Rectal cancer is a major health problem around the world, representing about one-third of the total colorectal cancer cases. Because of its anatomical location, there is a higher risk of local recurrence, and treatment often requires a complex multidisciplinary approach which includes neoadjuvant radiotherapy, chemotherapy, and a radical surgical procedure that commonly leads to a permanent colostomy. The cure rate with this strategy is good, with some patients having no residual disease in the surgical specimen. While the prognosis for those patients is excellent, their quality of life is permanently compromised. In this article, we review risks and benefits of the standard treatment approach and compare standard treatment with alternative methods aimed at rectal preservation.
Anatomically, the rectum begins above the dentate line, which marks the cephalic extent of the anal canal, and extends above the peritoneal reflection to the sigmoid colon. Although didactically divided into lower rectum, mid rectum, and upper rectum, the most valuable information one can obtain from the localization of a rectal tumor is whether or not it is surrounded by peritoneum. Generally, peritonealized tumors can be surgically and clinically managed as colon tumors. On the other hand, the lack of a peritoneal covering confers a higher risk of local recurrence (LR) of the rectal tumor, and different medical approaches, often including more radical surgical procedures, may be required.
In the latter scenario, total mesorectal excision (TME) and neoadjuvant chemoradiotherapy (CRT) have been proven to effectively treat the disease.[3-5] (See Table 1 for selected LR and overall survival (OS) rates reported with this approach.) Multidisciplinary treatment with neoadjuvant therapy followed by surgery with TME is now the standard of care for patients with deperitonealized T3 or N1 distal rectal tumors (DRTs).
In spite of progress in preventing LR, treatment of DRTs remains very aggressive. Very-low-lying rectal tumors usually require an abdominoperineal resection (APR), a procedure that completely removes the distal colon, rectum, and anal sphincter complex, resulting in a permanent colostomy.[6,7] This is the only way to assure the necessary surgical margins, free of neoplastic cells. APR is the standard of care even for patients with early-stage (T2N0) DRTs that may not require multimodality treatment.
Besides the need for a permanent colostomy, the sequelae of APR may manifest in a variety of ways. Perineal wound complications are not rare, and they may cause pain and pressure and lead to skin breaks and evisceration. Permanent sexual or urinary dysfunction occurs in about 60% of patients treated by APR.[10,11]
Sphincter-sparing resections (SSRs) can be an alternative approach for low rectal tumors localized at least 3–4 cm above the anal verge. However, difficulties with evacuation and incontinence in patients with very low SSRs can cause an equal detriment to the quality of life.[13-15]
For these reasons, the possibility of avoiding permanent stoma and even eliminating surgery without compromising the curability rate is one of the most important unmet needs of patients suffering from a DRT.
The Paradox of a Pathologic Complete Response After Neoadjuvant Treatment
With routine use of neoadjuvant CRT, it was possible to observe that some tumors are downstaged markedly at the time of surgery. Complete tumor response (indicated by a specimen without any residual tumor cells) and near-complete response (single cells or small groups of cancer cells) can be observed in approximately 15% to 30% of rectal cancer tumors managed with neoadjuvant CRT.[17,18] Interestingly, therapy-induced downsizing effects have widely been described as important prognostic factors, and these major responses to neoadjuvant treatment have been associated with a strongly favorable prognosis.[19-22] Indeed, it seems that response of the primary rectal cancer serves as a marker of effectiveness of systemic control and long-term oncological outcome. Local and distant failures are virtually absent in patients who achieved a pathologic complete response (pCR) after neoadjuvant CRT.[23,24] Based on these data, one can argue that the information that a particular patient has achieved a complete response (CR)postoperatively, without viable tumor cells in the rectum, is desirable and very welcome. Indeed, these selected patients with rectal cancer who obtained a pCR after preoperative CRT could, at least theoretically, be spared from APR and permanent colostomy with little risk of compromising their prognoses. If there were really no cancer cells remaining in the rectum, then surgery would be unnecessary.
