A predictive model for local recurrence after transanal endoscopic microsurgery for rectal cancer S.P. Bach’, J. Hill’, J. R. T. Monson’, J. N. L. Simson‘, L. Lane’, A. Merrie”, B. Warren® and N. J. McC. Mortensen’, on behalf of the Association of Coloproctology of Great Britain and Ireland ‘Transanal Endoscopic Microsurgery (TEM) Collaboration "Academie Department of Surgery, Queen Fizabeth Hospi, Birmingham, and “Deparment of Surgery, Manch Sorgery, Cay Hop, Aelnd, Sew Zesland Corropondence ts Me S.P. Bach, Academie Department of Surgery, Room 50, 4th Floor, Queen Kliabeth Hoyptl, Edgbarten, Birmingham 815 2TH, [UK (email ston back sok) Background: The outcome of local excision of early rectal cancer using transanal endoscopic microsurgery (TEM) lacks consensus. Screening has substantially increased the early diagnosis of ‘tumours. Patients need local treatments that are oncologically equivalent to radical surgery but safer and fanctionally superior. ‘Methods: A national database, collated prospectively from 21 regional centres, detailed TEM treatment in 487 subjects with rectal cancer, Data were used to construct a predictive model of local recurrence after ‘TEM using semiparametric survival analyses. The model was internally validated using measures of calibration and discrimination, Results: Postoperative morbidity and mortality were 14:9 and 1-4 per cent respectively. The Cox regression model predicted local recurrence with a concordance index of 0-76 using age, depth of tumour invasion, tumour diameter, presence of Iymphovascular invasion, poor differentiation and conversion to radical surgery after histopathological examination of the TEM specimen. Conclusion: Patient selection for TEM is frequently governed by fitness for radical surgery rather than suitable tumour biology. TEM can produce long-term outcomes similar to those published for radical total mesorectal excision surgery if applied to a select group of biologically favourable cumours, Conversion to radieal surgery based on adverse TEM histopathology appears safe for p TI and p T2 lesions. Presented to the Tripartite Mesting of the American Society of Colon and Rectal Surgeons, Roston, Massachusetts, USA, June 2008, and published in abstract form a Dis Coon Rctam 2008, 51: 638 Paper accepted 16 January 2009 Published online in Wiley InterScience (www b.coul). DOK: 10.1002/.656 Introduction ter Royal Infirmary, Manchester, UK "Univesity of Rochester Medial Center, Roches, New York, USA, ‘Deparauen of Surgery, St Richards Hospital, Royal West these, and Departments of Colorectal Surgery and “Histopathology, Jon Radlife Hospi, Oxford, UK. and "Department of Colorect sex NHS Rectal cancer affects 10000 new patients and causes 4700 deaths cach year in Kngland and Wales. A nationwide program of faecal occult blood testing (FOBT) for colorectal cancer was introduced in 2006, Pilot studies of FOBT indicate that 49 per cent of screen-detected ‘tumours are tumour node metastasis (TNM) stage I, that “The Bivors are saisied tha all authors contributed significantly co ‘this publication Copyright 2009 Bish Jour of Surgery Socey Lad Published jobs Wey He Sos Led is pathological tumour (pT) category 1 or 2, and NO!. If flexible sigmoidoscopy is used as the screening tool, figure increases to 62 per cent! Surgeons face a dilemma when treating carly rectal cancer. Although the tumour appears small and well localized, surgery for rectal cancer is classically a radical procedure that may precipitate serious morbidity and poor functional outcome. Patients undergo either anterior resection with coloanal or colorectal anastomosis (sphincter preserving) or abdominoperineal excision British Journal of Surgery 2009; 96; 280-290‘Transanal endoscople microsurgery for rectal cancer with permanent colostomy. Radical surgery with total mesorectal excision (TME) is oncologically appealing, as mesorectal Iymph nodes are removed en Bloc with the primary tumour. ‘These harbour tumour deposits in 11-18 per cent of unselected pTI rectal cancers!~ Radical TME resection of pT1 NO disease does not guarantee cure, as 1-7 percent of patients develop local recurrence within Syears®, This figure rises to 3-6 percent for cohorts of unselected pT tumours that include node-positive subjects “The adverse effects of TME. surgery are well docu- ‘mented both in terms of postoperative morbidity, mortality and long-term functional outcome. Mortality rates for non-irradiated patients in the Dutch TIME trial were 3.3 per cent”. Clinical leak rates were 16 per cent if a diverting stoma was not used’. Autonomic innervation to the bladder and sexual organs may be interrupted despite the advent of nerve-sparing techniques, leading to u nary incontinence (34 per cen‘), difficulty passing urine (@5 per cent) and sexual dysfunction*®, About 60 per cent of patients suffer some form of faecal incontinence, and 30-40 per cent are troubled by symptoms of urgency, incomplete emprying and stool frequency on a daily basis™"®, The question remains whether tis level of surgi- cal morbidity is necessary for the satisfactory treatment of carly rectal eancer. Early detection of rectal cancer through, screening may allow substitution of oncologically equiva- lent but safer and functionally