Improved structure preservation with neo-adjuvant platinum-based chemo in patients with resectable NPNSCC

Prof Nabil F. Saba - Winship Cancer Institute of Emory University, Atlanta, USA

This is an interesting trial, it’s a trial where we basically asked the question can we improve organ preservation for patients with sinonasal squamous cell carcinoma which is the most common subtype of sinonasal cancers. We know already from other rare sinonasal cancers that that could help their outcome in terms of surgery and in terms of overall outcome, however, this has not been tested in squamous cell cancers head-to-head between the surgical versus the neoadjuvant therapy arm. There have been studies that were reported from single institutions as well as retrospective series, most of them, encouraging the use of chemotherapy. However, the practices out there, still people did not adopt this as a standard approach even though some centres did adopt it but many centres did not.

So there was an urge to conduct such a study and what we did is we took patients who needed resection of these organs, namely the orbit and the base of skull, and they had locally advanced disease. We chose these patients to have T3, T4a and some T4b disease and we randomised them. Half of them went to surgery straight and got postoperative radiation therapy, which is the standard of care for these patients, and the other half got three cycles of chemotherapy, a platinum and a taxane, docetaxel and cisplatin, followed by surgery and the same postoperative care as the other arm. The questions were are we improving the chance of organ preservation and the two organs we looked at are the base of skull and the orbit. Those are organs when you resect them or compromise them they lead to quality of life issues. Obviously I don’t need to tell you why the orbit or the eye becomes a major issue for people when they have an orbital exenteration, but certainly the base of skull has its own complications.

Remember that in the retrospective single institution series people did not look at the initial presentation of the patients in detail. In other words, we don’t know for sure how many of these patients needed resection of the orbit or needed resection of the base of skull in these retrospective series. They are encouraging but they really did not start from a very clear starting point. EA3163 was the right set-up because patients on either of the arms, basically as we said, required resection of these organs.

So when we looked at the rate of preserving both the orbit and the base of skull, the rate of preservation for the control arm was 15%. The rate of preservation for the neoadjuvant arm was 50%. The trial was underpowered because it did not enrol the target number of patients, this is a very difficult study to enrol. It opened for several years and we enrolled a total of 29 patients and only 23 of these patients are evaluable for organ preservation because they ended up having surgery. So this is what we’re reporting at the ESMO meeting here.

If you look at the two arms of the study they are fairly well balanced in terms of the stage of the disease, in terms of the primary site of the disease. As you know, sinonasal cancer is not just one site, the most common is maxillary sinus but you have other also less common sinonasal tumours in terms of sites. It was clear, to our surprise, that there was a trend, as I told you, in the primary outcome for the organ preservation to be higher in the group that got neoadjuvant therapy.

So we looked further at specifically the pathologic stage T3/T4a disease because T4b disease are patients usually who are deemed in the majority not to be able to have surgery. However, the trial allowed some of these patients to go on, provided the surgeons would deem them to be able to have surgical resection of their tumour. So when we excluded these T4b, which were very few patients out of the total, we did get a significant difference which was statistically significant between the control arm and the neoadjuvant arm. Of course, again, the study is underpowered.

This information was really surprising to us and the degree of numerical differences when you look specifically at orbit preservation itself and you look at base of skull preservation itself also is trending strongly toward the neoadjuvant arm as favourable in terms of preserving these structures. When we looked further at the starting point of the same organ involvement, in other words we looked at patients who presented and needed orbital resection and patients who presented and needed base of skull resection and then looked at the outcome based on each arm, also the differences were about 50% difference between the two arms in terms of the chance of improving both orbit preservation and base of skull preservation.

So we’re very happy about the results. I think this raises several questions – should a randomised trial be continued or pursued given the challenges that EA3163 had in accrual, even though it was a multi-centre trial that was supported from different angles? Also the fact that these results are now supporting more neoadjuvant therapy, I think it would be very, very difficult to justify prospectively randomising patients to such a study.

Part of the reasons why we also decided to interrupt the trial is because the field of systemic therapy has moved, has evolved. The introduction of immunotherapy in the neoadjuvant setting is something that has gained momentum in different cancers, in lung cancer, and is being applied now also in head and neck cancer. So because there is this question of organ preservation, I think that takes priority as well in sinonasal squamous cell cancers.

So the future studies or questions that are worth asking, and some of these, the more recent trials, are already looking at that, is the value of chemoimmunotherapy, for example, or other targeted agents together with immunotherapy as a means of improving the chance of organ preservation for these patients. So the future along those lines looks brighter. The main take-home message from EA3163 is what now? Between now and the next generations of trials maturing and reporting, should we still do surgery as the primary modality if we know the patient will need orbital exenteration or base of skull resection and have surgically resectable disease? This is the group of patients where there’s going to be a revisiting, perhaps, of our approaches based on EA3163 and the other retrospective and single institution trials because they hinted to that. So EA3163 came in as supportive evidence to the literature that used this, even though it was not universally adopted as an approach.

After EA3163 I personally in my clinic will seriously challenge a situation where the clinical scenario is needing to have orbital exenteration and not offering a chance to improve on the organ preservation for these patients.