Minimally Invasive Therapy. 2014;23:63–69

REVIEW ARTICLE

Pitfalls of transanal endoscopic microsurgery for rectal cancer followingneoadjuvant chemoradiation therapy

ANGELITA HABR-GAMA1,2, GUILHERME PAGIN SÃO JULIÃO1,RODRIGO OLIVA PEREZ1,3,4

1Angelita & Joaquim Gama Institute/Hospital Alemão Oswaldo Cruz, São Paulo, Brazil, 2University of São PauloSchool of Medicine, São Paulo, Brazil, 3University of São Paulo School of Medicine, Colorectal Surgery Division,São Paulo, Brazil, and 4Ludwig Institute for Cancer Research – São Paulo Branch, São Paulo, Brazil

AbstractTransanal endoscopic microsurgery has become a very useful surgical tool for the management of selected cases of rectalcancer. However, the considerably high local recurrence rates led to the introduction of neoadjuvant therapies includingradiation with or without chemotherapy. This treatment strategy may result in significant rates of tumor regression allowing theprocedure to be offered to a significant proportion of cases. On the other hand, neoadjuvant chemoradiation (CRT) may alsodetermine wound-healing difficulties with significant postoperative pain. In addition, salvage total mesorectal excision in thecase of local recurrence may also be a challenging task. Finally, accurate selection criteria for this minimally invasive approachare still lacking and may be influenced by baseline staging, post-treatment staging and final pathology information. Ultimately,selection of patients for this treatment modality remains a significant challenge for the colorectal surgeon who should be awareof the pitfalls of this procedure in the setting of neoadjuvant CRT.

Key words: Rectal cancer, neoadjuvant chemoradiation therapy, transanal endoscopic microsurgery

Background

Transanal endoscopic microsurgery (TEM) has madea major impact on the surgical management of rectaltumors (1). This revolutionary approach incorporat-ing laparoscopic and endoscopic techniques tostandard transanal procedures allowed surgeons toovercome significant hurdles associated with standardtransanal resection of rectal tumors (2). Thisapproach allows excellent visualization of the surgicalfield, precise margin clearance and tissue hemostasiaand proper closure of defects created. In fact, theseadvantages led to immediate incorporation of thistechnique for the resection of benign tumors of therectum (3,4). Particularly useful in large adenomasand higher locations in the rectum, often requiringpiece-meal resection by the colonoscope (5), TEMoffered the opportunity of providing the pathologistwith a single oriented specimen with all layers or

submucosal resection of the rectum and occasionallywith perirectal nodes attached (4). Not only the auditof the surgical specimen was superior to standardtransanal techniques, but also allowed much easierteaching of other training surgeons in the technique(6). Finally, post-operative recovery was almostalways uneventful, presenting few and simple com-plications. Even in cases of entry into the peritonealcavity, hermetic closure led to an uncomplicatedpostoperative course in most situations (3).These observations led to the interest in using the

technique for selected rectal cancers (7). However,even though TEM could provide a superior qualityspecimen for the pathologist with minimal postoper-ative complications, local recurrence was still consid-ered a major limitation of any type of full-thicknesslocal excision (FTLE) (8,9). In fact, local recurrencerates among patients undergoing local excision arestill considered to be associated with the risk of lymph

Correspondence: A. Habr-Gama, Rua Manoel da Nóbrega 1564, São Paulo – SP, ZIP 04001-005, Brazil, Fax: +55 11 3884 8845;E-mail: gamange@uol.com.br

ISSN 1364-5706 print/ISSN 1365-2931 online � 2014 Informa HealthcareDOI: 10.3109/13645706.2014.893891

Min

im I

nvas

ive

The

r A

llied

Tec

hnol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/10/

14Fo

r pe

rson

al u

se o

nly.

node metastases rather than with the quality of theresected specimen. Series of patients with T1 andT2 rectal cancer managed by full-thickness localexcision (FTLE) showing local recurrence rates of10% and 25%, respectively, were a major drawbackfor this procedure in this setting. In fact, even whenTEM was performed for selected T1 cancers, localrecurrence was quite significant (10–14).The risk of local recurrence after FTLE raised

