How can we utilize local excision to help, not harm, geriatric patients with rectal cancer?

Journal Pre-proof How can we utilize local excision to help, not harm, geriatric patients with rectal cancer? Shruti Sevak, Tine Gregoir, Albert Wolthuis, Matthew Albert PII:

S0748-7983(19)31506-9

DOI:

https://doi.org/10.1016/j.ejso.2019.12.013

Reference:

YEJSO 5580

To appear in:

European Journal of Surgical Oncology

Received Date: 1 June 2019 Revised Date:

12 September 2019

Accepted Date: 13 December 2019

Please cite this article as: Sevak S, Gregoir T, Wolthuis A, Albert M, How can we utilize local excision to help, not harm, geriatric patients with rectal cancer?, European Journal of Surgical Oncology (2020), doi: https://doi.org/10.1016/j.ejso.2019.12.013. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

How can we utilize local excision to help, not harm, geriatric patients with rectal cancer? Shruti Sevak, MD1, Tine Gregoir, MD2, Albert Wolthuis, MD, PhD, FEBS, FACS, FASCRS2, Matthew Albert, MD, FACS, FASCRS1 1

Center for Colon and Rectal Surgery, AdventHealth, Orlando, Florida Department of Abdominal Surgery, University Hospital Leuven, Herestraat 48, 3000, Leuven, Belgium

2

ABSTRACT A majority of the morbidity and mortality burden of rectal cancer is distributed within the geriatric age group. Current surgical and medical treatment modalities pose significant challenges in treating complications specifically in the already pre-disposed senior population with baseline dysfunction. This chapter reviews the work-up, management, current data and oncologic outcomes of treating rectal cancer in the senior adult. HISTORY In the 1800’s Dr. Jacques Lisfranc was the first to describe transanal excision (TAE) by removal of a large, prolapsing rectal tumor. It was not until the 1960’s when Sir Alan Parks further refined the technique by fashioning self-retaining rectal retraction with elevation and dissection in the submucosal plane and primary closure of the subsequent mucosal defect. Consequently, the transanal technique became a popular approach given its obvious advantages of natural orifice surgery that provided direct access to a target lesion without the morbidities associated with intra-abdominal approaches.1,2 The technique, however, was limited in accessibility to lower third of the rectum and provided suboptimal visualization of larger, more proximal, or anterior lesions. On the heels of developing laparoscopic surgical advances in the 1980’s, Professor Gerhard Buess invented a reusable, cylindrical metal rectoscope with access ports and continuous rectal insufflation to circumvent these limitations, which is known today as transanal endoscopic microsurgery (TEM).3 Since then, additional platforms such as transanal endoscopic operation (TEO) have been developed with similar results to the TEM. Despite the advantages of access to larger (size > 3cm) and more proximal lesions (up to ~17cm from the anal verge), the technique was slow to garner momentum as the equipment was expensive, cumbersome to set up and complex enough to require specialized training. As advances in laparoscopic instrumentation created new access platforms, with it came the advent of transanal minimally invasive surgery (TAMIS) in 2010. Using the single-port laparoscopic platform with standard laparoscopic instruments a simpler and less-expensive approach to transanal surgery was now available. 4-5 Together, TAE, TEM, TEO and TAMIS form the basis of local excision techniques.

