February 2021's 'Paper of the Month' presents the follow up of the randomised control trial RAPIDO on the effect of short-course radiotherapy followed by chemotherapy before TME resection compared to preoperative chemoradiotherapy.

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.

Renu R Bahadoer, Esmée A Dijkstra, Boudewijn van Etten, Corrie A M Marijnen, Hein Putter, Elma Meershoek-Klein Kranenbarg, Annet G H Roodvoets, Iris D Nagtegaal, Regina G H Beets-Tan, Lennart K Blomqvist, Tone Fokstuen, Albert J Ten Tije, Jaume Capdevila, Mathijs P Hendriks , Ibrahim Edhemovic, Andrés Cervantes, Per J Nilsson, Bengt Glimelius, Cornelis J H van de Velde , Geke A P Hospers, RAPIDO collaborative investigators

Lancet Oncol. 2021 Jan;22(1):29-42. doi: 10.1016/S1470-2045(20)30555-6.

What is known about the subject?

A recent trend can be observed towards increasing neoadjuvant therapy in the treatment of rectal cancer. In some studies, this has resulted in higher complete pathological response rates and higher treatment compliance, especially with regard to perioperative chemotherapy. [1-3] It has also contributed to a greater focus on organ-preservation, especially in rectal cancer.

What the study adds?

This multicentre trial randomised 920 patients from Denmark, the Netherlands, Norway, Slovenia, Spain, Sweden, and the United States. Adults patients with an Eastern Cooperative Oncology Group performance status of 0-1 with a primary locally advanced high risk rectal adenocarcinoma (one or more of the following: stage cT4a/b, extramural vascular invasion, cN2, involved mesorectal fascia, or enlarged lateral lymph nodes) were considered for inclusion. A total of 912 patients were analysed after randomisation between the standard of care group, consisting of preoperative chemoradiation (28 x 1·8 or 25 x 2.0 Gy with concomitant oral capecitabine) or the experimental group. The latter consisted of short-course radiotherapy (5 × 5 Gy) followed by six cycles of CAPOX or nine cycles of FOLFOX4. After total mesorectal excision, depending on hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4 could be prescribed. The primary endpoint was 3-year disease-related treatment failure. This was defined as the first diagnosis of locoregional failure, new primary colorectal tumour, distant metastasis, or treatment-related death. Three years after randomisation, the cumulative probability of disease-related treatment failure was 30.4% (26·1-34·6) in the standard of care group vs. 23.7% (95% CI 19.8-27.6) in the experimental group (HR 0·75, 95% CI 0.60-0.95; p=0·019).

The most common grade >3 adverse event during preoperative therapy in both groups was diarrhoea (9% in the standard of care group vs. 18% in the experimental group); neurological toxicity during adjuvant chemotherapy was found in 9% of the standard of care group. Serious adverse events were reported for 34% in the standard of care group and for 38% in the experimental group. Four treatment-related deaths occurred in both groups.

Implications for colorectal practice

This paper has shown that short-course radiotherapy followed by chemotherapy before total mesorectal excision is a valid alternative for standard preoperative chemoradiation. With an acceptable rate of treatment-related adverse events, the experimental group performed significantly better than the standard of care group in terms of disease-related treatment failure and distant metastasis at three years. It will be interesting to read the future planned report on quality-of-life outcomes, as participants’ experiences will prove valuable for discussion of treatment options with patients. To what extent these data can be extrapolated to patients with lower performance scores remains to be investigated. Although the loco-regional failure rate was not significantly higher in the experimental group (8.3% versus 6.0% in the standard of care group, p=0.12), long term data may show a significant difference in the future.

In view of the COVID-19 pandemic, and in other resource-limited settings, the RAPIDO treatment schedule has logistical benefits over standard chemoradiation and its use will undoubtedly increase.


  1. Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, Kumar AS, Oommen S, Coutsoftides T, Hunt SR, Stamos MJ, Ternent CA, Herzig DO, Fichera A, Polite BN, Dietz DW, Patil S, Avila K; Timing of Rectal Cancer Response to Chemoradiation Consortium. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):957-66. doi: 10.1016/S1470-2045(15)00004-2.
  2. Fernandez-Martos C, Garcia-Albeniz X, Pericay C, Maurel J, Aparicio J, Montagut C, Safont MJ, Salud A, Vera R, Massuti B, Escudero P, Alonso V, Bosch C, Martin M, Minsky BD. 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 2015 Aug;26(8):1722-8.
    doi: 10.1093/annonc/mdv223.
  3. Cercek A, Roxburgh CSD, Strombom P, Smith JJ, Temple LKF, Nash GM, Guillem JG, Paty PB, Yaeger R, Stadler ZK, Seier K, Gonen M, Segal NH, Reidy DL, Varghese A, Shia J, Vakiani E, Wu AJ, Crane CH, Gollub MJ, Garcia-Aguilar J, Saltz LB, Weiser MR. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol 2018 Jun 14;4(6):e180071. doi: 10.1001/jamaoncol.2018.0071.
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