219. Smith JD, Paty PB, Guillem JG, et al. Anastomotic leak is not associated with oncologic outcome in

patients undergoing low anterior resection for rectal cancer. Ann Surg 2012;256(6):1034–1038.

220. Matthiessen P, Hallbook O, Andersson M, et al. Risk factors for anastomotic leakage after anterior

resection of the rectum. Colorectal Dis 2004; 6(6):462–469.

221. Tan WS, Tang CL, Shi L, et al. Meta-analysis of defunctioning stomas in low anterior resection for

rectal cancer. Br J Surg 2009;96(5):462–472.

222. Machado M, Hallbook O, Goldman S, et al. Defunctioning stoma in low anterior resection with

colonic pouch for rectal cancer: a comparison between two hospitals with a different policy. Dis

Colon Rectum 2002; 45(7):940–945.

223. Rondelli F, Reboldi P, Rulli A, et al. Loop ileostomy versus loop colostomy for fecal diversion after

colorectal or coloanal anastomosis: a meta-analysis. Int J Colorect Dis 2009;24(5):479–488.

224. Chun LJ, Haigh PI, Tam MS, et al. Defunctioning loop ileostomy for pelvic anastomoses: predictors

of morbidity and nonclosure. Dis Colon Rectum 2012;55(2):167–174.

225. Marr R, Birbeck K, Garvican J, et al. The modern abdominoperineal excision: the next challenge

after total mesorectal excision. Ann Surg 2005;242(1):74–82.

226. Perdawood SK, Lund T. Extralevator versus standard abdominoperineal excision for rectal cancer.

Tech Coloproctol 2014;19(3):145–152.

227. Musters GD, Buskens CJ, Bemelman WA, et al. Perineal wound healing after abdominoperineal

resection for rectal cancer: a systematic review and meta-analysis. Dis Colon Rectum

2014;57(9):1129–1139.

228. Yu HC, Peng H, He XS, et al. Comparison of short- and long-term outcomes after extralevator

abdominoperineal excision and standard abdominoperineal excision for rectal cancer: a systematic

review and meta-analysis. Int J Colorect Dis 2014;29(2):183–191.

229. de Campos-Lobato LF, Stocchi L, Dietz DW, et al. Prone or lithotomy positioning during an

abdominoperineal resection for rectal cancer results in comparable oncologic outcomes. Dis Colon

Rectum 2011;54(8):939–946.

230. Lujan J, Valero G, Hernandez Q, et al. Randomized clinical trial comparing laparoscopic and open

1822

surgery in patients with rectal cancer. Br J Surg 2009;96(9):982–989.

231. Ng KH, Ng DC, Cheung HY, et al. Laparoscopic resection for rectal cancers: lessons learned from

579 cases. Ann Surg 2009;249(1):82–86.

232. Greenblatt DY, Rajamanickam V, Pugely AJ, et al. Short-term outcomes after laparoscopic-assisted

proctectomy for rectal cancer: results from the ACS NSQIP. J Am Coll Surg 2011;212(5):844–854.

233. Yeo H, Niland J, Milne D, et al. Incidence of minimally invasive colorectal cancer surgery at

National Comprehensive Cancer Network centers. J Natl Cancer Inst 2015;107(1):362.

234. Jayne DG, Thorpe HC, Copeland J, et al. Five-year follow-up of the Medical Research Council

CLASICC trial of laparoscopically assisted versus open surgery for colorectal cancer. Br J Surg

2010;97(11):1638–1645.

235. Jeong SY, Park JW, Nam BH, et al. Open versus laparoscopic surgery for mid-rectal or low-rectal

cancer after neoadjuvant chemoradiotherapy (COREAN trial): survival outcomes of an open-label,

non-inferiority, randomised controlled trial. Lancet Oncol 2014;15(7):767–774.

236. van der Pas MH, Haglind E, Cuesta MA, et al. Laparoscopic versus open surgery for rectal cancer

(COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet Oncol 2013;14(3):210–218.

237. Vithiananthan S, Cooper Z, Betten K, et al. Hybrid laparoscopic flexure takedown and open

procedure for rectal resection is associated with significantly shorter length of stay than equivalent

open resection. Dis Colon Rectum 2001;44(7):927–935.

238. Xiong B, Ma L, Zhang C, et al. Robotic versus laparoscopic total mesorectal excision for rectal

cancer: a meta-analysis. J Surg Res 2014;188(2):404–414.

239. Collinson FJ, Jayne DG, Pigazzi A, et al. An international, multicentre, prospective, randomised,

controlled, unblinded, parallel-group trial of robotic-assisted versus standard laparoscopic surgery

for the curative treatment of rectal cancer. Int J Colorect Dis 2012;27(2):233–241.

240. de Lacy AM, Rattner DW, Adelsdorfer C, et al. Transanal natural orifice transluminal endoscopic

surgery (NOTES) rectal resection: “down-to-up” total mesorectal excision (TME)–short-term

outcomes in the first 20 cases. Surg Endosc 2013;27(9):3165–3172.

241. Rouanet P, Mourregot A, Azar CC, et al. Transanal endoscopic proctectomy: an innovative

procedure for difficult resection of rectal tumors in men with narrow pelvis. Dis Colon Rectum

2013;56(4):408–415.

242. Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal

Tumor Study Group. N Eng J Med 1985;312(23):1465–1472.

243. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy

for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 1988;80:21–29.

244. Gerard A, Buyse M, Nordlinger B, et al. Preoperative radiotherapy as adjuvant treatment in rectal

cancer: final results of a randomized study of the European Organization for Research and

Treatment of Cancer (EORTC). Ann Surg 1988;208:606–614.

245. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total

mesorectal excision for resectable rectal cancer. N Eng J Med 2001;345(9):638–646.

246. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by

combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Eng J

Med 1994;331(8):502–507.

247. Smalley SR, Benedetti JK, Williamson SK, et al. Phase III trial of fluorouracil-based chemotherapy

regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol

2006;24(22):3542–3547.

248. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal

cancer. N Eng J Med 2006;355(11):1114–1123.

249. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent

fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J Clin Oncol

2006;24(28):4620–4625.

250. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for

rectal cancer. N Eng J Med 2004;351(17):1731–1740.

251. Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves diseasefree survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol

2009;27(31):5124–5130.

1823

252. O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the preoperative

multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant

Breast and Bowel Project trial R-04. J Clin Oncol 2014;32(18):1927–1934.

253. Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for

locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet

Oncol 2012;13(6):579–588.

254. Gerard JP, Azria D, Gourgou-Bourgade S, et al. Comparison of two neoadjuvant chemoradiotherapy

regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige

2. J Clin Oncol 2010;28(10):1638–1644.

255. Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to preoperative chemoradiation with

or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01

randomized phase III trial. J Clin Oncol 2011;29(20):2773–2780.

256. Rodel C, Liersch T, Becker H, et al. Preoperative chemoradiotherapy and postoperative

chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal

cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol

2012;13(7):679–687.

257. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term results of a randomized trial

comparing preoperative short-course radiotherapy with preoperative conventionally fractionated

chemoradiation for rectal cancer. Br J Surg 2006;93(10):1215–1223.

258. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus longcourse chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: TransTasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012;30(31):3827–3833.

259. Schrag D, Chemotherapy alone or chemotherapy plus radiation therapy in treating patients with

locally advanced rectal cancer undergoing surgery. [cited 3/18/2015]; available from

http://clinicaltrials.gov/show/NCT01515787.

260. Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative

chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.

Lancet Oncol 2014; 15(2):184–190.

261. Petersen SH, Harling H, Kirkeby LT, et al. Postoperative adjuvant chemotherapy in rectal cancer

operated for cure. Cochrane Database Syst Rev 2012;3:CD004078.

262. Biagi JJ, Raphael M, Mackillop WJ, et al. Association between time to initiation of adjuvant

chemotherapy and survival in colorectal cancer: a systemic review and meta-analysis. JAMA

2011;305(22):2335–2342.

263. Chau I, Brown G, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin followed by

synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined

poor-risk rectal cancer. J Clin Oncol 2006;24(4):668–674.

264. Fernandez-Martos C, Pericay C, Aparicio J, et al. Phase II, randomized study of concomitant

chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX)

compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in

magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study.

J Clin Oncol 2010;28(5):859–865.

265. Cercek A, Goodman KA, Hajj C, et al. Neoadjuvant chemotherapy first, followed by chemoradiation

and then surgery, in the management of locally advanced rectal cancer. J Natl Compr Cancer Netw

2014; 12(4):513–519.

266. Marijnen CA, Kapiteijn E, van de Velde CJ, et al. Acute side effects and complications after shortterm preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer:

report of a multicenter randomized trial. J Clin Oncol 2002;20(3):817–825.

267. Paun BC, Cassie S, MacLean AR, et al. Postoperative complications following surgery for rectal

cancer. Ann Surg 2010;251(5):807–818.

268. Peeters KC, van de Velde CJ, Leer JW, et al. Late side effects of short-course preoperative

radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel

dysfunction in irradiated patients–a Dutch colorectal cancer group study. J Clin Oncol

2005;23(25):6199–6206.

269. Hendren SK, O’Connor BI, Liu M, et al. Prevalence of male and female sexual dysfunction is high

following surgery for rectal cancer. Ann Surg 2005;242(2):212–223.

1824

 

involvement with endoluminal US, CT, and MR imaging–a meta-analysis. Radiology

2004;232(3):773–783.

164. Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of

rectal cancer? J Clin Oncol 2008;26(2):303–312.

165. MERCURY Study Group. Diagnostic accuracy of preoperative magnetic resonance imaging in

predicting curative resection of rectal cancer: prospective observational study. BMJ

2006;333(7572):779.

166. Brown G, Radcliffe AG, Newcombe RG, et al. Preoperative assessment of prognostic factors in

rectal cancer using high-resolution magnetic resonance imaging. Br J Surg 2003;90(3):355–364.

167. Taylor FG, Quirke P, Heald RJ, et al. Preoperative magnetic resonance imaging assessment of

circumferential resection margin predicts disease-free survival and local recurrence: 5-year followup results of the MERCURY study. J Clin Oncol 2014;32(1):34–43.

168. Taylor FG, Quirke P, Heald RJ, et al. Preoperative high-resolution magnetic resonance imaging can

identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a

prospective, multicenter, European study. Ann Surg 2011;253(4):711–719.

169. Blomqvist L, Glimelius B. The ‘good’, the ‘bad’, and the ‘ugly’ rectal cancers. Acta Oncol

2008;47(1):5–8.

170. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0

distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg

2004;240(4):711–717; discussion 7–8.

171. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clinical complete responders

after chemoradiation for rectal cancer. J Clin Oncol 2011;29(35):4633–4640.

172. Guillem JG CD, Shia J, Moore HG, et al. Clinical examination following preoperative

chemoradiation for rectal cancer is not a reliable surrogate end point. J Clin Oncol

2005;23(15):3475–3479.