45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88

INTRODUCTION The overall incidence of rectal cancer has decreased since the 1970s in developed countries. Despite this, rectal cancer remains a significant contributor of cancer-related morbidity and specifically mortality. The majority of this burden is distributed within the geriatric age group. Over 40% of patients diagnosed with rectal cancer are 75 years or older at time of diagnosis.6 Specifically, incidence of rectal cancer in patients less than 65 years old is 7 per 100,000 compared to 44 per 100,000 in those greater than 65 years old based on SEER data from 20082014. This incidence peaks in the 80-84 year old age group at 51.7 per 100,000 and remains increased at 50.4 in those 85 and older.7 The standard of care in treating rectal cancer today is the total mesorectal excision (TME). As first described by Heald, it provides the best oncologic outcome for rectal cancer with low rates of local recurrence < 5% and excellent long-term survival > 80%, owing to an en bloc excision of the primary tumor with its draining mesorectal lymph node package.8 However, this is not without concomitant risks. Mortality rates of TME is 2-3% and anastomotic leak rates approach 12-16% without the use of a diverting stoma. Disruption of autonomic nerves to the bladder and sexual organs leads to significant risks of urinary incontinence and sexual dysfunction in up to 30-35% of patients. Even more alarming is the 60% risk of associated fecal incontinence or bowel dysfunction. 9 Although oncologically sound, a sphincter-preserving low anterior resection or abdominoperineal resection with permanent colostomy is appealing but can be functionally devastating and significantly impact a patient’s quality of life. Additionally, even in early stage pT1 rectal cancers, up to 1.7% of patients develop local recurrence within 5 years after TME.10 These are of significant consequence in the already pre-disposed senior population with baseline dysfunction. Older patients often present with multiple co-morbidities, prior surgeries, and/or poor functional status, which may lead clinicians to offer less aggressive oncological treatment. Indeed, morbidity and mortality rates are higher in older patients than their younger counterparts.11 Specifically in older adults, overall postoperative morbidity is 35-40%. Rectal cancer-related mortality increases by 37% for every half decade over age 70. In a European multi-center study, mortality increased from 0.5% in patients 50 years of age or younger to 13% in those older than 80 years.12 Additionally, those patients 75 years or older with cardiovascular and pulmonary co-morbidities fared worse than those without these conditions, 41% vs 23% respectively.13 The anastomotic leak rate after low colorectal anastomosis was 10% for those 75 years or older, and 12% for those younger than 75. However, after 6 months, 57% of patients older than 75 years died after anastomotic leak, compared to 8% in the younger cohort.14 In addition, patients older than 70 had overall decreased receipt of cancer-related surgery with increased rates of local excision compared to radical excision. In those patients who underwent a low anterior resection 50-60% had a diverting stoma at the end of the procedure, and after a 7-year follow-up, 19% of stomas were still present.15 Age was a significant risk factor associated with decreased likelihood of stoma reversal. Senior patients were also less likely to receive preor post-operative radiotherapy and adjuvant chemotherapy.

89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

However, multiple studies have shown that in older adults, frailty as defined by validated geriatric tools (eg. SIOG score), defined as a progressive loss of physical and mental functions, and not chronologic age has been deemed a more accurate surgical risk predictor.16-20 Interpretation of current available data should be done so with caution as they are either chronologically based or devoid of evidence regarding the geriatric population at all. The goals of surgical intervention are, therefore, to safely offer potentially curative, life-extending treatment in a manner that returns the patient to his or her baseline functional status in the shortest amount of time. Treating early rectal cancer with small, well-localized disease, therefore, presents surgeons with a dilemma. LYMPH NODE STATUS In early rectal cancer or benign rectal lesions, local excision may be a safer alternative to TME. The goal of local excision is en bloc excision of a target lesion under direct visualization with histopathologic confirmation of an R0 resection. Especially in the appropriately selected geriatric or frail patient, it confers the benefits organ preservation, improved functional outcomes, decreased overall morbidity, operating time and length of in-hospital stay.21-23 Notwithstanding, due to the incomplete resection of the draining lymph node package, local excision does portend an increased risk of local recurrence compared to TME.24-27 As expected, this correlates directly with the risk of lymph node metastases, which is dependent upon the Tstage and histolopathologic characteristics, which in the case of local excision includes T1 and T2 lesions. Even for pT1 rectal cancers, the risk of lymph node metastases is 12-13%. When subclassified, this risk increases proportionally with depth of submucosal invasion, namely, 0-3% for sm1, 811% for sm2, and 11-25% for sm3 lesions. For pT2 rectal cancers, the risk of lymph node metastases is 21%.28-30 The degree of submucosal involvement can also be evaluated by the morphologic pit pattern of each lesion as described by Kudo. The more regular the pattern, types I-III, the more likely the lesion is to be limited to the mucosa, while pit pattern irregularities or loss of architecture, types IV and V, suggest deeper submucosal involvement.31 Therefore, endoscopic resection of very early lesions with pit patterns I-III may also be considered. Additionally, lymphovascular invasion, poor differentiation and more distally located rectal cancers also conferred an increased risk of lymph node metastases. In both pT1 and pT2 lesions, if both lymphovascular invasion or poor differentiation were present, the risk of LNM was 100%.30 However, these histopathologic findings are not available for evaluation until after the lesion is excised. This brings to light the importance of pre-operative lymph node assessment, which plays a critical role in patient selection for local excision of rectal cancers. For lesions under consideration for local excision, reported stage-specific sensitivities and specificities of endoscopic rectal ultrasound (ERUS) are T1 (88% and 98%), T2 (81% and 96%) with corresponding sensitivity and specificity for nodal staging, 73% (95% CI, 71%-76%) and 76% (95% CI, 74%-78%). On the other hand, MRI is 75% accurate in T staging and 71% accurate in N