another relevant issue in the management of thesepatients. The possibility of salvage resection and itsimpact on survival became a relevant aspect of FTLE(regardless of the technique) for rectal cancer. Theobservation of poor survival among patients under-going salvage resection for recurrent disease afterTEM for T1 rectal cancer was quite disappointing(15). Therefore, in order to avoid local recurrenceand/or the unfavorable outcomes of salvage after alocal recurrence, two alternatives were suggested.First, early or immediate salvage could be offeredto patients with “unfavorable” pathological findings(including lymphovascular invasion, poor differenti-ation, tumor size >3 cm, ‡pT2) after a FTLE/TEM.Second, adjuvant or neoadjuvant therapy could alsohelp to minimize the risk of local recurrence (16).Immediate or early salvage of patients with unfa-

vorable pathological findings was less appealing sinceit would require the need for radical surgery in aconsiderable amount of patients leading to stomas,urinary, sexual dysfunctions and significant morbidityrates. The use of additional therapy including radia-tion with or without chemotherapy seemed to providea better chance of performing FTLE with TEM as thesole surgical procedure, minimizing functional dis-orders, need for stomas and major surgical morbidity(17,18).Even though postoperative (adjuvant) therapy

would have the benefit of offering patients treatmentafter confirmation of “unfavorable” pathological find-ings, the observation of decreased toxicity andimproved local disease control in prospective ran-domized trials of rectal cancer in the setting of radicalsurgery led to the utilization of radiation and chemo-therapy in the pre-operative period (neoadjuvant)(19–21). In addition, the exposure of healthy andwell-oxygenated tissue, as opposed to post-operativefibrotic tissue, to radiation would theoreticallyimprove its anti-neoplastic effects. Finally, perhapsone of the most beneficial aspects of offering patientspreoperative neoadjuvant therapy would be the effecton tumor shrinkage. The decrease in tumor size(downsizing) and shifts in tumor stage (downstaging)have been well documented after neoadjuvanttherapies with radiation and chemoradiation (CRT)(22–25). In fact, the addition of chemotherapy to

radiation has been shown to significantly increasethe effects on tumor size and stage when deliveredpreoperatively (22). Also, this downsizing and down-staging seem to be time-dependent and therefore, atleast six, eight or even 12 weeks may be required toobtain maximal results for tumor regression (26–28).It appeared that neoadjuvant therapy, particularly

CRT, was the answer to all prayers for TEM in rectalcancer: Improve local disease control, minimizetoxicity, decrease tumor size, downstage cancersand allow a minimally invasive approach without allthe downsides of radical total mesorectal excision(TME).However, the expected benefits of this strategy

came at a significant cost in terms of wound healingand salvage possibilities. Also, local recurrencesmay still be a concern depending on baseline andpost-treatment characteristics.

Wound healing

One of the most significant benefits of TEM after theresection of rectal tumors was the minimal associatedpostoperative morbidity. Postoperative complicationsare minimal and usually do not require readmission orreintervention.However,whenpreoperativeCRTisdelivered,TEM

resection leads to a rectal wound that allows primarysuturing without any technical difficulty, unless theproximal margin is very close to the anal canal/verge.In this situation, even though the upper border of thewound may retain its considerable elasticity, the lowerborder of the wound of the anal canal is rather fixed andwith little mobility. If the resection is wide enough toresult in significant separationof theproximal anddistalborders, significant tension will be present, a knownfeature to contribute to wound dehiscence. Also, theanal canal has ectodermic as opposed to endodermicnerve supply to the rectum. Therefore, wound separa-tion and mucosal discontinuity in this region may bequite painful. Finally, regardless of the level of suturing(rectal or anal canal), the borders to be sutured after aTEM resection in a previously irradiated rectum willnecessarily put together two previously irradiated bor-ders. This is actually quite different from a coloanalanastomosis following neoadjuvant CRT, where theproximal colon is never included in the radiation fieldand therefore a normal colon is sutured to an abnormalanalcanalpreviouslytreatedwithasignificantamountofRT (29). In fact, even after a coloanal anastomosis isconstructed, the riskofdehiscence is so significant that aloop ileostomy is almost always recommended (30).One can imagine the risk of wound dehiscence aftersuturing together two previously irradiated borders of

64 A. Habr-Gama et al.

Min

im I

nvas

ive

The

r A

llied

Tec

hnol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/10/

14Fo

r pe

rson

al u

se o

nly.

