The objective of this session is to provide some basic information on the definitive treatment of stage III non-small cell lung cancer with external beam radiation therapy. Pre-lecture question 1, the optimal treatment for a patient with inoperable stage III non-small cell lung cancer is, A, radiation therapy alone, B, chemotherapy followed by radiation therapy, C, chemotherapy followed by concurrent chemotherapy and radiation therapy, D, concurrent chemo radiotherapy, E, concurrent chemo radiotherapy followed by chemotherapy. So this is a schematic diagram to indicate the common scenario with stage III non-small cell lung cancer. So in that scenario, there's generally a primary tumor that's located in the lung. And then there are mediastinal lymph nodes that are also involved by cancer. And that's in addition typically to hilar lymph nodes as well. I should point out that stage II non-small cell lung cancer is when there's a primary treatment and hilar lymph node involvement without mediastinal lymph node involvement. And it's worth mentioning that when we're going to treat patients with stage II or stage III non-small cell lung cancer with radiotherapy without surgery, the management is similar. In terms of the management of stage III non-small cell lung cancer, it's worth pointing out that within stage III non-small cell lung cancer, the extent of disease can vary significantly. So we can have a very small primary tumor with just one mediastinal lymph node involved, for example. So that would be a T1aN2M0 or a subset of that. And then we can have very extensive tumors, T4 tumors, which, for instance, are tumors that can be invading into the mediastinum into structures that are unreceptable with M-3 disease. So that can be mediastinal nodes that are on both the ipsilateral side of the primary and the contralateral side with many, many nodes involved. And so as you might imagine, the prognosis within this subgroup, this stage III non-small cell lung cancer, can vary significantly with overall survivals at five years as low as 5%, extending all the way up to 30%. And so the treatment options can also vary significantly for these patients. In general, we break patients up into those who are inoperable, which is the majority of patients with stage III non-small cell lung cancer. And those patients are treated with radiotherapy, with or without concurrent or sequential chemotherapy in general. For operable stage III non-small cell lung cancer, patients, for instance, might go to surgery first and then be treated with post-operative chemotherapy, with or without radiotherapy, and we'll talk about that in a few minutes. Or they might be considered for pre-operative concurrent chemo radiotherapy, so-called trimodality therapy, which would be the most aggressive approach. So these are some data that were published, actually, quite awhile ago now, but this is a seminal study in which about 160 patients were randomized to either radiotherapy alone, or, in this case, chemotherapy followed by radiotherapy. So, we call that sequential treatment. And this is a slide showing overall survival. And, what you can see, might be a little hard to see, but the curve at the top is for sequential chemo radiotherapy with a higher survival as compared to patients who are treated with radiotherapy alone. And at five years, that difference was about 10%. Again, these outcomes are not very good, but that's the nature unfortunately of the fact that stage III non-small cell lung cancer patients frequently develop metastatic disease. But this really was a seminal study demonstrating the benefit of adding chemotherapy to radiation therapy for these patients. Over the years, people wondered whether or not we might be able to improve upon those results by giving chemotherapy concurrent with the radiation therapy, potentially to use the chemotherapy, not only to address microscopic metastatic disease, but also as a radiation sensitizer. And this was a meta analysis that was published about five years ago, about 1,000 patients from six trials. And they compared concurrent chemo radiotherapy to sequential treatment, in which the patients got chemotherapy first and then radiation therapy. And the gold line, again, this is looking at overall survival, showed superiority for concurrent treatment with a difference at 5 years of about 5%. And so that typically is now, for patients that are good candidates for aggressive treatment, the standard approach for inoperable stage III non-small cell lung cancer. Another question that has come up over the years is whether or not there's an advantage to escalating the dose of radiation therapy. So as I mentioned in an earlier lecture, a standard dose of conventionally fractionated radiation therapy. And this is true when given with concurrent chemotherapy is 60 gray in 30 treatments of 2 gray apiece. But there have been studies that have been done, including some research done at the University of Michigan, suggesting that patients might do better if treated with higher doses of radiation. And so these are data from a study that was recently published in which about 450 patients were randomized to either 60 gray or escalated dose radiation of 74 gray. In this study, patients were also randomized to the use of Cetuximab, which is an epidermal growth factor inhibitor, a monoclonal antibody. And a lot of these results were very surprising, or this particular result, which is looking at overall survival was very surprising to a lot of radiation oncologists. And what you see is that the patients that received the lower dose of radiation had an improved survival as compared to patients who received the