133 134 135 136 137 138 139

staging, suggesting that the specificity for the distinction of pT1 from pT2 is therefore improved with ERUS, even though sensitivity is similar between the two modalities.32 In sessile T1 cancers, invasion of the submucosa < 1000 μm was associated with 0% lymph node metastases even in the presence of lymphovascular invasion, which was more accurately detected by ERUS.33

High Risk T1

140 141 142 143 144 145

Poorly differentiated

Low Risk T1

Well or moderately differentiated

Sm 2-3

Sm1, < 1000 μm

> 3cm size

< 3 cm size

> 30% luminal involvement

< 30% luminal involvement

Lymphovascular or perineural invasion

No lymphovascular or perineural invasion

Therefore, recognition of risk factors for the presence of LNM by accurate staging is crucial for patient selection. Ideally, local excision would be reserved for patients with small lesions, amenable to access by transanal, TEM, or TAMIS, with minimal risk for lymph node metastases. (Table 1)

Resection margin < 2mm

Negative resection margin > 2mm

Tumor budding T2 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183

Any

Table 1: Assessment of risk of lymph node metastases and local recurrence.

INDICATIONS Local excision is performed for the following indications: - Rectal cancer removal with curative intent, T1 or T2 lesions only - Rectal cancer treatment in patients with significant co-morbidities precluding TME or patient aversion to TME - Rectal cancer palliative treatment in the face of metastatic disease - Excision of polypectomy bed due to presence of histologically-proven invasive disease - Excisional biopsy of large rectal lesion with high index of suspicion for malignancy - Excisional biopsy of benign rectal lesion Local excision is not indicated in T3 or T4 lesions given the increased risk of lymph node involvement. PRE-OPERATIVE EVALUATION All appropriately selected geriatric patients with rectal cancer should undergo multidisciplinary discussion, including geriatric specialty evaluation.34 Patients are evaluated with a complete history and physical examination, including assessment of co-morbidities, bowel function, and baseline continence. Digital rectal examination and proctoscopy are used to determine the location of the lesion from the anal verge, as well as the degree of circumferential involvement. Endoscopy can then allow for characterization of the overlying morphology and Kudo pit pattern, should endoscopic resection be an option in treatment of very early lesions (pit pattern I-III). Diagnostic biopsies can determine tumor

184 185 186 187 188

grade, but excisional biopsy is usually needed for assessment of lymphovascular invasion. As such, clinical staging with diagnostic imaging such as CT, MRI and endoscopic rectal ultrasound (ERUS) becomes critical in pre-operative clinical decision-making for rectal cancer.

189 190 191 192 193 194 195 196 197

Briefly, regardless of which technique is selected, careful consideration should be made for a full mechanical bowel preparation versus enema especially in older patients given that a full mechanical bowel preparation is not without risk of dehydration. Perioperative antibiotics are recommended. The procedure is usually performed under general anesthesia, which achieves complete patient relaxation and facilitates pneumorectum. In recent series, most patients undergoing local excision are able to tolerate general anesthesia independent of their age. Local anesthetic may be used in select patients depending on their specific needs. Patients are positioned on the operating table such that the lesion is in a dependent orientation with adequate padding of all boney prominences and protection of frail skin.

