrence free 5-yer survivl ws 77%. Ptients with RD detected during scheduled FU consulttions hd significntly (p = 0.001) higher survivl rte thn if RD ws dignosed during n intervl consulttion (Fig. 1). The medin FU time fter dignosis with RD ws 18 months (IQR 8 35). Discussion The purpose of this study ws to identify when nd how recurrences of rectl crcinom were detected during the 5-yer FU period fter tretment with curtive intent in order to ssess whether future FU could possibly be trnsferred to primry cre. Most of the 378 ptients included in our study received regulr FU consulttions ccording to the ntionl guideline. The 64 ptients (17%) who were dignosed with RD in our study were mostly detected during scheduled FU nd were symptomtic. The medin time until detection ws 15 months, which is comprble to the 14 months reported for colon cncer recurrence by our study group [15]. Only 2 ptients in this study were dignosed with RD more thn 3 yers fter surgery just over 1% of ptients with more thn 3 yers of FU. In this context, one could consider ending rectl cncer FU fter 3 yers, especilly since the benefit of intensive FU hs been questioned [5], nd potentil hrmful side-effects of FU possibly been underestimted [16]. Previous studies reported locoregionl recurrence rtes of 2 15%, nd overll recurrence rtes of 20 30% Cumultive survivl Regulr follow-up Intervl consulttion Regulr follow-up-censored Intervl consulttion-censored After surgery, months Fig. 1. Survivl rte comprison regulr FU versus intervl consulttion. Five-yer overll survivl rte of ptients with recurrence of rectl crcinom detected during regulr follow-up versus detection t intervl consulttions, p = [6 8, 17 22], which complies with the estimted 5-yer recurrence-free survivl rte of 77% found in our study. The vrince in locoregionl recurrence rtes is often explined by the qulity of surgery ccording to TME principles nd the use of neodjuvnt RT [19, 20]. In our study, 83% of ptients received neodjuvnt RT; besides surgicl qulity, this could explin the reltively low percentge (3%) of locoregionl recurrences we found. Furthermore, we excluded ll ptients with stge IV disese, wheres most other studies included stge IV ptients if they were treted with curtive intent [7, 8, 18, 19, 22]. This my explin why the overll recurrence rte in this study is reltively low compred to previous studies. While reltively few ptients missed 2 or more blood tests or rdiologicl exmintions, nerly one in 3 ptients did not hve surveillnce colonoscopy. These findings differ from the results of the study conducted by Sisler et l. [23], who reported concordnce of colonoscopies with the Cndin ntionl guideline of 80% within 3 yers. Most colonoscopies in tht study were performed by surgeons, while in the Netherlnds ptient needs to be referred to gstroenterologist for colonoscopy, which might explin the difference in colonoscopy surveillnce rtes. The function of colonoscopy is minly Color version vilble online Clinicl Pttern of RD during FU of Rectl Crcinom 39

6 to detect metchronous tumours nd inspect the nstomosis for locl recurrence (5% of recurrences in this study ws locted t the nstomosis). In this wy, it complements the other FU exmintions nd wrrnts continued recommendtion. Recurrences detected during scheduled consulttions were mostly found becuse of bnorml imging, rising CEA blood levels or combintion of both. Accordingly, lthough there seems to be room for improvement in conducting surveillnce colonoscopy, the FU schedule seems dequte in detecting RD t n symptomtic stge. Hlf of ptients with RD hd CEA level increse, which corresponds with Grossmnn et l. [6], who found rise in postopertive CEA levels in 41% of ptients with RD. Performing n ccurte comprison of efficiency of rdiologicl exmintion with previous reports is not fesible due to the heterogeneity of FU schedules [4, 5, 7, 22] or becuse tretment did not include neodjuvnt RT [24]. The few ptients detected outside of scheduled FU consulttions were more likely to present with symptoms, nd less likely to receive tretment with curtive intent. In our study, the low number of symptomtic ptients (n = 6) could be consequence of the intensity of the FU schedule in the Netherlnds. Previous studies reporting locoregionl recurrence rtes between 55 nd 86% or higher number of symptomtic ptients were ble to publish more extensive list of symptoms ssocited with locoregionl RD, such s pin, nl dischrge or blood loss, chnged bowel hbits or obstruction, urogenitl problems, plpble lump nd weight-loss [22, 25 28]. Strengths nd Limittions This study systemticlly studied ptients with stges I III rectl crcinom fter curtive tretment, nd ny subsequent RD, thereby creting cler overview of current rectl cncer FU. To our knowledge, this is the first study tht evluted the presenttion of both locoregionl nd distnt metstses in reltion to scheduled FU. Becuse the nlysis ws performed retrospectively, we were limited in our clssifiction of symptoms by the documenttion of the involved physicin, possibly resulting in n underestimtion of ctul symptoms. The medin FU time of 30 months is reltively short for surveillnce outcome study, lthough we feel it is unlikely tht longer FU would hve chnged our results, especilly since most recurrences occur within 3 yers. The difference in detection of RD between scheduled nd intervl consulttions is bsed on 9 ptients nd should therefore be interpreted with cution. Lstly, ny possible current involvement of GPs in the detection of RD is unknown. Conclusions A mjority of recurrences fter curtive tretment for rectl crcinom were detected during scheduled FU consulttions by mens of stndrd exmintions with nerly ll recurrences being detected within 3 yers fter surgery. Despite the low number of symptomtic ptients in our study, the difference in tretment options nd survivl between ptients dignosed with RD during or outside of scheduled FU consulttion is obvious. Our results encourge further explortion into more prominent role of GPs in future rectl cncer ftercre; seeing s how most recurrences were detected with stndrd exmintions during scheduled consulttions. Cn GPs execute the FU schedule in similr wy, while lso providing comprehensive cre (such s psychosocil support nd ttention to comorbid conditions)? The nswer to this question needs to be the subject of future studies. Disclosure Sttement The uthors declre tht they hve no conflicting interests. Sttement of Ethics The Reserch Ethics Committee of the AMC reviewed the protocol nd ssessed tht the Medicl Reserch Involving Humn Subjects Act does not pply to this study. An officil pprovl by the committee ws therefore not required nd written informed consent ws not obtined. References 1 The Dutch Cncer Registry: Comprehensive Cncer Centre the Netherlnds (IKNL) (ccessed Februry 24, 2016). 2 Oncoline: Ntionl Guideline Colorectlcrcinom 2014 (ccessed Februry 24, 2016). 3 Mrijnen CAM, Vegchel TV: Nieuwe multidisciplinire richtlijn voor de behndeling vn het colorectl crcinoom en colorectle levermetstsen. Nederlnds Tijdschrift Voor Oncologie 2014; Jeffery M, Hickey BE, Hider PN: Follow-up strtegies for ptients treted for non-metsttic colorectl cncer. Cochrne Dtbse Syst Rev 2007; 1:CD Primrose JN, Perer R, Gry A, Rose P, Fuller A, Corkhill A, et l: Effect of 3 to 5 yers of scheduled CEA nd CT follow-up to detect recurrence of colorectl cncer: the FACS rndomized clinicl tril. JAMA 2014; 311: Wieldrijer/Bruin/Duineveld/Tnis/ Smits/vn Weert/Wind

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