The optimal approach to the diagnosis and treatment of locally advanced rectal cancer involves multidisciplinary, integrated management. In the past 30 years, survival and freedom from disease have increased, but the ideal multidisciplinary management remains to be determined. The preferred integrated treatment modality is preoperative radio(chemo)therapy followed by total mesorectal excision. Certain aspects of this standard are still debated, and the European and American approaches vary. The chief recommendations per international guidelines are summarized, and the next generation of integrated treatments for locally advanced rectal cancer is discussed.
Worldwide, rectal cancer is a leading cause of death from cancer, affecting males and females equally.[1-3] In the United States, there were 39,870 new rectal cancer cases in 2011.
Since the 1980s, the outcomes of rectal cancer have improved; both survival and disease-free intervals have increased through advances in diagnostic imaging, pathology, surgery, and integrated treatments, including radiotherapy (RT) and chemotherapy (CT). More important, the integration of these different treatment modalities has led to the modern standards for rectal cancer treatment. Here, we summarize the principal aspects of current standards for integrated treatment of locally advanced rectal cancer (LARC), comparing the European and American approaches.
Must preoperative radio(chemo)therapy be added to optimal surgery?
Surgery is the historical cornerstone of rectal cancer treatment. In the 1970s, unsatisfactory results were associated with surgery alone; local failure rates were 50% for locally advanced and node-
involving presentations,[5,6] prompting attempts to increase local control and survival.
In the 1980s, adjuvant postoperative concurrent radiochemotherapy (RTCT) was evaluated in North America and was found to significantly improve survival and time to recurrence.[7,8] In 1990, the National Institutes of Health (NIH) Consensus Conference recommended postoperative integrated RTCT as the standard of care. Around the same time that the NIH consensus statement was issued, preoperative integrated treatments were developed in Europe. The 1997 Swedish Rectal Cancer Trial reported significant improvement in 5-year overall local control and survival with preoperative short-course (SC) RT (5 Gy per 5 fractions, total 25 Gy) followed by surgery, vs surgery alone. Most initial findings on the benefits of adjuvant RTCT in both the preoperative and postoperative settings came from series in which patients received what we now consider inadequate surgery.
The evolution of surgical techniques in European studies culminated in total mesorectal excision (TME), first promoted by Heald, wherein en bloc resection of the rectum with its mesorectum is performed to the levator muscles in the avascular plane outside of the mesorectum. The mesorectum is enveloped by the visceral rectal fascia, which separates it from the parietal endopelvic fascia; sandwiched between the two fasciae lies a thin layer of fat that is filled with loose tissue (the “holy plane of Heald”), containing nerves for the pelvic organs. Embryologically, the rectum and mesorectum (and their vessels and lymphatics) develop together; thus, the plane that describes this resection respects the anatomy and embryological origins.[12,13]
This achievement became the new standard: local failures after TME alone for pT3-4 and N1-2 disease with a medium-risk or low-risk presentation ranged from 15% to 21%, and 5-year local recurrence reached as low as 5%, causing integrated approaches with an adequate and meticulous surgical procedure to be questioned.
European studies concluded that surgical quality significantly influences local recurrence and survival. Quirke proposed three planes, classifying the quality of the respective resected specimens as high, acceptable, or poor: mesorectal plane (intact mesorectum—high quality), intramesorectal plane (minor irregularities of the mesorectal surface—acceptable), and muscularis propria plane (specimen with high loss of mesorectum—poor quality). This classification correlates significantly with survival outcomes.
