The background of the study is quite easy to tell because we have several entities that are treated currently with neoadjuvant treatment, an example given gastric cancer we have established in Germany and worldwide the FLOT4 regimen for gastric cancer for the perioperative regimen. Currently we see, today in the plenary session, the example given MATTERHORN data combining a neoadjuvant treatment with IO treatment. This is a strong rationale to combine therapies directly before initiating surgery because a lot of patients are not fit enough after surgery to receive an adjuvant treatment. All the patients in the adjuvant trials are filtered by the surgeons. Example given - if you have a good surgery, you have no complications, you are fit enough to receive an adjuvant treatment; if you are not fit enough you can’t have an adjuvant treatment. This is what we have shown in the GAIN trial, that the neoadjuvant treatment is better than the adjuvant treatment because the patients directly receive the treatment, on the one hand, and they are able to have a full dose pre-operatively, on the one hand, and this is also the fact that the patients have the possibility to have a pCR or a CR responding on the chemotherapy and not disseminating tumour cells intra-abdominally. All these complications are milder if you administer chemotherapy up front, right before surgery.
What was the methodology, and what were the findings?
The methodology was it was a randomised, open-label, 1:1 fashion, phase III trial with randomisation of gemcitabine cisplatin as standard of care in the palliative setting and [??] BTC, biliary tract cancer. It was a randomised study 1:1 between perioperative treatment, neoadjuvant GemCis followed by radical surgery then followed by another three cycles of GemCis randomised versus the pure adjuvant or pure radical surgery plus/minus adjuvant treatment if the patient was fit enough for adjuvant treatment.
The outcome was that we nearly doubled the overall survival rate and event free survival rate due to the neoadjuvant treatment compared to the adjuvant setting because, on the one hand, a lot of patients were after surgery not fit enough to receive an adjuvant treatment and also in Germany some centres are not convinced of the adjuvant treatment and therefore a lot of patients did not receive an adjuvant treatment. Nevertheless the trial, due to the slow accrual, was stopped early. Nevertheless the trial was significant regarding the event free survival, regarding the overall survival.
What are the clinical implications of these findings?
The clinical impact is currently, due to the small sample size, more or less signal generating on the one hand. On the other one the trial is positive regarding the statistics so surgeons are able to think and to administer neoadjuvant treatment based on this data. According to the NCCN guidelines it’s also possible to administer neoadjuvant treatment, but nevertheless the neoadjuvant treatment proposed in the NCCN guidelines is based only only four retrospective studies. Now we have a randomised trial supporting the neoadjuvant treatment for the patients and this is the most important fact that we have now randomised data for the patients.
I think the next step should be a new neoadjuvant trial combined with IO therapy, immunotherapy, for the patients. Nevertheless, always keep in mind to give systemic therapy as early as you can.
