New Concepts: Multimodal Approaches to Advanced NSCLC - Episode 2

Treatment of Locally Advanced NSCLC


Suresh Senan, MD: So, for patients who present with early-stage lung cancer, they have to be made aware of the fact that a cure is possible with minimum mobility. And it’s not bad news to have early-stage lung cancer present because cure is possible with minimal mobility and mortality. The key point is going to an expert center and getting the right treatment, and the risks of tumor recurring are limited.

In patients who present with locally advanced non—small cell lung cancer, there has been, unfortunately, a great deal of pessimism in the past because it was felt that only about 15% of long-term survivors—and undue focus was made on the fact that radiation, especially concurrent chemoradiotherapy—could give rise to considerable mobility. For example, problems with swallowing or radiation pneumonitis. But more recent data, even with standard chemoradiotherapy, suggest that it’s not the case. The incidence of a high-grade radiation pneumonitis is, in fact, less than about 6% in this patient population treated in large randomized trials in many continents. So, our techniques have been improving to the extent that radiation pneumonitis is no longer the feared toxicity.

The most troublesome toxicity is esophagitis, or problems with swallowing, and grade 3 or 4 esophagitis can occur in 10% to 20% of patients. However, this is a self-limiting toxicity that resolves in the weeks after radiation. So, if you combine the fact that some studies have shown that 5-year survivals of 30% are being achieved, plus the fact that the toxicity is manageable, I think we, as thoracic oncologists, have to convince the community that is clearly, for more than one-third of the patients, a curative disease. And with the new developments in immuno-oncology, it might even improve much more. So there’s no longer a reason to be pessimistic in communicating the diagnosis of locally advanced disease to our patients.

Presenting this in a positive light to patients is important in order to motivate them to go for the guideline-recommended concurrent chemoradiotherapy. In many countries, only a minority of patients undergo concurrent chemoradiotherapy because the patients are often elderly and the clinicians are less convinced of the merits of treatment. So, to bring these new treatment modalities over in a positive way would help improve the rate of usage of optimal concurrent chemoradiotherapy. And I think that would lead to more patients getting the appropriate treatment.

In stage 3A disease, it’s important to have a good tissue diagnosis to show which histological subtype the patient has in order to determine the choice of chemotherapy. It’s also essential to have histological or cytological confirmation of the nodal disease stage. This is not only important to make sure that we’re treating true stage 3A disease, but also the extent of nodal disease determines the extent of the radiation field and inadequate staging would mean the wrong radiation fields.

In addition to a PET/CT scan, which is a standard part of staging, an MRI scan of the brain is also essential because of the risk of cult brain metastases in a percentage of these patients, all of which will influence the treatment strategy and sequence. And I think the multidisciplinary tumor board is the best place to review all these factors, all the staging investigations, and the patient’s fitness in order to determine the optimal strategy for that patient, because it’s really a tailored treatment. Stage 3A is a very broad disease spectrum and it can occur and present in patients with a broad range of comorbidities and fitness.

Solange Peters, MD: In locally advanced non—small cell lung cancer—usually stage 3 as we define in our classification—the aim is also, like in early disease, to cure the disease and to cure the patient. The problem is that the disease is way more advanced, meaning that it imposes the problem of being marginally resectable very often or just of invading distant lymph nodes. The tumor has this biological capacity to leave the primary organ and to spread in distant lymph nodes; it might be that there are already some tumor cells in other organs. So, stage 3 is a biological signal of 2 very different scenarios. The first one is invasion, difficult to resect—so, invasion of novel organs, each one. And the other one is the scenario of a biology of an invading aggressive tumor. Both scenarios can be addressed in a curative intent context or intention, but the problem is it’s more difficult to reach. So, if you try to do so with surgery or with radiochemotherapy, you will not have a 50%, 60%, or 70% cure rate. You rather are around 15% or 20%, up to 25%, of cure rate but not more, meaning that you give lots of drugs and treatment for a probability of cure, which remains quite low.

For patients to be with you and fight, there are 2 very important parameters in any kind of disease for them to understand the context. There was a time we didn’t like to tell the whole truth to a patient. I think you have to do that because anyone is better in fighting if they know exactly the probabilities, the scenario, the risk, and so on. So, you have to tell the patient that locally advanced disease is endangering survival because of the risk of relapse. And then the treatment has really to focus on 2 aims. One is to locally control the whole tumor wherever it’s located, whichever is a number of lymph nodes affected by the tumor but also to keep in mind that there is a high risk, that the relapse would happen somewhere else in the body—in the liver, in the bone, in the brain—so that you need chemotherapy. And then none of the strategies have a sense if you dissociate it from the other one, so you need to do the multimodality treatment: the surgery or the radiotherapy and the chemotherapy. In early disease, it’s less clear. You can discuss adjuvant chemotherapy in patients. But in stage 3, you cannot because the risk of distant metastasis is very high.

The first unmet need in locally advanced non—small cell lung cancer is results. We would like to be able to improve the outcome of these patients. It is probably one of the group of patients where advances haven’t been met for a while. We’ve been trying vaccines. We’ve been trying to change the radiotherapy schedule. We’ve been trying to give more chemotherapy before, after, during. Nothing worked. So, nothing significantly changed the outcome of these patients with locally advanced disease to date in the last decade, which is very disappointing. That’s why we still stick to a low survival rate of, at maximum, 30%, but statistically, probably less. So, it means that you define a disease where there’s really a need for improvement in terms of survival, knowing that you give very intensive treatments. You don’t give light treatment. It’s very heavy treatment for patients.

I would say there are 2 new modalities we have been getting to know in the last decade in advanced disease. The first one is targeted therapy when you can define a driver and you can address a molecular target with, very often, a tyrosine kinase inhibitor. And the other field is immunotherapy. Unfortunately, at the time being, we don’t have good data with targeted therapy, and immunotherapy just started to be added in the early disease and locally advanced disease. But I think you have to try to exploit these new ways as much as possible. You otherwise will not be able to change the treatment fate of this disease.

The problem is also that by defining locally advanced non—small cell lung cancer, you still define 2 very different types of disease. One is just badly located, invading the esophagus, invading the vertebrae, invading the trachea, just because the location is central and invading novel organs. The other scenario is stage 3, but is also about a disease that is just not metastatic because lots of lymph nodes can be found, supraclavicular, just showing you that it is a bad disease. But both are in stage 3. So, you also have to be sure that you refine your strategy according to the exact pattern of the disease you have. At the time, we don’t. We give radiochemotherapy, surgery, chemotherapy, and that’s very simple, but not really personalized.

When you have to face a stage 3 locally advanced disease, the main problem is to express the truth to the patient but also to keep in mind—and there’s nothing more important than fighting for cure—that the whole process, the whole care there, and treatments that you propose to the patients are very important to be followed. Because at the end, the aim is that it’s the last time they are treated for this tumor. So, what you have to explain to the patient is that the disease can be cured, but it requires more intensive treatment as compared to a probable discovery of an earlier stage of disease, but still with the same aim. The multimodality is important, but time after time it’s really fighting for cure and they have to follow you. Patients are very happy to commit in this kind of a scenario because they understand that this is conditional. You need the multimodality treatment to be cured. But of course, it’s also creating anxiety because you have to be clear that it’s a whole pack of things the patient has to take and it’s not always a very easy way.

Transcript Edited for Clarity