198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225

The distance from the anal margin to the inferior-most extent of the tumor is recorded. A 1cm cuff of macroscopically normal mucosa around the lesion is selected as the resection margin, which is then circumferentially marked with electrocautery. Full-thickness excision down to perirectal fat is recommended although partial-thickness excision with intact muscularis propria is considered in lesions thought to be benign. Hemostasis is achieved and the excision site is irrigated. The defect may be closed primarily with absorbable sutures or left open depending upon surgeon or institutional preference. The specimen is then oriented and pinned to a corkboard before fixation and histopathological analysis.35

TECHNIQUE

OUTCOMES Overall mortality with local excision is 0-3%. Morbidity ranges from 10-45%, and is most commonly related to bleeding and rarely infection.36,37 Global morbidity increases with age in patients who undergo local excision from 20.3% in < 75 years, to 25.9% in those age > 75-84 and 34.1% in those aged > 85 years. Additionally, the older population is more likely to require surgical treatment in the event of an adverse event. Non-surgical complications, related to heart failure, arrhythmias etc, were recorded in ~7.3% of patients 75-84, and 15.9% in those older than 85 years. 38 Neoadjuvant chemoradiation is the most important risk factor for post-operative wound dehiscence and pain, related to breakdown of re-approximated irradiated mucosal edges. As such, local excision after neoadjuvant chemoradiation should be carefully selected in the older population. To date, there is no consensus on whether or not to leave the mucosal defect open or closed as post-operative pain control is comparable.39,40

T1 rectal cancer

226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269

In the 1990’s the Cancer and Leukemia Group B (CALGB) was the only prospective study evaluating local excision as the sole treatment modality in 59 patients with T1 rectal cancers.40 Long-term outcomes demonstrated an 8% local and 5% distal recurrence rate at 10 years. Since then, local recurrence rates with variable inclusion and exclusion criteria and no defined patient selection ranged between 0-30% with local excision alone. In 2010, a multi-center European collaboration including 21 centers with 500 early rectal cancers performing TEM defined that 3year local recurrence rates fell to < 5% in well-differentiated tumors that were small (< 3cm), sm1 and without lymphovascular invasion.42 Without these selection criteria, local recurrence in pT1 lesions ranges from 10-22%. Specifically, after TEM, local recurrence ranges from 3-4% with overlapping recurrence between pT1 sm2-3 and pT2 lesions.29 Possible etiologies for local recurrence may be attributable to R1 resection (microscopically positive margin), implants of tumor cells in the resection space or unknown lymph node involvement. Most recurrences had favorable histopathological features amenable to R0 resection (sm 1 invasion, no lymphovascular invasion or poor differentiation). Oncological and survival outcomes of immediate salvage TME, defined as within 30 days, was comparable to upfront TME. In one study, no local recurrence was noted following salvage TME after TEM for pT1 or pT2 lesions.36 However, it is important to consider that local excision does affect the quality of the TME specimen after salvage surgery and may necessitate abdominoperineal resection for definitive management. This is in part due to the violated mesorectal fascial plane during local excision that has the potential for tumor implantation into deeper layers. The risk of distant metastatic disease recurrence was 5% at 3 years and 7% at 5 years and correlates with the recurrence of local disease. In patients undergoing salvage TME, concurrent metastasectomy is safe and can be carefully considered in older patients after multidisciplinary evaluation with clearly defined goals to prolong life and function. Adjuvant therapy Adjuvant therapy offers patients the benefit of treatment after pathologic confirmation of low or high-risk findings. If patients are deemed at risk to undergo salvage TME, adjuvant chemoradiation may be administered for low or anterior tumors where the deep margin is close to the mesorectal fascia, T2 lesions, lymphovascular invasion or poor differentiation. In the CALGB study, all pT2 tumors were offered adjuvant chemoradiation with 18% local and 12% distant recurrence rates at 10 years. To date, multiple retrospective studies have affirmed that local excision alone for pT1 and pT2 lesions with favorable features with the addition of adjuvant chemoradiation in pT1 or pT2 lesions with high risk features resulted in 0% local recurrence. Local recurrences were therefore observed only in patients with high risk features who had not undergone adjuvant treatment.42-45 However, the exact adjuvant chemoradiation treatment algorithm is variable throughout these studies and is yet to be clearly delineated.