The obvious problem with this argument is that pathological responses can only be categorized based on findings extracted from the assessment of the entire resected specimen and therefore, after the radical surgery. The double-edged sword is that a patient can have had a very good oncological outcome but also have been subjected to unnecessary mutilation, with these conclusions drawn from the same pathological findings.
1. Kenig J, Richter P. Definition of the rectum and level of the peritoneal reflection - still a matter of debate? Wideochir Inne Tech Malo Inwazyjne. 2013;8:183-6.
2. Jones WE, 3rd, Thomas CR, Jr, Herman JM, et al. ACR appropriateness criteria® resectable rectal cancer. Radiat Oncol. 2012;7:161.
3. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731-40.
4. Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009;27:5124-30.
5. Lim YK, Law WL, Liu R, et al. Impact of neoadjuvant treatment on total mesorectal excision for ultra-low rectal cancers. World J Surg Oncol. 2010;8:23.
6. Stelzner S, Koehler C, Stelzer J, et al. Extended abdominoperineal excision vs. standard abdominoperineal excision in rectal cancer--a systematic overview. Int J Colorectal Dis. 2011;26:1227-40.
7. Olson C. Current status of surgical intervention for the management of rectal cancer. Crit Rev Oncog. 2012;17:373-82.
8. Stamos MJ, Murrell Z. Management of early rectal T1 and T2 cancers. Clin Cancer Res. 2007;13:6885s-9s.
9. Sabbagh C, Maggiori L, Panis Y. Management of failed low colorectal and coloanal anastomosis. J Visc Surg. 2013;150:181-7.
10. Camilleri-Brennan J, Steele RJ. Objective assessment of morbidity and quality of life after surgery for low rectal cancer. Colorectal Dis. 2002;4:61-6.
11. Arndt V, Merx H, Stegmaier C, et al. Restrictions in quality of life in colorectal cancer patients over three years after diagnosis: a population based study. Eur J Cancer. 2006;42:1848-57.
12. Wu JS, Fazio VW. Management of rectal cancer. J Gastrointest Surg. 2004;8:139-49.
13. Tsunoda A, Tsunoda Y, Narita K, et al. Quality of life after low anterior resection and temporary loop ileostomy. Dis Colon Rectum. 2008;51:218-22.
14. O’Leary DP, Fide CJ, Foy C, Lucarotti ME. Quality of life after low anterior resection with total mesorectal excision and temporary loop ileostomy for rectal carcinoma. Br J Surg. 2001;88:1216-20.
15. Pachler J, Wille-Jørgensen P. Quality of life after rectal resection for cancer, with or without permanent colostomy. Cochrane Database Syst Rev. 2012;12:CD004323.
16. Thies S, Langer R. Tumor regression grading of gastrointestinal carcinomas after neoadjuvant treatment. Front Oncol. 2013;3:262.
17. O’Neill BD, Brown G, Heald RJ, et al. Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer. Lancet Oncol. 2007;8:625-33.
18. Solanki AA, Chang DT, Liauw SL. Future directions in combined modality therapy for rectal cancer: reevaluating the role of total mesorectal excision after chemoradiotherapy. Onco Targets Ther. 2013;6:1097-110.
19. Rodel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23:8688-96.
20. Ruo L, Tickoo S, Klimstra DS, et al. Long-term prognostic significance of extent of rectal cancer response to preoperative radiation and chemotherapy. Ann Surg. 2002;236:75-81.
21. Agarwal A, Chang GJ, Hu CY, et al. Quantified pathologic response assessed as residual tumor burden is a predictor of recurrence-free survival in patients with rectal cancer who undergo resection after neoadjuvant chemoradiotherapy. Cancer. 2013;119:4231-41.
22. Santos MD, Silva C, Rocha A, et al. Tumor regression grades: can they influence rectal cancer therapy decision tree? Int J Surg Oncol. 2013;2013:572149.
23. Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg. 2012;99:918-28.
24. Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835-44.
25. Wang C, Zhou ZG, Yu YY, et al. Patterns of lateral pelvic lymph node metastases and micrometastases for patients with lower rectal cancer. Eur J Surg Oncol. 2007;33:463-7.