rectum or anus, sometimes with significant tensiondepending on the level of the suture.In fact, few studies compared the risk of wound

separation and its consequences with or without pre-viousexposure toCRT.However, retrospectivestudieshave suggested that the risk of wound dehiscence wassignificantly higher when CRT was delivered preoper-atively. In one of these studies, diagnosis of wounddehiscence wasmade aftermore than oneweek follow-ingTEMandhealing of thedehiscence took an averageofmorethaneightweeks tocomplete.Anoperation thatotherwise would almost never require a stoma, in thissituation diversion is occasionally required (31). Inanother study, even though none of the dehiscencesrequired stomas, pain management was quite signifi-cant requiring readmission for analgesia in a consider-able proportion of patients (32).Ultimately, these findings raised the issue whether

any attempt to close the wound defect created byTEM should even be performed. Leaving the woundopen could potentially avoid the complication ofwound dehiscence and minimize its consequences.However logical this may seem, there is no goodevidence to support this idea from any study andthe author’s clinical experience with unclosed woundsshowed no significant differences in pain control afterTEM following neoadjuvant CRT for rectal cancers.

Salvage

In any patient with a rectal cancer treated by neoadju-vant CRT and TEM, the only possible salvage afterrecurrent disease or unfavorable pathological findingswould be a total mesorectal excision (TME). Also,tumors that are candidates for TEM should ideallybe restricted to the rectal wall (ycT2N0) regardlessof the baseline staging features. Therefore, in theoryand unless the patient is already incontinent,these tumors are candidates for sphincter-savingprocedures such as low coloanal or even partial/totalintersphincteric resections.Therefore, one would expect that any salvage resec-

tion here would allow a safe TME and at least thepossibility of sphincter preservation. However, TEMfor themanagement of rectal cancers should preferablyinclude a significant amount of perirectal fat, oftenreaching themesorectal fascia for oncological purposes.Considering the fact thatwounddehiscence is frequent,scarring and fibrotic changes may be quite significantleading inevitably to perforation or violation of themesorectal fascia during TME attempt for salvage.This may be crucial in the setting of local tumor recur-rence and its clinical consequences are yet to bereported.

Even whenTME can be safely performed, sphincterpreservation may also be compromised. In a studywhere patients treated by neoadjuvant RT or CRTwere managed by FTLE (including TEM), the pres-ence of unfavorable pathology recommended subse-quent TME. None of these patients salvaged couldavoid an abdominal perineal resection. Interestingly, afewof thesepatientscouldhavebeenoriginallyofferedasphincter preserving operation with TME as an alter-native toFTLE(33). Inanother recently reportedstudyoffering TEM after CRT and salvage for patients withunfavorable pathology, patients undergoing radicalTME were able to undergo sphincter preservation.Curiously however, five out of seven patients (>71%)undergoing sphincter preservation developed anasto-motic dehiscence and two out of 11 (18%) requiredemergency reoperations (34). Therefore, sphincterpreservation after previous CRT&TEMmay be quitetechnically challenging and associated with significantpostoperative morbidity. Functional outcomes ofthese patients are yet to be known.

Local recurrence

Few studies have addressed the use of TEM afterneoadjuvant CRT. Most of the studies have includedFTLE, grouping together transanal standard resec-tions and TEM. There is no study in rectal cancershowing TEM superiority in oncological outcomesas compared to standard technique. However, consid-ering thatTEMhas shown to provide a better quality ofthe specimen, one could assume that TEM may offerbetter results when compared to standard FTLE.As mentioned earlier, local recurrence rates have

historically paralleled the risk of lymph node metas-tases in patients treated by FTLE for rectal cancer. pTstatus is one of the most relevant determinants of therisk of perirectal nodal metastases both with or with-out chemoradiation (10–12,14). In fact, studies havesuggested that the risk of lymph node metastases is<5–10% for ypT0, 10–15% for ypT1 and nearly 20%for ypT2 (13). Therefore, one could expect these ratesof local recurrence after treatment with CRT followedby TEM regardless of the original baseline staging.However, radiological imaging has evolved signif-

icantly over the years and nodal staging has improved.Even though accuracy is still far from 100%, magneticresonance (MR) and endorectal ultrasound have beenstudied extensively in order to improve detection oflymph node metastases. In fact, it has been suggestedthat MR could safely assign patients after CRT thatwould be appropriate candidates for FTLE by cor-rectly identifying ycT0-2N0 (accuracy ‡90%) (35).This suggests that ypT0, ypT1 and ypT2 would all be

Pitfalls of TEM for rectal CA after CRT 65

Min

im I

nvas

ive

The

r A

llied

Tec

hnol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/10/

14Fo

r pe

rson

al u

se o

nly.