superior treatments, similar 10 wide local excision for breast cancer, Transanal endoscopic microsurgery (TEM) isa modified technique of local resection that greatly improves acces- sibility, visualization and precision of resection for early rectal tumours compared with simple peranal excision” ‘The surgeon works via 2 40-mm operating proctoscope using magnified binocular vision, The rectum is insuf- flated with carbon dioxide and laparoscopic style tools are introduced through airtight ports. The rectal lesion is removed by sharp dissection under direct vision with a 1- ‘em margin of normal tissue. Both tumour and underlying. muscular wall of the rectum are removed en Hc. Series of 21-84 patients that have used TEM for rescetion of I'L tomours have demonstrated local recurrence rates of 4-10 per cent!?~6, Case-control studies have suggested ‘equivalence with radical transabdorninal surgery! A. ‘meta-analysis concluded that TEM produced much lower local recurrence rates than peranal excision'?. Clinicians remain sceptical as evidence from randomized trials is lack- ing and theres no consensus regarding long-term outcome following TEM for early rectal eancer'®, Current guide- lines are based on modest numbers of patients treated by peranal excision! Copyright 2009 Bish Jour of Surgery Socey Lad Pulled by Jobe Wiley & Sone Lee oy “Te present study used prospectively gathered data from 21 centres detailing use of TEM in 487 patients treated for recal cancer. These data represent real-life application of TEM throughout the UK. The aim of this study was to identify risk fretors associated with local recurrence after TEM and to develop a predictive model for risk stratification. These data are not the result ofa randomized controlled trial and so are suggestive, not conclusive. ‘The Association of Coloproctology of Great Britain and Ireland TEM Collaboration began in 1993. Some 21 centres participated in data collection (20 in the UK and cone in Belgium). Individual institutions maintained records of all TEM procedures. TEM was performed for the following indications: removal of a rectal cancer for cure; removal of a rectal cancer as a compromise that aimed to cure but was deemed oncologicaly suboptimal (in patients with significant co-morbidity or aversion to radical TME, surgery); removal of rectal eancee for palliation with no aim to cure in the presence of metastatic disease; excision of a polypectomy scar when a resected polyp was histologically shown to contain an invasive malignancy; excision biopsy (big biopsy) of a rectal lesion suspected of harbouring rmalignaney; and excision biopsy of a rectal lesion thought to be benign but subsequently shown to be malignant. Only patients with an unequivocal histopathological diagnosis of invasive malignaney were enrolled in # study. Nocases of severe dysplasia or carcinoma in stu were included. Diagnosis was based on positive preoperative polypectomy or examination of the TEM specimen. Preoperative evaluation Lesions defined as malignant before surgery were locally staged with pelvic computed tomography during the first half of the study and magnetic resonance imaging (MRI) daring the second half. The operating surgeon evaluated tumour position and morphology. Endorectal ultrasonography was not mandated but several units routinely performed this investigation and a total of 148. tests were carried out. ‘Transanal endoscopic microsurgery Full bowel preparation was administered. Using dedicated equipment (Richard Wolf, Knittlingen, Germany), TEM was performed as described previously"! Briefly, patients were positioned on the operating table so that the ‘tumour was orientated ina dependent fashion, The surgeon on biscoe Brith Journl of Surgery 2009; 96; 80-290a S.P.Bach, J. HI, RL. Monson, J.NeL. Simson, L. Lan recorded the distance from the anal margin to the lower pole of the tumour. Resection margins were marked using a series of diathermy burns to the surrounding mucosa, ‘The aim was to incorporate a I-cm cuff of macroscopically normal mucosa around the specimen where cancer was mown or suspected. In most patients a full-thickness resection was performed, and a diathermy knife or ultrasonic dissection shears penetrated the muscularis propria to reveal perirectal fat. Where the lesion was considered benign, a smaller margin was taken or even a partial-thickness excision performed with the muscularis propria left intact. Haemostasis was achieved and the cavity irrigated, Closure of the rectal wall defect with a running absorbable suture was routinely performed in some centres, Histopathological examination ‘The specimen was pinned to a corkboard before fixation in 10 per cent formal saline in order to preserve the margin of normal mucosa surrounding the tumour. Depth of tumour invasion (pT category) was reported according to TNM guidelines? pT1 tumours were subelassiied using the Kikuchi submucosal staging system (Sml-3)*. Resection margins were deemed positive where foci of invasive tumour cells were located within 1 mm of the deep for peripheral surgical resection margin. Tumour grade was assigned as well, moderately or poorly differentiated depending on preservation of glandular architecture Invasion of intramural blood vessels and lymphatics