Postoperative Radiotherapy in Resected Stage IIIA-N2 NSCLC

Neal Navani, MRCP, MSc, PhD: Can I ask you about your use of postoperative radiotherapy? There’s a patient who has had stage IIIA-N2 disease; they have undergone surgery with mediastinal lymph node dissection. They have pathologic IIIA-N2 disease. What was your practice historically, and are there any new data that has changed that?

Gary Doherty, MRCP, PhD: This is with the caveat that I’m not a radiation oncologist. These patients have a very high risk of recurrence, with a 5-year survival rate of 20% to 25% and 30% to 50% distant failure rates. We need to do better for these patients, but the question is, do we have to do more treatment locally or do we have to do better with systemic therapies? There’s an important but limited benefit from adjuvant chemotherapy for these patients, improving 5-year overall survival by about 4% or 5%. We really need to do better. Prior to the LUNG ART study, there were very heterogeneous standards in practice in patients with R0, and those you describe as having stage IIIA-N2 disease. The jury was really out. Because of changing practice standards, there were more questions being developed as technology advanced, so these were not clearly showing a survival advantage for postoperative radiotherapy. There was significant heterogeneity in practice, both in the United Kingdom and, I’m sure, worldwide. LUNG ART was a randomized phase 3 international study that randomized patients with N2 resection to either postoperative radiotherapy or to observation. These patients had chemotherapy—preoperation, postoperation, or both—and there were 501 patients that were randomized. The primary end point of the LUNG ART trial was disease-free survival. This was a significant improvement based on other trials and was meant to really draw the line either for PORT [postoperative radiotherapy] or against PORT.

It was a very good trial, and it was a feat to get these patients randomized, with fantastic, detailed follow-up on these patients. Ninety percent to 92% of patients, depending on the arm, had a pretreatment PET [positron emission tomography]. Overall the arms were very well balanced, and 96% of patients had chemotherapy preoperation, postoperation, or both; 96% to 98% had pathologic N2 disease; 89% had 3D radiotherapy; and 11% had IMRT [intensity-modulated radiation therapy]. It was a trial that reflected real-world practices. When it came to the primary end point, it was disease-free survival. In the control arm, the median disease-free survival rate was 22.8 months, and 30.5 months in the PORT arm, but this was not significant. The hazard ratio was 0.85, and the P value was 0.16, so the study did not meet its primary end point. The survival in the trial was higher than expected, presumably owing to very good patient selection and good staging with these patients. Whenever we broke down disease-free survival, PORT did reduce the rate of mediastinal relapse but not other relapses. When you look at the first event as disease-free survival, there was death at a rate of 5.3% in the control arm and 14.6% in the PORT arm. Now this was a really shocking result. These patients were trying to increase their survival duration and rate, but we ended up having an increase in death as their first disease-free-survival event.

Why is this? Because it’s a toxic treatment, and the authors did a fantastic job at breaking down these toxicities in terms of early and late toxicities. They showed that there was an increased rate of cardiac and pulmonary toxicity—severe toxicity—in patients receiving PORT. That’s why the secondary end point of overall survival showed no difference between the arms; essentially, the Kaplan-Meier curves were overlapping. In my opinion, based on this data, PORT can’t routinely be recommended after a complete resection in this space. However, if the patient has an incomplete resection, these patients are eligible for and should be offered PORT. That’s an important point. Within LUNG ART, interestingly, these patients didn’t have an R0 resection as would have been agreed upon central review. Only about 29% had a definitive R0 resection after review, so there’s a lot of work to do. There will be a lot of subgroup analyses that come out of the LUNG ART trial. Of course, there’s always the question: What do we do with more advanced radiotherapy techniques that would be predicted to and have been shown to reduce toxicity? In my opinion, we should not be offering it to patients routinely, but I suspect there will still be heterogeneity in practices based on particular caveats associated with the interpretation of the LUNG ART trial.

Neal Navani, MRCP, MSc, PhD: Thanks, Gary. It’s a really important study. LUNG ART is a negative trial that’s actually changing the standard of care. Certainly, in our own institution [University College London Hospitals NHS Foundation Trust], we were routinely giving radiotherapy to the patients with pathologic N2 disease after surgery, and we’ve stopped doing that based on the LUNG ART study, reserving it only for R1 cases or bulky N2 disease. Christian, can I get your view on this? What have the data from the LUNG ART study done for your institution? Has that represented a change in practice by your multidisciplinary team?

Christian Grohé, MD: On the 1 hand, it’s an important contribution that emphasizes understanding the need of optimizing multimodality treatment options in general. At our institution [Evangelical Lung Hospital] and a lot of other institutions, we have a problem where we recruit patients into a protocol—for instance, there’s concurrent chemotherapy-radiotherapy. This is basically the same problem we see in the adjuvant treatment options in our patient cohort because they’re old and frail. The same must be said with respect to our patient cohort at stage III. A lot of these patients do not qualify for these kinds of protocols, so overall there’s a selection bias for the LUNG ART trial. In our hands, we try to optimize treatment options using both chemotherapy and radiotherapy, but often this is still sequential therapy. Overall, the trial an important contribution, but only a minority of our patients qualify for that option.

Neal Navani, MRCP, MSc, PhD: Thank you. Solange, could you briefly describe your view of the LUNGART data and whether it has changed the practice in your institution?

Solange Peters, MD, PhD: Thanks a lot. I did qualify to be in the ESMO [European Society for Medical Oncology Congress] Presidential Symposium. We want them to change the practice. Sometimes, negative trials change the practice, because we were doing something that’s shown by the trial to be incorrect because it is deleterious, or at least it’s not useful. The LUNG ART study is a paradigm of these very difficult-to-conduct trials, which answers a dramatic need—or an unmet end point in terms of trying to understand the role of radiation. We all tried and failed. The LUNG ART trial took years but got there. Basically, it changed our standards. Here [Lausanne University Hospital], we already had performed a trial in Switzerland, which was published in The Lancet some years ago. It was a neoadjuvant trial, which was asking about the viability of neoadjuvant chemotherapy vs chemotherapy only when treating N2 disease. At that point, because of course it was neoadjuvant, we could show that radiation doesn’t add anything.

The LUNG ART trial tells you something: If you have a radical treatment locally that’s well performed— meaning there is a complete resection—it might be right to do complete radiation if you cannot perform surgery. One radical local treatment is enough, so systemic chemotherapy is playing another role, a systemic role, which is completely different. It teaches us that sometimes more is not better. I didn’t really change my practice, but it helps us make sure that what we do is right. If you have a complete resection of an N2 disease, you give chemotherapy, and you’ve done your work. This is quite important, particularly in Germany, France, and Switzerland, where we practice surgery to treat stage III diseases more aggressively than doctors in the United States. We tend to go for multistage treatment when treating patients with N2 disease if the surgeon finds it resectable. It’s a very important answer to these questions.

Neal Navani, MRCP, MSc, PhD: Thank you very much, Solange. It’s interesting to see how practice evolves with the LUNG ART data.

Transcript Edited for Clarity