173. Pastor C SJ, Sola J, Baixauli J, et al. Accuracy of endoscopic ultrasound to assess tumor response

after neoadjuvant treatment in rectal cancer: can we trust the findings? Dis Colon Rectum

2011;54(9):1141–1146.

174. Allen SD, Padhani AR, Dzik-Jurasz AS, et al. Rectal carcinoma: MRI with histologic correlation

before and after chemoradiation therapy. AJR Am J Roentgenol 2007;188(2):442–451.

175. Guillem JG, Ruby JA, Leibold T, et al. Neither FDG-PET nor CT is able to distinguish between a

pathological complete response and an incomplete response after neoadjuvant chemoradiation in

locally advanced rectal cancer: a prospective study. Ann Surg 2012;(2):289–295.

176. Gollub MJ, Gultekin DH, Akin O, et al. Dynamic contrast enhanced-MRI for the detection of

pathological complete response to neoadjuvant chemotherapy for locally advanced rectal cancer.

Eur Radiol 2012;22:821–831.

177. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology - Rectal

Cancer. Available at www.nccn.org. 2015 [cited February 2015].

178. Garcia-Aguilar J, Mellgren A, Sirivongs P, et al. Local excision of rectal cancer without adjuvant

therapy: a word of caution. Ann Surg 2000; 231(3):345–351.

179. Paty PB, Nash GM, Baron P, et al. Long-term results of local excision for rectal cancer. Ann Surg

2002;236(4):522–529; discussion 9–30.

180. Madbouly KM, Remzi FH, Erkek BA, et al. Recurrence after transanal excision of T1 rectal cancer:

should we be concerned? Dis Colon Rectum 2005;48(4):711–719; discussion 9–21.

181. Weiser MR, Landmann RG, Wong WD, et al. Surgical salvage of recurrent rectal cancer after

transanal excision. Dis Colon Rectum 2005;48(6):1169–1175.

182. Friel CM, Cromwell JW, Marra C, et al. Salvage radical surgery after failed local excision for early

rectal cancer. Dis Colon Rectum 2002;45(7):875–879.

183. You YN, Baxter NN, Stewart A, et al. Is the increasing rate of local excision for stage I rectal cancer

in the United States justified? a nationwide cohort study from the National Cancer Database. Ann

Surg 2007;245(5):726–733.

184. Peng J, Chen W, Sheng W, et al. Oncological outcome of T1 rectal cancer undergoing standard

resection and local excision. Colorectal Dis 2011;13(2):e14–e19.

185. Kidane B, Chadi SA, Kanters S, et al. Local resection compared with radical resection in the

1820

treatment of T1N0M0 rectal adenocarcinoma: a systematic review and meta-analysis. Dis Colon

Rectum 2015;58(1):122–140.

186. Clancy C, Burke JP, Albert MR, et al. Transanal endoscopic microsurgery versus standard transanal

excision for the removal of rectal neoplasms: A systematic review and meta-analysis. Dis Colon

Rectum 2015;58(2):254–261.

187. Mellgren A, Sirivongs P, Rothenberger DA, et al. Is local excision adequate therapy for early rectal

cancer? Dis Colon Rectum 2000;43(8):1064–1071; discussion 71–74.

188. Stitzenberg KB, Sanoff HK, Penn DC, et al. Practice patterns and long-term survival for early-stage

rectal cancer. J Clin Oncol 2013;31(34):4276–4282.

189. Bhangu A, Brown G, Nicholls RJ, et al. Survival outcome of local excision versus radical resection

of colon or rectal carcinoma: a surveillance, epidemiology, and end results (seer) population-based

study. Ann Surg 2013;258(4):563–571.

190. Minsky BD, Enker WE, Cohen AM, et al. Local excision and postoperative radiation therapy for

rectal cancer. Am J Clin Oncol 1994;17(5):411–416.

191. 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(1):49–54.

192. Bouvet M, Milas M, Giacco GG, et al. Predictors of recurrence after local excision and postoperative

chemoradiation therapy of adenocarcinoma of the rectum. Ann Surg Oncol 1999;6(1):26–32.

193. Benson R, Wong CS, Cummings BJ, et al. Local excision and postoperative radiotherapy for distal

rectal cancer. Int J Radiat Oncol Biol Phys 2001;50(5):1309–1316.

194. Greenberg JA, Shibata D, Herndon JE, 2nd, et al. Local excision of distal rectal cancer: an update of

cancer and leukemia group B 8984. Dis Colon Rectum 2008;51(8):1185–1191; discussion 91–94.

195. Kim CJ, Yeatman TJ, Coppola D, et al. Local excision of T2 and T3 rectal cancers after downstaging

chemoradiation. Ann Surg 2001;234(3):352–358; discussion 8–9.

196. Nair RM, Siegel EM, Chen DT, et al. Long-term results of transanal excision after neoadjuvant

chemoradiation for T2 and T3 adenocarcinomas of the rectum. J Gastrointest Surg

2008;12(10):1797–1805; discussion 805–806.

197. Lezoche E, Baldarelli M, Lezoche G, et al. Randomized clinical trial of endoluminal locoregional

resection versus laparoscopic total mesorectal excision for T2 rectal cancer after neoadjuvant

therapy. Br J Surg 2012;99(9):1211–1218.

198. 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(2):384–391.

199. Garcia-Aguilar J, Renfro LA, Chow, OS, et al. Organ preservation for clinical T2N0 distal rectal

cancer using neoadjuvant chemoradiotherapy and local excision (ACOSOG Z6041): results of an

open-label, single-arm, multi-institutional, phase 2 trial. Lancet Oncol 2015;15(15):1537–1546.

200. Rondelli F, Trastulli S, Cirocchi R, et al. Rectal washout and local recurrence in rectal resection for

cancer: a meta-analysis. Colorectal Dis 2012;14(11):1313–1321.

201. Lange MM, Buunen M, van de Velde CJ, et al. Level of arterial ligation in rectal cancer surgery:

low tie preferred over high tie. A review. Dis Colon Rectum 2008;51(7):1139–1145.

202. Zotti P, Del Bianco P, Serpentini S, et al. Validity and reliability of the MSKCC Bowel Function

instrument in a sample of Italian rectal cancer patients. Eur J Surg Oncol 2011;37(7):589–596.

203. Emmertsen KJ, Laurberg S. Low anterior resection syndrome score: development and validation of

a symptom-based scoring system for bowel dysfunction after low anterior resection for rectal

cancer. Ann Surg 2012;255(5):922–928.

204. Emmertsen KJ, Laurberg S. Bowel dysfunction after treatment for rectal cancer. Acta Oncol

2008;47(6):994–1003.

205. Lundby L, Krogh K, Jensen VJ, et al. Long-term anorectal dysfunction after postoperative

radiotherapy for rectal cancer. Dis Colon Rectum 2005;48(7):1343–1349; discussion 9–52; author

reply 52.

206. Chen TY, Wiltink LM, Nout RA, et al. Bowel function 14 years after preoperative short-course

radiotherapy and total mesorectal excision for rectal cancer: Report of a multicenter randomized

trial. Clin Colorectal Cancer 2014;14(2):106–114.

207. Lewis WG, Martin IG, Williamson ME, et al. Why do some patients experience poor functional

1821

results after anterior resection of the rectum for carcinoma? Dis Colon Rectum 1995;38(3):259–263.

208. Brown CJ, Fenech DS, McLeod RS. Reconstructive techniques after rectal resection for rectal

cancer. Cochrane Database Syst Rev 2008(2):Cd006040.

209. Parc R, Tiret E, Frileux P, et al. Resection and colo-anal anastomosis with colonic reservoir for

rectal carcinoma. Br J Surg 1986;73(2):139–141.

210. Seow-Choen F, Goh HS. Prospective randomized trial comparing J colonic pouch-anal anastomosis

and straight coloanal reconstruction. Br J Surg 1995;82(5):608–610.

211. Hida J, Yasutomi M, Fujimoto K, et al. Functional outcome after low anterior resection with low

anastomosis for rectal cancer using the colonic J-pouch. Prospective randomized study for

determination of optimum pouch size. Dis Colon Rectum 1996;39(9):986–991.

212. Lazorthes F, Gamagami R, Chiotasso P, et al. Prospective, randomized study comparing clinical

results between small and large colonic J-pouch following coloanal anastomosis. Dis Colon Rectum

1997;40(12):1409–1413.

213. Machado M, Nygren J, Goldman S, et al. Functional and physiologic assessment of the colonic

reservoir or side-to-end anastomosis after low anterior resection for rectal cancer: a two-year

follow-up. Dis Colon Rectum 2005;48(1):29–36.

214. Daams F, Wu Z, Lahaye MJ, et al. Prediction and diagnosis of colorectal anastomotic leakage: a

systematic review of literature. World J Gastrointest Surg 2014;6(2):14–26.

215. Jones OM, John SK, Horseman N, et al. Low anastomotic leak rate after colorectal surgery: a

single-centre study. Colorectal Dis 2007;9(8):740–744.

216. Eberl T, Jagoditsch M, Klingler A, et al. Risk factors for anastomotic leakage after resection for

rectal cancer. Am J Surg 2008;196(4):592–598.

217. McArdle CS, McMillan DC, Hole DJ. Impact of anastomotic leakage on long-term survival of

patients undergoing curative resection for colorectal cancer. Br J Surg 2005;92(9):1150–1154.

218. den Dulk M, Marijnen CA, Collette L, et al. Multicentre analysis of oncological and survival

outcomes following anastomotic leakage after rectal cancer surgery. Br J Surg 2009;96(9):1066–

1075.

 

120. Zhuang CL, Ye XZ, Zhang XD, et al. Enhanced recovery after surgery programs versus traditional

care for colorectal surgery: a meta-analysis of randomized controlled trials. Dis Colon Rectum

2013;56(5):667–678.

121. Spanjersberg WR, Reurings J, Keus F, et al. Fast track surgery versus conventional recovery

strategies for colorectal surgery. Cochrane Database Syst Rev 2011(2):Cd007635.

122. ERAS Compliance Group. The impact of enhanced recovery protocol compliance on elective

colorectal cancer resection: results from an international registry. Ann Surg 2015;261(6):1153–

1159.

123. Monson JR, Weiser MR, Buie WD, et al. Standards Practice Task Force of the American Society of

Colon and Rectal Surgeons. Practice parameters for the management of rectal cancer (revised). Dis

Colon Rectum 2013;56(5):535–550.

124. Shiozawa M, Akaike M, Yamada R, et al. Clinicopathological features of skip metastasis in

colorectal cancer. Hepatogastroenterology 2007; 54(73):81–84.

125. Toyota S, Ohta H, Anazawa S. Rationale for extent of lymph node dissection for right colon cancer.

Dis Colon Rectum 1995;38(7):705–711.

