Extramural Venous Invasion (EMVI) and Tumour Regression Grading (TRG) as Potential Prognostic Factors for Risk Stratification and Treatment Decision in Rectal Cancer

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1. 1.
   Fitzmaurice C, Dicker D, Pain A, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505–27.CrossRefPubMedGoogle Scholar
2. 2.
   Heald RJ. A new approach to rectal cancer. Br J Hosp Med. 1979;22(3):277–81.PubMedGoogle Scholar
3. 3.
   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(9666):821–8.CrossRefPubMedPubMedCentralGoogle Scholar
4. 4.
   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(9):638–46.CrossRefPubMedGoogle Scholar
5. 5.
   Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–40.CrossRefPubMedGoogle Scholar
6. 6.
   Marijnen CA, van de Velde CJ, Putter H, et al. Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol. 2005;23(9):1847–58.CrossRefPubMedGoogle Scholar
7. 7.
   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):6199–206.CrossRefPubMedGoogle Scholar
8. 8.
   Birgisson H, Påhlman L, Gunnarsson U, et al. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol. 2005;23(24):8697–705.CrossRefPubMedGoogle Scholar
9. 9.
   Brændengen M, Tveit KM, Bruheim K, et al. Late patient-reported toxicity after preoperative radiotherapy or chemoradiotherapy in nonresectable rectal cancer: results from a randomized Phase III study. Int J Radiat Oncol Biol Phys. 2011;81(4):1017–24.CrossRefPubMedGoogle Scholar
10. 10.
    Pachler J, Wille-Jorgensen P. Quality of life after rectal resection for cancer, with or without permanent colostomy. Cochrane Database Syst Rev. 2012;12:CD004323.PubMedGoogle Scholar
11. 11.
    Lange MM, van de Velde CJ. Urinary and sexual dysfunction after rectal cancer treatment. Nat Rev Urol. 2011;8(1):51–7.CrossRefPubMedGoogle Scholar
12. 12.
    Augestad KM, Bakaki PM, Rose J, et al. Metastatic spread pattern after curative colorectal cancer surgery. A retrospective, longitudinal analysis. Cancer Epidemiol. 2015;39(5):734–44.CrossRefPubMedGoogle Scholar
13. 13.
    Engelen SM, Maas M, Lahaye MJ, et al. Modern multidisciplinary treatment of rectal cancer based on staging with magnetic resonance imaging leads to excellent local control, but distant control remains a challenge. Eur J Cancer. 2013;49(10):2311–20.CrossRefPubMedGoogle Scholar
14. 14.
    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):711–9.CrossRefPubMedGoogle Scholar
15. 15.
    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(10):1109–17.CrossRefPubMedGoogle Scholar
16. 16.
    Schrag D, Weiser MR, Goodman KA, et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014;32(6):513–8.CrossRefPubMedGoogle Scholar
17. 17.
    Chua YJ, Barbachano Y, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010;11(3):241–8.CrossRefPubMedGoogle Scholar
18. 18.
    Dewdney A, Cunningham D, Tabernero J, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012;30(14):1620–7.CrossRefPubMedGoogle Scholar
19. 19.
    Sclafani F, Gonzalez D, Cunningham D, et al. TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial. J Natl Cancer Inst. 2014;106(7).Google Scholar
20. 20.
    Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol. 1986;150(3):195–203.CrossRefPubMedGoogle Scholar
21. 21.
    Blenkinsopp WK, Stewart-Brown S, Blesovsky L, et al. Histopathology reporting in large bowel cancer. J Clin Pathol. 1981;34(5):509–13.CrossRefPubMedPubMedCentralGoogle Scholar
22. 22.
    Labianca R, Nordlinger B, Beretta GD, et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi64–72.CrossRefPubMedGoogle Scholar
23. 23.
    NCCN Guidelines Version 3.2015 Colon Cancer. Available at: http://www.nccn.org
24. 24.
