New Concepts: Multimodal Approaches to Advanced NSCLC - Episode 7
Solange Peters, MD, PhD: After I do chemotherapy for stage 3, there are many attempts to improve the cure rate or to prevent the relapse. When you give radiochemotherapy, over time you start to observe a growing risk of prevalence of distant metastases; so distant relapses but also some local relapses. With time passing by, you have more and more distant metastases and less and less local metastases. But basically, you always have this dual risk of having a local relapse and a distant relapse. The oldest maintenance treatments were done to try to reduce both risks: local but, in particular, distant relapse, mostly because the Americans were used to doing that. They were used to giving radiochemotherapy followed by docetaxel. So, the level of evidence was extremely low, if any, but it was kind of a normal thing to do. So, this is something that was questioned in many clinical trials in Europe and in the United States. In basically the chemotherapy maintenance, if you give radiochemotherapy, like we said, it’s very important to do. Chemotherapy maintenance doesn’t add anything. So, you shouldn’t prolong chemotherapy for quality-of-life purposes. It will not change the prognosis of your patient.
So, this was the first kind of disappointing thing. Treatment should be short. It’s even contradictory, because you just give 2 cycles of chemotherapy. In the adjuvant setting, stage 1 and 2, you give 4 cycles, but here, 2 is enough. You give 2 cycles and radiotherapy. So, other strategies might be interesting in maintenance. There were some vaccine trials. Vaccine is nice because you are in the setting of minimal residual disease, not really a huge tumor burden at the time of radiochemotherapy completion. It would be good to try to make the immune system attack the small amount of cells that could remain. So, there was a vaccine trial called Stimuvax, which ultimately failed. The vaccine was not able to prevent local or distant relapse after radiochemotherapy. And then we moved into this new field of immunotherapy, and we got to know that checkpoint inhibitors might be a way to create a maintenance or consolidation treatment in the disease and improve the outcome of patients.
Adding targeted therapy as a maintenance treatment is a difficult question. For example, for the VEGF-targeted therapy, we use, really, bevacizumab. We don’t have it here after radiochemotherapy because you’re not allowed to give bevacizumab with radiotherapy. In the early trials, it was giving rise to fistulae between the bronchi and the esophagus, so it was really a dangerous strategy. You never give bevacizumab with the radiotherapy, so you don’t give it in maintenance because it’s not in the strategy.
About targeted therapies, there was one attempt to give gefitinib in unselected patients. This is an American way, radiochemotherapy and docetaxel, and then the patient could receive an EGFR TKI, which was gefitinib at the time, if I remember well. Unfortunately, these patients were not doing better. I would even say something else: They were doing worse than the other ones. So, by trying to treat more and more, there might be a point where you harm the patient instead of improving the outcome. In unselected patients, the ones we see every day, there is really no room beyond the radiochemotherapy in the 2 cycles to give chemotherapy or targeted therapy. So, you have to find your strategies.
Suresh Senan, MRCP, FRCR, PhD: Following chemoradiotherapy for locally advanced non—small cell lung cancer, immunotherapy may have a role because radiation causes many effects that upregulate the immune environment of the tumor. For example, by causing antigen release, we are changing the trafficking of T cells and permeability of immune cells into the microenvironment, all of which should make the activation to the immune system much easier and more effective for subsequent immunotherapy. Much of this work has been done in preclinical models, and there has been doubt about which dose and fractionation of tumor is best. But animal studies have always been of a limited number of fractions, and there’s still controversy out there.
But one concern of clinicians has been that administering immunotherapy during chemoradiotherapy may counterbalance the potential benefits of immunotherapy, because by repeating the radiation for weeks, you may, in fact, kill off some of the activated immune function, the T cells, and it might be a fine balance between efficacy and toxicity. So, radiotherapy has pro-immunogenic effects, antigen release, activating T cells, dendritic function, tumor T-cell trafficking, and killing off resistant cells. But it also has immunosuppressive effects, like, for example, increasing the presence of myeloid-derived suppressor cells. And so, in a patient model it’s quite difficult to predict what is happening, but we know that some of these theoretical things could play a role. And perhaps a very difficult problem is that we do not know what the preexisting immune function is—which of the tumors need extra help from chemoradiotherapy, which of the tumors are sufficiently immunoactive, and where perhaps radiation is not necessary or different fractionation scheme is necessary.
Transcript Edited for Clarity