Studies in the mid-1980s demonstrated that margin involvement was central in effecting local control and that the distance between microscopic tumor penetration and surgical circumferential resection margin (CRM) was more significant than the distal or proximal margin. European groups have recently reported that magnetic resonance imaging (MRI) predicts the risk of CRM involvement or threat before surgery. MRI can define involvement of the mesorectal fascia (MRF); if the MRF is involved or if the lesion gets as close as 1 mm from the MRF, there is a high risk of a positive CRM if only TME is performed—hence, the proposal of the term “MRF +/−”[18,19]
The “Dutch Trial” (2001) was a multicenter randomized study with certified quality of surgery; it compared TME alone to preoperative SC RT followed by TME. Of the 1861 subjects, local failure rates were better in the integrated treatment arm for stage II and stage III patients than in the surgery-alone arm: 2-year overall local failure was 2.4% and 8.2%, respectively (P < .001) (stage II: 1% vs 5.7%; stage III: 4.3% vs 15%). Survival did not differ (82.0% vs 81.8%). This study supported integrated treatment, even if adequate and certified TME was performed. In the 12-year follow-up update, the 10-year cumulative local recurrence rate was 5% for RT plus surgery and 11% for surgery alone(P < .0001). Overall survival did not differ between the two groups. Notably, in TNM stage III patients who had a negative CRM, 10-year survival was 50% in the RT-plus-surgery group compared with 40% in the surgery-alone group (P = .032). The “Dutch Trial” concluded that a positive CRM was a robust predictor of local recurrence, for which planned postoperative RT, in patients with pathological evidence of CRM positivity, could not compensate.
In 2009, a British group examined whether selective postoperative chemoradiation improved outcomes in the subset of patients with involved or threatened CRMs. The UK Medical Research Council Trial (MRC 07) randomized 1350 cStage I-III patients to preoperative SC RT followed by surgery or to initial surgery followed by postoperative long-course RTCT (with RTCT only for patients with involved or threatened CRMs after surgery). TME was not mandatory but was performed in 92% of cases. At a median of 4 years of follow-up, the preoperative arm had significantly lower local failure rates and better disease-free survival (DFS). In patients with a positive CRM, local recurrence rates did not differ significantly between groups. This trial did not have as an aim comparing SC and LC treatment; rather, it compared the preoperative and selective postoperative approaches.
A German group examined the efficacy of preoperative RTCT (the “German Trial”), randomizing 823 patients with cT3 or cT4 or node-positive disease. One arm received preoperative long-course RTCT (LCRTCT) followed by surgery (with mandatory TME), and the other arm underwent the same surgery, followed by postoperative RTCT; the same RTCT fluorouracil (5-FU)-based regimen (1.8 Gy per fraction, total 50.4 Gy) was administered, except for a boost of 540 cGy in the postoperative arm. The 5-year local failure rate was lower in the preoperative therapy arm (6% vs 13%; P = .006), as were acute and late toxicity rates. Five-year survival did not differ significantly. The 11-year follow-up update confirmed these results.
Based on this and subsequent evidence, the 1990 NIH guidelines are no longer followed in the US, and the postoperative approach is limited to patients with pathological evidence of high risk or who are unable to receive RT preoperatively. Thus, the preoperative RT approach is now preferred, even if adequate surgery is performed; this can be administered in an “SC RT alone” schedule or in LCRTCT (taking advantage of chemosensibilization). It improves local control and (primarily with LC administration) effects pathological complete responses (pCRs) and sphincter preservation, although it has not affected survival in any randomized study in the TME era.
The use of MRI preoperative parameters to tailor treatment can exploit the potential of LCRTCT to manage a positive MRF or a low-lying lesion, as LCRTCT can enhance downstaging more than SC RT.
Five meta-analyses have reported conflicting results on survival.[26-30] All demonstrated a decrease in local recurrence rates with preoperative irradiation. Camma et al and the Collaborative Colorectal Cancer Group reported a survival advantage for the use of preoperative RT. A systematic review of radiation therapy trials by the Swedish Council of Technology Assessment in Health Care (SBU) noted that preoperative RT improved survival by approximately 10%, whereas meta-analyses by Munro and Bentley and Fiorica and Cartei did not. A pooled analysis of post-2000 randomized trial data showed a survival benefit for preoperative RT.
1. Giovannucci E, Wu K. Cancers of the colon and rectum. In: Schottenfeld D, Fraumeni J, eds. Cancer. Epidemiology and prevention. 3rd ed. Oxford University Press; 2006.
2. American Cancer Society. Cancer facts & figures, 2010. Available at http://www.cancer.org/Research/CancerFactsFigures/index. Accessed April 26, 2011.
3. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533-43.