26. Habr-Gama A, Perez RO, Wynn G, et al. Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer: characterization of clinical and endoscopic findings for standardization. Dis Colon Rectum. 2010;53:1692-8.
27. Tranchart H, Lefevre JH, Svrcek M, et al. What is the incidence of metastatic lymph node involvement after significant pathologic response of primary tumor following neoadjuvant treatment for locally advanced rectal cancer? Ann Surg Oncol. 2013;20:1551-9.
28. Becker K, Mueller JD, Schulmacher C, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 2003;98:1521-30.
29. Park IJ, Yu CS. Current issues in locally advanced colorectal cancer treated by preoperative chemoradiotherapy. World J Gastroenterol. 2014;20:2023-29.
30. Perez RO, Habr-Gama A, Pereira GV, et al. Role of biopsies in patients with residual rectal cancer following neoadjuvant chemoradiation after downsizing: can they rule out persisting cancer? Colorectal Dis. 2012;14:714-20.
31. Barbaro B, Fiorucci C, Tebala C, et al. Locally advanced rectal cancer: MR imaging in prediction of response after preoperative chemotherapy and radiation therapy. Radiology. 2009;250:730-9.
32. Kim SH, Lee JM, Park HS, et al. Accuracy of MRI for predicting the circumferential resection margin, mesorectal fascia invasion, and tumor response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer. J Magn Reson Imaging. 2009;29:1093-101.
33. Koh DM, Chau I, Tait D, et al. Evaluating mesorectal lymph nodes in rectal cancer before and after neoadjuvant chemoradiation using thin-section T2-weighted magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 2008;71:456-61.
34. Patel UB, Taylor F, Blomqvist L, et al. Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience. J Clin Oncol. 2011;29:3753-60.
35. Perez RO, Habr-Gama A, São Julião GP, et al. Clinical relevance of positron emission tomography/computed tomography-positive inguinal nodes in rectal cancer after neoadjuvant chemoradiation. Colorectal Dis. 2013;15:674-82.
36. Cascini GL, Avallone A, Delrio P, et al. 18F-FDG PET is an early predictor of pathologic tumor response to preoperative radiochemotherapy in locally advanced rectal cancer. J Nucl Med. 2006;47:1241-8.
37. Choi H, Yoon HJ, Kim TS, et al. Voxel-based dual-time 18F-FDG parametric imaging for rectal cancer: differentiation of residual tumor from postchemoradiotherapy changes. Nucl Med Commun. 2013;34:1166-73.
38. Habr-Gama A, Gama-Rodrigues J, Perez RO. Is tailoring treatment of rectal cancer the only true benefit of long-course neoadjuvant chemoradiation? Dis Colon Rectum. 2013;56:264-6.
39. Habr-Gama A, Perez RO, São Julião GP, et al. Nonoperative approaches to rectal cancer: a critical evaluation. Semin Radiat Oncol. 2011;21:234-9.
40. Kosinski L, Habr-Gama A, Ludwig K, Perez R. Shifting concepts in rectal cancer management: a review of contemporary primary rectal cancer treatment strategies. CA Cancer J Clin. 2012;62:173-202.
41. 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;240:711-7.
42. Habr-Gama A, Perez RO, Sabbaga J, et al. Increasing the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of a prospective study using additional chemotherapy during the resting period. Dis Colon Rectum. 2009;52:1927-34.
43. Habr-Gama A, Sabbaga J, Gama-Rodrigues J, et al. Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer: are we getting closer to anal cancer management? Dis Colon Rectum. 2013;56:1109-17.
44. Smith JD, Ruby JA, Goodman KA, et al. Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg. 2012;256:965-72.
45. Dalton RS, Velineni R, Osborne ME, et al. A single-centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management? Colorectal Dis. 2012;14:567-71.
46. 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;29:4633-40.
47. Guerrieri M, Baldarelli M, Organetti L, et al. Transanal endoscopic microsurgery for the treatment of selected patients with distal rectal cancer: 15 years experience. Surg Endosc. 2008;22:2030-5.
