I'm Greg Kalemkerian, Professor of Medicine in Division of Hematology and Oncology at the University of Michigan. This lecture is going to be dealing with the combined-modality therapy for patients with locally advanced non-small cell lung cancer. The objectives of the talk are to review the role of systemic therapy in locally advanced non-small cell and to review the role of combined-modality therapy in people with locally advanced non-small cell lung cancer. About 30 percent of people with non-small cell lung cancer present with locally advanced stage III disease. This generally means that they have either mediastinal lymph nodes spread or invasion of the tumor into the mediastinum or other local structures. Stage III non-small cell is a curable disease with a five-year overall survival rate in the 15-25 percent range with current therapy. Most of the relapses after we treat people with stage III disease are due to hematogenous spread with distant metastases. We'll start with a pre-lecture question. Seventy three year old woman presents with shortness of breath. CT scan shows a large right lower lobe mass narrowing the right lower lobe bronchus with enlarged, bilateral mediastinal lymph nodes. A PET scan shows FDG-avid right lower lobe mass and bilateral lymph nodes with no distant metastases. MRI of the brain is normal. Bronchoscopic endobronchial ultrasound guided biopsy of the left paratracheal lymph node reveals squamous cell carcinoma. What is the most appropriate further management? Chemotherapy with concurrent definitive radiation, chemoradiotherapy followed by surgery, palliative radiotherapy, or palliative chemotherapy? We'll come back to the question at the end of the lecture and discuss the answers. For people at stage III non-small cell lung cancer, primary surgical resection is usually not the right answer. For patients who have clinical N2 lymph nodes, meaning they are enlarged on CT scan, or positive on PET scan, or a biopsy-proven to be involved with disease, the five-year survival of people undergoing primary surgical resection is quite low at less than 10 percent. Therefore, this is not an effective primary treatment option. Majority of people will undergo combined-modality therapy with a curative intent. Cure is achieved in approximately 20 percent of people and importantly, people need to have a good performance status on order to undergo such aggressive therapy. What do we mean by combined-modality treatment options? Well, there are a number of potential strategies depending on the individual that's going to be treated. We can either do sequential chemotherapy, followed by radiation. We know that that is better than radiation alone. We can do concurrent chemoradiotherapy. This is the most common scenario, and we know that that is better than doing a sequential chemoradiation approach. We can do chemotherapy with or without radiation, followed by surgery, so a neoadjuvant approach. We know that's better than surgery, but we've already said surgery is not a good primary treatment for most of these people. But we also know from at least one clinical trial that this approach with surgery is pretty similar to the approach without surgery, with just chemoradiation alone. So, do we really need surgery? We'll talk a little bit about that. We can do chemotherapy and radiation, followed by consolidation chemo or now consolidation immunotherapy as a potential option, or we can do induction chemotherapy, followed by chemo plus radiation. This is option that has fallen out of favor, though there are some individuals who may still require this kind of treatment. So, several studies explored the strategy of sequential chemo, followed by radiation versus radiation therapy alone. We can see that in all of these studies, the overall survival was improved with the sequential approach of adding chemotherapy before radiation therapy. Five-year survivals we're also better, though the numbers, as you can see, are relatively low. The next question to be answered is, what about sequential versus concurrent chemoradiotherapy? In this study, patients received either sequentially chemotherapy, and this is a regimen that's not used much anymore, followed by definitive radiation, or a concurrent chemoradiation strategy, and we see that the concurrent patients did better on this overall survival plot. There are very few studies that have evaluated comparisons between chemotherapy regimens in stage III non-small cell lung cancer. The primary regimens that have been used historically are cisplatin/etoposide, carboplatin/etoposide, or weekly carbo/taxol concurrently with radiation. But a more modern regimen of cisplatin and pemetrexed was compared in a randomized fashion to cisplatin and etoposide. This study included patients with previously untreated stage III nonsquamous non-small cell since we only use pemetrexed in people with nonsquamous disease, who had good functional status. Patients received two to three cycles of chemotherapy concurrently with a definitive dose of radiation, and then patients went on to consolidation therapy with either continuation pemetrexed or a choice of other consolidation regimens, platinum-based regimens for two cycles. We see from this overall survival plot that the survival was similar in both arms with no significant difference, and from toxicity analysis, the cisplatin/pemetrexed arm had lower severe toxicity. So, this tells us that cisplatin/pemetrexed is a reasonable treatment option concurrently with radiation in people with stage III non-small cell lung cancer and nonsquamous non-small cell lung cancer. What about the use of surgery in this situation? There are actually aren't too many good randomized studies that have evaluated this question, but the best one is the inner group 0139 trial that was published a number of years ago that looked at patients who had biopsy-proven stage III disease, meaning N2 positive disease by biopsy, who were treated either with standard therapy which would be concurrent chemoradiation to a definitive radiation dose with platinum/etoposide or platinum/etoposide with an abbreviated radiation course, followed by surgery, followed by consolidation chemotherapy. In looking at the results, we see that for progression-free survival, there was an improvement with surgery for progression-free survival. But for overall survival, though there was a numerical improvement with surgery, it was not statistically significant, and we can see, from looking at these curves of the entire population over here, why that's the case for overall survival, because early on, the people who did not have surgery did better and the curves kind of crossed over here around two-year point and later on in the course, patients did do somewhat better if they had had surgery. But overall, by logrank analysis, no significant improvement in outcome with the addition of surgery. Now, one observation in this study was that people who underwent a pneumonectomy had a worse outcome with surgery with a lot of complications. So, a secondary analysis was performed in which patients were selected based on the type of surgical procedure that they had done. In the upper graph, you see an evaluation of people who had lobectomies in the surgical arm and the non-surgical arm was a comparison of people who would have had a lobectomy if they had had surgery, which is always somewhat of a little bit of guesswork. But