126. Saha S, Johnston G, Korant A, et al. Aberrant drainage of sentinel lymph nodes in colon cancer and

its impact on staging and extent of operation. Am J Surg 2013;205(3):302–305; discussion 5–6.

127. Wiggers T, Jeekel J, Arends JW, et al. No-touch isolation technique in colon cancer: a controlled

prospective trial. Br J Surg 1988;75(5):409–415.

128. Heald RJ. The ‘Holy Plane’ of rectal surgery. J Royal Soc Med 1988;81(9):503–508.

129. MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet

1993;341(8843):457–460.

130. Hohenberger W, Weber K, Matzel K, et al. Standardized surgery for colonic cancer: complete

mesocolic excision and central ligation–technical notes and outcome. Colorectal Dis 2009;11(4):354–

364; discussion 64–65.

131. Bertelsen CA, Neuenschwander AU, Jansen JE, et al. Disease-free survival after complete mesocolic

excision compared with conventional colon cancer surgery: a retrospective, population-based study.

Lancet Oncol 2015;16(2):161–168.

132. Nivatvongs S. Surgical management of malignant colorectal polyps. Surg Clin North Am

2002;82(5):959–966.

133. Haggitt RC, Glotzbach RE, Soffer EE, et al. Prognostic factors in colorectal carcinomas arising in

adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology

1985;89(2):328–336.

134. Butte JM, Tang P, Gonen M, et al. Rate of residual disease after complete endoscopic resection of

malignant colonic polyp. Dis Colon Rectum 2012;55(2):122–127.

135. Okabe S, Shia J, Nash G, et al. Lymph node metastasis in T1 adenocarcinoma of the colon and

rectum. J Gastrointest Surg 2004;8(8):1032–1039; discussion 9–40.

136. Kessler H, Hohenberger W. Extended lymphadenectomy in colon cancer is crucial. World J Surg

2013;37(8):1789–1798.

137. Nosho K, Kure S, Irahara N, et al. A prospective cohort study shows unique epigenetic, genetic, and

prognostic features of synchronous colorectal cancers. Gastroenterology 2009;137(5):1609–1620.e1–

3.

138. Yang C, Wexner SD, Safar B, et al. Conversion in laparoscopic surgery: does intraoperative

complication influence outcome? Surg Endosc 2009;23(11):2454–2458.

139. Fung AK, Aly EH. Systematic review of single-incision laparoscopic colonic surgery. Br J Surg

2012;99(10):1353–1364.

140. Kim CW, Kim CH, Baik SH. Outcomes of robotic-assisted colorectal surgery compared with

laparoscopic and open surgery: a systematic review. J Gastrointest Surg 2014;18(4):816–830.

141. Laurie JA, Moertel C, Fleming TR, et al. Surgical adjuvant therapy of large bowel carcinoma: an

evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol

1989;7:1447–1456.

142. Moertel CG, Fleming TR, Macdonald JS, et al. Intergroup study of fluorouracil plus levamisole as

adjuvant therapy for stage II/Dukes’ B2 colon cancer. J Clin Oncol 1995;13(12):2936–2943.

143. Porschen R, Bermann A, Loffler T, et al. Fluorouracil plus leucovorin as effective adjuvant

1818

chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. J Clin

Oncol 2001;19(6):1787–1794.

144. Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy in

patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant

Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol

1999;17(5):1349–1355.

145. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for

resected colon cancer in elderly patients. N Eng J Med 2001;345(15):1091–1097.

146. Andre T, Boni C, Mounedi-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant

treatment for colon cancer. N Eng J Med 2004;350:2343–2351.

147. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and

leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol

2009;27(19):3109–3116.

148. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly

infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of Stage III

colon cancer: PETACC-3. J Clin Oncol 2009;27:3117–3125.

149. Allegra CJ, Yothers G, O’Connell MJ, et al. Bevacizumab in stage II-III colon cancer: 5-year update

of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol 2013;31(3):359–

364.

150. de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy

as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet

Oncol 2012; 13(12):1225–1233.

151. Alberts SR SD, Nair S, Mahoney MR, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or

without cetuximab on survival among patients with resected stage III colon cancer: a randomized

trial. JAMA 2012;307(13):1383–1393.

152. Schippinger W, Samonigg H, Schaberl-Moser R, et al. A prospective randomised phase III trial of

adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer. Br

J Cancer 2007; 97(8):1021–1027.

153. Gray R, Barnwell J, McConkey C, et al. Adjuvant chemotherapy versus observation in patients with

colorectal cancer: a randomised study. Lancet 2007;370(9604):2020–2029.

154. Figueredo A, Charette ML, Maroun J, et al. Adjuvant therapy for stage II colon cancer: a systematic

review from the Cancer Care Ontario Program in evidence-based care’s gastrointestinal cancer

disease site group. J Clin Oncol 2004;22(16):3395–3407.

155. Marshall JL. Risk assessment in Stage II colorectal cancer. Oncology (Williston Park, NY) 2010;24(1

Suppl 1):9–13.

156. Ribic CM SD, Moore MJ, Thibodeau SN, et al. Tumor microsatellite-instability status as a predictor

of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Eng J Med

2003;349(3):247–257.

157. Nicholls RJ, Mason AY, Morson BC, et al. The clinical staging of rectal cancer. Br J Surg

1982;69(7):404–409.

158. Garcia-Aguilar J, Pollack J, Lee SH, et al. Accuracy of endorectal ultrasonography in preoperative

staging of rectal tumors. Dis Colon Rectum 2002;45(1):10–15.

159. Beets-Tan RG, Lambregts DM, Maas M, et al. Magnetic resonance imaging for the clinical

management of rectal cancer patients: recommendations from the 2012 European Society of

Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol

2013;23(9):2522–2531.

160. Heijnen LA, Lambregts DM, Martens MH, et al. Performance of gadofosveset-enhanced MRI for

staging rectal cancer nodes: can the initial promising results be reproduced? Eur Radiol

2014;24(2):371–379.

161. Hotker AM, Garcia-Aguilar J, Gollub MJ. Multiparametric MRI of rectal cancer in the assessment of

response to therapy: a systematic review. Dis Colon Rectum 2014;57(6):790–799.

162. Kwok H, Bissett IP, Hill GL. Preoperative staging of rectal cancer. Int J Colorectal Dis 2000;15(1):9–

20.

163. Bipat S, Glas AS, Slors FJ, et al. Rectal cancer: local staging and assessment of lymph node

1819

 

51. Betge J, Pollheimer MJ, Lindtner RA, et al. Intramural and extramural vascular invasion in

colorectal cancer: prognostic significance and quality of pathology reporting. Cancer

2012;118(3):628–638.

52. Betge J, Kornprat P, Pollheimer MJ, et al. Tumor budding is an independent predictor of outcome

in AJCC/UICC stage II colorectal cancer. Ann Surg Oncol 2012;19(12):3706–3712.

53. Weiser MR, Landmann RG, Kattan MW, et al. Individualized prediction of colon cancer recurrence

using a nomogram. J Clin Oncol 2008;26(3):380–385.

54. Wong NA, Gonzalez D, Salto-Tellez M, et al. RAS testing of colorectal carcinoma—a guidance

document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Group.

J Clin Pathol 2014;67(9):751–757.

55. O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and

recurrence in four independent studies of patients with stage II/III colon cancer treated with

surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 2010;28(25):3937–

3944.

56. Gray RG, Quirke P, Handley K, et al. Validation study of a quantitative multigene reverse

transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with

stage II colon cancer. J Clin Oncol 2011;29(35):4611–4619.

57. Yothers G, O’Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in

NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with

fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol 2013; 31(36):4512–

4519.

58. Venook AP, Niedzwiecki D, Lopatin M, et al. Biologic determinants of tumor recurrence in stage II

colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B

(CALGB) 9581. J Clin Oncol 2013;31(14):1775–1781.

59. Salazar R, Roepman P, Capella G, et al. Gene expression signature to improve prognosis prediction

of stage II and III colorectal cancer. J Clin Oncol 2011;29(1):17–24.

60. Kopetz S, Tabernero J, Rosenberg R, et al. Genomic classifier ColoPrint predicts recurrence in stage

II colorectal cancer patients more accurately than clinical factors. Oncologist 2015;20(2):127–133.

61. Kennedy RD, Bylesjo M, Kerr P, et al. Development and independent validation of a prognostic

assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue. J Clin Oncol

2011;29(35):4620–4626.

62. Winawer SJ, Zauber A, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy.

The National Polyp Study Workgroup. N Eng J Med 1993;329(27):1977–1981.

63. Lieberman DA. Clinical practice. Screening for colorectal cancer. N Eng J Med 2009;361(12):1179–

1187.

64. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of

colorectal-cancer deaths. N Eng J Med 2012;366(8):687–696.

65. Shaukat A, Mongin SJ, Geisser MS, et al. Long-term mortality after screening for colorectal cancer.

N Eng J Med 2013;369(12):1106–1114.

66. Loberg M, Kalager M, Holme O, et al. Long-term colorectal-cancer mortality after adenoma

removal. N Eng J Med 2014;371(9):799–807.

67. Whitlock EP, Lin J, Liles E, et al. U.S. Preventive Services Task Force Evidence Syntheses, formerly

Systematic Evidence Reviews. Screening for Colorectal Cancer: An Updated Systematic Review. Rockville,

MD: Agency for Healthcare Research and Quality (US); 2008.

68. Whitlock EP, Lin JS, Liles E, et al. Screening for colorectal cancer: a targeted, updated systematic

review for the U.S. Preventive Services Task Force. Ann Intern Med 2008;149(9):638–658.

69. Lansdorp-Vogelaar I, Knudsen AB, Brenner H. Cost-effectiveness of colorectal cancer screening.

Epidemiol Rev 2011;33(1):88–100.

70. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for

fecal occult blood. Minnesota Colon Cancer Control Study. N Eng J Med 1993;328(19):1365–1371.

71. Jorgensen OD, Kronborg O, Fenger C. A randomised study of screening for colorectal cancer using

faecal occult blood testing: results after 13 years and seven biennial screening rounds. Gut

2002;50(1):29–32.

72. Lindholm E, Brevinge H, Haglind E. Survival benefit in a randomized clinical trial of faecal occult

1815

blood screening for colorectal cancer. Br J Surg 2008;95(8):1029–1036.

73. Brenner H, Tao S. Superior diagnostic performance of faecal immunochemical tests for haemoglobin

in a head-to-head comparison with guaiac based faecal occult blood test among 2235 participants of

screening colonoscopy. Eur J Cancer. 2013;49(14):3049–3054.

74. Hol L, van Leerdam ME, van Ballegooijen M, et al. Screening for colorectal cancer: randomised trial

comparing guaiac-based and immunochemical faecal occult blood testing and flexible

sigmoidoscopy. Gut 2010;59(1):62–68.