4. American Cancer Society. Cancer Facts and Figures 2011. Atlanta, Ga: American Cancer Society, 2011.
5. Gunderson LL, Sosin H. Areas of failure found at reoperation (second or symptomatic look) following “curative surgery” for adenocarcinoma of the rectum: clinicopathologic correlation and implications for adjuvant therapy. Cancer. 1974;34:1278-92.
6. Rich T, Gunderson LL, Lew R, et al. Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer. 1983;52:1317-29.
7 Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med. 1985;312:1465-72.
8. Douglass HO Jr, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med. 1986;315:1294-5.
9. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264:1444-50.
10. Preoperative short-term radiation therapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Rectal Cancer Study Group. Cancer. 1990;66:49-55.
11. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med. 1997;336:980-7.
12. Heald RJ, Moran BJ, Ryall RD, et al. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg. 1998;133:894-9.
13. Heald RJ. A new approach to rectal cancer. BrJ Hosp Med. 1979;22:277-81.
14. Valentini V, Aristei C, Glimelius B, et al. Multidisciplinary rectal cancer management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2). Radiother Oncol. 2009;92:148-63.
15. MacFarlane JK, Ryall RD, Heald RJ, et al. Mesorectal excision for rectal cancer. Lancet. 1993;341:457-60.
16.Quirke P, Steele R, Monson J, et al. Effect of the plane of surgery achieved on local recurrence in patients operated with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTGCO16 randomised clinical trial. Lancet. 2009;373:821-8.
17.Glimelius B, Beets-Tan R, Blomqvist L, et al. Mesorectal fascia instead of circumferential resection margin in preoperative staging of rectal cancer. J Clin Oncol. 2011;29:2142-3.
18. Blomqvist L, Rubio C, Holm T, et al. Rectal adenocarcinoma: assessment of tumour involvement of the lateral resection margin by MRI of resected specimen. Br J Radiol. 1999;72:18-23.
19. MERCURY Study Group. Extramural depth of tumor invasion at thinsection MR in patients with rectal cancer: results of the MERCURY study. Radiology. 2007; 243:132-9.
20. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638-46.
21. van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575-82.
22. Nagtegaal ID, Marijnen CA, Kranenbarg EK, et al. Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: not one millimeter but two millimeters is the limit. Am J Surg Pathol. 2002;26:350-7.
23.Sebag-Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009; 373:811-20.
24Sauer R, Becker H, Hoyhenberger W, et al. For the German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731-40.
25.Sauer R, liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30:1926-33.
26. Camma C, Giunta M, Fiorica F, et al. Preoperative radiotherapy for resectable rectal cancer: a metaanalysis. JAMA. 2000;284:1008-15.
27. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet. 2001;358:1291-1304.
28. Glimelius B, Gronberg H, Jarnhult J, et al. A systematic overview of radiation therapy effects in rectal cancer. Acta Oncol. 2003;42:476-92.
29. Munro AJ, Bentley A. Adjuvant radiotherapy in operable rectal cancer: a systematic review. Sem Colon Rectal Surg. 2002;13:31-42.
30. Fiorica F, Cartei F, Licata A, et al. Can chemotherapy concomitantly delivered with radiotherapy improve survival of patients with resectable rectal cancer? A meta-analysis of literature data. Cancer Treat Rev. 2010;36:539-49.
31. Valentini V, van Stiphout RG, Lammering G, et al. Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials. J Clin Oncol. 2011;29:3163-72.
32. Augestad KM, Lindsetmo RO, Stulberg J, et al. International preoperative rectal cancer management: staging, neoadjuvant treatment, and impact of multidisciplinary teams. World J Surg. 2010; 34:2689-700.
33. Minsky BD. Counterpoint: long-course chemoradiation is preferable in the neoadjuvant treatment of rectal cancer. Semin Radiat Oncol. 2011;21:228-33.
34.Glimelius B, Isacsson U, Jung B, Påhlman L. Radiotherapy in addition to radical surgery in rectal cancer. Acta Oncol. 1995;34:565-70.
35. 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;93:1215-23.