when we look at those people who underwent lobectomies, they did have a significant improvement in outcome with surgical resection. Now, this is a secondary analysis, unplanned analysis, so we have to take the findings with some skepticism. The question of consolidation chemotherapy was asked by the HOG trial several years ago. This was patients who had stage three non-small cell lung cancer and good functional status, who received either definitive chemoradiation or got chemoradiation in the same doses followed by three cycles of Docetaxel. We see from the survival numbers here that there was no difference in overall survival in patients who received the consolidation therapy, but at the end, we see a treatment-related death rate of five percent in those who underwent consolidation therapy. So, it was not easy therapy to tolerate and there was no evidence of benefit. More recently, consolidation has been evaluated with immunotherapy. So, this specific trial looked at patients who had stage three non-small cell lung cancer with a good performance status who had received platinum-based chemo and definitive radiation therapy and then were randomized to receive either Durvalumab, APD-L1 inhibitors, so immune checkpoint inhibitor or placebo every two weeks for one year. It's a large study with over 700 people enrolled with a relatively young median age, with median age of 64. Median age of people with lung cancer is about 71. Primary endpoint was progression-free survival and overall survival, but the median follow-up thus far on the report in the New England Journal of Medicine on this study was fairly short at only 14 months and there was no overall survival reported. The study did report the progression-free survival which is seen on this curve, and we see that there is a significant improvement in progression-free survival in the patients who received Durvalumab. However, the people who received placebo did remarkably poorly compared to what we would have expected from a historical population. Also, we do not yet have overall survival data, and in a curative situation, the overall survival data is very important, because for all we know, the people who relapsed on this trial and received immunotherapy after relapse may improve the outcomes in that placebo arm for overall survival. So, at this point in time, the use of Durvalumab is an option, it has been approved by the FDA as consolidation therapy in people who underwent definitive chemoradiation for stage three disease. So now, let's go through some clinical scenarios and how we would manage a patient with stage three non-small cell lung cancer. So, the commonest situation is somebody with stage three A, B or C with mediastinal node involvement, either ipsilateral or contralateral, who has a good performance status, they're fit, and has less than 10 percent weight loss. In these people, primary treatment is concurrent chemotherapy and definitive radiation therapy. For chemotherapy options, we can use either cisplatin or carboplatin plus etoposide for two cycles concurrently with radiation, carboplatin and taxol weekly during radiation, followed potentially by consolidation, carboplatin and paclitaxel for two cycles. Or in people who have non-squamous or adenocarcinoma, we can utilize platinum plus pemetrexed for four cycles, with two or three of those cycles concurrently with radiation therapy. In addition, we can consider consolidation therapy with Durvalumab after completion of concurrent chemotherapy and radiation therapy with the improvement in progression-free survival and yet to be seen as far as overall survival. For people who have Stage IIIA disease that have non-bulky N2 disease, or only N1 disease with T3 or T4 involvement, or T4 involvement and no lymph node involvement, preferably in patients who are younger, who have good functional status of PS0 or I, the options include either concurrent chemoradiation as we noted above with consolidation Durvalumab or if they do not require a pneumonectomy, neoadjuvant chemotherapy concurrently with an abbreviated course of radiation followed by resection of the disease within six weeks. So, lobectomy and mediastinal lymph node sampling. If the patient is unresectable or if incomplete resection is achieved after chemoradiation then radiation and potentially further chemotherapy would be recommended. For people who had stage three disease who have either marginal or decent performance status but are a bit elderly or frail or have significant weight loss, then we still can use sequential chemotherapy followed by definitive radiation in a curative intent manner. Another option would be concurrent chemoradiation utilizing a lower toxicity chemo regimen such as carbon etoposide, carboplatin taxol, or carboplatin pemetrexed for adenocarcinomas. For people at stage three disease we have large tumors that would require a large radiation volume that increases the toxicity, then utilizing a sequential approach with chemotherapy followed by definitive radiation therapy can be done in order to try and shrink the tumor down and radiate a smaller field with less toxicity or an induction chemo approach followed by concurrent chemoradiation. This is harder to do with more potential side effects. So, you really have to pick a population quite well in order to be able to do this safely. For people who have a poor performance status or very elderly or have had significant weight loss, then we always can consider definitive radiation therapy alone or even palliative radiation depending on what their comorbidities are and what you think their overall survival would be with or without treatment. Specific subset of patients have post-obstructive pneumonia due to a central tumor blocking one of the main bronchitis and in these situations is a concern for doing chemoradiation together with regard to worsening the infectious possibilities. So, we can start out with radiation therapy alone follow the patient closely treated with antibiotics and if the airway opens up during the radiation then we can consider adding concurrent weekly chemotherapy usually with carboplatin and paclitaxel. After any of these interventions with chemoradiation, we can then consider utilizing some consolidation therapy potentially with Durvalumab. So, we come back to our lecture of a woman with stage three and two positive non-small cell lung cancer, squamous cell carcinoma, and what is the most appropriate further management. Most appropriate management is chemotherapy with concurrent definitive radiation given with curative intent. This woman has N3 lymph nodes because we have a left paratracheal contralateral lymph node that was biopsied so surgical resection is not reasonable in that situation and we would not utilize a palliative approach since this is potentially curative disease. So, the take home points for this lecture; stage three non-small cell lung cancer is a curable disease, five-year survival rates are not as high as we would like but around the 20-25 percent range, standard treatment for most people is concurrent chemoradiation those selected patients may benefit from neoadjuvant chemo or chemoradiation followed by surgery, immunotherapy after chemoradiation is likely to become the standard treatment and individualized treatment is necessary based on the individual you're treating and their co-morbidities and general overall functional status. Thank you.