by tumour was noted. macroscopically as the maximum diameter of each lesion For large benign lesions with a small invasive component, tumour size was considered to be the maximum diameter fof malignant tissue. Tlistopathological assessment was routinely performed at the host institution, To achieve standardization of staging, a single histopathologist performed a central review of most of the work from cach institution Tumour size was recorded Data management and follow-up [A patient pro forma listed details of demographics, preop- ‘erative staging, neoadjuvant therapy, technical aspects of surgery including physical characteristics of the tumour, perioperative morbidity and mortality, and final patho logical staging. These data were collated centrally using 4 FileMaker® Pro database version 6 (FileMaker, Santa Clara, California, USA). The da notified if adjuvant therapies were administered or farther surgery performed, Outcome data detailing local and dis tant recurrence, cancer-specific survival and overall survival base coordinator was Copyright #2009 Bish Jour of Surgery Socey Ld Pulled by Jobe Wiley & Soe Lee A.Mernie ot were forwarded annually. Patients were followed according to the preference ofthe treating surgeon. For some patients a local hospital or general practitioner provided contin: ued surveillance. Most patients were seen every 6 months for the first 3 years by the TEM surgeon. General prac~ titioners were contacted annually for details of disease recurrence and mortality. Local recurrence was defined as any histopathologically or radiologically confirmed disease recurrence within the true pelvis. Distant recurrence was defined by radiological evidence of tumour spread. Classi- fications of recurrence patterns into local, local plus distant or distant were on the basis of all sites identified within 6 months of the first recurrence. Patients were followed until death or February 2007, whichever came first Statistical analysi Resection margin status was considered a dichotomous variable, with patients classified as RO (no residual disease) or RI (incorporating microscopic (R1), macroscopic (R2) and indeterminate (Rx) residval_ disease). Explanatory variables significantly associated with an RI margin were determined through construction of a multivariable logistic regression model of best ft (determined by Tog likelihood values). Local recurrence-free survival, the time between "TEM surgery and a histopathological or radiological diagnosis of tumour recurrence within the pelvis, was regarded as a continuous variable, Unifactorial Cox proportional hazards methodology identified individual risk factors associated with local recurrence. Observations were censored on the date of last examination for patients lost to follow-up or those who remained disease free at the end of the study. Patients who died from unrelated causes were also censored Explanatory variables with univariable P< 0.200 were included ina multivariable analysis. This significance level was chosen to incorporate all potentially important predic tor variables in the final modelling process. Fonly one level of a potential predictor was significant, chen that variable was converted into a dichotomous variable. To maxi- size information extracted from predictor and response variables, median imputation was used to substitute for incomplete Kikuchi staging data among pT1 tumours?" Mulivariable Cox regression analysis was performed by sequential incorporation of hstopathologicl variables. Confounding patient factors such as age at operation were then added. Finally, postoperative management vas included. Best fit was determined by log likelihood values and Alaike's information criterion (lower values indicating better fit, with a penalty for increasing the number of variables). The proportional. hazards so bis.coe Brith Journal of Surgery 2009; 96; 80-290‘Transanal endoscople microsurgery for rectal cancer assumption was tested using the link test. Co-variables were then interacted individually with time to verify that the effects of these interacted variables were not significant. A Bonferroni adjustment was used to determine the appropriate significance level. Schoenfeld residuals were also checked to ensure that the log hazard ratio function was 0 over time. ‘The model was internally validated using measures of discrimination and calibration, Discrimination was quantified using Harrell’, atest for the proportion of randomly selected patient pairs for whom, predictions and outcomes match”. Values ranging from 0-7 to 0.8 represent reasonable discrimination and values ‘exceeding 0-8 represent good discrimination. Calibration was measured by grouping subjects according co their probability of local recurrence-free survival at 24 months. Observed versus expected recurrence-free survival was calculated for each group and z scores derived, Scores between —2 and 2 denote good calibration. Point estimates for local disease-free survival were computed from the ‘model fora spectrum of histopathological tumour subtypes. Stata*/IC 10 (StataCorp, College Station, Texas, USA) was, used for the analysis, Results A total of 487 patients received TEM for rectal eancer. Of these, 39 received neoadjuvant long-course radiotherapy and were excluded from the main analysis owing to the possibility of stage migration. Details of many of these patients have been published?