appropriate candidates for FTLE or TEM, oncenodal metastases have been ruled out. Unfortunately,this has not been tested in a study yet, howeverpromising it may seem. In a review of patients withycT0-2N0 following long-course CRT and TEM,local recurrence rates were nearly 15% (36). In thisstudy, most patients had ypT1/ypT2 whereasypT0 were very few. In a recent report from a mul-ticenter study in Italy (Phase II), 63 patients under-went CRT for cT2-3N0-1 disease at baseline (34). Ofthese, 42 had ypT0 and were treated by FTLE alonewith no recurrence. One patient with ypT1 andTRG2 also did not recur. However, of the ninepatients with ypT2 who refused radical TME, twodeveloped local recurrences after FTLE alone (22%).Others have suggested that baseline staging is also

important and only cT2N0 followed by neoadjuvantCRT would be appropriate candidates for FTLE orTEM (37). In fact, the single randomized study thatcompared cT2N0 followed by neoadjuvant CRT andTEM or TME found in its first report advantages inearly/immediate outcomes favoring TEM (less trans-fusion and stoma requirements, less hospital stay andless need for ICU). Local recurrence rates were sim-ilar between groups (38). In a more recent update,local recurrence rates were still similar betweengroups. However, TEM resulted in more early recur-rences when compared to TME. Also, TEM wasconsidered to be an independent risk factor for thedevelopment of recurrent disease (metastatic or localrecurrence) after multivariate analysis (39). Ulti-mately local recurrence rates were all <10% in bothgroups. Still, it should be noted that nearly 1/3 of thepatients in each group (total of 50 patients in eachgroup) had complete pathological response (ypT0), aknown predictor of low risk for LN metastases. Also,all of the local recurrences were among patients withypT2 residual cancers. Finally, there is still an ongo-ing study specifically dealing with cT2N0 rectal can-cer patients managed by long-course CRT followedby FTLE (including but not necessarily TEM) (40).One could expect that local recurrence rates willultimately depend on the effectiveness of CRT. IfCRT was highly effective, with many ypT0, localrecurrences will probably be low. However, ifypT2 were frequent, one could expect higher localrecurrence rates.

Tumor fragmentation, tumor scatter and TEMafter CRT

In addition to the risk of lymph node metastasesinherent to ypT2 cancers despite proper stagingand restaging suggesting N0 disease there are other

risk factors for the development of local recurrence.Lymphatic or lymphovascular invasion has been con-sidered a risk factor in these patients and shouldprompt or at least consider additional therapy in thesepatients as previously mentioned. However, anotherfeature may play a role in local recurrence amongthese patients with residual cancer following CRT.A recent report after pathological measuring of

residual cancer after proctectomy identified invisiblenests of tumor cells away from the residual mucosalabnormality in up to 3 cm (41). This intriguingfinding of tumor fragmentation after neoadjuvantCRT is now being examined in different series ofpatients undergoing proctectomy and TEM. Thesenests of tumor cells separated from the primary resid-ual ulcer may be a result of tumor fragmentation dueto irregular response to CRT. Areas of the tumor thatare resistant to CRT may be surrounded by CRT-sensitive areas. CRT may lead to complete regressionof the sensitive areas leaving discontinuous “nests” oftumor cells viable.In this setting, excision of the visible residual muco-

sal abnormality may not allow excision of the entireresidual cancer as invisible residual cancer cells awayfrom the ulcer may still be present.Ultimately, unless there is significant regression of

the primary tumor ypT1 and/or £10% of residualcancer cells, rectal cancers may not be suitable forlocal excision despite significant downsizing if tumorfragmentation is present leaving viable cancer cellsaway from the visible residual mucosal abnormality.

ypT0: TEM or Watch & Wait?

Ultimately, the conclusion of this review could be thatTEM would perfectly fit patients with complete path-ological response after CRT due to the minimal risk oflocal recurrence and proper avoidance of radicalsurgery with its intrinsic morbidity and functionalconsequences. In fact, resection by TEM in thesepatients would merely serve as a confirmation ofthe excellent effects of CRT and no actual cancercells would be removed. Postoperative complicationsrelated to wound healing would still be an issue (asdiscussed previously) and even though the risk ofnodal metastases is low, it seems that it may reachup to 5–10%, meaning that ultimately a radical TMEis still a possibility in the case of local recurrence.No immediate surgery and observation alone has

been proposed for these patients with clinical andradiological evidence of a complete response toCRT (complete clinical response – cCR) (42,43).The absence of any residual ulceration, mass, irreg-ularity or stenosis, in the presence of normal

66 A. Habr-Gama et al.

Min

im I

nvas

ive

The

r A

llied

Tec

hnol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/10/

14Fo

r pe

rson

al u

se o

nly.

