Organ preservation in rectal cancer

Results from the GRECCAR12 randomised phase 3 trial

ESTRO 2024 Congress report

GRECCAR12 was a rectal preservation clinical trial of our hypothesis that induction chemotherapy (ICT) could be used to optimise tumour response and to increase the proportion of patients who could be treated with the aim of retaining organs. It followed from the GRECCAR2 trial, which, among rectal preservation clinical trials, was the first randomised phase 3 trial in which the use of total mesorectal excision (TME) was compared with that of local excision (LE) in good responders to chemoradiotherapy.

GRECCAR2 involved a three-step strategy: initial selection of patients with early tumours; a second selection according to clinical response after chemoradiotherapy; and confirmation of rectal preservation for patients with pathologically complete or subcomplete responses defined as pT0 or pT1, or of TME for patients with pT2 or pT3 tumours.

It showed the oncological safety of LE in rectal cancers after chemoradiotherapy, but failed to improve the functional outcomes, because of bad functional results for patients who needed a TME in an intent-to-treat analysis.

Moreover, metastatic evolution remained an issue for almost 20% of patients in both arms.

In the follow-up GRECCAR12 trial, 218 patients were randomised between a total neoadjuvant treatment arm, which involved four cycles of Folfirinow followed by long-course chemoradiotherapy (50Gy + capecitabine), and a control arm that comprised long-course chemoradiotherapy. The response assessment was performed eight to 10 weeks after the end of neoadjuvant treatment and included an MRI with central review.

For residual tumours of less than 2cm width that were classified as tumour regression grades (TRG) 1,2 or 3 by MRI, local excisions were performed but followed by completion TMEs in cases of poor pathological response (ypT3 or ypT2cN+ or R1). On the other hand, if the residual tumour size was greater than 2cm or the tumour was assessed as of TRG 4 or 5, patients underwent TMEs.

With 98% of patients able to receive the four cycles of ICT, the trial showed that ICT with Folfirinox was manageable despite toxicities of >Grade 3, and dose reductions were needed for one-third of patients without any compromise of chemoradiotherapy or surgery.

Moreover, the use of ICT achieved a significantly higher pathological complete response rate than chemoradiotherapy and an organ preservation rate of up to 71%. Accurate selection of complete responders remains an issue; a pathologically complete response was seen in 41% of patients who were treated by TME, and this figure suggests that our criteria or time of assessment should be questioned.

We think that a better response assessment is the main issue at present for rectal preservation strategies. Therefore, the next trial (GRECCAR20) will be focused on the implementation of an evaluation programme of tumour response that integrates shared medical decision-making into the organ preservation strategy in patients with rectal cancer.

Professor Véronique Vendrely, MD, PhD

Bordeaux University Hospital, University of Bordeaux, France

Department of Radiotherapy, Hospital Haut-LévêquePessac, France

veronique.vendrely@chu-bordeaux.fr