*, Of the remaining 448 patients, 24 were treated with palliative intent from the ‘outset, leaving 424 patients for evaluation (Table 1). Median follow-up for surviving patients was 36 (range 0-143) ‘months. Tumours were categorized as pT in 253 patients (59-7 per cent), pT? in 138 (32-5 per cent) and pT in 33 (7-8 per cent). TEM was a compromise treatment in 104 patients (24-5 per cent) because of significant co-morbidity ‘or an individual’ wishes ‘Complications Some 63 patients (14-9 per cent) had one or more complication following the TEM procedure (Table 2) Postoperative haemorrhage was the most common, occurring in 38 patients (9.0 per cent). were attributed directly to postoperative haemorrhage, Major medical complications occurred in eight patients (1.9 por cent), leading to four deaths. One patient had a ‘myocardial infarction following a significant intraoperative haemorrhage and subsequently died. The rectum was perforated in nine procedures (intentionally in one). Two deaths Copyright 2009 Bish Jour of Surgery Socey Lad Published jobs Wey He Sos Led a Table + Patient demographics, umour characteristics and ‘outcome data for 424 patients who had transanal endoscopic ricrosurgery for rectal cancer “Tumow sage pm pre ons No.of patients 2531697) 13825) 8378) Sex u 183605 7236 18 4) F so0pe5 Gees) 175) ‘gest operation year)" 7228-89) 75 (47-101) so 48-04) ‘Benign mawy erg 509 Malignant 3611557 95/688 28.85) ‘Tumour postion Posterior saps suze 1751) Later segoq 51875 1188) ater sopte 271955) Distance from anal verge em) <3 sry saeag 12 2) 6-10 s49 (504) a0 28) 14 42) 21 asq7s) 18139) 55) Depth of exison Fut 180757) 1191862) 35,000) Mie tees = 761) Paral a7ges) 287} “Tuenour dente) 31023) 1003) e2mts) 193818) e350) 7768) site) asieo, 31925 ean, 20% 25187) 8a) = seq zien) a) Resection mario 0 z2sies9) 107775) 19.88) Rt req sot 1442) Re 302) 1p) Ow) cen tage ‘mt 65430) sna 05a) Sm 312) Lymphevaseular invasion Ne zara 76a 27083 Yes s2nz6 21152) 8) Postoperative weatment plan ‘Obseraton 206(814) 604435) 12.86) Ragotrersny 2405) 47847) 1286) ageal surgery zen 31225, ean, ‘Values in parentheses are percentages unless indicted oxherwise; values are median range). Median follow up fr patente who were sive and recurrence free wa 6 (ange 0-148) months pT, pathological tsmour category: Residual disease Re, indetenminte residual doease Si, sven her ‘Suturing this defect using the TEM equipment successfully resolved the problem in six; one procedure was converted 10 a lowranterior resection and the other two patients received a temporary loop ileostomy that was later reversed without incident, Seven patients (1.7 per cent) had troublesome on biscoe Brith Journl of Surgery 2009; 96; 80-290a S.P.Bach, J. HI, RL. Monson, J.NeL. Simson, L. Lan ‘able 2 Incidence of perioperative events related tothe ransanal ‘endoscopic microsurgery procedure 2262) oe 138) 0 8 Mar medealeomptions 819) o 4 Peroration dung TEM 221) z 0 Postoperatve pertraion 1/02) 1 ° Pee sbacess or tla 70) z 0 Total s0q 604 ‘Values in parentheses are percentages TEM, tananal endoscopic eronargeny pelvic sepsis; ewo required faecal diversion. In one patient sepsis resulted in a neurogenic bladder. Sepsis resolved in all but two women who developed persistent rectovaginal fistulas, The overall mortality rate from TEM in this study was 1-4 per cent Resection margins Positive resection margins (with tumour up to Tm in diameter or indeterminate) occurred in 11-1, 22-5 and. 42 per cent of patients with pT1, pT2 and pT3 tumours respectively (Table 1). A multivariable logistie regression model was constructed to identify explanatory variables significantly associated with an RI margin (Table 3). Partal-thickness rectal wall excision and increasing pT stage cach increased the odds of an R1 margin (P < 0.000), Table 3 Multivariable analysis of predictors of residual disease in rosurgery the resection margin afer transanal endoscopic er 1 pre 351(180,728) 0001 prs 1551 6 19,9514 0001 Depth of exc'sion Pall 1 Moved 086 014,317 e610 Pari 647800, 1387) <0001 Inaeston Maignant 1 Boog 198101, 380) 0080. ‘Vales in pareahese are 95 per cent confidence ineras Thefllowing sribles were not sgnifcant predictor of residual eae (tumour 1mm (or ler fom the ext urfae, o indeterminate) inthis model: wentment snten (cue vers compromise, tumour diameter, unnou bight above ‘he anal verge, technical dficoles encountered athe time of gery and volume of ese performed by the operating surgeon. pT, puthologia tmoureategery.