The background was that in locally advanced rectal cancer, despite preoperative chemoradiation, the rate of metastasis was still high, up to 25% in all trials. So, there was a medical need for new treatment so that's the reason why we've done a trial on TNT.
What was the study design?
When we designed the study in 2010, the standard of care was preoperative chemoradiation in locally advanced rectal cancer and this is the standard of care arm. And we realised a randomised study comparing this standard of care, which is pre-op chemoradiation, TME surgery and adjuvant chemotherapy for all patients, whatever is the T and M stage, to the same procedure, the same sequence of treatment, but three months of preoperative chemotherapy using modified FOLFIRINOX than pre-op chemoradiation, TME and adjuvant chemotherapy, that time for three months and for all patients. So all patients received the same duration of chemotherapy, adjuvant or neoadjuvant, and that's an important point to interpret the results.
What did you find?
With seven years of follow up, we realised that mFOLFIRINOX was a safe regimen with the downstaging of a tumour and we already published the first result in Lancet Oncology. It does not affect the following treatment; the compliance, the chemoradiation and surgery was the same. Postoperative mortality was reduced. Quality of life was similar in the two groups, but a bit reduced during mFOLFIRINOX induction chemotherapy, but all symptoms of rectal cancer, including pain, tenesmus and diarrhoea, rectorrhagia, disappear very quickly, within five or six weeks. Then quality of life improves and patients had a higher and faster good score of quality of life as compared to the standard of care group. There was also a benefit in sexual life, especially for men, with reduction of impotence.
Looking at surgical results, zero surgery was performed in 95% of the cases with good, excellent, results looking at the mesorectum in both arms. Then we had 26% [inaudible] rate as compared to 12% in the standard of care arm. So when we look at the seven-year results, we have a durable improvement in DFS, a 40% reduction in metastatic rate, and when we look at the benefit in terms of months, there's a seven month benefit without metastasis. It means that each year patients in the TNT arm benefit of one month without metastasis.
There was no increase in local recurrence with the experimental arm, which is important because in TNT we've consolidation chemotherapy. In the RAPIDO trial there is an important increase in local recurrence in the experimental arm; this is not the case with induction chemotherapy. Then for the patients who had metastatic relapse, the survival was the same in both arms. It's an important point because in some neoadjuvant and adjuvant studies, including MOSAIC, adjuvant treatment with FOLFOX, PETACC, an important study looking at the role of oxaliplatin in rectal cancer, and also in the RAPIDO trial, patients who relapse in the experimental arm had reduced survival. It's not the case in PRODIGE 23, and patients with metastasis had a 44-month median survival as compared to 39 in the standard of care arm.
For all these reasons, this translated into an important survival benefit at five years and patients had an improved survival from 80% in the standard of care arm to 87%. So this is important for for the patients and for all our groups - four groups of French research and 35 centres participate to this trial. I thank the patients, families and investigators who participate within this trial.
How could this research impact the future treatment of rectal cancer?
These are important results and now the choice for the patients is important, with choice of [inaudible] and weight strategy for very early T2 or T3 N0 rectal cancer patients. Local excision in patients with T2 N+ or T3 N+ with less than four invaded lymph nodes at MRI and no bad prognostic factors, these patients can have with induction chemotherapy or with chemoradiation, more local excision and organ preservation. And in patients with bad prognostic factors as low rectal cancer extramural invasion, predicted lateral margin less than 1mm, large tumour, more than four lymph nodes invaded, the TNT strategy using modified FOLFIRNOX is the only one who had improved survival with also good quality of life results.
Anything you’d like to add?
Yes, I want to thank the promoter, which is UNICANCER, and the National Cancer Institute and the French League Against Cancer, who gave grants to go on with this study. And I want also to thank all the patients and families who participated in this trial.