Emerging data also have changed practice. For gastric cancer perioperative chemotherapy has been the standard in the West; in Asia typically up front surgery is done followed by adjuvant chemotherapy. So recent data from Germany now just published in Lancet within the last week or two indicate that the FLOT regimen, which is 5FU oxaliplatin docetaxel, was superior as a preoperative treatment compared to conventional ECF chemotherapy. The FLOT regimen resulted in improved rates of curative resection, better down-staging of patients, better response and it translated into progression free and overall survival benefit of about a 10% survival improvement at five years compared to ECF. So based on all the positive outcomes the FLOT regimen will become the new standard chemotherapy for perioperative chemotherapy in gastric cancer.
Another issue which I discussed is what’s the role of radiation in gastric cancer. Randomised trials, as long as you do good surgery, there does not appear to be a clear role for radiation in the treatment of gastric cancer. Certainly the FLOT study did not give post-operative radiation but a recent randomised trial called the CRITICS trial looked at perioperative chemotherapy, which is standard, with or without the addition of radiation postoperatively and there was no survival benefit. So we don’t routinely give patients radiation after perioperative chemotherapy because this trial in over 700 patients did not show a survival benefit. Should we give radiation therapy postoperatively if patients get up front surgery? That was addressed in a Korean study published a few years ago called ARTIST where patients all got high quality D2 surgery and they were randomised to get six months of adjuvant chemotherapy with capecitabine, cisplatin, with or without radiation. That trial showed no survival benefit as well for the addition of radiation as long as good surgery was done.
There was a suggestion that node positive patients might have had a small 4% benefit so actually upcoming at ASCO in a few months there will be presentation of the second Korean ARTIST-2 trial, the same trial design – up front surgery, adjuvant chemotherapy for six months with or without radiation – but it’s focussing on the subsets of patients from the previous trial that may have had a benefit which would include node positive intestinal histology. Outside of a trial, until I see that data, however, the standard of care is perioperative chemotherapy and surgery with no radiation or if you do up front surgery with a D2 resection adjuvant chemotherapy alone without radiation.
However, for oesophagus and G junction cancers I’m concerned about the anatomical issues in the mediastinum and G junction. If you look at large recent trials from Great Britain that treated nearly 2,000 patients if you do chemotherapy alone without radiation up to 30-40% of patients don’t get a negative margin resection. Similar data from the UK with preoperative chemotherapy if you have a gastric primary your curative resection rate is almost 90% but if you have an oesophagus and G junction tumour the curative resection rates are only in the 60s so arguing that you should give radiation to enhance the ability to get a negative margin.
Another potential benefit of combining chemotherapy and radiation for oesophagus and G junction cancers is much higher rates of pathologic complete response. Also from contemporary data, the CROSS trial from the Netherlands which looked at carboplatin paclitaxel radiation followed by surgery, very high rates of node negative disease which is important prognostically, high rates of curative resection and a significant reduction in local recurrence of disease compared to surgery alone. So my practice in oesophagus and G junction cancers is to combine chemotherapy and radiation followed by surgery. For the more distal gastric cancers I don’t think there’s compelling evidence that you need to give radiation and that either perioperative chemotherapy alone or adjuvant chemotherapy suffice.
In terms of new directions we await data from some of the targeted agents. HER2 positive disease is seen in about 20-30% of oesophageal gastric cancer so we are awaiting completion of the RTOG-1010 study which gives chemoradiation to HER2 positive oesophagus and G junction cancers and it’s a randomised trial with or without trastuzumab. We should get a read-out from that trastuzumab trial and chemoradiation from the RTOG in 2019. There also are some pilot studies in Europe looking at dual targeted HER2 therapy in combination with perioperative chemotherapy in gastric cancer. Trastuzumab pertuzumab added to perioperative chemotherapy, those are ongoing trials.
In terms of immunotherapy agents the trial that’s furthest along right now is a KEYNOTE study in which all patients get perioperative chemotherapy with 5FU cisplatinum and there’s a randomisation to get or not get pembrolizumab as part of adjuvant treatment. That trial is accruing quite vigorously and should complete accrual probably by early 2020. One of the criticisms of that trial is now the FLOT regimen, three drug chemotherapy, is the standard perioperative chemotherapy and the KEYNOTE study is only using 5FU cisplatinum so it’s two drugs. So there is a plan to incorporate some patients receiving FLOT but we’ll have to see how that plays out with the two different chemotherapy regimens and whether or not pembrolizumab adds a benefit in the adjuvant setting.
There’s an ongoing trial as well in oesophagus and G junction cancer patients who get chemotherapy and radiation and surgery and then usually just get observed. So that trial after chemoradiation surgery patients are randomised to get observation versus nivolumab, so looking at adjuvant nivolumab after chemoradiation and surgery.
There’s also provocative data about biomarker testing, MSI high may be a very favourable prognostic marker in gastric cancer. Data from the MAGIC adjuvant trial as well as the Korean CLASSIC trial that show that MSI high patients even when they get surgery alone have survivorship in excess of 80-85% and perhaps chemotherapy is not needed in a patient that is MSI high. So that needs to be validated in larger datasets and whether or not that can be used as a prognostic marker that may select patients that may not need chemotherapy is under active investigation.
Lastly we’ve got provocative data from the US looking at PET scan guiding chemotherapy during chemoradiation in oesophagus and G junction cancer. Data did indicate from our CALGB Alliance 80803 study that if you use chemotherapy early on and get a PET scan, if you don’t see adequate response you can potentially change the chemotherapy during subsequent radiation. Changing the chemotherapy in PET non-responders may potentially enhance the rate of response at surgery so it may be a way to more specifically tailor the chemotherapy during the radiation to patients by testing the chemotherapy first, assessing response on PET scan and then changing to a different chemotherapy during radiation. Data from our phase II trial show very impressive responses in patients that changed to a different chemotherapy when they weren’t responding to their initial chemotherapy. So we’re hoping to prepare the manuscript from that study to get for submission some time in 2019 or 2020.