“Logiie regression Copyright 2009 Bish Jour of Surgery Socey Lad Published jobs Wey He Sos Led A.Mernie ota as did a belief by the operating surgeon that the lesion ‘was benign (P < 0050). Before surgery, 44:3 per cent of pT 1 and 31:2 per cent of pT? lesions had been considered benign (Table 1). Where the surgeon had supposed lesions to be malignant and used appropriate resection techniques (fell thickness with a I-cm radial margin), margin positivity rates fell to 40per ent (five of 124) for pTl and 17 per cent (15 of 89) for pT2 tumours. Two patients who had mucosectomy for unexpected pT lesions (one was RI) hada second TEM procedure to achieve full-thickness local excision followed by observation, No further tumour was found and these procedures were considered RO. Postoperative management After histopathological examination of the TEM specimen, surveillance began in 206 patients (81-4 per cent) with pT and 60 (43-5 per cent) with pT2 tumours (Tube 1). External beam radiotherapy was administered to a further 24 patients (9-5 per cent) with pT'l and 47 (4-1 per cent) with pT2 tumours before surveillance, Conversion to radical surgery (typically within 3 months of TEM) was performed in 23 patients (91 per cent) with pT (21 low anterior resection, two abdominoperineal excision) and 31 (225 per cent) with pT2 (26 low anterior resection, five abdominoperineal excision) lesions. Recurrence Isolated local recurrence occurred in 49 patients; combined local and distanc recurrence occurred in 11, Median, time to recurrence, based on 60 patients, was 13 (range 3-55) months. Excluding 63 patients in whom radical CTME surgery had been performed immediately after ‘TEM, Kaplan-Meier estimates of local recurrence for pTI tumours at 2, 3 and years were 9-5, 12.9 and 186 per cent respectively (Fig. 1). For pT2 tumours the corresponding figures were 23-7, 27-1 and 29:3 per cent. For pT3 tumours, the estimated recurrence at 2 years was 47 per cont. ‘Univariable analyses of all variables potentially associ- ated with the development of local recurrence are given as, hazard ratios (Tale 4). Because Sm2 and Sm data failed to discriminate as individual categories, they were combined for the multivariable analysis (Table 5). “Tree histopathological variables independently pre- dicted local recurrence-free survival: depth of tumour invasion (a composite of pT’ and Sm category), maximum tumour diameter and presence of intramural Iymphovas- cular invasion, ‘Although Sml lesions were associated with the lowest risk of recurrence, hazard ratios for Sm2—3 and pT2 on bjs. conk Brith Journl of Surgery 2009; 96; 80-290‘Transanal endoscople microsurgery fr rect cance 20s “able 4 Univaiable analysis to determine rsk factors associated wit microsurgery the development of local recurrence after tansanal endoscopic No.of patents No.of events azarae ‘Age yeas) se 3° 105,01, 7.08) ort Sex ™ 38 F 2% oss os, sto Treatment tent cure 261 2° 1 Compromise ° 20 175(101,207) 0001 Incomplete potypectony Ne 200 =» 1 Yeo ot ° 083 041,179 sta Morphology Pobpoid 186 3s 1 Sesale 8 " 085 (49,16) 60 User a % 134,071,255) 0370 Preoperative dagrass Malignant 2 Pa 1 Benn 120 Es 125,078,208) «so Postion Posteror ve 2 1 Lateral 135 2 182,078,238) 0360 even 70 cy 140 (070,278) oso Distance rom anal verge fom) 351 sr 108 098,118) 0.0801 Depth of excision Pol heeness aoe s 1 ved 8 2 0591914, 2.4) aro Parl hekness * 4 087(021,157) 280 “Turow ameter fem) 385 8 126 (01,143) <0001t “Turmow grade Viol dterentited 7 2 1 Moderately cierertintod 250 0 108,057,208) 800 Poor aterentited ” 4 224,078,728) on4at em 20 2» 1 pr tor 2 +.49,08,327) onat P73 24 7 3146 (151,792) <001at Resecton marin RO ae 5 1 Rt 8 * 128,061,265) 530 ich tage Smt 6 * 1 sn 2 5 326(108, 977) 020} 573 a7 297 (301,870) 0st Lymphovascularinvaion Yes 2 5 250 (4, 458) 0010 Postoperatve testment plan” Radoterapy 8 18 137/078,239) 0260 TME suger, 3 1 008 607,083) ort No. ot operations pred =a ar 0 sar o7s,239 0260 ‘Values in parentheses ar 95 pe cent conidence interval Siaty-thee patients who had radial al mesorectal excision (TME) surgery afer trancanal «ndoscopie microvurgery (TEM) were excluded from the main analyst. "Comparison inchded all 424 patients. pT, pathological cumourextegoy,R, resis disease, Sm miaconllaye, Predictors wth P= 0200 were entered into mulvarabe analysis. #Cox proporsonal hvards mode Copyright 2009 Bish Jour of Surgery Socey Lad on biscoe Brith Journl of Surgery 2009; 96; 80-290 Pulled by Jobe Wiley & Sone Lee206 S.P.Bach, JH, J. Re: Monson, J.NeL. Simson, LL tumours were broadly similar. As the maximum tumour diameter increased by 1 cm, therisk of recurrence increased by 18 (95 per cent confidence interval (ci) 3 to 35) per cent (P= 0.014). The presence of Iymphovascular invasion increased the risk of recurrence by a factor of 1-86 (95 per cent ci, 1-01 to 341; P = 0.045). Patients who were observed after TEM (with or without adjuvant radiotherapy) were 15-22 (95 per cent ci. 2-04 to 113-73) {P = 0.08) times more likely to have local recurrence than, those who were converted to radical TME surgery on the basis of adverse histopathological findings in the TEM specimen, ‘A term for poor differentiation was incorporated into the model even though this variable was not quite significant because this stedy contained comparatively few poorly differentiated tumours and previous studies have shown that this may be an important factor’ First-order interactions and non-linear terms. (age’) were considered as independent risk factors in the multivariable model, but none was significant. Harrell’ © was 0-76, indicating that time to local recurrence was correctly ordered for randomly selected pairs of patients (where at leat one experienced local recurrence) T6per cent of the time on the basis of age, depth ‘of tumour invasion, tumour diameter, Iymphovascular invasion, poor differentiation