Neoadjuvant therapy

270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313

Neoadjuvant chemoradiation has been observed to decrease toxicity and improve local control of disease in multiple prospective randomized trials for rectal cancer patients undergoing TME with the most important benefit of tumor shrinkage and downstaging. Although the effects of treatment are still under study, a time period between 8-12 weeks is permitted to allow maximal tumor and nodal regression. Indeed, the risk of lymph node metastases in ypT0 tumors is 5-10%, and increases to 10-15% in ypT1, and 20% in ypT2 tumors. Re-staging imaging by means of MRI and ERUS could still qualify ypT0-2 lesions without metastatic disease amenable to local excision. In 2004 Bonnen et al demonstrated that in patients who had undergone neoadjuvant chemoradiation for T3 tumors, overall survival was 86% in the local excision group compared to 81% in the TME group and recurrence rates 6% vs 8% in the local vs TME group respectively after 5 years.44 Another retrospective evaluation of patients with locally advanced rectal cancer and down-staged tumors < 3cm, ycT0-T2N0 managed by TEM had recurrence rates of 15%. Subsequently, an Italian multicenter study included patients with cT2-T3, N0-1 who had undergone neoadjuvant treatment. Of these, all patients with a ypT0 response treated with local excision had 0% recurrence. Patients with ypT2 response and refused TME were the only ones who developed local recurrence after local excision at a rate of 22%.47,48 These findings have been affirmed in subsequent studies.50,51 The only randomized trial comparing TEM with TME in cT2N0 tumors followed by neoadjuvant treatment found that although early postoperative need for transfusion, stoma, hospital stay were improved, local recurrence rates were similar between the two groups and < 10%. In addition, local excision was an independent risk factor for local or distant recurrence and all local recurrences occurred in patients with ypT2 response.50 The preliminary results of the ACOSOG Z6041 trial also confirmed that nearly 50% of patients were complete responders and that all local recurrences were observed in incomplete or partial responders.52,53 Together, these data suggest that in patients with high-risk T1 or T2 lesions, neoadjuvant treatment has the potential to downstage the disease to a ypT0 response, and thereby decrease the risk of local recurrence. In those patients with ypT2 response, TME or palliative local excision should be considered due to higher local and distant recurrence rates. Palliative intent As evidenced above, curative intent should be the goal in any patient. However, patients with rectal lesions deemed to be too frail or with high-risk co-morbidities regardless of age should be discussed in a multidisciplinary committee with the presence of a geriatrician. In a recent study of 693 patients, palliative or consensus intent for local excision was performed in 10.5% of patients over the age of 75, and in 45.4% of patients older than 85 years of age.29,51-53 This group of patients was deemed suitable for less aggressive surgery with partial disease control as a reasonable choice to control of local symptoms of obstruction or bleeding, and to restore quality of life.

314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356

CONCLUSION (Take-home points) -

-

-

-

TME is not contraindicated in carefully selected patients with locally advanced rectal cancer in the older or frail patient after complete multidisciplinary and geriatric evaluation Local excision techniques include transanal excision (TAE), transanal microscopic surgery (TEM), transanal endoscopic operation (TEO), and transanal minimally invasive surgery (TAMIS) T1 and T2 lesions with node-negative disease are candidates for local excision Local and distant recurrence rates are lower in patients with favorable tumor characteristics, namely, tumor size < 3cm, well- or moderately-differentiated, Sm1, no lymphovascular or perineural invasion, < 1000 um invasion despite lymphovascular invasion, or negative resection margin > 2mm Adjuvant therapy should be offered to patients with high-risk histopathologic features after local excision if salvage TME is unable to be performed Local excision can be considered after neoadjuvant therapy in ypT0-2 response with comparable recurrence and survival to TME