36. Ngan S, Fischer R, Goldstein D, et al. A randomized trial comparing local recurrence (LR) rates between short-course (SC) and long-course (LC) radiotherapy (RT) for clinical T3 rectal cancer: an intergroup trial (TROG, AGITG, CSSANZ, RACS). J Clin Oncol. 2010;28(suppl):abstr 3509.
37. Bujko K, Bujko M. Point: short-course radiation therapy is preferable in the neoadjuvant treatment of rectal cancer. Semin Radiat Oncol. 2011;21:220-7.
38. Capirci C, Valentini V, Cionini L, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys. 2008;72:99-107.
39 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.
40. 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.
41.Lievens Y, Van den Bogaert W, Rijnders A, et al. Palliative radiotherapy practice within Western European countries: impact of the radiotherapy financing system? Radiother Oncol. 2000;56:289-95.
42. NCCN Clinical Practice Guidelines in Oncology – Rectal Cancer. Version 3.2012. Available from: http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed July 13, 2012.
43. National Cancer Institute: PDQ® Rectal Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified: 10/11/2011. Available at: http://cancer.gov/cancertopics/pdq/treatment/rectal/HealthProfessional. Accessed July 13, 2012.
44. Grávalos C, García-Alfonso P, Afonso R, et al. Recommendations and expert opinion on the treatment of locally advanced rectal cancer in Spain. Clin Transl Oncol. 2011;13:862-8.
45. Glimelius B, Påhlman L, Cervantes A. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v82-6.
46. Van Cutsem E, Dicato M, Haustermans K, et al. The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007. Ann Oncol. 2007;19(Suppl 6):vi1–vi8.
47. DCCG Danish national guidelines for rectal cancer treatment (2009). Available from: http://www.kirurgisk-selskab.dk/dks/krc.htm#top. Accessed 15 Jan 2010.
48. Association Française de Chirurgie. French national guidelines for rectal cancer treatment. Gastroenterol Clin Biol. 2007;31:1s9–1s22.
49. Norwegian Gastrointestinal Cancer Group. Kontrollopplegg ved kolorektalcancer (Norwegian Guidelines—2007). Available from: http:// www.ngicg.no/gronnbok/gronnbok.htm. Accessed 22 Jan 2010.
50. Dutch Association of Comprehensive Cancer Centres (ACCC). Oncoline—Cancer Clinical Practice Guidelines in Rectal Cancer, 2008. Available from: http://www.oncoline.nl/rectalcancer. Accessed July 13, 2012.
51. Pettersson D, Cedermark B, Holm T, et al. Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg. 2010;
52. Siegel R, Burock S, Wernecke KD, et al. Preoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society. BMC Cancer. 2009;9:50.
53. Randomized multicentre phase III study of short course radiation therapy followed by prolonged pre-operative chemotherapy and surgery in patients with high risk primary rectal cancer compared to standard preoperative chemoradiotherapy, surgery and optional adjuvant chemotherapy. Available from: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3230. Accessed July 13, 2012.
54. Preoperative downstaging of extraperitoneal T3 rectal cancer: XELOXRT versus XELACRT. A multicenter, phase III study (INTERACT). ClinicalTrials.gov Identifier: NCT01653301.
55. Hofheinz R, Wenz FK, Post S, et al. Capecitabine (Cape) versus 5-fluorouracil (5-FU) based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): long-term results of a randomized, phase III trial. J Clin Oncol. 2011;29(suppl):abstr 3504.
56. 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;28:1638-44.
57. 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;29:2773-80.
58. Mohiuddin M, Mohiuddin MM. Neoadjuvant chemoradiation in rectal cancer: time to start in a new direction. J Clin Oncol. 2011;29:e350-1; author reply e352-3. Epub 2011 Mar 14.
59. Minsky BD. Progress in the treatment of locally advanced clinically resectable rectal cancer. Clin Colorectal Cancer. 2011;10:227-37.
60. Sargent D, Yothers G, van Cutsem E, et al. Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: new data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, NSABP C-06 and C-07, and C89803. J Clin Oncol. 2009;27(suppl):4011.
61. Valentini V, van Stiphout R, Lammering G, et al. 2-Year disease free vs pathological complete response as a surrogate endpoint by using pooled data of randomized trials for locally advanced rectal cancer. In press.