higher dose of radiation. And obviously, the hypothesis of the study was opposite of this. Interestingly enough, there was also worse local control with the higher dose of radiation, which is also difficult to explain as well. And so right now the standard dose of radiation outside of a clinical trial is considered to be 60 gray. This is just a schematic showing treatment fields for stage III non-small cell lung cancer if we were treating a patient with radiotherapy. So the lungs are outlined in gray, the esophagus in orange, the spinal cord in green. The heart is sort of an amber color down here. And you can see this is depicting the primary tumor. So this would be sort of in the superior segment of the Left lower lobe with mediastinal, it's probably a node in the AP window region, and some hilar adenopath as well. The red is here is meant to indicate the carina. What we have here is treatment fields that are indicated by these shapes where we have one field that's coming in from the right anterior side exiting the patient like this. We have another field that opposing it from the the left posterior direction. And then we have a field that's coming in more as a lateral field, but from more of an anterior direction. And the idea is again that all of these fields intersect in the area that we're targeting, so that would be those mediastinal nodes in the primary tumor. And again, this is showing the area that we're targeting with an expansion and then these lines again are a topographical map basically of the dose. So this is indicating the 60 grey lines. So the area that's being treated with 60 grey, and as you can see the dose, we have another surface indicating 45 grey, 30 grey in the green and then the blue is 15 grey. So we're getting a much higher concentration of dose in the area of the tumor. With the dose falling off quickly as we move away from the area that we're targeting. And this is just another depiction of that in more of a coronal view with again the primary here and the mediastinal nodes being covered by the doses, with higher doses to the tumor and then doses falling off as we move away from the areas that are being targeted, trying to minimize the dose of radiation to the surrounding normal tissues. This slide is meant to show how treatment techniques with radio therapy for more advanced disease have changed over time. So traditionally, there was an approach where we would use what people consider more conventional radiation therapy. Where we would be targeting a tumor and treating the area that needed to be treated with a rectangular field of uniform intensity. And as you might imagine, that's not going to allow us to conform the dose a lot and we're going to be delivering higher doses to surrounding normal tissue, such as is indicated by this organ one. The next advance was to do what we refer to as three dimensional conformal radiation therapy. And in this treatment paradigm, we're using a device within the head of the machine, something called a Multi-Leaf Collimator, that allows us to shape the beam of radiation to mimic more closely the shape of the tumor. And we can even draw these leaves of this Multi-Leaf Collimator in and try to block more of the surrounding normal tissues to try to spare them from the high dose region. And then the latest iteration of this is something called intensity modulated radiation therapy. Where we actually still shape the beam, but we can break the beam into what people commonly refer to as beamlets. And then we can vary the intensity of the radiation dose within those beamlets. And so we can get a much more conformal dose of radiation and really decrease the dose to any surrounding normal tissues. So we can get good coverage, but good normal tissue sparing. Of course this can be a little bit challenging in the lung where the tumor might be moving and normal tissues might be moving as the patient breathes. Moving into the issue of what treatments we might deliver that might be helpful when treating inoperable patients with concurrent chemo radiotherapy who had stage three, two or three disease. One of the issues that was studied is whether there's a benefit to adding a chemotherapy before the chemo radiotherapy, so called induction chemotherapy. This was a study that was done of about four hundred patients and all had stage three disease and they randomized the patients to two cycles of induction or upfront chemotherapy. In this case it was Carboplatinum and Taxol. And concurrent chemotherapy and radiotherapy versus the concurrent chemo radiotherapy alone, without the induction chemotherapy. And as you can see this is looking at survival, the survival was the same for both approaches. There was more toxicity with induction chemotherapy. And so the standard approach now, outside of a clinical trial, is not to treat patients with induction chemotherapy. People also asked a similar, but different question. So in inoperable stage three, non-small cell lung cancer patients that are getting concurrent chemotherapy and radiotherapy, is there a benefit to adding chemotherapy after the radiation therapy was finished? And this was a study that was done of patients who completed chemo radiotherapy, and then they were randomized either observation or additional treatment with docetaxel chemotherapy. About 150 patients. And what you can see, again, looking at overall survival, was that there was no difference between the two approaches. And since there was increased toxicity with the addition of adjuvant chemotherapy, this approach again is not commonly used outside of a clinical trial. So what about operable stage three on non-small cell lung cancer? Previously, we've