I'm Greg Kalemkerian, Medical Oncologist and Professor of Medicine at the University of Michigan. This lecture is going to cover the adjuvant therapy for non-small cell lung cancer. The objective of the lecture is to review the role of adjuvant chemotherapy after surgical resection of early stage non-small cell lung cancer. About 25 percent of patients with non-small cell lung cancer present with surgically resectable disease. Stage-specific survival for these patients with early-stage cancer is suboptimal with surgery alone. Many of these patients relapse after resection, and these relapses tend to be due to hematogenous spread. So, our pre-lecture question is that a 62-year-old man undergoes right upper lobectomy for biopsy-proven adenocarcinoma. Pathology reveals a six-centimeter mass with clean margins but three hilar lymph nodes contain cancer. Mediastinal lymph nodes are negative. PET scan prior to surgery showed no evidence of distant metastases. What is the most appropriate step in further management? A, surveillance with annual chest x-rays. B, radiotherapy to the mediastinum. C, adjuvant chemotherapy. Or D, selenium for the prevention of second primary lung cancer. We'll come back to the answer of this question at the end of the lecture. Non-small cell lung cancer is a disease that tends to present with very advanced stage in either stage 3 or 4, as we can see from this slide, with 75 percent or more patients presenting with high stage disease. However, about 25-30 percent of people will present with early-stage of this, defined as stage I or II lung cancer, for which surgery is the primary treatment modality done with curative intent. Unfortunately, from looking at the right side of this slide we see that the five-year survival with stage I or II lung cancers is not quite as good as we would hope it would be, and nowhere near as good as it is in other common cancers such as breast, prostate, or colon cancer. So, that begs the question of, what can we do to try and improve the outcome of these patients? What's been evaluated are a number of studies that have looked at giving adjuvant chemotherapy to these patients. So, the term adjuvant refers to any treatment that is given without the presence of disease. So clearly, those patients who are going to recur do have some micro metastatic disease floating around in their body, but in general, we aren't able to identify it, and that's why they underwent a potentially curative surgery. In order to try and mop up those stray cancer cells, we can try giving chemotherapy. This slide lays out six of the most recent adjuvant chemotherapy trials that have been done. We can see that the stage of patients enrolled in these trials varies greatly between the studies. Most of them did include some stage I through IIIA patients. The chemo regiments also are quite varied that were used. However, all of them are based on cisplatinum-containing regimens except for one study, the CALGB study near the bottom, that incorporated a carboplatinum-based chemotherapy regimen. Some of the studies allowed radiation to be given primarily for people with stage III disease, while others excluded the ability to give radiation post-operatively. Of note, radiation has not been demonstrated to improve survival, though there is some potential evidence of improvement in survival in stage III patients. Most importantly, the median age of people enrolled onto this trial was relatively young, with a median age of about 60 years. Some studies excluded patients over the age of 75. We know that the median age at which people get lung cancer is around 70 or 71, so this is a relatively young population of patients. That's important when we look at trying to apply the results of these studies to patients we see in the clinic, because how well they apply to the elderly population is still in question. So, these are the results of those studies. Studies are listed in the same order here, and we see that some were quite large with over 1,000 patients being included. The results are such that the studies written in gray, with the gray shading, are studies that were positive from the IALT study with a four percent improvement in five-year survival, the JBR. 10 study with a 15 percent improvement in five-year survival, and the ANITA study with an eight percent improvement in five-year survival, all of which were statistically significant. So, let's take a closer look at one of these studies. Let's look at the JBR. 10 study that was done in Canada and the US, and in which the University of Michigan did participate. So, this study enrolled 482 patients. All of them had either stage IB or II non-small cell lung cancers that were completely resected. Patients were randomized very simply to either cisplatinum plus vinorelbine chemotherapy given for four cycles, or to observation with no further treatment. Radiation was not allowed on this study. The initial results of JBR. 10 were that there was a significant improvement in progression-free survival, or relapse-free survival, seen in the middle of this slide, and over on the right, we see an improvement in overall survival with a 15 percent jump in five-year survival that was statistically significant. This study was updated several years later with longer follow up, and we see that the median survival in the update over on the right is still maintained at a significant level now within eleven percent improvement in five-year overall survival. So, this is a durable improvement in the cure of lung cancer. Another aspect of the updated analysis was that the investigators looked at stage-specific survival. We see for stage II lung cancer in the left column, there is this 15 percent improvement in survival. But for all patients with stage IB cancer, there actually was not a statistically significant improvement in survival. However, when we then sub-classified the stage IB patients into low-risk, less than four centimeter tumors, or high risk, patients for relapse with tumors greater than or equal to four centimeters, that those with the bigger tumors, the higher risk of recurrence, do appear to have an improvement in survival though this did not reach statistical significance given in fairly small subset analysis. Putting together a number of the modern trials that looked at Adjuvant therapy, the LACE Meta analysis evaluated five of the trials since 1995, that incorporated of four and a half thousand