and performance of early “TME surgery. ‘The model was well calibrated with no significant difference between observed and expected local recurrence-free survival throughout the spectrum of risk (Table 6). ‘This model was used to caleulate point estimates for local recurrence 36 months after oa Time ater surgery (months) No. ate pT 20 two tz pre tr Sa mm Fe cir estimates of local recurrence-free survival in $61 patients after transanal endoscopie microsurgery for rectal cancer. P < 0.001, log rank test. pT, pathological tumour stage Copyright 2009 Bish Jour of Surgery Socey Lad Published jobs Wey He Sos Led A.Mernie ota ‘Table § Muluvariable analysis of predictors of local recurrence afer wansanal endoscopie microsurgery Hazard ato e Dept of aston It st 1 prt smz-3 2740113, 666) 028 pra 252 (101.626) ou? prs 408134 1232) oon arm date) 118 (108, 135) oot Lymphevaseuler invasion No 1 Yes 145 (101.341) 04s, Poor aterentared Ne 1 Yee 1930073, 478) 1st Ea THE surgry Ys 1 Ne 1522204, 1873) 0.008 ‘age > 80 yore Ne 1 Yes 192 (113,328) oor Values in parentheses are 5 per cent conidence intervals All subjects -were entered into the main analy. The following varsbles were not Peificant predictors ofloel recurrence in this model trestnent intent (care sev compromise and tusour distance fom the al verge TME, ‘wal mesorectal eison, ‘Coe regression, TEM for & range of histopathological tumour subtypes (able 7) According to USA guidelines, pT1 RO tumours that are well (Gl) or moderately (G2) diflerentiaced, with no Iymphovascular invasion and wp to 3 em in diameter are suitable for local excision, Fig. 2 shows local recurrence- free survival for all pT1 and pT2 tumours according to these criteria. In the study population, 93 per cent of subjects conforming to these criteria were free from recurrence at 36 months (Fig. 2). The model indicates that Table 6 Calibration of the Cox regression model Probabity treeurancesiee No. ot Nereeurence fee sui pions Obseved Expected 2 000-036 2 0 os 037-049 5 3 oe 050-082 8 128 089-074 4 ee 175 075-087 I 088-1.00 m4 1501584 051 Subjecte were stratified acording to individual probaly of loel reeurence-iee srvial wing the model. Group sare for observed nur expected recurrence-free survival were ealslted, and» sores Aerved nosing amalgamation ofthe is four groupe) = #9 represents ood elibraton on biscoe Brith Journl of Surgery 2009; 96; 80-290Jendoscopie merosurgery fr rectal cancer Table 7 Local recurrence rates at 36 months predicted using Cox segression model for well or moderately diferentated tumours locally excised using tansanal endoscopic microsurgery in patients younger than 80 yeats prismt No 30 36 44 54 66 a Yee 62 64-77 94 14187 pTisma-3 No 105 127 153 185 221 264 Yes 78 714 255 903 957 18 pr No 98 119 143 173 207 247 Yes 167 700 709 285 337 395 PIs No 197 236 780 332 90 54 Yee a2 378 441 S10 Ska 857 ‘Values ate percentages. pT, pathological rumour tage, Sm, Kikuchi shmconl sage srt at-2RoLyvo jemsinder Bos g£ gos : Bor i So 4a eS “ine ae sgt Int vo. atk SiGh2RoLwo 14 10s a sk ae Reward 3oy metros fig, 2 Comparison of local recurrence-free survival in patients swith curatvely resected (RO) pathological tumour (pT) category 1 tumours that are well or moderstly differentiated (G2), ‘with no ymphovsscular invasion (LyVO) and wp to 3 em in ameter, and patients with remaining histopathological subtypes of pT1 or pT2 tumours after transunal endoscopic microsurgery for rectal cancer, with 95 per cent confidence interval (bars). P= 0.001, Jog rank test local recurrence rates for pT1 G1-2 tumours with no Iymphovascular invasion and a diameter of 2-1-3 cm are about 98 per cent (Table 7) After TEM alone, there were six episodes of isolated disant recurrence among 361 patients, ‘The estimated rate of distant recurrence was S per cent at 3 years and 7 per cent at 5 years. ‘This estimate includes patients with isolated distant recurrence and a combination of local and. distant disease. ‘A total of 63 patients were converted to radical TME Copyright 2009 Bish Jour of Surgery Socey Lad Published jobs Wey He Sos Led a7 surgery based on analysis of their TEM specimen: 23 pT1 (19 breached guidelines"), 31 pT2 and nine pT3 tumours. Of the 63, 53 (84 per cent) had a restorative procedure. In patients with pTI lesions, there were no local recurrences and one isolated hepatic recurrence, which was treated by hepatectomy (the patient died from metastatic disease). In those with pT2 tumours, no local or distant recurrences ‘were recorded. In those with p13 tumours, one local and three isolated distant recurrences were recorded. Discussion Using daa from 424 patients who had TEM for rectal cancer, a model to predict local recurrence was constructed. ‘The model was well calibrated, with no significant difference between observed and expected local recurrence-free survival throughout the spectrum, of risk, and it allowed point estimates for local recurrence 3omonths after ‘TEM to be calculated for 2 range of histopathological tumour subtypes. “The introduction of colorectal cancer screening is expected to lead to a dramatic increase in detection of stage I disease!. TEM is a minimally invasive approach to resection of eatly rectal tumours with several advantages cover radical surgery. It