Our May Paper of the Month commentary concerns the organ preservation approach for small rectal cancers. It is the first randomized study comparing local excision to TME after radiochemotherapy.
The paper
Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial. Lancet. 2017 Jul 29;390(10093):469-479. doi: 10.1016/S0140-6736(17)31056-5. Epub 2017 Jun 7.
Background
Organ preservation is a concept proposed for patients with rectal cancer after a good clinical response to neoadjuvant chemotherapy, to potentially avoid morbidity and side-effects of rectal excision. The objective of this study was to compare local excision and total mesorectal excision in patients with a good response after chemoradiotherapy for lower rectal cancer.
Methods
Prospective, randomised, open-label, multicentre, phase 3 trial at 15 French centres of expertise in the treatment of rectal cancer. Patients aged ≥18 years with stage T2T3 lower rectal carcinoma, of maximum size 4 cm, with a good clinical response to neoadjuvant chemoradiotherapy (residual tumour ≤2 cm) were randomly allocated before surgery to either local excision or total mesorectal excision surgery on a 1:1 ratio without stratification and using permuted blocks of eight. In the local excision group, a completion total mesorectal excision was undertaken if tumour stage was ypT2–3. The primary endpoint was a composite outcome of death, recurrence, morbidity, and side-effects at two years after surgery. The aim was to show superiority of local excision over total mesorectal excision in the modified intention-to-treat (ITT) population based on expected proportions of patients having at least one event of 25% vs 60% respectively. This trial was registered with ClinicalTrials.gov, number NCT00427375.
Findings
From March 1, 2007, to Sept 24, 2012, 186 patients received chemoradiotherapy and were enrolled in the study. 148 good clinical responders were randomly assigned to treatment, three were excluded (because they had metastatic disease, tumour >8 cm from anal verge, and withdrew consent), and 145 were analysed: 74 in the local excision group and 71 in the total mesorectal excision group. In the local excision group, 26 patients had a completion total mesorectal excision. At two years in the modified ITT population, one or more events from the composite primary outcome occurred in 41 (56%) of 73 patients in the local excision group and 33 (48%) of 69 in the total mesorectal excision group (odds ratio 1·33, 95% CI 0·62–2·86; p=0·43). In the modified ITT analysis, there was no difference between the groups in all components of the composite outcome, and superiority was not shown for local excision over total mesorectal excision.
Interpretation
The study failed to show superiority of local excision over total mesorectal excision, because many patients in the local excision group received a completion total mesorectal excision that probably increased morbidity and side effects, and compromised the potential advantages of local excision. Better patient selection to avoid unnecessary completion total mesorectal excision could improve the strategy.
Commentary
What is known on the subject
Prior to the current study, the evidence base consisted only of retrospective or non-comparative assessments of oncological outcomes of local excision after chemoradiotherapy for rectal cancers. Moreover, confusion still exists between large tumours with excellent response or small tumours treated intentionally with an organ sparing approach with neoadjuvant treatment and local excision.
What this study adds
GRECCAR 2 was the first randomized study to address this question. A two-step selection was performed: initial staging with inclusion of small tumors (T2-T3 or less than 4 cm) and restaging MRI 8 weeks after RCT (residual scar < 2 cm). Further, the composite primary outcome encompassed all major aspects in relation to the real life of patients: oncological outcomes, of course, but also major morbidity or definitive stoma. The finding of similar primary outcomes in both arms of the trial reflected post-operative morbidity after completion TME in the local excision arm. This important finding, namely that morbidity of completion TME when needed (ypT2, R1 resection) after local excision leads to a 25% rate of definitive stoma and a 78% major morbidity is in keeping with previous observations of increased morbidity of TME after local excision for T1 rectal tumours. The radiochemotherapy increases the per-operative difficulties of dissection as the postoperative course.
Implications for colorectal practice
This study showed similar oncological outcomes of the two approaches. The major issue is that only 40% of patients will be in the 'good' group: RCT and local excision only. The remaining 60% will endure RCT, local excision and completion TME with a major morbidity for a small tumour that could have been treated with TME only. At the present time, it is impossible to predict tumour response. The new trial GRECCAR-12 will avoid the completion TME for ypT2 tumors without lymph nodes at the initial staging (cN0). With the reduction of completion TME, this trial may prove that an organ preservation approach is valid for small rectal tumors.