    QUASAR Collaborative Group, Gray R, Barnwell J, McConkey C, et al. QUASAR: a randomised study of adjuvant chemotherapy versus observation including 3239 colorectal cancer patients. Lancet. 2007;370(9604):2020–9.CrossRefGoogle Scholar
25. 25.••
    Talbot IC, Ritchie S, Leighton MH, et al. The clinical significance of invasion of veins by rectal cancer. Br J Surg. 1980;67(6):439–42. One of the first studies to demonstrate that tumour vascular invasion within the resection specimens is associated with poor prognosis of rectal cancer.CrossRefPubMedGoogle Scholar
26. 26.
    Knudsen JB, Nilsson T, Sprechler M, et al. Venous and nerve invasion as prognostic factors in postoperative survival of patients with resectable cancer of the rectum. Dis Colon Rectum. 1983;26(9):613–7.CrossRefPubMedGoogle Scholar
27. 27.
    Günther K, Dworak O, Remke S, et al. Prediction of distant metastases after curative surgery for rectal cancer. J Surg Res. 2002;103(1):68–78.CrossRefPubMedGoogle Scholar
28. 28.
    Nissan A, Stojadinovic A, Shia J, et al. Predictors of recurrence in patients with T2 and early T3, N0 adenocarcinoma of the rectum treated by surgery alone. J Clin Oncol. 2006;24(25):4078–84.CrossRefPubMedGoogle Scholar
29. 29.
    Talbot IC, Ritchie S, Leighton MH, et al. Spread of rectal cancer within veins. Histologic features and clinical significance. Am J Surg. 1981;141(1):15–7.CrossRefPubMedGoogle Scholar
30. 30.
    Freedman LS, Macaskill P, Smith AN. Multivariate analysis of prognostic factors for operable rectal cancer. Lancet. 1984;2(8405):733–6.CrossRefPubMedGoogle Scholar
31. 31.
    Harrison JC, Dean PJ, El-Zeky F, et al. From Dukes through Jass: pathological prognostic indicators in rectal cancer. Hum Pathol. 1994;25(5):498–505.CrossRefPubMedGoogle Scholar
32. 32.
    Chand M, Bhangu A, Wotherspoon A, et al. EMVI-positive stage II rectal cancer has similar clinical outcomes as stage III disease following pre-operative chemoradiotherapy. Ann Oncol. 2014;25(4):858–63.CrossRefPubMedGoogle Scholar
33. 33.••
    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):355–64. First study to demonstrate that invasion of large extramural veins by rectal cancer is detectable by MRI and can predict tumour vascular invasion within the resection specimens.CrossRefPubMedGoogle Scholar
34. 34.•
    Smith NJ, Barbachano Y, Norman AR, et al. Prognostic significance of magnetic resonance imaging detected extramural vascular invasion in rectal cancer. Br J Surg. 2008;95(2):229–36. Retrospective study showing that mrEMVI is a predictive factor of outcome in rectal cancer.CrossRefPubMedGoogle Scholar
35. 35.•
    Sohn B, Lim JS, Kim H, et al. MRI-detected extramural vascular invasion is an independent prognostic factor for synchronous metastasis in patients with rectal cancer. Eur Radiol. 2015;25(5):1347–55. Retrospective study showing that mrEMVI is associated with an increased risk of distant metastases from rectal cancer.CrossRefPubMedGoogle Scholar
36. 36.
    Koh DM, Smith NJ, Swift RI, et al. The relationship between MR demonstration of extramural venous invasion and nodal disease in rectal cancer. Clin Med Oncol. 2008;2:267–73.PubMedPubMedCentralGoogle Scholar
37. 37.
    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.CrossRefPubMedCentralGoogle Scholar
38. 38.
    MERCURY Study Group. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology. 2007;243(1):132–9.CrossRefGoogle Scholar
39. 39.
    Bugg WG, Andreou AK, Biswas D, et al. The prognostic significance of MRI-detected extramural venous invasion in rectal carcinoma. Clin Radiol. 2014;69(6):619–23.CrossRefPubMedGoogle Scholar
40. 40.
