Abstract
Changes in the multidisciplinary treatment of rectal cancer have been recently proposed. We performed a comprehensive review of the current data on neoadjuvant and adjuvant treatment of rectal cancer, focussing on chemoradiotherapy treatment and timing of surgery. Six components were proposed as the framework for the treatment of rectal cancer: neoadjuvant therapy and changing patterns in patient selection, long- or short-course radiotherapy, adverse effects of radiotherapy, timing of surgery, non-operative management of rectal cancer and postoperative adjuvant therapy. Lack of a consistent difference in terms of local recurrence has been observed between short-course radiotherapy and long-course chemoradiotherapy. Indications for preoperative radiotherapy have been reconsidered in the last years. An interval of 10–11 weeks seemed to be the optimal timing, with no impact on patient safety. Since assessment criteria of clinical complete response are not well defined, and the basis for non-operative management of rectal cancer is still not clear, further investigations are required. There is controversy about standard treatments for patients with locally advanced rectal cancer that are being analyzed by ongoing studies. Tailored treatments could avoid over-treatment for a large number of patients without any impairment of the oncologic results.
Similar content being viewed by others
References
Codina-Cazador A, Biondo S (2015) Specialized referral centers for rectal cancer. Cir Esp 93:273–275
Ortiz H, Ciga MA, Armendariz P et al (2014) Multicentre propensity score-matched analysis of conventional versus extended abdominoperineal excision for low rectal cancer. Br J Surg 101:874–882
Lujan J, Valero G, Biondo S, Espin E, Parrilla P, Ortiz H (2013) Laparoscopic versus open surgery for rectal cancer: results of a prospective multicentre analysis of 4970 patients. Surg Endosc 27:295–302
Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S (2012) Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 3:CD004078
DeSantis CE, Lin CC, Mariotto AB et al (2014) Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 64:252–271
Ortiz H, Wibe A, Lujan Ciga MA, Codina A, Biondo S (2013) Impact of a multidisciplinary team training programme on rectal cancer outcomes in Spain. Colorectal Dis 15:544–551
Heald RJ, Husband EM, Ryall RD (1982) The mesorectum in rectal cancer surgery—The clue to pelvic recurrence? Br J Surg 69:613–616
Ortiz H, Wibe A, Ciga MA et al (2014) Multicenter study of outcome in relation to the type of resection in rectal cancer. Dis Colon Rectum 57:811–822
Kapiteijn E, Marijnen CA, Nagtegaal ID et al (2001) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638–646
Van Gijn W, Marijnen CAM, Nagtegaal ID et al (2011) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 12:575–582
Swedish Rectal Cancer Trial (1997) Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980–987
Cammà C, Giunta M, Fiorica F, Pagliaro L, Craxì A, Cottone M (2000) Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA 284:1008–1015
Figueredo A, Zuraw L, Wong RKS, Agboola O, Rumble RB, Tandan V (2003) The use of preoperative radiotherapy in the management of patients with clinically resectable rectal cancer: a practice guideline. BMC Med 1:1
Glimelius B, Grönberg H, Järhult J, Wallgren A, Cavallin-Ståhl E (2003) A systematic overview of radiation therapy effects in rectal cancer. Acta Oncol 42:476–492
Fiorica F, Cartei F, Licata A et al (2010) Can chemotherapy concomitantly delivered with radiotherapy improve survival of patients with resectable rectal cancer? A meta-analysis of literature data. Cancer Treat Rev 36:539–549
Ceelen W, Fierens K, Van Nieuwenhove Y, Pattyn P (2009) Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: a systematic review and meta-analysis. Int J Cancer 124:2966–2972
Bosset JF, Calais G, Mineur L et al (2005) Enhanced tumourocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results–EORTC 22921. J Clin Oncol 23:5620–5627
Sauer R, Becker H, Hohenberger W et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740
Bosset JF, Collette L, Calais G et al (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123
Gerard JP, Conroy T, Bonnetain F et al (2006) Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 24:4620–4625
Frasson M, Garcia-Granero E, Roda D et al (2011) Preoperative chemoradiation may not always be needed for patients with T3 and T2N+ rectal cancer. Cancer 117:3118–3125
Garcia-Aguilar J, Smith DD, Avila K, Bergsland EK, Chu P, Krieg RM (2011) Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg 254:97–102
Schrag D, Weiser MR, Goodman KA, Bergsland EK, Chu P, Krieg RM, Timing of Rectal Cancer Response to Chemoradiation Consortium (2014) Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol 32:513–518
Van Dijk TH, Tamas K, Beukema JC et al (2013) Evaluation of short-course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer. Ann Oncol 24:1762–1769
