Buscar en
Cirugía Española (English Edition)
Toda la web
Inicio Cirugía Española (English Edition) The Controversy of Neoadjuvant Therapy in Rectal Cancer
Journal Information
Vol. 97. Issue 7.
Pages 361-363 (August - September 2019)
Vol. 97. Issue 7.
Pages 361-363 (August - September 2019)
DOI: 10.1016/j.cireng.2019.01.011
Full text access
The Controversy of Neoadjuvant Therapy in Rectal Cancer
Controversia en neoadyuvancia y cáncer de recto
Joan Maurela,
Corresponding author

Corresponding author.
, Leire Pedrosaa, Jordi Campsb
a Medical Oncology Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
b Gastrointestinal and Pancreatic Oncology Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
Article information
Full Text
Download PDF
Full Text

Rectal cancer accounts for approximately 35% of all colorectal cancers. In patients with localized rectal cancer, neoadjuvant treatments (prior to surgery) with short radiotherapy (5×5) or chemoradiotherapy (CHT-RDT) with fluoro-pyrimidines are considered standard treatment.1,2 When accompanied by total mesorectal excision, these 2 treatment options significantly reduce local recurrence rate, which is below 5%. The 2 strategies have recently been compared, and similar efficacy was found in terms of local and systemic control of the disease.3 Despite this, 30% of operated patients presented recurrence of their disease, mainly at a distance. Different groups, including ours, have associated the post-CHT-RDT pathological response with a risk of 3-year and 5-year recurrence.4,5

In order to reduce the risk of distant progression, several studies have evaluated the benefit of adjuvant chemotherapy after CHT-RDT. With the exception of the ADORE6 randomized phase II study, the remaining studies demonstrated a benefit of adjuvant chemotherapy in 3-year disease-free survival (DFS) (with oxaliplatin-fluoro-pyrimidines versus fluoro-pyrimidines,7,8 oxaliplatin-fluoro-pyrimidines versus placebo9 or fluoro-pyrimidines versus placebo10,11) at less than 5%. Recently, Carvalho and Glynne-Jones have suggested that to demonstrate statistically significant differences between the 2 strategies (control versus oxaliplatin-fluoro-pyrimidines) with an expected difference of 5% and a power of 80%, more than 2000 patients would be required.12 With the current evidence, the authors concluded that adjuvant chemotherapy cannot be considered standard treatment after neoadjuvant CHT-RDT.

Neoadjuvant chemotherapy and CHT-RDT has shown a better tolerance and compliance than adjuvant chemotherapy after CHT-RDT, with a similar efficacy,13 so it has been proposed as a new therapeutic option in rectal cancer. In spite of the use of neoadjuvant chemotherapy with oxaliplatin and fluoro-pyrimidines followed by CHT-RDT±cetuximab or FOLFOX±aflibercept followed by CHT-RDT, the percentage of patients with complete pathological response (ypT0N0) is between 10% and 25%,14,15 and the 3-year DFS is between 65% and 75%, suggesting that patients resistant to CHT-RDT could also be resistant to induction chemotherapy±directed therapies. Recently, a study by the Polish Group has been published comparing short RDT followed by FOLFOX (3 cycles) and then surgery versus CHT-RDT followed by surgery in patients with high-risk rectal tumors. No differences were found in 3-year DFS rates (53% vs 52%).16 The RAPIDO study comparing short RDT followed by CAPOX (6 cycles) versus CHT-RDT with capecitabine will definitely answer whether induction chemotherapy is superior to CHT-RDT. This study has included more than 800 patients and has sufficient power to demonstrate a benefit of more than 10% in 3-year DFS rates with the strategy of short RDT followed by CAPOX versus conventional CHT-RDT.17