radiological imaging studies (including preferablyMR with diffusion weighted series or PET/CT)have been considered key findings for the diagnosisof a cCR (44–46). With this non-operative approach(at least immediately after 8–12 weeks from CRTcompletion), patients could avoid any of the difficul-ties in wound healing associated with TEM afterCRT. In addition, surveillance of the rectal wallwould be facilitated by the absence of a scar, granu-lation tissue and other fibrotic changes. Finally, in theevent of a local recurrence, salvage with TME andsphincter preservation (when appropriate) would alsobe facilitated by no previous scarring and/or violationof the mesorectal fascia.Ultimately, TEM may be perfect for those patients

with suspicious residual cancers by clinical and radio-logical studies that pathology reveals complete path-ological response. This may in fact represent asignificant proportion of patients (47).

Perspectives

Sentinel node

In an effort to minimize the risk of leaving nodalmetastases behind after local excision, the conceptof sentinel node biopsy (primarily used for melanomaand breast cancer) has been applied to early rectalcancers during TEM (48). After injection of indocya-nine green solution (ICG) beneath or close to theprimary rectal lesion, the tumor is resected in a full-thickness fashion exposing the mesorectal fat in thevicinity of the tumor. Then, with the aid of nearinfrared (NIR) optic, illumination is switched tofluorescence-guided imaging allowing for the identi-fication and resection of previously injected ICGwithin local perirectal nodes. In a preliminary expe-rience with this technique, one study has reportedsuccessful identification and resection of one to threenodes/patient. The idea is to allow identification ofunsuspected lymph node metastases in patientsundergoing transanal local excision (TEM). Thesepatients could potentially be offered immediate con-version to total mesorectal excision, thus minimizingthe risk of local recurrences.In all three patients in that preliminary study (none

of them having received preoperative CRT), lymphnodes were small and negative after pathological exam-ination leading to no change in the actual managementof patients (48). Even though the technique is feasible,more studies with larger sample sizes are required todetermine the sensitivity and specificity rates of thisprocedure before it can be definitely implemented intoclinical practice. Also, identification of lymph nodes

may be particularly more difficult in a setting ofneoadjuvant CRT due to their significant numberand size reduction after treatment (49). Ultimatelythis may result in a considerable decrease in nodalharvest success rate with this approach.

Transanal total mesorectal excision

Another interesting alternative for the management ofrectal cancer has combined the radicality of totalmesorectal excision with the minimal invasiveness ofTEM. A limited number of reports describing thetechnical and immediate outcomes of total mesorectalexcision performed trananally using theTEMplatformare currently available showing promising results (50).With this approach, it would be possible to see in thenear future patients undergoing TEM for rectal can-cers after CRT for sentinel node biopsy. Those withpositive nodes could immediately be converted totransanal proctectomy with total mesorectal excisionwith no oncological compromise and still benefit fromthe advantages of this minimally invasive approach.However, longer follow-up and more experience areneeded prior to recommendation of this approach forthe management of selected rectal cancer patients.

Conclusions

TEM after CRT is definitely a promising tool for themanagement of patients with residual rectal cancer inorder to avoid postoperative morbidity and functionalconsequences of radical TME with or without sphinc-ter preservation. However, the use of CRT may resultin significant wound healing problems that the colo-rectal surgeon and patients should be aware of. Thesignificant scarring after these resections may turn outto be a technical challenge during salvage total mesor-ectal excision in cases of local recurrence. In addition,oncological outcomes of patients with ypT0 andypT1 following CRT and TEM seem to be thebest, particularly when there is incomplete clinical/radiological response. These patients may be consid-ered a clear indication for the procedure. Patients withypT2 should be considered with careful selection andperhaps pre-treatment staging is also relevant in thissubset of patients. Further understanding of mechan-isms involved in tumor regression may be importantfor the appropriate selection of ideal candidates forthis spectacular surgical tool in the near future.

Declaration of interest: The authors report noconflicts of interest. The authors alone are responsiblefor the content and writing of the paper.

Pitfalls of TEM for rectal CA after CRT 67

Min

im I

nvas

ive

The

r A

llied

Tec

hnol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/10/

14Fo

r pe

rson

al u

se o

nly.

References

1. Buess G, Kipfmuller K, Hack D, Grussner R, Heintz A,Junginger T. Technique of transanal endoscopic microsur-gery. Surg Endosc. 1988;2:71–5.