patients. Five of these trials were noted in the initial slides that I presented on the modern studies. All of them were to Cisplatin-based treatments versus no chemotherapy. Again, we see that there was a relatively young median age. Importantly, less than 10 percent of people on all of these trials combined, were over the age of 70. So again, becoming hard to necessarily apply this data to an elderly population. Overall, looking at the LACE Meta-analysis, there was a five and a half percent benefit in overall survival with Adjuvant chemotherapy. However, we see looking at this stage specific outcomes, that for stage one A patients, there actually was a detriment, though not statistically significant. Stage 1B patients trended towards benefit, but again non significantly and most of the benefit was seen in patients with stage two or three disease. So in general, when I discussed the situation with patients, I use a 10 percent improvement in outcome to describe the potential benefits of chemotherapy in patients with stage two and three disease, which is somewhat of an average of the IALT study and the JBR 10 study and the anita trial, the three positive studies in non-small cell lung cancer. Ten percent is also a number that is easy for patients to understand and get their heads around. So, in summarizing the use of Adjuvant chemotherapy in non-small cell lung cancer, we see on this slide the studies going up and down on the left side and the stage is going across the top of the slide with red boxes, meaning that there was no evidence of benefit in that study at that stage. Green boxes showing that yes, there is a benefit for Adjuvant therapy, and the yellow boxes signifying the stage 1B studies, in which there may be a benefit for patients with higher risk and larger tumors. So overall, no big benefit for patients with stage 1A or 1B tumors except perhaps those larger, more higher risk tumors in 1B. But for stage two's and three's, the overall preponderance of the evidence is favoring chemotherapy, particularly when we look at both the LACE Meta-analysis and other Meta-analyses that have been done of these trials in conglomerate. So, summarizing Adjuvant therapy, Adjuvant chemotherapy is used for completely resected stage two and three non-small cell lung cancer. It can be considered for high risk stage 1B patients. Patients have to have recovered from surgery well in an uncomplicated fashion by about eight weeks after surgery, which is when you want to start the chemotherapy by. They have to have good performance status, so they can tolerate treatment. It's preferable that chemotherapy be applied to younger individuals, generally people less than 75 years of age. Since two of the three positive studies, actually excluded people over this age due to concerns of toxicity. The chemotherapy applied can be platinum-based two-drug therapy for four cycles. We are yet to have any comparative studies of chemotherapy in the Adjuvant setting. So, we do not necessarily know which treatment is optimal. So, as an important aside, we know that we are now in the molecular age of cancer treatments and we do have some molecularly targeted therapies for people with non-small cell lung cancer. The most common targeted therapy we use is against the EGFR mutations, for which we have EGFR inhibitors. One of these inhibitors is called Erlotinib, and can be used in the advanced stage patients in order to improve response rates and improve progression-free survival. This was a study, the radiant study, that looked at incorporating EGFR inhibition with Erlotinib earlier into the treatment course as an Adjuvant treatment in people who had resected stage 1B through three A non-small cell lung cancer. Importantly, these patients were not selected based on having an EGFR mutation, this was a trial done in all comers. So as a randomized study, where people some people got Adjuvent chemotherapy, some did not. But then they were randomized to either receive Erlotinib or to receive placebo for two years. So, overall, in the Radiant trial, there was no overall survival benefit for the use of Erlotinib as Adjuvant therapy in non-small cell lung cancer, as we see on this slide looking at overall survival with curves that generally overlap throughout their course. Unfortunately, when we do a subset analysis and look only at the patients who have EGFR sensitizing mutations, we also see no benefit in overall survival. This is seen on the right of this slide, where again, the curves overlap throughout their course with placebo or Erlotinib use. However, when we look at the left side of this slide, at disease free survival or relapse free survival, we do see an improvement in survival in the patients who had Erlotinib though the curves do join at a later point. What this suggests is that, the Erlotinib is merely the laying recurrence and not absolutely preventing recurrence in these patients. Such that for patients on placebo who do recur, they can be placed on Erlotinib at time of progression and can gain the same type of benefit that the other patients gained by being on Erlotinib early on, thus having similar overall survival. So, returning to our question with a 62-year-old man, who underwent a right upper lobectomy for an adenocarcinoma, that revealed a six centimeter mass with clean margins but three hilar lymph nodes that contained cancer. Mediastinal lymph nodes were negative and PET scan showed no metastases prior to surgery. What is the most appropriate further management of this patient? So, this fellow has stage two non-small cell lung cancer, specifically stage 2B non-small cell lung cancer, and we see that the most appropriate therapy would be Adjuvant chemotherapy to give him approximately a 10 percent improvement in his chance for overall five year survival. So, what have we learned? We've learned that Adjuvant chemotherapy improves survival in patients with stages two and three and maybe larger stage 1B, non-small cell lung cancers, that have been surgically resected, that the overall five year survival improvement is between five and 15 percent, that people getting Adjuvent therapy should be younger, preferably less than 75 years of age, fit and have uncomplicated recoveries from surgery, so that they can tolerate therapy, and that the chemotherapy should consist of a platinum-based two-drug regimen given for four cycles. I want to thank you for taking the time to watch this lecture.