In most of the previously mentioned studies, magnetic resonance imaging (MRI) was not used for the staging of patients. MRI provides optimal staging of rectal cancer and predicts the risk of distant recurrence with extramural vascular invasion (EMVI) and local recurrence (mesorectal fascia of the middle and upper rectum and invasion of the sphincter in lower-third tumors).18 It is also a useful technique to identify patients with middle or upper-third involvement without invasion of the mesorectal fascia, who are candidates for clinical trials with systemic treatment without radiotherapy. MRI with neoadjuvant post-treatment diffusion also makes it possible to select patients with tumors of the lower third of the rectum with optimal radiological response, who are candidates for a “watch-and-wait” strategy.19

The characterization of the immunological component of the microenvironment has allowed new therapeutic strategies to be developed. In this sense, PD-1/PD-L1 checkpoint inhibitors are especially relevant. Tumors with loss of “mismatch repair” (MMR) protein expression show high levels of lymphocyte infiltration20 and present an elevated therapeutic response to PD-1/PD-L1 inhibitors.21 However, tumors with MMR only account for 5%–15% of all colorectal cancers. An immunoscore has recently been proposed for the rectum, in which the high density of CD3 and CD8 correlate with better clinical evolution.22 Nevertheless, preliminary results of our group show the presence of 3 clusters in metastatic colon cancer, based on the analysis of immune-related gene expression signatures using NanoString technology.

After 20 years of studies with adjuvant and neoadjuvant chemotherapy (including targeted therapies) in rectal cancer, progress in DFS and overall survival has been very modest at best. Although the results of the RAPIDO study have not yet been published, it seems unlikely that they will demonstrate a benefit of neoadjuvant therapy compared to conventional chemo-radiotherapy treatment of more than 10%. In the current era of MRI and potential immune signatures, the design of adaptive studies in neoadjuvant therapies would make it possible to select the most favorable patients for combinations of immunotherapy versus standard treatment. This strategy would represent a radical but necessary change in the design of rectal neoadjuvant therapy studies and would replace the current “chemotherapy-radiotherapy for all” with “personalized immunotherapy combinations”.


Joan Maurel: Instituto de Salud Carlos III (PI13/01728).

Jordi Camps: Instituto de Salud Carlos III, co-funded by the European Regional Development Fund (ERDF) (CP13/00160 and PI14/00783); Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya (2017 SGR 1035).