just been talking primarily about inoperable. So there are some situations where this might occur. There might be somewhat limited mediastinal nodal involvement. Or sometimes, the mediastinal nodal involvement isn't detected until the patients undergo surgery. So they might felt to be have stage one or stage two disease clinically, but then pathologically are found to have stage three disease. And so in this setting, people have explored the potential benefits of adjuvant chemotherapy. So these are patients, again, who underwent up-front surgery and then the question was, was there a benefit to adding chemotherapy after surgery? And these are data that come from a meta-analysis. There are about 4500 patients in five trials and they looked at patients who had surgery alone versus surgery followed by chemotherapy. And what you can see, in this graph, is that there was an improvement in overall survival associated with the use of chemotherapy, the addition of chemotherapy of about 5% at five years. And so for patients that are felt to be candidates for adjuvant chemotherapy, this is now routine practice. There are also studies that looked at the addition of radiation therapy after surgery for patients who are found to have stage three disease. And these are data that come from a meta-analysis of about 2300 patients, 11 trials. But actually these patients were a little more heterogeneous. Some had stage one, some had stage two and some had stage three disease. And what they found, looking at survival, this is overall survival Was that the patients that had treatment with radiotherapy, actually did worse than the patients who received surgery alone. And actually most of that difference, in terms of worse outcomes, were in the stage one and stage two patients, for whom now, most people agree, there's really no role for adjuvant radiation therapy. But there was, when you looked at the stage three subgroup, there was some potential data to suggest a benefit. So these are data looking at the addition of radio therapy after chemotherapy in patients that have had surgery for stage three non-small cell lung cancer. And this came from one of the adjuvant chemotherapy trials, commonly referred to as the ANITA trial. And in that trial, it was up to the investigators, it was left to the discretion of the physicians treating the patients as to whether or not they wanted to treat patients with postoperative radiation therapy after they had completed their chemotherapy. And when you look at the data for patients that had N2 disease, a stage three disease, what they found was that the patients who received chemotherapy and radiotherapy in terms of overall survival, actually had the best outcomes as compared to patients who just had the chemotherapy alone. Now the individuals that published this data were responsible enough to point out that these data are really just more hypothesis generating, rather than definitive data because the patients were not randomized to radiotherapy. And in fact, there is a trial going on right now that's trying to address this issue. And hopefully we'll have data to clarify this issue in the future. So another issue for operable stage three non-small cell lung cancer that comes up and I talked about this briefly earlier, was the potential for trimodality therapy. So that generally refers to the use of preoperative chemotherapy and radiation therapy, followed by surgery. And in a large study of about 400 patients, that approach was compared to treatment with concurrent chemotherapy and radiotherapy alone. And in the graph on the left, this is looking overall in that study at survival. What you'll see is that initially the green line is the patients that got chemoradiotherapy, the blue line is the trimodality therapy patients. And initially, the trimodality patients did worse, presumably due to some increased morbidity and mortality associated with surgery. But then, over time, if you follow them up long enough, they appear to do slightly better. And in an unplanned subgroup analysis from the trial, they looked at patients who just had lobectomy. So in this study, there was a smaller subgroup of patients that had pneumonectomy, but if you just look in the lobectomy arm at survival, what you see is that there are better outcomes with trimodality therapy as compared to concurrent chemoradiotherapy. Now the problem with these data are, well first, it's unplanned subset analysis. And secondly, sometimes you can't predict how someone's going to do when it comes to trimodality therapy. So right now, I think most people consider these data to be sort of hypothesis generating, although some institutions actually will routinely use trimodality therapy if they feel confident that a patient will have a lobectomy. So the take home points from this lecture are that for inoperable stage three non-small cell lung cancer, the best option is concurrent chemotherapy and radiotherapy. For operable stage three non-small cell lung cancer patients, the options include surgery, followed by sequential chemotherapy, with or without radiotherapy. Or preoperative concurrent chemoradiotherapy, followed by lobectomy. Post-lecture question. The optimal treatment for a patient with inoperable stage three non-small cell lung cancer is A, radiotherapy alone. B, chemotherapy followed by radiotherapy. C, chemotherapy followed by concurrent chemoradiotherapy. D, chemoradiotherapy, concurrently. E, concurrent chemoradiotherapy, followed by chemotherapy. And the answer is D, concurrent chemoradiotherapy. Thanks for listening, and in the next lecture, I'm going to be talking about the use of radiotherapy for palliation.