Bujko K, Nasierowska-Guttmejer A, Wyrwicz L et al (2013) Neoadjuvant treatment for unresectable rectal cancer: an interim analysis of a multicentre randomized study. Radiother Oncol 107:171–177
Julien LA, Thorson AG (2010) Current neoadjuvant strategies in rectal cancer. J Surg Oncol 101:321–326
Sebag-Montefiore D, Stephens RJ, Steele R et al (2009) Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373:811–820
Peeters KCMJ, Marijnen CAM, Nagtegaal ID et al (2007) The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246:693–701
Tyc-Szczepaniak D, Wyrwicz L, Kepka L et al (2013) Palliative radiotherapy and chemotherapy instead of surgery in symptomatic rectal cancer with synchronous unresectable metastases: a phase II study. Ann Oncol 24:2829–2834
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M (2006) Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93:1215–1223
Ngan SY, Burmeister B, Fisher RJ et al (2012) Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 30:3827–3833
Pettersson D, Lörinc E, Holm T et al (2015) Tumour regression in the randomized Stockholm III Trial of radiotherapy regimens for rectal cancer. Br J Surg 102:972–978
Pollack J, Holm T, Cedermark B et al (2006) Late adverse effects of short-course preoperative radiotherapy in rectal cancer. Br J Surg 93:1519–1525
Pettersson D, Cedermark B, Holm T et al (2010) Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg 97:580–587
Zhou Z-R, Liu S-X, Zhang T-S et al (2014) Short-course preoperative radiotherapy with immediate surgery versus long-course chemoradiation with delayed surgery in the treatment of rectal cancer: a systematic review and meta-analysis. Surg Oncol 23:211–221
Bujko K, Bujko M (2011) Point: short-course radiation therapy is preferable in the neoadjuvant treatment of rectal cancer. Semin Radiat Oncol 21:220–227
Nilsson PJ, van Etten B, Hospers GAP et al (2013) Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial. BMC Cancer 13:279
Dahlberg M, Glimelius B, Graf W, Påhlman L (1998) Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study. Dis Colon Rectum 41:543–549
Frykholm GJ, Glimelius B, Påhlman L (1993) Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 36:564–572
Frykholm GJ, Isacsson U, Nygård K et al (1996) Preoperative radiotherapy in rectal carcinoma. Aspects of acute adverse effects and radiation technique. Int J Radiat Oncol Biol Phys 35:1039–1048
Peeters KCMJ, van de Velde CJH, Leer JWH et al (2005) Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients—a Dutch Colo Rectal Cancer group study. J Clin Oncol 23:6199–6206
Birgisson H, Påhlman L, Gunnarsson U, Glimelius B, Swedish Rectal Cancer Trial Group (2005) Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 23:8697–8705
Holm T, Singnomklao T, Rutqvist LE, Cedermark B (1996) Adjuvant preoperative radiotherapy in patients with rectal carcinoma. Adverse effects during long term follow-up of two randomized trials. Cancer 78:968–976
Minsky BD, Conti JA, Huang Y, Knopf K (1995) Relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer. J Clin Oncol 13:1409–1416
Letschert JG, Lebesque JV, de Boer RW, Hart AA, Bartelink H (1990) Dose-volume correlation in radiation-related late small-bowel complications: a clinical study. Radiother Oncol 18:307–320
Syk E, Torkzad MR, Blomqvist L, Ljungqvist O, Glimelius B (2006) Radiological findings do not support lateral residual tumour as a major cause of local recurrence of rectal cancer. Br J Surg 93:113–119
Syk E, Torkzad MR, Blomqvist L, Nilsson PJ, Glimelius B (2008) Local recurrence in rectal cancer: anatomic localization and effect on radiation target. Int J Radiat Oncol Biol Phys 72:658–664
Bujko K, Bujko M, Pietrzak L (2006) Clinical target volume for rectal cancer: in regard to Roels et al. (Int J Radiat Oncol Biol Phys 2006;65:1129–142). Int J Radiat Oncol Biol Phys 68:313
Haustermans K, Roels S, Penninckx F (2007) In regards to Bujko et al. (Int J Radiat Oncol Biol Phys 2007;68:313–316). Int J Radiat Oncol Biol Phys 69:639–640
Motson RW, Khan JS, Arulampalam TH, Austin RC, Lacey N, Sizer B (2011) Laparoscopic total mesorectal excision following long course chemoradiotherapy for locally advanced rectal cancer. Surg Endosc 25:1753–1760
Foster JD, Jones EL, Falk S, Cooper EJ, Francis NK (2013) Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: a systematic review of the literature. Dis Colon Rectum 56:921–930
Sloothaak DAM, Geijsen DE, van Leersum NJ et al (2013) Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg 100:933–939
Probst CP, Becerra AZ, Aquina CT et al (2015) Extended intervals after neoadjuvant therapy in locally advanced rectal cancer: the key to improved tumour response and potential organ preservation. J Am Coll Surg 221:430–440
Maas M, Nelemans PJ, Valentini V et al (2010) Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 11:835–844
Biondo S, Ortiz H, Lujan J et al (2010) Quality of mesorectum after laparoscopic resection for rectal cancer—results of an audited teaching programme in Spain. Colorectal Dis 12:24–31