2. Buess G, Kipfmuller K, Ibald R, Heintz A, Hack D,Braunstein S, et al. Clinical results of transanal endoscopicmicrosurgery. Surg Endosc. 1988;2:245–50.

3. Bretagnol F, Merrie A, George B, Warren BF, Mortensen NJ.Local excision of rectal tumours by transanal endoscopicmicrosurgery. Br J Surg. 2007;94:627–33.

4. Kanehira E, Tanida T, Kamei A, Nakagi M, Hideshima A.A single surgeon’s experience with transanal endoscopicmicrosurgery over 20 years with 153 early cancer cases. MinimInvasive Ther Allied Technol. 2014;23:5–9.

5. Nastro P, Beral D, Hartley J, Monson JR. Local excision ofrectal cancer: review of literature. Dig Surg. 2005;22:6–15.

6. Christoforidis D, Cho HM, Dixon MR, Mellgren AF,Madoff RD, Finne CO. Transanal endoscopic microsurgeryversus conventional transanal excision for patients with earlyrectal cancer. Ann Surg. 2009;249:776–82.

7. Marks JH, Marchionni C, Marks GJ. Transanal endoscopicmicrosurgery in the treatment of select rectal cancers ortumors suspicious for cancer. Surg Endosc. 2003;17:1114–17.

8. De Graaf EJ, Doornebosch PG, Tollenaar RA, Meershoek-Klein Kranenbarg E, de Boer AC, Bekkering FC, et al.Transanal endoscopic microsurgery versus total mesorectalexcision of T1 rectal adenocarcinomas with curative intention.Eur J Surg Oncol. 2009;35:1280–5.

9. Suppiah A, Maslekar S, Alabi A, Hartley JE, Monson JR.Transanal endoscopic microsurgery in early rectal cancer:time for a trial? Colorectal Dis. 2008;10:314–27.

10. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Kepka L,Winkler-Spytkowska B, Suwinski R, et al. Prediction ofmesorectal nodal metastases after chemoradiation for rectalcancer: results of a randomised trial: implication for subse-quent local excision. Radiother Oncol. 2005;76:234–40.

11. Kim DW, Kim DY, Kim TH, Jung KH, Chang HJ,Sohn DK, et al. Is T classification still correlated with lymphnode status after preoperative chemoradiotherapy for rectalcancer? Cancer. 2006;106:1694–700.

12. Mignanelli ED, de Campos-Lobato LF, Stocchi L, Lavery IC,Dietz DW. Downstaging after chemoradiotherapy for locallyadvanced rectal cancer: is there more (tumor) than meets theeye? Dis Colon Rectum. 2010;53:251–6.

13. Perez RO, Habr-Gama A, Proscurshim I, Campos FG,Kiss D, Gama-Rodrigues J, et al. Local excision for ypT2rectal cancer–much ado about something. J Gastrointest Surg.2007;11:1431–8.

14. Park IJ, You YN, Skibber JM, Rodriguez-Bigas MA, Feig B,Nguyen S, et al. Comparative analysis of lymph nodemetastases in patients with ypT0-2 rectal cancers afterneoadjuvant chemoradiotherapy. Dis Colon Rectum. 2013;56:135–41.

15. Doornebosch PG, Ferenschild FT, de Wilt JH, Dawson I,Tetteroo GW, de Graaf EJ. Treatment of recurrence aftertransanal endoscopic microsurgery (TEM) for T1 rectalcancer. Dis Colon Rectum. 2010;53:1234–9.

16. Hahnloser D, Wolff BG, Larson DW, Ping J, Nivatvongs S.Immediate radical resection after local excision of rectalcancer: an oncologic compromise? Dis Colon Rectum.2005;48:429–37.

17. Ho VP, Lee Y, Stein SL, Temple LK. Sexual function aftertreatment for rectal cancer: a review. Dis Colon Rectum.2011;54:113–25.

18. Lange MM, van de Velde CJ. Urinary and sexual dysfunctionafter rectal cancer treatment. Nat Rev Urol. 2011;8:51–7.

19. Sauer R, Becker H, Hohenberger W, Rodel C,Wittekind C, Fietkau R, et al. Preoperative versus postop-erative chemoradiotherapy for rectal cancer. N Engl J Med.2004;351:1731–40.

20. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J,Grieve R, Khanna S, et al. Preoperative radiotherapy versusselective postoperative chemoradiotherapy in patients withrectal cancer (MRC CR07 and NCIC-CTG C016):a multicentre, randomised trial. Lancet. 2009;373:811–20.

21. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H,Steup WH, Wiggers T, et al. Preoperative radiotherapy com-bined with total mesorectal excision for resectable rectalcancer. N Engl J Med. 2001;345:638–46.

22. Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L,Daban A, et al. Enhanced tumorocidal effect of chemotherapywith preoperative radiotherapy for rectal cancer: preliminaryresults–EORTC 22921. J Clin Oncol. 2005;23:5620–7.

23. Das P, Skibber JM, Rodriguez-Bigas MA, Feig BW,Chang GJ, Wolff RA, et al. Predictors of tumor responseand downstaging in patients who receive preoperativechemoradiation for rectal cancer. Cancer. 2007;109:1750–5.

24. Vecchio FM, Valentini V, Minsky BD, Padula GD,Venkatraman ES, Balducci M, et al. The relationship ofpathologic tumor regression grade (TRG) and outcomes afterpreoperative therapy in rectal cancer. Int J Radiat Oncol BiolPhys. 2005;62:752–60.

25. Bujko K, Kolodziejczyk M, Nasierowska-Guttmejer A,Michalski W, Kepka L, Chmielik E, et al. Tumour regressiongrading in patients with residual rectal cancer after preoper-ative chemoradiation. Radiother Oncol. 2010;95:298–302.

26. Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean JP,Partensky C, et al. Influence of the interval between preop-erative radiation therapy and surgery on downstaging and onthe rate of sphincter-sparing surgery for rectal cancer: theLyon R90-01 randomized trial. J Clin Oncol. 1999;17:2396.

27. Tulchinsky H, Shmueli E, Figer A, Klausner JM,Rabau M. An interval >7 weeks between neoadjuvant therapyand surgery improves pathologic complete response anddisease-free survival in patients with locally advanced rectalcancer. Ann Surg Oncol. 2008;15:2661–7.

28. Kalady MF, de Campos-Lobato LF, Stocchi L, Geisler DP,Dietz D, Lavery IC, et al. Predictive factors of pathologiccomplete response after neoadjuvant chemoradiation for rectalcancer. Ann Surg. 2009;250:582–9.

29. Stone HB, Coleman CN, Anscher MS, McBride WH. Effectsof radiation on normal tissue: consequences and mechanisms.Lancet Oncol. 2003;4:529–36.

30. Matthiessen P, Hallbook O, Rutegard J, Simert G,Sjodahl R. Defunctioning stoma reduces symptomatic anas-tomotic leakage after low anterior resection of the rectum forcancer: a randomized multicenter trial. Ann Surg. 2007;246:207–14.

31. Marks JH, Valsdottir EB, DeNittis A, Yarandi SS,Newman DA, Nweze I, et al. Transanal endoscopic micro-surgery for the treatment of rectal cancer: comparison ofwound complication rates with and without neoadjuvant radi-ation therapy. Surg Endosc. 2009;23:1081–7.

32. Perez RO, Habr-Gama A, Sao Juliao GP, Proscurshim I,Scanavini Neto A, Gama-Rodrigues J. Transanal endoscopicmicrosurgery for residual rectal cancer after neoadjuvant che-moradiation therapy is associated with significant immediatepain and hospital readmission rates. Dis Colon Rectum. 2011;54:545–51.

68 A. Habr-Gama et al.

Min

im I

nvas

ive

The

r A

llied

Tec

hnol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/10/

14Fo

r pe

rson

al u

se o

nly.

33. Bujko K, Richter P, Kolodziejczyk M, Nowacki MP, Kulig J,Popiela T, et al. Preoperative radiotherapy and local excisionof rectal cancer with immediate radical re-operation for poorresponders. Radiother Oncol. 2009;92:195–201.

34. Pucciarelli S, De Paoli A, Guerrieri M, La Torre G,Maretto I, De Marchi F, et al. Local excision after preoper-ative chemoradiotherapy for rectal cancer: results of a multi-center phase II clinical trial. Dis Colon Rectum. 2013;56:1349–56.

35. Engelen SM, Beets-Tan RG, Lahaye MJ, Lammering G,Jansen RL, van Dam RM, et al. MRI after chemoradiotherapyof rectal cancer: a useful tool to select patients for localexcision. Dis Colon Rectum. 2010;53:979–86.

36. Perez RO, Habr-Gama A, Lynn PB, Sao Juliao GP,Bianchi R, Proscurshim I, et al. Transanal Endoscopic Micro-surgery for Residual Rectal Cancer (ypT0-2) FollowingNeoadjuvant Chemoradiation Therapy: Another Word ofCaution. Dis Colon Rectum. 2013;56:6–13.