has an established role in the treatment of benign rectal polyps and early rectal cancer in those considered medically unfit for major surgery. However, there is no consensus regarding the long-term outcome of patients undergoing TEM for early rectal cancer. This study presents data from 21 centres, including :most ofthe units performing TEM in the UK. Before surgery 44:3 per cent of pT and 31-2 per cent of pT2 lesions were thought to be benign (Table), This reflects an inability to evaluate the T category of early rectal cancer accurately using current technology, and is a consistent finding in recent reports of the TEM technique'®. Underestimation of T category led to partial- thickness rectal wall excision in 1846 per cent of pT1 and 8.7 per cent of pT2 rumours (including mucosectomy and submucosal plane excision). Such partal-thickness excision was associated with a sixfold increase in the odds of an RI margin in the present multivariable model (Table 3), Mixed partial- and full-thickness excisions were occasionally undertaken either to preserve the internal anal sphineter where a lesion encroached on the upper anal canal or to prevent perforation where itwas envisaged that an anterior tumour bridged the peritoneal reflection. ‘This strategy was not associated with increased risk of RI. Overall RI rates were undoubtedly high: 11-1 per cent for pT1, 22.5 percent for pT2 and 42 per cent for pT3 tumours. There was a close association between RI and on bjs. conk Brith Journl of Surgery 2009; 96; 80-290oy S.P.Bach, J. HI, RL. Monson, J.NeL. Simson, L. Lan pT category, with two additional effect modifiers: depth of excision and the surgeon's belief that the lesion was benign. There was no evidence of a relationship between, R1 and maximum tumour diameter. This suggests thatthe deep surgical margin was most at risk during TEM. This is logical, as i is possible to mark the mucosal resection, ‘margin clearly at the start ofthe procedure, but the deeper aspect is more difficult to visualize and evaluate. strategy of partial-thickness excision for presumed benign disease is reasonable when unidentified malignancy is to be treated with further surgery, whether radical TME surgery oF fall-thickness TEM. Otherwise fll-thickness rectal wall excision should be considered standard unless a specific contraindication exists. By following this practice, RI rates improve considerably to 3-8 per cent for pT! and 16-8 per cent for pT2 tumours. Future TEM trials should include quality assurance workshops to improve operative technique and reduce RI rates still further. The causes of local recurrence after TEM include incomplete excision of the primary tumour (a proportion of RI, unrecognized mesorectal nodal_involvernent, “unrecognized nodal involvement of the pelvic sidewall and tumour implantation. Radical TME surgery should avoid the first two and is the benchmark against which TEM is judged. A recent randomized controlled tial produced local recurrence rates of 1-7 per cent for 244 patients with, sage I disease treated by TME alone®, 4 population- based study from Norway incorporating 256 pT tumours (II per cent stage ITD) treated by radieal surgery gave a Figure of 6 per cent}. In the present study, Kaplan-Meier estimates of local recurrence for all pT and pT? tumours at 5 years were 18-6 and 29°3 per cent respectively (Fig. 1). If TME surgery followed TEM, the odds of recurrence were reduced 15-fold (Table 5). ‘There were no recorded ‘episodes of local recurrence in patients who had TME, surgery after TEM for pT1 and pT2 tumours Although these headline figures can in no way be considered satisfactory they are pethaps to be expected. Selection of TEM as the treatment of choice is frequently ‘based on a patients fitness for major surgery. In this study the operating surgeon felt that TEM represented a major compromise to patient care in 245 per cent of patients, and only 343 percent of TEM resections adhered to current guidelines for local excision of rectal cancer" Incorporation of a broad range of histopathological subtypes did, however, allow the model to take account of the impact of adverse histopathological features on local recurrence-free survival in the context of TEM surgery. Three histopathological variables were found to be independent predictors of local recurrence after TEM: depth of invasion (@ composite of pT and Sm category), Copyright #2009 Bish Jour of Surgery Socey Ld Pulled by Jobe Wiley & Soe Lee A.Mernie ot the presence of Iymphovascular invasion and maximum tumour diameter (Table 5). Sm tumours were least likely to recur, with local recurrence rates of 3-4 per cent for smaller lesions (Fable 7). Considerable overlap was observed in recurrence rates after excision of pTI Sm2-3 and pT2 tumours. Although this could simply. bbe an unrepresentative sample, separate predictors of biological aggressiveness may supersede depth of invasion in determining occult nodal involvement for these tumours. The presence of intramural Iymphovascular invasion within a specimen, a likely surrogate for such underlying behaviour, was stron recurrence. UK guidelines should be amended to reflect this increased level of risk?