REFERENCES 1. Corman ML. Jacques Lisfranc 1790–1847. Dis Colon Rectum. 1983;26(10):694–5. 2. Parks AG. A technique for excising extensive villous papilloma- tous change in the lower rectum. Proc R Soc Med. 1968; 61(5):441–2. 3. Buess G, Hutterer F, Theiss J, Böbel M, Isselhard W, Pichlmaier H. A system for a transanal endoscopic rectum operation. Chirurg. 1984;55(10):677–80. 4. Atallah S, Albert M, Larach S. Transanal minimally invasive sur- gery: a giant leap forward. Surg Endosc. 2010;24(9):2200–5. 5. Albert MR, Atallah SB, deBeche-Adams TC, Izfar S, Larach SW. Transanal minimally invasive surgery (TAMIS) for local excision of benign neoplasms and early-stage rectal cancer: efficacy and outcomes in the first 50 patients. Dis Colon Rectum. 2013;56(3):301–7. 6. Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2015, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2015/, based on November 2017 SEER data submission, posted to the SEER web site, April 2018. 7. Suhool A, Moszkowicz D, et al; Optimal oncologic treatment of rectal cancer in patients over 75 years old: Results of a strategy based on oncogeriatric evaluation. Journal of Visceral Surgery (2018) 155, 17—25 8. Heald RJ, Ryall RDH, Recurrence and survival after total mesorectal excision for rectal cancer. Lancet. 1986;11479- 1482 9. Marijnen CAM, Kapiteijn E, van de Velde CJH, Martijn H, Steup WH, Wiggers T et al. Acute side effects and complications after short-term preoperative radiotherapy

357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399

combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 2002; 20: 817 – 825. 10. Nascimbeni R, Burgart LJ, Nivatvongs S, Larson DR. Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 2002; 45: 200–206. 11. Nakamura T, Sato T, Miura H, Ikeda A, Tsutsui A, Naito M et al (2014) Feasibility and outcomes of surgical therapy in very elderly patients with colorectal cancer. Surg Laparosc Endosc Percutan Tech 24(1):85–88 12. Kessler H, Hermanek P, Wiebelt H. Operative mortality in carci- noma of the rectum. Results of the German Multicentre Study. Int J Colorectal Dis 1993;8(3):158—66. 13. Puig-La Calle J, Quayle J, Thaler HT, et al. Favorable short- term and long-term outcome after elective radical rectal cancer resection in patients 75 years of age or older. Dis Colon Rectum 2000;43(12):1704—9. 14. Rutten HJT, den Dulk M, Lemmens VEPP, van de Velde CJH, Mar- ijnen CAM. Controversies of total mesorectal excision for rectal cancer in elderly patients. Lancet Oncol 2008;9(5):494—501. 15. Law WL, Choi HK, Ho JW, Lee YM, Seto CL. Outcomes of surgery for mid and distal rectal cancer in the elderly. World J Surg 2006;30(4):598—604. 16. Bufalari A, Giustozzi G, Burattini MF, Servili S, Bussotti C, Lucaroni E, Ricci E, Sciannameo F: Rectal cancer surgery in the elderly: a multivariate analysis of outcome risk factors. J Surg Oncol 2006, 93:173–180. 17. Vironen JH, Sainio P, Husa AI, Kellokumpu IH: Complications and survival after surgery for rectal cancer in patients younger than and aged 75 years or older. Dis Colon Rectum 2004, 47:1225–1231. 18. Chiappa A, Zbar AP, Bertani E, Biella F, Audisio RA, Staudacher C: Surgical outcomes for colorectal cancer patients including the elderly. Hepatogastroenterology 2001, 48:440– 444. 19. Puig-La Calle J Jr, Quayle J, Thaler HT, Shi W, Paty PB, Quan SH, Cohen AM, Guillem JG: Favorable short-term and long-term outcome after elective radical rectal cancer resection in patients 75 years of age or older. Dis Colon Rectum 2000, 43:1704–1709. 20. Makela JT, Kiviniemi H, Laitinen S: Survival after operations for colorectal cancer in patients aged 75 years or over. Eur J Surg 2000, 166:473–479. 21. Bentrem DJ, Okabe S, Wong WD, Guillem JG, Weiser MR, Temple LK et al. T1 adenocarcinoma of the rectum: transanal excision or radical surgery? Ann Surg 2005; 242: 472 – 477. 22. Nascimbeni R, Burgart LJ, Nivatvongs S, Larson DR. Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 2002; 45: 200–206. 23. Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T et al. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007; 246: 693–701. 24. Buess G, Kipfmu ̈ ller K, Hack D, Gru ̈ ssner R, Heintz A, Junginger T. Technique of transanal endoscopic microsurgery. Surg Endosc 1988; 2: 71 – 75.