75. Quintero E, Castells A, Bujanda L, et al. Colonoscopy versus fecal immunochemical testing in

colorectal-cancer screening. N Eng J Med 2012; 366(8):697–706.

76. Ahlquist DA, Sargent DJ, Loprinzi CL, et al. Stool DNA and occult blood testing for screen detection

of colorectal neoplasia. Ann Intern Med 2008;149(7):441–450, w81.

77. Lidgard GP, Domanico MJ, Bruinsma JJ, et al. Clinical performance of an automated stool DNA

assay for detection of colorectal neoplasia. Clin Gastroenterol Hepatol 2013;11(10):1313–1318.

78. Imperiale TF RD, Itzkowitz SH, Levin TR, et al. Multitarget stool DNA testing for colorectal-cancer

screening. N Engl J Med 2014;370(14):1287–1297.

79. Selby JV, Friedman GD, Quesenberry CP Jr, et al. A case-control study of screening sigmoidoscopy

and mortality from colorectal cancer. N Eng J Med 1992;326(10):653–657.

80. Newcomb PA, Norfleet RG, Storer BE, et al. Screening sigmoidoscopy and colorectal cancer

mortality. J Natl Cancer Inst 1992;84(20):1572–1575.

81. Schoen RE, Pinsky PF, Weissfeld JL, et al. PLCO Project Team. Colorectal-cancer incidence and

mortality with screening flexible sigmoidoscopy. N Engl J Med 2012;355(25):2345–2357.

82. Holme Ø, L⊘berg M, Kalager M, et al. Effect of flexible sigmoidoscopy screening on colorectal

cancer incidence and mortality: a randomized clinical trial. JAMA 2014;312(6):606–615.

83. Segnan N, Armaroli P, Bonelli L, et al. Once-only sigmoidoscopy in colorectal cancer screening:

follow-up findings of the Italian Randomized Controlled Trial–SCORE. J Natl Cancer Inst

2011;103(17):1310–1322.

84. Atkin WS, Edwards R, Kralj-Hans I, et al. UK Flexible Sigmoidoscopy Trial Investigators. Once-only

flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised

controlled trial. Lancet 2010;375(9726):1624–1633.

85. Segnan N, Senore C, Andreoni B, et al. Randomized trial of different screening strategies for

colorectal cancer: patient response and detection rates. J Natl Cancer Inst 2005;97(5):347–357.

86. Rutter CM, Savarino JE. An evidence-based microsimulation model for colorectal cancer: validation

and application. Cancer Epidemiol Biomarkers Prev 2010;19(8):1992–2002.

87. Sharaf RN, Ladabaum U. Comparative effectiveness and cost-effectiveness of screening colonoscopy

vs. sigmoidoscopy and alternative strategies. Am J Gastroenterol 2013;108(1):120–132.

88. de Haan MC, Pickhardt PJ, Stoker J. CT colonography: accuracy, acceptance, safety and position in

organised population screening. Gut 2015;64(2):342–350.

89. Johnson CD, Chen MH, Toledano AY, et al. Accuracy of CT colonography for detection of large

adenomas and cancers. N Eng J Med 2008;359(12):1207–1217.

90. Burt RW, Cannon JA, David DS, et al. colorectal cancer screening. J Natl Compr Cancer Netw

2013;11(12):1538–1575.

91. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of

colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer

Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of

Radiology. Gastroenterology 2008;134(5):1570–1595.

92. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after

polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the

American Cancer Society. Gastroenterology 2006;130(6):1872–1885.

93. Pignone M, Saha S, Hoerger T, et al. Cost-effectiveness analyses of colorectal cancer screening: a

systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2002;137(2):96–104.

94. Maciosek MV, Coffield AB, Edwards NM, et al. Priorities among effective clinical preventive

services: results of a systematic review and analysis. Am J Prevent Med 2006;31(1):52–61.

95. Singh S, Singh PP, Murad MH, et al. Prevalence, risk factors, and outcomes of interval colorectal

cancers: a systematic review and meta-analysis. Am J Gastroenterol 2014;109(9):1375–1389.

1816

96. Samadder NJ, Curtin K, Tuohy TM, et al. Increased risk of colorectal neoplasia among family

members of patients with colorectal cancer: a population-based study in Utah. Gastroenterology

2014;147(4):814–821.e5.

97. Lairson DR, Dicarlo M, Deshmuk AA, et al. Cost-effectiveness of a standard intervention versus a

navigated intervention on colorectal cancer screening use in primary care. Cancer

2014;120(7):1042–1049.

98. Gupta S, Halm EA, Rockey DC, et al. Comparative effectiveness of fecal immunochemical test

outreach, colonoscopy outreach, and usual care for boosting colorectal cancer screening among the

underserved: a randomized clinical trial. JAMA Intern Med 2013;173(18):1725–1732.

99. Mulder SA, Kranse R, Damhuis RA, et al. Prevalence and prognosis of synchronous colorectal

cancer: a Dutch population-based study. Cancer Epidemiol 2011;35(5):442–447.

100. Latournerie M, Jooste V, Cottet V, et al. Epidemiology and prognosis of synchronous colorectal

cancers. Br J Surg 2008;95(12):1528–1533.

101. Eagye KJ, Nicolau DP. Deep and organ/space infections in patients undergoing elective colorectal

surgery: incidence and impact on hospital length of stay and costs. Am J Surg 2009;198(3):359–367.

102. Cima R, Dankbar E, Lovely J, et al. Colorectal surgery surgical site infection reduction program: a

national surgical quality improvement program–driven multidisciplinary single-institution

experience. J Am Coll Surg 2013;216(1):23–33.

103. Urban JA. Cost analysis of surgical site infections. Surg Infect (Larchmt) 2006;7(Suppl 1):S19–S22.

104. American College of Surgeons. American College of Surgeons National Surgical Quality

Improvement Program® (ACS NSQIP®). https://www.facs.org/quality-programs/acs-nsqip.

105. Cataife G, Weinberg DA, Wong HH, et al. The effect of Surgical Care Improvement Project (SCIP)

compliance on surgical site infections (SSI). Med Care 2014;52(2 Suppl 1):S66–S73.

106. Stephen AM, Cummings JH. The microbial contribution to human faecal mass. J Med Microbiol

1980;13(1):45–56.

107. Contant CM, Hop WC, van’t Sant HP, et al. Mechanical bowel preparation for elective colorectal

surgery: a multicentre randomised trial. Lancet 2007;370(9605):2112–2117.

108. Jung B, Pahlman L, Nystrom PO, et al. Multicentre randomized clinical trial of mechanical bowel

preparation in elective colonic resection. Br J Surg 2007;94(6):689–695.

109. Guenaga KF, Matos D, Wille-Jorgensen P. Mechanical bowel preparation for elective colorectal

surgery. Cochrane Database Syst Rev 2011(9):Cd001544.

110. Dahabreh IJ, Steele DW, Shah N, et al. AHRQ Comparative Effectiveness Reviews. Oral Mechanical

Bowel Preparation for Colorectal Surgery. Rockville, MD: Agency for Healthcare Research and Quality

(US); 2014.

111. Nelson RL, Gladman E, Barbateskovic M. Antimicrobial prophylaxis for colorectal surgery. Cochrane

Database Syst Rev 2014;5:Cd001181.

112. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial

prophylaxis in surgery. Am J Health Syst Pharm 2013;70(3):195–283.

113. Itani KM, Wilson SE, Awad SS, et al. Ertapenem versus cefotetan prophylaxis in elective colorectal

surgery. N Eng J Med 2006;355(25):2640–2651.

114. Poggio JL. Perioperative strategies to prevent surgical-site infection. Clin Colon Rectal Surg

2013;26(3):168–173.

115. Kakkos SK, Caprini JA, Geroulakos G, et al. Combined intermittent pneumatic leg compression and

pharmacological prophylaxis for prevention of venous thromboembolism in high-risk patients.

Cochrane Database Syst Rev 2008(4):Cd005258.

116. Danielsen AK, Burcharth J, Rosenberg J. Patient education has a positive effect in patients with a

stoma: a systematic review. Colorectal Dis 2013;15(6):e276–e283.

117. Bardram L, Funch-Jensen P, Jensen P, et al. Recovery after laparoscopic colonic surgery with

epidural analgesia, and early oral nutrition and mobilisation. Lancet 1995;345(8952):763–764.

118. Serclova Z, Dytrych P, Marvan J, et al. Fast-track in open intestinal surgery: prospective

randomized study (Clinical Trials Gov Identifier no. NCT00123456). Clin Nutr 2009;28(6):618–624.

119. Yang D, He W, Zhang S, et al. Fast-track surgery improves postoperative clinical recovery and

immunity after elective surgery for colorectal carcinoma: randomized controlled clinical trial.

World J Surg 2012;36(8):1874–1880.

1817

 

convert an unresectable patient to resectable status. The duration of treatment in these patients is

important. There is a need to balance the minimum time required to achieve a response that will make

the patient resectable, while avoiding hepatotoxicity from the chemotherapeutic agents. Both FOLFOX

and FOLFIRI increase resectability in 12.5% to 40% of patients initially considered unresectable. A

study has shown that adding irinotecan to FOLFOX (FOLFIRINOX) in patients with initially unresectable

metastasis increased the resection rate compared to FOLFOX alone.311 Adding EGFR inhibitors to

FOLFOX or FOLFIRI increased the resectability rate in patients with wild-type KRAS/NRAS tumors and

initially unresectable liver metastasis.312,313 Angiogenesis inhibitors combined with FOLFIRI modestly

increase resectability of initially unresectable liver metastasis compared to FOLFIRI alone, but have no

effect when combined with oxaliplatin-containing regimens.314,315 To limit FOLFOX- and FOLFIRIassociated toxicity, patients receiving systemic chemotherapy to increase resectability should be

evaluated for response every 2 months, and undergo surgery as soon as they become resectable.

Treatment of Peritoneal Carcinomatosis

Most patients with peritoneal carcinomatosis have widespread metastatic disease, and are treated with

systemic chemotherapy. The treatment of patients with the peritoneum as the only site of metastasis is

controversial.316,317 Complete cytoreductive surgery (CRS), with removal of all visible abdominal and

pelvic disease, and hyperthermic intraperitoneal chemotherapy (HIPEC) are now commonly used in

patients with peritoneum-only metastatic CRC. The most commonly used drug for intraperitoneal

chemotherapy is mitomycin C, which is minimally active against CRC. As experimental data do not

support any biologic benefit from the hyperthermia component, the role of HIPEC has been questioned.

Oxaliplatin, irinotecan, doxorubicin, paclitaxel, and carboplatin have also been tested. Comparative

studies have not shown a conclusive advantage of mitomycin C over oxaliplatin.318 This aggressive

treatment is associated with significant mortality (0.9% to 5%) and morbidity (12% to 52%), with the

most common complications being surgical site infection, hematologic toxicity, and intestinal fistula.

