Neoadjuvant chemoradiation therapy and pathological complete response in rectal cancer

Linda Ferrari, Alessandro Fichera, Linda Ferrari, Alessandro Fichera

Abstract

The management of rectal cancer has evolved significantly in the last few decades. Significant improvements in local disease control were achieved in the 1990s, with the introduction of total mesorectal excision and neoadjuvant radiotherapy. Level 1 evidence has shown that, with neoadjuvant chemoradiation therapy (CRT) the rates of local recurrence can be lower than 6% and, as a result, neoadjuvant CRT currently represents the accepted standard of care. This approach has led to reliable tumor down-staging, with 15-27% patients with a pathological complete response (pCR)-defined as no residual cancer found on histological examination of the specimen. Patients who achieve pCR after CRT have better long-term outcomes, less risk of developing local or distal recurrence and improved survival. For all these reasons, sphincter-preserving procedures or organ-preserving options have been suggested, such as local excision of residual tumor or the omission of surgery altogether. Although local recurrence rate has been stable at 5-6% with this multidisciplinary management method, distal recurrence rates for locally-advanced rectal cancers remain in excess of 25% and represent the main cause of death in these patients. For this reason, more recent trials have been looking at the administration of full-dose systemic chemotherapy in the neoadjuvant setting (in order to offer early treatment of disseminated micrometastases, thus improving control of systemic disease) and selective use of radiotherapy only in non-responders or for low rectal tumors smaller than 5 cm.

Keywords: neoadjuvant chemoradiation therapy; pathological complete response; rectal cancer.

© The Author(s) 2015. Published by Oxford University Press and the Digestive Science Publishing Co. Limited.

Figures

Figure 1.
Figure 1.
Management of rectal cancer in the USA according to NCCN guidelines [26] CRT = chemoradiotherapy; CT = chemotherapy; RT = radiotherapy
Figure 2.
Figure 2.
European management of rectal cancer [27–29] LR = local recurrence; MRF = mesorectal fascia; TME = total mesorectal excision
Figure 3.
Figure 3.
The PROSPECT trial CT = computed tomography; ERUS = endorectal ultrsound; MRI = magnetic resonance imaging