48. Maeda K, Koide Y, Katsuno H. When is local excision appropriate for “early” rectal cancer? Surg Today. 2013 Nov 21. [Epub ahead of print]
49. Perrotta S, Quarto G, Desiato V, et al. TEM in the treatment of recurrent rectal cancer in elderly. BMC Surg. 2013;13(Suppl 2):S56.
50. Heidary B, Phang TP, Raval MJ, Brown CJ. Transanal endoscopic microsurgery: a review. Can J Surg. 2014;57:127-38.
51. Mohiuddin M, Marks G, Bannon J. High-dose preoperative radiation and full thickness local excision: a new option for selected T3 distal rectal cancers. Int J Radiat Oncol Biol Phys. 1994;30:845-9.
52. Kim CJ, Yeatman TJ, Coppola D, et al. Local excision of T2 and T3 rectal cancers after downstaging chemoradiation. Ann Surg. 2001;234:352-8.
53. Ruo L, Guillem JG, Minsky BD, et al. Preoperative radiation with or without chemotherapy and full-thickness transanal excision for selected T2 and T3 distal rectal cancers. Int J Colorectal Dis. 2002;17:54-8.
54. Schell SR, Zlotecki RA, Mendenhall WM, et al. Transanal excision of locally advanced rectal cancers downstaged using neoadjuvant chemoradiotherapy. J Am Coll Surg. 2002;194:584-90.
55. Bonnen M, Crane C, Vauthey JN, et al. Long-term results using local excision after preoperative chemoradiation among selected T3 rectal cancer patients. Int J Radiat Oncol Biol Phys. 2004;60:1098-105.
56. Borschitz T, Wachtlin D, Mohler M, et al. Neoadjuvant chemoradiation and local excision for T2-3 rectal cancer. Ann Surg Oncol. 2008;15:712-20.
57. 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;12:1797-805.
58. Lezoche G, Baldarelli M, Guerrieri M, et al. A prospective randomized study with a 5-year minimum follow-up evaluation of transanal endoscopic microsurgery versus laparoscopic total mesorectal excision after neoadjuvant therapy. Surg Endosc. 2008;22:352-8.
59. 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;19:384-91.
60. Pucciarelli S, De Paoli A, Guerrieri M, et al. Local excision after preoperative chemoradiotherapy for rectal cancer: results of a multicenter phase II clinical trial. Dis Colon Rectum. 2013;56:1349-56.
61. Bujko K, Sopylo R, Kepka L. Local excision after radio(chemo)therapy for rectal cancer: Is it safe? Clin Oncol (R Coll Radiol). 2007;19:693-700.
62. Callender GG, Das P, Rodriguez-Bigas MA, et al. Local excision after preoperative chemoradiation results in an equivalent outcome to total mesorectal excision in selected patients with T3 rectal cancer. Ann Surg Oncol. 2010;17:441-7.
63. Levic K, Bulut O, Hesselfeldt P, Bulow S. The outcome of rectal cancer after early salvage TME following TEM compared with primary TME: a case-matched study. Tech Coloproctol. 2013;17:397-403.
64. Bach SP, Hill J, Monson JR, et al. A predictive model for local recurrence after transanal endoscopic microsurgery for rectal cancer. Br J Surg. 2009;96:280-90.
65. Garcia-Aguilar J. Transanal endoscopic microsurgery following neoadjuvant chemoradiation therapy in rectal cancer: a word of caution about patient selection? Dis Colon Rectum. 2013;56:1-3.
66. Wynn GR, Bhasin N, Macklin CP, George ML. Complete clinical response to neoadjuvant chemoradiotherapy in patients with rectal cancer: opinions of British and Irish specialists. Colorectal Dis. 2010;12:327-33.
67. Minsky BD. Rectal cancer: is ‘watch and wait’ a safe option for rectal cancer? Nat Rev Gastroenterol Hepatol. 2013;10:698-700.
68. Fichera A, Allaix ME. Paradigm-shifting new evidence for treatment of rectal cancer. J Gastrointest Surg. 2014;18:391-7.
69. Weiser MR, Beets-Tan R, Beets G. Management of complete response after chemoradiation in rectal cancer. Surg Oncol Clin N Am. 2014;23:113-25.
70. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114-23.