®. Alternatively, the risk of tumour implantation is likely to correlate with tumour surface area (or maximum diameter). This may explain how maximum diameter comes to be associated with increased local recurrence but does not affect the incidence of RU Previous reports have suggested that rumour diameter is an independent risk factor for nodal metastases in radically resected specimens!” Te was notable that no significant association was found between R1 and local recurrence. Eight local recurrences were recorded from 43 patients with RI resection (not converted to radical TME surgery) to give a hazard ratio of 1.28 (Table 4). OF these, 21 had adjuvant radiotherapy, including five of eight who developed a recurrence. AS 1 includes patients in whom tumour is found within mm of the cut margin, only a fraction will have residual tumour at the surgical margin. Its also possible to induce a false record of RI resection through poor handling of the 1thological specimen. Proper pinning out of the specimen preserves the relationship between the normal margin and tumour. This relationship is otherwise lost when the specimen is put in formalin, and a histopathologist may interpret a shrunken, rolled edge as tumour at the surgical margin. Standards for histopathological handling™™ and reporting” of local excision specimens should be adhered to. ‘The main theoretical concen when converting from. full-thickness TEM to radical TME is that the mesorectal fascial plane has been compromised by rumour implan- tation. ‘TEM could potentially create an R1 resection. Chemoradiation may be administered for low or ante- rior tumours where the deep TEM margin encroaches on the mesorectal fascia. A further technical factor is that, if the rectal wall is not reconstituted using sutures on completion of TEM, the rectal specimen may be weak: ened and fracture during TME surgery. Of 54 pl and pT2 tumours excised by TEM and subsequently converted to radical TME on the basis of adverse histopathology, so bis.coe Brith Journal of Surgery 2009; 96; 80-290‘Transanal endoscople microsurgery for rectal cancer no episodes of local recurrence were recorded. This sug- gests that, in the absence of accurate preoperative staging tools, excision biopsy followed by radical reoperation is reasonable for early tumours. Others have recorded local failure after using this approach, for one of 17 pTU8 and. ‘two of 17 pT2” tumours. In the present study, one of nine pT3 tumours recurred locally after radical reoper~ ation. Te seems that MRI staging remains an important ‘component of the preoperative assessment of patients with carly recta cancer to identify and exclude locally advanced ‘These results reinforce published data. indicating that TEM alone may provide excellent local control in the treatment of pT1 tumours with favourable histopathological features!®, Local recurrence rates of less than 5 per cent for locally excised pT'1 Sml lesions without Iymphovascular invasion and up to 3em in diameter approximate to those for radical surgery. For all other ‘tumour types, TEM in isolation represents a compromise, the relative magnitude of which may be judged on an individual basis. Patients will be able to make informed choices about treatment in light of the outcomes presented here, ‘These data suggest that there is a serious ris of undertreament for Sm2-3 and pT2 tumours, and as 2 consequence TEM alone cannot be recommended for this subgroup. Combining TEM with neoadjuvanc treatments that reduce tumour size, combat intramural lymphatic permeation and sterilize occult nodal deposits ray expand the role of TEM for the treatment of screen- detected cancer. The authors are developing randomized trials to test this hypothesis. though preoperative staging. lacks resolution with regard to depth of tumour invasion and lymphatic permeation, it is comforting that the use of TEM as 2 big biopsy to stage early tumours docs not prejudice outcome for those who proceed to radical surgery. Acknowledgements S. Bach performed data analysis and prepared the ‘manuscript. L, Lane organized data collection, A. Merrie instituted mechanisms for standardized data collection. B ‘Warren provided histopathological quality assurance. N. Mortensen developed and led the project, and also prepared the manuscript. J. Hill, J. Simson and J. Monson were integral to development and evolution of the project, and helped prepare the manuscript, Dr R, Ryan (Department ‘of General Practice and Primary Care, University. of Birmingham) and Dr A. Milner (Peter MacCallum Cancer Centre, Melbourne, Australia) kindly provided statistical advice. The authors declare no conflict of interest. Copyright 2009 Bish Jour of Surgery Socey Lad Pulled by Jobe Wiley & Sone Lee Collaborators TThe authors also wish to thank members of the Association of Coloproctology of Great Britain and Ireland TEM. Collaboration for their participation in this study: Mr A. Allan and Mr S. Korsgen, Good Hope Hospital; Mr S. Ambrose, StJames's, Leeds; MeN. Armitage and Professor J. Scholefield, Queen's Medical Centre, Nottingham, Mr N. Borley, Cheltenham; Professor Lord A. Darzi and Mr P. Ziprin, St Mary's Hospital, London; Mr P. Hainsworth, Freeman Hospital; Mr D. Hay, Gln Chuyd Hospital Mr M. Hershman, Charing Cross Hospital; Mr J. 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