400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442

25. Buess G, Kipfmu ̈ ller K, Ibald R, Heintz A, Hack D, Braunstein S et al. Clinical results of transanal endoscopic microsurgery. Surg Endosc 1988; 2: 245 – 250. 26. Lee W, Lee D, Choi S, Chun H. Transanal endoscopic microsurgery and radical surgery for T1 and T2 rectal cancer. Surg Endosc 2003; 17: 1283 – 1287. 27. Kikuchi R, Takano M, Takagi K, et al. Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum 1995;38(12):1286–1295 28. Maeda K, Koide Y, Katsuno H. When is local excision appropriate for “early” rectal cancer? Surg Today 2014;44(11):2000–2014 29. Chang HC, Huang SC, Chen JS, et al. Risk factors for lymph node metastasis in pT1 and pT2 rectal cancer: a single-institute experi- ence in 943 patients and literature review. Ann Surg Oncol 2012; 19(08):2477–2484 30. Moss A, Bourke MJ, Williams SJ, et al. Endoscopic mucosal resection outcomes and prediction of submucosal cancer from advanced colonic mucosal neoplasia. Gastroenterology. 2011; 140(7):1909–18. 31. Bipat S, Glas AS, Slors FJ, Zwinderman AH, Bossuyt PM, Stoker J. Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging–a meta-analysis. Radiology 2004;232(03):773–783 32. Santoro GA, Gizzi G, Pellegrini L, Battistella G, Di Falco G. The value of high-resolution three-dimensional endorectal ultrasonogra- phy in the management of submucosal invasive rectal tumors. Dis Colon Rectum 2009;52(11):1837–1843 33. Middleton PF, Sutherland LM, Maddern GJ. Transanal endoscopic microsurgery: a systematic review. Dis Colon Rectum 2005; 48(02):270–284 34. Montroni I, Ugolini G, et al; Personalized management of elderly patients with rectal cancer: Expert recommendations of the European Society of Surgical Oncology, European Society of Coloproctology, International Society of Geriatric Oncology, and American College of Surgeons Commission on Cancer. Eur J Surg Oncol. 2018 Nov;44(11):1685-1702. 35. Whiteford, M. Local excision of Rectal Neoplasia. The ASCRS Textbook of Colon and Rectal Surgery. Chapter 29: 495-506. DOI 10.1007/978-3-319-25970-3_29 36. Bach SP, Hill J, Monson JR, et al; Association of Coloproctology of Great Britain and Ireland Transanal Endoscopic Microsurgery (TEM) Collaboration. A predictive model for local recurrence after transanal endoscopic microsurgery for rectal cancer. Br J Surg 2009;96(03):280–290 37. Marks JH, Valsdottir EB, DeNittis A, et al. Transanal endoscopic microsurgery for the treatment of rectal cancer: comparison of wound complication rates with and without neoadjuvant radia- tion therapy. Surg Endosc 2009;23(05):1081–1087 38. Serra-Aracil, X, Serra-Pla, S, Mora-Lopez, L et al. Transanal endoscopic microsurgery in elderly and very elderly patients: a safe option? Observational study with prospective data collection. 39. Perez RO, Habr-Gama A, São Julião GP, Proscurshim I, Scanavini Neto A, GamaRodrigues J. Transanal endoscopic microsurgery for residual rectal cancer after neoadjuvant chemoradiation therapy is associated with significant immediate pain and hospital readmission rates. Dis Colon Rectum 2011;54(05): 545–551