References

    1. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 1985;312:1465–72.
    1. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709–15.
    1. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444–50.
    1. Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1986;1:1479–82.
    1. Arbman G, Nilsson E, Hallböök O, et al. Local recurrence following total mesorectal excision for rectal cancer. Br J Surg 1996;83:375–9.
    1. Kapiteijn E, Putter H, van de Velde CJ, Co-operative investigators of the Dutch ColoRectal Cancer Group Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands. Br J Surg 2002;89:1142–9.
    1. Sauer R, Becker H, Hohenberger W, et al. German Rectal Cancer Study Group. Pre-operative vs. post-operative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–40.
    1. Sauer R, Liersch T, Merkel S, et al. Pre-operative vs. post-operative 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.
    1. 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.
    1. 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.
    1. Habr-Gama A, Perez RO, Nadalin W, et al. Operative vs. nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004;240:711–18.
    1. Habr-Gama A, Perez RO, Proscurshim I, et al. Patterns of failure and survival for non-operative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy. J Gastrointest Surg 2006;10:1319–29.
    1. 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.
    1. 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.
    1. Fernandez-Martos C, Brown G, Estevan R, et al. Pre-operative chemotherapy in patients with intermediate-risk rectal adenocarcinoma selected by high-resolution magnetic resonance imaging: the GEMCAD 0801 Phase II Multicenter Trial. Oncologist 2014;19:1042–3.
    1. 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;32:513–18.
    1. Schrag D. Evolving role of neoadjuvant therapy in rectal cancer. Curr Treat Options Oncol 2013;14:350–64.
    1. Smith JJ, Garcia-Aguilar J. Advances and Challenges in Treatment of Locally Advanced Rectal Cancer . J Clin Oncol 2015;133:1797–808.
    1. Samdani T, Garcia-Aguilar J. Imaging in rectal cancer: magnetic resonance imaging vs. endorectal ultrasonography. Surg Oncol Clin N Am 2014;23:59–77.
    1. Brown G, Davies S, Williams GT, et al. Effectiveness of pre-operative staging in rectal cancer: digital rectal examination, endoluminal ultrasound or magnetic resonance imaging? Br J Cancer 2004;91:23–9.
    1. Al-Sukhni E, Milot L, Fruitman M, et al. Diagnostic accuracy of MRI for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol 2012;19:2212–23.
    1. MERCURY Study Group. Diagnostic accuracy of pre-operative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ 2006;333:779.
    1. Taylor FG, Quirke P, Heald RJ, et al. Magnetic Resonance Imaging in Rectal Cancer European Equivalence Study Study Group. Pre-operative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol 2014;32:34–43.
    1. Taylor FG, Quirke P, Heald RJ, et al. MERCURY study group. Pre-operative 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;253:711–19.
    1. Battersby NJ, How P, Moran B, et al. MERCURY II Study Group. Prospective Validation of a Low Rectal Cancer Magnetic Resonance Imaging Staging System and Development of a Local Recurrence Risk Stratification Model: the MERCURY II Study. Ann Surg 2015. Mar 27. [Epub ahead of print]
    1. Benson AB, Venook AP, Saltz L. NCCN Guidelines version 2.2015 (rectal cancer), 2015. .
    1. Smith N, Brown G. Pre-operative staging of rectal cancer. Acta Oncol 2008;47:20–31.
    1. Blomqvist L, Glimelius B. The ‘good’, the ‘bad’, and the ‘ugly’ rectal cancers. Acta Oncol 2008;47:5–8.
    1. Glynne-Jones R, Tan D, Goh V. Pelvic MRI for guiding treatment decisions in rectal cancer. Oncology (Williston Park) 2014;28:667–77.
    1. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Dutch Colorectal Cancer Group. Pre-operative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638–46.
    1. Bosset JF, Calais G, Mineur L, et al. Enhanced tumoricidal effect of chemotherapy with pre-operative radiotherapy for rectal cancer: preliminary results: EORTC 22921. J Clin Oncol 2005;23:5620–7.
    1. Bossett JF, Collete L, Calais G, et al. EORTC Radiotherapy Group Trial 22921. Chemotherapy with pre-operative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114–23.
    1. Gerard JP, Conroy T, Bonnetain F, et al. Pre-operative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-T4 rectal cancers: Results of FFCD9203. J Clin Oncol 2006;24:4620–5.
    1. Peeters KC, van de Velde CJ, Leer JW, et al. Late side effects of short-course pre-operative 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;23:6199–206.
    1. Roh MS, Colangelo LH, O’Connell MJ, et al. Pre-operative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009;27:5124–30.
    1. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term results of a randomized trial comparing pre-operative short-course radiotherapy with pre-operative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93:1215–23.
    1. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy vs. 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 2012;30:3827–33.
    1. Roh MS, Yothers GA, O’Connell MJ, et al. The impact of capecitabine and oxaliplatin in the pre-operative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. J Clin Oncol 2011; 29 Suppl:abstr 3503.
    1. Gérard 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.
    1. 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;30:1770–6.
    1. Tulchinsky H, Shmueli E, Figer A, et al. An interval >7 weeks between neoadjuvant therapy and surgery improves pathological complete response and disease-free survival in patients with locally advanced rectal cancer. Ann Surg Oncol 2008;15:2661–7.
    1. Kalady MF, de Campos-Lobato LF, Stocchi L, et al. Predictive factors of pathological complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg 2009;250:582–9.
    1. Moore HG, Gittleman AE, Minsky BD, et al. Rate of pathological complete response with increased interval between pre-operative combined modality therapy and rectal cancer resection. Dis Colon Rectum 2004;47:279–86.
    1. Zeng WG, Zhou ZX, Liang JW, et al. Impact of interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer on surgical and oncological outcome. J Surg Oncol 2014;110:463–7.
    1. 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.
    1. 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.
    1. Myerson RJ, Tan B, Hunt S, et al. Five fractions of radiation therapy followed by 4 cycles of FOLFOX chemotherapy as pre-operative treatment for rectal cancer. Int J Radiat Oncol Biol Phys 2014;88:829–36.