    Yu SK, Tait D, Chau I, et al. MRI predictive factors for tumor response in rectal cancer following neoadjuvant chemoradiation therapy--implications for induction chemotherapy? Int J Radiat Oncol Biol Phys. 2013;87(3):505–11.CrossRefPubMedGoogle Scholar
41. 41.
    Chand M, Swift RI, Tekkis PP, et al. Extramural venous invasion is a potential imaging predictive biomarker of neoadjuvant treatment in rectal cancer. Br J Cancer. 2014;110(1):19–25.CrossRefPubMedPubMedCentralGoogle Scholar
42. 42.
    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-yp of 11 years. J Clin Oncol. 2012;30(16):1926–33.CrossRefPubMedGoogle Scholar
43. 43.
    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(9666):811–20.CrossRefPubMedPubMedCentralGoogle Scholar
44. 44.
    Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012;30(15):1770–6.CrossRefPubMedPubMedCentralGoogle Scholar
45. 45.
    Martens MH, van Heeswijk MM, van den Broek JJ, et al. Prospective, multicenter validation study of magnetic resonance volumetry for response assessment after preoperative chemoradiation in rectal cancer: can the results in the literature be reproduced? Int J Radiat Oncol Biol Phys. 2015;93(5):1005–14.CrossRefPubMedGoogle Scholar
46. 46.
    MacGregor TP, Maughan TS, Sharma RA. Pathological grading of regression following neoadjuvant chemoradiation therapy: the clinical need is now. J Clin Pathol. 2012;65(10):867–71.CrossRefPubMedGoogle Scholar
47. 47.
    Kim NK, Baik SH, Min BS, et al. A comparative study of volumetric analysis, histopathologic downstaging, and tumor regression grade in evaluating tumor response in locally advanced rectal cancer following preoperative chemoradiation. Int J Radiat Oncol Biol Phys. 2007;67(1):204–10.CrossRefPubMedGoogle Scholar
48. 48.
    Memon S, Lynch AC, Akhurst T, et al. Systematic review of FDG-PET prediction of complete pathological response and survival in rectal cancer. Ann Surg Oncol. 2014;21(11):3598–607.CrossRefPubMedGoogle Scholar
49. 49.
    Glynne-Jones R, Mawdsley S, Pearce T, et al. Alternative clinical end points in rectal cancer--are we getting closer? Ann Oncol. 2006;17(8):1239–48.CrossRefPubMedGoogle Scholar
50. 50.
    Fernandez-Martos C, Guerrero A, Minsky B. Clinically relevant study end points in rectal cancer. Recent Results Cancer Res. 2012;196:3–19.CrossRefPubMedGoogle Scholar
51. 51.
    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(7):918–28.CrossRefPubMedGoogle Scholar
52. 52.
    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(9):835–44.CrossRefPubMedGoogle Scholar
53. 53.••
    Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis. 1997;12(1):19–23. First study to show that in rectal cancer it is feasible to classify response to pre-operative (chemo)radiotherapy by assessing the degree of tumour regression within resection specimens.CrossRefPubMedGoogle Scholar
54. 54.
    Mandard AM, Dalibard F, Mandard JC, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73(11):2680–6.CrossRefPubMedGoogle Scholar
55. 55.••
    Fokas E, Liersch T, Fietkau R, et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol. 2014;32(15):1554–62. Largest study to demonstrate that ypTRG after chemoradiotherapy in rectal cancer is an independent predictive factor for disease-free survival and distant metastases.CrossRefPubMedGoogle Scholar
56. 56.
    Vecchio FM, Valentini V, Minsky BD, et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys. 2005;62(3):752–60.CrossRefPubMedGoogle Scholar
57. 57.
    Benzoni E, Intersimone D, Terrosu G, et al. Prognostic value of tumour regression grading and depth of neoplastic infiltration within the perirectal fat after combined neoadjuvant chemo-radiotherapy and surgery for rectal cancer. J Clin Pathol. 2006;59(5):505–12.CrossRefPubMedPubMedCentralGoogle Scholar
58. 58.
