Actually there has been a lot of discussion and debate around the impact that postoperative radiotherapy could have in patients with some kind of locally advanced non-small cell lung cancer but who have surgery. This is stage 3a and 2 patients so they are the most advanced patients that can be operated. These patients actually for the last ten years the standard of care is surgery with adjuvant chemotherapy or with neoadjuvant chemotherapy. As they still have a mediastinal relapse rate of about 20-40% according to the study, there were always discussions about eventually adding postoperative radiotherapy.
The thing is that there had been some randomised evidence but more this is a publication of 1998 from The Lancet which said that for less advanced cancer it should not be done and for pN2, that is the population of LungART, and the question remained open.
This is based on the randomised evidence so radiotherapy needed to be evaluated again. But there have been a lot of retrospective studies, large database studies coming from the US, saying that postoperative radiotherapy could improve outcome. So really it was a debate in every centre so there were people who were always doing it, other people not doing it, so it was quite important to establish really a standard of care for these patients that we see every week at our multidisciplinary boards.
What criteria was set for including patients and evaluating endpoints in this clinical trial?
Actually the main endpoint of this study was disease free survival at three years so we needed 500 patients to evaluate that. Our statistical hypothesis was that we would have to increase and improve this disease free survival by 12% going from 30% to 42% with 500 patients if you wanted to say that postoperative radiotherapy did really improve DFS in a significant way. So actually the eligibility criteria were patients who had stage 3a and 2 that had complete surgery according to the guidelines of the European thoracic surgery, according to the international guidelines of complete resection. They could have chemotherapy, either neoadjuvant or adjuvant, and some patients even didn’t have any chemotherapy. We wanted really broad inclusion criteria so that it met all the needs of patients in everyday practice as long, and this is important, as long as they had N2 nodal involvement that was proven cytologically or pathologically and if they had complete resection or else it was another question. We wanted really to evaluate adjuvant, the role of adjuvant, postoperative radiotherapy.
What were the key outcomes observed between the groups that received PORT and those that did not?
Actually we were a bit surprised by the results because the disease free survival at three years was good, very good, in both arms. It was about 44% in the control group and it was 47% in the PORT group so that we have a 15% improvement in terms of DFS but, of course, this difference was not significant and the hazard ratio was 0.85 and the p-value was 0.16.
If we look at the disease free components in terms of first event actually we see that there is the rate of mediastinal relapses in the PORT group is divided by two as compared to the control group. So there is an effect but as there are many patients relapsing also elsewhere and a significant number also of patients who had brain metastases, that was not enough to improve disease free survival.
The other important information that we got is that the overall survival was very good compared to previous adjuvant trials in the sense that in this high risk population the OS is over 66%, 66% and 68%, so more than two-thirds of our patients are living at three years, this is very good. But when we look at the causes of death comparatively in the two arms, we see that there are less deaths due to recurrence or progression in the PORT arm but there are more deaths due to cardiopulmonary causes in the PORT arm. So that there is this safety issue and, indeed, we had more deaths, more cardiopulmonary death. They are not really related to radiotherapy, some of them probably but not all of them, but it’s true that adding this treatment to this population that is already at risk of cardiopulmonary events is maybe the treatment that is too much. So that based on this first analysis, because there will be many more to come, based on this first analysis we said clearly that postoperative radiotherapy should not be now considered as a standard of care in patients with stage 3 non-small cell lung cancer who have had a complete resection. The term complete resection is important because if they have an incomplete resection there it’s another story and indeed PORT can improve survival. But for patients who have a complete resection, so good surgery, it should not be administered based on the data that we gave yesterday at ESMO 2020.
What will further on this study involve?
There will be further study because we accumulated, thanks to all the co-investigators, I want to acknowledge all of them, it was mostly patients from the French Intergroup, IFCT, but also the UK and CRI group and from the SAKK and some German and Belgian centres. There will be a lot of data regarding the surgery, regarding the pathology, regarding the quality of radiotherapy so that maybe we will be able to identify a subgroup of patients which could benefit more from radiotherapy in terms of control of the disease and with as little harm as possible with fewer complications. I do not think personally that an improvement even bigger of conformal radiotherapy with IMRT, for instance, would make a difference. I believe that it’s more the fact that we are accumulating treatments in this rather fragile population at high risk of recurrence and that this trial is an important trial also because it’s a de-escalation in the treatment of these patients. We have to concentrate more probably on the systemic treatment, adjuvant treatment, and of course there are a lot of ongoing studies. Radiotherapy is very, very important for these patients but perhaps it’s combined with chemo, combined with immuno, like for instance the PACIFIC that gave excellent results for a more advanced population. LungART is a population that has been operated; PACIFIC was patients that could not be operated so they’re even more advanced.
So radiotherapy is a very valuable treatment with a lot of efficacy but probably these patients when they have complete surgery, one local treatment, if it’s well done, is enough.