443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485

40. Greenberg JA, Shibata D, Herndon JE II, Steele GD Jr, Mayer R, Bleday R. Local excision of distal rectal cancer: an update of cancer and leukemia group B 8984. Dis Colon Rectum 2008; 51(08):1185–1191, discussion 1191–1194 41. Tsai BM, Finne CO, Nordenstam JF, Christoforidis D, Madoff RD, Mellgren A. Transanal endoscopic microsurgery resection of rectal tumors: outcomes and recommendations. Dis Colon Rec- tum 2010;53(01):16–23 42. Russell AH, Harris J, Rosenberg PJ, et al. Anal sphincter conserva- tion for patients with adenocarcinoma of the distal rectum: long- term results of radiation therapy oncology group protocol 89-02. Int J Radiat Oncol Biol Phys 2000;46(02):313–322 43. Chakravarti A, Compton CC, Shellito PC, et al. Long-term follow-up of patients with rectal cancer managed by local excision with and without adjuvant irradiation. Ann Surg 1999;230(01):49–54 44. Balyasnikova S, Read J, Tait D, et al. The results of local excision with or without postoperative adjuvant chemoradiotherapy for early rectal cancer among patients choosing to avoid radical surgery. Colorectal Dis 2017;19(02):139–147 45. Borstlap WA, Coeymans TJ, Meta-analysis of oncological outcomes after local excision of pT1-2 rectal cancer requiring adjuvant (chemo)radiotherapy or completion surgery. Br J Surg. 2016 Aug;103(9):1105-16. 46. Bonnen M, Crane C, Vauthey JN, et al. Long-term results using local excision after preoperative chemoradiation among selected T3 rectal cancer patients. Int J Radiat Oncol Biol Phys 2004; 60(04):1098–1105 47. Perez RO, Habr-Gama A, Lynn PB, et al. Transanal endoscopic microsurgery for residual rectal cancer (ypT0-2) following neoad- juvant chemoradiation therapy: another word of caution. Dis Colon Rectum 2013;56(01):6–13 48. Pucciarelli S, De Paoli A, Guerrieri M, et al. Local excision after preoperative chemoradiotherapy for rectal cancer: results of a multicenter phase II clinical trial. Dis Colon Rectum 2013; 56(12):1349–1356 49. Verseveld M, de Graaf EJ, Verhoef C, et al; CARTS Study Group. Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery (CARTS study). Br J Surg 2015;102(07):853–860 50. Lezoche E, Baldarelli M, Lezoche G, Paganini AM, Gesuita R, Guerrieri M. Randomized clinical trial of endoluminal locoregio- nal resection versus laparoscopic total mesorectal excision for T2 rectal cancer after neoadjuvant therapy. Br J Surg 2012; 99(09):1211– 1218 51. Rullier E, Rouanet P, et al; Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial.Lancet. 2017 Jul 29;390(10093):469-479. doi: 10.1016/S0140-6736(17)31056-5. Epub 2017 Jun 7. 52. Garcia-Aguilar J, Shi Q, Thomas CR Jr, et al. A phase II trial of neoadjuvant chemoradiation and local excision for T2N0 rectal cancer: preliminary results of the ACOSOG Z6041 trial. Ann Surg Oncol 2012;19(02):384–391 53. São Julião, G, Celentano, J, Alexandre, F, Vailati, B Local excision and endoscopic resections for early rectal cancer. Clin Colon Rectal Surg 2017;30:313–323. 54. Young, D, Kumar, A. Local excision of rectal cancer. Surg Clin N Am 97 (2017) 573–585

486 487 488 489 490 491 492

55. Stornes, T, Wibe, A, Nesbakken, A, Myklebust, T, Endreseth, B. National early rectal cancer treatment revisited. Dis Colon Rectum 2016; 59: 623–629 56. Singh et al. Rectal cancer surgery in older people does not increase postoperative complications – a retrospective analysis. World Journal of Surgical Oncology 2014, 12:355