    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.CrossRefPubMedGoogle Scholar
59. 59.
    Lindebjerg J, Hansborg N, Ploen J, et al. Factors influencing reproducibility of tumour regression grading after high-dose chemoradiation of locally advanced rectal cancer. Histopathology. 2011;59(1):18–21.CrossRefPubMedGoogle Scholar
60. 60.
    Chetty R, Gill P, Govender D, et al. A multi-centre pathologist survey on pathological processing and regression grading of colorectal cancer resection specimens treated by neoadjuvant chemoradiation. Virchows Arch. 2012;460(2):151–5.CrossRefPubMedGoogle Scholar
61. 61.
    Chetty R, Gill P, Govender D, et al. International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems. Hum Pathol. 2012;43(11):1917–23.CrossRefPubMedGoogle Scholar
62. 62.
    Wheeler JM, Warren BF, Mortensen NJ, et al. Quantification of histologic regression of rectal cancer after irradiation: a proposal for a modified staging system. Dis Colon Rectum. 2002;45:1051–6.CrossRefPubMedGoogle Scholar
63. 63.
    Ryan R, Gibbons D, Hyland JM, et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology. 2005;47(2):141–6.CrossRefPubMedGoogle Scholar
64. 64.
    Losi L, Luppi G, Gavioli M, et al. Prognostic value of Dworak grade of regression (GR) in patients with rectal carcinoma treated with preoperative radiochemotherapy. Int J Colorectal Dis. 2006;21(7):645–51.CrossRefPubMedGoogle Scholar
65. 65.
    Beddy D, Hyland JM, Winter DC, et al. A simplified tumor regression grade correlates with survival in locally advanced rectal carcinoma treated with neoadjuvant chemoradiotherapy. Ann Surg Oncol. 2008;15(12):3471–7.CrossRefPubMedGoogle Scholar
66. 66.
    Suarez J, Vera R, Balén E, et al. Pathologic response assessed by Mandard grade is a better prognostic factor than down staging for disease-free survival after preoperative radiochemotherapy for advanced rectal cancer. Colorectal Dis. 2008;10(6):563–8.CrossRefPubMedGoogle Scholar
67. 67.
    Edge S, Fritz A, Byrd D, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010.Google Scholar
68. 68.
    Dhadda AS, Dickinson P, Zaitoun AM, et al. Prognostic importance of Mandard tumour regression grade following pre-operative chemo/radiotherapy for locally advanced rectal cancer. Eur J Cancer. 2011;47(8):1138–45.CrossRefPubMedGoogle Scholar
69. 69.
    Roy P, Serra S, Kennedy E, et al. The prognostic value of grade of regression and oncocytic change in rectal adenocarcinoma treated with neo-adjuvant chemoradiotherapy. J Surg Oncol. 2012;105(2):130–4.CrossRefPubMedGoogle Scholar
70. 70.
    Trakarnsanga A, Gönen M, Shia J, et al. Comparison of tumor regression grade systems for locally advanced rectal cancer after multimodality treatment. J Natl Cancer Inst. 2014;106(10).Google Scholar
71. 71.
    Pettersson D, Lörinc E, Holm T, et al. Tumour regression in the randomized Stockholm III Trial of radiotherapy regimens for rectal cancer. Br J Surg. 2015;102(8):972–8.CrossRefPubMedPubMedCentralGoogle Scholar
72. 72.••
    Salerno GV, Daniels IR, Moran BJ, et al. Magnetic resonance imaging prediction of an involved surgical resection margin in low rectal cancer. Dis Colon Rectum. 2009;52(4):632–9. First study to propose an MRI-based classification system to assess the degree of tumour regression after neoadjuvant (chemo)radiotherapy in rectal cancer.CrossRefPubMedGoogle Scholar
73. 73.••
    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(28):3753–60. First study in rectal cancer to demonstrate the prognostic role of tumour regression grade as assessed by MRI after neoadjuvant (chemo)radiotherapy.CrossRefPubMedGoogle Scholar
74. 74.