Many single institution case series have reported improved survival in patients treated with CRS and

HIPEC followed by systemic chemotherapy, compared to systemic chemotherapy alone. A recent review

of 19 studies conducted from 1999 to 2009 reported a median survival of 33 months for patients treated

with CRS and HIPEC versus 12.5 months for patients undergoing palliative surgery and/or systemic

chemotherapy.319 These studies have been criticized because of strong patient selection bias favoring

peritoneum-only disease in the CRS/HIPEC group, an undefined role for palliative treatment, and

suboptimal chemotherapy in the nonsurgical group. The only prospective trial published so far

randomized patients to 5-FU/LV with palliative surgery versus CRS, HIPEC, and postoperative 5-FU/LV.

OS was 12.6 months in the standard arm versus 22.2 months in the HIPEC group.320 This study has been

criticized because it also included patients with pseudomyxoma peritonei of appendiceal origin, and

because it was conducted before most of the drugs currently used in metastatic disease were available.

In spite of this criticism, CRS and HIPEC are commonly performed regimens for patients with

peritoneum-only colorectal metastasis.321

The selection criteria for this complex and potentially morbid treatment are not well defined. The

most important prognostic factors in patients undergoing CRS and HIPEC are the Peritoneal Cancer

Index (PCI), a grading of tumor burden at the time of surgery, and the completeness of cytoreduction

(CC) score. Unfortunately, the determinants of these scores are only available at the time of abdominal

exploration during surgery. Therefore, they have not been useful in selecting those patients more likely

to benefit from CRS and HIPEC. Recently, a Peritoneal Surface Disease Severity Score (PSDSS) that

includes patient symptoms, extent of peritoneal dissemination, and primary tumor histology has been

developed to stratify patients at the time of diagnosis, without the need of an operation.322 The PSDSS

score system has been found to be an independent prognostic factor in multivariate analysis, not only

for patients undergoing CRS and HIPEC, but also for patients treated with systemic chemotherapy. This

score may help eliminate selection bias in future comparisons of different treatments, in patients with

peritoneum-only metastatic CRC.

TREATMENT OF LOCALLY RECURRENT CRC

LR after curative-intent surgery is defined as a relapse of tumor in the surgical field of the initial

procedure, including the anastomosis, regional nodes, surgical scars, and drain tracts.323 While most

patients with LR also have distant metastasis, a few have isolated LR. A complete surgical resection is

the only curative option for patients with isolated locally recurrent CRC, but is associated with

1810

considerable morbidity and mortality.324 In spite of this criticism, CRS plus HIPEC is commonly

performed for patients with peritoneum-only colorectal metastasis.

The risk of LR is higher for rectal cancer compared to colon cancer, for advanced stage tumors (T4),

for tumors with high-risk histologic features (lymphovascular and perineural invasion, grade III or IV,

signet ring cell histology), perforating or obstructing tumors, and patients with close or involved CRM.

Most local recurrences present within 3 years after the primary surgery, but LR tends to occur later in

patients treated with CRT and surgery, compared to those treated with surgery alone. In the Dutch TME

trial, 10% of LRs occurred more than 3 years after surgery in patients treated with TME, versus 31% in

patients treated with preoperative RT and TME.325

While some LRs are detected though surveillance, while asymptomatic, most are diagnosed after they

become symptomatic. Symptoms of local recurrence include bowel obstruction, abdominal distension,

rectal or vaginal bleeding, and urinary problems.326 Pelvic pain is common, and is a predictor of

reduced long-term survival.327 A common manifestation in patients who have had abdominoperineal

resection (APR) is a nonhealing perineal wound. Whenever symptoms suggestive of recurrence arise, a

detailed history and complete physical examination must be done. This includes DRE in patients who

have undergone sphincter-preserving surgery, and a pelvic examination in females. If recurrent tumor is

identified, endoscopy and imaging studies will help assess extent of disease and surgical risk. A

complete colonoscopy should be performed if possible. Intraluminal recurrences are easily diagnosed

with endoscopy and biopsy. Cystoscopy is required for patients who present with urogenital symptoms,

as these strongly indicate tumoral invasion of the ureters and bladder.328 CEA is routinely measured

during follow-up surveillance after primary rectal cancer resection. Elevation of this tumor marker is

frequently the first sign of recurrence329; however, elevated CEA is present in only about 50% of

patients. Patients with elevated CEA should undergo further work-up with imaging studies.

A CT scan of the chest, abdomen, and pelvis is the primary imaging modality used in these patients,

and it is especially helpful in identifying metastases in the liver, lung, and peritoneum, and evaluating

regional adenopathy.330 MRI is more accurate than CT in detecting and staging pelvic LR331; although it

has been ineffective when added to routine follow-up in detecting ERUS it may be useful in diagnosing

LR after LE of distal rectal cancer.332 Positron emission tomography (PET) using the glucose analog

fluorodeoxyglucose (FDG), particularly when combined with a CT scan, is helpful in distinguishing

between postsurgical changes and tumor recurrence. In a recent meta-analysis comparing FDG-PET,

FDG-PET/CT, CT, and MRI in the detection of recurrent CRC in patients with high suspicion of

recurrent disease, based on symptoms or elevated CEA, FDG-PET and FDG-PET/CT performed more

accurately than CT scan.333 PET/CT also demonstrated greater accuracy than MRI in identification of

lymph node recurrence in a lesion levels analysis.334 Overall accuracy of FDG-PET/CT is slightly higher

than FDG-PET: 92.3% (94% sensitivity, 77.2% specificity) versus 89% (90.3% sensitivity, 80%

specificity).335 However, lesions measuring less than 1 cm in diameter are more difficult to detect with

PET scanning, as are mucinous tumors, due to poor FDG uptake. Finally, FDG-PET cannot be used to

detect or evaluate LR if there is residual inflammation of the tumor bed secondary to chronic leaks.

Regardless of the imaging studies used to help diagnose LR, histologic confirmation is imperative.

Anastomotic recurrences should be biopsied endoscopically; extraluminal recurrences can usually be

biopsied percutaneously, under radiologic (CT) guidance.

7 The treatment of locally recurrent CRC should be discussed in a multidisciplinary setting, since it

often involves colorectal surgical oncologists, radiation oncologists, medical oncologists, and other

specialists. Patients with multifocal LR should be treated with systemic chemotherapy, as in metastatic

disease. Only patients with localized LR and good performance status are candidates for surgical

resection. Even these patients may benefit from additional systemic chemotherapy or chemoradiation, if

they did not receive it at the time of treatment of the primary tumor.336 Some patients with recurrent

rectal cancer treated initially with standard doses of radiation (50.4 Gy in 180 cGy fractions, or

biologically equivalent total dose), can be re-irradiated to the gross tumor volume using small fractions

(180 to 200 cGy), with or without sensitizing chemotherapy.336 Re-irradiation seems to increase the

possibility of an R0 resection in patients with resectable disease, or provides good palliation in

unresectable patients. Following preoperative chemotherapy and/or radiotherapy, re-staging should be

done to exclude interim development of distant metastasis and to ascertain the extent of the LR.

Surgery is the only curative option for patients with locally recurrent rectal cancer. Without

treatment, median survival is typically 6 to 7 months

337; systemic chemotherapy can prolong survival,

similar to patients with systemic recurrence. Only patients with good performance status, with

recurrences that, based on anatomical location, are amenable to an R0 resection, should be considered

1811

surgical candidates. A resection with gross positive margins (R2) should not be attempted, because it

provides no oncologic advantage to the patient and is associated with significant morbidity. Patients

found to have microscopic positive margins (R1) may benefit from intraoperative radiation. However,

this modality is only available at some institutions, and requires preoperative planning. Therefore, the

treatment of locally recurrent CRC should be limited to institutions with appropriate expertise and

equipment.

Only about one-third of patients with isolated locally recurrent CRC are candidates for surgical

salvage with curative intent. In the Intergroup Study 0114, which investigated several chemotherapy

regimens in patients with locally advanced rectal cancer, only 159 (35%) of the 448 patients with

single-site first recurrences in the liver, lung, or pelvis had curative-intent surgery.326 The proportion of

patients undergoing resection was similar for liver, lung, or local recurrences. OS differed significantly

between the resected and nonresected groups, with 5-year OS of 27% and 6%, respectively (p < 0.001).

The 5-year DFS was in the range of 30% for patients undergoing resection of tumors in solitary sites of

the liver or lung, and 20% for those undergoing resection of LRs. Retrospective case series from

institutions with experience in the treatment of locally recurrent CRC report 5-year survival rates close

to 35% for patients with R0 resections, compared to 21% for patients with R1 resections.

Palliation is an important aspect of the treatment of patients with unresectable LR. Bowel obstruction

often requires palliative surgery, stomas, endoluminal stents, or percutaneous gastrostomy tubes.

Urinary obstruction is common, requiring stents or percutaneous nephrostomies. Pain is a common

symptom in these patients, often requiring the assistance of pain specialists and specialists in palliative

care.

1812

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65(1):5–29.

2. American Cancer Society. Global Cancer facts & Figures. 3rd ed. Available at www.cancer.org. 2015.

3. American Cancer Society. Colorectal cancer Facts & Figures 2014–2016. Atlanta; 2014.

4. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology

2010;138(6):2029–2043.e10.

5. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation

of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med

2000;343(2):78–85.

6. Song M, Garrett WS, Chan AT. Nutrients, foods, and colorectal cancer prevention. Gastroenterology

2015;148(6):1244–60.e16.

7. Larsson SC, Wolk A. Obesity and colon and rectal cancer risk: a meta-analysis of prospective

studies. Am J Clin Nutr 2007;86(3):556–565.

8. Bardou M, Barkun AN, Martel M. Obesity and colorectal cancer. Gut 2013;62(6):933–947.

9. Boyle T, Keegel T, Bull F, et al. Physical activity and risks of proximal and distal colon cancers: a

systematic review and meta-analysis. J Natl Cancer Inst 2012;104(20):1548–1561.

10. Monroe KR, Hankin JH, Pike MC, et al. Correlation of dietary intake and colorectal cancer

incidence among Mexican-American migrants: the multiethnic cohort study. Nutr Cancer

2003;45(2):133–147.

11. Kim E, Coelho D, Blachier F. Review of the association between meat consumption and risk of

colorectal cancer. Nutr Res 2013;33(12):983–994.

12. Bastide NM, Chenni F, Audebert M, et al. A central role for heme iron in colon carcinogenesis

associated with red meat intake. Cancer Res 2015;75(5):870–879.

13. Roswall N, Weiderpass E. Alcohol as a risk factor for cancer: existing evidence in a global

perspective. J Prev Med Public Health 2015;48(1):1–9.

14. Liang PS, Chen TY, Giovannucci E. Cigarette smoking and colorectal cancer incidence and

mortality: systematic review and meta-analysis. Int J Cancer 2009;124(10):2406–2415.