E. Kapiteijn, C.A. Marijnen, I.D. Nagtegaal, H. Putter, W.H. Steup, T. Wiggers, Dutch Colorectal Cancer Group, et al.
Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.
N Engl J Med, 345 (2001), pp. 638-646
R. Sauer, H. Becker, W. Hohenberger, C. Rödel, C. Wittekind, R. Fietkau, et al.
Preoperative versus postoperative chemoradiotherapy for rectal cancer.
N Engl J Med, 351 (2004), pp. 1731-1740
J. Erlandsson, T. Holm, D. Pettersson, Å. Berglund, B. Cedermark, C. Radu, et al.
Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial.
Lancet Oncol, 18 (2017), pp. 336-346
X. García-Albéniz, R. Gallego, R.D. Hofheinz, G. Fernández-Esparrach, J.R. Ayuso-Colella, J.A. Bombí, et al.
Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation.
World J Gastroenterol, 20 (2014), pp. 15820-15829
C. Rödel, P. Martus, T. Papadoupolos, L. Füzesi, M. Klimpfinger, R. Fietkau, et al.
Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer.
J Clin Oncol, 23 (2005), pp. 8688-8696
Y.S. Hong, B.H. Nam, K.P. Kim, J.E. Kim, S.J. Park, Y.S. Park, et al.
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 (2014), pp. 1245-1253
C. Rödel, U. Graeven, R. Fietkau, W. Hohenberger, T. Hothorn, D. Arnold, German Rectal Cancer Study Group, et al.
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 (2015), pp. 979-989
H. Schmoll, K. Haustermans, T. Price, B. Price, R. Nordlinger, J. Hofheinz, et al.
PETACC-6: preop chemoradiation and postop chemotherapy (capecitabine±oxaliplatin) in locally advanced rectal cancer: overall survival after long term follow-up.
Ann Oncol, 29 (2018), pp. mdy149.018
R. Glynne-Jones, N. Counsell, P. Quirke, N. Mortensen, A. Maraveyas, H.M. Meadows, 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, 25 (2014), pp. 1356-1362
A.J. Breugom, W. van Gijn, E.W. Muller, Å. Berglund, C.B. van den Broek, T. Fokstuen, Cooperative Investigators of Dutch Colorectal Cancer Group and Nordic Gastrointestinal Tumour Adjuvant Therapy Group, 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, 26 (2015), pp. 696-701
J.F. Bosset, G. Calais, L. Mineur, P. Maingon, S. Stojanovic-Rundic, R.J. Bensadoun, EORTC Radiation Oncology Group, et al.
Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.
Lancet Oncol, 15 (2014), pp. 184-190
C. Carvalho, R. Glynne-Jones.
Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer.
Lancet Oncol, 18 (2017), pp. 354-363
C. Fernandez-Martos, X. Garcia-Albeniz, C. Pericay, J. Maurel, J. Aparicio, C. Montagut, et al.
Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial.
Ann Oncol, 26 (2015), pp. 1722-1728
A. Dewdney, D. Cunningham, J. Tabernero, J. Capdevila, B. Glimelius, A. Cervantes, 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, 30 (2012), pp. 1620-1627
C. Fernandez-Martos, C. Pericay, F. Losa, R. Garcia-Carbonero, L. Layos, N. Rodriguez Salas, et al.
RIA: randomized phase II study comparing induction (I) mFOLFOX6 with or without aflibercept followed by chemoradiation (CRT) and total mesorectal excision (TME) in high risk-rectal cancer. GEMCAD 14-02 trial.
J Clin Oncol, 15 (2018), pp. 3518
K. Bujko, L. Wyrwicz, A. Rutkowski, M. Malinowska, L. Pietrzak, J. Kryński, Polish Colorectal Study Group, et al.
Long-course oxaliplatin-based preoperative chemoradiation versus 5×5Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study.
Ann Oncol, 27 (2016), pp. 834-842
P.J. Nilsson, B. van Etten, G.A. Hospers, L. Påhlman, C.J. van de Velde, R.G. Beets-Tan, et al.
Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectalcancer – the RAPIDO trial.
BMC Cancer, 13 (2013), pp. 279
M. Chand, J. Evans, R.I. Swift, P.P. Tekkis, N.P. West, G. Stamp, et al.
The prognostic significance of postchemoradiotherapy high-resolution MRI and histopathology detected extramural venous invasion in rectal cancer.
Ann Surg, 261 (2015), pp. 473-479
M.J.M. van der Valk, D.E. Hilling, E. Bastiaannet, E. Meershoek-Klein Kranenbarg, G.L. Beets, N.L. Figueiredo, IWWD Consortium, et al.
Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study.
Lancet, 391 (2018), pp. 2537-2545
N.J. Llosa, M. Cruise, A. Tam, E.C. Wicks, E.M. Hechenbleikner, J.M. Taube, et al.
The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints.
Cancer Discov, 5 (2015), pp. 43-51
D.T. Le, J.N. Uram, H. Wang, B.R. Bartlett, H. Kemberling, A.D. Eyring, et al.
PD-1 blockade in tumors with mismatch-repair deficiency.
N Engl J Med, 372 (2015), pp. 2509-2520
M.-G. Anitei, G. Zeitoun, B. Mlecnik, F. Marliot, N. Haicheur, A.M. Todosi, et al.
Prognostic and predictive values of the immunoscore in patients with rectal cancer.
Clin Cancer Res, 20 (2014), pp. 1891-1899

Please cite this article as: Maurel J, Pedrosa L, Camps J. Controversia en neoadyuvancia y cáncer de recto. Cir Esp. 2019;97:361–363.

Copyright © 2019. AEC
Article options
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos

es en pt
Política de cookies Cookies policy Política de cookies
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here. Utilizamos cookies próprios e de terceiros para melhorar nossos serviços e mostrar publicidade relacionada às suas preferências, analisando seus hábitos de navegação. Se continuar a navegar, consideramos que aceita o seu uso. Você pode alterar a configuração ou obter mais informações aqui.