    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(6):575–82.CrossRefPubMedGoogle Scholar
75. 75.
    André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343–51.CrossRefPubMedGoogle Scholar
76. 76.
    Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25(16):2198–204.CrossRefPubMedGoogle Scholar
77. 77.
    Petersen SH, Harling H, Kirkeby LT, et al. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev. 2012;3:CD004078.PubMedGoogle Scholar
78. 78.
    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):184–90.CrossRefPubMedGoogle Scholar
79. 79.
    Sainato A, Cernusco LNV, Valentini V, et al. 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. 2014;113(2):223–9.CrossRefPubMedGoogle Scholar
80. 80.
    Glynne-Jones R, Counsell N, Quirke P, et al. 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. 2014;25(7):1356–62.CrossRefPubMedGoogle Scholar
81. 81.
    Breugom AJ, van Gijn W, Muller EW, et al. 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. 2015;26(4):696–701.CrossRefPubMedGoogle Scholar
82. 82.
    Breugom AJ, Swets M, Bosset JF, et al. 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. 2015;16(2):200–7.CrossRefPubMedGoogle Scholar
83. 83.
    Maas M, Nelemans PJ, Valentini V, et al. Adjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection. Int J Cancer. 2015;137(1):212–20.CrossRefPubMedGoogle Scholar
84. 84.
    Collette L, Bosset JF, den Dulk M, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol. 2007;25(28):4379–86.CrossRefPubMedGoogle Scholar
85. 85.
    Rödel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23(34):8688–96.CrossRefPubMedGoogle Scholar
86. 86.
    Glimelius B, Tiret E, Cervantes A, et al. ESMO Guidelines Working Group. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi81-8.CrossRefPubMedGoogle Scholar
87. 87.
    Fernández-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 Cáncer de Recto 3 Study. J Clin Oncol. 2010;28(5):859–65.CrossRefPubMedGoogle Scholar
88. 88.
    Glynne-Jones R, Anyamene N, Moran B, et al. Neoadjuvant chemotherapy in MRI-staged high-risk rectal cancer in addition to or as an alternative to preoperative chemoradiation? Ann Oncol. 2012;23(10):2517–26.CrossRefPubMedGoogle Scholar
89. 89.
    Nilsson PJ, van Etten B, Hospers GA, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer--the RAPIDO trial. BMC Cancer. 2013;13:279.CrossRefPubMedPubMedCentralGoogle Scholar
90. 90.
    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):711–7.PubMedPubMedCentralGoogle Scholar
91. 91.
    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;16(15):1537–46.CrossRefPubMedGoogle Scholar
92. 92.
    Dhadda AS, Zaitoun AM, Bessell EM. Regression of rectal cancer with radiotherapy with or without concurrent capecitabine—optimising the timing of surgical resection. Clin Oncol. 2009;21(1):23–31.CrossRefGoogle Scholar
93. 93.
    Sloothaak DA, Geijsen DE, van Leersum NJ, et al. Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg. 2013;100(7):933–9.CrossRefPubMedGoogle Scholar
94. 94.
    Probst CP, Becerra AZ, Aquina CT, et al. Extended intervals after neoadjuvant therapy in locally advanced rectal cancer: the key to improved tumor response and potential organ preservation. J Am Coll Surg. 2015;221(2):430–40.CrossRefPubMedGoogle Scholar
95. 95.
    Huntington CR, Boselli D, Symanowski J, et al. Optimal timing of surgical resection after radiation in locally advanced rectal adenocarcinoma: an analysis of the National Cancer Database. Ann Surg Oncol. 2015;Oct 29 [Epub ahead of print].Google Scholar
96. 96.
    Sclafani F, Cunningham D. Neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer. Future Oncol. 2014;10(14):2243–57.CrossRefPubMedGoogle Scholar
97. 97.
    PROSPECT: chemotherapy alone or chemotherapy plus radiation therapy in treating patients with locally advanced rectal cancer undergoing surgery. Available at https://clinicaltrials.gov/ct2/show/NCT01515787