15. Parajuli R, Bjerkaas E, Tverdal A, et al. Cigarette smoking and colorectal cancer mortality among

602,242 Norwegian males and females. Clin Epidemiol 2014;6:137–145.

16. Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for

individuals with a family history: a meta-analysis. Eur J Cancer 2006;42(2):216–227.

17. Henrikson NB, Webber EM, Goddard KA, et al. Family history and the natural history of colorectal

cancer: systematic review. Genet Med 2015;17(9):702–712.

18. Mulder SA, Kranse R, Damhuis RA, et al. The incidence and risk factors of metachronous colorectal

cancer: an indication for follow-up. Dis Colon Rectum 2012;55(5):522–531.

19. Martinez ME, Baron JA, Lieberman DA, et al. A pooled analysis of advanced colorectal neoplasia

diagnoses after colonoscopic polypectomy. Gastroenterology 2009;136(3):832–841.

20. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a metaanalysis. Gut 2001;48(4):526–535.

21. Jess T, Gamborg M, Matzen P, et al. Increased risk of intestinal cancer in Crohn’s disease: a metaanalysis of population-based cohort studies. Am J Gastroenterol 2005;100(12):2724–2729.

22. Lutgens MW, van Oijen MG, van der Heijden GJ, et al. Declining risk of colorectal cancer in

inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm

Bowel Dis 2013;19(4):789–799.

23. Andersen NN, Jess T. Has the risk of colorectal cancer in inflammatory bowel disease decreased?

World J Gastroenterol 2013;19(43):7561–7568.

24. Peeters PJ, Bazelier MT, Leufkens HG, et al. The risk of colorectal cancer in patients with type 2

diabetes: associations with treatment stage and obesity. Diabetes Care 2015;38(3):495–502.

25. Mills KT, Bellows CF, Hoffman AE, et al. Diabetes mellitus and colorectal cancer prognosis: a metaanalysis. Dis Colon Rectum 2013;56(11):1304–1319.

26. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61(1):759–767.

1813

27. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and

rectal cancer. Nature 2012;487(7407):330–337.

28. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability–an evolving hallmark of cancer. Nat

Rev Mol Cell Biol 2010;11(3):220–228.

29. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin

Oncol 2010;7(3):153–162.

30. Nathke I. Cytoskeleton out of the cupboard: colon cancer and cytoskeletal changes induced by loss

of APC. Nat Rev Cancer 2006;6(12):967–974.

31. Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide

association studies. Nat Rev Genet 2009;10(6):353–358.

32. Ben-David E, Bester AC, Shifman S, et al. Transcriptional dynamics in colorectal carcinogenesis:

new insights into the role of c-Myc and miR17 in benign to cancer transformation. Cancer Res

2014;74(19):5532–5540.

33. Naccarati A, Polakova V, Pardini B, et al. Mutations and polymorphisms in TP53 gene–an overview

on the role in colorectal cancer. Mutagenesis 2012;27(2):211–218.

34. Segelov E, Chan D, Shapiro J, et al. The role of biological therapy in metastatic colorectal cancer

after first-line treatment: a meta-analysis of randomised trials. Br J Cancer 2014;111(6):1122–1131.

35. Francipane MG, Lagasse E. mTOR pathway in colorectal cancer: an update. Oncotarget

2014;5(1):49–66.

36. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that

associates cellular phenotype and responses to therapy. Nat Med 2013;19(5):619–625.

37. Marisa L, de Reynies A, Duval A, et al. Gene expression classification of colon cancer into molecular

subtypes: characterization, validation, and prognostic value. PLoS Med 2013;10(5):e1001453.

38. Zhang B, Wang J, Wang X, et al. Proteogenomic characterization of human colon and rectal cancer.

Nature 2014;513(7518):382–387.

39. Isella C, Terrasi A, Bellomo SE, et al. Stromal contribution to the colorectal cancer transcriptome.

Nat Genet 2015;47(4):312–319.

40. Calon A, Lonardo E, Berenguer-Llergo A, et al. Stromal gene expression defines poor-prognosis

subtypes in colorectal cancer. Nat Genet 2015; 47(4):320–329.

41. Mace AG, Pai RK, Stocchi L, et al. American Joint Committee on Cancer and College of American

Pathologists regression grade: a new prognostic factor in rectal cancer. Dis Colon Rectum

2015;58(1):32–44.

42. Edge S BD, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.

43. Costi R, Beggi F, Reggiani V, et al. Lymph node ratio improves TNM and Astler-Coller’s assessment

of colorectal cancer prognosis: an analysis of 761 node positive cases. J Gastrointest Surg

2014;18(10):1824–1836.

44. Ozawa T, Ishihara S, Nishikawa T, et al. Prognostic significance of the lymph node ratio in stage IV

colorectal cancer patients who have undergone curative resection. Ann Surg Oncol

2014;22(5):1513–1519.

45. Sloothaak DA, Sahami S, van der Zaag-Loonen HJ, et al. The prognostic value of micrometastases

and isolated tumour cells in histologically negative lymph nodes of patients with colorectal cancer:

a systematic review and meta-analysis. Eur J Surg Oncol 2014;40(3):263–269.

46. Mescoli C, Albertoni L, Pucciarelli S, et al. Isolated tumor cells in regional lymph nodes as relapse

predictors in stage I and II colorectal cancer. J Clin Oncol 2012;30(9):965–971.

47. Liebig C, Ayala G, Wilks J, et al. Perineural invasion is an independent predictor of outcome in

colorectal cancer. J Clin Oncol 2009;27(31):5131–5137.

48. Takagawa R, Fujii S, Ohta M, et al. Preoperative serum carcinoembryonic antigen level as a

predictive factor of recurrence after curative resection of colorectal cancer. Ann Surg Oncol

2008;15(12):3433–3439.

49. Sun LC, Chu KS, Cheng SC, et al. Preoperative serum carcinoembryonic antigen, albumin and age

are supplementary to UICC staging systems in predicting survival for colorectal cancer patients

undergoing surgical treatment. BMC Cancer 2009;9:288.

50. Ueno H, Shirouzu K, Eishi Y, et al. Characterization of perineural invasion as a component of

colorectal cancer staging. Am J Surg Pathol 2013;37(10):1542–1549.

1814

 

SURVEILLANCE AFTER CURATIVE RESECTION FOR COLON AND

RECTAL CANCER

Of the almost 1 million patients diagnosed with CRC worldwide every year, two-thirds have curative

intent surgery, but ultimately one-third of them will develop recurrence of disease or a second

colorectal primary. Most recurrences arise within 3 years of the initial treatment, and almost all arise

within 5 years. Recurrences are usually diagnosed at an advanced stage and have an ominous prognosis.

Surveillance regimens aim to identify recurrences before they become symptomatic, and while they are

still potentially resectable.293,294 Several meta-analyses of prospective, randomized trials comparing

intensive or minimal surveillance after curative resection in patients with stage I to III CRC suggest that

recurrences were diagnosed earlier and surgical salvage was more likely in patients undergoing

intensive surveillance.293,295 The survival benefit can only be partly attributed to the improved ability to

resect recurrences; other elements such as increased psychological support, behavior modifications, and

better treatment of comorbid conditions that accompany intensive surveillance regimens are also

thought to contribute to improved survival. Based on this evidence, cancer organizations have

established guidelines for surveillance after curative resection of CRC. All of them include a

combination of regular history and physical examination, determination of CEA level, endoscopy, and

imaging of the chest, abdomen, and pelvis (Table 68-10). Some clinicians recommend surveillance for

stage II/III disease, while others also include stage I. In the future, surveillance will be risk-adapted,

targeting patients more likely to benefit from intensive surveillance based on clinical and molecular

prognostic factors. Despite these recommendations, a recent population-based cohort study of 57

patients concluded that 70% were diagnosed between scheduled examinations.294

TREATMENT OF STAGE IV COLON AND RECTAL CANCER

Between 20% and 34% of all CRC patients have metastasis at the time of diagnosis; these are known as

synchronous metastases. Another one-third of patients will develop metastasis sometime after

undergoing treatment of the primary disease; this is known as metachronous metastasis. Synchronous

metastases are usually more extensive and, in general, carry a worse prognosis compared to

metachronous metastases.

The liver is the most common site of CRC metastasis, and liver metastasis is the most common cause

of cancer death in patients with CRC. Autopsy studies have revealed that 50% of patients dying from

CRC have liver metastasis and, in one-third of them, the liver is the only site of metastatic disease.296

Some patients with liver-only metastatic disease are resectable at the time of diagnosis. Others are not

resectable, due to the involvement of critical structures by large volume of metastatic disease. The

treatment of stage IV CRC patients is complex, and requires consideration of the number of organs

involved, the number and size of the metastasis, the location, the symptoms related to the primary in

the colon or rectum, whether the tumor is resectable or not, and the patient’s performance status.

Treatment decisions should be made after discussion in a multidisciplinary tumor board.297 A simplified

algorithm for the treatment of patients with stage IV CRC is presented in Algorithm 68-3. The discussion

is centered on patients with liver metastasis, but these principles are equally applicable to patients with

lung metastasis. Surgery is the only curative treatment for patients with colorectal metastasis. Other

forms of local therapy, such as ablation, may improve survival. Most patients with metastatic disease

benefit from systemic chemotherapy, either as adjuvant treatment to surgery or as the sole form of

treatment.

Table 68-10 Comparison of Surveillance Options After Curative Resectiona

1806

Algorithm 68-3. Stage IV rectal cancer treatment algorithm.

Treatment of the Primary Tumor in Stage IV CRC

In the past, all patients presenting with synchronous metastasis were recommended to have resection of

the primary tumor, to avoid complications such as obstruction or perforation during treatment of the

metastatic disease. However, recent data suggest that patients with unresectable metastasis and an

asymptomatic primary are unlikely to develop complications related to the primary tumor that require

surgical intervention while the patient is receiving systemic chemotherapy. Currently, primary tumor

resection is recommended for patients undergoing curative-intent resection of all metastatic disease, or

for patients with unresectable metastasis and a symptomatic primary tumor. The treatment of patients

1807

with asymptomatic primary tumor and unresectable metastasis is controversial. The benefit of avoiding

complications related to tumor progression should be balanced against the mortality and morbidity

associated with a noncurative resection, and the delay in starting systemic chemotherapy.

Observational studies and secondary analysis of prospective trials have reported an association

between primary tumor resection and improved survival. A recent meta-analysis found a difference of

6.4 months in survival in patients undergoing resection.298 However, these studies are limited by strong

patient selection bias and outdated chemotherapy regimens. Patients undergoing resection are more

likely to have liver-only disease, single metastasis, and tumors located in the colon. Rectal cancer

patients are less likely to undergo primary tumor resection compared to patients with colon cancer,

probably due to the higher complexity of rectal surgery, the possibility of using palliative CRT, and the

fear of a colostomy.