    1. Garcia-Aguilar J, Smith DD, Avila K, et al. Timing of Rectal Cancer Response to Chemoradiation Consortium. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg 2011;254:97–102.
    1. Garcia-Aguilar J, Marcet J, Coutsoftsides T, et al. Impact of neoadjuvant chemotherapy following chemoradiation on tumor response, adverse events, and surgical complications in patients with advanced rectal cancer tretment with TME. J Clin Oncol 2011;29 Suppl: abstr 3514.
    1. Benson AB, 3rd, Bekaii-Saab T, Chan E, et al. Rectal cancer. J Natl Compr Canc Netw 2012;10:1528–64.
    1. Bosset JF, Calais G, Mineur L, et al. EORTC Radiation Oncology Group. Fluorouracil-based adjuvant chemotherapy after pre-operative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014;15:184–90.
    1. Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after pre-operative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015;16:200–7.
    1. Hayden DM, Pinzon MC, Francescatti AB, et al. Hospital readmission for fluid and electrolyte abnormalities following ileostomy construction: preventable or unpredictable? J Gastrointest Surg 2013;17:298–303.
    1. Khrizman P, Niland JC, ter Veer A, et al. Post-operative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: a national comprehensive cancer network analysis. J Clin Oncol 2013;31:30–8.
    1. Biagi JJ, Raphael MJ, Mackillop WJ, et al. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA 2011;305:2335–42.
    1. 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;24:668–74.
    1. 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;11:241–8.
    1. 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 cancer de recto 3 study. J Clin Oncol 2010;28:859–65.
    1. Schou JV, Larsen FO, Rasch L, et al. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Ann Oncol 2012;23:2627–33.
    1. Maréchal R, Vos B, Polus M, et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol 2012;23:1525–30.
    1. 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 Canc Netw 2014;12:513–19.
    1. Capirci C, Valentini V, Cionini L, et al. Prognostic value of pathological 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.
    1. Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 2004;22:1785–96.
    1. Gunderson LL, Callister M, Marschke R, et al. Stratification of rectal cancer stage for selection of post-operative chemoradiotherapy: current status. Gastrointest Cancer Res 2008;2:25–33.
    1. Willett CG, Badizadegan K, Ancukiewicz M, et al. Prognostic factors in stage T3N0 rectal cancer: do all patients require post-operative pelvic irradiation and chemotherapy?. Dis Colon Rectum 1999;42:167–73.
    1. Birgisson H, Påhlman L, Gunnarsson U, Glimelius B; Swedish Rectal Cancer Trial Group. Adverse effects of pre-operative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 2005;23:8697–705.
    1. Joye I, Haustermans K. Early and late toxicity of radiotherapy for rectal cancer. Recent Results Cancer Res 2014;203:189–201.
    1. Smith FM, Rao C, Oliva Perez R, et al. Avoiding radical surgery improves early survival in elderly patients with rectal cancer, demonstrating complete clinical response after neoadjuvant therapy: results of a decision-analytic model. Dis Colon Rectum 2015;58:159–71.
    1. Rutten HJ, den Dulk M, Lemmens VE, et al. Controversies of total mesorectal excision for rectal cancer in elderly patients. Lancet Oncol 2008;9:494–501.
    1. Habr-Gama A, São Julião GP, Perez RO. Nonoperative management of rectal cancer: identifying the ideal patients. Hematol Oncol Clin North Am 2015;29:135–51.
    1. 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.
    1. Duldulao MP, Lee W, Streja L, et al. Distribution of residual cancer cells in the bowel wall after neoadjuvant chemoradiation in patients with rectal cancer. Dis Colon Rectum 2013;56:142–9.
    1. Habr-Gama A, Gama-Rodrigues J, São Julião GP, et al. Local recurrence after complete clinical response and ‘watch and wait’ in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys 2014;88:822–8.
    1. Habr-Gama A, São Julião GP, Perez RO. Nonoperative management of rectal cancer: identifying the ideal patients. Hematol Oncol Clin North Am 2015;29:135–51.
    1. Murad-Regadas SM, Regadas FS, Rodrigues LV, et al. Role of three-dimensional anorectal ultrasonography in the assessment of rectal cancer after neoadjuvant chemotherapy. Preliminary results. Surg Endosc 2009;23:1286–91.
    1. Murad-Regadas SM, Regadas FS, Rodrigues LV, et al. Criteria for three-dimensional anorectal ultrasound assessment of response to chemoradiotherapy in rectal cancer patients. Colorectal Dis 2011;13:1344–50.
    1. Van der Paardt MP, Zagers MB, Beets-Tan RG, et al. Patients who undergo pre-operative chemoradiotherapy for locally advanced rectal cancer re-staged by using diagnostic MR imaging: a systematic review and meta-analysis. Radiology 2013;269:101–12.
    1. Hötker 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;57:790–9.
    1. Song I, Kim SH, Lee SJ, et al. Value of diffusion-weighted imaging in the detection of viable tumor after neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer: comparison with T2 weighted and PET/CT imaging. Br J Radiol 2012;85:577–86.
    1. Lambrecht M, Vandecaveye V, De Keyzer F, et al. Value od diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results. Int J Radiol Oncol Biol Phys 2012;82:863–70.
    1. Lambregts DM, Vandecaveye V, Barbaro B, et al. Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study. Ann Surg Oncol 2011;18:2224–31.
    1. Lim JS, Kim D, Baek SE, et al. Perfusion MRI for the prediction of treatment response after pre-operative chemoradiotherapy in locally advanced rectal cancer. Eur J Radiol 2005;53:514–19.
    1. 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;22:821–31.
    1. Lambregts DM, Beets GL, Maas M, et al. Accuracy of gadofosveset-enhanced MRI for nodal staging and re-staging in rectal cancer. Ann Surg 2011;253:539–45.
    1. Lambregts DM, Heijnen LA, Maas M, et al. Gadofosveset-enhanced MRI fr the assessment for rectal cancer lymph nodes: predictive criteria. Abdomin Imaging 2013;38:720–7.
    1. Perez RO, Habr-Gama A, Gama-Rodrigues J, et al. Accuracy of positron emission tomography/computed tomography and clinical assessment in the detection of complete rectal tumor regression after neoadjuvant chemoradiation: long-term results of a prospective trial (National Clinical Trial 00254683). Cancer 2012;118:3501–11.
    1. Guillem JG, Ruby JA, Leibold T, et al. Neither FDG-PET nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study. Ann Surg 2013;258:289–95.
    1. Kleiman A, Al-Khamis A, Farsi A, et al. Normalization of CEA Levels Post-Neoadjuvant Therapy is a Strong Predictor of Pathological Complete Response in Rectal Cancer. J Gastrointest Surg 2015;19:1106–12.

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