Augestad KM, Lindsetmo R-O, Stulberg J et al (2010) International preoperative rectal cancer management: staging, neoadjuvant treatment, and impact of multidisciplinary teams. World J Surg 34:2689–2700
Habr-Gama A, Perez RO, Nadalin W et al (2004) Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 240:711–717
Habr-Gama A, Perez RO, Proscurshim I et al (2006) Patterns of failure and survival for nonoperative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy. J Gastrointest Surg 10:1319–1328
Smith JD, Ruby JA, Goodman KA et al (2012) Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg 256:965–972
Maas M, Beets-Tan RGH, Lambregts DMJ et al (2011) Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol 29:4633–4640
Dalton RSJ, Velineni R, Osborne ME et al (2012) A single-centre experience of chemoRT for rectal cancer: is there potential for nonoperative management? Colorectal Dis 14:567–571
Hiotis SP, Weber SM, Cohen AM et al (2002) Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. J Am Coll Surg 194:131–135
Guillem JG, Chessin DB, Shia J et al (2005) Clinical examination following preoperative chemoradiation for rectal cancer is not a reliable surrogate end point. J Clin Oncol 23:3475–3479
Habr-Gama A, Perez RO, Wynn G, Marks J, Kessler H, Gama-Rodrigues J (2010) Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer: characterization of clinical and endoscopic findings for standardization. Dis Colon Rectum 53:1692–1698
Garcia-Aguilar J, Shi Q, Thomas CR et al (2012) A phase II trial of neoadjuvant chemoradiation and local excision for T2N0 rectal cancer: preliminary results of the ACOSOG Z6041 trial. Ann Surg Oncol 19:384–391
Kuo L-J, Chiou J-F, Tai C-J et al (2012) Can we predict pathologic complete response before surgery for locally advanced rectal cancer treated with preoperative chemoradiation therapy? Int J Colorectal Dis 27:613–621
Hötker AM, Garcia-Aguilar J, Gollub MJ (2014) Multiparametric MRI of rectal cancer in the assessment of response to therapy: a systematic review. Dis Colon Rectum 57:790–799
Habr-Gama A, Gama-Rodrigues J, Perez RO et al (2008) Late assessment of local control by PET in patients with distal rectal cancer managed non-operatively after complete tumour regression following neoadjuvant chemoradiation. Tech Coloproctol 12:74–76
Bujko K, Michalski W, Kepka L et al (2007) Association between pathologic response in metastatic lymph nodes after preoperative chemoradiotherapy and risk of distant metastases in rectal cancer: an analysis of outcomes in a randomized trial. Int J Radiat Oncol Biol Phys 67:369–377
Leibold T, Shia J, Ruo L et al (2008) Prognostic implications of the distribution of lymph node metastases in rectal cancer after neoadjuvant chemoradiotherapy. J Clin Oncol 26:2106–2111
Mawdsley S, Glynne-Jones R, Grainger J et al (2005) Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3–T4 rectal cancer predict for 3-year disease-free survival? Int J Radiat Oncol Biol Phys 63:745–752
Bujko K, Glynne-Jones R, Bujko M (2010) Adjuvant chemotherapy for rectal cancer. Ann Oncol 21:2443
André T, Boni C, Navarro M et al (2009) 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 27:3109–3116
Wolpin BM, Mayer RJ (2008) Systemic treatment of colorectal cancer. Gastroenterology 134:1296–1310
Bujko K, Glynne-Jones R, Bujko M (2010) Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol 21:1743–1750
Bosset JF, Calais G, Mineur L et al (2014) Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 15:184–190
Breugom AJ, van Gijn W, Muller EW et al (2015) Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo) radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol 26:696–701
Sainato A, Cernusco Luna NV, Valentini V et al (2014) No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): long term results of a randomized trial (I-CNR-RT). Radiother Oncol 113:223–229
Glynne-Jones R, Counsell N, Quirke P et al (2014) Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol 25:1356–1362
Breugom AJ, Swets M, Bosset JF et al (2015) Adjuvant chemotherapy after preoperative (chemo) radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 16:200–207
Hong YS, Nam B-H, Kim K-P et al (2014) Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol 15:1245–1253
Rödel C, Graeven U, Fietkau R et al (2015) Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 16:979–989
Maas M, Nelemans PJ, Valentini V et al (2015) Adjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection: A pooled analysis of 3,313 patients. Int J Cancer 137:212–220
Van de Velde CJH, Boelens PG, Borras JM et al (2014) EURECCA colorectal: multidisciplinary management: European consensus conference colon and rectum. Eur J Cancer 50:1.e1–1.e34
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
In this article, no patient care was involved.
Rights and permissions
About this article
Cite this article
Biondo, S., Fraccalvieri, D., Golda, T. et al. Update on advances and controversy in rectal cancer treatment. Tech Coloproctol 20, 145–152 (2016). https://doi.org/10.1007/s10151-015-1418-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10151-015-1418-y