Resection of asymptomatic tumors in stage IV disease has not consistently shown improvements in

survival, nor does it necessarily reduce the risk of complications.299 A recent analysis of the SEER

database revealed that the proportion of patients with stage IV CRC undergoing primary tumor

resection has been progressively decreasing in the last decade.300 Despite this decrease in primary tumor

resection, relative survival has been increasing during the same period of time. The improvement in

survival has coincided with the introduction of more effective chemotherapy agents. However, the

relative contribution of the declining rate of primary resection and the more active chemotherapeutic

agents is unknown. These data lend support to current guidelines that do not recommend primary tumor

resection in asymptomatic patients with unresectable metastasis.177,301 In the SEER data analysis, more

than half of the patients with stage IV CRC, diagnosed in 2009, had resection of the primary tumor,

suggesting that current treatment practice lags behind evidence-based treatment guidelines.

Surgical Treatment of Colorectal Metastasis

Overall, only 6% of CRC patients with liver metastasis survive beyond 5 years, but in patients with

resectable liver metastasis the reported 5-year survival rate ranges from 25% to 40%. Patients with a

single, isolated liver metastasis have 5-year overall survival rates as high as 71%. Liver metastases are

considered resectable with curative intent if all disease can be removed, with negative resection margin,

while preserving adequate liver reserve. Incomplete resection or tumor debulking is not recommended,

because it is associated with morbidity without impacting survival. The size of the metastasis is not a

contraindication for surgery. When a curative liver resection may potentially result in insufficient liver

remnant, portal vein embolization of the involved liver lobe is recommended to induce hypertrophy of

the contralateral lobe of the liver. Repeated resection of recurrent liver metastasis is feasible, but the

probability of survival decreases with each subsequent resection.

The role of nonsurgical liver-directed therapy for the treatment of liver-only or liver-dominant

metastatic disease is controversial. Tumor ablation is indicated in patients who are amenable to local

therapy, but are not candidates for surgical resection due to comorbidities. It can also be combined with

surgery in patients with mixed resectable and unresectable lesions due to their anatomical location or

insufficient liver remnant.302 Other liver-directed therapies for which there is no consensus regarding

efficacy are liver-directed chemotherapy using a hepatic artery infusion pump, transarterial hepatic

chemoembolization/radioembolization, and liver-directed radiation.

Colorectal lung metastasis can also be surgically removed following the same principles outlined for

liver metastasis. Resection must be complete, based on the anatomic location of the disease, and with

maintenance of adequate respiratory function. Resection of both liver and lung metastasis is feasible in

selected cases, but resection in the presence of nonhepatic extra-pulmonary disease should be reserved

for carefully selected patients. Ablation and radiation are also options for patients with nonresectable

lung metastasis.301

Chemotherapy for Metastatic Disease

Principles of Chemotherapy

6 A number of antineoplastic agents such 5-FU or capecitabine, oxaliplatin, and irinotecan, and new

biologic agents, such as bevacizumab, ziv-aflibercept, cetuximab, panitumumab, and regorafenib, are

currently used in combination or as single agents in patients with metastatic CRC. The putative

mechanism of action and the toxicity profile of each drug are presented in Table 68-11. The choice of

the treatment regimen is based on the goals of therapy, the type and time of previous therapy, and the

toxicity profile of the constituent drugs.177,301 The chemotherapy regimens commonly used as first-line

therapy in patients appropriate for intensive therapy include: FOLFOX (5-FU/LV/oxaliplatin), FOLFIRI

1808

(5-FU/LV/irinotecan), CapeOx (capecitabine/oxaliplatin), infusional 5-FU/LV, capecitabine as a single

agent, or FOLFIRINOX (5-FU/LV/oxaliplatin/irinotecan). Cetuximab or bevacizumab can be added to

first-line therapy in patients with KRAS/NRAS wild-type CRC, and other combinations such as

FOLFOXIRI with bevacizumab have shown promising results.303,304 The role of maintenance therapy

after first-line therapy, and treatment after progression of metastatic disease on first-line therapy, is

beyond the scope of this chapter. Median survival of patients with unresectable metastatic CRC, which

previously rarely exceeded 12 months, now exceeds 30 months when these agents are used. Increasing

evidence suggests that the selection of chemotherapeutic agents will continue to be guided by molecular

and genomic characterizations. Early reports have indicated that combined therapy with BRAF and

EGFR inhibitors may be effective in treating BRAF V600E metastatic CRCs specifically.305

Adjuvant Chemotherapy in Resectable Disease

The majority of patients who undergo resection for CRC liver metastasis ultimately relapse in the liver.

It is theorized that the addition of systemic therapy provides treatment of occult micrometastatic

disease, reducing the risk of relapse. A number of randomized controlled trials have found a modest

improvement in RFS, but not in OS, with chemotherapy delivered before or after liver resection,

compared with resection alone. The optimal timing of chemotherapy remains unknown.306 The potential

advantages of preoperative therapy include earlier treatment of micrometastatic disease, evaluation of

tumor responsiveness, and the possibility of avoiding resection in patients with tumor progression

during therapy. The main disadvantages of preoperative chemotherapy are the progression of

nonresponsive tumors that become unresectable during systemic chemotherapy, and the increase in

perioperative morbidity due to chemotherapy-induced liver toxicity. The EORTC Intergroup Trial – the

only randomized trial evaluating the role of perioperative FOLFOX (3 months before and 3 months after

liver surgery) in the management of resectable liver metastases – demonstrated an absolute increase of

7.3% in 3-year progression-free survival in the combined treatment group, compared with the resectionalone group.307,308 This trial demonstrated an increased rate of postoperative complications in the

chemotherapy group (25%) compared with surgery-alone (16%), specifically showing a doubling in

biliary fistula and hepatic failure rates. The study concluded that perioperative chemotherapy may

improve cancer-specific outcomes, but at the cost of increased rates of postoperative complications,

including liver dysfunction. Long-term follow-up has revealed the same benefit in progression-free

survival, but no difference in OS with the addition of perioperative chemotherapy. The chemotherapy

regimens used in the adjuvant setting are the same as those used in first-line therapy. However,

bevacizumab can be added as long as it is discontinued at least 6 to 8 weeks before surgery and not restarted for 8 weeks after surgery, because it interferes with wound healing.309 Cetuximab and

panitumumab have been added to first-line regimens in patients with KRAS/NRAS wild type, but the

benefits have been inconsistent. In fact, recent data suggest these could even be detrimental; therefore,

they are not recommended at this time.310

Table 68-11 Main Chemotherapeutic Agents

Chemotherapy in Borderline Resectable Disease

A few patients present with liver-only metastases that are not amenable to a complete resection, due to

close proximity to essential anatomical structures. Systemic chemotherapy in this setting aims to

1809

 

demonstrating that each 4-week delay in treatment correlated with a 14% decrease in OS.262 The low

compliance with postoperative adjuvant chemotherapy has been attributed to postoperative

complications, slow recovery after surgery, delays due to closure of the temporary ileostomy, or simply

patient refusal. Delivering systemic chemotherapy before surgery has the potential advantage of

increasing treatment compliance, potentially enhancing the efficacy of CT in preventing DM, and

ultimately improving survival. In addition, it increases response of the primary tumor, and shortens the

time to temporary ileostomy reversal. A number of studies have shown that compliance with systemic

chemotherapy is higher when it is delivered before CRT and TME, compared with conventional

postoperative adjuvant chemotherapy in patients LARC patients who are candidates for curative

surgery.263–265 Although solid data from large prospective studies are still lacking, in the most recent

edition of the NCCN guidelines neoadjuvant chemotherapy before CRT and TME is contemplated as an

option in the treatment of LARC patients.

Outcomes of Multimodality Treatment in Patients with Locally Advanced Rectal Cancer

Perioperative mortality in patients undergoing multimodality therapy, including total mesorectal

excision for LARC, ranges from 1% to 3.5%, and between 23% and 48% of patients develop

perioperative complications.250,266,267 Sepsis is the most common complication after rectal cancer

surgery. A recent systematic review of the literature, including 53 prospective cohort studies and 45

randomized trials, found a 2% postoperative death rate, 7% rate of surgical wound infection, 11% rate

of anastomotic leakage, and a 12% rate of pelvic sepsis.267 In addition to pelvic sepsis, perineal wound

dehiscence is the most common complication after APE. In a large systematic review of 32 studies, the

rate of perineal wound complication was 15.3% for patients treated with surgery alone, and 32% in

those treated with surgery and RT.227 Many of these patients also had pelvic sepsis. The proportion of

patients with perineal complication was similar for those who had ELAP: 14.8% for surgery alone and

37.6% for surgery and radiation. The rate of perineal hernia was also similar for patients treated with

SAPE and ELAPE: 1.8% versus 2%. Other common postoperative complications include urinary

retention, pneumonia, and thromboembolic disease.

Surgery for rectal cancer, particularly when combined with CRT or SCRT, has iatrogenic long-term

consequences including urinary, sexual, and bowel dysfunction. Up to 39% of patients develop urinary

complications, 45% sexual dysfunction, and even a larger proportion, bowel dysfunction.268,269 A recent

population-based study found a 26% rate of moderate bowel problems, 17% urinary dysfunction, and

25% severe problems with sexual function among patients treated for rectal cancer. Patients with a

stoma were more likely to have difficulty with body image and sexual activity compared to patients

with no stoma. Less than 30% of rectal cancer patients reported perfect health; rectal cancer patients

were more likely to report problems, compared to patients with colon cancer. A follow-up study of the

Dutch TME trial recently reported that these treatment-related symptoms persist 14 years after

treatment; they reported increased sexual dysfunction, and a small decrease in overall functioning, as

measured by a variety of quality of life questionnaires distributed to the general population.270

Algorithm 68-1. Approach to rectal cancer according to clinical staging.

Contemporary cohorts of stage II/III rectal cancer treated with neoadjuvant CRT, TME, and

postoperative chemotherapy have mostly reported 5-year LR rates between 5% and 10%, 5-year DFS of

around 60%, and 5-year OS around 70%.

1802

Treatment Selection in Patients with Localized Rectal Cancer

Unlike patients with localized colon cancer, who all require oncologic resection as the initial form of

therapy, patients with rectal cancer have multiple treatment options. The selection among different

options depends primarily on the clinical stage of the tumor, as determined by DRE, proctoscopy, and

imaging studies, on the distance of tumor from the anal verge, and on patient performance status and

expectations.

The standard treatment for patients with stage I rectal cancer (T1N0 or T2N0) is TME, but LE has

increasingly been chosen as a reasonable and acceptable alternative for patients with distal T1N0

tumors. CRT and LE may also be considered as an alternative to TME in patients with T2N0 tumors

interested in sphincter preservation, in whom a TME would require a permanent colostomy.

