«Defining oligometastatic disease is rather complex»

<p class="article-intro">During the first Lung Cancer Summit Dr. Joshua Bauml talked about oligometastatic disease in patients with non-small-cell lung cancer (NSCLC). In an interview he provided an insight into this topic and talked about his own preference when treating such patients.</p> <hr /> <p class="article-content"><p><em><strong>Dr. Bauml, how is oligometastatic disease defined? </strong></em><br /><em><strong>J. Bauml:</strong></em> Oligometastatic disease is the concept that sometimes patients can have metastatic cancer that has only spread to a few sites. It&rsquo;s a deviation from the older theory of metastatic spread, the Halsted theory from 1894. This theory said that once cancer has spread to lymph nodes and has caused distant metastases it is metastatic and incurable. From colorectal cancer we know that some patients with a disease that has spread only to the liver can be cured by a partial hepatectomy. This questions the theory of Halsted. So, Dr. Hellmann and Dr. Weichselbaum have put together an alternate paradigm which says that tumour metastases occur along a continuum. The cell needs to gain the ability to spread in general and then the ability to spread to a specific location. As a result you can have a patient who has metastatic disease spread to a limited number of sites. By ablating those sites with surgery and radiation, the patient might be able to achieve long-term disease control or even a cure. So, that&rsquo;s sort of what oligometastatic disease in general refers to. In recent years, there has been a number of trials looking into the use of local ablative therapy in oligometastatic lung cancer. Two studies, led by Dr. Gomez and Dr. Iyengar, investigated the effect of local ablative therapy &ndash; meaning surgery, radiotherapy or both &ndash; applied after induction chemotherapy in NSCLC. The induction chemotherapy allowed them to identify patients with, what I call, oligoresidual disease. They found good outcomes and had to stop their trials early due to the improvement in progression- free survival. The issue is that those studies really documented outcomes in oligoresidual disease not in patients with oligometastatic disease at diagnosis. While most of the patients might have had oligometastatic disease at diagnosis there still exists a selection due to the fact that patients with progressive disease never have gotten the local ablative therapy. So, this doesn&rsquo;t represent the whole population. Another recent study, the SABR COMET study, included patients with different types of tumours, not only lung cancer patients. As a result, there was some imbalance between the frequency of the different tumour types in the two arms of the study. The patients received definitive therapy to their primary tumour and were then randomized to either local ablative therapy to all metastatic disease with systemic therapy or to systemic chemotherapy alone. Again, they found an improvement in overall and progression- free survival. Questions here became notable because the definition of statistical significance was changed in this study. As a screening phase II study they used a p-value cut-off of 0.2. This is statistically valid but clinically confusing. When we hear the words statistically significant, it has a certain meaning to us. The most recent study that was presented on this topic is a study that I was able to lead. This study looked at the use of pembrolizumab after local ablative therapy in NSCLC patients with oligometastatic disease. We were able to find very good outcomes with a median progression-free survival of about 19 months. This compared favourably to a historical control of around 6.6 months. Now obviously, comparison to a historical control is complex given the heterogeneity of available data, but we were excited about these data. All of these studies were small &ndash; these data have to be confirmed in larger phase III randomized studies both to evaluate the role of local ablative therapy in this setting as well as to evaluate the contribution of immunotherapy. There are multiple ongoing phase III studies to try to answer these questions.</p> <p><em><strong>What are these ongoing trials? </strong></em><br /><em><strong>J. Bauml:</strong></em> There is the LU-002 study, a phase II/III study investigating maintenance systemic therapy versus consolidative stereotactic body radiation therapy plus maintenance systemic therapy. Then there is SABR COMET 3, the phase III randomized controlled trial and economic evaluation of stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic cancer. Oligometastatic here means 1 to 3 metastases. SABR COMET 10 includes patients with 4 to 10 metastases. The SARON study is done in the UK and assesses the addition of stereotactic ablative radiotherapy to standard chemotherapy in patients with oligometastatic non-small-cell lung cancer. Patients will be randomised to receive either standard treatment alone, which is a platinum-based doublet chemotherapy, or standard treatment with conventional radiotherapy and stereotactic ablative radiotherapy. And then there is also BR-002 which is done in patients with breast cancer.</p> <p><em><strong>Outside of studies, are there any guidelines on how to treat patients with oligometastatic disease? </strong></em><br /><em><strong>J. Bauml:</strong></em> There aren&rsquo;t clear guidelines. This is really an emerging field. As there are two positive studies, some people already treat their patients accordingly. The problem is that defining oligometastatic disease is rather complex. We usually define it by the number of metastases but that cut-off is often arbitrary. Some use 3 metastases as cutoff, some use 4 or 5 etc. There is the ongoing SABR COMET 10, led by Dr. Palma, that even uses 10 metastases as cut-off. People have gotten a bit upset about that saying that 10 isn&rsquo;t oligometastatic. My counter to this would be: we don&rsquo;t even know if 2 is oligometastatic. I think, we don&rsquo;t know enough about the underlying biology to claim that 10 isn&rsquo;t oligometastatic. I think SABR COMET 10 has a reasonable design and is trying to answer a good question.</p> <p><em><strong>What is your own preferred way of treating oligometastatic disease? </strong></em><br /><em><strong>J. Bauml:</strong></em> If I have a patient with oligometastatic disease my general preference is to discuss the role of local ablative therapy. The toxicity of this approach depends on the location of the tumour. But I do utilize it. I don&rsquo;t incorporate immunotherapy at this time because I think this needs to be proven in a randomized trial.</p> <p><em><strong>The title of your talk at the Lung Cancer Summit mentioned that there might be a new treatment paradigm for these patients. What would this be? </strong></em><br /><em><strong>J. Bauml:</strong></em> I think at this point local ablative therapy is a treatment approach, it&rsquo;s not the treatment approach. I think phase III studies are required to prove this.</p> <p><em><strong>Thank you very much for this interview!</strong></em></p></p>