37. Garcia-Aguilar J. Transanal endoscopic microsurgery follow-ing neoadjuvant chemoradiation therapy in rectal cancer:a word of caution about patient selection? Dis Colon Rectum.2013;56:1–3.

38. Lezoche G, Baldarelli M, Guerrieri M, Paganini AM,De Sanctis A, Bartolacci S, et al. A prospective randomizedstudy with a 5-year minimum follow-up evaluation of transa-nal endoscopic microsurgery versus laparoscopic total mesor-ectal excision after neoadjuvant therapy. Surg Endosc. 2008;22:352–8.

39. Lezoche E, Baldarelli M, Lezoche G, Paganini AM,Gesuita R, Guerrieri M. Randomized clinical trial of endo-luminal locoregional resection versus laparoscopic totalmesorectal excision for T2 rectal cancer after neoadjuvanttherapy. Br J Surg. 2012;99:1211–18.

40. Garcia-Aguilar J, Shi Q, Thomas CR Jr, Chan E,Cataldo P, Marcet J, et al. A phase II trial of neoadjuvantchemoradiation and local excision for T2N0 rectal cancer:preliminary results of the ACOSOG Z6041 trial. Ann SurgOncol. 2012;19:384–91.

41. Hayden DM, Jakate S, Pinzon MC, Giusto D,Francescatti AB, Brand MI, et al. Tumor scatter after neoad-juvant therapy for rectal cancer: are we dealing with aninvisible margin? Dis Colon Rectum. 2012;55:1206–12.

42. Habr-Gama A, Perez RO, Wynn G, Marks J, Kessler H,Gama-Rodrigues J. Complete clinical response after neoad-juvant chemoradiation therapy for distal rectal cancer: char-acterization of clinical and endoscopic findings forstandardization. Dis Colon Rectum. 2010;53:1692–8.

43. Habr-Gama A, Perez RO,NadalinW, Sabbaga J, Ribeiro U Jr,Silva e Sousa AH Jr, et al. Operative versus nonoperativetreatment for stage 0 distal rectal cancer following chemoradia-tion therapy: long-term results. Ann Surg. 2004;240:711–17.

44. Lambregts DM, Maas M, Bakers FC, Cappendijk VC,Lammering G, Beets GL, et al. Long-term follow-up featureson rectal MRI during a wait-and-see approach after a clinicalcomplete response in patients with rectal cancer treated withchemoradiotherapy. Dis Colon Rectum. 2011;54:1521–8.

45. Lambregts DM, Vandecaveye V, Barbaro B, Bakers FC,Lambrecht M, Maas M, et al. Diffusion-Weighted MRI forSelection of Complete Responders After Chemoradiation forLocally Advanced Rectal Cancer: A Multicenter Study. AnnSurg Oncol; published online 23 February 2011.

46. Perez RO, Habr-Gama A, Gama-Rodrigues J, Proscurshim I,Juliao GP, Lynn P, et al. Accuracy of positron emissiontomography/computed tomography and clinical assessmentin the detection of complete rectal tumor regression afterneoadjuvant chemoradiation: Long-term results of a prospec-tive trial (National Clinical Trial 00254683). Cancer. 2012;118:3501–11.

47. Smith FM, Chang KH, Sheahan K, Hyland J, O’Connell PR,Winter DC. The surgical significance of residual mucosalabnormalities in rectal cancer following neoadjuvant chemor-adiotherapy. Br J Surg. 2012;99:993–1001.

48. Arezzo A, Arolfo S, Mistrangelo M, Mussa B, Cassoni P,Morino M. Transrectal sentinel lymph node biopsy for earlyrectal cancer during transanal endoscopic microsurgery.Minim Invasive Ther Allied Technol. 2014;23:17–20.

49. Perez RO, Pereira DD, Proscurshim I, Gama-Rodrigues J,Rawet V, Sao Juliao GP, et al. Lymph node size in rectalcancer following neoadjuvant chemoradiation–can we rely onradiologic nodal staging after chemoradiation? Dis ColonRectum. 2009;52:1278–84.

50. Atallah S. Transanal minimally invasive surgery for totalmesorectal excision. Minim Invasive Ther Allied Technol.2014;23:10–16.

Pitfalls of TEM for rectal CA after CRT 69

Min

im I

nvas

ive

The

r A

llied

Tec

hnol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/10/

14Fo

r pe

rson

al u

se o

nly.