More advanced tumors – those penetrating beyond the muscularis propria (T3–4, any N) and/or

involving the regional lymph nodes (any T, N+), and without evidence of distance metastasis – have

several treatment options. In the United States and many other countries, where decisions regarding the

treatment of rectal cancer are based on clinical TNM staging, patients with locally advanced disease are

treated with 5-FU or capecitabine-based CRT, followed by TME, with consideration given to FOLFOX

prior to CRT as an acceptable option (Algorithm 68-1).

In Europe and Scandinavia, where rectal cancer patients are stratified into different risk categories

based on MRI features, patients are recommended for different treatment approaches according to their

individual risk category (Algorithm 68-2). The MRI-based risk stratification system uses a number of

features, such as the proximity of the primary tumor to the MRF, the depth of tumor penetration into

the mesorectum, the presence of large venous invasion, and the presence of metastatic lymph nodes.168

Based on these features, they have developed a three-tier classification scheme that includes low risk

(the good), intermediate risk (the bad), and high risk (the ugly); each group with a different risk of

relapse, and therefore requiring different treatment strategies.169,271 The low-risk group is

recommended TME alone. The intermediate group is recommended SCRT followed by TME, while the

high-risk group is recommended neoadjuvant CRT followed by TME. This treatment approach, guided

by MRI risk categorization, is based mainly on results of prospective observational studies conducted in

institutions with significant expertise in rectal cancer, but has not yet been tested in prospective,

randomized trials.

Algorithm 68-2. Approach to locally advanced rectal cancer based on a three-tier risk stratification system (“the good, the bad, and

the ugly”).

For patients requiring a TME, the decision between an APE and an SSP depends on the relationship of

the tumor with the anal sphincter and the levator muscle. In general, an APE is required when the

tumor directly involves these structures, or is so close to the sphincter that resection with a negative

resection margin will result in a loss of sphincter function. In borderline cases, baseline anal sphincter

and bowel function, as well as patient wishes and desires should be taken into consideration. The

patient should be counseled about LR rates and expected long-term surgical outcomes.

1803

TUMOR-RELATED EMERGENCIES

Between 15% and 30% of all CRC patients present as surgical emergencies, obstruction (78%) being the

most common presentation, followed by perforation (10%) and bleeding (4%).272–274 Chronic bleeding

leading to severe anemia is common, particularly in right-sided tumors; but acute hemorrhage requiring

surgical or endovascular intervention is infrequent. Obstruction is the presenting symptom in more than

15% of patients diagnosed with CRC, and CRC is responsible for more than 50% of all cases of acute

colonic obstruction.275 Rectal cancers seldom present as an emergency (5.9%); this is much more likely

with colon cancers (21.7%),273 most of which are in the left colon where the feces are solid, the lumen

is smaller, and tumors are more likely to be annular. Large bowel obstruction may be secondary to

other conditions such as diverticular disease and volvulus, which are the differential diagnosis of CRC.

The obstructed bowel undergoes significant changes in motility, secretion, and blood flow, which are

responsible for the clinical manifestations. Proximal to the obstructed segment, particularly in left-sided

obstructions, the colon develops mass action contractions, which cause colic pain. Persistent obstruction

and progressive distension lead to colonic hypomotility. Colonic obstruction causes progressive

abdominal distension as a result of the accumulation of gas (mostly nitrogen from swallowed air),

increased fluid secretion, and hyperproliferation of anaerobic bacteria. The accumulation of fluid in the

distended colon can lead to dehydration. Progressive distension in the presence of a competent ileocecal

valve results in a closed-loop obstruction. The increase in intraluminal pressure can compromise the

mucosal blood flow and lead to irreversible ischemia. Tension in the wall of the distended bowel

increases in proportion to the fourth power of the radius; the risk of ischemia and subsequent

perforation is therefore high, particularly in the cecum, the segment of colon with the largest

diameter.276 The risk of perforation is related not only to the caliber of the colon, but also to the onset

of obstruction (higher risk when acute) and the duration of the obstruction. Mucosal ischemia has been

implicated as the cause of a nonspecific form of colitis that, in some patients, develops proximal to the

site of obstruction. The presence of ischemia, which can only be diagnosed at the time of surgery,

should influence the extent of resection.

Acute colonic obstruction manifests as abdominal discomfort or frank pain (depending on the onset of

the obstruction), reduction or complete cessation of the passage of flatus and feces, and progressive

abdominal distension. Abdominal tenderness, particularly if associated with fever and leukocytosis,

requires immediate evaluation to exclude perforation or ischemia. DRE reveals an empty rectum in most

patients with large bowel obstruction.

Colonic obstruction must be distinguished from pseudo-obstruction. While the symptoms are similar,

colonic pseudo-obstruction often presents in a specific clinical setting (patient immobilization, use of

opioids, electrolyte imbalance), is still associated with passage of small amounts of stool and flatus, and

is not associated with tenderness.277 However, definitive diagnosis often requires specific radiologic

tests, such as a water-soluble contrast enema or CT.

A plain abdominal film demonstrates colonic distension, with air-fluid levels, and a cut-off at the site

of obstruction. The absence of small bowel distension indicates a competent ileocecal valve, with an

increased risk of cecal perforation. The presence of gas in the small bowel and rectum raises the

possibility of ileus or colonic pseudo-obstruction, but radiologic findings can be misleading. The

presence of intramural gas indicates advanced ischemia. A chest radiograph should always be obtained

to exclude the presence of pneumoperitoneum.

A water-soluble contrast enema may help to determine the degree and level of obstruction. The flow

of contrast to the cecum and the absence of mucosal abnormalities suggest pseudo-obstruction. The

osmotic effect of the water-soluble contrast material may have a therapeutic effect in decompressing the

colon in these patients.278 The mucosal detail at the site of obstruction may help to define the cause of

obstruction. However, endoscopy is a better alternative to contrast enema when confirming the

presence of cancer. CT of the chest, abdomen, and pelvis often locates the transition point between the

distended bowel above the obstruction and the collapsed bowel distal to that point. It also helps define

the cause of the obstruction and, if malignant obstruction is confirmed, it is useful in staging the

tumor.279

When compared with elective surgery, patients requiring emergency surgery have more advanced

disease. Even when stratified by stage, however, survival is worse for patients undergoing emergency

surgery.273,280 Also, an R1 resection is 10 times more likely for patients receiving emergency surgery.281

Patients presenting with obstructing CRC have higher operative mortality and morbidity and a poorer

long-term prognosis than patients undergoing elective resection.274,282 Perioperative mortality is three

times higher in surgery performed for obstruction, compared with elective surgery.274 Cardiopulmonary

1804

complications and abdominal sepsis are the major causes of in-hospital mortality and morbidity. The

aim of surgery is therefore to minimize morbidity while obtaining functional results similar to those

obtained for patients undergoing elective resection.

Patients with colonic obstruction are often dehydrated, and require preoperative fluid resuscitation

and correction of electrolyte imbalances before surgery. A urinary catheter facilitates fluid

management. Unstable patients should be monitored appropriately in the intensive care unit. A

nasogastric tube prevents accumulation of swallowed air. Given the large fecal load proximal to the

point of obstruction, antibiotic prophylaxis with a second-generation cephalosporin or a combination of

an aminoglycoside and metronidazole should be given at the time of surgery.

The surgical management depends on the location of the obstruction. Lesions proximal to the splenic

flexure are commonly treated by an extended right hemicolectomy, with primary anastomosis between

the terminal ileum and the nonobstructed colon distal to the lesion. This is a single procedure that

removes the entire segment of distended and potentially ischemic bowel, and eliminates the risk of

leaving a synchronous tumor in the obstructed colon. Some of these patients develop mild diarrhea,

which is usually temporary.

The management of a lesion located distal to the splenic flexure is more controversial. The earlier

described three-stage procedure is rarely used today (1 – Diverting colostomy, 2 – Tumor resection and

anastomosis, 3 – Colostomy closure). A safe choice is the two-stage procedure, with initial resection of

the segment containing the tumor, closure of the rectal stump as a Hartmann pouch, and construction of

an end colostomy, followed by bowel anastomosis at a later date. However, the cumulative mortality

and morbidity of both procedures is significant, and at least 30% of patients are left with a permanent

colostomy.283 In most tertiary centers, this operation is now limited to situations in which a primary

anastomosis is contraindicated (e.g., extensive peritoneal contamination and/or severe sepsis).

The goal of surgery today is to relieve the obstruction and treat the cancer in a single operative

procedure. Options include: (1) self-expanding metallic stents (SEMS) as a bridge to elective segmental

colon resection, (2) subtotal colectomy and ileorectal anastomosis, (3) segmental colon resection,

intraoperative colonic lavage, and primary anastomosis.

The rationale for the use of SEMS is temporary relief of the obstruction, avoiding the morbidity

associated with an emergency operation, allowing medical stabilization, full staging work-up, one-stage

surgery with primary anastomosis, and a minimally invasive approach. Most of the experience with this

method comes from retrospective case-series studies; the success in relieving the obstruction ranges

from 40% to 100%.284 SEMS also has associated complications, such as re-obstruction (12%), migration

(11%), and perforation (4.5%).284

Several randomized, controlled trials comparing SEMS with emergency surgery have been published,

with conflicting results.285–289 Overall, the clinical success rate of relieving obstruction with SEMS

ranges from 40% to 97%. It is important to recognize that the overall complication rate across these

trials is variable (8.3% to 35%) and a recent prospective trial conducted in the Netherlands was stopped

prematurely, due to an increased number of colonic perforations in the SEMS arm.289 Perforation from

the use of stents may result in a shorter DFS.290

A subtotal colectomy with ileorectal anastomosis is a quick operation in which nondistended bowel is

used for the anastomosis. This procedure minimizes the risk of fecal spillage, eliminates the risk of

missing a synchronous tumor in the obstructed portion of the colon, and facilitates surveillance. The

disadvantages, however, include a higher incidence of bowel obstruction after ileorectal anastomosis

and the development of postoperative diarrhea, which may become incapacitating in elderly patients.291

A segmental resection with intraoperative colonic lavage and primary anastomosis avoids the risk of

postoperative diarrhea, but carries a risk of fecal spillage and missing synchronous tumor. In addition, it

requires using previously obstructed bowel for the construction of the anastomosis. Surgical tradition

has condemned the performance of an anastomosis in an unprepared colon. Experience accumulated

from the management of patients with civilian colon trauma has demonstrated that, under specific

circumstances, a primary anastomosis can be performed safely in an unprepared colon, provided the

bowel appears healthy and there is no extensive soiling in the peritoneal cavity. This experience has

been transferred to the treatment of malignant colonic obstruction. Therefore, a segmental resection

with colonic lavage and primary anastomosis is a viable option, as long as the colon is not ischemic and

there is in no spillage during the operation. The use of a temporary diverting ileostomy may be

necessary, but when the safety of a primary anastomosis is questionable, a staged procedure with a

segmental resection, a Hartmann pouch, and an end colostomy, may be preferable.292

1805